Molecular epidemiology of respiratory syncytial virus in hospitalised children in Heidelberg, Southern Germany, 2014-2017.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of hopitalisation in young children with respiratory tract infections (RTI). The aim of this research project was to analyse RSV genotypes and the diversification of RSV strains among hospitalised children in Heidelberg, Germany. METHODS: We prospectively analysed nasopharyngeal swabs (NPS) from children who were hospitalised with acute RTI at the University Hospital Heidelberg, Germany, during winter seasons 2014 to 2017. RSV RT-PCR and RSV sequence analysis of the G gene coding for the attachment glycoprotein were performed. Clinical data was obtained using a standardised questionnaire. RESULTS: RSV was detected in 405 out of 946 samples from hospitalised children. Most RSV positive children were below the age of two years (84.4%) and had a lower RTI (78.8%). The majority of RSV positive children was male, significantly younger than RSV negative children with a median age of 0.39 years and with more severe respiratory symptoms. Out of 405 positive samples, 317 RSV strains were successfully sub-grouped into RSV subtypes A (57.4%; 182/317) and B (42.6%; 135/317). Both RSV subtypes cocirculated in all analysed winter seasons. Phylogenetic analysis of 317 isolates revealed that the majority of RSV-A strains (180/182) belonged to the ON1 genotype, most RSV-B strains could be attributed to the BAIX genotype (132/135). ON1 and BAIX strains showed a sub-differentiation into different lineages and we were able to identify new (sub)genotypes. CONCLUSION: Analysis of the molecular epidemiology of RSV from different seasons revealed the cocirculation and diversification of RSV genotypes ON1 and BAIX.

Recent developments in drug delivery strategies for targeting DNA damage response in glioblastoma.

Glioblastoma is the most frequent and malignant brain tumor. The median survival for this disease is approximately 15 months, and despite all the available treatment strategies employed, it remains an incurable disease. Preclinical and clinical research have shown that the resistance process related to DNA damage repair pathways, glioma stem cells, blood-brain barrier selectivity, and dose-limiting toxicity of systemic treatment leads to poor clinical outcomes. In this context, the advent of drug delivery systems associated with localized treatment seems to be a promising and versatile alternative to overcome the failure of the current treatment approaches. In order to bypass therapeutic tumor resistance mechanisms, more effective combinatorial therapies should be identified, such as the use of cytotoxic drugs combined with the inhibition of DNA damage response (DDR)-related targets. Additionally, critical reasoning about the delivery approach and administration route in brain tumors treatment innovation is essential. The outcomes of future experimental studies regarding the association of delivery systems, alternative treatment routes, and DDR targets are expected to lead to the development of refined therapeutic interventions. Novel therapeutic approaches could improve the life's quality of glioblastoma patients and increase their survival rate.

Full Angle Dependence of the Four-Loop Cusp Anomalous Dimension in QED.

The angle-dependent cusp anomalous dimension governs divergences coming from soft gluon exchanges between heavy particles, such as top quarks. We focus on the matter-dependent contributions and compute the first truly nonplanar terms. They appear at four loops and are proportional to a quartic Casimir operator in color space. Specializing our general gauge theory result to U(1), we obtain the full QED four-loop angle-dependent cusp anomalous dimension. While more complicated functions appear at intermediate steps, the analytic answer depends only on multiple polylogarithms with singularities at fourth roots of unity. It can be written in terms of four rational structures and contains functions of up to maximal transcendental weight seven. Despite this complexity, we find that numerically the answer is tantalizingly close to the appropriately rescaled one-loop formula, over most of the kinematic range. We take several limits of our analytic result, which serves as a check and allows us to obtain new, power-suppressed terms. In the antiparallel lines limit, which corresponds to production of two massive particles at threshold, we find that the subleading power correction vanishes. Finally, we compute the quartic Casimir contribution for scalars in the loop. Taking into account a supersymmetric decomposition, we derive the first nonplanar corrections to the quark antiquark potential in maximally supersymmetric gauge theory.

