Outbreak of severe community-acquired bacterial infections among children in North Rhine-Westphalia (Germany), October to December 2022.

PURPOSE: In late 2022, a surge of severe S. pyogenes infections was reported in several European countries. This study assessed hospitalizations and disease severity of community-acquired bacterial infections with S. pyogenes, S. pneumoniae, N. meningitidis, and H. influenzae among children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences. METHODS: Hospital cases due to bacterial infections between October and December 2022 were collected in a multicenter study (MC) from 59/62 (95%) children's hospitals in NRW and combined with surveillance data (2016-2023) from the national reference laboratories for streptococci, N. meningitidis, and H. influenzae. Overall and pathogen-specific incidence rates (IR) from January 2016 to March 2023 were estimated via capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics. RESULTS: In the MC study, 153 cases with high overall disease severity were reported with pneumonia being most common (59%, n = 91). IRs of bacterial infections declined at the beginning of the COVID-19 pandemic and massively surged to unprecedented levels in late 2022 and early 2023 (overall hospitalizations 3.5-fold), with S. pyogenes and S. pneumoniae as main drivers (18-fold and threefold). Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9). DISCUSSION: The unprecedented peak of bacterial infections and deaths in late 2022 and early 2023 was caused mainly by S. pyogenes and S. pneumoniae. Improved precautionary measures are needed to attenuate future outbreaks.

Attenuation correction in CZT myocardial perfusion imaging comparison of supine-prone and low-dose CT-corrected supine acquisitions.

AIMS: The study aimed to investigate whether additional prone imaging delivers comparable results to supine imaging with low-dose computed tomography (CT) attenuation correction (CTAC) in cadmium, zinc and telluride (CZT) myocardial perfusion imaging. METHODS AND RESULTS: Thirty-four patients with an indication for myocardial perfusion imaging were studied with a CZT camera in the supine and then prone position. Furthermore, a low-dose CT was acquired. Three data sets were reconstructed and considered for analysis: (1) supine CZT, (2) supine CZT with CTAC and (3) supine CZT with additional prone CZT. Based on 17-segment polartomograms, we compared radiopharmaceutical uptake percentage, summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), total ischemic and scarred segments, and finally scan classification and clinical decision-making. SSS of supine/supine-CTAC/supine-prone was 341/229/253 (P < 0.05), SRS was 246/156/164 (P < 0.05) and SDS was 104/88/96 (ns), respectively. Total ischemic segments were 65/67/65 (ns) and total scarred segments 96/62/69 (P < 0.05), respectively. The frequency of normal scans was highest for supine-prone, followed by supine-CTAC and supine (41/35/24%, respectively). Supine imaging indicated 23% of patients for invasive coronary angiography, both supine-CTAC and supine-prone 18%. These two showed a significant intercorrelation. CONCLUSION: Additional prone imaging and CTAC are mainly correct for the amount and extent of myocardial scars. Both methods increase the frequency of normal scans and show a significant agreement in clinical decision-making. Additional prone imaging appears as a useful alternative when a low-dose CT for attenuation correction is not available.

Antiproliferative Activity of Functionalized Histidine-derived Au(I) bis-NHC Complexes for Bioconjugation.

A series of histidine derived Au(I) bis-NHC complexes bearing different ester, amide and carboxylic acid functionalities as well as wingtip substituents is synthesized and characterized. The stability in aqueous media, in vitro cytotoxicity in a set of cancer cell lines (MCF7, PC3 and A2780/A2780cisR) along with the cellular uptake are evaluated. Stability tests suggest hydrolysis of the ester within 8 h, which might lead to deactivation. Furthermore, the bis-NHC system shows a sufficient stability against cysteine and the thiol containing peptide GSH. The benzyl ester and amide show the highest activity comparable to the benchmark compound cisplatin, with the ester only displaying a slightly lower cytotoxicity than the amide. A cellular uptake study revealed that the benzyl ester and the amide could have different intracellular distribution profiles but both complexes induce perturbations of the cellular physiological processes. The simple modifiability and high stability of the complexes provides a promising system for upcoming post modifications to enable targeted cancer therapy.

