Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation.

BACKGROUND: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. METHODS: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. RESULTS: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p = .025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p < .001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6 months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2 months (95% confidence interval [CI], 0.3-80.5) versus 80.1 months (95% CI, 0.5-80.1), respectively (p < .001). There was no significant difference in overall survival between the two groups (p = .41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p < .001). The impact of pretransplant MRD status was retained in most of the examined subgroups. CONCLUSIONS: In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

Impact of revised International Staging System 2 risk stratification on outcomes of patients with multiple myeloma receiving autologous haematopoietic stem cell transplantation.

The second revision of the International Staging System (R2-ISS) is a simple tool to risk-stratify newly diagnosed multiple myeloma (NDMM) patients. Here, we completed a retrospective analysis to evaluate the utility of R2-ISS in NDMM patients who underwent up-front autologous haematopoietic stem cell transplantation (auto-HCT). A total of 1291 patients were included, with a median age of 62 years (range 29-83). The distribution of R2-ISS stages was: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III and 131 (10%) stage IV. With a median follow-up of 42.2 months (range 0.3-181.0), the median PFS was 73.0, 65.2, 44.0 and 24.8 months, (p < 0.001) and the median OS was 130.8, 128.5, 94.2 and 61.4 months (p < 0.001) for patients with R2-ISS stages I, II, III and IV respectively. On multivariable analysis (MVA) for PFS, using R2-ISS stage I as reference, R2-ISS stages III (hazard ratio [95% confidence interval], 1.55 [1.05-2.29]; p = 0.028) and IV (2.04 [1.24-3.36]; p = 0.005) were associated with significantly inferior PFS. In the MVA of OS, using R2-ISS stage I as reference, only R2-ISS stage IV was associated with significantly inferior OS (2.43 [1.18-5.01]; p = 0.017). Overall, we found that R2-ISS is a reliable prognostic tool for NDMM patients undergoing up-front auto-HCT.

Psychosocial outcomes of children born via embryo donation.

STUDY QUESTION: What are parents' perceptions of their relationships with and the psychosocial adjustments of their children who are born via embryo donation? SUMMARY ANSWER: Families created through embryo donation have well-adjusted parent-child relationships and reassuring child psychosocial outcomes. WHAT IS KNOWN ALREADY: Embryo donation is an effective and growing form of third-party reproduction, but there is limited research in this field. Prior studies suggest that families created through gamete donation function well regarding parent-child relationship quality and child behavioral and socioemotional adjustment. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional survey study with 187 total participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parents of children born via embryo donation were recruited nationally by contacting all embryo donation programs registered with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) as well as medically directed embryo donation or 'embryo adoption' centers. Participants completed three online Qualtrics questionnaires. The first was a survey including 33 questions on demographics, the procurement process, and self-reported obstetric outcomes. Participants also completed two standardized measures assessing children's behavior and parents' adjustment to parenthood: the Strengths and Difficulties Questionnaire (SDQ) and the Parental Acceptance-Rejection Questionnaire (PARQ). Scoring of the SDQ and PARQ was totaled and compared to standardized values (SDQ) or previously published results on other forms of gamete donation (PARQ), such as oocyte donation and sperm donation. MAIN RESULTS AND THE ROLE OF CHANCE: On the SDQ (n = 46), the average total difficulties scores by age were: 8.2 ± 0.98 for ages 2-4, 7.6 ± 0.93 for ages 5-10, and 3.5 ± 0.77 for ages 11-17; this is compared to the normal reported range of 0-13, which indicates that clinically significant psychosocial problems are unlikely. Across all ages and individual categories (emotional symptoms, conduct problem, hyperactivity, peer problem, prosocial), scores on the SDQ were within the normal ranges. The average PARQ score (n = 70) for all respondents was 27.5 ± 1.18 (range: 24-96), suggesting perceived parental acceptance. LIMITATIONS, REASONS FOR CAUTION: Because this study was cross-sectional, it could not capture familial relationships over time. This survey-based study design allows for potential selection bias (parents of well-adjusted children may be more likely to participate). Additionally, the overall sample size is relatively small; however, it remains one of the largest published to date. Another significant limitation to this study is the lack of generalizability: most participants were recruited from private, faith-based, embryo donation programs who are demographically similar. WIDER IMPLICATIONS OF THE FINDINGS: Though embryo donation is an established form of third-party reproduction, it is significantly less robustly studied compared to other forms of gamete donation (oocyte or sperm donation). This study provides a larger data set with a more expanded age range of children compared to the limited number of previously published studies. Furthermore, these findings indicate a high parental disclosure rate with respect to the use of embryo donation which contrasts previous findings. STUDY FUNDING/COMPETING INTEREST(S): No external funding source was utilized for the completion of this study. No conflicts are disclosed. TRIAL REGISTRATION NUMBER: N/A.