Analytic Form of the Full Two-Loop Five-Gluon All-Plus Helicity Amplitude.

We compute the full-color two-loop five-gluon amplitude for the all-plus helicity configuration. In order to achieve this, we calculate the required master integrals for all permutations of the external legs, in the physical scattering region. We verify the expected divergence structure of the amplitude and extract the finite hard function. We further validate our result by checking the factorization properties in the collinear limit. Our result is fully analytic and valid in the physical scattering region. We express it in a compact form containing logarithms, dilogarithms, and rational functions.

All Master Integrals for Three-Jet Production at Next-to-Next-to-Leading Order.

We evaluate analytically all previously unknown nonplanar master integrals for massless five-particle scattering at two loops, using the differential equations method. A canonical form of the differential equations is obtained by identifying integrals with constant leading singularities, in D space-time dimensions. These integrals evaluate to Q-linear combinations of multiple polylogarithms of uniform weight at each order in the expansion in the dimensional regularization parameter and are in agreement with previous conjectures for nonplanar pentagon functions. Our results provide the complete set of two-loop Feynman integrals for any massless 2→3 scattering process, thereby opening up a new level of precision collider phenomenology.

Matter Dependence of the Four-Loop Cusp Anomalous Dimension.

We compute analytically the matter-dependent contributions to the quartic Casimir term of the four-loop lightlike cusp anomalous dimension in QCD, with n_{f} fermion and n_{s} scalar flavors. The result is extracted from the double pole of a scalar form factor. We adopt a new strategy for the choice of master integrals with simple analytic and infrared properties, which significantly simplifies our calculation. To this end, we first identify a set of integrals for which the integrands have a d log form, and are hence expected to have uniform transcendental weight. We then perform a systematic analysis of the soft and collinear regions of loop integration and build linear combinations of integrals with a simpler infrared pole structure. In this way, only integrals with ten or fewer propagators are needed for obtaining the cusp anomalous dimension. These integrals are then computed via the method of differential equations through the addition of an auxiliary scale. Combining our result with that of a parallel paper, we obtain the complete n_{f} dependence of the four-loop cusp anomalous dimension in QCD. Finally, using known numerical results for the gluonic contributions, we obtain an improved numerical prediction for the cusp anomalous dimension in N=4 super Yang-Mills theory.

Analytic Result for a Two-Loop Five-Particle Amplitude.

We compute the symbol of the full-color two-loop five-particle amplitude in N=4 super Yang-Mills theory, including all nonplanar subleading-color terms. The amplitude is written in terms of permutations of Parke-Taylor tree-level amplitudes and pure functions to all orders in the dimensional regularization parameter, in agreement with previous conjectures. The answer has the correct collinear limits and infrared factorization properties, allowing us to define a finite remainder function. We study the multi-Regge limit of the nonplanar terms, analyze its subleading power corrections, and analytically present the leading logarithmic terms.

Azulene revisited: solid-state structure, invariom modeling and lattice-energy minimization of a classical example of disorder.

The molecular and solid-state structure of azulene both raise fundamental questions. Therefore, the disordered crystal structure of azulene was re-refined with invariom non-spherical atomic scattering factors from new single-crystal X-ray diffraction data with a resolution of d = 0.45 Å. An unconstrained refinement results in a molecular geometry with Cs symmetry. Refinements constrained to fulfill C2v symmetry, as observed in the gas phase and in high-level ab initio calculations, lead to similar figures of merit and residual densities as unconstrained ones. Such models are consistent with the structures from microwave spectroscopy and electron diffraction, albeit they are not the same. It is shown that for the disorder present in azulene, the invariom model describes valence electron density as successfully as it does for non-disordered structures, although the disorder still leads to high correlations mainly between positional parameters. Lattice-energy minimizations on a variety of ordered model structures using dispersion-corrected DFT calculations reveal that the local deviations from the average structure are small. Despite the molecular dipole moment there is no significant molecular ordering in any spatial direction. A superposition of all ordered model structures leads to a calculated average structure, which explains not only the experimental determined atomic coordinates, but also the apparently unusual experimental anisotropic displacement parameters.

