Optimal kidney graft outcomes after simultaneous liver-kidney (SLK) transplant may be threatened by the increased cold ischemia time and hemodynamic perturbations of dual organ transplantation. Hypothermic machine perfusion (MP) of kidney allografts may mitigate these effects. We analyzed U.S. trends and renal outcomes of hypothermic non-oxygenated MP vs. static cold storage (CS) of kidney grafts from 6,689 SLK transplants performed between 2005 and 2020 using the United Network for Organ Sharing database. Outcomes included delayed graft function (DGF), primary non-function (PNF), and kidney graft survival (GS). Overall, 17.2% of kidney allografts were placed on MP. Kidney cold ischemia time was longer in the MP group (median 12.8 vs. 10.0 h; p < 0.001). Nationally, MP utilization in SLK increased from <3% in 2005 to >25% by 2019. Center preference was the primary determinant of whether a graft underwent MP vs. CS (intraclass correlation coefficient 65.0%). MP reduced DGF (adjusted OR 0.74; p = 0.008), but not PNF (p = 0.637). Improved GS with MP was only observed with Kidney Donor Profile Index <20% (HR 0.71; p = 0.030). Kidney MP has increased significantly in SLK in the U.S. in a heterogeneous manner and with variable short-term benefits. Additional studies are needed to determine the ideal utilization for MP in SLK.

To highlight the role of pancreas transplantation in pancreatogenic diabetes and to familiarize the reader with disease processes that can result in both problematic diabetes and exocrine insufficiency that even when maximally medically managed, can adversely impact quality of life and increase the risk of morbidity and mortality. Successful simultaneous lung/liver/pancreas transplant and the first sequential simultaneous kidney pancreas transplant after lung transplant for cystic fibrosis have recently been reported, spurring renewed interest for the application of pancreas transplantation for type 3c diabetes. Given the known post-transplant risks of diabetes and calcineurin inhibitor toxicity, more awareness of the utility and outcomes of pancreas transplantation for pancreatogenic diabetes is needed.

Abstract Background Lymphopenia has been associated with inferior cancer outcomes, but there is limited data in breast cancer. We describe the effects of neoadjuvant chemotherapy on circulating immune cells and its association with pathological complete response (pCR) rates in triple negative breast cancer (TNBC). Methods We constructed a database of patients with early stage TNBC treated with neoadjuvant chemotherapy. Circulating lymphocytes and monocytes were assessed before and after neoadjuvant chemotherapy. These were correlated with pCR rates and disease‐free survival (DFS) using Fisher's exact test, logistic regression, and the log‐rank test. Results From 2000 to 2015, we identified 95 eligible patients. Median age was 50; 29 (31%) were treated with platinum‐containing chemotherapy; and 66 (69%) with nonplatinum‐containing chemotherapy (anthracycline‐taxane, or either alone). About 32 (34%) patients achieved a pCR; and 33 (35%) had recurrence events. Median follow‐up time was 47 months. No significant associations were found between changes in lymphocytes and pCR or DFS. There was a correlation between lower monocyte levels after neoadjuvant chemotherapy and pCR (mean monocyte 0.56 in those with no‐pCR vs 0.46 in those with pCR, P = .049, multivariate P = .078) and DFS (median DFS in highest monocyte quartile was 30 vs 107 months in lowest quartile, P = .022, multivariate P = .023). In patients who received nonplatinum regimens, DFS was better among those who had larger decreases in monocytes. Conclusions Development of lymphopenia from neoadjuvant chemotherapy was not associated with pCR in patients with TNBC. However, lower absolute circulating monocytes after neoadjuvant chemotherapy was associated with improved outcomes.

Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow–derived CD133+ and CD34+ endothelial progenitor cells and Ym1/2+ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.