Incident traumatic spinal cord injury and risk of Alzheimer's disease and related dementia: longitudinal case and control cohort study.

STUDY DESIGN: Retrospective case/control longitudinal cohort study OBJECTIVES: Prevalent traumatic spinal cord injury (TSCI) is associated with Alzheimer's disease and related dementia (ADRD). We examined the hazard ratio for ADRD after incident TSCI and hypothesized that ADRD hazard is greater among adults with incident TSCI compared with their matched control of adults without TSCI. SETTING: Using 2010-2020 U.S. national private administrative claims data, we identified adults aged 45 years and older with probable (likely and highly likely) incident TSCI (n = 657). Our controls included one-to-ten matched cohort of people without TSCI (n = 6553). METHODS: We applied Cox survival models and adjusted them for age, sex, years of living with certain chronic conditions, exposure to six classes of prescribed medications, and neighborhood characteristics of place of residence. Hazard ratios were used to compare the results within a 4-year follow-up. RESULTS: Our fully adjusted model without any interaction showed that incident TSCI increased the risk for ADRD (HR = 1.30; 95% CI, 1.01-1.67). People aged 45-64 with incident TSCI were at high risk for ADRD (HR = 5.14; 95% CI, 2.27-11.67) and no significant risk after age 65 (HR = 1.20; 95% CI, .92-1.55). Our sensitivity analyses confirmed a higher hazard ratio for ADRD after incident TSCI at 45-64 years of age compared with the matched controls. CONCLUSIONS: TSCI is associated with a higher hazard of ADRD. This study informs the need to update clinical guidelines for cognitive screening after TSCI to address the heightened risk of cognitive decline and to shed light on the causality between TSCI and ADRD.

Outcomes of young adults (aged ≤ 40 years) with newly diagnosed multiple myeloma after up-front autologous stem cell transplant.

Multiple myeloma (MM) primarily affects older patients. There are scarce data on the outcomes of young adults undergoing autologous transplantation (auto-HCT). In this single-centre analysis, we included 117 younger patients, with a median age of 37 years (range 22-40) at transplant. Seventeen (15%) patients had high-risk cytogenetics. Before transplant, 10% of patients achieved ≥CR and 44% achieved ≥VGPR. At best post-transplant response, 56% and 77% of patients achieved ≥CR and ≥VGPR respectively. With a median follow-up for survivors of 72.6 months (range 0.9-238.0), median PFS and OS were 43.1 months (95% CI 31.2-65.0) and 146.6 months (95% CI 100.0-208.1) respectively. Patients who underwent auto-HCT after 2010 had better median PFS (84.9 months vs. 28.2 months, p < 0.001) and OS (NR vs. 91.8 months, p < 0.001) compared with those transplanted earlier. In multi-variate analysis, achieving ≥CR as best post-transplant response was associated with improved PFS (HR [95% CI] 0.55 [0.32-0.95], p = 0.032), while achieving ≥VGPR was predictive of superior OS (0.32 [0.16-0.62], p < 0.001). Three patients (3%) developed a second primary malignancy. Younger MM patients had durable survival after auto-HCT, which further improved after the availability of novel anti-myeloma drugs in recent years. Depth of response following transplant remains a key predictor of survival.

Single-agent lenalidomide maintenance after upfront autologous stem cell transplant for newly diagnosed multiple myeloma: The MD Anderson experience.

