Mortality Risk Factors Among Patients With Cirrhosis and a Low Model for End-Stage Liver Disease Sodium Score (≤15): An Analysis of Liver Transplant Allocation Policy Using Aggregated Electronic Health Record Data.

Although the Model for End-Stage Liver Disease sodium (MELD Na) score is now used for liver transplant allocation in the United States, mortality prediction may be underestimated by the score. Using aggregated electronic health record data from 7834 adult patients with cirrhosis, we determined whether the cause of cirrhosis or cirrhosis complications was associated with an increased risk of death among patients with a MELD Na score ≤15 and whether patients with the greatest risk of death could benefit from liver transplantation (LT). Over median follow-up of 2.3 years, 3715 patients had a maximum MELD Na score ≤15. Overall, 3.4% were waitlisted for LT. Severe hypoalbuminemia, hepatorenal syndrome, and hepatic hydrothorax conferred the greatest risk of death independent of MELD Na score with 1-year predicted mortality >14%. Approximately 10% possessed these risk factors. Of these high-risk patients, only 4% were waitlisted for LT, despite no difference in nonliver comorbidities between waitlisted patients and those not listed. In addition, risk factors for death among waitlisted patients were the same as those for patients not waitlisted, although the effect of malnutrition was significantly greater for waitlisted patients (hazard ratio 8.65 [95% CI 2.57-29.11] vs. 1.47 [95% CI 1.08-1.98]). Using the MELD Na score for allocation may continue to limit access to LT.

Psychological Outcomes of Living Liver Donors From a Multicenter Prospective Study: Results From the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2).

Although single-center and cross-sectional studies have suggested a modest impact of liver donation on donor psychological well-being, few studies have assessed these outcomes prospectively among a large cohort. We conducted one of the largest, prospective, multicenter studies of psychological outcomes in living liver donors within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2) consortium. In total, 271 (91%) of 297 eligible donors were interviewed at least once before donation and at 3, 6, 12, and 24 mo after donation using validated measures. We found that living liver donors reported low rates of major depressive (0-3%), alcohol abuse (2-5%), and anxiety syndromes (2-3%) at any given assessment in their first 2 years after donation. Between 4.7% and 9.6% of donors reported impaired mental well-being at various time points. We identified significant predictors for donors' perceptions of being better people and experiencing psychological growth following donation, including age, sex, relationship to recipient, ambivalence and motivation regarding donation, and feeling that donation would make life more worthwhile. Our results highlight the need for close psychosocial monitoring for those donors whose recipients died (n=27); some of those donors experienced guilt and concerns about responsibility. Careful screening and targeted, data-driven follow-up hold promise for optimizing psychological outcomes following this procedure for potentially vulnerable donors.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2).

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

Applying the WHO conceptual framework for the International Classification for Patient Safety to a surgical population.

OBJECTIVE: Efforts to improve patient safety are challenged by the lack of universally agreed upon terms. The International Classification for Patient Safety (ICPS) was developed by the World Health Organization for this purpose. This study aimed to test the applicability of the ICPS to a surgical population. DESIGN: A web-based safety debriefing was sent to clinicians involved in surgical care of abdominal organ transplant patients. A multidisciplinary team of patient safety experts, surgeons and researchers used the data to develop a system of classification based on the ICPS. Disagreements were reconciled via consensus, and a codebook was developed for future use by researchers. RESULTS: A total of 320 debriefing responses were used for the initial review and codebook development. In total, the 320 debriefing responses contained 227 patient safety incidents (range: 0-7 per debriefing) and 156 contributing factors/hazards (0-5 per response). The most common severity classification was 'reportable circumstance,' followed by 'near miss.' The most common incident types were 'resources/organizational management,' followed by 'medical device/equipment.' Several aspects of surgical care were encompassed by more than one classification, including operating room scheduling, delays in care, trainee-related incidents, interruptions and handoffs. CONCLUSIONS: This study demonstrates that a framework for patient safety can be applied to facilitate the organization and analysis of surgical safety data. Several unique aspects of surgical care require consideration, and by using a standardized framework for describing concepts, research findings can be compared and disseminated across surgical specialties. The codebook is intended for use as a framework for other specialties and institutions.

Screening recipients of increased-risk donor organs: a survey of transplant infectious diseases physician practices.