Scattering Amplitudes from Superconformal Ward Identities.

We consider finite superamplitudes of N=1 matter, and use superconformal symmetry to derive powerful first-order differential equations for them. Because of on-shell collinear singularities, the Ward identities have an anomaly, which is obtained from lower-loop information. We show that in the five-particle case, the solution to the equations is uniquely fixed by the expected analytic behavior. We apply the method to a nonplanar two-loop five-particle integral.

[What rheumatologists can learn from ophthalmologists]. / Was der Rheumatologe vom Augenarzt lernen kann.

Intraocular inflammation with the imprecise and broad umbrella term "uveitis" is a diagnostic and therapeutic challenge in ophthalmology. Uveitis is one of the most common causes of blindness worldwide and due to the associated costs is comparable to diabetic retinopathy. Patients can be affected by uveitis at any age. Any part of the eye may be affected. The symptoms range from complete absence of symptoms, through all types of vision deterioration up to a red and even very painful eye. Uveitis can be strictly unilateral (also alternating from the left to the right eye) or bilateral with a relapsing or chronic course. The transitions are smooth and the differential diagnoses are very broad. In addition to infectious forms and ocular syndromes restricted to the eye, it also includes those with extraocular systemic diseases, such as ankylosing spondylitis or sarcoidosis. All commonly administered immunosuppressive treatment strategies in rheumatology can be used for non-infectious forms in addition to local and regional forms of treatment. The diagnostic and therapeutic impulses of this interdisciplinary interface between rheumatology and ophthalmology is discussed in more detail in this article.

Transition to adult diabetes care in Germany-High risk for acute complications and declining metabolic control during the transition phase.

OBJECTIVE: There is evidence that transition from pediatric to adult health care is frequently associated with deterioration of health in youths with type 1 diabetes (T1D). The aim of this study was to compare metabolic control, acute complications and microvascular complications in adolescents and young adults before and after transfer to an adult treatment center with respect to the time between first visit in the adult center and last visit in pediatric treatment. METHODS: All data were collected during routine care and retrieved from the German/Austrian DPV database. We analyzed data as of March 2017. RESULTS: We found 1283 young adults with available data of the last pediatric treatment year and the first year after transition to adult care. HbA1c increased significantly from 8.95% (74 mmol/mol) before to 9.20% (77 mmol/mol) in the first year after transition. Frequency of DKA with hospitalization (0.10-0.191 per annum, P < .0001) and severe hypoglycemia (0.23-0.46 per annum, P = .013) doubled during transition. Microvascular complications increased dramatically depending on the time between first visit in adult treatment and last visit in pediatric care. We could not find a significant correlation of this rise of microvascular complications to the duration of transition (short or long). CONCLUSION: This phase of life bears a high risk for detrimental outcome in young adults with T1D. Structured transition programs with case management are therefore needed to improve the transition process and outcomes.

Four-Gluon Scattering at Three Loops, Infrared Structure, and the Regge Limit.

We compute the three-loop four-gluon scattering amplitude in maximally supersymmetric Yang-Mills theory, including its full color dependence. Our result is the first complete computation of a nonplanar four-particle scattering amplitude to three loops in four-dimensional gauge theory and consequently provides highly nontrivial data for the study of nonplanar scattering amplitudes. We present the amplitude as a Laurent expansion in the dimensional regulator to finite order, with coefficients composed of harmonic polylogarithms of uniform transcendental weight, and simple rational prefactors. Our computation provides an independent check of a recent result for three-loop corrections to the soft anomalous dimension matrix that predicts the general infrared singularity structure of massless gauge theory scattering amplitudes. Taking the Regge limit of our result, we determine the three-loop gluon Regge trajectory. We also find agreement with very recent predictions for subleading logarithms.

