Recurrent Mild Acute Rejections and Donor-specific Antibodies as Risk Factors for Cardiac Allograft Vasculopathy in a National Pediatric Heart Transplant Cohort.

Background: Immune-mediated factors such as acute cellular rejections and donor-specific antibodies (DSAs) are risk factors for cardiac allograft vasculopathy (CAV). We studied a national cohort with a unified setting and thorough protocol endomyocardial biopsy (EMB) data for an association between cellular rejections, especially when mild and recurrent, and DSAs with CAV in pediatric heart transplant (HTx) patients. Methods: This is a retrospective, national cohort study of 94 pediatric HTxs performed between 1991 and 2019 and followed until December 31, 2020. Diagnosis of CAV was based on reevaluation of angiographies. Protocol and indication EMB findings with other patient data were collected from medical records. Associations between nonimmune and immune-mediated factors and CAV were analyzed with univariable and multivariable Cox regression analyses. Results: Angiographies performed on 76 patients revealed CAV in 23 patients (30%). Altogether 1138 EMBs (92% protocol biopsies) were performed on 78 patients (83%). During the first posttransplant year, grade 1 rejection (G1R) appeared in 45 patients (58%), and recurrent (≥2) G1R findings in 14 patients (18%). Pretransplant DSAs occurred in 13 patients (17%) and posttransplant DSAs in 37 patients (39%). In univariable analysis, pretransplant DSAs, appearance and recurrence of G1R findings, and total rejection score during the first posttransplant year, as well as recurrent G1R during follow-up, were all associated with CAV. In multivariable analysis, pretransplant DSAs and recurrent G1R during the first posttransplant year were found to be associated with CAV. Conclusions: Our results indicate that pretransplant DSA and recurrent G1R findings, especially during the first posttransplant year, are associated with CAV after pediatric HTx.

The educational paradigm shift-a phenomenographic study of medical teachers' experiences of practices.

BACKGROUND: This paper proposes a novel approach to the development of competence-oriented higher education, a national transformation aimed at harmonising and digitising undergraduate medical and dental education in Finland. METHODS: We apply phenomenography as a viable qualitative method for medical education research. To better understand medical teachers' expectations towards the change in the educational paradigm, we need to study teachers' experiences of the current practices in undergraduate medical and dental education. The phenomenographic approach facilitates solid links between research, educational development, and change. RESULTS: The phenomenographic study maps the qualitatively different ways in which medical teachers experience undergraduate medical and dental education practices. The answers reflect the changing educational paradigm in medical schools, suggesting practical implications for further development of medical and dental education and training. Core content analysis is preferred instructional scaffold for both teachers and students to prioritise the extensive medical education objectives. The change towards competence-based orientation is in progress and national co-operation accelerates its impact. CONCLUSION: There is an obvious need to enrich the content of the current curriculum with national guidelines that aim for congruence in assessment and objectives. Our results suggest an assessment application for the theoretical concepts presented and promote the competence orientation of education throughout the curricula of medical and dental undergraduate education. Moreover, our results contribute to current European discourses on competence-based approaches in higher education. Up-to-date pedagogical faculty development programmes are a key prerequisite for teacher empowerment and future orientation in teaching and learning for healthcare professions.

Hurdles for adopting mobile learning devices at the outset of clinical courses.

BACKGROUND: Mobile devices provide medical students with easy access to medical information and educational resources. Since 2013, we have followed the study use of iPads among medical students. In 2016, we observed a notable drop in the mobile device usage in the first cohort of medical students entering their clinical courses. METHODS: The aim of the study was to identify the hurdles for adopting mobile devices at the beginning of the clinical courses. We examined how students evaluated their own and the clinical teachers' ability to use the iPad, how the study assignments fit into digital learning, and how students used the mobile device with patients. The data were collected with online surveys among three consecutive student cohorts and the distributions of closed-ended questions analyzed. RESULTS: Response rates ranged from 67.5 to 90.8%. Students evaluated their own ability to use the iPad as good or excellent and teachers' skills as relatively poor and wanted more digitally tailored assignments. They reported negative attitudes towards mobile device use in the clinical setting and were hesitant to use them in patient contact. Teachers seldom communicated suitable quality medical applications to students. CONCLUSIONS: Clinical teachers need support and training to implement a learning environment and assignments appropriate for mobile devices. Both students and teachers were concerned about using these devices with patients. To achieve the full potential of digitalisation in clinical courses, their use should be developed collectively with students.