INTRODUCTION: Granulomatosis with Polyangiitis (GPA) is a systemic autoimmune disease that mainly affects small vessels and can affect any organ system. It is one of the ANCA associated vasculitides, defined by vascular inflammation associated with autoantibodies known as ANCA. Although rarely seen, GPA can affect the GI system and present with GI complications. CASE DESCRIPTION/METHODS: A 27-year-old female initially presented to the ED with lower extremity weakness, joint pain and swelling, then returned a month later after recent diagnosis of rheumatoid arthritis (RA) with epigastric and right upper quadrant pain. CT abdomen/pelvis and labwork were insignificant. She returned the following day for persistent symptoms. Abdominal ultrasound confirmed cholelithiasis and possibly cholecystitis. She underwent cholecystectomy and was subsequently discharged but soon returned with fevers, nausea, chills, sweats and epigastric pain radiating to the right shoulder. EGD showed findings of gastritis. MRCP and ERCP were unremarkable. Gallbladder pathology showed cholelithiasis and findings consistent with small vessel vasculitis. Further workup was positive for protease 3 antibody, consistent with GPA. She was treated with pulse dose steroids, plasmapheresis and started on Rituxan infusion. Non-opioid pain medications were given while opioids and steroids were tapered. Her abdominal pain improved and she was discharged with outpatient follow up. DISCUSSION: In a retrospective review, GI involvement, most commonly abdominal pain, was found in varying percentages of patients with polyarteritis nodosa, ANCA vasculitides including GPA and RA associated vasculitis. Biopsies from 36 patients via EGD found no signs of vasculitis. Four of five patients with cholecystectomy for cholecystitis were shown to have vasculitis. In an analysis of case records of 34 patients with GPA, nine of 34 had GI complications. EGD samples revealed nonspecific inflammation. The insignificant findings on EGD in the patient cases as well as the unremarkable ERCP and MRCP on our patient show that it is worthwhile to question the necessity of continuous procedures in patients with GPA who present with persistent abdominal pain. It is important to consider systemic vasculitis in patients with unclear causes of GI symptoms especially in those with history of rheumatological disorder. Benefits include avoiding unnecessary imaging and procedures as well as decreased hospital stay thereby utilizing high value care and improving patient experience.Figure 1.: Ultrasound showing cholelithiasis without any wall thickening. There was positive Murphy's sign while obtaining the imaging.Figure 2.: Images show a small artery with fibrinoid necrosis of the vessel wall. There is infiltration in the vessel wall and in the surrounding tissue by neutrophils and lymphocytes. Each image shows varying degrees of obliteration of the vessel lumen with Figures 2.1 and 2.2 showing complete obliteration.

Introduction: The lifetime incidence of foot ulcers has been estimated to be 19% to 34% among persons with diabetes. Diabetic wound healing(DWH) remains a challenge. Given the promising role of stem cells in wound healing, the current study proposed to improve DWH by mobilizing and recruiting bone marrow stem cells pharmacologically with combination of AMD3100 and low-dose FK506 (AF) in rats. Methods: T2 GK rats and STZ induced T1DM SD rats were used. To determine the role of bone marrow stem cells, bone marrow from GFP tg Lewis were transplanted into wt Lewis rats and T1 rats were induced by STZ injection at 2 months following bone marrow transplantation. Full-thickness wounds were created in the dorsal skin or in the foot skin at 6 weeks after STZ injection or GK rats at 4 month old. Wounded rats were divided into two experimental groups and received saline or a combination of AMD3100 (1mg/kg) and FK506 (0.1mg/kg) immediately after wounding and every 2 days until complete healing. Results: At the time of wounding, all animals developed peripheral artery disease and neuropathy. The back wound healing time was reduced from 27 to 19 days and the foot wound healing time was reduced from 25 to 20 days in T1DM rats treated with AF. Similarly, the back wound healing time was reduced from 26(S) to 21(AF) days in GK rats. Equally important, healing was accompanied by reduced scar and regeneration of hair follicles. Searching for the mechanisms, we found that AF therapy mobilized bone marrow stem cells to peripheral blood and recruited bone marrow-derived CD31+CD133+ endothelial progenitor cells, CD34+ stem cells and Ym1/2+ M2 macrophages into the wound sites and enhanced capillary and hair follicle neogenesis. Conclusion: Combination of AMD3100 and low-dose FK506 results in better and faster healing of diabetic wounds in rats with diabetic peripheral artery disease and neuropathy. Our findings offer a significant therapeutic approach to healing of DFU. Disclosure L. Qi: None. A.R. Ahmadi: None. J. Huang: None. Q. Lin: None. M. Chen: None. H. Kuwabara: None. K. Iwasaki: None. J. Burdick: None. Z. Sun: None.

