Association of peri-operative prescription of non-steroidal anti-inflammatory drugs with continued prescription of opioids after total knee arthroplasty: a retrospective claims-based cohort study.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the mainstays of multimodal pain management. While effective for acute pain control, recent pre-clinical evidence has raised concerns regarding an association between NSAIDs and chronic pain and potential opioid use. Our objective was to explore the association between peri-operative use of prescription NSAIDs and the need for continued opioid prescriptions lasting 90-180 days in previously opioid-naïve patients undergoing total knee arthroplasty. A database of health claims in the USA was used to identify all opioid-naïve adult patients who underwent primary knee arthroplasty between January 2010 and October 2021. We evaluated the magnitude of association between peri-operative prescription NSAID claims and claims for opioids at 90 days postoperatively using multivariable logistic regression models. Secondary outcomes included: the magnitude of association between peri-operative NSAID prescription and claims for opioids at 180 days postoperatively; and identifying other potential factors associated with opioid claims at 90 days postoperatively. After risk adjustment using multivariable logistic regression models in the 789,736-patient cohort, the adjusted odds ratio (95%CI) for a continuous claim of opioids at 90 and 180 days postoperatively among patients with a peri-operative NSAID prescription within 30 days was 1.32 (1.30-1.35), p < 0.001; and 1.12 (1.10-1.15), p < 0.001, respectively. This estimate of effect remained robust at 90 days after accounting for known potential confounders, including pre-existing knee pain and acute postoperative pain severity. Similar analysis of other pain medications (e.g. paracetamol) did not detect such an association. This population-based cohort study suggests that peri-operative prescription NSAID use may be associated with continued opioid prescription claims at 90 and 180 days after knee arthroplasty, even after adjusting for other observed covariates for continuous opioid claims. These novel findings can inform clinical decision-making for post-surgical pain management, risk-benefit discussions with patients and future research.

OPTN/SRTR 2020 Annual Data Report: Intestine.

Despite small increases in additions to the intestine transplant wait- list, total waitlist numbers, overall intestine transplant rates, and overall transplants performed from 2019 to 2020, the trend over the last decade is still toward less intestine transplant activity. Waitlist mortality continues to fall for pediatric populations and is relatively stable for adults. While 1- year graft survival continues to improve, there has been no noticeable improvement in 3- and 5-year graft survival. Immunosuppression practices continue to favor use of an induction agent followed by tacrolimus-based regimens. Patient survival at 5 years is currently identical for isolated intestines and liver-inclusive allograft recipients.

Mobile telephone delivered contingency management for encouraging adherence to supervised methadone consumption: feasibility study for an RCT of clinical and cost-effectiveness (TIES).

BACKGROUND: Prescription methadone or buprenorphine enables people with opioid use disorder to stop heroin use safely while avoiding withdrawal. To ensure methadone is taken as prescribed and to prevent diversion onto the illicit market, people starting methadone take their daily dose under a pharmacist's supervision. Many patients miss their daily methadone dose risking withdrawal, craving for heroin and overdose due to loss of heroin tolerance. Contingency management (CM) can improve medication adherence, but remote delivery using technology may be resource-light and cost-effective. We developed an innovative way to deliver CM by mobile telephone. Software monitors patients' attendance and supervised methadone consumption through an internet self-login at the pharmacy and sends reinforcing text messages to patients' mobile telephones. A linked system sends medication adherence reports to prescribers and provides early warning alerts of missed doses. A pre-paid debit card system provides financial incentives. METHODS: A cluster randomised controlled trial design was used to test the feasibility of conducting a future trial of mobile telephone CM to encourage adherence to supervised methadone in community pharmacies. Each cluster (drug service/3 allied pharmacies) was randomly allocated to provide patient's presenting for a new episode of opiate agonist treatment (OAT) with either (a) mobile telephone text message CM, (b) mobile telephone text message reminders, or (c) no text messages. We assessed acceptability of the interventions, recruitment, and follow-up procedures. RESULTS: Four drug clinics were approached and three recruited. Thirty-three pharmacists were approached and 9 recruited. Over 3 months, 173 individuals were screened and 10 enrolled. Few patients presented for OAT and high numbers were excluded due to receiving buprenorphine or not attending participating pharmacies. There was 96% consistency in recording medication adherence by self-login vs. pharmacy records. In focus groups, CM participants were positive about using self-login, the text messages, and debit card. Prescribers found weekly reporting, time saving, and allowed closer monitoring of patients. Pharmacists reported that the tablet device was easy to host. CONCLUSION: Mobile telephone CM worked well, but a planned future trial will use modified eligibility criteria (existing OAT patients who regularly miss their methadone/buprenorphine doses) and increase the number of participating pharmacies. TRIAL REGISTRATION: The trial is retrospectively registered, ISRCTN 58958179 .