Diabetes care in pediatric refugees from Africa or Middle East: experiences from Germany and Austria based on real-world data from the DPV registry.

OBJECTIVE: With increasing migration to Europe, diabetes diagnosis and treatment of refugees became challenging. To describe the current experience with pediatric refugees in Germany and Austria. DESIGN AND METHODS: 43,137 patients (<21 years) with type 1 diabetes from the diabetes patient follow-up registry (DPV) were studied and divided by refugee status into patients born in Middle East (n = 365) or Africa (n = 175) and native patients (child and parents born in Germany/Austria; G/A: n = 42,597). Groups were compared using multivariable regression adjusted for age, sex and diabetes duration (SAS 9.4). In refugees the first year after arrival was studied, and for native children the most recent year of care. RESULTS: After adjustment, HbA1c was highest in refugees (1. ME and 2. AFR vs 3. G/A: 72.3 ± 1.0 and 75.0 ± 1.4 vs 66.0 ± 0.1 mmol/mol, 1 vs 3: P < 0.001 and 2 vs 3: P < 0.001) and microalbuminuria (9.9 and 13.6 vs 6.5%, 1 vs 3: P = 0.039 and 2 vs 3: P = 0.002) was more prevalent. African children experienced severe hypoglycemia (17.8 ± 4.3 and 25.4 ± 8.7 vs 11.5 ± 0.3 per 100 patient years, 1 vs 3: P > 0.05 and 2 vs 3: P = 0.045) significantly more often, whereas hypoglycemia with coma (5.1 ± 1.1 and 4.1 ± 1.6 vs 2.6 ± 0.1 per 100 patient years, 1 vs 3: P = 0.006 and 2 vs 3: P > 0.05) and retinopathy (2.1 and n/a vs 0.2%, 1 vs 3: P < 0.001) were significantly more common in children from Middle East compared to natives. Insulin pumps were used in a markedly larger proportion of native patients (7.4 and 13.2 vs 43.0%, 1 vs 3: P < 0.001 and 2 vs 3: P < 0.001). CONCLUSIONS: A relevant number of pediatric refugees with type 1 diabetes are treated in German/Austrian diabetes clinics. Refugee children, parents and caregivers are faced with several problems in diabetes therapy and outcome that should be addressed more intensively by pediatric diabetes teams.

Impact of c-MYC expression on proliferation, differentiation, and risk of neoplastic transformation of human mesenchymal stromal cells.

BACKGROUND: Mesenchymal stromal cells isolated from bone marrow (MSC) represent an attractive source of adult stem cells for regenerative medicine. However, thorough research is required into their clinical application safety issues concerning a risk of potential neoplastic degeneration in a process of MSC propagation in cell culture for therapeutic applications. Expansion protocols could preselect MSC with elevated levels of growth-promoting transcription factors with oncogenic potential, such as c-MYC. We addressed the question whether c-MYC expression affects the growth and differentiation potential of human MSC upon extensive passaging in cell culture and assessed a risk of tumorigenic transformation caused by MSC overexpressing c-MYC in vivo. METHODS: MSC were subjected to retroviral transduction to induce expression of c-MYC, or GFP, as a control. Cells were expanded, and effects of c-MYC overexpression on osteogenesis, adipogenesis, and chondrogenesis were monitored. Ectopic bone formation properties were tested in SCID mice. A potential risk of tumorigenesis imposed by MSC with c-MYC overexpression was evaluated. RESULTS: C-MYC levels accumulated during ex vivo passaging, and overexpression enabled the transformed MSC to significantly overgrow competing control cells in culture. C-MYC-MSC acquired enhanced biological functions of c-MYC: its increased DNA-binding activity, elevated expression of the c-MYC-binding partner MAX, and induction of antagonists P19ARF/P16INK4A. Overexpression of c-MYC stimulated MSC proliferation and reduced osteogenic, adipogenic, and chondrogenic differentiation. Surprisingly, c-MYC overexpression also caused an increased COL10A1/COL2A1 expression ratio upon chondrogenesis, suggesting a role in hypertrophic degeneration. However, the in vivo ectopic bone formation ability of c-MYC-transduced MSC remained comparable to control GFP-MSC. There was no indication of tumor growth in any tissue after transplantation of c-MYC-MSC in mice. CONCLUSIONS: C-MYC expression promoted high proliferation rates of MSC, attenuated but not abrogated their differentiation capacity, and did not immediately lead to tumor formation in the tested in vivo mouse model. However, upregulation of MYC antagonists P19ARF/P16INK4A promoting apoptosis and senescence, as well as an observed shift towards a hypertrophic collagen phenotype and cartilage degeneration, point to lack of safety for clinical application of MSC that were manipulated to overexpress c-MYC for their better expansion.

