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Background: With the advancement of next-generation sequencing, clinicians are now able to detect ultra-rare mutations that are barely encountered by the majority of physicians. Ultra-rare and rare diseases cumulatively acquire a prevalence equivalent to type 2 diabetes with 80% being genetic in origin and more prevalent among high consanguinity communities including Saudi Arabia. The challenge of these diseases is the ability to predict their prevalence and define clear phenotypic features., Methods: This is a non-interventional retrospective multicenter study. We included pediatric patients with a pathogenic variant designated as ultra-rare according to the National Institute for Clinical Excellence's criteria. Demographic, clinical, laboratory, and radiological data of all patients were collected and analyzed using multinomial regression models., Results: We included 30 patients. Their mean age of diagnosis was 16.77 months (range 3-96 months) and their current age was 8.83 years (range = 2-15 years). Eleven patients were females and 19 were males. The majority were of Arab ethnicity (96.77%). Twelve patients were West-Saudis and 8 patients were South-Saudis. SCN1A mutation was reported among 19 patients. Other mutations included SZT2, ROGDI, PRF1, ATP1A3, and SHANK3. The heterozygous mutation was reported among 67.86%. Twenty-nine patients experienced seizures with GTC being the most frequently reported semiology. The mean response to ASMs was 45.50% (range 0-100%)., Conclusion: The results suggest that ultra-rare diseases must be viewed as a distinct category from rare diseases with potential demographic and clinical hallmarks. Additional objective and descriptive criteria to detect such cases are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Muthaffar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Malaria, a major global health concern, requires effective diagnostic tools for patient care, disease control, and elimination. The pathway from concept to the adoption of diagnostic products is complex, involving multiple steps and stakeholders. To map this process, our study introduces a malaria-specific diagnostic pathway, synthesising existing frameworks with expert insights. Comprising six major stages and 31 related activities, the pathway retains the core stages from existing frameworks and integrates essential malaria diagnostic activities, such as WHO prequalification processes, global stakeholder involvement, and broader health systems considerations. To understand the scope and availability of evidence guiding the activities along this pathway, we conducted an online survey with 113 participants from various stages of the malaria diagnostic pathway. The survey assessed perceptions on four critical attributes of evidence: clear requirements, alignment with user needs, accuracy and reliability, and public and free availability. It also explored the types of evidence used and the challenges and potential solutions related to evidence generation and use. Respondents reported using a broad range of formal and informal data sources. Findings indicated differing levels of agreement on the attributes across pathway stages, with notable challenges in the Approvals and Manufacturing stage and consistent concerns regarding the public availability of data/evidence. The study offers valuable insights for optimising evidence generation and utilisation across the malaria diagnostic pathway. It highlights the need for enhanced stakeholder collaboration, improved data availability, and increased funding to support effective evidence generation, sharing, and use. We propose actionable solutions, including the use of public data repositories, progressive data sharing policies, open-access publishing, capacity-building initiatives, stakeholder engagement forums, and innovative funding solutions. The developed framework and study insights have broader applications, offering a model adaptable for other diseases, particularly for neglected tropical diseases, which face similar diagnostic challenges., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Simmons et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Rapid Diagnostic Tests (RDTs) have become the cornerstone for the management of malaria in many endemic settings, but their use is constrained for several reasons: (i) persistent malaria antigen (histidine-rich protein 2; HRP2) leading to false positive test results; (ii) hrp2 deletions leading to false negative PfHRP2 results; and (iii) limited sensitivity with a detection threshold of around 100 parasites/μl blood (pLDH- and HRP2-based) leading to false negative tests. Microscopy is still the gold standard for malaria diagnosis, and allows for species determination and quantitation, but requires trained microscopists, maintained microscopes and has detection limit issues. Consequently, there is a pressing need to develop and evaluate more sensitive and accurate diagnostic tests. To address this need we have developed a direct on blood mini PCR-NALFIA test that combines the benefits of molecular biology with low infrastructural requirements and extensive training., Methods: This is a Phase 3 diagnostic evaluation in 5 African countries. Study sites (Sudan, Ethiopia, Burkina, Kenya and Namibia) were selected to ensure wide geographical coverage of Africa and to address various malaria epidemiological contexts ranging from high transmission to near elimination settings with different clinical scenarios and diagnostic challenges. Study participants will be enrolled at the study health facilities after obtaining written informed consent. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practices in place at the selected sites and to quantitative PCR as the reference test., Discussion: This phase 3 study is designed to validate the clinical performance and feasibility of implementing a new diagnostic tool for the detection of malaria in real clinical settings. If successful, the proposed technology will improve the diagnosis of malaria. Enrolment started in November 2022 (Kenya) with assessment of long term outcome to be completed by 2023 at all recruitment sites., Trial Registration: Pan African Clinical Trial Registry (www.pactr.org) PACTR202202766889963 on 01/02/2022 and ISCRTN (www.isrctn.com/) ISRCTN13334317 on 22/02/2022., Competing Interests: The authors have declared that no competing interests exist.

