The Interplay of Electronic Configuration and Anion Ordering on the Magnetic Behavior of Hydroxyfluoride Diaspores.

We report a new nickel hydroxyfluoride diaspore Ni(OH)F prepared using hydrothermal synthesis from NiCl2·6H2O and NaF. Magnetic characterization reveals that, contrary to other reported transition-metal hydroxyfluoride diaspores, Ni(OH)F displays weak ferromagnetism below the magnetic ordering temperature. To understand this difference, neutron diffraction is used to determine the long-range magnetic structure. The magnetic structure is found to be distinct from those reported for other hydroxyfluoride diaspores and shows an antiferromagnetic spin ordering in which ferromagnetic canting is allowed by symmetry. Furthermore, neutron powder diffraction on a deuterated sample, Ni(OD)F, reveals partial anion ordering that is distinctive to what has previously been reported for Co(OH)F and Fe(OH)F. Density functional theory calculations show that OH/F ordering can have a directing influence on the lowest energy magnetic ground state. Our results point toward a subtle interplay between the sign of magnetic exchange interactions, the electronic configuration, and anion disordering.

PROviding Better ACcess To ORgans: A comprehensive overview of organ-access initiatives from the ASTS PROACTOR Task Force.

The American Society of Transplant Surgeons (ASTS) PROviding better Access To Organs (PROACTOR) Task Force was created to inform ongoing ASTS organ access efforts. Task force members were charged with comprehensively cataloguing current organ access activities and organizing them according to stakeholder type. This white paper summarizes the task force findings and makes recommendations for future ASTS organ access initiatives.

Waitlist Outcomes of Liver Transplant Candidates Who Were Reprioritized Under Share 35.

Under Share 35, deceased donor (DD) livers are offered regionally to candidates with Model for End-Stage Liver Disease (MELD) scores ≥35 before being offered locally to candidates with MELD scores <35. Using Scientific Registry of Transplant Recipients data from June 2013 to June 2015, we identified 1768 DD livers exported to regional candidates with MELD scores ≥35 who were transplanted at a median MELD score of 39 (interquartile range [IQR] 37-40) with 30-day posttransplant survival of 96%. In total, 1764 (99.8%) exports had an ABO-compatible candidate in the recovering organ procurement organization (OPO), representing 1219 unique reprioritized candidates who would have had priority over the regional candidate under pre-Share 35 allocation. Reprioritized candidates had a median waitlist MELD score of 31 (IQR 27-34) when the liver was exported. Overall, 291 (24%) reprioritized candidates had a comparable MELD score (within 3 points of the regional recipient), and 209 (72%) were eventually transplanted in 11 days (IQR 3-38 days) using a local (50%), regional (50%) or national (<1%) liver; 60 (21%) died, 13 (4.5%) remained on the waitlist and nine (3.1%) were removed for other reasons. Of those eventually transplanted, MELD score did not increase in 57%; it increased by 1-3 points in 37% and by ≥4 points in 5.7% after the export. In three cases, OPOs exchanged regional exports within a 24-h window. The majority of comparable reprioritized candidates were not disadvantaged; however, 21% died after an export.

Beyond the Billboard: The Facebook-Based Application, Donor, and Its Guided Approach to Facilitating Living Organ Donation.

Living donor solicitation can raise ethical concerns, regardless of the medium used: newspaper, television, pulpit, billboard or Internet. Moving the search for a living donor into the social media realm introduces the risk of unguided and coercive patient narratives as well as decoupling or even total absence of information that could aid the consent process. The Facebook application (app) for living donors, called Donor (restricted to patient use), aims to address these concerns in several ways: (i) by directing the patient's initial appeal to friends and family; (ii) by guiding the patient's narrative; and (iii) by providing a library of clinical, ethical and regulatory information that informs the consent process. In this paper, we explored these features and contrasted them with billboard solicitation activities and current independent social media efforts. We concluded that the proactive ethical design of the Donor app is a permissible way to help satisfy the shortfall of deceased donor livers and kidneys.