The optimal duration of lenalidomide (Len) maintenance for patients with multiple myeloma (MM) after autologous stem cell transplantation (autoHCT) is unknown. We conducted a retrospective single-center analysis of adult MM patients that received upfront autoHCT between 2005 and 2021, followed by single-agent Len maintenance. A total of 1167 patients were included with a median age of 61.4 (range 25.4-82.3) years, and high-risk chromosomal abnormalities in 19%. Median duration of maintenance was 22.3 (range 0.03-139.6) months. After a median follow-up of 47.9 (range 2.9-171.7) months, median PFS and OS for the entire cohort were 56.6 (95% CI 48.2-61.4) months and 111.3 (95% CI 101.7-121.5) months, respectively. In MVA, high-risk cytogenetics was associated with a worse PFS (HR 1.91) and OS (HR 1.73) (p < .001 for both). Use of KRD induction and achievement of MRD-negative ≥ VGPR before autoHCT were associated with an improved PFS (HR 0.53 and HR 0.57, respectively; p < .001 for both). Longer maintenance duration, even with a 5-year cutoff, was associated with superior PFS and OS (HR 0.17 and 0.12, respectively; p < .001 for both). A total of 106 patients (9%) developed a second primary malignancy (SPM), mostly solid tumors (39%) and myeloid malignancies (30%). Longer maintenance duration was associated with a higher risk of SPM, reaching statistical significance after >2 years (odds ratio 2.25; p < .001). In conclusion, outcomes with Len maintenance were comparable to those reported in large clinical trials. Longer duration of maintenance, even beyond 5 years, was associated with improved survival.

Conceptualizing lifer versus destination patients for optimized care delivery.

BACKGROUND: Patients presenting to academic medical centers (AMC) typically receive primary care, specialty care, or both. Resources needed for each type of care vary, requiring different levels of care coordination. We propose a novel method to determine whether a patient primarily receives primary or specialty care to allow for optimization of care coordination. OBJECTIVES: We aimed to define the concepts of a Lifer Patient and Destination Patient and analyze the current state of care utilization in those groups to inform opportunities for improving care coordination. METHODS: Using AMC data for a 36-month study period (FY17-19), we evaluated the number of unique patients by residence zip code. Patients with at least one primary care visit and patients without a primary care visit were classified as Lifer and Destination patients, respectively. Cohen's effect sizes were used to evaluate differences in mean utilization of different care delivery settings. RESULTS: The AMC saw 35,909 Lifer patients and 744,037 Destination patients during the study period. Most patients were white, non-Hispanic females; however, the average age of a Lifer was seventy-two years whereas that of a Destination patient was thirty-eight. On average, a Lifer had three times more ambulatory care visits than a Destination patient. The proportion of Inpatient encounters is similar between the groups. Mean Inpatient length of stay (LOS) is similar between the groups, but Destination patients have more variance in LOS. The rate of admission from the emergency department (ED) for Destination patients is nearly double Lifers'. CONCLUSION: There were differences in ED, ambulatory care, and inpatient utilization between the Lifer and Destination patients. Furthermore, there were incongruities between rate of hospital admissions and LOS between two groups. The Lifer and Destination patient definitions allow for identification of opportunities to tailor care coordination to these unique groups and to allocate resources more efficiently.

Racial and Ethnic Inequities in Use of Preventive Services Among Privately Insured Adults With a Pediatric-Onset Disability.

