Acute Drop Research Articles

534 Persistent Copper and Zinc Deficiency in Excess of 30 Days Post Burn Injury

Abstract Introduction Copper and zinc deficiencies are common after burn injury, with the lowest levels usually occurring within seven days. Both trace elements are important for wound healing, but due to competition for absorption in the small intestine, oral replacement of zinc and copper may not be sufficient. Nutritional guidelines recommend copper and zinc replacement for up to 30 days, but little data is available to guide long-term trace element replacement. Methods This case series includes four patients with 15% or larger total body surface area burns who had hypocupremia at least 30 days after admission despite receiving at least the recommended daily allowance of copper via tube feeds. Results In two patients, copper levels increased following discontinuation of oral zinc tablets. However, one patient had continued hypocupremia and increasing zinc levels while receiving zinc only from tube feeds, suggesting this amount of zinc may decrease dietary copper absorption. For one patient with 95% TBSA burns, hypocupremia was associated with polyneuropathy and osteopenia. Another patient experienced an acute drop in zinc levels associated with bacteremia and sepsis. Conclusions In this case series, hypocupremia was associated with anemia and zinc deficiency with poor wound healing. Additional multicenter practice reviews of copper and zinc supplementation in burn centers would be beneficial.

Passenger Lymphocyte Syndrome in a Pediatric Lung Transplant Recipient with Previous Bone Marrow Transplantation

Introduction Passenger lymphocyte syndrome (PLS) is a rare complication following solid organ transplantation (SOT). It consists of immune-mediated hemolysis due to antibodies produced by donor B-lymphocytes against recipient red blood cells [1]. Incidence across all SOT is as low as 0.5% in adults, with the highest rates being in lung and heart [2,3,4]. There have been no cases reported in children post-lung transplantation to our knowledge. Case Report A 12-year-old female received a double lung transplantation for bronchiolitis obliterans due to graft versus-host disease (GHVD). She had undergone allogeneic BMT 6 years prior for myelodysplastic syndrome (MDS). Her post-BMT course was complicated by lung, skin, and gastrointestinal GVHD. Lung transplant was uncomplicated: with donor blood group O+, recipient blood group A+, and crossmatch negative. On post-operative day 13, there was an acute drop in hemoglobin: from 131 g/L day 7, to 87 g/L day 13, to 66 g/L the same day. Septic workup was negative. Direct antiglobulin test was positive. Hemolysis markers were present with high LDH, high unconjugated bilirubin, and low haptoglobin. Eluate test was positive for anti-A1 antibody, consistent with a diagnosis of PLS. She received donor-type (O+) red cells, and was given IVIG 600 mg/kg for hypogammaglobulinemia. Hemoglobin recovered after day 21. Given her BMT history, concern around recurrent MDS was also raised. A chimerism study was sent on day 22 for this with the added benefit of examining for circulating lung-donor lymphocytes. No MDS was revealed. FISH revealed all cells were chromosomally XX (recipient had received BMT from a female donor), indicating no persistent circulating lung-donor lymphocytes since lung donor was male. Summary We report PLS following lung transplant in a 12-year-old post-BMT. Risk factors included minor ABO mismatch and organ type transplanted, with a high lymphocyte burden in lungs compared to other organs [3,4]. It is unclear whether prior allogeneic BMT and GVHD were added risk factors. Given higher PLS rates post-BMT [5], one could postulate that this may have also predisposed to PLS in this case. Albeit self-limiting, transfusion with donor blood group is necessary to prevent further hemolysis. Finally, a chimerism study for MDS has the added benefit of searching for lung-donor lymphocytes, if still present in circulation.

Gestational Age-Specific Complete Blood Count Signatures in Necrotizing Enterocolitis.

