Postpartum Outcomes in Patients Receiving Venous Thromboembolism Prophylaxis during Antepartum Admission.

OBJECTIVE: We evaluated if venous thromboembolism (VTE) prophylaxis in the inpatient antepartum period was associated with wound hematomas, VTE occurrence, and other adverse outcomes. STUDY DESIGN: This study is a secondary analysis of a retrospective cohort of patients who delivered at University of Alabama at Birmingham (UAB). Patients receiving outpatient anticoagulation (AC) were excluded. We grouped patients into those who received inpatient antepartum prophylactic AC and those who did not. The primary outcome was wound hematomas from delivery to 6 weeks postpartum (PP). Secondary outcomes included VTE occurrence and select adverse outcomes, including other wound complications, unplanned procedures, mode of anesthesia, and intensive care unit (ICU) admission. Analyses were performed with no AC group as the reference. A sensitivity analysis excluding those who received inpatient PP AC was performed. RESULTS: Of 1,035 included patients, only 169 patients received inpatient prophylactic AC. They were older, had higher body mass indices, and more comorbidities. Patients receiving inpatient antepartum AC had higher wound hematomas (adjusted odds ratio [aOR] 23.81; 95% confidence interval [CI] 7.04-80.47). They had similar risk for developing VTE as the control group (aOR 2.68; 95% CI 0.19-37.49) but were more likely to have wound complications (aOR 2.36; 95% CI 1.24-4.47), maternal deaths (p < 0.05), and require PP ICU admission (aOR 13.38; 95% CI 4.79-37.35). When excluding those receiving any PP AC, there was no difference in bleeding complications between the two groups and VTE rates remained unchanged. Rates of maternal deaths and PP ICU admissions remained higher in those who received inpatient antepartum AC prophylaxis. CONCLUSION: In this small cohort study, increased wound hematomas were found in those who received inpatient antepartum AC prophylaxis with no difference in VTE occurrence. While adverse events were increased in the inpatient AC group, this was mostly associated with PP AC prophylaxis. Larger studies should be conducted to describe the true benefits and risks of antepartum AC prophylaxis and determine efficacy of this widely used practice. KEY POINTS: · Peripartum chemoprophylaxis is associated with increased wound hematomas.. · VTE is rare, despite its association with significant peripartum morbidity/mortality.. · Large studies are needed to guide practices that optimize the risk/benefit ratio of chemoprophylaxis..

A More Selective vs a Standard Risk-Stratified, Heparin-Based, Obstetric Thromboprophylaxis Protocol.

Importance: In 2016, our institution adopted a pregnancy-related venous thromboembolism (VTE) prophylaxis protocol based on American College of Obstetricians and Gynecologists guidelines that recommended postpartum heparin-based chemoprophylaxis (enoxaparin) based on a risk-stratified algorithm. In response to increased wound hematomas without significant reduction in VTE using this protocol, a more selective risk-stratified approach was adopted in 2021. Objective: To evaluate outcomes of the more selective risk-stratified approach to heparin-based obstetric thromboprophylaxis (enoxaparin) protocol. Design, Setting, and Participants: Retrospective observational study of 17 489 patients who delivered at a single tertiary care center in the southeast US between January 1, 2016, and December 31, 2018 (original protocol), and between December 1, 2021, and May 31, 2023 (more selective protocol). Patients receiving outpatient anticoagulation for active VTE or high VTE risk during pregnancy were excluded. Exposure: Standard risk-stratified and more selective postpartum VTE chemoprophylaxis protocols. Main Outcomes and Measures: The primary outcome was clinical diagnosis of wound hematoma up to 6 weeks pos tpartum. The secondary outcome was new diagnosis of VTE up to 6 weeks post partum. We compared baseline characteristics and outcomes between groups and estimated adjusted odds ratios with 95% CIs of primary and secondary outcomes using the original protocol group as reference. Results: Of 17 489 patients included in the analysis, 12 430 (71%) were in the original protocol group and 5029 (29%) were in the more selective group. Rates of chemoprophylaxis decreased from 16% (original protocol) to 8% (more selective protocol). Patients in the more selective group were more likely to be older, be married, and have obesity or other comorbidities (hypertension, diabetes, cardiac disease). Compared with the original protocol, the more selective protocol was associated with a decrease in any wound hematoma (0.7% vs 0.3%; adjusted odds ratio [aOR], 0.38; 95% CI, 0.21-0.67), specifically due to a lower rate of superficial wound hematomas (0.6% vs 0.3%; aOR, 0.43; 95% CI, 0.24-0.75). There was no significant increase in VTE or individual types of VTE (0.1% vs 0.1%; aOR, 0.40; 95% CI, 0.12-1.36). Conclusions and Relevance: A more selective risk-stratified approach to an enoxaparin thromboprophylaxis protocol for VTE was associated with decreased rates of wound hematomas without increased rates of postpartum VTE.