PURPOSE: Cerebral palsy (CP) and spina bifida (SB) are pediatric-onset disabilities. Adults living with CP/SB are in a greater need of preventive care than the general population due to their increased risk for chronic diseases. Our objective was to compare White/Black and White/Hispanic inequities in the use of preventive services. METHODS: Using 2007-2017 private claims data, we identified a total of 11,635 adults with CP/BS. Of these, 8,935 were White, 1,457 Black, and 1,243 Hispanic. We matched health-related variables (age, sex, comorbid conditions) between White adults and those in each minority subpopulation. Generalized estimating equations were used and all models were adjusted for age, sex, comorbidities, income, education, and US Census divisions. Outcomes of interest were: (1) any office visit; (2) any physical/occupational therapy; (3) wellness visit; (4) bone density screening; (5) cholesterol screening; and (6) diabetes screening. RESULTS: The rate of recommended services for all subpopulations of adults with CP/SB was low. Compared with White adults, Hispanic adults had lower odds of wellness visits (odds ratio [OR] = 0.71, 95% CI, 0.53-0.96) but higher odds of diabetes screening (OR = 1.48, 95% CI, 1.13-1.93). Compared with White adults, Black adults had lower odds of wellness visits (OR = 0.50, 95% CI, 0.24-1.00) and bone density screening (OR = 0.54, 95% CI, 0.31-0.95). CONCLUSIONS: Preventive service use among adults with CP/SB was low. Large White-minority disparities in wellness visits were observed. Interventions to address physical accessibility, adoption of telehealth, and increased clinician education may mitigate these disparities, particularly if initiatives target minority populations.

Risk of early- and late-onset Alzheimer disease and related dementia in adults with cerebral palsy.

AIM: To examine the risk of Alzheimer disease and related dementia (ADRD) among adults with cerebral palsy (CP). METHOD: Using administrative insurance claims data for 2007 to 2017 in the USA, we identified adults (45y or older) with a diagnosis of CP (n=5176). Adults without a diagnosis of CP were included as a typically developing comparison group (n=1 119 131). Using age, sex, ethnicity, other demographic variables, and a set of chronic morbidities, we propensity-matched individuals with and without CP (n=5038). Cox survival models were used to estimate ADRD risk within a 3-year follow up. RESULTS: The unadjusted incidence of ADRD was 9 and 2.4 times higher among cohorts of adults 45 to 64 years (1.8%) and 65 years and older (4.8%) with CP than the respective unmatched individuals without CP (0.2% and 2.0% among 45-64y and 65y or older respectively). Fully adjusted survival models indicated that adults with CP had a greater hazard for ADRD (among 45-64y: unmatched hazard ratio 7.48 [95% confidence interval {CI} 6.05-9.25], matched hazard ratio 4.73 [95% CI 2.72-8.29]; among 65y or older: unmatched hazard ratio 2.21 [95% CI 1.95-2.51], matched hazard ratio 1.73 [1.39-2.15]). INTERPRETATION: Clinical guidelines for early screening of cognitive function among individuals with CP need updating, and preventative and/or therapeutic services should be used to reduce the risk of ADRD.

Attending guidance advised: educational quality of surgical videos on YouTube.

INTRODUCTION: YouTube is the most used platform for case preparation by surgical trainees. Despite its popular use, studies have noted limitations in surgical technique, safety, and vetting of these videos. This study identified the most viewed laparoscopic cholecystectomy (LC) videos on YouTube and analyzed the ability of attendings, residents, and medical students to identify critical portions of the procedure, technique, and limitations of the videos. METHODS: An incognito search was conducted on YouTube using the term "laparoscopic cholecystectomy." Results were screened for length, publication date, and language. The top ten most viewed videos were presented to general surgery attendings, residents, and medical students at a single academic institution. Established rubrics were used for evaluation, including the Critical View of Safety (CVS) for LC, a modified Global Operative Assessment of Laparoscopic Skills (GOALS) score, a task-specific checklist, and visual analog scales for case difficulty and operator competence. Educational quality and likelihood of video recommendation for case preparation were evaluated using a Likert scale. Attending assessments were considered the gold standard. RESULTS: Six attending surgeons achieved excellent internal consistency on CVS, educational quality, and likelihood of recommendation scales, with Cronbach alpha (⍺) of 0.93, 0.92, and 0.92, respectively. ⍺ was ≥ 0.7 in all the other scales measured. Attending evaluations revealed that only one of the ten videos attained all three established CVS criteria. Four videos demonstrated none of the CVS criteria. The mean educational quality (mEQ) was 4.63 on a 10-point scale. The mean likelihood of recommendation (mLoR) for case preparation was 2.3 on a 5-point scale. Senior resident assessments (Postgraduate Year (PGY)4 + , n = 12) aligned with attending surgeons, with no statistically significant differences in CVS attainment, mEQ, and mLoR. Junior residents (PGY1-3, n = 17) and medical students (MS3-4, n = 20) exhibited significant difference with attendings in CVS attainment, mEQ, and mLoR for more than half the videos. Both groups tended to overrate videos compared to attendings. CONCLUSION: YouTube is the most popular unvetted resource used for case presentation by surgical trainees. Attending evaluations revealed that the most viewed LC videos on YouTube did not attain the CVS, and were deemed as inappropriate for case preparation, with low educational value. Senior resident video assessments closely aligned with attendings, while junior trainees were more likely to overstate video quality and value. Attending guidance and direction of trainees to high-quality, vetted resources for surgical case preparation is needed. This may also suggest a need for surgical societies with platforms for video sharing to prioritize the creation and dissemination of high-quality videos on easily accessible public platforms.