Objective: Necrotizing enterocolitis (NEC) is characterized by peripheral cell abnormalities, yet few studies have analyzed the complete blood count (CBC) specifically by gestational age (GA). Our objective was to describe GA-specific immune abnormalities in NEC through a comprehensive analysis of the CBC differential.Methods: Using a cohort of 246 infants (177 cases, 69 controls) admitted to neonatal intensive care units at a single institution, we retrospectively analyzed CBCs around illness onset in NEC cases compared with controls. Cases included surgical NEC (S-NEC, 34.5%) and medical NEC (M-NEC, 65.5%). Infants were divided into those born at GA <33 and ≥33 weeks. Differences in CBC values were described as absolute and percent changes at NEC onset from baseline and at antibiotic completion after NEC. We used machine learning algorithms based on the CBC at NEC to generate predictive models for diagnosis.Results: At NEC onset, there was an acute drop in monocytes and lymphocytes along with a rise in bands in S-NEC infants born <33 weeks compared with M-NEC. In comparison, both M-NEC and S-NEC ≥33 weeks had a percent drop in neutrophils at diagnosis compared with controls. At antibiotic completion, monocytes in S-NEC <33 weeks significantly rose compared with M-NEC, yet for S-NEC ≥33 weeks, bands significantly dropped compared with M-NEC. Predictive modeling was able to accurately predict S-NEC from M-NEC and controls.Conclusion: There are discrete leukocyte patterns in NEC based on GA. The CBC at diagnosis may be useful in identifying patients who will require surgery.

Acute bilateral foot drop with or without cauda equina syndrome\u2014a case series

IntroductionIsolated acute bilateral foot drop due to degenerative spine disease is an extremely rare neurosurgical presentation, whilst the literature is rich with accounts of chronic bilateral foot drop occurring as a sequela of systemic illnesses. We present, to our knowledge, the largest case series of acute bilateral foot drop, with trauma and relevant systemic illness excluded.MethodsData from three different centres had been collected at the time of historic treatment, and records were subsequently reviewed retrospectively, documenting the clinical presentation, radiological level of compression, timing of surgery, and degree of neurological recovery.ResultsSeven patients are presented. The mean age at presentation was 52.1 years (range 41–66). All patients but one were male. All had a painful radiculopathic presentation. Relevant discopathy was observed from L2/3 to L5/S1, the commonest level being L3/4. Five were treated within 24 h of presentation, and two within 48 h. Three had concomitant cauda equina syndrome; of these, the first two made a full motor recovery, one by 6 weeks follow-up and the second on the same-day post-op evaluation. Overall, five out of seven cases had full resolution of their ankle dorsiflexion pareses. One patient with 1/5 power has not improved. Another with 1/5 weakness improved to normal on the one side and to 3/5 on the other.ConclusionWhen bilateral foot drop occurs acutely, we encourage the consideration of degenerative spinal disease. Relevant discopathy was observed from L2/3 to L5/S1; aberrant innervation may be at play. Cauda equina syndrome is not necessarily associated with acute bilateral foot drop. The prognosis seems to be pretty good with respect to recovery of the foot drop, especially if partial at presentation and if treated within 48 h.

Acetate, a Short-Chain Fatty Acid, Acutely Lowers Heart Rate and Cardiac Contractility Along with Blood Pressure.

Short-chain fatty acids (SCFAs) are metabolites produced almost exclusively by the gut microbiota and are an essential mechanism by which gut microbes influence host physiology. Given that SCFAs induce vasodilation, we hypothesized that they might have additional cardiovascular effects. In this study, novel mechanisms of SCFA action were uncovered by examining the acute effects of SCFAs on cardiovascular physiology in vivo and ex vivo. Acute delivery of SCFAs in conscious radiotelemetry-implanted mice results in a simultaneous decrease in both mean arterial pressure and heart rate (HR). Inhibition of sympathetic tone by the selective β-1 adrenergic receptor antagonist atenolol blocks the acute drop in HR seen with acetate administration, yet the decrease in mean arterial pressure persists. Treatment with tyramine, an indirect sympathomimetic, also blocks the acetate-induced acute drop in HR. Langendorff preparations show that acetate lowers HR only after long-term exposure and at a smaller magnitude than seen in vivo. Pressure-volume loops after acetate injection show a decrease in load-independent measures of cardiac contractility. Isolated trabecular muscle preparations also show a reduction in force generation upon SCFA treatment, though only at supraphysiological concentrations. These experiments demonstrate a direct cardiac component of the SCFA cardiovascular response. These data show that acetate affects blood pressure and cardiac function through parallel mechanisms and establish a role for SCFAs in modulating sympathetic tone and cardiac contractility, further advancing our understanding of the role of SCFAs in blood pressure regulation. SIGNIFICANCE STATEMENT: Acetate, a short-chain fatty acid, acutely lowers heart rate (HR) as well as mean arterial pressure in vivo in radiotelemetry-implanted mice. Acetate is acting in a sympatholytic manner on HR and exerts negative inotropic effects in vivo. This work has implications for potential short-chain fatty acid therapeutics as well as gut dysbiosis-related disease states.

Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

High dialysis clearance of drugs predicts intradialytic hypertension in hemodialysis patients

Abstract Introduction/Purpose An acute drop in highly dialyzable antihypertensive drug levels is considered to be one of the pathophysiological mechanisms of blood pressure rise during hemodialysis (HD). The study aimed to assess the prevalence of intradialytic hypertension (ID-HTN) and identify the most significant risk factors of its development. Methods We performed a retrospective case-control single-center study of HD patients from January 1st, 2014 to December 30th, 2016. Baseline evaluation included recording of antihypertensive medications with a focus on dialyzability of drugs. ID-HTN was defined as an increase in systolic blood pressure more than 10 mmHg after HD session. Results We enrolled 131 HD patients (52% males, median age 55.7 [53.5; 58.0] years, dialysis vintage 59.3 [51.8; 66.8] months). 79 patients suffered from ID-HTN. Highly dialyzable drugs were used in 61% of patients, most often – in 68% of cases – in the group of beta-blockers, less often among inhibitors of angiotensin-converting enzyme (32%). ID-HTN was associated with use of beta-blockers (Spearman's rank correlation coefficient (r)=0.212; p=0.015), moxonidine (r=0.313; p=0.001) and highly dialyzable drugs (r=0.440; p&amp;lt;0.0001). Using the identified risk factors, a prediction model for ID-HTN based on logistic regression was constructed: y = −1.015 + 1.720 × highly dialyzed drugs + 0.993 × moxonidine; p = exp (y) / (1 + exp (y)). Table 1 displays actual and predicted values on the sample of HD patients. Conclusion In present study 60% of dialysis patients suffered from ID-HTN. Drugs with high dialysis clearance were widely used (61%) in dialysis population. Highly dialyzable drugs were associated with increased risk of ID-HTN (OR 5.585; 95% CI 2.49–12.54; p&amp;lt;0.0001). The low specificity (65.4%) of the prediction model limits its use in clinical practice. Figure 1 shows the covariate-adjusted ROC curve by logistic regression model. Funding Acknowledgement Type of funding source: None

A Case of Colonic Ischaemia Masquerading as a Colonic Mass

Intestinal ischaemia is an uncommon vascular syndrome resulting from an acute or chronic drop in blood supply to the bowel, with varied clinical presentations. Intestinal ischaemia can present similarly to other conditions, leaving the clinician with a diagnostic dilemma. In this case report, we present a 69-year-old male who presented with abdominal pain, distention, anorexia and per rectal bleeding. Endoscopy showed a left-sided mass-like, ulcerated lesion, endoscopically thought to be colonic carcinoma. Histology later revealed this mass to be intestinal ischaemia, with no features of invasive carcinoma. This was confirmed at an interval endoscopy, which showed a largely healed mucosa and nil evidence of a mass. Raising awareness of this disease and its ability to mimic other presentations, both clinically and endoscopically, is key to establishing an early diagnosis and intervention.

Plasma Membrane Protein Nce102 Modulates Morphology and Function of the Yeast Vacuole.

Membrane proteins are targeted not only to specific membranes in the cell architecture, but also to distinct lateral microdomains within individual membranes to properly execute their biological functions. Yeast tetraspan protein Nce102 has been shown to migrate between such microdomains within the plasma membrane in response to an acute drop in sphingolipid levels. Combining microscopy and biochemistry methods, we show that upon gradual ageing of a yeast culture, when sphingolipid demand increases, Nce102 migrates from the plasma membrane to the vacuole. Instead of being targeted for degradation it localizes to V-ATPase-poor, i.e., ergosterol-enriched, domains of the vacuolar membrane, analogous to its plasma membrane localization. We discovered that, together with its homologue Fhn1, Nce102 modulates vacuolar morphology, dynamics, and physiology. Specifically, the fusing of vacuoles, accompanying a switch of fermenting yeast culture to respiration, is retarded in the strain missing both proteins. Furthermore, the absence of either causes an enlargement of ergosterol-rich vacuolar membrane domains, while the vacuoles themselves become smaller. Our results clearly show decreased stability of the V-ATPase in the absence of either Nce102 or Fhn1, a possible result of the disruption of normal microdomain morphology of the vacuolar membrane. Therefore, the functionality of the vacuole as a whole might be compromised in these cells.