[Procedural skills of students qualifying as a doctor - towards blended learning]. / Valmistuvan Iääkärin toimenpidetaidot - kohti sulautuvaa opetusta.

Medical students feel that their ability to carry out procedures is lower than desired. Whereas supervised learning is easily arranged at scheduled appointment clinics, experience in emergency procedures often accumulates only during practical training. A large part of the students had turned to the internet in search for advice or repetition about typical emergency procedures. With the growing yearly intake by the faculties it will be difficult to increase contact teaching at the clinical stage, but it is possible to improve its quality through flipped classroom. Procedural videos found in the internet are well suited for stimuli prior to contact teaching.

Pre-transplant donor-specific anti-human leukocyte antigen antibodies are associated with high risk of delayed graft function after renal transplantation.

BACKGROUND: Sensitive screening methods have revealed that many patients have donor-specific human leucocyte antigen antibodies (DSAs) prior to transplantation, regardless of negative crossmatch results. The clinical significance of pre-transplant (pre-Tx) DSAs for early graft function has remained unclear. Our aim was to examine the association of DSAs with delayed graft function (DGF). METHODS: Pre-Tx sera of 771 patients who received kidney transplants in our single-centre study were retrospectively screened. All transplantations were performed after negative complement-dependent cytotoxicity (CDC) crossmatch. RESULTS: DSAs were detected in 13% of the patients. The overall DGF rate in our study was 29%. Patients with DSAs had a higher incidence of DGF when compared with non-sensitized patients (48 and 26%, respectively; P < 0.0001). Third-party antibodies had no effect for DGF incidence (28%; P = 0.6098). The relative risk (RR) of DGF for patients with DSAs in the multivariate analysis was 2.039 (95% CI 1.246-3.335; P = 0.0046). Analyses of the cumulative mean fluorescent intensity (MFI) value of the DSAs revealed a rate of DGF more than two times higher in patients with a cumulative value of 3000-5000 MFI compared with a cumulative value of 1000-3000 (65 versus 31%; P = 0.0351). DSAs against any loci showed an elevated DGF incidence of 44-69% when compared with patients without DSA (27%). CONCLUSIONS: The risk of DGF is twice as high in patients having pre-formed DSAs. Pre-Tx DSAs is a modifiable risk factor that can be obviated with careful organ allocation relying on careful pre-Tx analysis of non-accepted mismatches determined with sensitive solid phase methods.

[Flipped classroom in basic medical education]. / Käänteinen oppiminen lääketieteen peruskoulutuksessa.

Medical education is facing changes in order to improve young doctors' competency to respond better to current needs of the patients and the society. Both curriculum content and teaching methods are revised. In addition to vibrant research in academic medical education, teachers are supported by the improved web-based learning environments and novel technical tools. Flipped classroom, a new paradigm that benefits from technical development, provides many opportunities for medical education. This teaching method always consists of two mutually complementary parts. The first part of the learning action takes place independently off classroom with video lectures or other stimuli for learning. The second part takes place in conjunction with the teacher and other students, and requires student group interactions.

Disparities in treatment rates of paediatric end-stage renal disease across Europe: insights from the ESPN/ERA-EDTA registry.

BACKGROUND: Considerable disparities exist in the provision of paediatric renal replacement therapy (RRT) across Europe. This study aims to determine whether these disparities arise from geographical differences in the occurrence of renal disease, or whether country-level access-to-care factors may be responsible. METHODS: Incidence was defined as the number of new patients aged 0-14 years starting RRT per year, between 2007 and 2011, per million children (pmc), and was extracted from the ESPN/ERA-EDTA registry database for 35 European countries. Country-level indicators on macroeconomics, perinatal care and physical access to treatment were collected through an online survey and from the World Bank database. The estimated effect is presented per 1SD increase for each indicator. RESULTS: The incidence of paediatric RRT in Europe was 5.4 cases pmc. Incidence decreased from Western to Eastern Europe (-1.91 pmc/1321 km, P < 0.0001), and increased from Southern to Northern Europe (0.93 pmc/838 km, P = 0.002). Regional differences in the occurrence of specific renal diseases were marginal. Higher RRT treatment rates were found in wealthier countries (2.47 pmc/€10 378 GDP per capita, P < 0.0001), among those that tend to spend more on healthcare (1.45 pmc/1.7% public health expenditure, P < 0.0001), and among countries where patients pay less out-of-pocket for healthcare (-1.29 pmc/11.7% out-of-pocket health expenditure, P < 0.0001). Country neonatal mortality was inversely related with incidence in the youngest patients (ages 0-4, -1.1 pmc/2.1 deaths per 1000 births, P = 0.10). Countries with a higher incidence had a lower average age at RRT start, which was fully explained by country GDP per capita. CONCLUSIONS: Inequalities exist in the provision of paediatric RRT throughout Europe, most of which are explained by differences in country macroeconomics, which limit the provision of treatment particularly in the youngest patients. This poses a challenge for healthcare policy makers in their aim to ensure universal and equal access to high-quality healthcare services across Europe.