A Smartphone App for Increasing Live Organ Donation.

The incidence of live donor transplantation has declined over the past decade, and waitlisted candidates report substantial barriers to identifying a live donor. Since asking someone to donate feels awkward and unfamiliar, candidates are hesitant to ask directly and may be more comfortable with a passive approach. In collaboration with Facebook leadership (Facebook Inc., Menlo Park, CA), we developed a mobile application-an app-that enables waitlisted candidates to create a Facebook post about their experience with organ failure and their need for a live donor. We conducted a single-center prospective cohort study of 54 adult kidney-only and liver-only waitlisted candidates using the Facebook app. Cox proportional hazards models were used to describe donor referral on behalf of candidates using the app compared with matched controls. The majority of candidates who used the app reported it to be "good" or "excellent" with regard to the installation process (82.9%), readability (88.6%), simplicity (70.6%), clarity (87.5%) and the information provided (85.3%). Compared with controls, candidates using the Facebook app were 2.43 6.6117.98 times more likely to have a donor come forward on their behalf (p < 0.001). The Facebook app is an easy-to-use instrument that enables waitlisted candidates to passively communicate with their social network about their need for a live donor.

Chimeric Allografts Induced by Short-Term Treatment With Stem Cell-Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: A Study in Rats.

Transplant tolerance allowing the elimination of lifelong immunosuppression has been the goal of research for 60 years. The induction of mixed chimerism has shown promise and has been extended successfully to large animals and to the clinic; however, it remains cumbersome and requires heavy early immunosuppression. In this study, we reported that four injections of AMD3100, a CXCR4 antagonist, plus eight injections of low-dose FK506 (0.05 mg/kg per day) in the first week after kidney transplantation extended survival, but death from renal failure occurred at 30-90 days. Repeating the same course of AMD3100 and FK506 at 1, 2 and 3 mo after transplant resulted in 92% allograft acceptance (n = 12) at 7 mo, normal kidney function and histology with no further treatment. Transplant acceptance was associated with the influx of host stem cells, resulting in a hybrid kidney and a modulated host immune response. Confirmation of these results could initiate a paradigm shift in posttransplant therapy.

Chimeric Allografts Induced by Short-Term Treatment With Stem Cell Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine.

Transplantation is now lifesaving therapy for patients with end-stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor-recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplantation and pharmacological mobilization, resulting in a chimeric, repopulated organ. We now confirm these findings in a well-characterized large animal preclinical model. Here, we show that AMD3100 and FK506 mobilization of endogenous stem cells immediately post kidney transplantation combined with repeat therapy at 1, 2, and 3 months led to drug-free long-term survival in maximally immunologically mismatched swine. Three long-term recipients have stable chimeric transplants, preserved antidonor skin graft responses, and normal serum creatinine levels despite withdrawal of all medication for 3 years.

Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy.

BACKGROUND: Hypertrophic scarring carries a large burden of disease, including disfigurement, pain and disability. There is currently no effective medical treatment to reduce or prevent hypertrophic scarring. Flightless I (Flii), a member of the gelsolin family of actin remodelling proteins, is an important negative regulator of wound repair. OBJECTIVES: The objective of this study was to investigate the role of Flii as a potential regulator of hypertrophic scarring. METHODS: Using human skin samples and an animal model of bleomycin-induced hypertrophic scarring in mice that overexpress or have reduced expression of Flii, we investigated its effect on dermal fibrosis and hypertrophic scarring. RESULTS: Flii expression was increased in human burns and hypertrophic scars. A similar increase in Flii was observed in hypertrophic scars formed in mice post-treatment with bleomycin. However, Flii-deficient (Flii(+/-) ) mice had reduced scarring in response to bleomycin evidenced by decreased dermal thickness, smaller cross-sectional scar areas, fewer myofibroblasts and a decreased collagen I/III ratio. In contrast, bleomycin-treated Flii-overexpressing mice (Flii(Tg/Tg) ) showed increased scar dermal thickness, larger cross-sectional scar areas, more myofibroblasts and an increased collagen I/III ratio. Injecting developing scars with a Flii neutralizing antibody led to a significant reduction in the size of the scars and a reduction in the collagen I/III ratio. CONCLUSIONS: This study identifies Flii as a profibrotic agent that contributes to excessive scar formation. Reducing its activity using neutralizing antibodies is a promising approach for reducing hypertrophic scarring.