<b>Background and Objective:</b> Chronic Myelogenous Leukaemia (CML) is a clonal myeloproliferative tumor distinguished by the existence of the Philadelphia chromosome (Ph) resulting from the t (9, 22) (q34, q11) translocation. The BCR-ABL gene and the fusion protein, which has constitutive tyrosine kinase activity, are the outcome of this translocation. The purpose of this study is to determine the prevalence of the BCR-ABL T315I mutation in CML patients. <b>Materials and Methods:</b> Descriptive cross-sectional studies were conducted on 100 CML patients who visited RICK hospital between May, 2018-2019. T315I mutation analysis was done on all patients utilizing (RT/PCR) followed by RLFP to quantify the prevalence of Kinase Domain Mutation analysis (KDM) in CML. <b>Results:</b> The link between haematological parameters and ABL mutations in CML patients was shown to be a substantial positive correlation between T315I and haematological parameters (HB and WBC) but no correlation with PLT. The data revealed that 43 out of 99 CML had T315I, with highly prevalent gene express (43.4%) detected in all CML 56.6%. The correlation of T315I mutations with clinical status was positive significant (p-000). <b>Conclusion:</b> It can be concluded that T315I mutation became significantly higher in CML patients than in other groups of mutations. The detection of ABL kinase domain mutations may be a proper and valuable strategy for optimizing therapeutic methods and preventing treatment delays.

Due to the proliferation of Internet of Things (IoT) and application/user demands that challenge communication and computation, edge computing has emerged as the paradigm to bring computing resources closer to users. In this paper, we present Whispering , an analytical model for the migration of services (service offloading) from the cloud to the edge, in order to minimize the completion time of computational tasks offloaded by user devices and improve the utilization of resources. We also empirically investigate the impact of reusing the results of previously executed tasks for the execution of newly received tasks (computation reuse) and propose an adaptive task offloading scheme between edge and cloud. Our evaluation results show that Whispering achieves up to 35% and 97% (when coupled with computation reuse) lower task completion times than cases where tasks are executed exclusively at the edge or the cloud.

In recent years, edge computing has emerged as an effective solution to extend cloud computing and satisfy the demand of applications for low latency. However, with today's explosion of innovative applications ( e.g., augmented reality, natural language processing, virtual reality), processing services for mobile and smart devices have become computation-intensive, consisting of multiple interconnected computations. This coupled with the need for delay-sensitivity and high quality of service put massive pressure on edge servers. Meanwhile, tasks invoking these services may involve similar inputs that could lead to the same output. In this paper, we present CoxNet , an efficient computation reuse architecture for edge computing. CoxNet enables edge servers to reuse previous computations while scheduling dependent incoming computations. We provide an analytical model for computation reuse joined with dependent task offloading and design a novel computing offloading scheduling scheme. We also evaluate the efficiency and effectiveness of CoxNet via synthetic and real-world datasets. Our results show that CoxNet is able to reduce the task execution time up to 66% based on a synthetic dataset and up to 50% based on a real-world dataset.

In recent years, there has been a massive increase in the amount of Internet of Things (IoT) devices as well as the data generated by such devices. The participating devices in IoT networks can be problematic due to their resource-constrained nature, and integrating security on these devices is often overlooked. This has resulted in attackers having an increased incentive to target IoT devices. As the number of attacks possible on a network increases, it becomes more difficult for traditional intrusion detection systems (IDS) to cope with these attacks efficiently. In this paper, we highlight several machine learning (ML) methods such as k-nearest neighbour (KNN), support vector machine (SVM), decision tree (DT), naive Bayes (NB), random forest (RF), artificial neural network (ANN), and logistic regression (LR) that can be used in IDS. In this work, ML algorithms are compared for both binary and multi-class classification on Bot-IoT dataset. Based on several parameters such as accuracy, precision, recall, F1 score, and log loss, we experimentally compared the aforementioned ML algorithms. In the case of HTTP distributed denial-of-service (DDoS) attack, the accuracy of RF is 99%. Furthermore, other simulation results-based precision, recall, F1 score, and log loss metric reveal that RF outperforms on all types of attacks in binary classification. However, in multi-class classification, KNN outperforms other ML algorithms with an accuracy of 99%, which is 4% higher than RF.

Information-Centric Networking (ICN) has emerged as a paradigm to cope with the lack of built-in security primitives and efficient mechanisms for content distribution of today's Internet. However, deploying ICN in a wireless environment poses a different set of challenges compared to a wired environment, especially when it comes to security. In this paper, we present the security issues that may arise and the attacks that may occur from different points of view when ICN is deployed in wireless environments. The discussed attacks may target both applications and the ICN network itself by exploiting elements of the ICN architecture, such as content names and in-network content caches. Furthermore, we discuss potential solutions to the presented issues and countermeasures to the presented attacks. Finally, we identify future research opportunities and directions.

Delay-sensitive applications have been driving the move away from cloud computing, which cannot meet their low-latency requirements. Edge computing and programmable switches have been among the first steps toward pushing computation closer to end-users in order to reduce cost, latency, and overall resource utilization. This article presents the "compute-less" paradigm, which builds on top of the well known edge computing paradigm through a set of communication and computation optimization mechanisms (e.g.,, in-network computing, task clustering and aggregation, computation reuse). The main objective of the compute-less paradigm is to reduce the migration of computation and the usage of network and computing resources, while maintaining high Quality of Experience for end-users. We discuss the new perspectives, challenges, limitations, and opportunities of this compute-less paradigm.

