Pig kidney xenotransplantation: Progress toward clinical trials

Pig organ xenotransplantation offers a solution to the shortage of deceased human organs for transplantation. The pathobiological response to a pig xenograft is complex, involving antibody, complement, coagulation, inflammatory, and cellular responses. To overcome these barriers, genetic manipulation of the organ‐source pigs has largely been directed to two major aims—(a) deletion of expression of the known carbohydrate xenoantigens against which humans have natural (preformed) antibodies, and (b) transgenic expression of human protective proteins, for example, complement‐ and coagulation‐regulatory proteins. Conventional (FDA‐approved) immunosuppressive therapy is unsuccessful in preventing an adaptive immune response to pig cells, but blockade of the CD40:CD154 costimulation pathway is successful. Survival of genetically engineered pig kidneys in immunosuppressed nonhuman primates can now be measured in months. Non‐immunological aspects, for example, pig renal function, a hypovolemia syndrome, and rapid growth of the pig kidney after transplantation, are briefly discussed. We suggest that patients on the wait‐list for a deceased human kidney graft who are unlikely to receive one due to long waiting times are those for whom kidney xenotransplantation might first be considered. The potential risk of infection, public attitudes to xenotransplantation, and ethical, regulatory, and financial aspects are briefly addressed.     

Molded,Gamma-radiated,Argon-processed Polyethylene Components of Rotating Hinge Knee Megaprostheses Have a Lower Failure Hazard and Revision Rates Than Air-sterilized,Machined, Ram-extruded Bar Stock Components

BackgroundMegaprostheses are commonly used for reconstruction after distal femoral resection in orthopaedic oncology. The polyethylene bearings in these reconstructions experience wear and wear-related complications that may result in revision surgery. Improved manufacturing and processing of polyethylene has increased the durability of components commonly used for routine arthroplasty. Alterations in the manufacture of polyethylene is expected to reduce the revision risk of oncologic megaprostheses, resulting in fewer revision procedures, but this has not been proven.Questions/purposesIs there a difference in the hazard of polyethylene wear or breakage leading to prosthetic revision between differences in polyethylene manufacture and processing based on a competing risk analysis?MethodsThis was a single-center, observational, retrospective comparative study of 224 patients who had distal femur megaprostheses with identical rotating hinge articulations and knee kinematics after oncologic surgery from 1993 to 2015. No differences in surgical indications, joint articular components and kinematics, age, sex, diagnosis, BMI, use of chemotherapy, or tumor stage were seen with the patient numbers available. Prosthetic survivorship free from prosthetic revision surgery because of polyethylene wear-related revisions, defined as breakage, increased excursion on varus-valgus stress, or new locking or giving way was compared between two groups of patients: group 1 polyethylene (P1) (66 patients) who had air-sterilized machined ram-extruded bar stock or group 2 polyethylene (P2) (158 patients) molded gamma-radiated argon-processed polyethylene components. The mean follow-up duration for the P1 group (89 ± 55 months) was not different from that of patients with P2 polyethylene (79 ± 63 months; p = 0.24) including 27% (18 of 66) of patients in the P1 group and 25% (40 of 158) of patients in the P2 group followed for more than 10 years. More patients in the P2 group were lost to follow-up (9.2%, 16 of 174) than in the P1 group (5.7%, 4 of 70) but this was not statistically different (chi square; p = 0.37). The hazard of revision because of polyethylene wear or breakage was calculated with a competing risk analysis using the Fine‐Gray subdistribution hazard model.ResultsThe P1 implants had a higher hazard ratio for revision caused by polyethylene damage at 120 months than did the P2 polyethylene implants (P1 HR 0.24 [95% CI 0.13 to 0.36] versus HR 0.07 [95% CI 0.03 to 0.12]), which represents an estimated absolute risk reduction of 17% (95% CI 6.15 to 27.9).ConclusionPolyethylene damage can result in megaprosthetic revisions in patients undergoing oncologic procedures. The hazard of polyethylene failure resulting in revision surgery was lower in patients who received recent polyethylene than in patients with polyethylene produced by previous methods, enhancing the durability of distal femoral megaprosthetic reconstructions. Despite improvements in polyethylene manufacture and clinical results, revision solely because of polyethylene damage still occurs in 7% of patients by the 10-year timepoint; thus, more improvement is needed. Patients who receive these implants should be monitored for signs and symptoms of polyethylene damage.Level of EvidenceLevel III, therapeutic study.     

