A review of medical malpractice cases involving trainees in the emergency department.

Background: This study characterizes medical malpractice lawsuits involving trainees providing care in the emergency department (ED), affording insight into the types of patients involved, clinical scenarios, and legal outcomes of these cases. Methods: Cases were identified using the legal database, Westlaw. Per chart review methods, relevant information was abstracted by 2 trained reviewers onto a standardized data abstraction form, with a senior author arbitrating disagreements. Results: We identified 60 cases reported between 1982 and 2017 in which a trainee was named in a lawsuit related to patient care provided in the ED. The most common alleged errors included diagnostic (n = 37, 61%), treatment (n = 13, 21%), and procedural errors (n = 19, 16%). In 21 cases (35%), it was alleged that no attending physician was directly involved in the care at any time. The attending was noted to have seen the patient in person at any point in only 11 total cases (18%). Of the 50 cases with known outcomes, 15 (30%) decided in favor of the patient, 21 (42%) were resolved in the physician's favor, and 14 (28%) were settled. Conclusion: This study underscores that trainees are vulnerable to malpractice cases and that lack of direct supervision is a prominent theme in these cases. This information suggests areas for further work and may help training programs, trainees, and supervising physicians design their practice patterns in ways that mitigate these risks in the future.

Expression of circadian regulatory genes is dysregulated by increased cytokine production in mice subjected to concomitant intestinal injury and parenteral nutrition.

BACKGROUND: We have developed a mouse model of Parenteral Nutrition Associated Cholestasis (PNAC) in which combining intestinal inflammation and PN infusion results in cholestasis, hepatic macrophage activation, and transcriptional suppression of bile acid and sterol signaling and transport. In the liver, the master circadian gene regulators Bmal/Arntl and Clock drive circadian modulation of hepatic functions, including bile acid synthesis. Once activated, Bmal and Clock are downregulated by several transcription factors including Reverbα (Nr1d1), Dbp (Dbp), Dec1/2 (Bhlhe40/41), Cry1/2 (Cry1/2) and Per1/2 (Per1/2). The aim of this study was to examine the effects of PN on expression of hepatic circadian rhythm (CR) regulatory genes in mice. METHODS: WT, IL1KO or TNFRKO mice were exposed to dextran sulfate sodium (DSS) for 4 days followed by soy-oil lipid emulsion-based PN infusion through a central venous catheter for 14 days (DSS-PN) and the expression of key CR regulatory transcription factors evaluated. Animals were NPO on a 14 hr light-dark cycle and were administered PN continuously over 24 hrs. Mice were sacrificed, and hepatic tissue obtained at 9-10AM (Zeitgeber Z+3/Z+4 hrs). PNAC was defined by increased serum aspartate aminotransferase, alanine aminotransferase, total bile acids, and total bilirubin and the effect of i.p. injection of recombinant IL-1ß (200ng/mouse) or TNFα (200ng/mouse) on CR expression was examined after 4 hrs. RESULTS: In the PNAC model, DSS-PN increased serum biomarkers of hepatic injury (ALT, AST, serum bile acids) which was suppressed in both DSS-PN IL1KO and DSS-PN TNFRKO mice. In WT DSS-PN, mRNA expression of Arntl and Dec1 was suppressed corresponding to increased Nr1d1, Per2, Dbp and Dec2. These effects were ameliorated in both DSS-PN IL1KO and DSS-PN TNFRKO groups. Western analysis of the circadian transcription factor network revealed in WT mice DSS-PN significantly suppressed Reverbα, Bmal, Dbp, Per2 and Mtnr1b. With the exception of Dbp, DSS-PN mediated suppression was ameliorated by both IL1KO and TNFRKO. Intraperitoneal injection of IL-1ß or TNFα into WT mice increased serum AST and ALT and suppressed mRNA expression of Nr1d1, Arntl and Clock and increased Dbp and Per2. CONCLUSIONS: Altered expression of CR-dependent regulatory genes during PNAC accompanies cholestasis and is, in part, due to increased cytokine (IL-1ß and TNFα) production. Evaluation of the effects of modulating CR in PNAC thus deserves further investigation.