Social media and organ donor registration: the Facebook effect.

Despite countless media campaigns, organ donation rates in the United States have remained static while need has risen dramatically. New efforts to increase organ donation through public education are necessary to address the waiting list of over 100,000 patients. On May 1, 2012, the online social network, Facebook, altered its platform to allow members to specify "Organ Donor" as part of their profile. Upon such choice, members were offered a link to their state registry to complete an official designation, and their "friends" in the network were made aware of the new status as a donor. Educational links regarding donation were offered to those considering the new organ donor status. On the first day of the Facebook organ donor initiative, there were 13 054 new online registrations, representing a 21.1-fold increase over the baseline average of 616 registrations. This first-day effect ranged from 6.9× (Michigan) to 108.9× (Georgia). Registration rates remained elevated in the following 12 days. During the same time period, no increase was seen in registrations from the DMV. Novel applications of social media may prove effective in increasing organ donation rates and likewise might be utilized in other refractory public health problems in which communication and education are essential.

The aggressive phenotype revisited: utilization of higher-risk liver allografts.

Organ shortage has led to increased utilization of higher risk liver allografts. In kidneys, aggressive center-level use of one type of higher risk graft clustered with aggressive use of other types. In this study, we explored center-level behavior in liver utilization. We aggregated national liver transplant recipient data between 2005 and 2009 to the center-level, assigning each center an aggressiveness score based on relative utilization of higher risk livers. Aggressive centers had significantly more patients reaching high MELDs (RR 2.19, 2.33 and 2.28 for number of patients reaching MELD>20, MELD>25 and MELD>30, p<0.001), a higher organ shortage ratio (RR 1.51, 1.60 and 1.51 for number of patients reaching MELD>20, MELD>25 and MELD>30 divided by number of organs recovered at the OPO, p<0.04), and were clustered within various geographic regions, particularly regions 2, 3 and 9. Median MELD at transplant was similar between aggressive and nonaggressive centers, but average annual transplant volume was significantly higher at aggressive centers (RR 2.27, 95% CI 1.47-3.51, p<0.001). In cluster analysis, there were no obvious phenotypic patterns among centers with intermediate levels of aggressiveness. In conclusion, highwaitlist disease severity, geographic differences in organ availability, and transplant volume are the main factors associated with the aggressive utilization of higher risk livers.

Successful transplantation of reduced-sized rat alcoholic fatty livers made possible by mobilization of host stem cells.

Livers from Lewis rats fed with 7% alcohol for 5 weeks were used for transplantation. Reduced sized (50%) livers or whole livers were transplanted into normal DA recipients, which, in this strain combination, survive indefinitely when the donor has not been fed alcohol. However, none of the rats survived a whole fatty liver transplant while six of seven recipients of reduced sized alcoholic liver grafts survived long term. SDF-1 and HGF were significantly increased in reduced size liver grafts compared to whole liver grafts. Lineage-negative Thy-1+CXCR4+CD133+ stem cells were significantly increased in the peripheral blood and in allografts after reduced size fatty liver transplantation. In contrast, there were meager increases in cells reactive with anti Thy-1, CXCR4 and CD133 in peripheral blood and allografts in whole alcoholic liver recipients. The provision of plerixafor, a stem cell mobilizer, salvaged 5 of 10 whole fatty liver grafts. Conversely, blocking SDF-1 activity with neutralizing antibodies diminished stem cell recruitment and four of five reduced sized fatty liver recipients died. Thus chemokine insufficiency was associated with transplant failure of whole grafts, which was overcome by the increased regenerative requirements promoted by the small grafts and mediated by SDF-1 resulting in stem cell influx.

Mobilization of host stem cells enables long-term liver transplant acceptance in a strongly rejecting rat strain combination.