OPTN/SRTR 2018 Annual Data Report: Intestine.

Despite medical and surgical advances in treatment of intestinal failure, intestine transplant still plays an important role. However, the number of new patients added to the intestine transplant waiting list has decreased over the past decade, reaching a low of 135 in 2018. The number of intestine donors also decreased, reaching a low of 106 in 2018, and the number of intestine transplants performed declined to its lowest level, 104, of which 59% were intestine-liver transplants. Graft failure has plateaued over the past decade. Patient survival for transplants in 2011-2013 varied by age and transplant type. Patient survival was lowest for adult intestine-liver recipients (1-and 5-year survival 66.7% and 49.1%, respectively) and highest for pediatric intestine recipients (1-and 5-year survival 89.1% and 76.4%, respectively).

Bacterial killing is enhanced by exogenous administration of lysozyme in the lungs.

OBJECTIVE: Lysozyme, a 14-kDa protein, is one of the most abundant antimicrobials in the lungs. Its concentration in airway surface sufficient to kill several bacterial pathogens in vitro. The purpose of this study was to determine if administration of exogenous lysozyme would further enhance bacterial killing in vivo. METHODS: To assess the effect of acute lung infection on endogenous lysozyme protein levels, mice were infected by intratracheal instillation of Pseudomonas aeruginosa and bronchoalveolar (BAL) fluid assessed for lysozyme concentration and for muramidase activity. In order to inform in vivo testing, species-specific bacterial killing efficacy was determined by incubating mucoid P. aeruginosa with 2×105 units of chicken lysozyme, human lysozyme or with vehicle at 37°C for 2hours. Subsequently, mice challenged with intratracheally-administered mucoid P. aeruginosa, were reintubated and injected with 2×105 Units of native human lysozyme, recombinant human lysozyme or with vehicle. Lung bacterial burden was enumerated subsequently. RESULTS: The concentration of lysozyme protein in BAL fluid from mice challenged with mucoid clinical isolate of P. aeruginosa was increased 4-fold at 6hours post-infection. Quantitative culture showed that the number of recoverable bacteria was significantly decreased by both chicken and human lysozyme compared to vehicle but human lysozyme was significantly more effective than chicken egg lysozyme. In vivo, 24hours post-infection quantitative culture of lung homogenates showed that the number of viable bacteria recovered from mice treated with either native or recombinant lysozyme was decreased with 0.76±0.25×104 and 0.84±0.16×104, respectively, vs. 7.0±2.52×104 CFU/g protein in mice treated with HBSS, both P<0.05. CONCLUSIONS: These results indicate that endogenous lysozyme is increased during acute lung infection and that early administration of exogenous lysozyme further enhances bacterial killing in vivo.

OPTN/SRTR 2017 Annual Data Report: Intestine.