Stat3 role in the protective effect of FXR Agonist in parenteral nutrition-associated cholestasis.

BACKGROUND AND AIMS: Parenteral nutrition (PN) in patients with intestinal failure can lead to cholestasis (PNAC). In a PNAC mouse model, farnesoid X receptor (FXR) agonist (GW4064) treatment alleviated IL-1ß-dependent cholestatic liver injury. The objective of this study was to determine whether this hepatic protection of FXR activation is mediated through IL-6-STAT3 signaling. APPROACH AND RESULTS: Hepatic apoptotic pathways [Fas-associated protein with death domain (Fas) mRNA, caspase 8 protein, and cleaved caspase 3] and IL-6-STAT3 signaling, and expression of its downstream effectors Socs1/3 were all upregulated in the mouse PNAC model (dextran sulfate sodium enterally × 4 d followed by total PN for 14 d). Il1r-/- mice were protected from PNAC in conjunction with suppression of the FAS pathway. GW4064 treatment in the PNAC mouse increased hepatic FXR binding to the Stat3 promoter, further increased STAT3 phosphorylation and upregulated Socs1 and Socs3 mRNA, and prevented cholestasis. In HepG2 cells and primary mouse hepatocytes, IL-1ß induced IL-6 mRNA and protein, which were suppressed by GW4064. In IL-1ß or phytosterols treated HepG2 and Huh7 cells, siRNA knockdown of STAT3 significantly reduced GW4064-upregulated transcription of hepatoprotective nuclear receptor subfamily 0, group B, member 2 (NR0B2) and ABCG8. CONCLUSIONS: STAT3 signaling mediated in part the protective effects of GW4064 in the PNAC mouse, and in HepG2 cells and hepatocytes exposed to either IL-1ß or phytosterols, 2 factors critical in PNAC pathogenesis. These data demonstrate that FXR agonists may mediate hepatoprotective effects in cholestasis by inducing STAT3 signaling.

Thioredoxin reductase 1 regulates hepatic inflammation and macrophage activation during acute cholestatic liver injury.

BACKGROUND AND AIMS: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by periportal inflammation with progression to hepatic fibrosis and ultimately cirrhosis. We recently reported that the thioredoxin antioxidant response is dysregulated during primary sclerosing cholangitis. The objective of this study was to examine the impact of genetic and pharmacological targeting of thioredoxin reductase 1 (TrxR1) on hepatic inflammation and liver injury during acute cholestatic injury. APPROACH AND RESULTS: Primary mouse hepatocytes and intrahepatic macrophages were isolated from 3-day bile duct ligated (BDL) mice and controls. Using wildtype and mice with a liver-specific deletion of TrxR1 (TrxR1LKO), we analyzed the effect of inhibition or ablation of TrxR1 signaling on liver injury and inflammation. Immunohistochemical analysis of livers from BDL mice and human cholestatic patients revealed increased TrxR1 staining in periportal macrophages and hepatocytes surrounding fibrosis. qPCR analysis of primary hepatocytes and intrahepatic macrophages revealed increased TrxR1 mRNA expression following BDL. Compared with sham controls, BDL mice exhibited increased inflammation, necrosis, and increased mRNA expression of pro-inflammatory cytokines, fibrogenesis, the NLRP3 inflammatory complex, and increased activation of NFkB, all of which were ameliorated in TrxR1LKO mice. Importantly, following BDL, TrxR1LKO induced periportal hepatocyte expression of Nrf2-dependent antioxidant proteins and increased mRNA expression of basolateral bile acid transporters with reduced expression of bile acid synthesis genes. In the acute BDL model, the TrxR1 inhibitor auranofin (10 mg/kg/1 d preincubation, 3 d BDL) ameliorated BDL-dependent increases in Nlrp3, GsdmD, Il1ß, and TNFα mRNA expression despite increasing serum alanine aminotransferase, aspartate aminotransferase, bile acids, and bilirubin. CONCLUSIONS: These data implicate TrxR1-signaling as an important regulator of inflammation and bile acid homeostasis in cholestatic liver injury.

