Update to the Minimum Requirements for Core Competency in Pediatric Hospital Pharmacy Practice.

Colleges of pharmacy provide varying amounts of didactic and clinical experiential hours in pediatrics therapeutics, resulting in variability in the knowledge, skills, and perceptions of new graduates toward the pharmacist role in providing care to pediatric patients. The Pediatric Pharmacy Association continues to endorse a minimum set of core competencies for all pharmacists involved in the care of hospitalized pediatric patients of all ages. To that end, we have updated our 2015 Position Statement.

Limited utility of endomyocardial biopsy in the first year after heart transplantation.

BACKGROUND: Surveillance endomyocardial biopsies (EMBs) are used for the early diagnosis of acute cardiac allograft rejection. Protocols became standardized in an earlier era and their utility with contemporary immunosuppression has not been investigated. METHODS: We studied 258 patients after orthotopic heart transplantation comparing 135 patients immunosuppressed by mycophenolate mofetil (MMF) with 123 patients treated by azathioprine (AZA); both with cyclosporine and corticosteroids after induction therapy with rabbit antithymocyte globulin. Fifteen EMBs were scheduled in the first year. Additional EMBs were performed for suspected rejection, after treatment, or for inadequate samples. The MMF group had 1875 EMBs vs. 1854 in the AZA group. RESULTS: The yield of International Society for Heart and Lung Transplantation (ISHLT) grade> or =3A biopsy-proven acute rejection (BPAR) was 1.87% per biopsy (35 of 1875) with MMF vs. 3.13% (58 of 1854) with AZA P=0.024. The number of clinically silent BPAR ISHLT grade > or =3A (the true yield of surveillance EMBs) was 1.39% (26 of 1875) of biopsies MMF vs. 2.1% (39 of 1854) AZA, P=0.48. There were five serious complications requiring intervention or causing long-term sequelae; 0.13% (5 of 3729) per biopsy and 1.94% (5 of 258) per patient. The incidence of all definite and potential complications was 1.42% (53 of 3729) per biopsy and 20.5% (53 of 258) per patient. There was no biopsy-related mortality. CONCLUSION: The yield of BPAR was low in the AZA group and very low in the MMF group. The incidence of complications was also low, but repeated biopsies led to a higher rate per patient. Routine surveillance EMBs and the frequency of such biopsies should be reevaluated in the light of their low yield with current immunosuppression.

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.

Delivery After 40 Weeks of Gestation in Pregnant Women With Well-Controlled Human Immunodeficiency Virus.

OBJECTIVE: To evaluate whether there is increased mother-to-child transmission of human immunodeficiency virus (HIV)-1 associated with deliveries at 40 weeks of estimated gestational age (EGA) or greater in pregnant women with HIV-1 viral loads of 1,000 copies/mL or less. METHODS: We performed a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Perinatal and Longitudinal Study in Latin American Countries and International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 cohorts. We included pregnant women with HIV-1 with recent viral loads of 1,000 copies/mL or less at the time of delivery and compared delivery outcomes at between 38 and less than 40 weeks EGA with delivery outcomes at 40 weeks EGA or greater, the exposure of interest. Our primary outcome of interest was mother-to-child transmission, and secondary outcomes included indicators of maternal and neonatal morbidity. We examined the association between EGA and mother-to-child transmission using Poisson distribution. Associations between EGA and secondary outcomes were examined through bivariate analyses using Pearson χ and Fisher exact test or the nonparametric Mann-Whitney U test. RESULTS: Among the 2,250 eligible neonates, eight neonates were infected with HIV-1 (overall transmission rate 0.4%, 95% CI 0.2-8.1%, 40 weeks EGA or greater 0.5% [3/621, 95% CI 0.2-1.4%], less than 40 weeks EGA 0.3% [5/1,629, 95% CI 0.1-0.7%]); there was no significant difference in transmission by EGA (rate ratio 1.57, 95% CI 0.24-8.09, P=.77). There was no difference in maternal viral load between the two groups nor was there a difference in timing of transmission among neonates born with HIV-1. CONCLUSION: In pregnant women with well-controlled HIV-1, the risk of mother-to-child transmission did not differ significantly by EGA at delivery, although we were not powered to demonstrate equivalence of proportions of mother-to-child transmission between EGA groups.

Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases.

