A Case of Immune Checkpoint Inhibitor-Induced Duodenitis.

Immune checkpoint inhibitors improve patient survival in multiple cancers, but immune-related adverse events, including new immunologic conditions arising during therapy, pose a significant challenge. Gastrointestinal immune-related adverse events, although common, exhibit diverse presentations. We present a case of duodenitis resembling celiac disease because of the anti-programmed cell death protein-1 antibody, pembrolizumab. Despite diagnostic uncertainty and therapeutic interventions, including gluten-free diet, symptoms stabilized even with resuming gluten. In addition, endoscopic abnormalities after pembrolizumab therapy have neither progressed nor completely resolved. This case underscores the need for investigation into the pathogenesis of immune checkpoint inhibitor-induced duodenitis, with implications for care of patients on immunotherapies.

Preoperative electroencephalographic alpha-power changes with eyes opening are associated with postoperative attention impairment and inattention-related delirium severity.

BACKGROUND: In the eyes-closed, awake condition, EEG oscillatory power in the alpha band (7-13 Hz) dominates human spectral activity. With eyes open, however, EEG alpha power substantially decreases. Less alpha attenuation with eyes opening has been associated with inattention; thus, we analysed whether reduced preoperative alpha attenuation with eyes opening is associated with postoperative inattention, a delirium-defining feature. METHODS: Preoperative awake 32-channel EEG was recorded with eyes open and eyes closed in 71 non-neurological, noncardiac surgery patients aged ≥ 60 years. Inattention and other delirium features were assessed before surgery and twice daily after surgery until discharge. Eyes-opening EEG alpha-attenuation magnitude was analysed for associations with postoperative inattention, primarily, and with delirium severity, secondarily, using multivariate age- and Mini-Mental Status Examination (MMSE)-adjusted logistic and proportional-odds regression analyses. RESULTS: Preoperative alpha attenuation with eyes opening was inversely associated with postoperative inattention (odds ratio [OR] 0.73, 95% confidence interval [CI]: 0.57, 0.94; P=0.038). Sensitivity analyses showed an inverse relationship between alpha-attenuation magnitude and inattention chronicity, defined as 'never', 'newly', or 'chronically' inattentive (OR 0.76, 95% CI: 0.62, 0.93; P=0.019). In addition, preoperative alpha-attenuation magnitude was inversely associated with postoperative delirium severity (OR 0.79, 95% CI: 0.65, 0.95; P=0.040), predominantly as a result of the inattention feature. CONCLUSIONS: Preoperative awake, resting, EEG alpha attenuation with eyes opening might represent a neural biomarker for risk of postoperative attentional impairment. Further, eyes-opening alpha attenuation could provide insight into the neural mechanisms underlying postoperative inattention risk.

Same-teams versus different-teams for long distance lung procurement: A cost analysis.

OBJECTIVE: In an era of broader lung sharing, different-team transplantation (DT, procuring team from nonrecipient center) may streamline procurement logistics; however, safety and cost implications of DT remain unclear. To understand whether DT represents a safe means to reduce lung transplant (LTx) costs, we compared posttransplant outcomes and lung procurement and index hospitalization costs among matched DT and same-team transplantation (ST, procuring team from recipient center) cohorts at a single, high-volume institution. We hypothesized that DT reduces costs without compromising outcomes after LTx. METHODS: Patients who underwent DT between January 2016 to May 2020 were included. A cohort of patients who underwent ST was matched 1:3 (nearest neighbor) based on recipient age, disease group, lung allocation score, history of previous LTx, and bilateral versus single LTx. Posttransplant outcomes and costs were compared between groups. RESULTS: In total, 23 DT and 69 matched ST recipients were included. Perioperative outcomes and posttransplant survival were similar between groups. Compared with ST, DT was associated with similar lung procurement and index hospitalization costs (DT vs ST, procurement: median $65,991 vs $58,847, P = .16; index hospitalization: median $294,346 vs $322,189, P = .7). On average, procurement costs increased $3263 less per 100 nautical miles for DT versus ST; DT offered cost-savings when travel distances exceeded approximately 363 nautical miles. CONCLUSIONS: At our institution, DT and ST were associated with similar post-LTx outcomes; DT offered cost-savings with increasing procurement travel distance. These findings suggest that DT may mitigate logistical and financial burdens of lung procurement; however, further investigation in a multi-institutional cohort is warranted.