Hybrid Work from Home Clinical Academic Environment: A One-Year Follow-Up Survey of Attitudes and Beliefs of Members of a Department of Palliative Care, Rehabilitation, and Integrative Medicine.

Context: Palliative, Rehabilitation, and Integrative Medicine (PRIM) department members anonymously reported a positive experience with work from home (WFH) two months after its rapid pandemic transition in March 2020. Data are limited on the stability of such preferences and experiences over time. Objectives: The objectives of this study were to survey the attitudes and beliefs of PRIM employees toward remote work 16 months after the start of the coronavirus disease 2019 (COVID-19) pandemic since vaccines and to determine changes in perceptions of WFH. Methods: All 138 PRIM employees were invited to participate in an anonymous survey from mid-July to mid-August 2021. The 30-question survey included demographics, perceptions toward WFH, and the pandemic. Results: One hundred fifteen (83%) employees completed the survey: 29 (74%) research, 62 (83%) clinicians, and 24 (100%) administrative personnel. Most were female (76%), 30-59 years old (88%), PRIM employees before May 2020 (89%), shared office space (52%), and had received either first or second dose of the COVID-19 vaccine (88%). Overall experience (86%) and emotional response (74%) with WFH were positive and not significantly different from 2020 (p = 0.128 and 0.782, respectively). Positive experience was associated with having adequate equipment (p = 0.002), perception of productivity (p = 0.002), financial advantage (p = 0.002), and time demands caring for dependents (p = 0.038). Clinicians reported less positive response (78%, p = 0.002) and less productivity (49%, p = 0.002) with WFH and higher level of stress (54%, p = 0.026) since COVID-19. Employees continued to support WFH permanently (79%) for two or more days/week (82%). There was continued increased emotional exhaustion (71%) similar to 2020 (p = 0.868), and being asked to work partially or completely from home permanently was favored by 64% versus 97% and 96% of clinicians, research, and administrative, respectively (p = 0.002). Conclusions: Support for WFH was sustained a year later and after three pandemic waves. These findings serve as a model for future rapid work transitions and can help elucidate factors associated with stress and emotional exhaustion in a new post-COVID-19 work environment.

Patterns of opioid use among Texas dental practitioners during the COVID-19 pandemic.

OBJECTIVE: The primary objective of this study is to assess factors that influence opioid prescribing by dentists and the role of these factors in the practice of dental pain control. DESIGN: A 25-question survey instrument was distributed to the study population for anonymous responses, covering dentist and practice demographics and opioid prescribing characteristics. SETTING: Private solo and group practice settings, including general practitioners and dental specialists. PARTICIPANTS: Potential participants included all active members of a large state dental professional association. MAIN OUTCOME MEASURES: They were practitioner and practice demographic traits, types of opioids prescribed, and statistical correlations. Outcome variables included practice type, practitioner gender, practice location, practice model, and years in practice. Categorical covariates were summarized statistically by frequencies and percentages, and continuous covariates were summarized by means, medians, ranges, and standard deviations. RESULTS: Strongest correlations with opioid prescribing included general practitioner (vs specialist) and male gender. The coronavirus disease 2019 pandemic was confirmed as having exerted a significant impact on opioid prescribing among the survey respondents. CONCLUSIONS: Further research is warranted to assess post-pandemic opioid prescribing patterns, and additional educational strategies regarding limitations of opioid prescriptions should be applied to general, rather than specialty, dental practitioners.

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease.

Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12, Lamp1, Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His123, Cys128, His174, His181, Lys238, Cys290, His340, Lys341 and His385. These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction.

Interdisciplinary intervention for the management of nonmedical opioid use among patients with cancer pain.

