International comparisons of laboratory values from the 4CE collaborative to predict COVID-19 mortality.

Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 (68.6% male), 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach.

International Comparisons of Harmonized Laboratory Value Trajectories to Predict Severe COVID-19: Leveraging the 4CE Collaborative Across 342 Hospitals and 6 Countries: A Retrospective Cohort Study.

Objectives: To perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions. Design: Retrospective cohort study. Setting: The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe. Participants: Patients hospitalized with COVID-19, admitted before or after PCR-confirmed result for SARS-CoV-2. Primary and secondary outcome measures: Patients were categorized as "ever-severe" or "never-severe" using the validated 4CE severity criteria. Eighteen laboratory tests associated with poor COVID-19-related outcomes were evaluated for predictive accuracy by area under the curve (AUC), compared between the severity categories. Subgroup analysis was performed to validate a subset of laboratory values as predictive of severity against a published algorithm. A subset of laboratory values (CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin) was compared between North American and European sites for severity prediction. Results: Of 36,447 patients with COVID-19, 19,953 (43.7%) were categorized as ever-severe. Most patients (78.7%) were 50 years of age or older and male (60.5%). Longitudinal trajectories of CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin showed association with disease severity. Significant differences of laboratory values at admission were found between the two groups. With the exception of D-dimer, predictive discrimination of laboratory values did not improve after admission. Sub-group analysis using age, D-dimer, CRP, and lymphocyte count as predictive of severity at admission showed similar discrimination to a published algorithm (AUC=0.88 and 0.91, respectively). Both models deteriorated in predictive accuracy as the disease progressed. On average, no difference in severity prediction was found between North American and European sites. Conclusions: Laboratory test values at admission can be used to predict severity in patients with COVID-19. Prediction models show consistency across international sites highlighting the potential generalizability of these models.

Morphological analysis of ischemia-reperfusion injury in a cold ischemia model of jejunal free flap for hypopharyngeal reconstruction.

BACKGROUND: Jejunal free flap (JFF) reconstruction is a popular treatment option for advanced hypopharyngeal cancer. Several factors including ischemia-reperfusion injury (IRI) can cause mucosal damage and progressive flap necrosis. We investigated the development and time-related progression of morphological and cellular changes in patients with JFF reconstruction including cold preservation of the graft. METHODS: Eleven patients were enrolled. Biopsies were taken during surgery from normally perfused tissue, before loop isolation (T0), at the end of back-table surgery (T1), immediately before reperfusion (T2), 15' after reperfusion (T3), and at the end of the digestive anastomoses (T4) and from the external monitor daily from the 1st to the 5th postoperative day (M1-M5). Histomorphological and immunohistochemical parameters in the intraoperative and postoperative samples were evaluated and compared. RESULTS: Delayed flap necrosis was observed in 2 patients. The cold ischemia phase did not negatively affect mucosal regeneration after reperfusion; morphological and cellular damage parameters returned to normal by the end of surgery or along the early postoperative period. Significant enterocyte replication activity was observed at the end of revascularization, which continued in the postoperative phase, leading to recovery of the epithelial morphological integrity and disappearance of apoptotic cells. An inflammatory infiltrate persisted in the M samples, and in a significant proportion of samples, mucosal fibrosis developed by the end of the postoperative observation. CONCLUSION: Cold perfusion and preservation of the JFF can effectively limit the negative effects of IRI and to prevent short- and medium-term complications that can compromise the final outcome.

Preoperative Oral Carbohydrate Load Versus Placebo in Major Elective Abdominal Surgery (PROCY): A Randomized, Placebo-controlled, Multicenter, Phase III Trial.

OBJECTIVE: To explore whether preoperative oral carbohydrate (CHO) loading could achieve a reduction in the occurrence of postoperative infections. BACKGROUND: Hyperglycemia may increase the risk of infection. Preoperative CHO loading can achieve postoperative glycemic control. METHODS: This was a randomized, controlled, multicenter, open-label trial. Nondiabetic adult patients who were candidates for elective major abdominal operation were randomized (1:1) to a CHO (preoperative oral intake of 800 mL of water containing 100 g of CHO) or placebo group (intake of 800 mL of water). The blood glucose level was measured every 4 hours for 4 days. Insulin was administered when the blood glucose level was >180 mg/dL. The primary endpoint was the occurrence of postoperative infection. The secondary endpoint was the number of patients needing insulin. RESULTS: From January 2011 through December 2015, 880 patients were randomly allocated to the CHO (n = 438) or placebo (n = 442) group. From each group, 331 patients were available for the analysis. Postoperative infection occurred in 16.3% (54/331) of CHO group patients and 16.0% (53/331) of placebo group patients (relative risk 1.019, 95% confidence interval 0.720-1.442, P = 1.00). Insulin was needed in 8 (2.4%) CHO group patients and 53 (16.0%) placebo group patients (relative risk 0.15, 95% confidence interval 0.07-0.31, P < 0.001). CONCLUSIONS: Oral preoperative CHO load is effective for avoiding a blood glucose level >180 mg/dL, but without affecting the risk of postoperative infectious complication.