The impact of regional anesthesia on opioid demand in distal radius fracture surgery.

PURPOSE: Regional anesthesia (RA) is commonly used in distal radius fracture surgery to reduce pain and opioid consumption. The purpose of this study was to evaluate the real-world impact of RA on inpatient and outpatient opioid consumption and demand in patients undergoing distal radius fracture surgery. METHODS: All patients ages 18 and older undergoing distal radius fracture surgery between 7/2013 and 7/2018 at a single institution (n = 969) were identified. Inpatient opioid consumption and outpatient opioid prescribing in oxycodone 5-mg equivalents (OE's) up to 90-d post-operative were recorded for patients with and without RA. Adjusted models were used to evaluate the impact of RA on opioid outcomes. RESULTS: Adjusted models demonstrated decreases in inpatient opioid consumption in patients with RA (10.7 estimated OE's without RA vs. 7.6 OE's with RA from 0 to 24 h post-op, 10.2 vs. 5.3 from 24 to 48 h post-op and 7.5 vs. 5.0 from 48 to 72 h post-op, p<.05). Estimated cumulative outpatient opioid demand was significantly higher in patients with RA (65.3 OE's without RA vs. 81.0 with RA from 1-month pre-op to 2-week post-discharge, 76.1 vs. 87.7 OE's to 6-weeks, and 80.8 vs. 93.5 OE's to 90-d, all p values for RA <.05) though rates of refill were significantly lower in patients with RA from 2-week to 6-week post-op compared to patients without RA. CONCLUSIONS: Patients undergoing RA in distal radius fracture surgery had decreased inpatient opioid consumption but increased outpatient demand after adjustment for patient and operative characteristics. LEVEL OF EVIDENCE: Level III, retrospective, therapeutic cohort study.

Textbook surgical outcome in lung transplantation: Analysis of a US national registry.

INTRO: Textbook surgical outcome (TO) is a novel composite quality measure in lung transplantation (LTx). Compared to 1-year survival metrics, TO may better differentiate center performance, and motivate improvements in care. To understand the feasibility of implementing this metric, we defined TO in LTx using US national data, and evaluated its ability to predict post-transplant outcomes and differentiate center performance. METHODS: Adult patients who underwent isolated LTx between 2016 and 2019 were included. TO was defined as freedom from post-transplant length of stay > 30 days, 90-day mortality, intubation or extracorporeal membrane oxygenation at 72 h post-transplant, post-transplant ventilator support lasting ≥5 days, postoperative airway dehiscence, inpatient dialysis, pre-discharge acute rejection, and grade 3 primary graft dysfunction at 72 h. Recipient and donor characteristics and post-transplant outcomes were compared between patients who achieved and failed TO. RESULTS: Of 8959 lung transplant recipients, 4664 (52.1%) achieved TO. Patient and graft survival were improved among patients who achieved TO (both log-rank P < .0001). Among 62 centers, adjusted rates of TO ranged from 27.0% to 72.4% reflecting a wide variability in center-level performance. CONCLUSION: TO defined using national data may represent a novel composite metric to guide quality improvement in LTx across US transplant centers. SUMMARY: In this study we defined textbook outcome (TO) for lung transplantation (LTx) using US national data. We found that achievement of TO was associated with improved post-transplant survival, and wide variability in center-level LTx performance. These findings suggest that TO could be readily implemented to compare quality of care among US LTx centers.

Regional anesthesia reduces inpatient and outpatient perioperative opioid demand in periarticular elbow surgery.