Careful examination of liver, kidney and heart transplants in human recipients has revealed small numbers of host bone marrow derived stem cells in the graft. If the limited recipient repopulation of a donor graft that is currently observed could be facilitated, it is possible that conversion to a predominantly host phenotype would permit long-term graft function without immunosuppression. We proposed to "engineer" repopulation after transplant in a strain combination (dark agouti [DA] to Lewis green fluorescent protein+[LEW GFP+]) which rejects liver grafts strongly, a model that more closely resembles the situation in humans. Treatment on days 0, 1, 2, 3 and 7 after transplantation with low-dose (0.1 mg/kg) tacrolimus (T) designed to blunt rejection combined with plerixafor (P) to mobilize host stem cells resulted in greater than 180 days graft survival with extensive albeit spotty conversion of a small (50%) DA graft to the recipient LEW GFP+ genotype. Subsequent skin grafting revealed donor-specific graft prolongation. The T plus P treatment resulted in higher levels of Lin-Thy1+CD34+CD133+ stem cells and Foxp3+ regulatory T cells in the blood and liver at day 7. Thus, pharmacological mobilization of host stem cells sustains liver allografts by two mechanisms: repopulation of injured donor cells and regulation of the immune response.

Histidine-tryptophan-ketoglutarate (HTK) is associated with reduced graft survival in pancreas transplantation.

Prior single-center studies have reported that pancreas allograft survival is not affected by preservation in histidine-tryptophan-ketoglutarate (HTK) versus University of Wisconsin (UW) solution. To expand on these studies, we analyzed the United Network for Organ Sharing (UNOS) database of pancreas transplants from July 2004, through February 2008, to determine if preservation with HTK (N = 1081) versus UW (N = 3311) impacted graft survival. HTK preservation of pancreas allografts increased significantly in this time frame, from 15.4% in 2004 to 25.4% in 2008. After adjusting for other recipient, donor, graft and transplant center factors that impact graft survival, HTK preservation was independently associated with an increased risk of pancreas graft loss (hazard ratio [HR] 1.30, p = 0.014), especially in pancreas allografts with cold ischemia time (CIT) >or=12 h (HR 1.42, p = 0.017). This reduced survival with HTK preservation as compared to UW preservation was seen in both simultaneous pancreas-kidney (SPK) transplants and pancreas alone (PA) transplants. Furthermore, HTK preservation was also associated with a 1.54-fold higher odds of early (<30 days) pancreas graft loss as compared to UW (OR 1.54, p = 0.008). These results suggest that the increasing use of HTK for abdominal organ preservation should be re-examined.

Histidine-Tryptophan-Ketoglutarate (HTK) is associated with reduced graft survival in deceased donor livers, especially those donated after cardiac death.

Single-center studies have reported that liver allograft survival is not affected by preservation in histidine-tryptophan-ketoglutarate (HTK) versus University of Wisconsin (UW) solution. We analyzed the UNOS database of liver transplants performed from July, 2004, through February, 2008, to determine if preservation with HTK (n = 4755) versus UW (n = 12 673) impacted graft survival. HTK preservation of allografts increased from 16.8% in 2004 to 26.9% in 2008; this was particularly striking among donor after cardiac death (DCD) allografts, rising from 20.7% in 2004 to 40.9% in 2008. After adjusting for donor, recipient and graft factors that affect graft survival, HTK preservation was associated with an increased risk of graft loss (HR 1.14, p = 0.002), especially with DCD allografts (HR 1.44, P = 0.025) and those with cold ischemia time over 8 h (HR 1.16, P = 0.009). Furthermore, HTK preservation was associated with a 1.2-fold higher odds of early (< 30 days) graft loss as compared to UW preservation (OR 1.20, p = 0.012), with a more pronounced effect on allografts with cold ischemia time over 8 h (OR 1.31, p = 0.007), DCD allografts (OR 1.63, p = 0.09) and donors over 70 years (OR 1.67, p = 0.081). These results suggest that the increasing use of HTK for abdominal organ preservation should be reexamined.