The hidden consequence of intraventricular hemorrhage: persistent cerebral desaturation after IVH in preterm infants.

Background:Previous studies describe a short-term decrease in cerebral oxygen saturation (StO2) after intraventricular hemorrhage (IVH) in premature infants; little is known about long-term implications.Methods:Infants born <30 weeks gestational age (GA) were included. Clinical characteristics, hemoglobin measurements, highest grade of IVH, and white matter injury (WMI) were noted.NIRS monitoring occurred daily or every other day for four weeks; weekly through 36 weeks GA. Recordings were error-corrected before calculation of mean StO2 and fractional tissue oxygen extraction (FTOE). Mean StO2 and FTOE were plotted by postnatal age and injury group (IVH/no IVH; WMI/no WMI). Non-linear regression by locally-estimated scatterplot smoothing was used to generate the best-fit line and CI.Results:1237 recordings from 185 infants were included; mean length=6.5h; mean GA=26.3w; mean BW=951g; overall/severe IVH incidence was 29/8%, WMI incidence was 16%. IVH was independently associated with an acute drop in StO2 which remained lower for 68d. Severe IVH was associated with lower StO2 values than mild IVH. WMI was associated with early and persistent elevation of FTOE.Conclusion:IVH of any grade is associated with a prolonged cerebral desaturation, WMI is associated with prolonged elevation of FTOE. This finding is exacerbated for infants with severe IVH.

Trajectory of Quality of Life Before and After Entering a Nursing Home: A Longitudinal Study.

The objective of this longitudinal study was to compare the trajectory of subjective quality of life in 2 groups of older adults: those who entered a nursing home and those who remained living in the community with similar clinical conditions. PAQUID is a prospective population-based study. It included, at baseline, 3777 community-dwelling participants aged 65 years and over. Participants were followed-up for up to 27 years. Among people living at home at baseline, 2 groups were compared: participants who entered a nursing home over a 20-year follow-up (n = 528) and those who remained community dwellers (n = 2273). We used latent process mixed models to estimate the relationship between mean trajectory of subjective quality of life and admission into a nursing home. We computed univariate and multivariate models taking into account potential confounders (age, gender, education, income, comorbidities, dementia, disability and depression). Nursing home placement was significantly associated with a drop in quality of life between the last visit before and after institutionalization. Nevertheless, we found no difference in quality of life trajectory after this initial drop. Older adults exhibit an acute drop in quality of life after nursing home admission, probably reflecting the associated psychological distress. Even though their quality of life does not go back to pre-admission levels, the residents do not show a steeper decline when compared to the "natural" evolution of quality of life in older adults living in the community, which suggests a relative adaptation to their new living conditions.

S2178 A Shock to All: A Rare Case of a Systemic Varix Causing Hemorrhagic Shock

INTRODUCTION: Variceal bleeding is a common complication of cirrhosis and usually occurs within the esophagus or stomach. Sometimes, large portosystemic collaterals known as ectopic varices form outside of the portal system. Though they only account for a small portion of variceal bleeding, mortality is high and prompt identification is critical. We describe a rare case of a gentleman with a history of cirrhosis that developed a massive bleed due an abdominal wall varix. CASE DESCRIPTION/METHODS: A 64-year-old incarcerated male with a history of cirrhosis was transferred from an outside hospital with the chief complaint of unwitnessed hematemesis. Vitals at outside hospital were stable and initial hemoglobin was 13.3 g/dL. A repeat hemoglobin prior to transfer was 6.0 g/dL even though the patient had no further episodes of hematemesis, melena or hematochezia. He was transfused 4 units of packed red blood cells and transferred to our institution. On arrival, the patient was stable however complained of abdominal pain and shortness of breath with new abdominal distention. Shortly after, the patient became diaphoretic, hypotensive and ultimately suffered a cardiopulmonary arrest. Post-arrest labs revealed a hemoglobin of 4.5 g/dL, platelets of 50 thou/cmm and lactate of 8 mmol/L. The Gastroenterology team performed an EGD at bedside which showed no evidence of active variceal bleeding. The patient was emergently taken to the OR for an exploratory laparotomy and seven liters of blood were encountered within the intraabdominal cavity from a bleeding lateral abdominal wall varix. Post-surgery, the patient unfortunately suffered another cardiac arrest due to hemorrhagic shock and expired. DISCUSSION: Ectopic varices are collaterals that can form along the gastrointestinal tract where the portal venous system comes into contact with the systemic system. Ectopic varices are rare and account for 1-4% of variceal bleeding. Unfortunately, bleeding is life-threatening and mortality occurs in about 40% of patients. In our patient, the acute drop in hemoglobin without typical symptoms of gastroesophageal bleeding should have prompted further imaging to evaluate for hemoperitoneum. In absence of imaging, clinical indicators for intraabdominal bleeding include rapid abdominal distention, acute blood loss anemia and hemodynamic instability. Thus, ectopic varices should remain on the differential in cirrhotic patients who present with acute blood loss anemia.

