Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 µg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 µg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 µg/mL, interquartile rate [IQR], 12.3-18.5 µg/mL versus 15.9 µg/mL, IQR, 10.1-22.7 µg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal. CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Early VTE prophylaxis in severe traumatic brain injury: A propensity score weighted EAST multicenter study.

BACKGROUND: Patients with traumatic brain injury (TBI) are at high risk of venous thromboembolism events (VTE). We hypothesized that early chemical VTE prophylaxis initiation (≤24 hours of a stable head CT) in severe TBI would reduce VTE without increasing risk of intracranial hemorrhage expansion (ICHE). METHODS: A retrospective review of adult patients 18 years or older with isolated severe TBI (Abbreviated Injury Scale score, ≥ 3) who were admitted to 24 Level I and Level II trauma centers from January 1, 2014 to December 31 2020 was conducted. Patients were divided into those who did not receive any VTE prophylaxis (NO VTEP), who received VTE prophylaxis ≤24 hours after stable head CT (VTEP ≤24) and who received VTE prophylaxis >24 hours after stable head CT (VTEP>24). Primary outcomes were VTE and ICHE. Covariate balancing propensity score weighting was utilized to balance demographic and clinical characteristics across three groups. Weighted univariate logistic regression models were estimated for VTE and ICHE with patient group as predictor of interest. RESULTS: Of 3,936 patients, 1,784 met inclusion criteria. Incidences of VTE was significantly higher in the VTEP>24 group, with higher incidences of DVT in the group. Higher incidences of ICHE were observed in the VTEP≤24 and VTEP>24 groups. After propensity score weighting, there was a higher risk of VTE in patients in VTEP >24 compared with those in VTEP≤24 (odds ratio, 1.51; 95% confidence interval, 0.69-3.30; p = 0.307), however was not significant. Although, the No VTEP group had decreased odds of having ICHE compared with VTEP≤24 (odds ratio, 0.75; 95% confidence interval, 0.55-1.02, p = 0.070), the result was not statistically significant. CONCLUSION: In this large multi-center analysis, there were no significant differences in VTE based on timing of initiation of VTE prophylaxis. Patients who never received VTE prophylaxis had decreased odds of ICHE. Further evaluation of VTE prophylaxis in larger randomized studies will be necessary for definitive conclusions. LEVEL OF EVIDENCE: Therapeutic Care Management; Level III.

Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study.

OBJECTIVE: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. BACKGROUND: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. METHODS: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. RESULTS: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P <0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients ( P <0.0001). CONCLUSIONS: Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.

The ACS-TQIP palliative care guidelines at two level I trauma centres: a prospective study of patient and caregiver satisfaction.

OBJECTIVES: To measure trauma patient and caregiver satisfaction before and after implementation of standardised palliative care (PC) guidelines. METHODS: Prospective pre-post study at two level-I trauma centres. PC satisfaction surveys were administered prior to discharge for consented trauma patients (Family Satisfaction with Advanced Cancer Scale, Patient (FAMCARE-P13) survey)≥55 years, and their caregivers (FAMCARE survey), from 1 November 2016 to 30 November 2018. Standardised PC guidelines were implemented January 2018 and included consultations, prognostication assessments, identification of proxies, review of advanced directives and do not resuscitate orders within 24 hours of admission, while advanced goals of care, formal family meetings and spiritual care support were recommended within 72 hours of admission. Generalised linear models were used to determine whether differences in patient or caregiver satisfaction existed pre versus post implementation. RESULTS: There were 572 patients (299 pre; 273 post) and 595 caregivers (334 pre; 261 post) included. Overall patient satisfaction significantly increased post implementation (82.0 vs 86.0, p=0.001). After adjustment, the implementation of the guidelines was an independent predictor of higher overall patient satisfaction (least squares mean (LSM= (83.8% (95%CI 81.2%-86.5%) vs 80.3% (77.7%-82.9%), p=0.003)). Compared with preimplementation, patient satisfaction was significantly higher post implementation in the following domains: information giving (80.9 vs 85.5, p=0.001), followed by physical care (82.2 vs 86.0, p=0.002), availability of care (83.4 vs 86.8, p=0.007) and psychosocial care (84.7 vs 87.6, p=0.04). No significant differences in caregiver satisfaction were found before or after adjustment (LSMpre: 83.1% (95%CI 80.9%-85.3%) vs. post: 82.4% (80.3%-84.5%), p=0.56)) CONCLUSIONS: Our data suggest that the implementation of PC guidelines significantly improved patient satisfaction following traumatic injury, while maintaining robust caregiver satisfaction.

Is preexisting mental illness associated with lower patient satisfaction for older trauma patients? A cross-sectional descriptive study.