BACKGROUND: Few studies have assessed interventions aimed at managing nonmedical opioid use (NMOU) behavior among patients with cancer. The authors developed the Compassionate High-Alert Team (CHAT) intervention to manage patients receiving opioids for cancer pain who demonstrate NMOU behavior. The objective of this study was to determine the change in frequency of NMOU behaviors, pain intensity, and opioid requirements among those who received the intervention. METHODS: A total of 130 patients receiving opioids for cancer pain that had documented evidence of NMOU and received the CHAT intervention were reviewed. Demographic and clinical information such as NMOU behaviors, pain scores, and morphine equivalent daily dose at baseline, 3, and 6 months post-intervention was obtained. RESULTS: NMOU behaviors significantly decreased from a median (interquartile range) of 2 (1-3) at baseline to 0 (0-1) at both 3 and 6 months post-intervention (p < .001). A total of 45 of 75 (60%) and 31 of 50 (62%) of CHAT recipients achieved complete response to the intervention at 3 and 6 months, respectively. Higher baseline number of NMOU behaviors was independently associated with patient response to the intervention (odds ratio [OR], 1.97; 95% confidence interval [CI],1.09-4.28, p = .049 at 3 months; OR, 2.5; 95% CI, 1.20-6.47, p = .03 at 6 months). The median pain score decreased from 7 at baseline to 6 at both 3 and 6 months (p = .01). Morphine equivalent daily dose did not significantly change during that same period (143 mg/day vs. 139 mg/day, p = .13). CONCLUSIONS: Most patients who received the CHAT intervention improved in their NMOU behaviors and pain intensity scores 3 and 6 months post-intervention. These preliminary findings support the efficacy of CHAT in managing patients receiving opioids for cancer pain who demonstrate NMOU behavior.

Frequency and Prediction of Burnout Among Physicians Who Completed Palliative Care Fellowship Training - A 10 Year Survey.

CONTEXT: Palliative Care (PC) physicians are vulnerable to burnout given the nature of practice. Reports suggest that burnout frequency is variable across different countries. OBJECTIVE: The main objective of our study was to determine knowledge, attitudes and frequency of burnout among Hospice and Palliative Medicine (HPM) Fellowship graduates trained at a comprehensive cancer center. METHODS: We conducted a survey to determine the knowledge, attitudes, and frequency of burnout in former fellows, consisting of the Maslach Burnout Inventory (MBI) and 41 custom questions. Palliative care fellows who trained at a Comprehensive Cancer Center from 2008 to 2018 were included in the survey. RESULTS: Eighty-four percent of the 52 eligible physicians completed surveys. Median age was 38 years, with 68% females. Seventy-seven percent practiced PC more than 50% of time. Median practice duration was four years, and 84% were board certified. Most common disease types treated were cancer (89%), cardiac (43%) and pulmonary (43%). Burnout rate was high at 52% (n=20). The median scores for emotional exhaustion were 25.5, depersonalization 9, and personal accomplishment 48. Female gender (P=0.07) and having administration as a component in the job description (P=0.044) were associated with risk of burnout. Clinical care setting, work hours/week, frequency of weekend calls, and size of team were not significantly associated with burnout. CONCLUSION: Burnout among former fellows trained in HPM between 2008 and 2018 is high. More research is needed to develop strategies to better prevent and manage burnout among HPM fellowship trained PC physicians.

Interrupting tumor necrosis factor-alpha signaling prevents parenteral nutrition-associated cholestasis in mice.