Preventative Services Use and Risk Reduction for Potentially Preventative Hospitalizations Among People With Traumatic Spinal Cord Injury.

OBJECTIVE: To examine the risk of potentially preventable hospitalizations (PPHs) for adults (18 years or older) with traumatic spinal cord injury (TSCI) to identify the most common types of preventable hospitalizations and their associative risk factors. DESIGN: Cohort study. SETTING: Using 2007-2017 U.S. claims data from the Optum Clinformatics Data Mart, we identified adults (18 years or older) with diagnosis of TSCI (n=5380). Adults without TSCI diagnosis were included as controls (n=1,074,729). Using age and sex, we matched individuals with and without TSCI (n=5173) with propensity scores to address potential selection bias. Generalized linear regression was applied to examine the risk of TSCI on PPHs. Models were adjusted for age; sex; race and ethnicity; Elixhauser comorbidity count; any cardiometabolic, psychological, and musculoskeletal chronic conditions; U.S. Census Division; socioeconomic variables; and use of certain preventative care services. Adjusted odds ratios were compared within a 4-year follow-up period. PARTICIPANTS: Adults with and without TSCI (N=5,173). INTERVENTION: Not applicable. MAIN OUTCOMES MEASURES: Any PPH and specific PPHs RESULTS: Adults with TSCI had higher risk for any PPH (odds ratio [OR], 1.67; 95% CI,1.20-2.32), as well as PPHs because of urinary tract infection (UTI) (OR, 3.78; 95% CI, 2.47-5.79), hypertension (OR, 3.77; 95% CI, 1.54-9.21), diabetes long-term complications (OR, 2.54; 95% CI, 1.34-4.80), and pneumonia (OR, 1.71; 95% CI. 1.21-2.41). Annual wellness visit was associated with reduced PPH risk compared with cases and controls without annual wellness visit (OR, 0.57; 95% CI, 0.46-0.71) and among people with TSCI (OR, 0.69; 95% CI, 0.55-0.86) compared with cases without annual wellness visit. CONCLUSIONS: Adults with TSCI are at a heightened risk for PPH. They are also more susceptible to certain PPHs such as UTIs, pneumonia, and heart failure. Encouraging the use of preventative or health-promoting services, especially for respiratory and urinary outcomes, may reduce PPHs among adults with TSCI.

Psychological morbidity following spinal cord injury and among those without spinal cord injury: the impact of chronic centralized and neuropathic pain.

STUDY DESIGN: Longitudinal cohort study of privately insured beneficiaries with and without traumatic spinal cord injury (SCI). OBJECTIVES: Compare the incidence of and adjusted hazards for psychological morbidities among adults with and without traumatic SCI, and examine the effect of chronic centralized and neuropathic pain on outcomes. SETTING: Privately insured beneficiaries were included if they had an ICD-9-CM diagnostic code for traumatic SCI (n = 9081). Adults without SCI were also included (n = 1,474,232). METHODS: Incidence of common psychological morbidities were compared at 5-years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident psychological morbidities. RESULTS: Adults with SCI had a higher incidence of any psychological morbidity (59.1% vs. 30.9%) as compared to adults without SCI, and differences were to a clinically meaningful extent. Survival models demonstrated that adults with SCI had a greater hazard for any psychological morbidity (HR: 1.67; 95%CI: 1.61, 1.74), and all but one psychological disorder (impulse control disorders), and ranged from HR: 1.31 (1.24, 1.39) for insomnia to HR: 2.10 (1.77, 2.49) for post-traumatic stress disorder. Centralized and neuropathic pain was associated with all psychological disorders, and ranged from HR: 1.31 (1.23, 1.39) for dementia to HR: 3.83 (3.10, 3.68) for anxiety. CONCLUSIONS: Adults with SCI have a higher incidence of and risk for common psychological morbidities, as compared to adults without SCI. Efforts are needed to facilitate the development of early interventions to reduce risk of chronic centralized and neuropathic pain and psychological morbidity onset/progression in this higher risk population.