Serum neutrophil gelatinase-associated lipocalin and recovery of kidney graft function after transplantation.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a marker for acute kidney injury. We studied whether serum NGAL predicts delayed graft function (DGF) and recovery of kidney function after transplantation. METHODS: Serum NGAL was analyzed using commercial ELISA and point-of-care (POC) (Triage®, Biosite) methods. Serum samples were collected from 176 consecutive, deceased-donor kidney recipients just before transplant surgery and on day 1 and 14 after transplantation. The first 132 samples were analyzed with both methods and the remaining samples with the POC method. RESULTS: The correlation between the ELISA and POC methods was 0.89, p < 0.0001 and hence the POC method was used for the remaining analyses. DGF was seen in 66/176 patients. Day 1 sNGAL was significantly higher in DGF (588 ng/ml, SD 189.6) compared to early graft function (355 ng/ml, SD 166.2, p < 0.0001) and this difference persisted on day 14. Day 1 sNGAL predicted DGF with an area under the curve (AUC) of 0.853 (CI 0.792-0.914, p < 0.0001). At the optimal cutoff level of 423 ng/ml the sensitivity was 87% and the specificity 77%. In a multivariate analysis, day 1 sNGAL emerged as an independent predictor of DGF. The sNGAL also predicted DGF lasting longer than 14 days with an AUC of 0.825 (CI 0.751-0.899, p < 0.0001). At the optimal cutoff level of 486 ng/ml, the sensitivity was 80% and specificity 75%. CONCLUSION: Serum NGAL predicts clinically significant DGF and is useful in the care of kidney transplant recipients.

Outcome of pediatric heart transplantation recipients treated with ventricular assist device.

This study was conducted to evaluate the long-term prognosis of pediatric HTx patients treated with VAD before transplantation. The clinical data of six patients bridged to HTx with Berlin Heart EXCOR pediatric device were analyzed retrospectively. Information about graft function, CA results, and EMB findings as well as appearance DSA was collected. Also, information about growth and cognitive function was analyzed. These findings were compared with age-, gender-, and diagnosis-matched HTx patients. During the median follow-up time of four and half yr after HTx, the prognosis including graft function, number of rejection episodes, and incidence of coronary artery vasculopathy, growth and cognitive development did not differ between VAD-bridged HTx patients compared with control patients. In both groups, one patient developed positive DSA titer after HTx. Our single-center experience suggests that the prognosis of pediatric HTx patients treated with VAD before transplantation is not inferior to that of other HTx patients.

[Cystic kidney disease and diabetes--an underdiagnosed monogenic developmental disorder]. / Kystinen munuaissairaus ja diabetes--alidiagnosoitu yksigeeninen kehityshäiriö.

Heterozygous mutations in the TCF2 gene encoding the transcription factor HNF-11 cause a dominantly inherited developmental disorder that may be associated with various dysplastic and cystic lesions of the kidneys and renal insufficiency, disorder of pancreatic development and insulin-deficient MODY diabetes, aberrant hepatic enzyme levels, gout and genital anomalies. Symptoms and findings vary in their degree of severity. When an isolated abnormality is detected, recognition of the syndrome is essential in order to diagnose the other organ manifestations. Since the mid-2000's, 10 to 20 patients have been diagnosed in Finland.

Donor-specific HLA antibodies and graft function in children after renal transplantation.

