Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Identifying factors and causal chains associated with optimal implementation of Lynch syndrome tumor screening: An application of coincidence analysis.

PURPOSE: This study compared Lynch syndrome universal tumor screening (UTS) across multiple health systems (some of which had two or more distinct UTS programs) to understand multi-level factors that may impact the successful implementation of complex programs. METHODS: Data from 66 stakeholder interviews were used to conduct multi-value coincidence analysis (mv-CNA) and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level. RESULTS: The selected CNA model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 non-optimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to non-optimized programs: 1) positive attitudes and a mixed inner setting, or 2) limited planning & engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation. CONCLUSION: The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.

Temporal gene expression profiling during early-stage traumatic temporomandibular joint bony ankylosis in a sheep model.

BACKGROUND: Investigating the molecular biology underpinning the early-stage of traumatic temporomandibular joint (TMJ) ankylosis is crucial for discovering new ways to prevent the disease. This study aimed to explore the dynamic changes of transcriptome from the intra-articular hematoma or the newly generated ankylosed callus during the onset and early progression of TMJ ankylosis. METHODS: Based on a well-established sheep model of TMJ bony ankylosis, the genome-wide microarray data were obtained from samples at postoperative Days 1, 4, 7, 9, 11, 14 and 28, with intra-articular hematoma at Day 1 serving as controls. Fold changes in gene expression values were measured, and genes were identified via clustering based on time series analysis and further categorised into three major temporal classes: increased, variable and decreased expression groups. The genes in these three temporal groups were further analysed to reveal pathways and establish their biological significance. RESULTS: Osteoblastic and angiogenetic genes were found to be significantly expressed in the increased expression group. Genes linked to inflammation and osteoclasts were found in the decreased expression group. The various biological processes and pathways related to each temporal expression group were identified, and the increased expression group comprised genes exclusively involved in the following pathways: Hippo signaling pathway, Wnt signaling pathway and Rap 1 signaling pathway. The decreased expression group comprised genes exclusively involved in immune-related pathways and osteoclast differentiation. The variable expression group consisted of genes associated with DNA replication, DNA repair and DNA recombination. Significant biological pathways and transcription factors expressed at each time point postoperatively were also identified. CONCLUSIONS: These data, for the first time, presented the temporal gene expression profiling and reveal the important process of molecular biology in the early-stage of traumatic TMJ bony ankylosis. The findings might contributed to identifying potential targets for the treatment of TMJ ankylosis.

Mammographic Screening in Routine Practice: Multisite Study of Digital Breast Tomosynthesis and Digital Mammography Screenings.

Background The use of digital breast tomosynthesis (DBT) is increasing over digital mammography (DM) following studies demonstrating lower recall rates (RRs) and higher cancer detection rates (CDRs). However, inconsistent interpretation of evidence on the risks and benefits of mammography has resulted in varying screening mammography recommendations. Purpose To evaluate screening outcomes among women in the United States who underwent routine DM or DBT mammographic screening. Materials and Methods This retrospective cohort study included women aged 40-79 years who underwent DM or DBT screening mammograms between January 2014 and December 2020. Outcomes of RR, CDR, positive predictive value of recall (PPV1), biopsy rate, and positive predictive value of biopsy (PPV3) were compared between DM and DBT with use of adjusted multivariable logistic regression models. Results A total of 2 528 063 screening mammograms from 1 100 447 women (mean age, 57 years ± 10 [SD]) were included. In crude analyses, DBT (1 693 727 screening mammograms vs 834 336 DM screening mammograms) demonstrated lower RR (10.3% [95% CI: 10.3, 10.4] for DM vs 8.9% [95% CI: 8.9, 9.0] for DBT; P < .001) and higher CDR (4.5 of 1000 screening mammograms [95% CI: 4.3, 4.6] vs 5.3 of 1000 [95% CI: 5.2, 5.5]; P < .001), PPV1 (4.3% [95% CI: 4.2, 4.5] vs 5.9% [95% CI: 5.7, 6.0]; P < .001), and biopsy rates (14.5 of 1000 screening mammograms [95% CI: 14.2, 14.7] vs 17.6 of 1000 [95% CI: 17.4, 17.8]; P < .001). PPV3 was similar between cohorts (30.0% [95% CI: 29.2, 30.9] for DM vs 29.3% [95% CI: 28.7, 29.9] for DBT; P = .16). After adjustment for age, breast density, site, and index year, associations remained stable with respect to statistical significance. Conclusion Women undergoing digital breast tomosynthesis had improved screening mammography outcomes compared with women who underwent digital mammography. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae and Seo in this issue.