Lipid Droplets in Lung Cancers Are Crucial for the Cell Growth and Starvation Survival.

For rapid and unlimited cell growth and proliferation, cancer cells require large quantities of nutrients. Many metabolic pathways and nutrient uptake systems are frequently reprogrammed and upregulated to meet the demand from cancer cells, including the demand for lipids. The lipids for most adult normal cells are mainly acquired from the circulatory system. Whether different cancer cells adopt identical mechanisms to ensure sufficient lipid supply, and whether the lipid demand and supply meet each other, remains unclear, and was investigated in lung cancer cells. Results showed that, despite frequent upregulation in de novo lipogenesis and the lipid transporter system, different lung cancer cells adopt different proteins to acquire sufficient lipids, and the lipid supply frequently exceeds the demand, as significant amounts of lipids stored in the lipid droplets could be found within lung cancer cells. Lipid droplet surface protein, PLIN3, was found frequently overexpressed since the early stage in lung cancer tissues. Although the expression is not significantly associated with a specific gender, age, histology type, disease stage, and smoking habit, the frequently elevated expression of PLIN3 protein indicates the importance of lipid droplets for lung cancer. These lipid droplets are not only for nutrient storage, but are also crucial for tumor growth and proliferation, as well as survival in starvation. These results suggest that manipulation of lipid droplet formation or TG storage in lung cancer cells could potentially decrease the progression of lung cancer. Further exploration of lipid biology in lung cancer could help design novel treatment strategies.

The PrEDICT-DGE score as a simple preoperative screening tool identifies patients at increased risk for delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Morbidity after Pancreaticoduodenectomy (PD) has remained unchanged over the past decade. Delayed Gastric Emptying (DGE) is a major contributor with significant impact on healthcare-costs, quality of life and, for malignancies, even survival. We sought to develop a scoring system to aid in easy preoperative identification of patients at risk for DGE. METHODS: The ACS-NSQIP dataset from 2014 to 2018 was queried for patients undergoing PD with Whipple or pylorus preserving reconstruction. 15,154 patients were analyzed using multivariable logistic regression to identify risk factors for DGE, which were incorporated into a prediction model. Subgroup analysis of patients without SSI or fistula (primary DGE) was performed. RESULTS: We identified 9 factors independently associated with DGE to compile the PrEDICT-DGE score: Procedures (Concurrent adhesiolysis, feeding jejunostomy, vascular reconstruction with vein graft), Elderly (Age>70), Ductal stent (Lack of biliary stent), Invagination (Pancreatic reconstruction technique), COPD, Tobacco use, Disease, systemic (ASA>2), Gender (Male) and Erythrocytes (preoperative RBC-transfusion). PrEDICT-DGE scoring strongly correlated with actual DGE rates (R2 = 0.95) and predicted patients at low, intermediate, and high risk. Subgroup analysis of patients with primary DGE, retained all predictive factors, except for age>70 (p = 0.07) and ASA(p = 0.30). CONCLUSION: PrEDICT-DGE scoring accurately identifies patients at high risk for DGE and can help guide perioperative management.

Impact of preoperative biliary drainage on 30 Day outcomes of patients undergoing pancreaticoduodenectomy for malignancy.