A preferred sequence for organelle inheritance during polarized cell growth.

Some organelles cannot be synthesized anew, so they are segregated into daughter cells during cell division. In Saccharomyces cerevisiae, daughter cells bud from mother cells and are populated by organelles inherited from the mothers. To determine whether this organelle inheritance occurs in a stereotyped manner, we tracked organelles using fluorescence microscopy. We describe a program for organelle inheritance in budding yeast. The cortical endoplasmic reticulum (ER) and peroxisomes are inherited concomitantly with bud emergence. Next, vacuoles are inherited in small buds, followed closely by mitochondria. Finally, the nucleus and perinuclear ER are inherited when buds have nearly reached their maximal size. Because organelle inheritance timing correlates with bud morphology, which is coupled to the cell cycle, we tested whether disrupting the cell cycle alters organelle inheritance order. By arresting cell cycle progression but allowing continued bud growth, we determined that organelle inheritance still occurs when DNA replication is blocked, and that the general inheritance order is maintained. Thus, organelle inheritance follows a preferred order during polarized cell division and does not require completion of S-phase.

High Rates of Pediatric Venous Thromboembolism After Elective Laparoscopic Splenectomy Suggest Need for Perioperative Prophylaxis.

INTRODUCTION: In adult populations, postoperative venous thromboembolism (VTE) is a reported complication of up to 8% of elective laparoscopic splenectomy (LS) cases. VTE is a rare event in the pediatric population, affecting less than 1% of all pediatric surgical patients. We hypothesized that pediatric patients are at a higher risk of postoperative VTE after undergoing elective LS relative to other laparoscopic procedures and may warrant prophylactic treatment. MATERIALS AND METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database from 2012 to 2020. Patients were identified using the Current Procedural Terminology code 38120 and only elective cases were analyzed. RESULTS: The incidence of VTE in all pediatric patients undergoing surgery in the American College of Surgeons NSQIP-P database was 0.13%. The incidence of VTE in pediatric patients undergoing elective laparoscopic abdominopelvic procedures was 0.17%. There were seven total cases of VTE (0.41%) in pediatric patients undergoing elective LS, more than twice the rate of the general population (P = 0.001). Eighty percent of pediatric patients undergoing elective LS had an underlying hematological disorder. CONCLUSIONS: By analyzing the NSQIP-P database, we evaluated the largest cohort of pediatric patients undergoing elective LS to date. We identified a higher incidence of VTE following this procedure relative to the rate of VTE in the overall population in the NSQIP-P database, as well as those undergoing elective laparoscopic abdominopelvic operations. The relatively higher incidence of VTE after elective LS is likely due to the presence of underlying hematological conditions. Given the low incidence of complications associated with pharmacologic VTE prophylaxis, the results of this study suggest that further research is warranted to establish the efficacy of perioperative pharmacological VTE prophylaxis in pediatric patients undergoing elective LS.

Nutritional needs, resources, and barriers among unhoused adults cared for by a street medicine organization in Chicago, Illinois: a cross-sectional study.