Factors associated with adherence to provider referrals for lung cancer screening with low dose computed tomography before and during COVID-19 pandemic.

BACKGROUND: Lung cancer has been the leading cause of American deaths from cancer. Although Medicare started covering lung cancer screening (LCS) with low-dose computed tomography (LDCT) in 2015, the uptake of LDCT-LCS remains low. This study examines the changes in adherence to provider referrals for LDCT-LCS and the factors at patient, provider, and health system levels that influence the completion rate of LDCT-LCS orders before and during the COVID-19 pandemic. METHODS: Our study examined electronic health record data (December 2013 - December 2020) from a large, community-based clinical healthcare delivery system in California. We plotted monthly trends in the frequency of LDCT-LCS orders and completion rate and compared the annual LDCT-LCS completion rate between LCS-eligible, LCS-ineligible, and unknown eligibility groups. We then explored multilevel factors associated with the completion of LDCT-LCS orders using hierarchical generalized linear models. RESULTS: There was an increase in LDCT-LCS orders (N = 12,469) from 2013 to 2019, followed by a sharp decline in March 2020 due to the onset of the COVID-19 pandemic. Thereafter, LDCT-LCS orders slowly increased again in June 2020. The completion rate of LDCT-LCS increased from 0% in December 2013 to approximately 70% in 2018-2019 but declined to 50-60% in 2020 during the pandemic. Ineligible patients had lower completion rates of LDCT-LCS. Patients who were new to the healthcare system, Black, received the LDCT-LCS order in the first few years after Medicare coverage (2016 or 2017), during the pandemic, had major comorbidities, and smoked less than 30 pack-years were less likely to complete an order. Patients were more likely to complete LDCT-LCS orders if they were younger, received the LDCT-LCS order from a physician (vs. nonphysician provider), from family medicine or other specialties (vs. internal medicine), or saw a provider with more experience in LDCT-LCS. CONCLUSIONS: The beginning of the COVID-19 pandemic largely decreased the volume of LDCT-LCS orders, but rates have since been slowing recovering. Future interventions to improve lung cancer screening should consider doing more targeted outreach to new patients and Black patients as well as providing additional education to nonphysician practitioners and those providers with lower rates of LDCT-LCS referral orders.

Sequential Targeted Therapy for Advanced, Metastatic, and Recurrent Cervical Cancer: A Cost-Effectiveness Analysis of the Patient Journey.

OBJECTIVES: To evaluate outcomes and cost-effectiveness of targeted therapy sequencing for metastatic and recurrent cervical cancer. METHOD: Models were simulated based on phase II and III trials on bevacizumab (bev) from GOG-240, cemiplimab (cemi) from GOG 3016, pembrolizumab (pembro) from KEYNOTE-826, and tisotumab vedotin (tiso) from GOG 3023. Costs were based on IBM Micromedex RED BOOK™ and company listed costs. RESULTS: For [chemo + bev → chemo], total cost was $125,918.04, with median overall survival (mOS) of 21.8 months, and cost-effectiveness ratio (CER) of $119,835.79. For [chemo + bev → cemi], total cost was $187,562.99 with mOS of 28.5 months and CER of $162,039.16. For [chemo + bev + pembro → chemo], total cost was $319,963.78 with mOS 32.9 months and CER of $249,930.10. For [chemo + bev + pembro → tiso], total cost was $455,204.45, with mOS 36.5 months and CER of $320,072.99. CONCLUSION: The combination of immunotherapies and biologics have significantly increased overall survival, but with associated higher costs, primarily related to drug costs.

The relationship between vitamin D receptor gene polymorphisms and ankylosing spondylitis: a systematic review, meta-analysis and trial sequential analysis.