Objectives: We evaluate the crimping strain, sealing stress and contact forces on a Nitinol stent deployed in the aorta during endovascular aortic (or aneurysm) repair (EVAR) procedures. Nitinol shape memory effect (SME) is used. We also study the fluid-structure interaction (FSI) of the blood flow on the stented aorta., Methods: We employ Solidworks to generate a closed-cell honeycomb stent structure used to treat abdominal aortic aneurysm (AAA). We use the commercial Abaqus/Simulia finite element (FEM) simulation package to study the displacements and stresses experienced by the stent during the crimping phase and deployment into the aortic segment. The Nitinol stent is covered with Dacron, a popular graft material. We implement our own user-material (UMAT) subroutines to model the shape memory effect (SME) of Nitinol. The effect of the stent geometry is analyzed. We use the FSI analysis in Abaqus/Simulia to understand the effect of hemodynamic loading on the stent., Results: Results indicate that the crimping strain increases as the stent strut spacing increases. This is also the case for the radius of curvature. Maximum strains developed on the stent during crimping are in the order of 10%. Stresses exerted by the stent needed to completely seal the aorta are found to be below the yield stress values of Nitinol (700 MPa). Wall shear stresses (WSS) on the stented aorta are close to WSS obtained on the aorta alone., Conclusion: Using Nitinol's thermo-reactivity property as opposed to its superelasticity causes the stent-graft to deploy more gently., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The effect of hemodynamic load on various stent-graft designs used for endovascular aneurysm repair (EVAR) in cardiovascular treatments is studied using a numerical fluid-structure interaction (FSI) analysis that couples computational fluid dynamics (CFD) and finite element analysis (FEA). Radial displacements, mechanical stresses, wall shear stress and wall compliance quantities are evaluated for four stent materials and one graft material. The strut thickness is varied from 0.3 mm to 1 mm. The materials are assumed linearly elastic and isotropic while blood is assumed as a Newtonian and incompressible medium with a pulsatile and turbulent flow profile. Time dependent pressure conditions are assumed at the inlet and outlet. Results are benchmarked against a study taken from the literature and indicate that the stent material and the strut thickness greatly influence the mechanical behavior of the structure. This computational study will serve as an additional tool to vascular surgeons when assessing the choice of material and design for stent-graft recipients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aortic dissection (AD) is a serious medical condition characterized by a tear in the intima, the inner layer of the aortic walls. In such occurrence, blood is being diverted to the media (middle) layer and may result in patient death if not quickly attended. In the case where the diseased portion of the aorta needs to be replaced, one common surgical technique is to use a graft made of Dacron, a synthetic fabric. We investigate the response of a composite human aortic segment-Dacron graft structure subjected to blood flow using the three-dimensional fluid-structure-interaction (FSI) capability in Abaqus. We obtain stress and strain profiles in each of the three layers of the aortic walls as well as in the Dacron graft. Results are compared when elastic and hyperelastic models are used and when isotropy vs. anisotropy is assumed. The more complex case (hyperelastic-anisotropy) is represented by the Holzapfel-Gasser-Ogden (HGO) model which also accounts for the orientation of the fibers present in the tissues. The fluid flow is taken as Newtonian, incompressible, pulsatile and turbulent. The simulation show that for all the cases, the von Mises stress distribution at aorta-Dacron interface is well below the ultimate strength of the aorta. No significant change in radial displacement at the interface of the two materials due to blood flow is observed. Computation cost is also addressed and results show that the hyperelastic-anisotropic model takes about three times longer to run than the elastic isotropic case. Trade-off between accuracy and computational cost has to be weighted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Polymorphic genetic markers and especially microsatellite analysis can be used to investigate multiple aspects of the biology of Plasmodium species. In the current study, we characterized 7 polymorphic microsatellites in a total of 281 Plasmodium vivax isolates to determine the genetic diversity and population structure of P. vivax populations from Sudan, Madagascar, French Guiana, and Armenia. All four parasite populations were highly polymorphic with 3-32 alleles per locus. Mean genetic diversity values was 0.83, 0.79, 0.78 and 0.67 for Madagascar, French Guiana, Sudan, and Armenia, respectively. Significant genetic differentiation between all four populations was observed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Acute portomesenteric vein thrombosis is an uncommon but serious condition with potential sequelae, such as small-bowel gangrene and end-stage hepatic failure. It is known to be caused by various pro-thrombotic states, including hyperhomocysteinemia. We describe what is, to the best of our knowledge, the first reported case of concomitant thrombosis of portal, superior mesenteric and splenic veins due to hyperhomocysteinemia secondary to pernicious anemia and no other risk factors., Case Presentation: A 60-year-old Indian man presented with epigastric pain, diarrhea and vomiting. An abdominal imaging scan showed that he had concomitant pernicious anemia and concomitant portal, superior mesenteric and splenic vein thrombosis. A work-up for the patient's hypercoagulable state revealed hyperhomocysteinemia, an undetectable vitamin B12 level and pernicious anemia with no other thrombophilic state. He developed infarction with perforation of the small bowel and subsequent septic shock with multi-organ dysfunction syndrome, and he ultimately died due to progressive hepatic failure., Conclusion: This report demonstrates that pernicious anemia, on its own, can lead to hyperhomocysteinemia significant enough to lead to lethal multiple splanchnic vein thrombosis. Our case also underscores the need to (1) consider portomesenteric thrombosis in the differential diagnosis of epigastric abdominal pain, (2) perform a complete thrombotic work-up to elucidate metabolic abnormalities that could be contributing to a pro-thrombotic state and (3) initiate aggressive measures, including early consideration of multi-visceral transplantation, in order to avoid decompensation and a significant adverse outcome.