Despite improvements in medical and surgical treatment of intestinal failure, intestine transplant continues to play an important role. In 2017, 109 intestine transplants were performed, 62 in adults and 47 in children, reflecting the changed age distribution over the past decade of candidates waitlisted for intestine and intestine-liver transplant from largely pediatric to increasing proportions of adults. In 2017, 56.0% of candidates on the intestine list at any time during the year were aged younger than 18 years, with a decrease over time in those aged younger than 6 years and an increase in those aged 6-17 years. Adults accounted for 44.0% of candidates on the list at any time during the year, with an increase since 2013 in those aged 18-34 years and a decrease in those aged 35 years or older. By age, the pretransplant mortality rate was highest for adult candidates at 7.9 per 100 waitlist-years and lowest for pediatric candidates at 3.7 per 100 waitlist-years. Patient survival varied by age and type of transplant, and was lowest for adult intestine-liver recipients (1- and 5-year survival 66.7% and 42.6%, respectively) and highest for pediatric intestine recipients (1- and 5-year survival 86.2% and 75.4%, respectively).

Positive reinforcement targeting abstinence in substance misuse (PRAISe): Study protocol for a Cluster RCT & process evaluation of contingency management.

There are approximately 256,000 heroin and other opiate users in England of whom 155,000 are in treatment for heroin (or opiate) addiction. The majority of people in treatment receive opiate substitution treatment (OST) (methadone and buprenorphine). However, OST suffers from high attrition and persistent heroin use even whilst in treatment. Contingency management (CM) is a psychological intervention based on the principles of operant conditioning. It is delivered as an adjunct to existing evidence based treatments to amplify patient benefit and involves the systematic application of positive reinforcement (financial or material incentives) to promote behaviours consistent with treatment goals. With an international evidence base for CM, NICE recommended that CM be implemented in UK drug treatment settings alongside OST to target attendance and the reduction of illicit drug use. While there was a growing evidence base for CM, there had been no examination of its delivery in UK NHS addiction services. The PRAISe trial evaluates the feasibility, acceptability, clinical and cost effectiveness of CM in UK addiction services. It is a cluster randomised controlled effectiveness trial of CM (praise and financial incentives) targeted at either abstinence from opiates or attendance at treatment sessions versus no CM among individuals receiving OST. The trial includes an economic evaluation which explores the relative costs and cost effectiveness of the two CM intervention strategies compared to TAU and an embedded process evaluation to identify contextual factors and causal mechanisms associated with variations in outcome. This study will inform UK drug treatment policy and practice. Trial registration ISRCTN 01591254.

OPTN/SRTR 2016 Annual Data Report: Intestine.

Despite improvements in medical and surgical treatment of intestinal failure, intestine transplant continues to play an important role. In 2016, a total of 147 intestine transplants were performed, 80 intestine-without-liver and 67 intestine-liver. Over the past decade, the age distribution of candidates waitlisted for intestine and intestine-liver transplant shifted from primarily pediatric to increasing proportions of adults. In 2016, 58.2% of candidates on the intestine list at any time during the year were aged younger than 18 years, with a decrease over time in those aged younger than 6 years and an increase in those aged 6-17 years. Adults accounted for 41.9% of candidates on the list at any time during the year, with a stable proportion of those aged 18-34 years and a decrease in those aged 35 years or older. By age, pretransplant mortality rate was highest for adult candidates at 11.7 per 100 waitlist years and lowest for children aged younger than 6 years at 2.2 per 100 waitlist years. For intestine transplants with or without a liver in 2009-2011, 1- and 5-year graft survival was 72.0% and 54.1%, respectively, for recipients aged younger than 18 years, and 70.5% and 44.1%, respectively, for recipients aged 18 years or older.

Emergence of dalbavancin non-susceptible, vancomycin-intermediate Staphylococcus aureus (VISA) after treatment of MRSA central line-associated bloodstream infection with a dalbavancin- and vancomycin-containing regimen.