BACKGROUND: The presence of circulating donor-specific human leukocyte antigen antibodies (HLA-DSA) has been associated with chronic antibody-mediated rejection, leading to progressive graft dysfunction and poor graft survival.The aim of this study was to investigate the incidence and significance of HLA-DSA in paediatric renal transplantation(RTx) patients. METHODS: A total of 294 post-transplant serum samples from 123 RTx patients were retrospectively analysed for HLA antibodies. Positive samples were further tested for HLADSA by a Luminex Single Antigen bead assay. The antibody findings were correlated to measured glomerular filtration rate(GFR) and clinical outcome. RESULTS: HLA antibodies were detected in half of the routine samples (140/294) taken 1 month to 10 years after RTx, and 40% (62/140) of these were HLA-DSA. Overall, one-third(42/123) of the patients had HLA-DSA, which mostly(65%) reacted against class II antigens. Detection of HLADSA was not associated with poor GFR at the time of sampling, and no exceptional deterioration of GFR after the HLA-DSA detection was noted in individual patients regardless of the antibody level. The presence of HLA-DSA in the first 2 years posttransplantation was not associated with poorer graft function later on. CONCLUSION: Detection of HLA antibodies is common in children after RTx, and this finding, as such, does not predict any deterioration of graft function.

Deceased donor neutrophil gelatinase-associated lipocalin and delayed graft function after kidney transplantation: a prospective study.

INTRODUCTION: Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) and complicates kidney transplant outcome. We studied whether donor neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker for acute kidney injury, could predict DGF after transplantation. METHODS: We included 99 consecutive, deceased donors and their 176 kidney recipients. For NGAL detection, donor serum and urine samples were collected before the donor operation. The samples were analyzed using a commercial enzyme-linked immunosorbent assay kit (serum) and the ARCHITECT method (urine). RESULTS: Mean donor serum NGAL (S-NGAL) concentration was 218 ng/mL (range 27 to 658, standard deviation (SD) 145.1) and mean donor urine NGAL (U-NGAL) concentration was 18 ng/mL (range 0 to 177, SD 27.1). Donor S-NGAL and U-NGAL concentrations correlated directly with donor plasma creatinine levels and indirectly with estimated glomerular filtration rate (eGFR) calculated using the modification of diet in renal disease equation for glomerular filtration rate. In transplantations with high (greater than the mean) donor U-NGAL concentrations, prolonged DGF lasting longer than 14 days occurred more often than in transplantations with low (less than the mean) U-NGAL concentration (23% vs. 11%, P = 0.028), and 1-year graft survival was worse (90.3% vs. 97.4%, P = 0.048). High U-NGAL concentration was also associated with significantly more histological changes in the donor kidney biopsies than the low U-NGAL concentration. In a multivariate analysis, U-NGAL, expanded criteria donor status and eGFR emerged as independent risk factors for prolonged DGF. U-NGAL concentration failed to predict DGF on the basis of receiver operating characteristic curve analysis. CONCLUSIONS: This first report on S-NGAL and U-NGAL levels in deceased donors shows that donor U-NGAL, but not donor S-NGAL, measurements give added value when evaluating the suitability of a potential deceased kidney donor.

Early prednisone therapy in Henoch-Schönlein purpura: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of early prednisone therapy in preventing renal and treating extrarenal and renal symptoms in Henoch-Schönlein purpura (HSP) in a placebo-controlled trial. STUDY DESIGN: A total of 171 patients (84 treated with prednisone and 87 receiving placebo) were included and followed up for 6 months. The endpoints were renal involvement at 1, 3, and 6 months and healing of extrarenal symptoms. The analyses were performed on an intent-to-treat basis. RESULTS: Prednisone (1 mg/kg/day for 2 weeks, with weaning over the subsequent 2 weeks) was effective in reducing the intensity of abdominal pain (pain score, 2.5 vs 4.8; P = .029) and joint pain (4.6 vs 7.3; P = .030). Prednisone did not prevent the development of renal symptoms but was effective in treating them; renal symptoms resolved in 61% of the prednisone patients after treatment, compared with 34% of the placebo patients (difference = 27%; 95% confidence interval = 3% to 47%; P = .024). CONCLUSIONS: The general use of prednisone in HSP is not supported, but patients with disturbing symptoms may benefit from early treatment, because prednisone reduces extrarenal symptoms and is effective in altering (but not preventing) the course of renal involvement.

Long-term outcome 19 years after childhood IgA nephritis: a retrospective cohort study.