Influence of Surgical Technique, Performance Status, and Peritonitis Exposure on Surgical Site Infection in Acute Complicated Diverticulitis: A Matched Case-Control Study.

BACKGROUND: Acute generalized peritonitis secondary to complicated diverticulitis is a life-threatening condition; the standard treatment is surgery. Despite advances in peri-operative care, this condition is accompanied by a high peri-operative complication rate (22%-25%). No definitive evidence is available to recommend a preferred surgical technique in patients with Hinchey stage III/IV disease. METHODS: A matched case-control study enrolling patients from four surgical units at Italian university hospital was planned to assess the most appropriate surgical treatment on the basis of patient performance status and peritonitis exposure, with the aim of minimizing the surgical site infection (SSI). A series of 1,175 patients undergoing surgery for Hinchey III/IV peritonitis in 2003-2013 were analyzed. Cases (n=145) were selected from among those patients who developed an SSI. THE CASE: control ratio was 1:3. Cases and control groups were matched by age, gender, body mass index, and Hinchey grade. We considered three surgical techniques: T1=Hartman's procedure; T2=sigmoid resection, anastomosis, and ileostomy; and T3=sigmoid resection and anastomosis. Six scoring systems were analyzed to assess performance status; subsequently, patients were divided into low, mild, and high risk (LR, MR, HR) according to the system producing the highest area under the curve. We classified peritonitis exposition as P1=<12 h; P2=12-24 h; P3=>24 h. Univariable and multivariable analyses were performed. RESULTS: The Apgar scoring system defined the risk groups according to performance status. Lowest SSI risk was expected when applying T3 in P1 (OR=0.22), P2 (OR=0.5) for LR and in P1 (OR=0.63) for MR; T2 in P2 (OR=0.5) in LR and in P1 (OR=0.61) in MR; T1 in P3 (OR=0.56) in LR; in P2 (OR=0.63) and P3 (OR=0.54) in MR patients, and in each P subgroup (OR=0.93;0.97;1.01) in HR. CONCLUSIONS: Pre-operative assessment based on Apgar scoring system integrated with peritonitis exposure in complicated diverticulitis may offer a ready-to-use tool for reducing SSI-related complications and applying appropriate treatment, reducing the need for disabling ostomy.

Peritonitis secondary to spontaneous perforation of a primary gastrointestinal stromal tumour of the small intestine: A case report and a literature review.

INTRODUCTION: A few cases of acute abdomen caused by perforation of small-intestinal gastrointestinal stromal tumours (GISTs) have been reported in the literature. PRESENTATION OF CASE: Together with a review of the published cases, here we report a case of an elderly patient with peritonitis due to spontaneous perforation of a GIST of the jejunum. An 82-year-old man was admitted to the emergency unit of our hospital with fever and severe abdominal pain. An abdominal enhanced computed tomography scan detected a 6cm solid mass in the left upper quadrant adherent to a jejunal loop and surrounded by free fluid and free air. Due to the radiological features of the mass, the diagnosis of a perforation of a GIST arising from the jejunum wall was suspected. The patient underwent emergency laparotomy. Intraoperative findings confirmed diffuse peritonitis secondary to jejunal tumour perforation. A segmental resection of the jejunum containing the mass was performed followed by a mechanical end-to-side anastomosis. The histopathologic examination of the mass confirmed the diagnosis of a perforated GIST of the small intestine (high-risk category). The post-operative course was uneventful and the patient was treated with adjuvant imatinib therapy. DISCUSSION: Twenty-one other cases of spontaneous perforation of small intestine GISTs are reported in the literature and are summarized in the present review. CONCLUSION: The described case is the tip of the iceberg and spontaneous rupture or perforation of GISTs are a far more frequent first presentation of this rare tumour.

The challenge of extraabdominal desmoid tumour management in patients with Gardner's syndrome: radiofrequency ablation, a promising option.