BACKGROUND: We have recently reported a mouse model of PN-associated cholestasis (PNAC) in which combining intestinal inflammation and PN infusion results in cholestasis, hepatic macrophage activation, and transcriptional suppression of canalicular bile acid, bilirubin and sterol transporters Abcb11, Abcc2 and Abcg5/8. The aim of this study was to examine the role of TNFα in promoting PNAC in mice. METHODS: First, recombinant TNFα was administered to mice as well as in hepatocyte cell culture. Second, Tnfr1/2KO or wild-type (WT) mice were exposed to dextran sulfate sodium (DSS) for 4 days followed by soy-oil lipid emulsion-based PN infusion through a central venous catheter for 14 days (DSS-PN). Finally, WT/DSS-PN mice were also infused with infliximab at 10 mg/kg on days 3 and 10 of PN. PNAC was defined by increased serum aspartate aminotransferase, alanine aminotransferase, total bile acids, and bilirubin. RESULTS: Intraperitoneal injection of TNFα into WT mice or TNFα treatment of Huh7 hepatocarcinoma cells and primary mouse hepatocytes suppressed messenger RNA (mRNA) transcription of bile (Abcb11, Abcc2]) and sterol transporters (Abcg5/8) and their regulators Nr1h3 and Nr1h4. DSS-PN mice with PNAC had increased hepatic TNFα mRNA expression and significant reduction of mRNA expression of Abcb11, Abcc2, Abcg5/8, Nr1h3, and Nr1h4. In contrast, PNAC development was prevented and mRNA expression normalized in both Tnfr1/2KO /DSS-PN mice and DSS-PN mice treated with infliximab. CONCLUSIONS: TNFα is a key mediator in the pathogenesis of PNAC through suppression of hepatocyte Abcb11, Abcc2, and Abcg5/8. Pharmacologic targeting of TNFα as a therapeutic strategy for PNAC thus deserves further investigation.

Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in mice.

BACKGROUND AND AIMS: Parenteral nutrition (PN)-associated cholestasis (PNAC) complicates the care of patients with intestinal failure. In PNAC, phytosterol containing PN synergizes with intestinal injury and IL-1ß derived from activated hepatic macrophages to suppress hepatocyte farnesoid X receptor (FXR) signaling and promote PNAC. We hypothesized that pharmacological activation of FXR would prevent PNAC in a mouse model. APPROACH AND RESULTS: To induce PNAC, male C57BL/6 mice were subjected to intestinal injury (2% dextran sulfate sodium [DSS] for 4 days) followed by central venous catheterization and 14-day infusion of PN with or without the FXR agonist GW4064. Following sacrifice, hepatocellular injury, inflammation, and biliary and sterol transporter expression were determined. GW4064 (30 mg/kg/day) added to PN on days 4-14 prevented hepatic injury and cholestasis; reversed the suppressed mRNA expression of nuclear receptor subfamily 1, group H, member 4 (Nr1h4)/FXR, ATP-binding cassette subfamily B member 11 (Abcb11)/bile salt export pump, ATP-binding cassette subfamily C member 2 (Abcc2), ATP binding cassette subfamily B member 4(Abcb4), and ATP-binding cassette subfamily G members 5/8(Abcg5/8); and normalized serum bile acids. Chromatin immunoprecipitation of liver showed that GW4064 increased FXR binding to the Abcb11 promoter. Furthermore, GW4064 prevented DSS-PN-induced hepatic macrophage accumulation, hepatic expression of genes associated with macrophage recruitment and activation (ll-1b, C-C motif chemokine receptor 2, integrin subunit alpha M, lymphocyte antigen 6 complex locus C), and hepatic macrophage cytokine transcription in response to lipopolysaccharide in vitro. In primary mouse hepatocytes, GW4064 activated transcription of FXR canonical targets, irrespective of IL-1ß exposure. Intestinal inflammation and ileal mRNAs (Nr1h4, Fgf15, and organic solute transporter alpha) were not different among groups, supporting a liver-specific effect of GW4064 in this model. CONCLUSIONS: GW4064 prevents PNAC in mice through restoration of hepatic FXR signaling, resulting in increased expression of canalicular bile and of sterol and phospholipid transporters and suppression of macrophage recruitment and activation. These data support augmenting FXR activity as a therapeutic strategy to alleviate or prevent PNAC.