Adhesions are a very common complication in the abdominal surgery. Animal studies and human trials have evaluated strategies designed to reduce and prevent postsurgical adhesions but few have an evidence base that justifies routine use. A strategy to prevent adhesions effectively remains an urgent need. We studied a reproducible model of intra-peritoneal adhesion formation in rats using laparotomy with several peritoneal sutures to produce the adhesions. Here we show that entraining endogenous stem cells into injury sites using the combined effect of AMD3100 and low-dose FK-506 (AF) can reduce the adhesion score significantly and abolish peritoneal adhesions in 45% of animals in a rat model of severe postsurgical intra-abdominal adhesions, compared with saline controls. Searching for mechanisms, we found AF treatment dramatically increased SDF-1 expressing cells, HGF expressing Ym1+ M2 macrophages and CD133+ stem cells in the injury sites of peritoneal surface at day 5 post-operation. Our results demonstrate that medically induced recruitment of autologous stem cells using AF significantly reduced postsurgical intra-abdominal adhesions. These findings suggest a novel effective therapeutic approach to preventing adhesions in patients.

Background: Postsurgical adhesions are a very common complication causing various symptoms from pain to bowel obstruction. We have developed a stem cell mobilizing strategy that enables long-term liver and kidney allograft survival without sustained immunosuppression in animals using a combination of AMD3100 and low-dose FK506 (AF). Serendipitously we have noted a subjective decrease in adhesion formation in animals with AF combination treatment. The purpose of this study was to evaluate the effect of a new stem cell mobilizing strategy on preventing postsurgical adhesion formation in rats.

Chen, Melissa E. MD; Kuwabara, Hiroshi MD; Katsumata, Kenji MD, FACS; Tsuchida, Akihiko MD, PhD; Philosophe, Benjamin MD, PhD; Sun, Zhaoli MD, PhD Author Information

BACKGROUND: Critically ill cirrhotics require liver transplantation urgently, but are at high risk for perioperative mortality. The Model for End-stage Liver Disease (MELD) score, recently updated to incorporate serum sodium, estimates survival probability in patients with cirrhosis, but needs additional evaluation in the critically ill. The purpose of this study was to evaluate the predictive power of ICU admission MELD scores and identify clinical risk factors associated with increased mortality.STUDY DESIGN: This was a retrospective review of cirrhotic patients admitted to the ICU between January 2011 and December 2014. Patients who were discharged or underwent transplantation (survivors) were compared with those who died (nonsurvivors). Demographic characteristics, admission MELD scores, and clinical risk factors were recorded. Multivariate regression was used to identify independent predictors of mortality, and measures of model performance were assessed to determine predictive accuracy.RESULTS: Of 276 patients who met inclusion criteria, 153 were considered survivors and 123 were nonsurvivors. Survivor and nonsurvivor cohorts had similar demographic characteristics. Nonsurvivors had increased MELD, gastrointestinal bleeding, infection, mechanical ventilation, encephalopathy, vasopressors, dialysis, renal replacement therapy, requirement of blood products, and ICU length of stay. The MELD demonstrated low predictive power (c-statistic 0.73). Multivariate analysis identified MELD score (adjusted odds ratio [AOR] = 1.05), mechanical ventilation (AOR = 4.55), vasopressors (AOR = 3.87), and continuous renal replacement therapy (AOR = 2.43) as independent predictors of mortality, with stronger predictive accuracy (c-statistic 0.87).CONCLUSIONS: The MELD demonstrated relatively poor predictive accuracy in critically ill patients with cirrhosis and might not be the best indicator for prognosis in the ICU population. Prognostic accuracy is significantly improved when variables indicating organ support (mechanical ventilation, vasopressors, and continuous renal replacement therapy) are included in the model. (C) 2016 Published by Elsevier Inc. on behalf of the American College of Surgeons.