Effects of crude hydroalcoholic extract of Syzygium cumini (L.) Skeels leaves and continuous aerobic training in rats with diabetes induced by a high-fat diet and low doses of streptozotocin.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Syzygium cumini (L.) or Skeels (Myrtaceae) are widely used in Brazilian folk medicine to treat diabetes. AIM OF THE STUDY: The present study evaluated the functional capacity, biochemical parameters, oxidative stress and DNA damage from eight weeks of intervention with a crude hydroalcoholic extract of S. cumini leaves (EBH) and continuous aerobic training (TAC) in diabetic (D) rats. MATERIALS AND METHODS: A hydroalcoholic (50%) extract was prepared by ultrasound and phytochemical parameters (total phenols, total tannins and myricetin content) were analyzed. Thirty-seven male Wistar rats were divided into five groups: normoglycemic controls (CONT), diabetic controls (D-CONT), diabetics treated with extract (D+EBH), trained diabetic (D+TAC) and diabetics treated with extract and trained (D+EBH+TAC). Functional capacity was assessed with a maximum exercise capacity test; biochemical parameters with enzymatic kits; oxidative stress by superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS) and oxidized dichlorofluorescein (DCF), and the DNA damage by the comet assay. RESULTS: The D+TAC and D+EBH+TAC groups showed better functional capacity at the end of interventions. The D+EBH group showed glucose and triglyceride reduction, lowest DNA damage index in the blood, liver, kidney, heart, lung and gastrocnemius muscle, improved SOD levels in the liver, kidney and lung, improved CAT levels in the kidney and lower lipid peroxidation in all tissues studied, compared to the D-CONT group. The exercise (D+TAC) was effective in reducing triglycerides, improving SOD levels in the lung, reducing lipid peroxidation in all tissues studied and reducing the DCF oxidation in the kidney, in addition to protecting against DNA damage in the blood and heart. However, the additive effect of the intervention protocols when combined (EBH+TAC) was observed only in improving the gastrocnemius SOD levels. The phytochemical analyses showed a high content of phenols and the presence of myricetin glycosides. CONCLUSION: The findings in this study suggest a crude hydroalcoholic extract of S. cumini leaves has potential hypoglycemic, hypolipidemic and protective properties acting against oxidative stress and against DNA damage, probably due to its phenols and myricetin glycoside content and the antioxidant properties of these constituents. Moreover, exercise was suggested to have beneficial effects on diabetes, improving functional capacity, ameliorating blood triglyceride control and decreasing lipid peroxidation, but with no effects on ameliorating blood glucose levels. The association of intervention protocols presented an additive effect on the antioxidant SOD activity in the muscle cells of diabetic rats.

Erratum: Analytic Form of the Two-Loop Planar Five-Gluon All-Plus-Helicity Amplitude in QCD [Phys. Rev. Lett. 116, 062001 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.116.062001.

Analytic Form of the Two-Loop Planar Five-Gluon All-Plus-Helicity Amplitude in QCD.

Virtual two-loop corrections to scattering amplitudes are a key ingredient to precision physics at collider experiments. We compute the full set of planar master integrals relevant to five-point functions in massless QCD, and use these to derive an analytical expression for the two-loop five-gluon all-plus-helicity amplitude. After subtracting terms that are related to the universal infrared and ultraviolet pole structure, we obtain a remarkably simple and compact finite remainder function, consisting only of dilogarithms.

Determination of the equation parameters of carbon flow curves and estimated carbon flow and CO2 emissions from broiler production.