EP28 A case of ANCA vasculitis presenting with Sjögren’s serology

EP28 A case of ANCA vasculitis presenting with Sjögren’s serology

S1982 Life-Threatening Massive Upper Gastrointestinal (GI) Bleed and Airway Obstruction in a Patient With Megaesophagus From Longstanding Achalasia

INTRODUCTION: In 10% of patients, untreated or poorly managed Achalasia can cause progressive esophageal dilation and loss of functionality, forming a sigmoidolichomegaesopahagus, with less than 5% of cases requiring an esophagectomy. In extremely rare situations, this megaesopahagus can cause airway obstruction from the regurgitation of food and life-threatening esophageal bleeding from underlying pressure mucosal ulcers from the retained food debris. CASE DESCRIPTION/METHODS: A 65 year-old female with a past medical history of Achalasia, presented to the emergency department (ED) with complaints of worsening shortness of breath, chest pain, nausea, non-bilious hematemesis with regurgitated food and water since one day. These symptoms were accompanied by diaphoresis, fatigue and chronic intermittent dysphagia for both solid foods and liquids. In the ED, she experienced another massive episode of bright red hematemesis accompanied by severe dizziness with an acute drop in hemoglobin, resulting in a blood transfusion. Her chest x-ray showed a dilated megaesophagus occupying most of the right hemithorax and CTangiography displayed significant distention of the esophagus with intraluminal Solid material and fluid containing a small amount of gas as well partially obstructing the Right mainstem Bronchi (Image 1,2). Emergent Esophagogastroduodenoscopy was conducted, which revealed a large amount of food debris with areas of esophageal necrosis and dark red blood seen throughout, preventing visualization of the bleeding source (Image 3). The bleeding was likely from an ulcer caused by pressure necrosis from retained food. The patient was then transferred for an emergent esophagectomy to another Health care facility. DISCUSSION: Upper GI bleeding in Achalasia is usually associated with underlying mucosal ulcers caused by pill and infectious esophagitis, malignancies, excessive ingestion of tannins. Pressure ulcers from retained food debris is a rare but lethal etiology of Upper GI bleed in patient with Achalasia. The three factors that play an important role in the pathogenesis of this pressure ulcer formation in Achalasia are immobility from esophageal aperistalsis, non-uniform shearing forces induced from the regurgitation of food and the increased tendency of self-vomiting in these patients, and lastly, mucosal barrier disruption from gastric acid reflux and malnutrition. We hope to contribute to the current understanding of this topic and increase awareness among physicians about it by presenting this rare case.Figure 1.: Computed tomography Angiogram of Chest, Axial Scout (Left) with corresponding Coronal section (Right) showing dilated megaesophagus occupying most of the right hemithorax with intraluminal Solid and fluid material containing a small amount of gas partially obstructing the Right main Bronchi (Arrow).Figure 2.: Again Computed tomography Angiogram of Chest at lower level, Axial Scout (Left) with corresponding Coronal section (Right) showing severely dilated esophagus occupying most of the right hemithorax, with intraluminal Solid and fluid material containing a small amount of gas.Figure 3.: Esophagogastroduodenoscopy showing areas of esophageal necrosis and dark red blood seen throughout, preventing visualization of the exact bleeding source.