HYPOTHESIS: Regional anesthesia (RA) can be used to manage perioperative pain in the treatment of periarticular elbow fracture fixation. However, the opioid-sparing benefit is not well-characterized. The hypothesis of this study was that RA had reduced inpatient opioid consumption and outpatient opioid demand in patients who had undergone periarticular elbow fracture surgery. METHODS: This study retrospectively reviews inpatient opioid consumption and outpatient opioid demand in all patients aged ≥18 years at a single Level I trauma center undergoing fixation of periarticular elbow (distal humerus and proximal forearm) fracture surgery (n=418 patients). In addition to RA vs. no RA, additional patient and operative characteristics were recorded. Unadjusted and adjusted models were constructed to evaluate the impact of RA and other factors on inpatient opioid consumption and outpatient opioid demand. RESULTS: Adjusted models demonstrated decreases in inpatient opioid consumption postoperation in patients with RA (13.7 estimated oxycodone 5-mg equivalents or OEs without RA vs. 10.4 OEs with RA from 0 to 24 hours postoperation, P = .003; 12.3 vs. 9.2 OEs from 24 to 48 hours postoperation, P = .045). Estimated cumulative outpatient opioid demand differed significantly in patients with RA (166.1 vs. 132.1 OEs to 6 weeks, P = .002; and 181 vs. 138.6 OEs to 90 days, P < .001). DISCUSSION: In proximal forearm and distal humerus fracture surgery, RA was associated with decreased inpatient and outpatient opioid demand after adjusting for baseline patient and treatment characteristics. These results encourage utilization of perioperative RA to reduce opioid use.

Lung transplantation after ex vivo lung perfusion versus static cold storage: An institutional cost analysis.

Ex vivo lung perfusion (EVLP) is a novel lung preservation strategy that facilitates the use of marginal allografts; however, it is more expensive than static cold storage (SCS). To understand how preservation method might affect postoperative costs, we compared outcomes and index hospitalization costs among matched EVLP and SCS preserved lung transplant (LTx) recipients at a single, high-volume institution. A total of 22 EVLP and 66 matched SCS LTx recipients were included; SCS grafts were further stratified as either standard-criteria (SCD) or extended-criteria donors (ECD). Median total preservation time was 857, 409, and 438 min for EVLP, SCD, and ECD lungs, respectively (p < .0001). EVLP patients had similar perioperative outcomes and posttransplant survival compared to SCS SCD and ECD recipients. Excluding device-specific costs, total direct variable costs were similar among EVLP, SCD, and ECD recipients (median $200,404, vs. $154,709 vs. $168,334, p =  .11). The median direct contribution margin was positive for EVLP recipients, and similar to that for SCD and ECD graft recipients (all p > .99). These findings demonstrate that the use of EVLP was profitable at an institutional level; however, further investigation is needed to better understand the financial implications of EVLP in facilitating donor pool expansion in an era of broader lung sharing.

Electroencephalogram-Based Complexity Measures as Predictors of Post-operative Neurocognitive Dysfunction.

Physiologic signals such as the electroencephalogram (EEG) demonstrate irregular behaviors due to the interaction of multiple control processes operating over different time scales. The complexity of this behavior can be quantified using multi-scale entropy (MSE). High physiologic complexity denotes health, and a loss of complexity can predict adverse outcomes. Since postoperative delirium is particularly hard to predict, we investigated whether the complexity of preoperative and intraoperative frontal EEG signals could predict postoperative delirium and its endophenotype, inattention. To calculate MSE, the sample entropy of EEG recordings was computed at different time scales, then plotted against scale; complexity is the total area under the curve. MSE of frontal EEG recordings was computed in 50 patients ≥ age 60 before and during surgery. Average MSE was higher intra-operatively than pre-operatively (p = 0.0003). However, intraoperative EEG MSE was lower than preoperative MSE at smaller scales, but higher at larger scales (interaction p < 0.001), creating a crossover point where, by definition, preoperative, and intraoperative MSE curves met. Overall, EEG complexity was not associated with delirium or attention. In 42/50 patients with single crossover points, the scale at which the intraoperative and preoperative entropy curves crossed showed an inverse relationship with delirium-severity score change (Spearman ρ = -0.31, p = 0.054). Thus, average EEG complexity increases intra-operatively in older adults, but is scale dependent. The scale at which preoperative and intraoperative complexity is equal (i.e., the crossover point) may predict delirium. Future studies should assess whether the crossover point represents changes in neural control mechanisms that predispose patients to postoperative delirium.