BACKGROUND: In 1994, the Public Health Service published guidelines to minimize the risk of human immunodeficiency virus (HIV) transmission and to monitor recipients following the transplantation of organs from increased-risk donors. A 2007 survey revealed the post-transplant surveillance of recipients of organs from increased-risk donors (ROIRD) is variable. METHODS: An electronic survey was sent to transplant infectious diseases physicians at US solid organ transplant centers. RESULTS: A total of 126 surveys were sent to infectious diseases physicians, and we received 51 (40%) responses. We found that 22% of respondents obtain only verbal, 69% verbal and written, and 8% do not obtain any special consent from ROIRD, despite an Organ Procurement and Transplantation Network policy requiring such consent. Post-solid organ transplantation serologies for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) are performed by 6-8% of respondents in all recipients, by 69% of respondents in ROIRD only, and 25% of respondents do not perform them at all. Post-transplant nucleic acid testing is carried out by 55-64% of respondents in ROIRD, by 0-2% in all recipients, and not performed by 35-43% of respondents. CONCLUSION: Screening RIORD for HIV, HBV, and HCV has increased since 2007, but remains less than optimal and is incomplete when screening for disease transmission at many centers.

Deceased organ donor screening for HIV, hepatitis B, and hepatitis C viruses: a survey of organ procurement organization practices.

Although Organ Procurement and Transplantation Network (OPTN) policy requires that all potential deceased organ donors are screened for human immunodeficiency (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses by serology, no current policy requires the use of nucleic acid testing (NAT) for organ donor screening. An electronic survey was sent to 58 organ procurement organizations (OPO) in the United States to assess current screening practices of potential deceased organ donors. Fifty-seven responses were collected for data analysis; not all respondents answered all questions. All OPOs performed required HIV, HBV and HCV serology screening and 48 (84%) performed confirmatory testing for seropositive donors. Ninety-eight percent, 75% and 97% of OPOs performed prospective HIV, HBV and HCV NAT, respectively. Fifty-two percent and 47% used a transcription-mediated amplification assay for HIV and HCV NAT, respectively. Of the 56 respondents that performed HIV NAT and 55 respondents that performed HCV NAT, 39 tested all donors. Seventeen (32%) OPOs performed confirmatory testing for all HIV-positive NAT results, and 15 (27%) OPOs performed confirmatory testing for all HCV-positive NAT results. Since 2008, the number of OPOs performing NAT has increased and more OPOs are testing all donors.

BK virus replication and nephropathy after alemtuzumab-induced kidney transplantation.

BK virus nephropathy (BKVN) is a recognized cause of graft failure in kidney transplant recipients. There are limited data on the epidemiology of BK virus (BKV) infection after alemtuzumab induction. By clinical protocol, the kidney transplant recipients at our center were screened with BKV plasma PCR monthly for the first 4 months posttransplant then every 2-3 months for 2 years. A single center retrospective cohort study of all kidney transplant recipients from January 2008 to August 2010 was conducted to determine incidence and outcomes of BKV infection. Descriptive statistics and Kaplan-Meier analysis was performed. Of 666 recipients, 250 (37.5%) developed viruria, 80 (12%) developed viremia and 31 (4.7%) developed BKVN at a median of 17, 21 and 30 weeks, respectively. Induction with alemtuzumab did not significantly affect incidence of BKVN. Increased recipient age, African American race, acute graft rejection and CMV infection were significantly associated with the development of BKVN in multivariate analysis. The incidence of BK viruria, viremia and nephropathy was not significantly different among kidney transplant recipients who received alemtuzumab induction compared to patients receiving less potent induction.

Preventable errors in organ transplantation: an emerging patient safety issue?

Several widely publicized errors in transplantation including a death due to ABO incompatibility, two HIV transmissions and two hepatitis C virus (HCV) transmissions have raised concerns about medical errors in organ transplantation. The root cause analysis of each of these events revealed preventable failures in the systems and processes of care as the underlying causes. In each event, no standardized system or redundant process was in place to mitigate the failures that led to the error. Additional system and process vulnerabilities such as poor clinician communication, erroneous data transcription and transmission were also identified. Organ transplantation, because it is highly complex, often stresses the systems and processes of care and, therefore, offers a unique opportunity to proactively identify vulnerabilities and potential failures. Initial steps have been taken to understand such issues through the OPTN/UNOS Operations and Safety Committee, the OPTN/UNOS Disease Transmission Advisory Committee (DTAC) and the current A2ALL ancillary Safety Study. However, to effectively improve patient safety in organ transplantation, the development of a process for reporting of preventable errors that affords protection and the support of empiric research is critical. Further, the transplant community needs to embrace the implementation of evidence-based system and process improvements that will mitigate existing safety vulnerabilities.