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension, regarded by some as distinct entities. However, their presentations are similar and both are associated with poor prognoses. We therefore reviewed 38 specimens [autopsies (n=15), surgical biopsies (n=15), explants (n=7), and pneumonectomy (1 case)] from 35 patients diagnosed as either PVOD (n=30; av. age 34 y, range 4 to 68 y; 19M:11F) or PCH (n=5, av. age 42 y, ranging from 9 months to 60 years; 3M:2F) to assess their interrelationship. PCH was identified in 24 (73%) cases diagnosed as PVOD, either as perivenular foci or diffuse involvement of the pulmonary parenchyma. Other features seen in PVOD were arterial medial hypertrophy and/or intimal fibrosis (88%), hemosiderosis (79%), venulitis (12%), infarction (9%), interstitial fibrosis (sometimes as localized scars) (48%), and a mild lymphocytic infiltrate (67%). In cases diagnosed as PCH, 4 showed venous and arterial changes of PVOD. Cases with PCH also all showed a mild interstitial lymphocytic infiltrate but there was no venulitis or infarction. Capillary proliferation was particularly well demonstrated by CD34 immunostaining and predominantly involved the alveoli, but was also seen within walls of bronchi and pulmonary vessels. Our data suggest that in the majority of cases PCH represents a secondary angioproliferative process caused by postcapillary obstruction rather than a separate disease. The cause of the venous obliteration was not identified but the occasional identification of phlebitis suggests this plays a role in venous damage in some cases.

Pulmonary capillaritis and its relationship to development of emphysema in hypocomplementaemic urticarial vasculitis syndrome.

Hypocomplementaemic urticarial vasculitis syndrome (HUVS) is a rare disorder characterised by complement activation and the presence of C1q precipitins together with a syndrome of urticarial vasculitis, angioedema, arthralgia, ocular inflammation, glomerulonephritis and obstructive lung disease. The pathophysiology of the obstructive airways disease is poorly understood. We report a 46 year-old woman with HUVS who developed progressive obstructive airways disease. Lung biopsy early in the course of her disease revealed pulmonary capillaritis. The disease progressed despite treatment with steroids and cyclosporin and the patient eventually underwent successful double lung transplantation. The explanted lung showed the coexistence of a patchy active vasculitis with severe panacinar emphysema. This is the first description of the histopathological process of HUVS in an explanted lung. Through analysis of serial histopathological specimens and clinical data we show the evolution of pulmonary capillaritis to emphysema, and demonstrate that active vasculitis can coexist with emphysema in patients with HUVS and obstructive airways disease. We suggest that there is a role for ongoing immunosuppressive therapy in these patients.

Minimum Requirements for Core Competency in Pediatric Pharmacy Practice.

Colleges of pharmacy provide varying amounts of didactic and clinical hours in pediatrics resulting in variability in the knowledge, skills, and perceptions of new graduates toward pediatric pharmaceutical care. The Pediatric Pharmacy Advocacy Group (PPAG) endorses the application of a minimum set of core competencies for all pharmacists involved in the care of hospitalized children.

Risk of lymphoid neoplasia after cardiothoracic transplantation: the influence of underlying disease and human leukocyte antigen type and matching.

BACKGROUND: It has been known for more than 20 years that there is an increased risk of lymphoid neoplasia after cardiothoracic transplantation. Recent studies have demonstrated the importance of primary Epstein-Barr virus (EBV) infection and type of immunosuppressive therapy to the cause of these neoplasms, but the contribution of other factors remains equivocal. METHODS: The authors followed 1,562 patients undergoing cardiothoracic transplantation at Harefield Hospital, United Kingdom, and used standard cohort methods of analysis to examine whether posttransplant lymphoma risk was related to the underlying disease requiring transplantation or the human leukocyte antigen (HLA) type and matching. Lymphomas were categorized into EBV-associated lymphoproliferative disease (LPD) and EBV-negative non-Hodgkin's lymphoma (NHL), and the authors carried out separate analyses of these. RESULTS: The authors found no significant association between the underlying disease necessitating transplantation and the risk of lymphoid neoplasia. There was also no evidence of a relation of lymphoma risk with the presence or absence of any particular HLA antigen, although significant protective effects of HLA-B14 and -B57 were found when analyses were conducted without adjustment for multiple testing. Risk of LPD was not associated with degree of HLA mismatching, but there was a significant effect of mismatching on risk of EBV-negative tumors. CONCLUSIONS: The differential effect of HLA mismatching on the risks of LPD and EBV-negative NHL provides further evidence that these two tumors are distinct etiologic entities. The authors' results suggest that the immunologic cause of EBV-negative NHL may be different from that of LPD. Investigation of the relation of risk of EBV-negative NHL to degree of immunosuppression is needed.

Cardiac transplantation for amyloid heart disease: the United Kingdom experience.