Noninvasive tests to differentiate the basis for acute dysfunction of the kidney allograft are preferable to invasive allograft biopsies. We measured absolute levels of 26 prespecified mRNAs in urine samples collected from kidney graft recipients at the time of for-cause biopsy for acute allograft dysfunction and investigated whether differential diagnosis of acute graft dysfunction is feasible using urinary cell mRNA profiles. We profiled 52 urine samples from 52 patients with biopsy specimens indicating acute rejection (26 acute T cell-mediated rejection and 26 acute antibody-mediated rejection) and 32 urine samples from 32 patients with acute tubular injury without acute rejection. A stepwise quadratic discriminant analysis of mRNA measures identified a linear combination of mRNAs for CD3ε, CD105, TLR4, CD14, complement factor B, and vimentin that distinguishes acute rejection from acute tubular injury; 10-fold cross-validation of the six-gene signature yielded an estimate of the area under the curve of 0.92 (95% confidence interval, 0.86 to 0.98). In a decision analysis, the six-gene signature yielded the highest net benefit across a range of reasonable threshold probabilities for biopsy. Next, among patients diagnosed with acute rejection, a similar statistical approach identified a linear combination of mRNAs for CD3ε, CD105, CD14, CD46, and 18S rRNA that distinguishes T cell-mediated rejection from antibody-mediated rejection, with a cross-validated estimate of the area under the curve of 0.81 (95% confidence interval, 0.68 to 0.93). Incorporation of these urinary cell mRNA signatures in clinical decisions may reduce the number of biopsies in patients with acute dysfunction of the kidney allograft., (Copyright © 2014 by the American Society of Nephrology.)

To identify and assess the level of knowledge and attitudes of health care professionals (HCP) in Qatar toward organ donation and transplantation, this cross-sectional study was carried out from October 2007 to February 2008 in the Accident and Emergency Departments and Intensive Care Units of the hospitals of the Hamad Medical Corporation (HMC). A representative sample of 585 HCP working in the hospitals of the HMC was approached and 418 staff gave consent to participate in the study (71.5%). 36.8% were physicians, 48.6% nurses and 14.6% Emergency Medical Service (EMS) technicians. Of the surveyed HCP, 40.7% were males and 59.3% were females. Majority of the staff were in the age group of 30-39 years (58.6%). More than half of the physicians (59.7%) and technicians (57.4%) assumed that organs can be bought and sold in the State of Qatar. Most of the physicians (76.6%) and nurses (75.9%) knew that brain-dead persons are eligible for organ donation, whereas only 57.4% of the EMS technicians thought so. Majority of the HCP supported organ donation; physicians (89.0%), nurses (82.3%) and technicians (70.5%). The attitude of the physicians (24.0%) and nurses (20.2%) to donate a kidney to a family member was very poor compared with the attitude of the technicians (44.3%). Although the HCP support organ donation (83%), more than half of the physicians (51.3%), nurses (61.6%) and technicians (54.1%) wanted to be buried with all their organs intact. The findings, although they give cause for hope, suggest that there is much work yet to be done before organ donation and transplantation can become fully accepted by the medical community in Qatar.

Concern has increasingly been expressed about the growing number of reports of medical personnel participating in the transplantation of human organs or tissues taken from the bodies of executed prisoners, handicapped patients, or poor persons who have agreed to part with their organs for commercial purposes. Such behavior has been universally considered as ethically and morally reprehensible, yet in some parts of the world the practice continues to flourish. The concept of justice demands that every person have an equal right to life, and to protect this right, society has an obligation to ensure that every person has equal access to medical care. Regrettably, the Egyptian system does not legally recognize brain death and continues to allow the buying and selling of organs. For more than 30 years in Egypt, the ability to pay has determined who receives an organ and economic need has determined who will be the donor. As transplant professionals, it is important that we advocate on behalf of all patients, potential recipients, and donors and for those who are left out and not likely to receive a donor organ in an economically based system. Current issues associated with this debate are reviewed and recommendations about how to address them in Egypt are discussed.