We evaluated the natural long-term outcome after childhood IgA nephritis. Altogether 55 patients with biopsy-proven IgA nephritis were identified, 37 (67%) responded to the health questionnaire and 31 (56%) participated in the medical examination after a mean follow-up of 18.7 years (SD 6.2; range 8.5-29.8). The results of medical examination, onset data and the re-analysis of original biopsies of 31 participants were used when analyzing the predictive factors for persistent nephropathy, i.e. constant proteinuria/hematuria or end-stage renal disease (ESRD). All patients' medical history data were obtained from regional hospitals and renal survival data from the national kidney register. Six (11%) of the 55 identified patients had developed ESRD. Sixteen (52%) of the 31 participants were not attending for regular follow-up visits after the acute phase. Twenty-two (71%) had renal symptoms and 12 (39%) were receiving drugs for hypertension/proteinuria at their latest follow-up visit. The chronicity index and total biopsy score in the first renal biopsy were higher in patients with persistent nephropathy or ESRD than in those without (p=0.022 and p=0.014, respectively). Nine (69%) of the 13 subjects who had been over 16 years of age at diagnosis had persistent nephropathy or ESRD, compared with 4 (22%) of the 18 subjects who had been under 16 years of age (relative risk 3.1, 95% CI 1.2-8.0). Pregnancy complications were common: 12 (55%) of the 22 pregnancies had been complicated by proteinuria and/or hypertension, and the prematurity rate was 30%. Long-term follow-up during adulthood is needed even after mild childhood IgA nephritis, especially in women during and after pregnancy.

Recombinant human growth hormone treatment after liver transplantation in childhood: the 5-year outcome.

BACKGROUND: Because the results of short-term recombinant human growth hormone (rhGH) treatment in children with growth impairment after liver transplantation (LTx) have been promising, we have studied the long-term effects of rhGH on growth and graft function after LTx. METHODS: Indications for rhGH treatment were height standard deviation score (hSDS) below -2.0 or growth velocity SDS below 0 and LTx at least 18 months before inclusion. Eight growth-retarded children were treated with rhGH for more than 5 years. RESULTS: During the first year, median growth rate improved from 3.3 to 7.0 cm/year. In the second and third year, growth velocity remained high at 6.6 cm/year and 6.2 cm/year, respectively (P=0.008). In the fourth year, median growth velocity started to decline but still remained above baseline during the fifth year of treatment (4.2 cm/year). The median hSDS improved from -3.6 to -2.7. During the rhGH treatment, no acute rejection episodes were detected, and graft function remained stable in all except one patient. She was diagnosed with chronic rejection in the third year of rhGH treatment. The patient had elevated liver enzymes and abnormal liver function tests already before rhGH treatment. CONCLUSIONS: The efficacy of rhGH treatment is sustained after the first year in liver-transplant children with non-GH-deficient growth retardation. Because of a potential risk of side effects, close monitoring of these patients is required.

Testis determination requires insulin receptor family function in mice.

In mice, gonads are formed shortly before embryonic day 10.5 by the thickening of the mesonephros and consist of somatic cells and migratory primordial germ cells. The male sex-determining process is set in motion by the sex-determining region of the Y chromosome (Sry), which triggers differentiation of the Sertoli cell lineage. In turn, Sertoli cells function as organizing centres and direct differentiation of the testis. In the absence of Sry expression, neither XX nor XY gonads develop testes, and alterations in Sry expression are often associated with abnormal sexual differentiation. The molecular signalling mechanisms by which Sry specifies the male pathway and models the undifferentiated gonad are unknown. Here we show that the insulin receptor tyrosine kinase family, comprising Ir, Igf1r and Irr, is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that are mutant for all three receptors develop ovaries and show a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 indicates that the insulin signalling pathway is required for male sex determination.

Anti-alpha-fetoprotein imaging is useful for staging hepatoblastoma.

BACKGROUND: Liver transplantation (Tx) has become an alternative treatment of malignant childhood liver tumors, and the importance of careful pretransplantation evaluation has been emphasized. Anti-alpha-fetoprotein (AFP) imaging has been suggested for evaluation of adult patients with AFP-positive tumors. METHODS: Antibody imaging utilizing Tc-99 m-labeled monoclonal anti-AFP Fab' fragments was used to demonstrate pathologic uptake in hepatoblastoma (HB). RESULTS: Radical operation or liver Tx was not possible after four cycles of chemotherapy in a child with HB because of a single extrahepatic metastasis. Chemotherapy was continued, and reevaluation with anti-AFP imaging demonstrated a pathologic uptake only in the liver. Subsequently, a right liver lobe resection was performed. Along with a new rise in serum AFP, repeated anti-AFP imaging revealed active liver tumor but no metastases. A liver Tx was performed, and the child is well with a normal serum AFP level 18 months after the operation. CONCLUSION: This is the first case of pediatric HB in which anti-AFP imaging has been successfully used for patient management.