We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7–36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7–36] amide would restore MIR and impact the course of DCM in older beagles.

In 2008, a large Salmonella outbreak caused by contamination of the municipal drinking water supply occurred in Alamosa, Colorado. The objectives of this assessment were to determine the full economic costs associated with the outbreak and the long-term health impacts on the community of Alamosa. We conducted a postal survey of City of Alamosa (2008 population: 8,746) households and businesses, and conducted in-depth interviews with local, state, and nongovernmental agencies, and City of Alamosa healthcare facilities and schools to assess the economic and long-term health impacts of the outbreak. Twenty-one percent of household survey respondents (n = 369/1,732) reported diarrheal illness during the outbreak. Of those, 29% (n = 108) reported experiencing potential long-term health consequences. Most households (n = 699/771, 91%) reported municipal water as their main drinking water source at home before the outbreak; afterwards, only 30% (n = 233) drank unfiltered municipal tap water. The outbreak's estimated total cost to residents and businesses of Alamosa using a Monte Carlo simulation model (10,000 iterations) was approximately $1.5 million dollars (range: $196,677-$6,002,879), and rose to $2.6 million dollars (range: $1,123,471-$7,792,973) with the inclusion of outbreak response costs to local, state and nongovernmental agencies and City of Alamosa healthcare facilities and schools. This investigation documents the significant economic and health impacts associated with waterborne disease outbreaks and highlights the potential for loss of trust in public water systems following such outbreaks.

Introduction: It has been thought that the primary driver of renal dysfunction (RD) in heart failure (HF) is diminished renal perfusion secondary to reduced cardiac output. However, this relationship has not been confirmed in recent clinical studies. Rather, strong associations between RD and right ventricular (RV) dysfunction/venous congestion have been identified. Hypothesis: If RV dysfunction/venous congestion are causative of HF induced RD, the addition of RV dysfunction to a standard left ventricular (LV) HF model should produce incremental RD, independent of changes in cardiac output. Methods: Eleven swine were chronically instrumented with intravascular catheters, intra-cardiac pressure transducers, and vascular flow probes on the ascending aorta and renal artery. After 2 weeks of recovery, biventricular failure was induced by serial microembolization of the pulmonary vascular bed (2-3 mg/kg of 65 micron glass spheres, times 6 infusions) followed by ventricular pacing at 170 BPM (RV+LV group, n=7). The remaining 4 pigs served as a pacing only control (LV group). Measurements of cardiac and renal parameters were made in the conscious state at baseline and after 2 weeks of pacing. Results: Baseline renal and cardiac parameters were similar between groups. After 2 weeks of pacing, LV end diastolic pressure was increased and LV dP/dT and cardiac output were decreased (p<0.05), however these parameters did not differ between groups (p≥ 0.19 for all). Notably, right atrial pressure was significantly higher (LV group=4.7 ± 1.3 vs. RV+LV group= 12.1 ± 1.1 mmHg, p=0.02) and renal blood flow was significantly lower in the RV+LV group (LV=144.0 ± 3.2 vs. RV+LV= 94.4 ± 16.0 ml/min, p=0.03) despite a similar mean cardiac output between groups (LV group=3.8 ± 0.3 vs. RV+LV group=4.0 ± 0.4 l/min, p=0.76). Conclusion: Despite a comparable degree of LV dysfunction and similar reductions in cardiac output, conscious swine with biventricular dysfunction had a disproportionate impairment in renal perfusion. These results provide mechanistic support for human observational studies linking RV dysfunction/venous congestion with RD.