The relation between vitamin D receptor (VDR) gene polymorphisms and ankylosing spondylitis (AS) remains unclear. A systematic review and meta-analysis were conducted using six databases, including PubMed, Web of Science, EMBASE, CNKI, Wanfang and Cochrane Library. The selection of each study was based on inclusion and exclusion criteria. The Newcastle-Ottawa Scale was applied to assess the quality of the included studies, while the strength was evaluated by odds ratios and 95% confidence intervals. The following contrasts were used: allele contrast (H vs h), homozygous contrast (HH vs hh), heterozygous contrast (Hh vs hh), dominant contrast (HH + Hh vs hh) and recessive contrast (HH vs Hh + hh). For the BsmI-rs1544410 polymorphism, three studies were included of 782 cases and 863 controls. The data showed a significant relationship under allele contrast H vs h (OR = 1.66, 95% CI 1.20-2.30 (P = 0.002)). For the TaqI-rs731236 polymorphism, 675 cases and 697 controls were included in two studies. The data showed a significant relationship under allele contrast H vs h (OR = 1.57, 95% CI 1.11-2.21 (P < 0.05)), homozygous contrast Hh vs hh (OR = 1.65, 95% CI 1.12-2.43 (P < 0.05)), and recessive contrast HH + Hh vs hh (OR = 1.66, 95% CI 1.13-2.43 (P < 0.05)). There were significant relationships between VDR gene BsmI-rs1544410 and TaqI-rs731236 polymorphisms and AS, while no associations were found between FokI-rs2228570 and ApaI-rs7975232 polymorphisms and AS. In the future, additional studies with larger case numbers are need.

"Go ahead and screen" - advice to healthcare systems for routine lynch syndrome screening from interviews with newly diagnosed colorectal cancer patients.

BACKGROUND: Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. METHODS: To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed.  RESULTS: We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: "knowledge is power"; "family knowledge"; "prevention and detection"; and "treatment and surveillance." Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one's health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. CONCLUSION: Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. TRIAL REGISTRATION: Not available: not a clinical trial.

Road to Better Work-Life Balance? Lean Redesigns and Daily Work Time among Primary Care Physicians.

PURPOSE: To assess the impact of Lean primary care redesigns on the amount of time that physicians spent working each day. METHODS: This observational study was based on 92 million time-stamped Epic® EHR access logs captured among 317 primary care physicians in a large ambulatory care delivery system. Seventeen clinic facilities housing 46 primary care departments were included for study. We conducted interrupted time series analysis to monitor changes in physician work patterns over 6 years. Key measures included total daily work time; time spent on "desktop medicine" outside the exam room; time spent with patients during office visits; time still working after clinic, i.e., after seeing the last patient each day; and remote work time. RESULTS: The amount of time that physicians spent on desktop EHR activities throughout the day, including after clinic hours, decreased by 10.9% (95% CI: -22.2, -2.03) and 8.3% (95% CI: -13.8, -2.12), respectively, during the first year of Lean implementation. Total daily work hours among physicians, which included both desktop activity and time in office visits, decreased by 20% (95% CI: -29.2, -9.60) by the third year of Lean implementation. CONCLUSIONS: These findings suggest that Lean redesign may be associated with time savings for primary care physicians. However, since this was an observational analysis, further study is warranted (e.g., randomized trial) -to determine the impact of Lean interventions on physician work experiences.

Unveiling the Differences in Biological Properties of Dental Pulp Stem Cells from Normal and Inflamed Pulp: A Comprehensive Comparative Study.