Desmoid tumours are benign, myofibroblastic stromal neoplasms common in Gardner's syndrome, which is a subtype of familial adenomatous polyposis characterized by colonic polyps, osteomas, thyroid cancer, epidermoid cysts, fibromas and sebaceous cysts. The primary treatment is surgery, followed by adjuvant radiotherapy, but the local recurrence rate is high, and wide resection can result in debilitating loss of function. We report the case of a 39-year-old man with Gardner's syndrome who had already undergone a total prophylactic colectomy. He developed desmoid tumours localized in the mesenteric root, abdominal wall and dorsal region, which were treated from 2003 through 2013 with several surgical procedures and percutaneous radiofrequency ablation. In 2008 and 2013, RFA was applied under ultrasonographic guidance to two desmoid tumours localized in the dorsal thoracic wall. The outcomes were low-grade pain and one case of superficial skin necrosis, but so far there has been no recurrence of desmoid tumours in these locations. Surgical resection remains the first-line therapy for patients with desmoid tumours, but wide resection may lead to a poor quality of life. Radiofrequency ablation is less invasive and expensive and is a possible therapeutic option for desmoid tumours in patients with Gardner's syndrome.

Successful non-operative management of spontaneous type II gallbladder perforation in a patient with Alzheimer's disease.

A 77-year-old man with Alzheimer's disease was admitted to a rural hospital in June 2012 and an acute cholecistytis was first diagnosed. Surgery was not considered as a possible option due to the critical condition of the patient and his severe comorbidities. After 2 days of broad-spectrum antibiotics, the patient worsened and developed severe sepsis. A gallbladder perforation with intrahepatic abscess formation was diagnosed on ultrasonography (US) and abdominal CT scan. The patient underwent percutaneous US-guided gallbladder drainage with resolution of the sepsis and rapid clinical improvement. After 1 month, the drainage was removed and the patient was discharged. He survived in good condition for 18 months and he passed away from pneumonitis in December 2013. This case shows that in a case of acute cholecystitis with gallbladder perforation, percutaneous gallbladder drainage can be a lifesaving procedure in elderly patients with severe comorbidities (including Alzheimer's disease) who are not candidates for elective surgery.

Ventriculoperitoneal shunt and the need to remove a gallbladder: Time to definitely overcome the feeling that laparoscopic surgery is contraindicated.

Since Baskin et al. reported the first documented case of failure of a laparoscopically-induced ventriculoperitoneal shunt (VP) in 1998, the cerebrospinal fluid shunt has been generally considered a relative contraindication to laparoscopy. Although the literature is limited there is a small body of evidence indicating that it is safe to perform laparoscopic surgery on these patients with routine anaesthetic monitoring. In this study we report the case of a laparoscopic cholecystectomy in the presence of a ventriculoperitoneal shunt. A review of the literature suggests that laparoscopic cholecystectomy can be safely performed in patients with a ventriculoperitoneal shunt. The only related contraindication should be if a catheter has recently been placed.

Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection.

UNLABELLED: Hepatitis C virus (HCV) persistence in the host results from inefficiencies of innate and adaptive immune responses. Most studies addressing the role of innate immunity concentrated on peripheral blood (PB) natural killer (NK) cells, whereas only limited information is available on intrahepatic (IH) NK cells. We therefore examined phenotypic and functional features of IH and PB NK cells in paired liver biopsy and venous blood samples from 70 patients with chronic HCV infection and 26 control persons subjected to cholecystectomy for gallstones as controls. Ex vivo isolated IH NK cells from HCV-infected patients displayed unique phenotypic features, including increased expression of NKp46-activating receptor in the face of reduced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cluster of differentiation (CD) 107a expression, which resulted in impaired degranulation compared with controls. To gain insights into the effect of HCV on NK cells, we exposed peripheral blood mononuclear cells (PBMCs) from patients and healthy donors to cell-culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL, and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. Exposure of PBMCs to HCVcc significantly boosted NK degranulation, pERK1/2, and TRAIL expression in healthy donors, but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-alpha. Purified NK cells showed a minimal, though significant, increase in degranulation and TRAIL expression, both in patients and controls, after exposure to HCVcc. CONCLUSIONS: These findings indicate dysfunctional IH NK cell cytotoxicity associated with TRAIL down-regulation in chronic HCV infection, which may contribute to virus persistence. PB NK cell impairment upon exposure to HCVcc suggests the existence of an accessory cell-dependent NK cell lytic defect in chronic HCV infection predominantly involving the TRAIL pathway.