BACKGROUND: Those experiencing houselessness rely on obtaining food from community organizers and donations. Simultaneously, the houseless face disproportionally high rates of medical conditions that may be affected by diet including diabetes, hypertension, and hyperlipidemia. There is limited literature on the resources and barriers of the houseless community regarding optimal nutrition from an actionable perspective. Further, less data is available on how street medicine organizations may best impact the nutrition of the unhoused they serve. Elucidating this information will inform how organizational efforts may best support the nutrition of the houseless community. METHODS: In partnership with the medical student-run organization, Chicago Street Medicine, at Northwestern University Feinberg School of Medicine, twenty adults experiencing houselessness in Chicago, Illinois participated in the cross-sectional study. A 10-item survey was verbally administered to characterize the participants' daily food intake, food sources, barriers, resources, and nutritional preferences and needs. All data was directly transcribed into REDCap. Descriptive statistics were generated. RESULTS: Individuals consumed a median of 2 snacks and meals per day (IQR: 1-3). No participant consumed adequate servings of every food group, with only one participant meeting the dietary intake requirements for one food group. Participants most often received their food from donations (n = 15), purchasing themselves (n = 11), food pantries (n = 4), and shelters (n = 3). Eleven of nineteen participants endorsed dental concerns as a major barrier to consuming certain foods. Twelve participants had access to a can opener and twelve could heat their meals on a stove or microwave. Seven had access to kitchen facilities where they may prepare a meal. Approximately half of participants had been counseled by a physician to maintain a particular diet, with most related to reducing sugar intake. CONCLUSION: Most houseless participants were unable to acquire a balanced diet and often relied on organizational efforts to eat. Organizations should consider the chronic health conditions, dentition needs, and physical resources and barriers to optimal nutrition when obtaining food to distribute to the unhoused.

Echocardiographic correlates of major adverse cardiac events at 1 year in patients with apical ballooning takotsubo syndrome.

INTRODUCTION: Takotsubo syndrome (TTS) is characterized by transient left ventricular dysfunction and associated with considerable morbidity and mortality. We sought to evaluate the association between change in cardiac mechanics after diagnosis of TTS with 1-year incidence of major adverse cardiovascular events (MACE). METHODS: We retrospectively identified 85 patients with apical TTS based on ICD 9/10 codes and chart adjudication, who had a follow-up echocardiogram within 6 months of diagnosis. Echocardiograms were analyzed for left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), GLS ratio, global circumferential strain (GCS), and global radial strain (GRS). Multivariable logistic regression was performed to identify parameters associated with MACE (all-cause mortality, heart failure, stroke, and coronary artery disease [CAD] requiring percutaneous coronary intervention [PCI]) at 1 year. Event-free survival was assessed in patients with GLS (≤-18% vs. >18%) and LVEF (≥53% vs. <53%). RESULTS: Within 1 year of diagnosis, MACE occurred in 15 (18%) patients. Between baseline and follow-up echocardiogram (median 15 [range 1-151] days), there were significant differences in change in LVEF and GLS in patients with versus without incident MACE. In multivariate analysis, change in LVEF (odds ratio [OR] = .93 [.87, .98], p = .013) and change in GLS (OR = 1.32 [1.04, 1.67], p = .022) were independently associated with MACE; however, the association with change in GLS was attenuated (odds ratio [OR] = 1.13 [.94, 1.36], p = .21) after adjustment for baseline and change in LVEF. Among patients with normalized LVEF at follow-up, there were five (14.7%) MACE; whereas, there were no events among patients with normalized GLS. CONCLUSIONS: In patients with apical TTS, recovery in GLS and LVEF at follow-up was associated with significantly lower MACE at 1 year. Normalization of GLS at follow-up was better able to discriminate event-free survival than normalization of LVEF.

Contemporary Trends in Cesarean Delivery Rates and Indications.