BACKGROUND The aims of the study were to comprehensively compare the morphology, immunophenotype, proliferation, migration, and regeneration potential of normal dental pulp stem cells (DPSCs) versus inflammatory dental pulp stem cells (iDPSCs). MATERIAL AND METHODS Healthy pulp or inflamed pulp tissue was used to isolate and culture DPSCs and iDPSCs, respectively. These cell populations were characterized by flow cytometry, colony formation assay, transwell assay, and multi-directional differentiation in vitro. RESULTS No difference was observed in the morphology, cell-surface markers, or cell migration between DPSCs and iDPSCs. DPSCs showed a higher colony-forming capacity, proliferative viability, and osteo/dentinogenesis ability compared with iDPSCs. However, iDPSCs demonstrated enhanced neurogenesis, angiogenesis, adipogenesis, and chondrogenesis capacities in comparison to DPSCs. CONCLUSIONS Our data revealed the differences of biological properties between DPSCs and iDPSCs. The highly angiogenic and neurogenic potential of iDPSCs indicate their possible use in the regeneration of the dentin-pulp complex and support the critical role of angiogenesis and neurogenesis in pulp regeneration.

Genetic counselors' experience with reimbursement and patient out-of-pocket cost for multi-cancer gene panel testing for hereditary cancer syndromes.

Multi-cancer gene panels for hereditary cancer syndromes (hereditary cancer panels, HCPs) are widely available, and some laboratories have programs that limit patients' out-of-pocket (OOP) cost share. However, little is known about practices by cancer genetic counselors for discussing and ordering an HCP and how insurance reimbursement and patient out-of-pocket share impact these practices. We conducted a survey of cancer genetic counselors based in the United States through the National Society of Genetic Counselors to assess the impact of reimbursement and patient OOP share on ordering of an HCP and hereditary cancer genetic counseling. Data analyses were conducted using chi-square and t tests. We received 135 responses (16% response rate). We found that the vast majority of respondents (94%, 127/135) ordered an HCP for patients rather than single-gene tests to assess hereditary cancer predisposition. Two-thirds of respondents reported that their institution had no protocol related to discussing HCPs with patients. Most respondents (84%, 114/135) indicated clinical indications and patients' requests as important in selecting and ordering HCPs, while 42%, 57/135, considered reimbursement and patient OOP share factors important. We found statistically significant differences in reporting of insurance as a frequently used payment method for HCPs and in-person genetic counseling (84% versus 59%, respectively, p < 0.0001). Perceived patient willingness to pay more than $100 was significantly higher for HCPs than for genetic counseling(41% versus 22%, respectively, p < 0.01). In sum, genetic counselors' widespread selection and ordering of HCPs is driven more by clinical indications and patient preferences than payment considerations. Respondents perceived that testing is more often reimbursed by insurance than genetic counseling, and patients are more willing to pay for an HCP than for genetic counseling. Policy efforts should address this incongruence in reimbursement and patient OOP share. Patient-centered communication should educate patients on the benefit of genetic counseling.

Implementing Lean Quality Improvement in Primary Care: Impact on Efficiency in Performing Common Clinical Tasks.

BACKGROUND: Many primary care practices have adopted Lean techniques to reduce the amount of time spent completing routine tasks. Few studies have evaluated both immediate and sustained impacts of Lean to improve this aspect of primary care work efficiency. OBJECTIVE: To examine 3-year impacts of Lean implementation on the amount of time taken for physicians to complete common clinical tasks. DESIGN: Non-randomized stepped wedge with segmented regression and interrupted time series analysis (January 2011-December 2016). PARTICIPANTS: A total of 317 physician-led teams in 46 primary care departments in a large ambulatory care delivery system. INTERVENTION: Lean redesign was initiated in one pilot site followed by system-wide spread across all primary care departments. Redesigns included standardization of exam room equipment and supplies, streamlining of call management processes, care team co-location, and team management of the electronic inbox. MEASURES: Time-stamped EHR tracking of physicians' completion time for 4 common tasks: (1) office visit documentation and closure of patient charts; (2) telephone call resolution; (3) prescription refill renewal; and (4) response to electronic patient messages. RESULTS: After Lean implementation, we found decreases in the amount of time to complete: office visit documentation (- 29.2% [95% CI: - 44.2, - 10.1]), telephone resolution (- 22.2% [95% CI: - 38.1, - 2.27]), and renewal of prescription refills (- 2.96% per month [95% CI: - 4.21, - 1.78]). These decreases were sustained over several years. Response time to electronic patient messages did not change significantly. CONCLUSIONS: Lean redesigns led to improvements in timely completion of 3 out of 4 common clinical tasks. Our findings support the use of Lean techniques to engage teams in routine aspects of patient care. More research is warranted to understand the mechanisms by which Lean promotes quality improvement and effectiveness of care team workflows.