BACKGROUND: Preoperative biliary drainage (PBD) has been advocated to address the plethora of physiologic derangements associated with cholestasis. However, available literature reports mixed outcomes and is based on largely outdated and/or single-institution studies. METHODS: Patients undergoing PBD prior to pancreaticoduodenectomy (PD) for periampullary malignancy between 2014-2018 were identified in the ACS-NSQIP pancreatectomy dataset. Patients with PBD were propensity-score-matched to those without PBD and 30-day outcomes compared. RESULTS: 8,970 patients met our inclusion criteria. 4,473 with obstruction and PBD were matched to 829 with no preoperative drainage procedure. In the non-jaundiced cohort, 711 stented patients were matched to 2,957 without prior intervention. PBD did not influence 30-day mortality (2.2% versus 2.4%) or major morbidity (19.8% versus 20%) in patients with obstructive jaundice. Superficial surgical site infections (SSIs) were more common with PBD (6.8% versus 9.2%), however, no differences in deep or organ-space SSIs were found. Patients without obstruction prior to PBD exhibited a 3-fold increase in wound dehiscence (0.5% versus 1.5%) additionally to increased superficial SSIs. CONCLUSION: PBD was not associated with an increase in 30-day mortality or major morbidity but increased superficial SSIs. PBD should be limited to symptomatic, profoundly jaundiced patients or those with a delay prior to PD.

Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis.

BACKGROUND & AIMS: We studied interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis. METHODS: We collected data on DNA sequences, messenger RNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases, and a separate set of 594 samples of colorectal adenocarcinomas, in The Cancer Genome Atlas. We performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in TGFB signaling (Sptbn1+/- and Smad4+/-/Sptbn1+/-) to identify changes in microbiota composition before development of colon tumors. CEACAM protein and its mutants were overexpressed in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and proliferation and colony formation assays. RESULTS: In colorectal adenocarcinomas, high expression levels of genes encoding CEACAM proteins, especially CEACAM5, were associated with reduced survival times of patients. There was an inverse correlation between expression of CEACAM genes and expression of TGFB pathway genes (TGFBR1, TGFBR2, and SMAD3). In colorectal adenocarcinomas, we also found an inverse correlation between expression of genes in the TGFB signaling pathway and genes that regulate stem cell features of cells. We found mutations encoding L640I and A643T in the B3 domain of human CEACAM5 in colorectal adenocarcinomas; structural studies indicated that these mutations would alter the interaction between CEACAM5 and TGFBR1. Overexpression of these mutants in SW480 and HCT116 colorectal cancer cell lines increased their anchorage-independent growth and inhibited TGFB signaling to a greater extent than overexpression of wild-type CEACAM5, indicating that they are gain-of-function mutations. Compared with feces from wild-type mice, feces from mice with defects in TGFB signaling had increased abundance of bacterial species that have been associated with the development of colon tumors, including Clostridium septicum, and decreased amounts of beneficial bacteria, such as Bacteroides vulgatus and Parabacteroides distasonis. CONCLUSION: We found expression of CEACAMs and genes that regulate stem cell features of cells to be increased in colorectal adenocarcinomas and inversely correlated with expression of TGFB pathway genes. We found colorectal adenocarcinomas to express mutant forms of CEACAM5 that inhibit TGFB signaling and increase proliferation and colony formation. We propose that CEACAM proteins disrupt TGFB signaling, which alters the composition of the intestinal microbiome to promote colorectal carcinogenesis.

Psychological morbidity among adults with cerebral palsy and spina bifida.

BACKGROUND: Very little is known about the risk of developing psychological morbidities among adults living with cerebral palsy (CP) or spina bifida (SB). The objective of this study was to compare the incidence of and adjusted hazards for psychological morbidities among adults with and without CP or SB. METHODS: Privately insured beneficiaries were included if they had an International Classification of Diseases, Ninth revision, Clinical Modification diagnostic code for CP or SB (n = 15 302). Adults without CP or SB were also included (n = 1 935 480). Incidence estimates of common psychological morbidities were compared at 4-years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident psychological morbidities. RESULTS: Adults living with CP or SB had a higher 4-year incidence of any psychological morbidity (38.8% v. 24.2%) as compared to adults without CP or SB, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with CP or SB had a greater hazard for any psychological morbidity [hazard ratio (HR): 1.60; 95% CI 1.55-1.65], and all but one psychological disorder (alcohol-related disorders), and ranged from HR: 1.32 (1.23, 1.42) for substance disorders, to HR: 4.12 (3.24, 5.25) for impulse control disorders. CONCLUSIONS: Adults with CP or SB have a significantly higher incidence of and risk for common psychological morbidities, as compared to adults without CP or SB. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce the risk of disease onset/progression in these higher-risk populations.