Functionalized nanoparticle interactions with polymeric membranes.

A series of experiments was performed to measure the retention of a class of functionalized nanoparticles (NPs) on porous (microfiltration and ultrafiltration) membranes. The findings impact engineered water and wastewater treatment using membrane technology, characterization and analytical schemes for NP detection, and the use of NPs in waste treatment scenarios. The NPs studied were composed of silver, titanium dioxide, and gold; had organic coatings to yield either positive or negative surface charge; and were between 2 and 10nm in diameter. NP solutions were applied to polymeric membranes composed of different materials and pore sizes (ranging from ≈ 2 nm [3 kDa molecular weight cutoff] to 0.2 µm). Greater than 99% rejection was observed of positively charged NPs by negatively charged membranes even though pore diameters were up to 20 times the NP diameter; thus, sorption caused rejection. Negatively charged NPs were less well rejected, but behavior was dependent not only on surface functionality but on NP core material (Ag, TiO(2), or Au). NP rejection depended more upon NP properties than membrane properties; all of the negatively charged polymeric membranes behaved similarly. The NP-membrane interaction behavior fell into four categories, which are defined and described here.

Transplant center provision of education and culturally and linguistically competent care: a national study.

Although transplant centers are required to educate patients about kidney transplantation (KT) and living donation (LD), little is known about the educational format, and cultural and linguistic competence necessary for patients to make informed treatment decisions. This study surveyed US transplant administrators about education provided concerning KT and LD and culturally and linguistically competent care. Transplant administrators were invited to participate in an anonymous Internet-based survey about education format, education providers, promoting LD, culturally and linguistically competent care and center characteristics. Most (61%) transplant administrators contacted (N = 280/461) completed the survey. Most administrators (91%) reported that their center provides any type of formal education in their pre-KT evaluation. Education was mostly provided by: nurses (97%), social workers (72%) and surgeons (55%), and predominantly as one-on-one (80%) versus group discussions (60%). Education was primarily delivered through written materials (93%). Written educational materials in Spanish (86%) and the provision of interpreters (82%) were emphasized over educational sessions in Spanish (39%), or employing bilingual (51%) and bicultural staff (39%). Half (55%) promoted LD as the best option. Transplant centers need to take greater efforts to consistently provide appropriate education, promote LD, and provide culturally and linguistically competent care to ensure effective communication with all patients.

Perception versus reality?: Virtual crossmatch--how to overcome some of the technical and logistic limitations.

The goal of this work was to evaluate concordance between (a) actual flow cytometric crossmatch (FCXM) that is performed by the OPO laboratory servicing our transplant center and (b) virtual XM (vXM) prediction based on antibody identification by solid-phase methods performed in our laboratory. A total of 1586 FCXM, performed between June 2007 and September 2008, between all potential deceased donors in our region and sera from patients awaiting kidney or kidney-pancreas transplant, listed at Northwestern Memorial Hospital were evaluated. A key finding of this analysis was the understanding that a thorough vXM cannot be performed in some donor/recipient pairs due to the lack of certain antibody profile data specific to the donor in question. Obtaining more in depth and stringent information regarding antibody specificities, we demonstrate an excellent sensitivity and specificity of the vXM assays- 86.1% and 96.8%, respectively, with a positive likelihood ratio and negative likelihood ratios of 26.9 and 0.14, respectively. The vXM can serve as an outstanding tool to predict HLA compatibility between donor and recipient, with the caveat that the presence/absence of all antibodies against the potential donor and their strength have been thoroughly investigated.

Multiplex detection of hotspot mutations by rolling circle-enabled universal microarrays.