OBJECTIVE: This study aimed to describe cesarean delivery rates and indications at a single center in order to assess the impact of the guidelines published by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine on trends in labor management. STUDY DESIGN: This is a retrospective cohort study of patients ≥23 weeks' gestation delivering at a single tertiary care referral center from 2013 to 2018. Demographic characteristics, mode of delivery, and main indication for cesarean delivery were ascertained by individual chart review. Cesarean delivery indications (mutually exclusive) were the following: repeat cesarean delivery, nonreassuring fetal status, malpresentation, maternal indications (e.g., placenta previa or genital herpes simplex virus), failed labor (any stage labor arrest), or other (i.e., fetal anomaly and elective). Polynomial (cubic) regression models were used to model rates of cesarean delivery and indications over time. Subgroup analyses further examined trends in nulliparous women. RESULTS: Of the 24,637 patients delivered during the study period, 24,050 were included in the analysis; 7,835 (32.6%) had a cesarean delivery. The rates of overall cesarean delivery were significantly different over time (p < 0.001), declining to a minimum of 30.9% in 2014 and peaking at 34.6% in 2018. With regard to the overall cesarean delivery indications, there were no significant differences over time. When limited to nulliparous patients, the rates of cesarean delivery were also noted to be significantly different over time (p = 0.02) nadiring at 30% in 2015 from 35.4% in 2013 and then rising up to 33.9% in 2018. As for nulliparous patients, there was no significant difference in primary cesarean delivery indications over time except for nonreassuring fetal status (p = 0.049). CONCLUSION: Despite changes in labor management definitions and guidelines encouraging vaginal birth, the rates of overall cesarean delivery did not decrease over time. The indications for delivery, particularly failed labor, repeat cesarean delivery, and malpresentation have not significantly changed over time. KEY POINTS: · The rates of overall cesarean deliveries did not decrease despite the 2014 published recommendations for the reduction in cesarean deliveries.. · There were no significant differences in the indications of cesarean deliveries among nulliparous or multiparous women.. · Despite the adoption of strategies to reduce the overall and primary cesarean delivery rates, these trends remain unchanged.. · Indications for delivery, particularly failed labor, repeat cesarean delivery, and malpresentation have also not significantly changed over time.. · Additional strategies to encourage and increase vaginal delivery rates must be adopted..

Perioperative Skeletal Muscle Fluctuations in High-Acuity Liver Transplantation.

BACKGROUND: Frailty has been implicated as a negative predictor of Liver Transplant (LT) outcomes. However, an understanding of changes in patient muscle mass peri-LT, and their effect in high-acuity patients remains lacking. We examined the impact of perioperative muscle mass changes (ΔSMI) on high-acuity (MELD ≥35) LT recipients. MATERIALS AND METHODS: Skeletal muscle index (SMI) was calculated using CT imaging. Patients were divided into two groups, based on severity of peri-operative SMI decrease. LT recipients with chronic end-stage liver disease, MELD ≥35, and abdominal CT ≤30 days prior, and 30-90 days post LT were included. [1011 adult LT recipients reviewed, 2012-2018]. RESULTS: Of 1011 patients reviewed, 88 met inclusion criteria (median MELD 41.1). The median ΔSMI was -5.0 (-29.4 - +21.1 cm2/m2) (fig A). Patients were classified into two groups: ΔSMI<-5.0 (median ΔSMI: -0.4, n = 44) and ΔSMI>-5.0 (median ΔSMI: -9.2, n = 44). Recipients with ΔSMI<-5.0 had higher pre-LT SMI (35.4 versus 31.2 cm2/m2, P <0.001) and lower post-LT SMI (26.0 versus 30.8 cm2/m2, P <0.001). The ΔSMI<-5.0 group had higher early allograft dysfunction (40.9 versus 20.5%, P = 0.037), and inferior patient and graft survival (P = 0.015, 0.017, respectively). Multivariate analysis identified ΔSMI<-5.0 (HR: 2.938, P = 0.048), long cold-ischemia time (≥9h, HR: 7.332, P = 0.008), HCV (HR: 5.614, p = 0.001), and tracheostomy after LT (HR:9.218, P <0.001) as negative prognostic factors for patient survival . CONCLUSIONS: Progressive perioperative sarcopenic deterioration was associated with inferior patient and graft survival in high acuity LT. These findings may guide pre and post-operative patient care and rehabilitation efforts in this challenging patient population.