S2207 Disseminated Mucormycosis: A Rare Cause of GI Bleeding

INTRODUCTION: Mucormycosis is an unusual infection in humans, almost always seen in immunocompromised patients. The usual presentations are rhino-orbital-cerebral, pulmonary, or cutaneous mucormycosis. Gastrointestinal involvement is rare, with the stomach, colon, and ileum being potential sites of infection. CASE DESCRIPTION/METHODS: A 74-year-old male with past medical history of cervical schwannoma s/p resection and radiation therapy on steroids due to cord compression was admitted for diabetic ketoacidosis and sepsis secondary to emphysematous pyelonephritis. He underwent bilateral nephrectomy and was admitted to the ICU for CVVHD following which his clinical condition deteriorated and he was intubated. The surgical specimens were concerning for angioinvasive fungal infection, and BAL analysis showed potential mucormycosis. He was started on Amphotericin B and Isavuconazole. 10 days after ICU admission, he had an acute hemoglobin drop and NG tube output showed frank blood. Upper GI endoscopy revealed multiple ulcerations in the nasopharynx, oropharynx and epiglottis. The esophagus had many cratered ulcers, 10mm in largest dimension, and LA Grade D esophagitis. The lesser curvature of the stomach had few oozing, cratered ulcers with a visible vessel. The ulcers, 30mm in largest dimension, were marked by black discoloration with white fuzz on top, concerning for Mucor (Figures 1 and 2). The ulcers were injected with epinephrine and treated with bipolar cautery. Pathology revealed fungal organisms compatible with Mucor, and ulcers with crystalline iron deposits. DISCUSSION: Disseminated mucormycosis occurs in the setting of severely immunocompromised patients with steroid use, diabetes, and deferoxamine being strong risk factors. When the gastrointestinal tract is involved, the stomach is the most common site, showing multiple deep necrotic ulcerations as described above. Diagnosis requires a high index of suspicion, and is by histopathological examination of the affected area showing the characteristic wide, non-septate hyphae. Treatment involves surgical resection of the affected tissue and antifungal therapy with amphotericin B and posaconazole or isavuconazole for several weeks.Figure 1.: Endoscopy showing gastric ulcer with black discoloration and white fuzz.Figure 2.: Endoscopy showing cratered gastric ulcer with black discoloration and white fuzz.

An experimental evaluation of a concept to improve conventional aortic prostheses

Conventionally used textile prosthesis for traditional open surgical repair (OSR) of aortic aneurysms have a lower compliance than the native aortic tissue. Graft placements lead to an acute drop in compliance which effects cardiovascular risk and the development of graft related complications. A custom-made spring casing was applied to a Dacron graft segment under physiological pressure conditions within a five-element biventricular mock circulation loop, to investigate experimentally a concept to improve the compliance of a conventional aortic prosthesis by changing the transverse graft cross-section. Two different prosthesis locations, proximal and distal of compliant silicone tubing were used to study uniaxial graft compression with an elastic device. To characterise the devices’ performance by means of pulse pressure (PP), diastolic pressure (Pdia) and pulse wave velocity(PWV), fluid pressures and flow were recorded.In a proximal graft setting (ascending aorta repair) elastic uniaxial compression with a custom-made spring casing (2 cm width) could significantly reduce PP by 10–14% (p < .001) and slowed PWV from 6.7 to 5.2 m/s (22%, p = .002). Applied to a graft in a distal position, the spring casing demonstrated less impact on PP (2–10%), but significantly reduced PWV in this mock aorta segment from 13.7 to 5.5 m/s (60%, p = .004). In conclusion, a newly conceptualised spring casing applied to the external wall of synthetic aortic grafts can reduce PP and slow PWV. By restoring elastic aortic recoil in stiff textile aortic prostheses, the presented concept is a potential solution to improve long-term aortic prosthesis related complications.

The results of surgical decompression in the treatment of foot drop due to peroneal nerve entrapment after bariatric surgery.