A template for physical resilience research in older adults: Methods of the PRIME-KNEE study.

BACKGROUND: Older adults with similar health conditions often experience widely divergent outcomes following health stressors. Variable recovery after a health stressor may be due in part to differences in biological mechanisms at the molecular, cellular, or system level, that are elicited in response to stressors. We describe the PRIME-KNEE study as an example of ongoing research to validate provocative clinical tests and biomarkers that predict resilience to specific health stressors. METHODS: PRIME-KNEE is an ongoing, prospective cohort study that will enroll 250 adults ≥60 years undergoing total knee arthroplasty. Data are collected at baseline (pre-surgery), during surgery, daily for 7 days after surgery, and at 1, 2, 4, and 6 months post-surgery. Provocative tests include a cognition-motor dual-task walking test, cerebrovascular reactivity assessed by functional near-infrared spectroscopy, peripheral blood mononuclear cell reactivity ex vivo to lipopolysaccharide toxin and influenza vaccine, and heart rate variability during surgery. Cognitive, psychological, and physical performance batteries are collected at baseline to estimate prestressor reserve. Demographics, medications, comorbidities, and stressor characteristics are abstracted from the electronic medical record and via participant interview. Blood-based biomarkers are collected at baseline and postoperative day 1. Repeated measures after surgery include items from a delirium assessment tool and pain scales administered daily by telephone for 7 days and cognitive change index (participant and informant), lower extremity activities of daily living, pain scales, and step counts assessed by Garmin actigraphy at 1, 2, 4, and 6 months after surgery. Statistical models use these measures to characterize resilience phenotypes and evaluate prestressor clinical indicators associated with poststressor resilience. CONCLUSION: If PRIME-KNEE validates feasible clinical tests and biomarkers that predict recovery trajectories in older surgical patients, these tools may inform surgical decision-making, guide pre-habilitation efforts, and elucidate mechanisms underlying resilience. This study design could motivate future geriatric research on resilience.

Lung transplantation using allografts with more than 8 hours of ischemic time: A single-institution experience.

BACKGROUND: Six hours was historically regarded as the limit of acceptable ischemic time for lung allografts. However, broader sharing of donor lungs often necessitates use of allografts with ischemic time >6 hours. We characterized the association between ischemic time ≥8 hours and outcomes after lung transplantation using a contemporary cohort from a high-volume institution. METHODS: Patients who underwent primary isolated bilateral lung transplantation between 1/2016 and 5/2020 were included. Patients bridged to transplant with extracorporeal membrane oxygenation or mechanical ventilation, and ex-vivo perfusion cases were excluded. Recipients were stratified by total allograft ischemic time <8 hours (standard) vs ≥8 hours (long). Perioperative outcomes and post-transplant survival were compared between groups. RESULTS: Of 358 patients, 95 (26.5%) received long ischemic time (≥8 hours) lungs. Long ischemic time recipients were more likely to be male and have donation after circulatory death donors than standard ischemic time recipients. On unadjusted analysis, long and standard ischemic time recipients had similar survival, and similar rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation post-transplant, acute rejection within 30 days, reintubation, and post-transplant length of stay. After adjustment, long and standard ischemic time recipients had comparable risks of mortality or graft failure. CONCLUSIONS: In a modern cohort, use of lung allografts with "long" ischemic time ≥8 hours were associated with acceptable perioperative outcomes and post-transplant survival. Further investigation is required to better understand how broader use impacts post-lung transplant outcomes and the implications for smarter sharing under an evolving national allocation policy.

The Impact of the 2017 Kidney Allocation Policy Change on Simultaneous Liver-Kidney Utilization and Outcomes.