Ischemia-reperfusion injury and its relationship with early allograft dysfunction in liver transplant patients.

Ischemia-reperfusion injury (IRI) is believed to contribute to graft dysfunction after liver transplantation (LT). However, studies on IRI and the impact of early allograft dysfunction (EAD) in IRI grafts are limited. Histological IRI was graded in 506 grafts from patients who had undergone LT and classified based on IRI severity (no, minimal, mild, moderate, and severe). Of the 506 grafts, 87.4% had IRI (no: 12.6%, minimal: 38.1%, mild: 35.4%, moderate: 13.0%, and severe: 0.8%). IRI severity correlated with the incidence of EAD and graft survival at 6 months. Longer cold/warm ischemia time, recipient/donor hypertension, and having a male donor were identified as independent risk factors for moderate to severe IRI. Among 70 grafts with moderate to severe IRI, 42.9% of grafts developed EAD, and grafts with EAD had significantly inferior survival compared to grafts without EAD. Longer cold ischemia time and large droplet macrovesicular steatosis (≥20%) were identified as independent risk factors for EAD. Our study demonstrated that increased IRI severity was correlated with inferior short-term graft outcomes. Careful consideration of IRI risk factors during donor-recipient matching may assist in optimizing graft utilization and LT outcomes. Furthermore, identification of risk factors of IRI-associated EAD may guide patient management and possible timely graft replacement.

The impact of marijuana use on liver transplant recipients: A 900 patient single center experience.

INTRODUCTION: Increased societal prevalence of marijuana continues to challenge liver transplant (LT) programs. This study aimed to examine the potential effects of marijuana use on outcomes. METHODS: This retrospective study included recipients who underwent LT between 1/2012 and 6/2018. According to pre-LT marijuana use, patients were classified into recent (≤6 months of LT), former (chronic use but not ≤6 months), or non-users. Additionally, the impact of post-LT marijuana use on survival was assessed. RESULTS: Of 926 eligible patients, 184 were pre-LT marijuana users (42 recent; 142 former) (median follow-up: 30.3 months). Pre-users were more likely to be male, White, and have histories of tobacco, alcohol, and illicit drug use. Additionally, recent users were of higher acuity, with higher MELD and requiring ICU admission. Patient survival at 1-year was 89% in non-users, 94% (HR: 0.494, 95% CI: 0.239-1.022 vs. non-users) in former users, and 83% (HR: 1.516, 95% CI: 0.701-3.282) in recent users. Post-operative complications in pre-LT users and the survival analysis for post-LT marijuana users vs. non-users did not show significance. CONCLUSIONS: Our results demonstrated that marijuana use did not have an adverse impact on post-LT outcomes; however, further studies utilizing larger cohorts are warranted.

Characteristics of older adults living with HIV accessing home and community care services in British Columbia, Canada.

Over half of people living with HIV (PLHIV) engaged in care in British Columbia (BC) are age ≥50. The public home and community care (HCC) system offers formal support that PLHIV may turn to as they age, but little is known about access specific to PLHIV. Using data from the STOP HIV/AIDS cohort, which includes linked treatment and demographic records for PLHIV accessing care in BC, we compared older PLHIV (defined as those age ≥50) who did and did not access HCC services. We estimated adjusted odds ratios (aORs) for factors associated with HCC service utilization using logistic regression. This study included 5,603 PLHIV age ≥50, 837 (14.94%) of whom accessed any HCC service between 2005 and 2015. Services most commonly used were community nursing (8.98%, n = 503) and rehabilitation (7.73%, n = 433). Those who received HCC were more likely to be female (aOR = 1.56, 95% CI = 1.24, 1.98), have a history of injection drug use (aOR = 1.88, 95% CI = 1.57, 2.25), have a higher Charlson comorbidity score (aOR = 1.11, 95% CI:1.07, 1.15) and to have visited a general practitioner in the past year (aOR = 2.17, 95% CI = 1.77, 2.67). Approximately 15% of older PLHIV have accessed HCC, but the extent of potential unmet need for these services requires further research.