Objectives: The current shortage of suitable donor organs and clinical urgency can lead to implanting grafts from ABO-mismatched donors. One-year graft survival rates for patients in this scenario have been reported as ranging between 25% and 75% less than those for ABO-identical or ABOcompatible grafts. We review and compare our experiences with transplanting ABO-identical and ABO-compatible mismatched livers., Materials and Methods: Considering orthotopic liver transplantation (OLTx), 520 were performed at our institution between November 1992 and May 2003, 55 of which were ABO-compatible mismatched transplants. We retrospectively reviewed the data and compared patient and graft survival rates., Results: Overall 1-month and 1-, 5-, and 10-year patient survival rates among identical (group 1) and mismatched (group 2) groups were 97% and 91%, 90%, and 88.5%, and 79%, and 74%, 66%, and 65%, respectively. No significant difference existed between the 2 groups (P>.05). Similarly, 1-month, and 1-, 5-, and 10-year graft survival rates among groups 1 and 2 were 96% and 87%, 89% and 83%, 78% and 71% and 66% and 59%, respectively; these were not significant either (P>.05). All of the patients in the mismatched group had a high status according to the United Network for Organ Sharing (UNOS). Only 1 person received an incompatible mismatched graft (B to A), which subsequently developed primary nonfunction., Conclusions: ABO-compatible mismatch OLTx is unavoidable given the current state of organ shortage. Our results suggest that this type of OLTx can be performed with minimal risk among patients who require urgent transplantation and have high rankings according to the UNOS and the model for end-stage liver disease (MELD) system.

Transplant assessment of pedophiles and stalkers presents a challenge for clinicians and requires the ability to separate the science from the hysteria. Although rarely seen in organ transplant clinics, the presence of psychosexual disorders can result in both criminal charges and harsh societal reactions. Clinicians must be able to assess and make informed recommendations about the suitability of the candidate and any potential risks for staff, other patients, and society at large. Six patients (5 pedophiles and 1 stalker) were assessed at our major regional multiorgan transplant program; each patient presented with unique and challenging assessment, treatment, and selection issues for the transplant team. The objectives of this article are to raise awareness of the issues associated with pedophiles and stalkers, and to provide the basis for better-informed discussions based on one program's struggles with its candidate selection and follow-up.

Aim: To evaluate the impact of hepatitis B virus (HBV) on US health care system, we reviewed the Organ Procurement and Transplantation (OPTN, formerly UNOS) HBV database., Method: We reviewed records of liver transplantations (LTx) performed in the United States listed for the diagnoses of HBV between 1993 and mid-October 2004. Both acute as well as chronic cases were included. Coinfection with hepatitis C virus was excluded from study. The specific states selected for review were chosen from those areas that are receiving large numbers of new immigrants from high HBV endemic areas (ie, Texas, Pennsylvania, California, New York, and Florida). One-, 3-, and 5-year patient survival rates for both cadaveric and living related donors were analyzed. Survival rates were obtained from OPTN database as Kaplan-Meyer survival test., Results: Between 1993 and mid-October 2004, 53,312 LTx had been performed nationwide. Of these, 2314 (4.34%) were performed for the diagnosis of HBV; 1816 cases (78%) were due to chronic HBV infection (45 of them were living donor LTx) and 498 cases (22%) were due to HBV-induced acute liver failure (seven of them were living donor LTx). Three- and 5-year survival rates of chronic HBV-related LTx patients were better than acute HBV-related and overall LTx patients., Conclusion: HBV is generally considered to have a minor health significance by many community gastroenterologists. With growing immigration from overseas, it may eventually have a higher impact on LTx. Therefore, it is crucial to further educate gastroenterologists and primary care physicians caring for this specific group of patients.

Currently available prognostic tools are inadequate to discern the molecular basis of the heterogenic response in hepatitis C virus (HCV)-infected patients treated with the current standard of therapy. The expression and biological function of immune mediators have been shown to be critical in all phases of the immune response to HCV infection and likely therefore influence host response. Herein, a biometric multiplex serum cytokine assay was utilized to characterize the immunomodulatory effects of host response in 10 HCV patients. Serum levels of 17 cytokines were compared before and after 1 month of treatment and against controls. Overall serum cytokine levels were significantly higher in patients (P < 0.05) than controls. Additionally, viral titers decreased in all patients after 1 month of therapy, as did overall serum cytokine levels in the cohort (P < 0.05). To assess relationships between changes in cytokine levels and changes in viral titer, the cohort was divided into three statistically distinct subgroups based on changes in viral titers. Specific sets of cytokines decreased in each group: decreases in CCL4, interleukin (IL)-2, CXCL8, and IL-1beta correlated with the greatest drops in viral titer, decreases in IL-5, granulocyte colony stimulating factor (G-CSF), and CCL4 correlated with moderate drops in viral titer, and only CCL2 correlated with the lowest drops in viral titer. Interestingly, decreases in CCL4 levels correlated with decreases in viral titers in all patients. CCL4 controls leukocyte influx and thus propagates inflammation. In conclusion, these data raise the possibility that characteristic changes in host response modulate the therapeutic response, demonstrating the prognostic power of serum cytokine profiling in chronic HCV.

Disseminated cryptococcal infection often occurs in the setting of an immuncompromised patient. We report a case of disseminated Cryptococcus neoformans in a cirrhotic patient, referred for Orthotopic Liver Transplantation evaluation due to acute hepatic decompensation.

Surgical intervention among cirrhotic individuals carries a high risk for peri-and postoperative complications. We review the literature regarding the frequency and consequences of pulmonary complications in cases of cirrhosis. The experience with hepato-pulmonary syndrome and porto-pulmonary hypertension in liver transplant recipients is also presented.

Spontaneous rupture of the liver during pregnancy associated with preeclampsia is an uncommon and frequently fatal complication. A case of a 61-year-old non-pregnant female is described here who took estrogen replacement for 16 years and presented with spontaneous rupture of the right lobe of the liver with hemoperitoneum. The underlying cause of the rupture was not clear.