Skin and kidney histological changes in graft-versus-host disease (GVHD) after kidney transplantation.

Kidney transplantation (Ktx) is generally performed during end stage renal disease due to a loss of the kidneys' ability to filter wastes from the circulatory system. Acute graft-versus-host disease (GVHD) after Ktx is a life-threatening complication that progresses to organ failure, systemic complications, and death. The current study evaluated the significance of histologic findings of GVHD as obtained from skin biopsies following Ktx in swine. A swine model of Ktx with tacrolimus-based immunosuppression was used to assess possible correlations between acute-graft-cellular rejection and skin histological findings for prediction of GVHD. Animals were divided into a Ktx treatment group or a control group with no Ktx and skin and kidney biopsies were histologically assessed at postoperative days 0, 15, 30, 45 and 60. Skin samples were analyzed and classified from grade 1 to 4 of skin GVHD and the major histopathological changes of kidney acute cellular rejection were described using Banff's score system. We observed a significant linear correlation between the histological grading values of skin biopsy changes and the histological grading values of kidney biopsies (Kendall's tau_b=0.993) in the Ktx experimental group. No histological changes were observed in controls. Our findings demonstrate the diagnostic value of staging skin GVHD after Ktx and suggest it's future utility for monitoring long term Ktx-induced changes.

Unique vascular tumor primary arising in the liver and exhibiting histopathological features consistent with so-called polymorphous hemangioendothelioma.

Reported herein is an unusual vascular tumor primary arising in the liver and exhibiting unique histopathological features. A 47-year-old woman underwent left hepatectomy because of a large hepatic mass. On histology the tumor had a composite pattern, consisting of angiomatous, retiform and solid areas, formed by oval to cuboidal to spindle cells, that expressed only endothelial markers (CD31 and factor VIII-related antigen). These findings led to the diagnosis of a low-grade vascular neoplasm with morphological features consistent with so-called polymorphous hemangioendothelioma. The tumor was completely resected. At 24 month follow up the patient was alive, without evidence of disease. Polymorphous hemangioendothelioma is a rare vascular neoplasm, with borderline malignant potential, which usually occurs in lymph nodes and, rarely, at extranodal sites. Its classification as an entity has been questioned recently. The unusual morphological features of the present case, which do not fit neatly with any other recognized hemangioendothelioma subtype, indicate that the family of vascular tumors is broader than currently accepted. In addition the present case widens the spectrum of primary vascular tumors arising in the liver.

A novel technique for rat liver transplantation using Quick Linker system: a preliminary result.

BACKGROUND: The clinical success of liver transplantation is founded upon years of experimental research. Since Kamada and colleagues developed the "two-cuff" technique, the rat has become the best model for extensive investigations. Although the Kamada technique is technically complex and not easy to master, it is still the mainstay of orthotopic liver transplantation in rodents. We have developed a modified three-cuff version of this technique that facilitates anastomosis and markedly reduces warm ischemia time. MATERIALS AND METHODS: The new technique involves a set of five microinstruments (the Quick-Linker system) designed and manufactured by our group. It was tested in male Lewis rats (group 1, donors n = 10, recipients n = 10). The graft was explanted as usual and standard cuffs were attached to the portal vein and the supra- and infrahepatic vena cavae. Corresponding vessels in the recipient were isolated, and Quicker-Linker holding rings were attached to each. The vessels were then clamped and the native organ removed. Once the graft was positioned in the recipient's abdomen, the holding rings attached to the recipient vessels and the cuffs applied to graft vessels were automatically aligned and joined with the aid of a special alignment tool. RESULTS: Warm ischemia times were always inferior to 6 minutes. Survival at postoperative day 10 was 80%. Liver function was well preserved in all of the surviving rats. CONCLUSIONS: The Quick-Linker technique significantly shortens warm ischemia time and allows rapid anastomosis that is relatively independent of operator skill. It can be considered a reliable option for microsurgeons looking for quick results and high success rates.

Reconstruction of the hypopharynx after free jejunum flap failure: is a second free jejunum transfer feasible?

Reconstruction after circumferential pharyngolaryngectomy is a challenging problem. Reconstruction methods should ensure an appropriate mucosa lining of the digestive tract, preferably already tubulized, and peristalsis. Despite the high reported success rates, the jejunum flap is still occasionally lost due to thrombosis of the pedicle and/or fistula formation. Five cases of circumferential pharyngolaryngectomy in which failure of the jejunum loop was managed with a second free or pedicle flap are presented. A second free jejunum was reliable in selected patients, depending on time of detection of flap necrosis, on bacterial control of the wound and on the vascular or general conditions. For this reason, careful monitoring of the flap and clinical signs of necrosis in the first 5 post-operative days is crucial to prevent the formation of fistulas and infection and to increase the possibility of using this kind of salvage surgery. Pedicle flaps should be used only in the event of severe complications because of their high risk of post-operative salivary fistulas.