Leaflet Mechanical Properties of Carpentier-Edwards Perimount Magna Pericardial Aortic Bioprostheses.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has recently been shown to be equivalent to surgical aortic valve replacement (SAVR) in intermediate-risk patients. As TAVR expands towards the traditionally SAVR population, TAVR versus SAVR durability becomes increasingly important. While the durability of TAVR is unknown, valve design - particularly with regards to leaflet stress - impacts on valve durability. Although leaflet stress cannot be measured directly, it can be determined using finite element modeling, with such models requiring the mechanical properties of the leaflets. Balloon-expandable TAVR involves the use of bovine pericardial leaflets treated in the same manner as surgical bioprosthetic leaflets. The study aim was to determine the leaflet mechanical properties of Carpentier-Edwards bioprostheses for future TAVR and SAVR computational models. METHODS: A total of 35 leaflets were excised from 12 Carpentier-Edwards Model 3000TFX Perimount Magna aortic bioprostheses (21 mm, 23 mm, and 25 mm) and subjected to displacement-controlled equibiaxial stretch testing. The stress-strain data acquired were fitted to a Fung constitutive model to describe the material properties in circumferential and radial directions. Leaflet stiffness was calculated at specified physiological stress, corresponding to zero pressure, systemic pressure, and between zero and systemic pressure. RESULTS: The 21-mm bioprostheses had significantly thinner leaflets than the larger bioprostheses. A non-linear stress-strain relationship was observed in all leaflets along the circumferential and radial directions. No significant difference in leaflet stiffness at systemic pressure, or between zero and systemic pressure, was found among the three bioprosthesis sizes. However, the leaflets from the 23 mm bioprosthesis were significantly more compliant than those of the 21 mm and 25 mm bioprostheses at zero pressure in the circumferential direction. No differences were observed in leaflet stiffness in circumferential versus radial directions. CONCLUSIONS: The bovine pericardial leaflets from Carpentier-Edwards Perimount Magna bioprostheses showed no differences in material properties among different valve sizes at systemic pressure. The thinner 21 mm leaflets did not show any corresponding differences in leaflet stiffness, which suggests that the thinner TAV leaflets may have a similar stiffness to their thicker SAV counterparts.

Molecular pathways regulating mitotic spindle orientation in animal cells.

Orientation of the cell division axis is essential for the correct development and maintenance of tissue morphology, both for symmetric cell divisions and for the asymmetric distribution of fate determinants during, for example, stem cell divisions. Oriented cell division depends on the positioning of the mitotic spindle relative to an axis of polarity. Recent studies have illuminated an expanding list of spindle orientation regulators, and a molecular model for how cells couple cortical polarity with spindle positioning has begun to emerge. Here, we review both the well-established spindle orientation pathways and recently identified regulators, focusing on how communication between the cell cortex and the spindle is achieved, to provide a contemporary view of how positioning of the mitotic spindle occurs.

Formin-mediated actin polymerization cooperates with Mushroom body defect (Mud)-Dynein during Frizzled-Dishevelled spindle orientation.