Historically in the United States, kidneys for simultaneous liver-kidney transplantation (SLKT) candidates were allocated with livers, prioritizing SLKT recipients over much of the kidney waiting list. A 2017 change in policy delineated renal function criteria for SLKT and implemented a safety net for kidney-after-liver transplantation. We compared the use and outcomes of SLKT and kidney-after-liver transplant with the 2017 policy. United Network for Organ Sharing Standard Transplant Analysis and Research files were used to identify adults who received liver transplantations (LT) from August 10, 2007 to August 10, 2012; from August 11, 2012 to August 10, 2017; and from August 11, 2017 to June 12, 2019. LT recipients with end-stage renal disease (ESRD) were defined by dialysis requirement or estimated glomerular filtration rate <25. We evaluated outcomes and center-level, regional, and national practice before and after the policy change. Nonparametric cumulative incidence of kidney-after-liver listing and transplant were modeled by era. A total of 6332 patients received SLKTs during the study period; fewer patients with glomerular filtration rate (GFR) ≥50 mL/min underwent SLKT over time (5.8%, 4.8%, 3.0%; P = 0.01 ). There was also less variability in GFR at transplant after policy implementation on center and regional levels. We then evaluated LT-alone (LTA) recipients with ESRD (n = 5408 from 2012-2017; n = 2321 after the policy). Listing for a kidney within a year of LT increased from 2.9% before the policy change to 8.8% after the policy change, and the rate of kidney transplantation within 1 year increased from 0.7% to 4% (P < 0.001). After the policy change, there was no difference in patient survival rates between SLKT and LTA among patients with ESRD. Implementation of the 2017 SLKT policy change resulted in reduced variability in SLKT recipient kidney function and increased access to deceased donor kidney transplantation for LTA recipients with kidney disease without negatively affecting outcomes.

Visual motion perception predicts driving hazard perception ability.

PURPOSE: To examine the basis of previous findings of an association between indices of driving safety and visual motion sensitivity and to examine whether this association could be explained by low-level changes in visual function. METHODS: A total of 36 visually normal participants (aged 19-80 years) completed a battery of standard vision tests including visual acuity, contrast sensitivity and automated visual fields and two tests of motion perception including sensitivity for movement of a drifting Gabor stimulus and sensitivity for displacement in a random dot kinematogram (Dmin ). Participants also completed a hazard perception test (HPT), which measured participants' response times to hazards embedded in video recordings of real-world driving, which has been shown to be linked to crash risk. RESULTS: Dmin for the random dot stimulus ranged from -0.88 to -0.12 log minutes of arc, and the minimum drift rate for the Gabor stimulus ranged from 0.01 to 0.35 cycles per second. Both measures of motion sensitivity significantly predicted response times on the HPT. In addition, while the relationship involving the HPT and motion sensitivity for the random dot kinematogram was partially explained by the other visual function measures, the relationship with sensitivity for detection of the drifting Gabor stimulus remained significant even after controlling for these variables. CONCLUSION: These findings suggest that motion perception plays an important role in the visual perception of driving-relevant hazards independent of other areas of visual function and should be further explored as a predictive test of driving safety. Future research should explore the causes of reduced motion perception to develop better interventions to improve road safety.

The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function.

The function of the NH(2)-terminal propeptide of type I procollagen (N-propeptide) is poorly understood. We now show that a recombinant trimeric N-propeptide interacts with transforming growth factor-beta1 and BMP2 and exhibits functional effects in stably transfected cells. The synthesis of N-propeptide by COS-7 cells results in an increase in phosphorylation of Akt and Smad3 and is associated with a marked reduction in type I procollagen synthesis and impairment in adhesion. In C2C12 cells, N-propeptide inhibits the osteoblastic differentiation induced by BMP2. Our data suggest that these effects are mediated by the interaction of N-propeptide with an intracellular receptor in the secretory pathway, because they are not observed when recombinant N-propeptide is added to the culture medium of either COS-7 or C2C12 cells. Both the binding of N-propeptide to cytokines and its functional properties are entirely dependent on the exon 2-encoded globular domain, and a mutation that substitutes a serine for a highly conserved cysteine in exon 2 abolishes its function. Our findings suggest that N-propeptide performs an important feedback regulatory function and provides a rationale for the prominence of a homotrimeric form of type I procollagen (alpha1 trimer) during vertebrate development.