The loss of the fat pad surrounding the fibular head after rapid and excessive weight loss after bariatric surgery can lead to foot drop symptoms due to peroneal nerve entrapment (PNE). Conservative and surgical approaches have been described for the treatment of this condition, but there is some controversy over the effectiveness of the treatment modalities. We aimed to investigate the causes and frequency of foot drop due to PNE after bariatric surgery and to investigate the effects of peroneal nerve decompression (PND) as a surgical treatment for PNE. Single center, university surgical department. We retrospectively evaluated a series of 2607 patients in terms of neurologic complications after bariatric surgery. Patients' age, sex, co-morbid diseases, vitamin and electrolyte levels, body mass index and postoperative excess weight loss, affected limb, duration of symptoms, and muscle strength scores (according to the Medical Research Council scale) were recorded. A total of 14 (.5%) patients had foot drop symptoms due to PNE. Of these patients, 9 underwent PND. The mean excess weight loss of PND patients at postoperative months 6 and 12 were 68.8 ± 13.5 and 100.9 ± 10.8, respectively. Foot drop symptoms became evident 5 to 11 months after bariatric surgery, affecting only a unilateral lower extremity in all patients. In laboratory analysis, there were no signs of nutritional and vitamin deficiency or insufficiency in any of the PND cases. Muscular strength was Medical Research Council grade 0 in all patients. The median duration of symptoms was 9 days, and the median complete recovery time was 40 days after PND. Patients who had a duration of symptoms for a maximum of 12 days were completely healed 30 days after PND. PND should be the first-choice treatment procedure for acute foot drop due to PNE afterbariatric surgery.

Vestibular stimulation by 2G hypergravity modifies resynchronization in temperature rhythm in rats

Input from the light/dark (LD) cycle constitutes the primary synchronizing stimulus for the suprachiasmatic nucleus (SCN) circadian clock. However, the SCN can also be synchronized by non-photic inputs. Here, we hypothesized that the vestibular system, which detects head motion and orientation relative to gravity, may provide sensory inputs to synchronize circadian rhythmicity. We investigated the resynchronization of core temperature (Tc) circadian rhythm to a six-hour phase advance of the LD cycle (LD + 6) using hypergravity (2 G) as a vestibular stimulation in control and bilateral vestibular loss (BVL) rats. Three conditions were tested: an LD + 6 exposure alone, a series of seven 2 G pulses without LD + 6, and a series of seven one-hour 2 G pulses (once a day) following LD + 6. First, following LD + 6, sham rats exposed to 2 G pulses resynchronized earlier than BVL rats (p = 0.01), and earlier than sham rats exposed to LD + 6 alone (p = 0.002). Each 2 G pulse caused an acute drop of Tc in sham rats (−2.8 ± 0.3 °C; p < 0.001), while BVL rats remained unaffected. This confirms that the vestibular system influences chronobiological regulation and supports the hypothesis that vestibular input, like physical activity, should be considered as a potent time cue for biological rhythm synchronization, acting in synergy with the visual system.