Dark adaptation recovery of human rod bipolar cell response kinetics estimated from scotopic b-wave measurements.

We recorded ganzfeld scotopic ERGs to examine the responses of human rod bipolar cells in vivo, during dark adaptation recovery following bleaching exposures, as well as during adaptation to steady background lights. In order to be able to record responses at relatively early times in recovery, we utilized a 'criterion response amplitude' protocol in which the test flash strength was adjusted to elicit responses of nearly constant amplitude. In order to provide accurate and unbiased measures of response kinetics, we utilized a curve-fitting procedure to fit a smooth function to the measured responses in the vicinity of the peak, thereby extracting both the time-to-peak and the amplitude of the responses. Following bleaching exposures, the responses exhibited both desensitization and accelerated kinetics. During early post-bleach recovery, the flash sensitivity and time-to-peak varied according to a power-law expression (with an exponent of 6), as found in the presence of steady background light. This light-like phenomenon, however, appeared to be set against the backdrop of a second, more slowly recovering 'pure' desensitization, most clearly evident at late post-bleach times. The post-bleach 'equivalent background intensity' derived from measurements of flash sensitivity faded initially with an S2 slope of approximately 0.24 decades min(-1), and later as a gentle S3 tail. When calculated from kinetics, the results displayed only the S2 slope. While the recovery of rod bipolar cell response kinetics can be described accurately by a declining level of opsin in the rods, the sensitivity of these cells is reduced further than expected by this mechanism alone.

Factors affecting graft survival after adult/child split-liver transplantation: analysis of the UNOS/OPTN data base.

When considering advocacy of split-liver transplantation, it is important to understand whether comparable outcomes can be achieved. The goal of this study was to identify donor and transplant characteristics predictive of comparable outcomes by risk factor analysis. Using the United Network for Organ Sharing/ Organ Procurement and Transplantation Network data base between January 1996 and May 2006, first time adult/child split cases (568 adults, 508 children) were examined. In multivariate analysis, recipient medical condition (hospitalization), status 1 assignment, ABO incompatibility, donor age (>40 years), donor body weight (< or = 40 kg), calculated whole graft volume to recipient body weight ratio (cGRWR < or = 1.5%) and no sharing between centers were significant risk factors in adult recipients. Recipient diagnosis of tumor, dialysis prior to transplant, recipient body weight (< or = 6 kg), donor age (>30 years), donor history of cardiac arrest after declaration of death and cold ischemia time (CIT > 6 h) increased the risk of graft failure in pediatric recipients. The livers from young donors showed comparable outcomes to whole deceased liver transplantation (LT) when other transplant-related risk factors were minimized in adult recipients. Reducing CIT is important to obtain comparable outcomes to living donor LT in pediatric recipients.

Effect modification in liver allografts with prolonged cold ischemic time.

Although prolonged cold ischemia time (PCIT) is generally associated with worse outcomes following liver transplantation, evidence suggests that some recipients and some donors might be more sensitive to PCIT than others. The purpose of this study was to identify factors that predict a higher risk of graft loss after a transplant with PCIT when compared with a similar transplant with average CIT (ACIT). 14 637 recipients reported to United Network for Organ Sharing (UNOS) in the model for end-stage liver disease (MELD) era were studied by interaction term analysis in proportional hazards models. Recipient diabetes, obesity and donor African American (AA) ethnicity were found to significantly amplify the adverse effects of PCIT. Graft loss was 1.85-fold higher in diabetic or obese PCIT recipients compared with diabetic or obese ACIT recipients, (vs. 1.17 for the same comparison in non-diabetic non-obese recipients). Similarly, graft loss was 1.80-fold higher in AA PCIT donors compared with AA ACIT donors, (vs. 1.31 for the same comparison in non-AA donors). Other factors may also exist, but current clinical practices might already mitigate the risks from those factors. As such, we recommend expanding clinical practice to include our findings, but not abandoning current judgment based on factors already perceived to amplify the adverse effects of PCIT.