BACKGROUND: The purpose of this study was to examine if satisfaction with care differs among older trauma patients with and without preexisting mental illness (PMI+/PMI-). METHODS: Data from two level I trauma centers were examined from 11/2016 through 12/2017. Trauma patients ≥55 years were included and satisfaction of those who had a diagnosis of mental illness prior to the trauma admission (PMI+) to those without a diagnosis (PMI-) (n = 299; 62 PMI+ and 237 PMI-) were compared. Enrolled patients completed the Family Satisfaction with Advanced Care Cancer Scale Patient Survey (FAMCARE-P13) prior to discharge. Associations between mental illness status and patient baseline characteristics, overall mean satisfaction, and mean satisfaction by question were compared. Generalized linear models adjusted for differences in patient satisfaction by mental illness status. Analyses were stratified by hospital to account for the interaction between hospital and mental illness status. RESULTS: Compared to PMI- patients, PMI+ patients were more likely to be younger, female, have multiple comorbidities, and to report lower overall satisfaction with care. Among PMI+ patients, the most common diagnoses were depression and anxiety. After adjustment, PMI+ was associated with lower patient satisfaction at hospital 1; after examining individual questions lower satisfaction was associated with information provided on procedures and questions surrounding "Physical care." Conversely, PMI+ did not affect satisfaction at hospital 2 after adjustment. CONCLUSIONS: At hospital 1, room for improvement was identified in providing information about prognosis and procedures, symptom management, and continuity of care. Reexamining practices for older PMI+ trauma patients is warranted.

Comparing satisfaction of trauma patients 55 years or older to their caregivers during palliative care: Who faces the burden?

BACKGROUND: Many studies report on the patient-caregiver relationship during palliative care (PC); however, this relationship has yet to be examined following traumatic injury. METHODS: This prospective cohort study included trauma patients (≥55 years) and their primary caregivers admitted at two level I trauma centers for 2 years (November 2016 to November 2018), who received PC and who completed satisfaction surveys before discharge; surveys were analyzed by four domains: information giving, availability of care, physical care, and psychosocial care, and by PC assessments: consultations, prognostications, formal family meetings (FFMs), and advanced goals of care discussions. The primary outcome was the percentage of patients and caregivers who were satisfied (defined as ≥80%) and was analyzed using McNemar's test. Adjusted mixed models identified PC assessments that were associated with satisfaction scores ≥80% for patients and caregivers. RESULTS: Of the 441-patient and 441-caregiver pairs, caregivers were significantly less satisfied than patients during prognostications (information giving, physical care), FFMs (information giving, physical care), and consultations (physical care), while caregivers were significantly more satisfied than patients during advanced goals of care discussions (availability of care, psychosocial care). After adjustment, significant predictors of caregiver satisfaction (≥80%) included longer patient hospital length of stay (>4 days), caring for a male patient (physical care, availability of care), higher caregiver age (≥55 years; availability of care), and higher patient age (≥65 years; psychosocial care). Conversely, all PC assessments decreased odds of satisfaction for caregivers in every domain except physical care. Significant predictors of higher patient satisfaction included FFMs (for every domain) and PC consultations (psychosocial care), and decreased odds included advanced goals of care discussions and prognostication assessments (information giving, psychosocial care). CONCLUSIONS: Palliative care increased satisfaction of patients, especially family meetings and consultations, while assessments were predictive of lower caregiver satisfaction, suggesting that caregivers may be experiencing some of the patient burden. LEVEL OF EVIDENCE: Therapeutic/Care Management, level IV.

Serological Epithelial Component Proteins Identify Intestinal Complications in Crohn's Disease.

Crohn's Disease (CD) is a relapsing inflammation of the gastrointestinal tract that affects a young working age population and is increasing in developing countries. Half of all sufferers will experience stricturing or fistulizing intestinal complications that require extensive surgical interventions and neither genes nor clinical risk factors can predict this debilitating natural history. We applied discovery and verification phase studies as part of an NCI-FDA modeled biomarker pipeline to identify differences in the low-mass (<25kDa) blood-serum proteome between CD behavioral phenotypes. A significant enrichment of epithelial component proteins was identified in CD patients with intestinal complications using quantitative proteomic profiling with label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). DAVID 6.7 (NIH) was used for functional annotation analysis of detected proteins and immunoblotting and multiple reaction monitoring (MRM) to verify a priori findings in a secondary independent cohort of complicated CD (CCD), uncomplicated inflammatory CD (ICD), Th1/17 pathway inflammation controls (rheumatoid arthritis), inflammatory bowel disease controls (ulcerative colitis), and healthy controls. Seventy-six high-confidence serum proteins were modulated in CCD versus ICD by LC-MS/MS (p < 0.05, FDR q<0.01), annotating to pathways of epithelial barrier homeostasis (p < 0.01). In verification phase, a putative serology panel developed from discovery proteomics data consisting of desmoglein-1, desmoplakin, and fatty acid-binding protein 5 (FABP5) distinguished CCD from all other groups (p = 0.041) and discriminated complication in CD (70% sensitivity and 72.5% specificity at score ≥1.907, AUC = 0.777, p = 0.007). An MRM assay secondarily confirmed increased FABP5 levels in CCD (p < 0.001). In a longitudinal subanalysis-cohort, FABP5 levels were stable over a two-month period with no behavioral changes (p = 0.099). These studies along the biomarker development pipeline provide substantial proof-of-principle that a blood test can be developed specific to transmural intestinal injury. Data are available via the PRIDE proteomics data repository under identifier PXD001821 and PeptideAtlas with identifier PASS00661.