Stay Home, Work Safe: Attitudes and Beliefs of Members of a Department of Palliative Care, Rehabilitation, and Integrative Medicine Regarding Remote Work during the COVID-19 Pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic compelled rapid transition to work from home for the University of Texas MD Anderson Cancer Center Palliative, Rehabilitation, and Integrative Medicine (PRIM) department to ensure social distancing and prevention of transmission. Objectives: To survey the attitudes and beliefs of personnel toward remote work during the COVID-19 pandemic. Methods: One hundred forty-eight clinical, research, and administrative PRIM department employees were invited to participate in an anonymous voluntary survey in May 2020, two months after the beginning of the COVID-19 pandemic and transition to work from home in the geographic location of Houston, Texas. The survey comprised 25 questions, including employee demographics and attitudes and beliefs toward working from home and the COVID-19 pandemic. Results: Ninety-four percent (139) of employees responded, with high response rates among all three employee arms. The majority of respondents were female (74%), between the ages of 30 and 59 years (87%), had broadband Internet (93%), and shared office space before working from home (59%). There were overall positive reports of experience (87%) and emotional response (79%) toward working from home, especially for those more concerned about COVID-19 illness and spread, shared office space, and those reporting adequate resources and equipment for remote work. Clinical role, however, was associated with a less positive response (80%), less productivity (29%), and higher levels of stress (62%). Most of the department also reported increased emotional exhaustion (68%). When surveyed about permanently working from home, most of the department responded favorably (69%). Conclusions: The PRIM rapid transition to remote work was associated with positive perceptions by most members of the clinical, research, and administrative teams. Insight from this survey can serve as a model for future rapid transitions in remote work and merits follow-up studies to prepare us for a postpandemic work environment. Clinical Trial Registration number NCI-2021-01265.

NF-κB Regulation of LRH-1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition-Associated Cholestasis.

BACKGROUND AND AIMS: Chronically administered parenteral nutrition (PN) in patients with intestinal failure carries the risk for developing PN-associated cholestasis (PNAC). We have demonstrated that farnesoid X receptor (FXR) and liver X receptor (LXR), proinflammatory interleukin-1 beta (IL-1ß), and infused phytosterols are important in murine PNAC pathogenesis. In this study we examined the role of nuclear receptor liver receptor homolog 1 (LRH-1) and phytosterols in PNAC. APPROACH AND RESULTS: In a C57BL/6 PNAC mouse model (dextran sulfate sodium [DSS] pretreatment followed by 14 days of PN; DSS-PN), hepatic nuclear receptor subfamily 5, group A, member 2/LRH-1 mRNA, LRH-1 protein expression, and binding of LRH-1 at the Abcg5/8 and Cyp7a1 promoter was reduced. Interleukin-1 receptor-deficient mice (Il-1r-/- /DSS-PN) were protected from PNAC and had significantly increased hepatic mRNA and protein expression of LRH-1. NF-κB activation and binding to the LRH-1 promoter were increased in DSS-PN PNAC mice and normalized in Il-1r-/- /DSS-PN mice. Knockdown of NF-κB in IL-1ß-exposed HepG2 cells increased expression of LRH-1 and ABCG5. Treatment of HepG2 cells and primary mouse hepatocytes with an LRH-1 inverse agonist, ML179, significantly reduced mRNA expression of FXR targets ATP binding cassette subfamily C member 2/multidrug resistance associated protein 2 (ABCC2/MRP2), nuclear receptor subfamily 0, groupB, member 2/small heterodimer partner (NR0B2/SHP), and ATP binding cassette subfamily B member 11/bile salt export pump (ABCB11/BSEP). Co-incubation with phytosterols further reduced expression of these genes. Similar results were obtained by suppressing the LRH-1 targets ABCG5/8 by treatment with small interfering RNA, IL-1ß, or LXR antagonist GSK2033. Liquid chromatography-mass spectrometry and chromatin immunoprecipitation experiments in HepG2 cells showed that ATP binding cassette subfamily G member 5/8 (ABCG5/8) suppression by GSK2033 increased the accumulation of phytosterols and reduced binding of FXR to the SHP promoter. Finally, treatment with LRH-1 agonist, dilauroyl phosphatidylcholine (DLPC) protected DSS-PN mice from PNAC. CONCLUSIONS: This study suggests that NF-κB regulation of LRH-1 and downstream genes may affect phytosterol-mediated antagonism of FXR signaling in the pathogenesis of PNAC. LRH-1 could be a potential therapeutic target for PNAC.