BACKGROUND: Heart transplantation (TX) for cardiac amyloidosis is uncommon because of concern about progression of amyloid in other organs and the possibility of amyloid deposition in the donor heart. METHODS: Records of all 24 patients with amyloid heart disease who have undergone TX in the United Kingdom were examined. Seventeen patients had AL amyloidosis (AL) and 7 had non-AL forms of amyloidosis (non-AL). RESULTS: Survival of the 10 patients with AL who underwent TX but had no additional chemotherapy was 50%, 50%, and 20% at 1, 2, and 5 years, respectively; amyloid recurred in the grafts of these patients after a median of 11 months, and extra-cardiac amyloid deposition contributed to mortality in 70% of these patients. Survival of 7 patients with AL who also had chemotherapy was 71%, 71%, and 36% respectively and 2 patients remain alive. Survival of the 7 patients with non-AL was 86%, 86%, and 64% at 1, 2, and 5 years, respectively; 5 patients remain alive. One patient from this group had recurrence of amyloid in the graft at 60 months. Five-year survival for all 24 amyloid patients was 38%, compared to patients undergoing TX in the UK for other indications (n = 4,058) for whom it was 67% (p = 0.013). CONCLUSION: Regardless of the use of adjunctive chemotherapy, the 5-year survival after TX for cardiac AL amyloidosis was less than that after TX for other indications, and progression of the systemic disease contributed substantially to the increased mortality. In contrast, the 5-year survival after TX for non-AL amyloid, combined as necessary with liver or kidney TX, was similar to that after TX in general.

Pre-transplant donor HLA-specific antibodies: characteristics causing detrimental effects on survival after lung transplantation.

BACKGROUND: The impact of Luminex-detected HLA antibodies on outcomes after lung transplantation is unclear. Herein we have undertaken a retrospective study of pre-transplant sera from 425 lung transplants performed between 1991 and 2003. METHODS: Pre-transplant sera, originally screened by complement-dependent cytotoxicity (CDC) assays, were retrospectively tested for the presence of HLA-specific antibodies using HLA-coated Luminex beads and C4d deposition on Luminex beads. The results were correlated with graft survival at 1 year. RESULTS: Twenty-seven patients were retrospectively identified as having been transplanted against donor-specific HLA antibodies (DSA) and 36 patients against non-donor-specific HLA antibodies (NDSA). DSA-positive patients had 1-year survival of 51.9% compared with 77.8% for NDSA and 71.8% for antibody-negative patients (p = 0.029). One-year survival of patients with complement-fixing DSA was 12.5% compared with 62.5% for non-complement-fixing DSA, 75.8% for non-complement-fixing NDSA and 71.8% for antibody-negative patients (p < 0.0001). DSA-positive patients with mean fluorescence intensity (MFI) >5,000 had 1-year survival of 33.3% compared with 71.4% for MFI 2,000 to 5000 and 62.5% for MFI <2,000 (p = 0.0046). Multivariable analysis revealed DSA to be an independent predictor of poor patient survival within 1 year (p = 0.0010, hazard ratio [HR] = 3.569) as well as complement-fixing DSA (p < 0.0001, HR = 11.083) and DSA with MFI >5,000 (p = 0.0001, HR = 5.512). CONCLUSIONS: Pre-formed DSA, particularly complement-fixing DSA, and high MFI are associated with poor survival within the first year after lung transplantation. Risk stratification according to complement fixation or MFI levels may allow for increased transplantation in sensitized patients.

The multifaceted responses of primary human astrocytes and brain microvascular endothelial cells to the Lyme disease spirochete, Borrelia burgdorferi.

The vector-borne pathogen, Borrelia burgdorferi, causes a multi-system disorder including neurological complications. These neurological disorders, collectively termed neuroborreliosis, can occur in up to 15% of untreated patients. The neurological symptoms are probably a result of a glial-driven, host inflammatory response to the bacterium. However, the specific contributions of individual glial and other support cell types to the pathogenesis of neuroborreliosis are relatively unexplored. The goal of this project was to characterize specific astrocyte and endothelial cell responses to B. burgdorferi. Primary human astrocytes and primary HBMEC (human brain microvascular endothelial cells) were incubated with B. burgdorferi over a 72-h period and the transcriptional responses to the bacterium were analyzed by real-time PCR arrays. There was a robust increase in several surveyed chemokine and related genes, including IL (interleukin)-8, for both primary astrocytes and HBMEC. Array results were confirmed with individual sets of PCR primers. The production of specific chemokines by both astrocytes and HBMEC in response to B. burgdorferi, including IL-8, CXCL-1, and CXCL-10, were confirmed by ELISA. These results demonstrate that primary astrocytes and HBMEC respond to virulent B. burgdorferi by producing a number of chemokines. These data suggest that infiltrating phagocytic cells, particularly neutrophils, attracted by chemokines expressed at the BBB (blood-brain barrier) may be important contributors to the early inflammatory events associated with neuroborreliosis.

The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation.