Low Mass Blood Peptides Discriminative of Inflammatory Bowel Disease (IBD) Severity: A Quantitative Proteomic Perspective.

Breakdown of the protective gut barrier releases effector molecules and degradation products into the blood stream making serum and plasma ideal as a diagnostic medium. The enriched low mass proteome is unexplored as a source of differentiators for diagnosing and monitoring inflammatory bowel disease (IBD) activity, that is less invasive than colonoscopy. Differences in the enriched low mass plasma proteome (<25 kDa) were assessed by label-free quantitative mass-spectrometry. A panel of marker candidates were progressed to validation phase and "Tier-2" FDA-level validated quantitative assay. Proteins important in maintaining gut barrier function and homeostasis at the epithelial interface have been quantitated by multiple reaction monitoring in plasma and serum including both inflammatory; rheumatoid arthritis controls, and non-inflammatory healthy controls; ulcerative colitis (UC), and Crohn's disease (CD) patients. Detection by immunoblot confirmed presence at the protein level in plasma. Correlation analysis and receiver operator characteristics were used to report the sensitivity and specificity. Peptides differentiating controls from IBD originate from secreted phosphoprotein 24 (SPP24, p = 0.000086, 0.009); whereas those in remission and healthy can be differentiated in UC by SPP24 (p = 0.00023, 0.001), α-1-microglobulin (AMBP, p = 0.006) and CD by SPP24 (p = 0.019, 0.05). UC and CD can be differentiated by Guanylin (GUC2A, p = 0.001), and Secretogranin-1 (CHGB p = 0.035). Active and quiescent disease can also be differentiated in UC and CD by CHGB (p ≤ 0.023) SPP24 (p ≤ 0.023) and AMBP (UC p = 0.046). Five peptides discriminating IBD activity and severity had very little-to-no correlation to erythrocyte sedimentation rate, C-reactive protein, white cell or platelet counts. Three of these peptides were found to be binding partners to SPP24 protein alongside other known matrix proteins. These proteins have the potential to improve diagnosis and evaluate IBD activity, reducing the need for more invasive techniques. Data are available via ProteomeXchange with identifier PXD002821.

The use of patient pictures and verification screens to reduce computerized provider order entry errors.

OBJECTIVE: To determine whether an order verification screen, including a patient photograph, is an effective strategy for reducing the risk that providers will place orders in an unintended patient's electronic medical record (EMR). METHODS: We describe several changes to the EMR/provider interface and ordering workflow that were implemented as one part of a hospital-wide quality improvement effort to improve patient identification and verification practices. We measured the impact by comparing the number of reported incidents of care being provided to any patient other than for whom it was intended before the intervention, and directly after the intervention. RESULTS: For the year before the interventions described herein, placement of orders in the incorrect patient's chart was the second most common cause of care being provided to the wrong patient, comprising 24% of the reported errors. In the 15 months after the implementation of an order verification screen with the patient's photo centrally placed on the screen, no patient whose picture was in the EMR was reported to have received unintended care based on erroneous order placement in his or her chart. CONCLUSIONS: The incorporation of patient pictures within a computerized order entry verification process is an effective strategy for reducing the risk that erroneous placement of orders in a patient's EMR will result in unintended care being provided to an incorrect patient.

Colorectal cancer screening practise is influenced by ethnicity of medical practitioner and patient.