Background/aims: Our aim was to assess the efficacy of the liver dialysis unit (LDU) in the treatment of patients with acetaminophen-induced fulminant hepatic failure., Methods: Seventeen patients with acetaminophen-induced fulminant hepatic failure between January 1996 and December 2001 were retrospectively studied. A liver dialysis unit became available in our Unit in July 2000, and as of December 2001, four of these 17 patients had undergone treatment with liver dialysis., Results: Mean age was 29 years (range: 14-47) and 76% were women. Four of 17 patients underwent a total of 12 (range: 1-4) LDU sessions. Ammonia level tended to be lower following the LDU and all four patients recovered without a need for orthotopic liver transplantation (OLT). Prior to July 2000, eight of 13 patients survived with supportive therapy, three expired and two underwent OLT. No major bleeding episodes were observed during the LDU course. A significant difference was found between the three cases who died and the cases that survived with respect to the grade of encephalopathy (p<0.001). There was significant difference in the admission serum creatinine among survivors (p<0.05)., Conclusion: In conclusion, the Liver Dialysis Unit treatment appeared to benefit patients with acetaminophen-induced fulminant hepatic failure by reverse of the encephalopathy and spontaneous recovery of the damaged liver in selected patients.

Epithelioid hemangioendothelioma and angiosarcoma of the liver are rare neoplasms of vascular origin. They can present with nonspecific symptoms such as malaise and weight loss, as well as with liver-related symptoms such as abdominal pain, tender hepatomegaly and jaundice. Portal hypertension and rarely liver failure can occur. We hereby report two cases of fulminant hepatic failure that were eventually diagnosed with epithelioid hemangioendothelioma and angiosarcoma of the liver.

As a potent immunosuppressive agent, Tacrolimus is widely used in organ transplantation. Although complications due to chronic Tacrolimus use are rather well recognized, little is known about acute overdose and its treatment. Phenytoin, an anti-convulsant agent, can induce the Cytochrome P450 enzyme in the liver, which metabolizes Tacrolimus. Therefore, it can be considered as a potential treatment option for acute Tacrolimus toxicity. We hereby report two cases of acute Tacrolimus overdose after Orthotopic Liver Transplantation and the treatment with Phenytoin. Probable mechanisms of metabolism and interactions of these two drugs are discussed and the literature is reviewed.

Incidence of esophagitis among cirrhotics is similar to the general population; post-OLT course of this entity is not well known. The aim of this study was to assess the incidence of non-infectious esophagitis among OLT recipients. Patients with chronic liver disease who have been considered for transplantation have undergone esophagogastroduodenoscopy (EGD) for examination of the upper gastrointestinal tract. Following transplantation, some of these patients have required EGD for various reasons. EGD findings following transplantation were compared to that individual's pre-transplant findings. There were 173 patients and the median age was 49. The incidence of pre-transplant esophagitis was 7.5%, which increased to 22% after OLT (p > 0.0001). None had specific etiology. Etiology of this increase needs to be further investigated and the effects of immunosuppressive drugs on lower esophageal sprinter and gastric motility should be clarified. Use of acid suppressing drugs during the early post-transplant period should be considered.

Psychosocial assessment of transplant candidates is a challenging task. Securing adequate information is made more difficult when patients present with fulminant hepatic failure. When the patient cannot be interviewed and the family is reluctant to provide vital information, a comprehensive pretransplant psychosocial evaluation is virtually impossible. However, even the most difficult cases have the potential for a positive result when a good psychosocial profile of the patient is obtained after transplantation, a team treatment plan is developed and carried out which addresses current and anticipated problems, and the patient obtains mental health treatment.

The question of patient nonadherence has always been an important factor in determining candidate suitability for organ transplantation. Data that explore the association of financial problems and posttransplant medication nonadherence are limited. Findings suggest that medication nonadherence was more likely to occur when recipients did not have insurance coverage and had to rely on Medicaid or indigent drug programs. Our center developed a formalized program within the outpatient pharmacy, including a full-time medication counselor who helped recipients secure resources to pay for pre- and posttransplant medications. To determine whether the availability of posttransplant medications could reduce medication nonadherence, we conducted a survey with 50 consecutive liver transplant recipients in the outpatient clinic. Nonadherence rates were significantly reduced from 25% to 10% (P < .01) compared with recipients who had been transplanted before the development of our drug program. These results suggest that optimum medication adherence can be obtained when recipients are provided guidance in securing their necessary medications without financial restriction.

In situ split of the liver was performed in a heart-beating cadaveric organ donor for the first time in the U.S.A. by two geographically distant transplant centers. The procedure, initiated by a transplant team in Oklahoma City, was a joint project of the transplant teams from Oklahoma City and New York City. The in situ split resulted in two liver grafts. A left graft (left lateral segment) which was transplanted into a 7-year-old pediatric recipient in Oklahoma City and a right graft (right lobe and segment IV) which was transplanted into a 52-year-old adult recipient in New York City. Initial graft function was excellent in the two patients. The adult recipient was discharged home 10 days after the transplant and is doing well. The pediatric recipient died two and a half months later from multi-system organ failure. The recently introduced in situ split technique provides two excellent liver grafts from one donor and enhances sharing of liver grafts between transplant centers.