Reassessing the role of surgery in the elderly or chronically sick with proximal extrahepatic cholangiocarcinoma

BackgroundMost data on postoperative outcomes among patients with proximal extrahepatic cholangiocarcinoma are reported by single institutions. The purpose of this study was to analyze postoperative outcomes stratified by age and comorbidities.MethodsPatients with proximal extrahepatic cholangiocarcinoma who underwent a resection were identified in the National Cancer Database. Pathologic, postoperative, and survival outcomes were compared based on age and Charlson-Deyo comorbidity index.ResultsAmong the 1,579 patients, the average age was 66 years, and 9.4% of patients were older than 80 years. Most patients had a Charlson-Deyo score of 0 (72.4%), with the minority having scores of 1 (20.5%) or ≥2 (7.1%). Patients ≥80 years had a higher 90-day mortality rate compared with patients 65 to 79 and <65 years (21.3% vs 12.0% vs 7.4%, P < .001). Patients with a Charlson-Deyo score ≥2 had longer duration of stay, greater likelihood of requiring an unplanned readmission, and a higher 90-day mortality rate compared with patients with a lower comorbidity index. Median survival of patients <65, 65 to 79, and ≥80 years was 31, 24, and 17 months, respectively. A similar trend was seen with increasing Charlson-Deyo score (0: 27 months, 1: 25 months, ≥2: 20 months). On multivariable analysis, age ≥80 years (hazard ratio = 1.52, P = .01) and Charlson-Deyo score ≥2 (hazard ratio = 1.45, P = .01) were associated with poor survival.ConclusionIn patients with proximal extrahepatic cholangiocarcinoma, age ≥80 years and greater comorbidity index are associated with increased risk of 90-day mortality and poor overall survival. This suggests that resections in high-risk patient populations should be approached with caution.     

T cell antigenicity and immunogenicity of allogeneic exosomes

Extracellular vesicles, including exosomes, are regularly released by allogeneic cells after transplantation. Recipient antigen-presenting cells (APCs) capture these vesicles and subsequently display donor MHC molecules on their surface. Recent evidence suggests that activation of alloreactive T cells by the so-called cross-dressed APCs plays an important role in initiating the alloresponse associated with allograft rejection. On the other hand, whether allogeneic exosomes can bind to T cells on their own and activate them remains unclear. In this study, we showed that allogeneic exosomes can bind to T cells but do not stimulate them in vitro unless they are cultured with APCs. On the other hand, allogeneic exosomes activate T cells in vivo and sensitize mice to alloantigens but only when delivered in an inflammatory environment.     

Bladder preservation versus radical cystectomy in transitional cell carcinoma and squamous cell carcinoma muscle invasive bladder cancer

Background:Randomizing patients to bladder preservation or radical cystectomy (RC) for the treatment of bladder cancer has not been practical, due to patient and physician preferences. Therefore, continually comparing the 2 treatment modalities is needed, in order to make the proper choice for each patient.Patients and methods:The records of T1–4N0M0 bladder cancer patients, who presented to the South Egypt Cancer Institute between 2007 and 2017 and were treated by either bladder preservation or RC were reviewed.Results:Out of the 166 included patients, 81 (48.8%) patients were treated by bladder preservation and 85 (51.2%) patients had RC. For the patients treated by bladder preservation and the patients treated by RC, the 5-year overall survival (OS) was 56% and 60% (p = 0.67), the 5-year local recurrence-free survival was 69% and 73% (p = 0.69), and the 5-year disease-free survival was 45% and 53% (p = 0.16), respectively. After propensity matching analysis, the mean 5-year OS was 58% for the bladder preservation patients and 61% for the RC patients (p = 0.51). It is notable that among the bladder preservation group, 8 patients (10%) had squamous cell carcinoma (SCC) pathology and refused RC. Their OS was 56% compared to 53% for the SCC patients treated by RC (p = 0.6).Conclusion:Bladder preservation is a safe alternative to cystectomy in transitional cell carcinoma stages T1–4aN0M0, and its use in SCC bladder cancer should be further studied, as it could be feasible to spare them from initial cystectomy.     