Genetic Factors Associated With Pain Severity, Daily Opioid Dose Requirement, and Pain Response Among Advanced Cancer Patients Receiving Supportive Care.

BACKGROUND: Current understanding of genetic factors associated with pain severity, and improvement of pain with opioids in advanced cancer patients (AC) is inadequate for delivery of personalized pain therapy (PPT). Therefore, the aim of this study was to determine the genetic factors associated with pain severity, daily opioid dose, and pain response in AC patients receiving supportive care. METHODS: In this prospective study, AC patients were eligible if they had cancer pain ≥4/10 on Edmonton Symptom Assessment Scale (ESAS) - Pain Item and needed opioid rotation for pain control by specialist at the outpatient supportive care center. Association of genetic factors with pain phenotype was assessed using logistic regression models and SKATO (Gene-block) analysis. RESULTS: About 174/178 (98%) patient samples were analyzed. After adjustment for demographic and clinical variables, pain severity was negatively associated with intron variant alleles in OPRM1 rs9322446, P = 0.02; rs2270459, P = 0.038; rs62052210, P = 0.038. Opioid daily dose was positively associated NFKBIA rs2233419, P = 0.008; rs2233417, P = 0.007; rs3138054, P = 0.008; rs1050851, P = 0.015; ORPM1 rs9479759, P = 0.046; rs2003185, P = 0.047; rs636433, P = 0.044; COMT (rs9306234, P = 0.014; rs165728, P = 0.014; rs2020917, P = 0.036; rs165728, P = 0.034); ARRB2 (rs1045280, P = 0.045); and pain response to opioids was negatively associated OPRM1 rs1319339, P = 0.024; rs34427887, P = 0.048; and COMT rs4646316, P = 0.03; rs35478083, P = 0.028, respectively. SKATO analysis showed association between pain severity and CXCL8 (P = 0.0056), and STAT6 (P = 0.0297) genes respectively, and pain response with IL-6 (P = 0.00499). CONCLUSIONS: This study identified that SNPs of OPRM1, COMT, NFKBIA, CXCL8, IL-6, STAT6, and ARRB2 genes were associated with pain severity, opioid daily dose, and pain response in AC receiving supportive care. Additional studies are needed to validate our findings for PPT.

Rapid Transition to Virtual Care during the COVID-19 Epidemic: Experience of a Supportive Care Clinic at a Tertiary Care Cancer Center.

Background: COVID-19 pandemic necessitated rapid adoption of telemedicine at our supportive care center (SCC) to ensure continuity of care while maintaining social distancing. Objective: To document the process of transition from in-person to virtual care. Design: The charts of 1744 consecutive patients in our SCC located in the United States were retrospectively reviewed during the four weeks before transition (February 14-March 12), four weeks after transition (March 20-April 16), and transition week (March 13-March 19). Patient demographics, vital aspects of a supportive care visit such as assessments (Edmonton Symptom Assessment Scale-Financial and Spiritual [ESAS-FS], Cut-down, Annoyed, Guilty, Eye-opener Screen-Adapted to Include Drugs [CAGE-AID], and Memorial Delirium Assessment Scale [MDAS]), interdisciplinary team involvement, and visit type were recorded. Results: In total 763 patients were seen before transition, 168 during the transition week, and 813 after transitioning to virtual care. Patient characteristics, ESAS-FS, CAGE-AID, and nurse assessment did not significantly differ among the three groups. The after-transition group had a small reduction in counseling intervention compared with before (20.2% vs. 26.2%; p = 0.0068). MDAS completion was higher after transition (99.6% vs. 98%; p = 0.007). In-person visits decreased from 100% before to 12.7% after transition (p < 0.0001) and virtual visits increased to 49.3% (video) and 38% (telephone). In-person visits decreased to 49% in the week one, 3% in week two, and <2% in week four after transition (p < 0.0001). Conclusions: Our supportive care team transitioned from in-person care to virtual visits within weeks while maintaining a high patient volume, continuity of care, and adherence to social distancing. Our transition can serve as a model for other centers.