Living related liver transplantation (LRLT) presents several advantages as compared to cadaveric liver transplantation, and it has become an increasingly popular option for children with end-stage liver diseases. Since 1995, five LRLT procedures have been performed at the authors' facility. Recipients were three boys and two girls, whose mean age was 2.6 years. Recipients' primary diagnoses were primary hyperoxaluria (PH) (n = 3), Alagille's syndrome (n = 1), and Byler's disease (n = 1). Left lateral segments harvested from their parents were used as the liver grafts on all patients. The donors included three mothers and two fathers, with a mean age of 29 years. Tacrolimus with steroids was used as immunosuppressive therapy. In all cases (mean follow-up time of 11 months), graft function was excellent and four children are doing very well. One boy died of post-transplant lymphoproliferative disorder (PTLD) 7 months after LRLT. All donors are doing very well with no postoperative complications. The authors believe that LRLT is a safe procedure for both the donor and the recipient, and provides, in children, an excellent alternative to cadaveric liver transplantation.

Ornithine transcarbamylase (OTC) deficiency is an X chromosome-linked disorder causing hyperammonemic encephalopathy with a very poor prognosis. We describe here two patients with OTC deficiency, one a late on-set female patient (case 1) and the other a neonatal-onset male patient (case 2), who were successfully treated with orthotopic liver transplantation (OLTx). The OTC activity in the excised liver was 10% and 0% of control, respectively. Hyperammonemic encephalopathy was controlled with medical therapy in case 1 until the of 5 years, but the complicated course in case 2 in which hyperammonemia required peritoneal dialysis and hemodialysis in the neonatal period necessitated OLTx with a reduced-size liver at the age of 80 days. Both patients had restoration of serum ammonia level to normal in 2 and 3 days after liver replacement, and both patients have normal neurological and developmental status after 2 and 0.5 years of postoperative follow-up. These cases illustrate not only the metabolic cure of this disorder, but also the need to preserve neurological integrity by aggressive medical management of the hyperammonemia preoperatively and early surgical intervention when indicated, even if this is required very early in life.

A retrospective survey of nosocomial rotavirus infection in pediatric liver transplant recipients was performed. Immunocompetent children with nosocomial infections served as controls. Co-pathogens were not identified. A total of 12 transplant cases and 12 controls could be evaluated. New onset vomiting occurred in 7/8 cases and 6/11 controls lasting an average of 2.8 days per case and 0.8 days per control (p < .05). New onset fever (>38 degrees C) was noted in 8/12 cases and 9/12 controls. New onset occult blood was noted in 7/11 cases and 1/12 controls (p < .01). A concomitant rise and fall in transaminases was noted in 5/12 transplant recipients. Eleven of the 12 were maintained on constant or increased immunosuppression doses without the development of fulminant disease. The presence of increased days of vomiting and occult blood in stools suggests that rotavirus causes a more invasive process in the intestinal mucosa of transplant recipients compared to immunocompetent children. However, the process remains self-limited despite the use of potent immunosuppressives.

Intestinal failure is a concept developed to define the situation wherein either severe primary gastrointestinal disease or a surgically induced short bowel syndrome exists and prevents an adequate oral intake of nutrients such that parenteral nutrition is required. Typically, because of disease associated problems, total parenteral nutrition is required in most cases of intestinal failure. The major cause of intestinal failure in both adults and children is surgical resection resulting in a short bowel syndrome. The clinical signs and symptoms of a short bowel syndrome include any combination of the following: intractable diarrhea, steatorrhea, failure to thrive, acidosis, dehydration, trace element deficiency syndromes, hypoproteinemia, hypovitaminosis, and anemia. It is often difficult to predict at the time of a bowel resection whether or not a short bowel syndrome will occur postoperatively. This is the case because any of a number of confounding problems such as (a) difficulty in precisely estimating the length of the remaining small bowel at the time of the operation, (b) the presence of disease in the residual small bowel that can produce further shortening or impair residual intestinal function, and (c) the presence or absence of the ileal cecal valve, which can be critical in determining the adaptability of the residual bowel.

Although liver biopsy is a very useful procedure used frequently in the diagnosis and management of liver dysfunction occurring after orthotopic liver transplantation, complications can occur with its use. An unusual complication of arterioportal fistula is reported here. Based upon this small series of an unusual event and the knowledge that the posttransplant liver may be more hypervascular than prior to OLTx and that it is uniquely susceptible to hepatic infarction and abscess formation, any attempt at fistula closure should be considered carefully prior to initiating the therapy (15). Unless a serious complication occurs [such as a transient biliary obstruction due to hemobilia as occurred in case 2, portal hypertension as also occurred in case 2, or systemic sepsis or other symptoms develop related directly to the fistula], simple observation may be the best choice of action. Should therapy be required, hepatic arterial embolization should be reserved for adults with intrahepatic fistulas. Primary surgical closure of intrahepatic fistula should be reserved for cases of extrahepatic fistula.