Efficiency of Soil Amendments for Copper Removal and Brassica Juncea (L.) Growth in Wastewater Irrigated Agricultural Soil

Wastewater irrigation is becoming a massive challenge for sustainable agriculture. Particularly, copper (Cu) presence in wastewater poses a great threat to the food chain quality. Thus, scientists need to address this issue by using chemical and organic soil amendments to restore the soil ecosystem. Therefore, this study aims to examine the efficacy of sulphur, compost, acidified animal manure and sesame straw biochar for Cu immobilization, adsorption and Brassica growth in wastewater irrigated soil. The current findings presented that all the soil amendments prominently improved brassica yield and significantly minimized the Cu uptake by Brassica shoots and roots in sesame straw biochar (SB) (64.2% and 50.2%), compost (CP) (48% and 32.5%), acidified manure (AM) (37% and 23.2%) and Sulphur (SP) (16% and 3.1%) respectively relative to untreated soil. In addition, Cu bioavailability was reduced by 51%, 34%, 16.6%, and 7.4% when SB, CP, AM, and SP were incorporated in wastewater irrigated polluted soil. The Cu adsorption isotherm results also revealed that SB treated soil has great potential to increase Cu adsorption capacity by 223 mg g^??1 over control 89 mg g^??1. Among all the treatments, SB and CP were considered suitable candidates for the restoration of Cu polluted alkaline nature soil.

     

Female Genital Cutting and Deinfibulation: Applying the Theory of Planned Behavior to Research and Practice

At least 200 million girls and women across the world have experienced female genital cutting (FGC). International migration has grown substantially in recent decades, leading to a need for health care providers in regions of the world that do not practice FGC to become knowledgeable and skilled in their care of women who have undergone the procedure. There are four commonly recognized types of FGC (Types I, II, III, and IV). To adhere to recommendations advanced by the World Health Organization (WHO) and numerous professional organizations, providers should discuss and offer deinfibulation to female patients who have undergone infibulation (Type III FGC), particularly before intercourse and childbirth. Infibulation involves narrowing the vaginal orifice through cutting and appositioning the labia minora and/or labia majora, and creating a covering seal over the vagina with appositioned tissue. The WHO has published a handbook for health care providers that includes guidance in counseling patients about deinfibulation and performing the procedure. Providers may benefit from additional guidance in how to discuss FGC and deinfibulation in a manner that is sensitive to each patient’s culture, community, and values. Little research is available to describe decision-making about deinfibulation among women. This article introduces a theoretically informed conceptual model to guide future research and clinical conversations about FGC and deinfibulation with women who have undergone FGC, as well as their partners and families. This conceptual model, based on the Theory of Planned Behavior, may facilitate conversations that lead to shared decision-making between providers and patients.

     

Engaging religious leaders to promote safe burial practices during the 2014–2016 Ebola virus disease outbreak,Sierra Leone

ObjectiveTo quantify the potential impact of engaging religious leaders in promoting safe burial practices during the 2014–2016 Ebola virus disease outbreak in Sierra Leone.MethodsWe analysed population-based household survey data from 3540 respondents collected around the peak of the outbreak in Sierra Leone, December 2014. Respondents were asked if in the past month they had heard an imam or pastor say that people should not touch or wash a dead body. We used multilevel logistic regression modelling to examine if exposure to religious leaders’ messages was associated with protective burial intentions if a family member died at home and other Ebola protective behaviours.FindingsOf the respondents, 3148 (89%) had been exposed to faith-based messages from religious leaders on safe Ebola burials and 369 (10%) were unexposed. Exposure to religious leaders’ messages was associated with a nearly twofold increase in the intention to accept safe alternatives to traditional burials and the intention to wait ≥ 2 days for burial teams (adjusted odds ratio, aOR: 1.69; 95% confidence interval, CI: 1.23–2.31 and aOR: 1.84; 95% CI: 1.38–2.44, respectively). Exposure to messages from religious leaders was also associated with avoidance of traditional burials and of contact with suspected Ebola patients (aOR: 1.46; 95% CI: 1.14–1.89 and aOR: 1.65; 95% CI: 1.27–2.13, respectively).ConclusionPublic health messages promoted by religious leaders may have influenced safe burial behaviours during the Ebola outbreak in Sierra Leone. Engagement of religious leaders in risk communication should be prioritized during health emergencies in similar settings.