OBJECTIVES: Dalbavancin is a long-acting lipoglycopeptide with activity against gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA). The potential for lipoglycopeptides, with half-lives greater than 1 week, to select for resistance is unknown. Here we explore a case of MRSA central line-associated bloodstream infection in which dalbavancin and vancomycin non-susceptibility emerged in a urine isolate collected after the patient was treated with vancomycin and dalbavancin sequentially. METHODS: Isolates from blood and urine underwent susceptibility testing, and whole genome sequencing (WGS). The blood isolate was subjected to successive passage in vitro in the presence of escalating dalbavancin concentrations and the emergent isolate was subjected to repeat susceptibility testing and WGS. RESULTS: The blood isolate was fully susceptible to vancomycin; however, MICs of the urine isolate to dalbavancin, vancomycin, telavancin, and daptomycin were at least fourfold higher than the blood-derived strain. Both strains were indistinguishable by spa and variable number tandem repeat (VNTR) typing, and WGS revealed only seven variants, indicating clonality. Four variants affected genes, including a 3bp in-frame deletion in yvqF, a gene which has been implicated in glycopeptide resistance. Vancomycin and dalbavancin non-susceptibility emerged in the blood isolate after successive passage in vitro in the presence of dalbavancin, and WGS identified a single non-synonymous variant in yvqF. CONCLUSIONS: This is the first case in which VISA has emerged in the context of a dalbavancin-containing regimen. The selection for cross-resistance to vancomycin in vitro by dalbavancin exposure alone is troubling. Clinicians should be aware of the possibility for emergence of dalbavancin non-susceptibility and glycopeptide cross-resistance arising following therapy.

The association between pediatric injury risks and parenting behaviours.

BACKGROUND: Unintentional injuries are the leading cause of death in children ages 1-18 years. Many of these injuries to young children occur in their own homes. Although research has explored injury risk prevention strategies, historically, much of this research has focused on environmental changes and teaching safety practices. Currently, there appears to be a gap in current research exploring how parenting influences children's risk of injury. METHODS: Mothers (n = 119) of children 5 years and younger were recruited from a paediatric clinic as a part of a larger study and completed measures of parenting challenges, developmentally sensitive parenting, child neglect, parental efficacy, and risk of potential injury situations. Hierarchical logistic regression was used to explore the extent to which developmentally insensitive parenting behaviours put parents at higher risk for behaviours that lead to unintentional injury in children and whether developmentally sensitive parenting behaviours protects children from injury. The association between demographic characteristics and injury risk behaviours was also examined. RESULTS: Parents who reported more frequent insensitive parenting behaviours (i.e., yelling, spanking, and putting child in time out) were more likely to report putting their child in an incorrect car seat or taking their child out of a car seat while the car is still moving. In addition, younger parents were at greater risk of storing cleaners and medications unsafely. CONCLUSION: Results from this study highlight the importance of supporting younger mothers and educating parents on effective parenting strategies when trying to prevent unintentional injury risks.

Longitudinal study of Salmonella 1,4,[5],12:i:- shedding in five Australian pig herds.

The shedding patterns of Salmonella spp. and MLVA profiles of Salmonella enterica subspecies enterica (I) serotype 1,4,[5],12:i:- were monitored in a 12-month longitudinal observational study of five pig herds to inform management; provide indications of potential hazard load at slaughter; and assist evaluation of MLVA for use by animal and public health practitioners. Twenty pooled faecal samples, stratified by age group, were collected quarterly. When Salmonella was cultured, multiple colonies were characterized by serotyping and where S. Typhimurium-like serovars were confirmed, isolates were further characterized by phage typing and multiple locus variable number tandem repeat analysis (MLVA). Salmonella was detected in 43% of samples. Salmonella 1,4,[5],12:i- was one of several serovars that persisted within the herds and was found among colonies from each production stage. Virtually all Salmonella 1,4,[5],12:i:- isolates were phage type 193, but exhibited 12 different, closely-related MLVA profiles. Salmonella 1,4,[5],12:i:- diversity within herds was low and MLVA profiles were stable indicating colonization throughout the herds and suggesting each farm had an endemic strain. High prevalence of S. 1,4,[5],12:i:- specific shedding among terminal animals indicated high hazard load at slaughter, suggesting that primary production may be an important pathway of S. 1,4,[5],12:i:- into the human food chain, this has implications for on-farm management and the application and targeting control measures and further evidence of the need for effective process control procedures to be in place during slaughter and in pork boning rooms. These findings have implications for animal health and food safety risk mitigation and risk management.