RAF inhibitors that evade paradoxical MAPK pathway activation.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.

Traumatic Spinal Cord Injury and Risk of Early and Late Onset Alzheimer's Disease and Related Dementia: Large Longitudinal Study.

OBJECTIVE: Traumatic spinal cord injury (TSCI) is a life altering event most often causing permanent physical disability. Little is known about the risk of developing Alzheimer disease and related dementia (ADRD) among middle-aged and older adults living with TSCI. Time to diagnosis of and adjusted hazard for ADRD was assessed. DESIGN: Cohort study. SETTING: Using 2007-2017 claims data from the Optum Clinformatics Data Mart, we identified adults (45+) with diagnosis of TSCI (n=7019). Adults without TSCI diagnosis were included as comparators (n=916,516). Using age, sex, race/ethnicity, cardiometabolic, psychological, and musculoskeletal chronic conditions, US Census division, and socioeconomic variables, we propensity score matched persons with and without TSCI (n=6083). Incidence estimates of ADRD were compared at 4 years of enrollment. Survival models were used to quantify unadjusted, fully adjusted, and propensity-matched unadjusted and adjusted hazard ratios (HRs) for incident ADRD. PARTICIPANTS: Adults with and without TSCI (N=6083). INTERVENTION: Not applicable. MAIN OUTCOMES MEASURES: Diagnosis of ADRD. RESULTS: Both middle-aged and older adults with TSCI had higher incident ADRD compared to those without TSCI (0.5% vs 0.2% and 11.7% vs 3.3% among 45-64 and 65+ y old unmatched cohorts, respectively) (0.5% vs 0.3% and 10.6% vs 6.2% among 45-64 and 65+ y old matched cohorts, respectively). Fully adjusted survival models indicated that adults with TSCI had a greater hazard for ADRD (among 45-64y old: unmatched HR: 3.19 [95% confidence interval, 95% CI, 2.30-4.44], matched HR: 1.93 [95% CI, 1.06-3.51]; among 65+ years old: unmatched HR: 1.90 [95% CI, 1.77-2.04], matched HR: 1.77 [1.55-2.02]). CONCLUSIONS: Adults with TSCI are at a heightened risk for ADRD. Improved clinical screening and early interventions aiming to preserve cognitive function are of paramount importance for this patient cohort.

Construction and evolution of an Escherichia coli strain relying on nonoxidative glycolysis for sugar catabolism.

The Embden-Meyerhoff-Parnas (EMP) pathway, commonly known as glycolysis, represents the fundamental biochemical infrastructure for sugar catabolism in almost all organisms, as it provides key components for biosynthesis, energy metabolism, and global regulation. EMP-based metabolism synthesizes three-carbon (C3) metabolites before two-carbon (C2) metabolites and must emit one CO2 in the synthesis of the C2 building block, acetyl-CoA, a precursor for many industrially important products. Using rational design, genome editing, and evolution, here we replaced the native glycolytic pathways in Escherichia coli with the previously designed nonoxidative glycolysis (NOG), which bypasses initial C3 formation and directly generates stoichiometric amounts of C2 metabolites. The resulting strain, which contains 11 gene overexpressions, 10 gene deletions by design, and more than 50 genomic mutations (including 3 global regulators) through evolution, grows aerobically in glucose minimal medium but can ferment anaerobically to products with nearly complete carbon conservation. We confirmed that the strain metabolizes glucose through NOG by 13C tracer experiments. This redesigned E. coli strain represents a different approach for carbon catabolism and may serve as a useful platform for bioproduction.