To position the mitotic spindle, cytoskeletal components must be coordinated to generate cortical forces on astral microtubules. Although the dynein motor is common to many spindle orientation systems, 'accessory pathways' are often also required. In this work, we identified an accessory spindle orientation pathway in Drosophila that functions with Dynein during planar cell polarity, downstream of the Frizzled (Fz) effector Dishevelled (Dsh). Dsh contains a PDZ ligand and a Dynein-recruiting DEP domain that are both required for spindle orientation. The Dsh PDZ ligand recruits Canoe/Afadin and ultimately leads to Rho GTPase signaling mediated through RhoGEF2. The formin Diaphanous (Dia) functions as the Rho effector in this pathway, inducing F-actin enrichment at sites of cortical Dsh. Chimeric protein experiments show that the Dia-actin accessory pathway can be replaced by an independent kinesin (Khc73) accessory pathway for Dsh-mediated spindle orientation. Our results define two 'modular' spindle orientation pathways and show an essential role for actin regulation in Dsh-mediated spindle orientation.

Synthesis and patterning of tunable multiscale materials with engineered cells.

Many natural biological systems--such as biofilms, shells and skeletal tissues--are able to assemble multifunctional and environmentally responsive multiscale assemblies of living and non-living components. Here, by using inducible genetic circuits and cellular communication circuits to regulate Escherichia coli curli amyloid production, we show that E. coli cells can organize self-assembling amyloid fibrils across multiple length scales, producing amyloid-based materials that are either externally controllable or undergo autonomous patterning. We also interfaced curli fibrils with inorganic materials, such as gold nanoparticles (AuNPs) and quantum dots (QDs), and used these capabilities to create an environmentally responsive biofilm-based electrical switch, produce gold nanowires and nanorods, co-localize AuNPs with CdTe/CdS QDs to modulate QD fluorescence lifetimes, and nucleate the formation of fluorescent ZnS QDs. This work lays a foundation for synthesizing, patterning, and controlling functional composite materials with engineered cells.

Secondary peristalsis and esophagogastric junction distensibility in symptomatic post-fundoplication patients.

BACKGROUND: The impact of esophageal dysmotility among patients with post-fundoplication esophageal symptoms is not fully understood. This study aimed to investigate secondary peristalsis and esophagogastric junction (EGJ) opening biomechanics using functional lumen imaging probe (FLIP) panometry in symptomatic post-fundoplication patients. METHODS: Eighty-seven adult patients post-fundoplication who completed FLIP for symptomatic esophageal evaluation were included. Secondary peristaltic contractile response (CR) patterns and EGJ opening metrics (EGJ distensibility index (EGJ-DI) and maximum EGJ diameter) were evaluated on FLIP panometry and analyzed against high-resolution manometry (HRM), patient-reported outcomes, and fundoplication condition seen on esophagram and/or endoscopy. KEY RESULTS: FLIP CR patterns included 14 (16%) normal CR, 30 (34%) borderline CR, 28 (32%) impaired/disordered CR, 13 (15%) absent CR, and 2 (2%) spastic reactive CR. Compared with normal and borderline CRs (i.e., CR patterns with distinct, antegrade peristalsis), patients with impaired/disordered and absent CRs demonstrated significantly greater time since fundoplication (2.4 (0.6-6.8) vs. 8.9 (2.6-14.5) years; p = 0.002), greater esophageal body width on esophagram (n = 50; 2.3 (2.0-2.8) vs. 2.9 (2.4-3.6) cm; p = 0.013), and lower EGJ-DI (4.3 (2.7-5.4) vs. 2.6 (1.7-3.7) mm2/mmHg; p = 0.001). Intact fundoplications had significantly higher rates of normal CRs compared to anatomically abnormal (i.e., tight, disrupted, slipped, herniated) fundoplications (9 (28%) vs. 5 (9%); p = 0.032), but there were no differences in EGJ-DI or EGJ maximum diameter. CONCLUSIONS & INFERENCES: Symptomatic post-fundoplication patients were characterized by frequent abnormal secondary peristalsis after fundoplication, potentially worsening with time after fundoplication or related to EGJ outflow resistance.

B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.

Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence.

Evaluating transformative health leadership education for Indigenous health: a mixed methods study.