Detection of somatic low abundance mutations in early cancer development requires a discriminatory, specific, and high-throughput methodology. In this study we report specific, discriminatory detection of low abundance mutations through a novel combination of rolling circle amplification (Nat Genet 1998; 19:225-232) and PCR ligation detection reaction on a universal oligonucleotide microarray (J Mol Biol 1999; 292:251-262). After mutation-specific multiplex ligation and hybridization of 17 pairs of probes to a generic microarray, the ligated probes were visualized. The multiplex mutation-specific ligation is possible only because rolling circle amplification permits quantification of previously undetectable hybridization events conducive to the detection of a single mutation from within a pool of over 100 wild-type alleles. This system is readily adaptable to high-throughput automation using a robot such as the Biomek platform.

Photodynamic diagnosis of breast tumours after oral application of aminolevulinic acid.

Photodynamic diagnosis is of increasing interest for diagnosis in oncology. It is based on a more intense incorporation of a fluorescent dye in tumours compared to normal tissue. As a feasibility study we investigated the effectiveness of oral application of 5-aminolevulinic acid for photodynamic diagnosis of human primary mammary tumours. The study included 16 patients with palpable breast tumours. Aminolevulinic acid was administered at a concentration of 40 mg kg(-1)bodyweight 150-420 min prior to tumourectomy. Intraoperatively blue light (405 nm) was applied to the operation site. Sections of the excised tumour and some lymph nodes were prepared and analysed with a fluorescent microscope. All primary mammary tumour tissues showed significantly higher fluorescence intensity than surrounding normal mammary tissue. Fluorescence of the mammary tumours could also be discriminated macroscopically and intraoperatively. Fluorescence intensity in nonmetastatic lymph node tissue was higher in 2 out of 3 patients than in primary tumour tissue. By photodynamic diagnosis using aminolevulinic acid we were able to reliably distinguish primary mammary tumours from normal mammary tissue microscopically and macroscopically in all our patients. We suggest that photodynamic diagnosis with aminolevulinic acid for breast tumours should be further investigated and developed for intraoperative use and may well be a simple tool for better intraoperative diagnosis and recognition of tumour margins. We hypothesize that lymph node metastasis of breast tumours will not be detectable by this method.

Molecular basis for prostaglandin potency. III. Tests of the significance of the "hairpin conformation" in biorecognition phenomena.

Prostaglandin analogs of the PGF2 alpha, 15-epi-PGF2 alpha, and PGE2 type bearing the following methyl substitution patterns -- 15-Me, 16, 16-(Me)2, 17, 17-(Me)2, and 18, 18, 20-(Me)3 -- and analogs constrained to "hairpin" alignment [via 1, (omega-1)-olide formation] and to "non-hairpin" arrangements [via 1, 9- and 1, 15-olide formation] are compared in the following biological assays: contraction of uterine and gastro-intestinal smooth muscle strips, luteolytic antifertility potency in the hamster, binding affinity to two different PGF2 alpha-receptor preparations from bovine corpora lutea, binding to the PGE-specific receptors from rat kidney and liver, inhibition of ADP- induced aggregation of human platelet-rich-plasma, and the effect on rat blood blood pressure. The methylated prostaglandins were also concerted to the corresponding prostacyclins and examined as to action on the platelet and on rat blood pressure. All evidence points to topographically distinct receptors for F2 alpha-, E- and I2- type prostaglandins. Cross-reactivity is reduced in most of the analogs examined. Independent of the target organ or tissue, the receptors show common features based on the functional class of PG recognized. "Hairpin" alignment improves binding (and potency) only for the PGF2 alpha specific assays. PGE-specific binding and potency is disrupted to an increasing extent as the chain branching point is moved further from the 15-hydroxyl center. In contrast 16, 16-dimethylation is particularly disruptive for the PGI2/E1 platelet receptor interaction.

Omega chain methylated analogs of PGF2 alpha and PGE2.

Our previously published prostaglandin (PG) synthesis route, in which the omega-chain is added in the penultimate step, provides facile access to a wide variety of omega-chain variant PG analogs. Each series requires only the synthesis of the appropriate methylated acylphosphonate for the Emmons' condensation. The syntheses of analogs bearing the following methylation patterns are detailed: 15-Me; 17,17-(Me) 2; 17, 17, 20-(Me) 3; 18, 18, 20-(Me) 3; 15, 18, 18, 20-(Me) 4; and 15-OMe-18, 18, 20- (Me) 3. The well-known 16., 16-dimethyl prostaglandins have also been prepared by this sequence. The synthesis of 16, 16-tetramethylene-PG analogs is also described.