The objective of this study was to determine the equation parameters of carbon (i.e., C) flow curves and to estimate C flow and carbon dioxide (i.e., CO2) emissions from the production of 1- to 49-day-old broilers from different genetic strains. In total, 384 1-day-old chicks were used, distributed into 4 groups: high-performance males (Cobb-M) and females (Cobb-F), and intermediate-performance males (C44-M) and females (C44-F), with 6 replicates/treatment according to a completely randomized study design. Carbon intake and retention were calculated based on diet and body C composition, and expired C was stoichiometrically estimated as digestible C intake-C retention-C in the urine. Litter C emission was estimated as initial litter C+C in the excreta-final litter C. Carbon flow curves were determined fitting data by nonlinear regression using the Gompertz function. Expired CO2 was calculated based on expired C. The applied nonlinear model presented goodness-of-fit for all responses (R2>0.99). Carbon dioxide production was highly correlated with growth rate. At 42 d age, CO2 expiration (g/bird) was 3,384.4 for Cobb-M, 2,947.9 for Cobb-F, 2,512.5 for C44-M, and 2185.1 for C44-F. Age also significantly affected CO2 production: to achieve 2.0 kg BW, CO2 expiration (g/bird) was 1,794.3 for Cobb-M, 2,016.5 for Cobb-F, 2617.7 for C44-M, and 3,092.3 for C44-F. The obtained equations present high predictability to estimate individual CO2 emissions in strains of Cobb and C44 broilers of any weight, or age, reared between 1 and 49 d age.

Treatment of young patients with HNF1A mutations (HNF1A-MODY).

AIM: Children and adolescents with a molecular diagnosis of HNF1A-MODY should be treated with oral sulfonylurea according to current International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines. METHODS: We surveyed the German-Austrian DPV database of 50 043 people and included 114 patients with a confirmed molecular-genetic diagnosis of HNF1A mutation and diabetes onset at below age 18 years. We analysed hypoglycaemic episodes, metabolic control (HbA1c ) and other clinical variables according to treatment groups. RESULTS: People with HNF1A-MODY were included and analysed according to treatment with insulin alone (n = 34), sulfonylurea (n = 30), meglitinides (n = 22) or lifestyle (n = 28). In those receiving any drug treatment (n = 86), severe hypoglycaemia did not occur with meglitinide and was highest (at 3.6 events per 100 patient-years) with insulin. HbA1c was highest with insulin treatment (insulin = 58 mmol/mol, 7.5%; sulfonylurea = 55 mmol/mol, 7.2%; meglitinides = 52 mmol/mol, 6.9%; P = 0.008), whereas weight (BMI SD score), serum lipids and blood pressure were not different. CONCLUSIONS: Of note, 40% of people with HNF1A-MODY and medical treatment were receiving insulin alone and thus were not being treated in line with up-to-date International Society for Pediatric and Adolescent Diabetes/International Diabetes Federation guidelines, despite insulin treatment being associated with worse metabolic control and the risk of hypoglycaemia. The unlicensed use of oral drugs in patients below age 18 years and adherence by both doctors and patients to the initial insulin treatment might contribute to this finding.

Moderate weight reduction in an outpatient obesity intervention program significantly reduces insulin resistance and risk factors for cardiovascular disease in severely obese adolescents.

Background. Metabolic risk factors like insulin resistance and dyslipidemia are frequently observed in severly obese children. We investigated the hypothesis that moderate weight reduction by a low-threshold intervention is already able to reduce insulin resistance and cardiovascular risk factors in severely obese children. Methods. A group of 58 severely obese children and adolescents between 8 and 17 years participating in a six-month-long outpatient program was studied before and after treatment. The program included behavioral treatment, dietary education and specific physical training. Metabolic parameters were measured in the fasting state, insulin resistance was evaluated in an oral glucose tolerance test. Results. Mean standard deviation score of the body mass index (SDS-BMI) in the study group dropped significantly from +2.5 ± 0.5 to 2.3 ± 0.6 (P < 0.0001) after participation in the program. A significant decrease was observed in HOMA (6.3 ± 4.2 versus 4.9 ± 2.4, P < 0.03, and in peak insulin levels (232.7 ± 132.4 versus 179.2 ± 73.3 µU/mL, P < 0.006). Significant reductions were also observed in mean levels of hemoglobin A(1c), total cholesterol and LDL cholesterol. Conclusions. These data demonstrate that already moderate weight reduction is able to decrease insulin resistance and dyslipidemia in severely obese children and adolescents.