How, when, and why individuals with stage IV cancer seen in an outpatient setting are referred to palliative care: a mixed methods study.

PURPOSE: Early palliative care (PC) for individuals with advanced cancer improves patient and family outcomes and experience. However, it is unknown when, why, and how in an outpatient setting individuals with stage IV cancer are referred to PC. METHODS: At a large multi-specialty group in the USA with outpatient PC implemented beginning in 2011, clinical records were used to identify adults diagnosed with stage IV cancer after January 1, 2012 and deceased by December 31, 2017 and their PC referrals and hospice use. In-depth interviews were also conducted with 25 members of medical oncology, gynecological oncology, and PC teams and thematically analyzed. RESULTS: A total of 705 individuals were diagnosed and died between 2012 and 2017: of these, 332 (47%) were referred to PC, with 48.5% referred early (within 60 days of diagnosis). Among referred patients, 79% received hospice care, versus 55% among patients not referred. Oncologists varied dramatically in their rates of referral to PC. Interviews revealed four referral pathways: early referrals, referrals without active anti-cancer treatment, problem-based referrals, and late referrals (when stopping treatment). Participants described PC's benefits as enhancing pain/symptom management, advance care planning, transitions to hospice, end-of-life experiences, a larger team, and more flexible patient care. Challenges reported included variation in oncologist practices, patient fears and misconceptions, and access to PC teams. CONCLUSION: We found high rates of use and appreciation of PC. However, interviews revealed that exclusively focusing on rates of referrals may obscure how referrals vary in timing, reason for referral, and usefulness to patients, families, and clinical teams.

Microarray Analysis of Differential Gene Expression Between Traumatic Temporomandibular Joint Fibrous and Bony Ankylosis in a Sheep Model.

BACKGROUND The type of traumatic temporomandibular joint (TMJ) ankylosis depends on the degree of severity of TMJ trauma. Here, we performed comprehensive differential molecular profiling between TMJ fibrous and bony ankylosis. MATERIAL AND METHODS Six sheep were used and a bilateral different degree of TMJ trauma was performed to induce fibrous ankylosis in one side and bony ankylosis in the other side. The ankylosed calluses were harvested at days 14 and 28 postoperatively and analyzed by Affymetrix OviGene-1_0-ST microarrays. DAVID was used to perform the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis for the different expression genes (DEGs). The DEGs were also typed into protein-protein interaction (PPI) networks to get the interaction data. Ten DEGs, including 7 hub genes from PPI analysis, were confirmed by real-time PCR. RESULTS We found 90 and 323 DEGs at least 2-fold at days 14 and 28, respectively. At day 14, bony ankylosis showed upregulated DEGs, such as TLR8, SYK, NFKBIA, PTPRC, CD86, ITGAM, and ITGAL, indicating a stronger immune and inflammatory response and cell adhesion, while genes associated with anti-adhesion (PRG4) and inhibition of osteoblast differentiation (SFRP1) had higher expression in fibrous ankylosis. At day 28, bony ankylosis showed increased biological process related to new bone formation, while fibrous ankylosis was characterized by a prolonged immune and inflammatory reaction. CONCLUSIONS This study provides a differential gene expression profile between TMJ fibrous and bony ankylosis. Further study of these key genes may provide new ideas for future treatment of TMJ bony ankylosis.

Insights From a Temporal Assessment of Increases in US Private Payer Coverage of Tumor Sequencing From 2015 to 2019.