Impact of Maternal Country of Birth on Type-1-Diabetes Therapy and Outcome in 27,643 Children and Adolescents from the DPV Registry.

OBJECTIVE: To study the impact of maternal country of birth on type-1-diabetes (T1D) therapy and outcome. STUDY DESIGN AND METHODS: 27,643 T1D patients aged ≤20 years with documented maternal country of birth from the multicenter German/Austrian diabetes patient registry (DPV) were analyzed. Patients were categorized based on their mother's origin: Germany/Austria (reference), Turkey, Southern Europe, and Eastern Europe. To compare BMI standard deviation score (BMI-SDS), diabetes therapy and outcome between groups, multivariable regression was applied with adjustments for age, sex and duration of diabetes. Based on observed marginal frequencies, adjusted estimates were calculated. Linear regression was used for continuous data, logistic regression for binary data and Poisson regression for count data. All statistical analyses were performed using SAS 9.4. Significance was set at a two-tailed p<0.05. RESULTS: 83.3% of patients were offspring of native mothers. A Turkish, Southern or Eastern European background was documented in 2.4%, 1.7% and 4.3% of individuals. After demographic adjustment, patients with migration background had a higher mean BMI-SDS (Turkey, Southern Europe or Eastern Europe vs. Germany/Austria: 0.58±0.03, 0.40±0.04, or 0.37±0.02 vs. 0.31±0.01; ±SE) and a lower use of insulin pumps (26.8%, 27.9%, or 32.6% vs. 37.9%) compared to offspring of native mothers. Mean HbA1c was worst in individuals of Turkish mothers (Turkey vs. Germany/Austria: 69.7±0.7 vs. 66.6±0.1 mmol/mol; ±SE). Patients of Eastern European descent had an increased rate of severe hypoglycemia (22.09±0.13 vs. 16.13±0.02 events per 100 patient-years) and ketoacidosis was more prevalent in offspring of Turkish or Southern European mothers (7.50±0.10, or 7.13±0.11 vs. 6.54±0.02 events per 100 patient-years). Patients of Turkish descent were more often hospitalized (57.2±2.7 vs. 48.5±0.4 per 100 patient-years). All differences were significant. CONCLUSION: The differences in diabetes therapy and outcome among patients with distinct migration background suggest that specific challenges have to be considered in clinical care.

Making oxidation potentials predictable: coordination of additives applied to the electronic fine tuning of an iron(II) complex.

This work examines the impact of axially coordinating additives on the electronic structure of a bioinspired octahedral low-spin iron(II) N-heterocyclic carbene (Fe-NHC) complex. Bearing two labile trans-acetonitrile ligands, the Fe-NHC complex, which is also an excellent oxidation catalyst, is prone to axial ligand exchange. Phosphine- and pyridine-based additives are used for substitution of the acetonitrile ligands. On the basis of the resulting defined complexes, predictability of the oxidation potentials is demonstrated, based on a correlation between cyclic voltammetry experiments and density functional theory calculated molecular orbital energies. Fundamental insights into changes of the electronic properties upon axial ligand exchange and the impact on related attributes will finally lead to target-oriented manipulation of the electronic properties and consequently to the effective tuning of the reactivity of bioinspired systems.