Developing tailored positive parenting messages for a clinic-based communication programme.

BACKGROUND: Health care providers fill a central role in the prevention of both child abuse and neglect (CA/N) and unintentional childhood injury. Health communication interventions hold promise for promoting attitudes and behaviours among parents that increase positive parenting practices, which may be linked to decreased rates of intentional and unintentional childhood injuries. This manuscript describes the development of 'RISE Up', an ambulatory clinic-based childhood injury prevention programme that provides tailored, injury prevention print materials to parents of children ages 0-5. METHODS: Fifteen semi-structured key informant interviews were conducted with clinic healthcare providers and staff to develop communication strategies and materials for caregivers. Cognitive response testing was then conducted with 20 caregivers of the priority population to assess all materials. Interviews were recorded, transcribed and analyzed using thematic coding methods. RESULTS: Formative research revealed that health care providers and caregivers were very responsive to messages and materials. Health care providers reported that abuse and neglect were particularly relevant to their patients and noted several benefits to implementing the RISE Up programme in a health care setting. Caregivers generally found messages on reducing the risks of injuries, as well as the graphics displayed in the RISE Up programme to be helpful. CONCLUSIONS: Addressing the common determinants of both intentional and unintentional childhood injury through customized print materials may be a useful component of comprehensive prevention efforts to address childhood injury risk with greater impact. Providers and parents responded favourably to this communication strategy.

Long-term decline in grassland productivity driven by increasing dryness.

Increasing aridity and drought severity forecast for many land areas could reduce the land carbon (C) sink. However, with limited long-term direct measures, it is difficult to distinguish direct drying effects from counter effects of CO2 enrichment and nitrogen (N) deposition. Here, we document a >50% decline in production of a native C3 grassland over four decades and assign the forcing and timing to increasing aridity and specifically to declining late-summer rainfall. Analysis of C and N stable isotopes in biomass suggests that enhanced water use efficiency via CO2 enrichment may have slightly ameliorated the productivity decline but that changes in N had no effects. Identical declines in a long-term snow-addition experiment definitively identified increasing late-summer dryness as the cause. Our results demonstrate lasting consequences of recent climate change on grassland production and underscore the importance of understanding past climate-ecosystem coupling to predicting future responses to changing climate.

Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion.

Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, nonlymphocyte depleting, belatacept-based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept-treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, nondepleting, CNI-free, steroid-sparing immunomodulatory regimen that promotes sustained rejection-free allograft survival after renal transplantation.

Platelet-derived CD154: ultrastructural localization and clinical correlation in organ transplantation.

CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation.

Low-pass genome-wide sequencing and variant inference using identity-by-descent in an isolated human population.

Whole-genome sequencing in an isolated population with few founders directly ascertains variants from the population bottleneck that may be rare elsewhere. In such populations, shared haplotypes allow imputation of variants in unsequenced samples without resorting to complex statistical methods as in studies of outbred cohorts. We focus on an isolated population cohort from the Pacific Island of Kosrae, Micronesia, where we previously collected SNP array and rich phenotype data for the majority of the population. We report identification of long regions with haplotypes co-inherited between pairs of individuals and methodology to leverage such shared genetic content for imputation. Our estimates show that sequencing as few as 40 personal genomes allows for inference in up to 60% of the 3000-person cohort at the average locus. We ascertained a pilot data set of whole-genome sequences from seven Kosraean individuals, with average 5× coverage. This assay identified 5,735,306 unique sites of which 1,212,831 were previously unknown. Additionally, these variants are unusually enriched for alleles that are rare in other populations when compared to geographic neighbors (published Korean genome SJK). We used the presence of shared haplotypes between the seven Kosraen individuals to estimate expected imputation accuracy of known and novel homozygous variants at 99.6% and 97.3%, respectively. This study presents whole-genome analysis of a homogenous isolate population with emphasis on optimal rare variant inference.

Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression.

Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8(+) effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8(+) CD2(hi) CD28(-) T cells contained the highest proportion of cells with polyfunctional cytokine (IFNγ, TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.

Child involvement in the paediatric consultation: a qualitative study of children and carers' views.

BACKGROUND: This study aimed to investigate child and carers' attitudes towards child involvement in paediatric consultations. METHODS: Semi-structured qualitative interviews explored child and carers' attitudes towards child involvement at different stages of the paediatric consultation process. Twenty families (21 children, 17 mothers and 5 fathers) were interviewed following a paediatric (index) consultation in two UK paediatric inpatient and outpatient departments. RESULTS: All but one family felt the child should be involved at some stage of the consultation process but the desired extent and nature of involvement depended on child, family and illness characteristics, as well as on the stages of the consultation. During history gathering, some parents and children felt it was the decision and responsibility of the parent to facilitate communication between the child and the doctor. Others expected the doctor to decide when and how to facilitate this process. At diagnosis the desired amount of information given to the child increased with increasing maturity in the child. Some felt making a diagnosis should be a collaborative process; others felt it was solely the domain of the doctor. In discussing and making a treatment plan, some children wanted to be given the choice of being involved and some wanted their parents to be responsible for implementing the plan. Some families with a seriously ill child, however, wanted the burden of involvement in the management plan taken away from them. CONCLUSIONS: Families vary in their views about involvement of children in paediatric consultations in a way that may be unique to each child, family and illness. Moreover, different views were expressed about involvement in each stage of the consultative process and in management of the child's health. The challenge for doctors is to determine the level of involvement and information exchange favoured by a particular parent and child. Good practice recommendations emerging from the analysis are described.

Portal venous donor-specific transfusion in conjunction with sirolimus prolongs renal allograft survival in nonhuman primates.

Pretransplant exposure to donor antigen is known to modulate recipient alloimmunity, and frequently results in sensitization. However, donor-specific transfusion (DST) can have a protolerant effect that is dependent on route, dose and coadministered immunosuppression. Rodent studies have shown in some strain combinations that portal venous (PV) DST alone can induce tolerance, and uncontrolled clinical use of PVDST has been reported. In order to determine if pretransplant PVDST has a clinically relevant salutary effect, we studied it and the influence of concomitant immunosuppression in rhesus monkeys undergoing renal allotransplantation. Animals received PVDST with unfractionated bone marrow and/or tacrolimus or sirolimus 1 week prior to transplantation. Graft survival was assessed without any posttransplant immunosuppression. PVDST alone or in combination with tacrolimus was ineffective. However, PVDST in combination with sirolimus significantly prolonged renal allograft survival to a mean of 24 days. Preoperative sirolimus alone had no effect, and peripheral DST with sirolimus prolonged graft survival in 2/4 animals, but resulted in accelerated rejection in 2/4 animals. These data demonstrate that PVDST in combination with sirolimus delays rejection in a modest but measurable way in a rigorous model. It may thus be a preferable method for donor antigen administration.

NMR and spin relaxation in systems with magnetic nanoparticles: effects of size and molecular motion.

To better understand the specifics of nuclear magnetic resonance and spin relaxation in systems with magnetic nanoparticles and test the limits of the outer sphere model for the diffusion-related relaxation, iron oxide nanoparticle suspensions are studied in dependence on the particle concentration and size (5-40 nm). The model is modified to account for aggregation of the particles into clusters with an enlarged effective radius. For liquid suspensions containing small particles or clusters, both the longitudinal and transverse spin relaxation rates, T(1)(-1) and T(2)(-1), correspond well to the theory, which predicts passing of T(1)(-1) through a maximum and monotonic increase in T(2)(-1) with increasing particle size. For the largest particle sizes, as well as in the case of strong aggregation, the relaxation rates are significantly lower than theoretical predictions. An abrupt change in both the relaxation rates is observed in a narrow temperature range around the melting point of paraffin wax doped with magnetic nanoparticles. The applicability of fast-motion and fast-diffusion approximations is discussed for large effective sizes and limiting molecular motion cases.