BACKGROUND: There is an urgent need to improve structural competency and anti-racism education across health systems. Many leaders in health systems have the ability and responsibility to play a significant role in policy change and transforming healthcare delivery to address health inequities and injustices. The aim of this project was to evaluate a new health leadership Indigenous health course: PLUS4I. METHODS: A mixed methods design grounded in a pragmatic paradigm was used. Attendees to the first four cohorts (n=75) were sent an invitation to complete a survey evaluating their learning immediately after the completion of PLUS4I. We retrospectively collected self-efficacy ratings from participants who were also invited to participate in a semi-structured interview about their experience in PLUS4I. Descriptive statistical analysis was conducted for the quantitative assessment of the survey data. A qualitative descriptive approach to thematic analysis was used for the qualitative interview data. RESULTS: A total of 45 completed quantitative evaluations (n=45) were completed across all four cohorts. Paired t-tests were used to show pre-changes and post-changes in self-reported confidence on a 6-point Likert scale across four categories of activities. Improvements were seen in the ratings across all categories of activities, and all were statistically significant (p<0.001). Two overarching themes emerged from the qualitative analysis: breaking down previous knowledge and critical applications; building new knowledge and change-making competencies. The qualitative interviews (n=25) averaged 32:23 min, with 18 female (72%) and 7 male (28%) interview participants. CONCLUSION: Future work will support expansion of the PLUS4I course into other work environments and faculties, where the learning environment, structure and relevant Truth and Reconciliation Calls to Action may be different. This work responds to the urgent need to create systems-level change to address structural racism and implement high-quality Indigenous health and anti-racism education.

Patient experiences of virtual care across specialist neuroscience and psychiatry clinics related to the second wave of the COVID-19 pandemic in Calgary, Alberta.

Purpose: The emergence of the COVID-19 (SARS-CoV-2) pandemic has led to public health restrictions and a shift towards virtual care and telehealth. The aim of this study was to explore barriers and facilitators of virtual care from the perspective of neurological and psychiatric patients. Methods: One-on-one interviews were conducted remotely using telephone and online video teleconferencing. There was a total of 57 participants, and a thematic content analysis was conducted using NVivo software. Results: The two main themes were (1) virtual health service delivery and (2) virtual physician/patient interaction, with subthemes around how virtual care improved accessibility of care for patients and improved patient-centered care; how privacy and technical issues impact patients using virtual care; and the need for relationality and connection between health care providers and patients while using virtual care. Conclusions: This study showed that virtual care can increase accessibility and efficiency for patients and providers, indicating its potential for ongoing use in the delivery of clinical care. Virtual care was found to be an acceptable mode of healthcare delivery from the perspective of patients; however, there is a continued need for relationship-building between care providers and patients.

Targeting PEA3 transcription factors to mitigate small cell lung cancer progression.

Small cell lung cancer (SCLC) remains a lethal disease with a dismal overall survival rate of 6% despite promising responses to upfront combination chemotherapy. The key drivers of such rapid mortality include early metastatic dissemination in the natural course of the disease and the near guaranteed emergence of chemoresistant disease. Here, we found that we could model the regression and relapse seen in clinical SCLC in vitro. We utilized time-course resolved RNA-sequencing to globally profile transcriptome changes as SCLC cells responded to a combination of cisplatin and etoposide-the standard-of-care in SCLC. Comparisons across time points demonstrated a distinct transient transcriptional state resembling embryonic diapause. Differential gene expression analysis revealed that expression of the PEA3 transcription factors ETV4 and ETV5 were transiently upregulated in the surviving fraction of cells which we determined to be necessary for efficient clonogenic expansion following chemotherapy. The FGFR-PEA3 signaling axis guided the identification of a pan-FGFR inhibitor demonstrating in vitro and in vivo efficacy in delaying progression following combination chemotherapy, observed inhibition of phosphorylation of the FGFR adaptor FRS2 and corresponding downstream MAPK and PI3K-Akt signaling pathways. Taken together, these data nominate PEA3 transcription factors as key mediators of relapse progression in SCLC and identify a clinically actionable small molecule candidate for delaying relapse of SCLC.