Antiviral prophylaxis and recurrence of hepatocellular carcinoma following liver transplantation in patients with hepatitis B.

BACKGROUND: Orthotopic liver transplantation (OLT) is a viable treatment option for patients with hepatitis B (HBV) and concomitant hepatocellular carcinoma (HCC). However, cancer recurrence following transplantation approaches 20%. This study sought to identify the clinical and pathological factors associated with post-OLT survival. METHODS: Univariate and multivariate analyses considered the following variables: combination viral prophylaxis, HBV recurrence, tumor stage, vascular invasion, distribution, nodularity, pre- and post-OLT tumor size, pre-OLT alpha-fetoprotein (AFP), Milan and UCSF criteria, and Asian race. RESULTS: Cumulatively, HCC recurrence-free survival was 77%, 62%, and 53% at 1, 3, and 5 years, respectively, and was significantly better in patients who were free of viral recurrence post-OLT. Similarly, patients treated with combination prophylaxis had a significantly lower mortality than those who were not. CONCLUSIONS: Multivariate analysis revealed that AFP>500 ng/mL, presence of vascular invasion by explant, HBV recurrence, and combination prophylaxis were independent predictors of HCC recurrence-free survival.

Dark adaptation of human rod bipolar cells measured from the b-wave of the scotopic electroretinogram.

To examine the dark adaptation of human rod bipolar cells in vivo, we recorded ganzfeld ERGs to (a) a family of flashes of increasing intensity, (b) dim test flashes presented on a range of background intensities, and (c) dim test flashes presented before, and up to 40 min after, exposure to intense illumination eliciting bleaches from a few per cent to near total. The dim flash ERG was characterized by a prominent b-wave response generated principally by rod bipolar cells. In the presence of background illumination the response reached peak earlier and desensitized according to Weber's Law. Following bleaching exposures, the response was initially greatly desensitized, but thereafter recovered slowly with time. For small bleaches, the desensitization was accompanied by acceleration, in much the same way as for real light. Following a near-total bleach, the response was unrecordable for >10 min, but after approximately 23 min half-maximal sensitivity was reached, and full sensitivity was restored between approximately 35 and 40 min. With smaller bleaches, recovery commenced earlier. We converted the post-bleach measurements of desensitization into 'equivalent background intensities' using a Crawford transformation. Across the range of bleaching levels, the results were described by a prominent 'S2' component (0.24 decades min(-1)) together with a smaller and slower 'S3' component (0.06 decades min(-1)), as is found for dark adaptation of the scotopic visual system. We attribute the S2 component to the presence of unregenerated opsin, and we speculate that the S3 component results from ion channel closure by all-trans retinal.

Split liver transplantation.

Seventy-five thousand Americans develop organ failure each year. Fifteen percent of those on the list for transplantation die while waiting. Several possible mechanisms to expand the organ pool are being pursued including the use of extended criteria donors, living donation, and split deceased donor transplants. Cadaveric organ splitting results from improved understanding of the surgical anatomy of the liver derived from Couinaud. Early efforts focused on reduced-liver transplantation (RLT) reported by both Bismuth and Broelsch in the mid-1980s. These techniques were soon modified to create both a left lateral segment graft appropriate for a pediatric recipient and a right trisegment for an appropriately sized adult. Techniques of split liver transplantation (SLT) were also modified to create living donor liver transplantation. Pichlmayr and Bismuth reported successful split liver transplantation in 1989 and Emond reported a larger series of nine split procedures in 1990. Broelsch and Busuttil described a technical modification in which the split was performed in situ at the donor institution with surgical division completed in the heart beating cadaveric donor. In situ splitting reduces cold ischemia, simplifies identification of biliary and vascular structures, and reduces reperfusion hemorrhage. However, in situ splits require specialized skills, prolonged operating room time, and increased logistical coordination at the donor institution. At UCLA over 120 in situ splits have been performed and this technique is the default when an optimal donor is available. Split liver transplantation now accounts for 10% of adult transplantations at UCLA and 40% of pediatric transplantations.