This trial assessed alum-formulated glutamic acid decarboxylase, the 65-kD isoform (GAD65), a major autoantigen in type 1 diabetes. In patients with recent-onset disease; the compound did not ...significantly alter the loss of C peptide or improve clinical outcomes.
The clinical onset of type 1 diabetes is manifested by the effects of inadequate insulin secretion due to the immunologic destruction of pancreatic-islet beta cells.
1
Despite replacement therapy with exogenous insulin, type 1 diabetes is associated with substantial morbidity and mortality.
2
,
3
Even modest preservation of insulin secretion appears to reduce short- and long-term complications of type 1 diabetes.
4
–
9
Initial attempts at immunosuppression to treat type 1 diabetes had a positive effect but one that was outweighed by treatment-related adverse events.
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More recently, selective immunosuppression has been attempted. Phase 2 trials showed promising efficacy, but phase 3 studies . . .
Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result ...from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death.
Multicenter prospective cohort study.
Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded.
Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year.
Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events.
The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years’ initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year.
Current follow-up can only detect large differences in ESKD and death outcomes.
Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.
Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF ...targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient's liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.
The NAPRTCS has collected clinical information on children undergoing renal transplantation since 1987 and now includes information on 12 920 renal transplants in 11 870 patients. Since the first ...data analysis in 1989, NAPRTCS reports have documented marked improvements in patient and allograft outcomes after pediatric renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation and also provides historical perspective. This report highlights current practices in an era of major changes in DD kidney allocation and continuing steroid minimization. This report presents outcomes of the patients in the NAPRTCS transplant registry up to end of 2017. In particular, an increase in the cumulative incidence of late first AR has occurred in the most recent cohort, while all prior cohorts had a lower cumulative incidence of late first AR.
Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the ...presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell activity and high level of soluble interleukin-2 receptor.
Here we present a 6-month-old girl with parents from Southern Italy. She suffered from hepatosplenomegaly and a recurrent high fever for 3 months' duration. On admission, she showed neurological symptoms including irritability and neck stiffness. Blood analysis revealed bicytopenia, namely anemia and thrombocytopenia. The first bone marrow aspirate was indicative for neither malignancies nor HLH. At this time, additional investigations indicated macrophage activation syndrome with elevated ferritin value (11.741ng/ml), soluble interleukin-2 receptor (CD25) levels (16.018U/ml), hypertriglyceridemia (582mg/dl) supportive of the diagnosis of HLH. Because of the worsening of her clinical condition, a second bone marrow aspirate and biopsy was performed 5 days later when the child became pancytopenic. The second bone marrow aspirate still did not show morphological signs of HLH, but microorganisms were detected in at least one macrophage, which were consecutively diagnosed as Leishmania amastigotes within macrophages by positive Leishmanial polymerase chain reaction from bone marrow specimen. Consistent with the diagnosis of visceral Leishmaniasis Amphotericin B (liposomal) therapy was initiated which resulted in dramatic resolution of fever, splenomegaly, ferritin levels, and recovery of blood counts within 96 hours.
Familial hemophagocytic lymphohistiocytosis (FHL) manifests as acute illness with prolonged fever, cytopenias and hepatosplenomegaly. Onset typically occurs within the first months of life. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months. Acquired HLH is typically associated with T-/NK-cell lymphomas and autoimmune diseases but also with infections including EBV, malaria and Leishmaniasis. Even in non-endemic areas, our case of vertically transmitted Leishmaniasis highlights the importance of recognizing infectious etiologies of HLH compared with hereditary forms of HLH in early infancy to initiate appropriate therapy to prevent life-threatening complications.
Russo:Novo Nordisk: Other: conference fee, travel and accomodation support ; Octapharma: Other: conference fee, travel and accomodation support. Lammle:Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support ; Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support .
Abstract
Introduction
Regarding pediatric diabetes, hospital admission for
acute complications of type 1 diabetes (T1D) has often been investigated,
but little is known about other causes of ...hospitalization. This study aimed
to explore the total burden of hospitalization in individuals with
diabetes<20 years of age in Germany.
Methods
Using the German Diagnosis-Related Groups data for 2015, we
examined the frequencies of hospitalization with diabetes (20 251
inpatient cases), stratified by diabetes type T1D, type 2 diabetes (T2D),
other specified diabetes types (T3D), and unclear diabetes, and without
diabetes (1 269 631 inpatient cases). Using estimates of the
population at risk with T1D, T2D, and without diabetes, we evaluated
hospitalization rates (per patient-year) by Poisson regression. For T1D,
T2D, and T3D, we investigated the most frequent diagnoses and the median
length of stay. Most analyses were stratified by sex, age-group and
east/west residence.
Results
Children and adolescents with diabetes had a 6 to 9 times
higher hospitalization risk than peers without diabetes (hospitalization
rate 0.09). The hospitalization rate was higher for T2D compared with T1D
(0.84 vs. 0.53, P<0.001). In T2D, two-third of inpatient cases were
not directly related to diabetes, and stay was shorter compared with T1D and
T3D (3 vs. 4 and 5 days, respectively). In T1D, hospitalization was more
frequent among girls than boys (0.58 vs. 0.49, P<0.001), and mostly
due to “diabetes without complications” (65.7%).
Hospitalization tended to be more frequent and longer in the youngest
patients, and in those with east residence.
Conclusion
Hospitalization rate in pediatric diabetes in Germany
remained high, especially for T2D patients, girls with T1D, and young
children.
There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort ...study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β 95% CI for composite PROMIS score in children, -5.2 -7.1 to -3.4; for composite PROMIS score in adults, -6.1 -7.4 to -4.9). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.
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IMPORTANCE: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific ...cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. OBJECTIVE: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. MAIN OUTCOMES AND MEASURES: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. RESULTS: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; P = 9.6 × 10−7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. CONCLUSIONS AND RELEVANCE: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.
In pediatric diabetes, insulin pump therapy is associated with less acute complications but inpatient pump education may lead to more hospital days. We investigated the number of hospital days ...associated with pump vs. injection therapy between 2009 and 2018 in 48,756 patients with type 1 diabetes < 20 years of age from the German Diabetes Prospective Follow-up Registry (DPV). Analyses were performed separately for hospitalizations at diagnosis (hierarchical linear models adjusted for sex, age, and migration), and for hospitalizations in the subsequent course of the disease (hierarchical Poisson models stratified by sex, age, migration, and therapy switch). At diagnosis, the length of hospital stay was longer with pump therapy than with injection therapy (mean estimate with 95% CI: 13.6 13.3–13.9 days vs. 12.8 12.5–13.1 days,
P
< 0.0001), whereas during the whole follow-up beyond diagnosis, the number of hospital days per person-year (/PY) was higher with injection therapy than with pump therapy (4.4 4.1–4.8 vs. 3.9 3.6–4.2 days/PY), especially for children under 5 years of age (4.9 4.4–5.6 vs. 3.5 3.1–3.9 days/PY).
Conclusions:
Even in countries with hospitalizations at diabetes diagnosis of longer duration, the use of pump therapy is associated with a reduced number of hospital days in the long-term.
What is known:
• In pediatric diabetes, insulin pump therapy is associated with better glycemic control and less acute complications compared with injection therapy.
• However, pump therapy implies more costs and resources for education and management.
What is new:
• Even in countries where pump education is predominantly given in an inpatient setting
,
the use of pump therapy is associated with a reduced number of hospital days in the long-term.
• Lower rates of hospitalization due to acute complications during the course of the disease counterbalance longer hospitalizations due to initial pump education
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