Genetic and clinical characteristics of patients with HNF1A gene variations from the German-Austrian DPV database.

OBJECTIVE: To determine prevalence, genetic and phenotype characteristics of patients with hepatocyte nuclear factor-1α (HNF1A) variants in the Diabetes Patienten Verlaufsdokumenation (DPV) multicentre database and to examine the influence of HNF1A mutation type, or location on clinical phenotypes. PATIENTS AND METHODS: Seventy-one DPV patients were labelled as HNF1A-MODY (MODY3). Forty-four patients carried HNF1A mutations, while 27 patients were found to have HNF1A polymorphisms only. Associations between mutation type/position and age at disease onset, HbAlc, body mass index (BMI), diagnosis, family history and treatment modality were analysed using non-parametric statistics (Wilcoxon test). RESULTS: Patients with HNF1A mutations were 36% male, aged 14.1±5.8 years at diagnosis, and slightly overweight (BMI-SDS: +0.8±1.1). Treatment was lifestyle intervention (20.5%), insulin (35.3%), oral anti-diabetic (OAD, 43%) and both insulin+OAD (15.9%). More patients with missense mutations (60%) than patients with nonsense mutations/frameshift (23.8%) did not use insulin (P=0.03). No differences were found with regard to mutation types, isoform or domain. We identified several previously undescribed mutations in the cohort including c.-158insGGGTTGG in the promoter region, G31X, E41X, Q130X, L162P, R245I, A269P, S355X, Q398X, Q473X, Q495X, E508X, P588fs-insGCCA and P588fs-delAC. Patients carrying HNF1A polymorphisms were significantly younger at diagnosis than patients with HNF1A mutations (10.9±4.2 vs 14.19±5.8 years; P=0.027), and all carried I27L, S487N and A98V (n=3). CONCLUSION: HNF1A-MODY is the second most frequent MODY diagnosis registered in the DPV database, and previously undescribed HNF1A mutations account for about one-third of HNF1A-MODY cases. Patients with HNF1A polymorphisms documented as HNF1A-MODY were misclassified. They may have autoantibody-negative type 1B or type 2 diabetes or may have other MODY types.

Entities and frequency of neonatal diabetes: data from the diabetes documentation and quality management system (DPV).

AIMS: The aim of this study was to elucidate the entities and the frequency of neonatal diabetes mellitus (NDM) in a large representative database for paediatric diabetes patients in Germany and Austria. METHODS: Based on the continuous diabetes data acquisition system for prospective surveillance (DPV), which includes 51,587 patients with onset of diabetes before the age of 18 years from 299 centres in Germany and Austria, we searched for patients with onset of diabetes mellitus in the first 6 months of life. RESULTS: Ninety patients were identified, comprising 0.17% of all paediatric cases in the DPV registry. This represented an incidence of approximately one case in 89,000 live births in Germany. A monogenic basis for NDM was established in 30 subjects (seven UPD6, 10 KCNJ11, seven ABCC8, two FOXP3, two PDX1, one INS, one EIF2AK3). Pancreatic hypoplasia or agenesis was reported in 10 patients and seven subjects were classified as having Type 1 diabetes by their centres. Transient neonatal diabetes (TNDM) accounted for approximately 10% of all cases with NDM. No aetiology was defined in 41 subjects, which may reflect incomplete genetic testing or novel genetic aetiologies. CONCLUSION: Based on a large database, we identified a higher rate of NDM in Germany than has been reported previously. Full molecular genetic testing should be performed in all patients diagnosed before 6 months of age.