BACKGROUND AND AIM: Colorectal cancer (CRC) screening improves survival and requires appropriate recommendation by general practitioners (GPs). Screening practises may be influenced by barriers related to ethnicity and training. METHODS: A mail survey assessed GPs' practises and the barriers towards CRC screening. The association of screening practises and demography, including GP ethnicity, medical training and practise characteristics, were evaluated. RESULTS: Of 212 GPs (median age 54 years, 73% men, 27% Caucasian, 38% foreign graduates), 87% agreed that fecal occult blood test (FOBT) screening improved survival in the average-risk patient. Considerable variations existed in the starting age (40-49 years: 31%; 50 years: 65%) and frequency (1-2 years: 77%; 3-5 years: 22%) of screening. FOBT was used for indications other than screening: anemia (59%), altered bowel habits (54%), abdominal pain (24%), and rectal bleeding (23%), and these were significantly more frequent in Asian GPs independent of medical training. GPs were less likely to recommend screening to immigrants, and most reported that immigrants were less likely to participate. More Asian and Middle Eastern GPs reported a major barrier with FOBT inaccuracy compared with Caucasian GPs (22% vs 9%, P = 0.03; and 27% vs 9%, P = 0.03, respectively). CONCLUSIONS: Considerable differences existed in GPs' CRC screening practises. Indications for use of FOBT and the subsequent investigation of a positive FOBT also varied according to GPs' ethnicity, independent of medical training. Patient's ethnicity and associated language and cultural barriers may affect screening uptake, which may negatively affect the health of immigrants. Resources and culture-specific interventions are recommended to improve overall screening participation.

Knowledge, perception and practices of colorectal cancer screening in an ethnically diverse population.

BACKGROUND: Colorectal cancer (CRC) screening improves survival and its success depends on the participation of the at-risk population. Few studies have adequately assessed screening knowledge, perception and participation according to birthplace. This study assesses the knowledge and perception of CRC in an ethnically diverse population, and evaluates the association with screening participation and intention. Identification of specific predictors of screening may aid the development of interventions to improve overall CRC screening. METHODS: An interview-based survey, conducted on subjects aged 30-70 years, assessed knowledge and perception towards CRC and screening tests. Primary endpoints were screening participation and intent. Statistical methods used were Chi-square, Mann-Whitney U and logistic regression. RESULTS: A total of 543 subjects (43% males, 53% Australian-born (AB), 63% aged 50 years and above) were recruited. Compared with AB, non-Australian-born (NAB) respondents had poorer knowledge, and NAB background predicted for poorer knowledge independent of sex, education, media and familiarity with CRC patient. Compared with AB respondents aged 50 years and above, NAB respondents had lower screening participation (17.4% vs. 31.8%; P=0.01), lesser intention (75.8% vs. 90.5%; P<0.001), and had received fewer doctors' screening recommendations (16.5% vs. 27.1%; P=0.04). In multivariate analysis, doctors' recommendation, media and improved perception independently predicted screening participation; knowledge and media exposure predicted intent. CONCLUSIONS: The knowledge of CRC and screening is significantly poorer in the immigrant population. Knowledge predicts for greater screening intent. Therefore, implementing language- and culture-specific educational programs involving medical practitioners and media are necessary to improve CRC screening participation rates.

Protection studies in sheep using affinity-purified and recombinant cysteine proteinases of adult Haemonchus contortus.

Vaccination with a membrane-bound thiol Sepharose-binding fraction (TSBP) of adult Haemonchus contortus has been shown to confer significant levels of protection against homologous challenge in sheep. This fraction is greatly enriched for cysteine proteinase activity. Following fractionation of TSBP by anion-exchange chromatography on MonoQ, protection was found to partition with those fractions further enriched for cysteine proteinase activity. In this study, the cysteine proteinases of adult H. contortus TSBP were specifically purified by affinity chromatography using recombinant H. contortus cystatin, a potent cysteine proteinase inhibitor. Although only 1-1.5% of total TSBP bound to cystatin-Sepharose, this fraction contained 100% of the cysteine proteinase activity, as determined by gelatin substrate gel analysis. When used to immunise sheep, less than 3microg per dose of this cysteine proteinase fraction was found to confer a substantial and repeatable level of protection against homologous challenge infection, reducing faecal egg counts by 48 and 28% and worm burdens by 44 and 46% over two trials. Host serum immunoglobulin levels and abomasal mast cell and eosinophil numbers were evaluated, although no correlation with protection was observed. Three cathepsin B-like cysteine proteinases present in TSBP (hmcp1, 4 and 6) have been identified previously by cDNA library immunoscreening. The predicted mature forms of these three cysteine proteinases were expressed in bacteria as insoluble, GST-fusion proteins. Following solubilisation in urea/DTT, the protective capacity of a cocktail of recombinant proteins was evaluated in sheep. Although no reduction in faecal egg counts was observed, sheep vaccinated with recombinant cysteine proteinases showed a highly significant 38% reduction (P <0.01) in worm burdens.