OBJECTIVES: To examine the temporal trajectory of insurance coverage for next-generation tumor sequencing (sequencing) by private US payers, describe the characteristics of coverage adopters and nonadopters, and explore adoption trends relative to the Centers for Medicare and Medicaid Services' National Coverage Determination (CMS NCD) for sequencing. METHODS: We identified payers with positive coverage (adopters) or negative coverage (nonadopters) of sequencing on or before April 1, 2019, and abstracted their characteristics including size, membership in the BlueCross BlueShield Association, and whether they used a third-party policy. Using descriptive statistics, payer characteristics were compared between adopters and nonadopters and between pre-NCD and post-NCD adopters. An adoption timeline was constructed. RESULTS: Sixty-nine payers had a sequencing policy. Positive coverage started November 30, 2015, with 1 payer and increased to 33 (48%) as of April 1, 2019. Adopters were less likely to be BlueCross BlueShield members (P < .05) and more likely to use a third-party policy (P < .001). Fifty-eight percent of adopters were small payers. Among adopters, 52% initiated coverage pre-NCD over a 25-month period and 48% post-NCD over 17 months. CONCLUSIONS: We found an increase, but continued variability, in coverage over 3.5 years. Temporal analyses revealed important trends: the possible contribution of the CMS NCD to a faster pace of coverage adoption, the interdependence in coverage timing among BlueCross BlueShield members, the impact of using a third-party policy on coverage timing, and the importance of small payers in early adoption. Our study is a step toward systematic temporal research of coverage for precision medicine, which will inform policy and affordability assessments.

Implementing universal Lynch syndrome screening (IMPULSS): protocol for a multi-site study to identify strategies to implement, adapt, and sustain genomic medicine programs in different organizational contexts.

BACKGROUND: Systematic screening of all colorectal tumors for Lynch Syndrome (LS) has been recommended since 2009. Currently, implementation of LS screening in healthcare systems remains variable, likely because LS screening involves the complex coordination of multiple departments and individuals across the healthcare system. Our specific aims are to (1) describe variation in LS screening implementation across multiple healthcare systems; (2) identify conditions associated with both practice variation and optimal implementation; (3) determine the relative effectiveness, efficiency, and costs of different LS screening protocols by healthcare system; and (4) develop and test in a real-world setting an organizational toolkit for LS screening program implementation and improvement. This toolkit will promote effective implementation of LS screening in various complex health systems. METHODS: This study includes eight healthcare systems with 22 clinical sites at varied stages of implementing LS screening programs. Guided by the Consolidated Framework for Implementation Research (CFIR), we will conduct in-depth semi-structured interviews with patients and organizational stakeholders and perform economic evaluation of site-specific implementation costs. These processes will result in a comprehensive cross-case analysis of different organizational contexts. We will utilize qualitative data analysis and configurational comparative methodology to identify facilitators and barriers at the organizational level that are minimally sufficient and necessary for optimal LS screening implementation. DISCUSSION: The overarching goal of this project is to combine our data with theories and tools from implementation science to create an organizational toolkit to facilitate implementation of LS screening in various real-world settings. Our organizational toolkit will account for issues of complex coordination of care involving multiple stakeholders to enhance implementation, sustainability, and ongoing improvement of evidence-based LS screening programs. Successful implementation of such programs will ultimately reduce suffering of patients and their family members from preventable cancers, decrease waste in healthcare system costs, and inform strategies to facilitate the promise of precision medicine. TRIAL REGISTRATION: N/A.

Preserving the Fibrous Layer of the Mandibular Condyle Reduces the Risk of Ankylosis in a Sheep Model of Intracapsular Condylar Fracture.

PURPOSE: The aim of this experimental study was to investigate the role of the fibrous layer of the condylar head in the formation of temporomandibular joint (TMJ) ankylosis in a sheep model of intracapsular condylar fracture. MATERIALS AND METHODS: Six growing Xiao-wei Han sheep were used in the study, and bilateral TMJ surgery was performed in each sheep. In the left TMJ, sagittal fracture of the condyle, removal of the fibrous layer of the condylar head, excision of two thirds of the disc, and removal of the fibrous zone of the glenoid fossa were performed. In the right TMJ, the same surgical management was performed, except that in each sheep, the fibrous layer of the condylar head was preserved. Three sheep were killed humanely at 1 month postoperatively, and the other 3 sheep were killed humanely at 3 months postoperatively. The TMJ complexes were examined by histologic evaluation. RESULTS: Fibrous ankylosis was observed on the left side in 3 sheep at 1 month postoperatively and in 2 of 3 sheep at 3 months postoperatively. Fibro-osseous ankylosis was achieved on the left side in 1 sheep at 3 months postoperatively. In the right TMJ, the main postoperative histologic findings included condylar fracture healing, topical rupture or exfoliation of the fibrous layer of the condyle, and fissure between the fibrous layer and the proliferative zone of the condyle. However, no evidence of ankylosis was observed. The TMJ ankylosis scores on the right side were significantly lower than those on the left side at different time points (P < .05). CONCLUSIONS: This study showed that the presence of the fibrous layer of the condylar head prevented the development of TMJ ankylosis in a sheep model of intracapsular condylar fracture.