Atypical reconstructions with free jejunum flap after circumferential pharyngolaryngectomy.

The ideal reconstruction after circumferential pharyngolaryngectomy is represented by the jejunum free flap, but when the resection extends to the oro- or nasopharynx, the discrepancy between the lumen of the flap and the pharyngeal defect represents a disadvantage. Two reconstructions to overcome this problem are presented: end-to-side anastomosis between the pharynx and the antimesenteric side of the jejunum; and a jejunal "reservoir." The type 1 technique is quicker to perform, but can result in dysphagia; the type 2 technique is more complex, but usually no dysphagia is observed. In our opinion, no ideal surgical technique exists to equal the jejunum loop. The choice must be tailored to the single patient, bearing in mind the degree of the defect, the stage of the tumor removed, the general conditions of the patient, and personal surgical experience. Whatever procedure is chosen, it should provide the best possible quality of life for the expected life span of the patient.

Uretero-neocystostomy in a swine model of kidney transplantation: a new technique.

BACKGROUND: Swine constitute a well-characterized large animal model for kidney transplantation (K-Tx) although the uretero-neocystostomy represents a crucial aspect because of the very small caliber of the ureter and the mucosal susceptibility to the edema during surgical management. Besides infectious and occlusive complications limited the employment of a stent and the peculiar anatomy of the species prevents its removal without an operative approach. These features find an equivalent in children (<4 year old) candidates to urological surgery. We investigated an uretero-neocystostomy technique to be applied in case of narrow caliber without using endoluminal device. MATERIALS AND METHODS: Thirty unrelated large-white piglets, divided into three equal groups (n = 10) on the basis of the uretero-neocystostomy technique used, underwent K-Tx while receiving a double immunosuppressive regimen. We developed a direct uretero-neocystostomy (Direct) technique and compare this with the gold standard Lich-Gregoir (LG) and Leadbetter-Politano (LP) techniques. RESULTS: After 60 days, the ureteral complication rates were: group 1 (LG): 60% (6/10, three early and three late strictures); group 2 (LP): 40% (4/10, two leakages, one early stricture, and one isolated ureteral dilatation); group 3 (Direct): 10% (1/10, one isolated ureteral dilatation). No bacterial cystitis or nephritis occurred; retrograde cystograms were negative for refluxes in every group. CONCLUSIONS: The comparison between the old techniques and the new one (LG and LP versus Direct) showed a lower incidence of complications among the animals that underwent the new direct technique (P < 0.05). This technique could be applied clinically in selected pediatric cases either of transplantation or reflux.

The influence of surgery, immunosuppressive drugs, and rejection, on graft function after small bowel transplantation: a large-animal study.

In this study we assessed functional changes (motility and absorption) of intestinal allografts in a large-animal model of orthotopic small bowel transplantation in swine. Studies were performed on non-rejecting animals in the early and late stages after transplantation and after induction of different grades of acute rejection. Immunosuppression consisted of oral FK506 and mycophenolate mofetil. In each study group we regulated drug administration, in terms of dosage and timing, in order to induce different grades of acute rejection or to prevent it. Migrating myoelectrical complexes were recorded in fasting animals so that motility could be assessed. Mucosal biopsy of the allograft and D-xylose absorption tests were performed on the same day as the motility study. In the early stages following intestinal transplantation, we observed in non-rejecting animals a slightly increased graft motility and a marked carbohydrate malabsorption. Recovery of the carbohydrate absorption capacity occurs within 2 months, but the persistence of diarrhea leads to partial malabsorption and to a lack of normal weight gain. Motility reduction correlates with the grade of acute rejection and becomes significant at a later stage, when rejection is severe. Allograft carbohydrate absorption, on the contrary, is markedly reduced in all rejecting pigs, irrespective of the grade of rejection. In summary, the early functional impairment of non-rejecting animals has multifactorial causes due to surgery and immunosuppression (drug toxicity), and its occurrence suggests the need for specific guidelines for clinical early postoperative enteral feeding. The functional studies adopted here are helpful in defining the grade of functional impairment with or without acute rejection; however, they are not useful for early detection of ongoing acute rejection of the small bowel graft.