Empowering the Health and Well-Being of the Palliative Care Workforce: Evaluation of a Weekly Self-Care Checklist.

BACKGROUND: Workplace interventions are needed to prevent burnout and support the well-being of the palliative care workforce. MEASURES: We conducted a survey of all palliative care clinical staff to evaluate the usefulness and feasibility of checklist items and the checklist itself. We collected demographics, perceptions of professional satisfaction and burnout, and qualitative feedback aimed at improving the checklist. INTERVENTION: We implemented a 13-item self-care checklist, included in a handbook on palliative care carried in the laboratory coat of all clinical personnel, to remind them to care of their own well-being. OUTCOMES: Of 39 personnel contacted, 32 (82%) responded. Most (20; 62%) found the checklist useful. Exercise was the most highly ranked item, whereas watching visual arts was the lowest ranked item. CONCLUSIONS/LESSONS LEARNED: Numerous opportunities were identified to improve the checklist and facilitate achievement of checklist items. Survey data will be used in the next checklist version.

Hepatic thermal injury promotes colorectal cancer engraftment in C57/black 6 mice.

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.

A Comparison of Burnout Frequency Among Oncology Physicians and Nurses Working on the Frontline and Usual Wards During the COVID-19 Epidemic in Wuhan, China.

CONTEXT: The epidemic of coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China and has now spread worldwide. In the affected countries, physicians and nurses are under heavy workload conditions and are at high risk of infection. OBJECTIVES: The aim of this study was to compare the frequency of burnout between physicians and nurses on the frontline (FL) wards and those working in usual wards (UWs). METHODS: A survey with a total of 49 questions was administered to 220 medical staff members from the COVID-19 FL and UWs, with a ratio of 1:1. General information, such as age, gender, marriage status, and the Maslach Burnout Inventory-medical personnel, were gathered and compared. RESULTS: The group working on the FLs had a lower frequency of burnout (13% vs. 39%; P < 0.0001) and were less worried about being infected compared with the UW group. CONCLUSION: Compared with medical staff working on their UWs for uninfected patients, medical staff working on the COVID-19 FL ward had a lower frequency of burnout. These results suggest that in the face of the COVID-19 crisis, both FL ward and UW staff should be considered when policies and procedures to support the well-being of health care workers are devised.

Frequency of Burnout Among Palliative Care Physicians Participating in a Continuing Medical Education Course.

CONTEXT: Palliative care (PC) physicians are vulnerable for burnout given the nature of practice. The burnout frequency may be variable and reported between 24% and 38% across different countries. OBJECTIVE: The main objective of our study was to determine the frequency of burnout among PC physicians participating in PC continuing medical education course. METHODS: A survey including the Maslach Burnout Inventory-General along with 41 custom questions were administered to determine the frequency of burnout among physicians attending the 2018 Hospice and Palliative Medicine Board review course. RESULTS: Of 110 physicians, 91 (83%) completed the survey. The median age was 48 years with 65% being females, 81% married, 46% in community practice, 38% in practice for 6-15 years. PC was practiced ≥50% of the time by 62%, and 76% were doing clinical work. About 73 (80%) reported that PC is appreciated at their work, 58 (64%) reported insurance to be a burden, and 58 (64%) reported that the electronic medical record was a burden. About 82 (90%) felt optimistic about continuing PC in future. Maslach Burnout Inventory results suggest that 35 (38%) participants reported at least one symptom of burnout. Only being single/separated showed trend toward significance with burnout (P = 0.056). CONCLUSION: Burnout among PC physicians who attended a board review course was 38%. Being single/separated showed trend toward association with burnout. Physicians who choose to attend continuing medical education may have unique motivating characteristics allowing them to better cope with stress and avoid burnout.

Macrophage-derived IL-1ß/NF-κB signaling mediates parenteral nutrition-associated cholestasis.

In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1ß in PNAC. Pharmacological antagonism of  IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1ß) prevents PNAC in mice. IL-1ß increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes (Abcc2, Abcb11, and Abcg5/8), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1ß, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.