The research progress of farm animal genomics based on sequencing technologies.

Various farm animal breeds have been domesticated and bred for thousands years, and they provide adequate animal-derived proteins to meet the human nutrition requirement. Although quantitative genetics was applied in animal breeding, which launched a technological revolution in the past century, a number of complex traits remain difficult to be selected based on pedigree derived breeding, due to complicated animal genetics and development mechanisms. Farm animal's genetic potential hasn't yet to be fully exploited. The concept and technology from the Human Genome Project have greatly promoted farm animal genomic researches. It is possible to fine map the causal variations at the whole genome level and then exploit their biological functions, thus providing the theoretical basis for molecular designed breeding. In this review, we summarize the genomics research progress of main farm animals during the past decade, including pigs, cattle, yaks, goats, sheep, chickens, ducks and geese. We focus on the reference genome sequencing and follow-up population-level genomic studies based on high throughput resequencing technologies, and meanwhile envision the future work of farm animal genomics.

Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer.

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castration-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), highly lipophilic (logP = 6.49), poorly soluble in water (0.28 µg/mL), and highly plasma protein bound (>98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for four consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls.

Identification of Serum Markers of Esophageal Adenocarcinoma by Global and Targeted Metabolic Profiling.

BACKGROUND & AIMS: We aimed to identify new serum biomarkers of esophageal adenocarcinoma (EAC). METHODS: We performed metabolomic analyses of serum samples from 2 sets of case-control pairs in the discovery phase, each consisting of 30 patients with histologically confirmed EAC (cases) from the University of Texas MD Anderson Cancer Center and 30 matched subjects without EAC (controls). We identified metabolites whose levels differed significantly between cases and controls and validated those with the greatest difference in an analysis of 321 EAC cases and 331 controls. We generated a metabolite risk score (MRS) for the metabolites. RESULTS: The levels of 64 metabolites differed significantly between EAC cases and controls in the discovery phase. The metabolites with the greatest difference were amino acid L-proline (LP), ketone body 3-hydroxybutyrate (BHBA), and carbohydrate D-mannose (DM); these differences were confirmed in the validation set. Cases had lower mean levels of LP than controls (22.78 ± 6.79 µg/mL vs 28.24 ± 8.64 µg/mL; P < .001) and higher levels of BHBA (18.06 ± 17.84 µg/mL vs 7.73 ± 9.92 µg/mL; P < .001) and DM (9.87 ± 4.28 µg/mL vs 6.28 ± 3.61 µg/mL; P < .001). Levels of DM were significantly higher in patients with late-stage EAC than early-stage EAC (10.61 ± 4.79 µg/mL vs 8.97 ± 3.36 µg/mL; P = .005). Higher levels of LP were associated with significant decrease in risk of EAC (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.18-0.38). A significant increase in risk of EAC was associated with higher levels of BHBA (OR, 4.05; 95% CI, 2.84-5.78) and DM (OR, 7.04; 95% CI, 4.79-10.34). Levels of all 3 metabolites associated with EAC risk in a dose response manner; the level of risk conferred by the metabolites increased jointly with smoking status and body mass index. Individuals with high MRS had significant (7.76-fold) increase in risk of EAC vs those with low MRS. Smokers with high MRS had the greatest risk of EAC (OR, 23.40; 95% CI, 10.95-50.00), compared with never smokers with low MRS. CONCLUSIONS: On the basis of a case vs control metabolic profile analysis, levels of LP, BHBA, and DM are associated with risk of EAC. These markers might be used as risk and prognostic factors for patients with EAC.