During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

BACKGROUND: Duchenne muscular dystrophy (DMD), which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD) model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot". METHODOLOGY/PRINCIPAL FINDINGS: Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD). The dogs harbour a missense mutation in the 5' donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression. CONCLUSIONS/SIGNIFICANCE: Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD.

Reversible loss of pre-excitation as a sign of acute cardiac rejection.

A 50-year-old woman presented with signs of mild heart failure 16 months after orthotopic heart transplantation. Cardiac biopsy revealed ISHLT Grade 2R rejection, which was treated with corticosteroids. Electrocardiograms (ECGs) after transplantation showed a pre-excitation pattern; the presenting ECG showed complete loss of pre-excitation, which returned fully within 7 days of steroid therapy. Intermittent pre-excitation had been present for 4 weeks prior to any other clinical sign of rejection. Accessory pathways can display reversible loss of function during acute cellular rejection, and this may precede other clinical signs. This rare but significant finding may have clinical relevance to other transplanted patients with pre-excitation.

Emergency surgical treatment of advanced endomyocardial fibrosis in Mozambique.

BACKGROUND: An 11-year-old girl presented to a specialist cardiac facility in Mozambique. She had severe heart failure and massive cardiac enlargement, herniation of the heart into the epigastrium, atrial fibrillation, signs of severe pulmonary hypertension and a low cardiac output. INVESTIGATIONS: Chest radiography, echocardiography, 24 h Holter monitoring, and cardiac catheterization. DIAGNOSIS: Left and right endomyocardial fibrosis in conjunction with an aneurysmal left atrium, severe heart failure, and atrial fibrillation. MANAGEMENT: Left ventricular endocardiectomy with mobilization of the chordae tendineae, mitral valve repair, tricuspid annuloplasty, and left atrial resection.

Amyloidosis presenting as bilateral transudative pleural effusions with normal cardiac investigations: a case report.

A 66-year-old man with a diagnosis of monoclonal gammopathy of unknown significance was referred for investigation of bilateral transudative pleural effusions by the cardiology team. Echocardiography, myocardial perfusion scanning and left heart catheterisation were all normal or non diagnostic. Given significant occupational asbestos exposure in his twenties he underwent thoracoscopic pleural biopsy. This showed fibrous inflammation only. He subsequently developed proteinuria and peripheral oedema. Reanalysis of the pleural biopsy specimen for amyloidosis was positive. Pleural disease is an uncommon presentation of systemic amyloidosis. The aetiology of the pleural effusions is unclear and is not simply a consequence of cardiac or renal impairment.

A reevaluation of the role of IgM Non-HLA antibodies in cardiac transplantation.

BACKGROUND: Preexisting IgG antibodies to donor human leukocyte antigens (HLA) are a risk factor for rapid allograft rejection. However, non-HLA antibodies, of the IgM class, also called autoreactive antibodies, are not believed to affect graft survival. The aim of this study was to determine the incidence and clinical relevance of pretransplant lymphocytotoxic non-HLA IgM antibodies on long-term cardiac allograft survival. METHODS: A retrospective study of 616 adult recipients of cardiac allografts, transplanted at this center between 1991 and 2003, has been performed. Antibodies in pretransplant sera were initially defined using complement-dependent cytotoxicity assays, and subsequently analyzed for HLA specificities using solid phase assays. RESULTS: HLA antibodies were present in 69 of 616 heart recipients (58 IgG, 11 IgM); in 22 of these, the antibodies were donor-specific. Non-HLA IgM antibodies were detected in 59 of 616 recipients who did not have HLA-specific antibodies; these patients had a 1, 2, 5, and 10 year survival of 55.9%, 54.2%, 49.9%, and 43.3% compared with 75.8%, 73.7%, 66.6%, and 52.8% for those without antibodies (P=0.0085 log-rank test). Multivariate analysis demonstrated pretransplant non-HLA IgM antibodies to be an independent risk factor for mortality (P=0.0001). Myocardial histology of postmortem heart and cardiac biopsies suggested an association with ischemic damage and "primary" allograft failure. CONCLUSIONS: We propose the hypothesis that the presence of cytotoxic IgM antibodies to non-HLAs before heart transplantation maybe a risk factor for early allograft failure.

Native valve Aspergillus endocarditis complicating lung transplantation.

We present 2 cases of Aspergillus endocarditis occurring in lung transplant recipients, both of whom were treated with early surgical intervention and triazole anti-fungal agents. Neither had evidence of airway colonization/infection with Aspergillus post-transplant, suggesting hematogenous spread of fungi at the time of surgery as a possible mechanism of infection. One case was successfully treated and discharged from the hospital, but, despite initial recovery, death occurred 10 months later due to a recurrence of Aspergillus endocarditis. Aspergillus endocarditis should be considered a relapsing disease and survivors of the condition should receive ongoing anti-fungal therapy.