Under FK506-based immunosuppression, 13 abdominal multivisceral transplantations were performed in 6 children and 7 adults. Of the 13 recipients, 7 (53.8%) are alive and well with functioning grafts after 9 to 31 months. Six recipients died: three from PTLD, one from rejection, one from sepsis, and one from respiratory failure. In addition to rejection, postoperative complications occurring in more than isolated cases included PTLD (n = 6), abdominal abscess formation (n = 5), pancreatitis (n = 3), and ampullary dysfunction (n = 2). In addition, infection by enteric microorganisms was common during the early postoperative period. Currently, all 7 survivors are on an oral diet and have normal liver function. Two recipients (one insulin-dependent) require antidiabetes treatment, in one case following distal pancreatectomy and in the other after two episodes of pancreatic rejection. Thus, abdominal multivisceral transplantation is a difficult but feasible operation that demands complex and prolonged posttransplantation management. It is not yet ready for application and awaits a better strategy of immune modulation.

Background: Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinoma, some lymphomas, and lymphoproliferative disease after organ transplantation. Many lymphoproliferative tumors that occur after transplantation are clonal, a property that classifies them as neoplastic. Clonality can be determined by analysis of the extrachromosomal circular DNA episomes produced by EBV infection., Methods: We describe three young children in whom smooth-muscle tumors developed 18 months to 5 1/2 years after liver transplantation with immunosuppression. We examined the tumors by microscopy and with immunohistochemical studies and molecular genetic analyses of the EBV DNA:, Results: The tumors were composed of spindle cells with smooth-muscle features and resembled those described in patients with the acquired immunodeficiency syndrome. Immunohistochemical analysis was negative for EBV latent membrane protein and EBV receptor (CD21), but positive for EBV nuclear antigen 2. In situ hybridization revealed nuclear EBV sequences, and molecular genetic analysis showed the EBV genome to be clonal in all three patients., Conclusions: Smooth-muscle tumors that developed after organ transplantation contained clonal EBV, suggesting that the virus has a role in the development of these neoplastic lesions.

Background: After the successful evolution of hepatic transplantation during the last decade, small bowel and multivisceral transplantation remains the sole elusive achievement for the next era of transplant surgeons. Until recently, and for the last thirty years, the results of the sporadic attempts of intestinal transplantation worldwide were discouraging because of unsatisfactory graft and patient survival. The experimental and clinical demonstration of the superior therapeutic efficacy of FK 506, a new immunosuppressive drug, ushered in the current era of small bowel and multivisceral transplantation with initial promising results., Study Design: Forty-three consecutive patients with short bowel syndrome, intestinal insufficiency, or malignant tumors with or without associated liver disease, were given intestinal (n = 15), hepatic and intestinal (n = 21), or multivisceral allografts that contained four or more organs (n = 7). Treatment was with FK 506 based immunosuppression. The ascending and right transverse colon were included with the small intestine in 13 of the 43 grafts, almost evenly distributed between the three groups., Results: After six to 39 months, 30 of the 43 patients are alive, 29 bearing grafts. The most rapid convalescence and resumption of diet, as well as the highest three month patient survival (100 percent) and graft survival (88 percent) were with the isolated intestinal procedure. However, this advantage was slowly eroded during the first two postoperative years, in part because the isolated intestine was more prone to rejection. By the end of this time, the best survival rate (86 percent) was with the multivisceral procedure. With all three operations, most of the patients were able to resume diet and discontinue parenteral alimentation, and in the best instances, the quality of life approached normal. However, the surveillance and intensity of care required for these patients for the first year, and in most instances thereafter, was very high, being far more than required for patients having transplants of the liver, kidney or heart., Conclusions: Although intestinal transplantation has gone through the feasibility phase, strategies will be required to increase its practicality. One possibility is to combine intestinal transplantation with contemporaneous autologous bone marrow transplantation.

Nonshivering thermogenesis (NST) is a normal physiological response of the neonate to cold exposure, characterized by increased blood flow to metabolically active brown fat stores. It is standard practice during neonatal surgery to warm the ambient environment in order to avoid consuming vital energy stores. While NST has been well-studied in the neonate, the response during anesthesia and paralysis has not been fully characterized. Rabbit pups (aged 1 to 7 days) were randomized into several groups. The experimental groups consisted of animals mechanically ventilated and administered either metocurine, pancuronium, curare, fentanyl, nitrous oxide (N2O), or halothane. The controls were spontaneously breathing animals. Oxygen consumption (VO2), an index of metabolic activity, was measured at thermoneutrality (39 degrees C) and after cold exposure (25 degrees C). Control and metocurine animals had a significant increase in VO2 in response to cold exposure. The increase in VO2 was not noted in animals that received curare, pancuronium, fentanyl, N2O, or halothane. To test the effect of anesthetic withdrawal during cold exposure on VO2, additional series of animals were studied. One group received continuous halothane throughout the period of cold exposure; the other had cessation of the halothane during cold exposure. Both groups were rewarmed subsequently. The animals that had withdrawal of halothane during cold exposure had a marked and significant increase in VO2 compared with the control group (continuous halothane). VO2 returned to near-baseline levels upon rewarming. The authors conclude that many commonly used anesthetic and paralyzing agents inhibit the thermogenic response to cold exposure. However, cessation of anesthesia (halothane) in a cold environment results in a marked increase in metabolic activity.