P0117DOSE ESCALATING TOXICOLOGY STUDY OF ELP-VEGF, A NOVEL BIOLOGIC FOR RENAL THERAPEUTIC ANGIOGENESIS

Abstract Background and Aims Chronic renal disease, irrespective of the etiology, is hallmarked by renal microvascular rarefaction. This rarefaction is associated with a reduced bioavailability of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF). Recently, we developed a therapeutic intervention for ischemic renal conditions using therapeutic angiogenesis – supplementing renal VEGF levels. This was achieved by administration of a biopolymer-stabilized form of VEGF using a fusion protein between human VEGF-A121 and an elastin-like polypeptide carrier protein (ELP-VEGF). ELP-VEGF induced microvascular remodeling and increased microvascular density when administered intra-renally in swine models of unilateral renovascular disease (RVD) and chronic kidney disease (CKD), which was associated with improved renal function, reduced renal inflammation, and reduced renal fibrosis. Also, ELP-VEGF targeted the kidney when administered systemically and induced similar beneficial effects on renal function and renal vascular density. The therapeutic dose of ELP-VEGF in the swine models was 0.1 mg/kg when administered intra-renally and 1.0 mg/kg when administered intravenously. The aims of the present study were to determine the maximum tolerated dose of ELP-VEGF and assess its dose-related toxicity. We hypothesize that ELP-VEGF will not exhibit toxicity at therapeutic doses. Method A dose escalating toxicology experiment was performed in Sprague Dawley. Female rats were instrumented with either carotid catheters or carotid artery telemeters for blood pressure monitoring. After a recovery period, a baseline 24-hour urine sample was collected, and baseline glomerular filtration rate (GFR) was measured by monitoring FITC-sinistrin clearance via transdermal fluorescence. A single injection of saline control or ELP-VEGF (0.1, 1, 10, 100, or 200 mg/kg) was administered, and blood pressure was monitored by telemetry or by direct carotid arterial pressure measurements. Body weights were monitored daily throughout the study, and 24-hour urine collections and GFR measurements were repeated 7 and 14 days after protein injection. On day 14 after injection, blood was collected, one kidney was collected and fixed for histological examination, and the second kidney was perfused with Microfil vascular contrast agent for quantification of renal vascular density by micro-CT. Results ELP-VEGF caused no significant changes in body weight at any dose. At the highest doses there was an acute drop in blood pressure (20 – 30 mm Hg at 100 and 200 mg/kg dose, respectively) for approximately twenty minutes post-injection which then normalized. GFR was unchanged by ELP-VEGF at doses up to 100 mg/kg. However, GFR was significantly increased 14 days after treatment with 200 mg/kg ELP-VEGF (1.5 +/- 0.3 versus 2.7 +/- 0.3 mL/min/100 g body weight, p=0.0021). Plasma toxicology revealed no changes in markers of liver or kidney toxicity (AST, ALT, BUN, creatinine, LDH, bilirubin) at any dose or time point. Renal vascular density was unaffected by ELP-VEGF at doses up to 10 mg/kg. However, at 200 mg/kg ELP-VEGF, renal vascular density was significantly decreased for small (0 – 100 micron, p=0.0007) and intermediate (100 – 200 micron, p=0.028) sized vessels Conclusion ELP-VEGF has a proven therapeutic potential for treatment of RVD and CKD at therapeutic doses ranging from 0.1 – 1.0 mg/kg in swine models. Dose escalating toxicity assessment in rats found no effect of ELP-VEGF on body weight, blood pressure, plasma markers of liver and renal toxicity, GFR, or renal vascular density at these therapeutic doses. ELP-VEGF doses of 100 – 200 mg/kg caused transient hypotension immediately after the injection and were associated with increased GFR and loss of renal vascular density, possibly indicating renal damage at ultra-high doses. We conclude that the therapeutic window for ELP-VEGF is 100 – 1,000 times the effective therapeutic dose.

MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe

IntroductionImmune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients.Patients and MethodsWe retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembrolizumab). Symptoms, pituitary hormone assessment, pituitary imaging and patient survival were assessed.ResultsOf 189 patients, 23 patients (12.2%, 13 male; age 59.2±11.8 years) presented with hypophysitis, two having received ipilimumab monotherapy. The median onset was at 17.3 weeks (range: 6.7-160 weeks) after treatment start, occurring in 57% after the fourth infusion (n=13). Five patients developed late-onset IH (range: 30.1-160 weeks) whilst on treatment with PD-1 inhibitors. Three of the patients developing hypophysitis (13%) received only a single ipilimumab infusion. Additional irAEs were diagnosed in 16 patients (70%) with IH, including six cases of destructive thyroiditis and one of autoimmune diabetes.The main presenting symptom of IH was lethargy (n=18, 78%) followed by headache (n=8, 35%). Corticotroph deficiency with cortisol levels <83 nmol/l (<3μg/dL) at presentation were observed in all patients. At diagnosis, a drop in cortisol level of >70% over a median time of 22 days (range: 3-39 days) was evident in 87% patients. A fall in fT4 level of at least 20% from baseline was observed in ten patients (59%, 10/17 – after excluding patients with thyroiditis) at a median of 4 weeks (range: 0-8 weeks) prior to the diagnosis of IH. Gonadotroph deficiency was detected in three male patients.At the end of follow-up (median 14.3 months, range: 1-61.5 months after IH diagnosis), corticotroph deficiency was persistent in all patients; seven of ten patients recovered thyrotroph function and gonadotroph deficit resolved in one patient. Three patients with hypophysitis died within the first year of immunotherapy.ConclusionThe incidence of IH was 12.2%, predominantly occurring after the fourth infusion. IH is characterised by acute severe drop in cortisol levels to less than 3μg/dL. A falling fT4 may herald development of ACTH deficiency.