Zinc (Zn) and Zn-based alloys have been proposed as a new generation of absorbable metals mainly owing to the moderate degradation behavior of zinc between magnesium and iron. Nonetheless, mechanical ...strength of pure Zn is relatively poor, making it insufficient for the majority of clinical applications. In this study, a novel Zn-2Ag-1.8Au-0.2V (wt.%) alloy (Zn-Ag-Au-V) was fabricated and investigated for use as a potential absorbable biocompatible material. Microstructural characterization indicated an effective grain-refining effect on the Zn alloy after a thermomechanical treatment. Compared to pure Zn, the Zn-Ag-Au-V alloy showed significantly enhanced mechanical properties, with a yield strength of 168 MPa, an ultimate tensile strength of 233 MPa, and an elongation of 17%. Immersion test indicated that the degradation rate of the Zn-Ag-Au-V alloy in Dulbecco's phosphate buffered saline was approximately 7.34 ± 0.64 μm/year, thus being slightly lower than that of pure Zn. Biocompatibility tests with L929 and Saos-2 cells showed a moderate cytotoxicity, alloy extracts at 16.7%, and 10% concentration did not affect metabolic activity and cell proliferation. Plaque formation in vitro was reduced, the Zn-Ag-Au-V surface inhibited adhesion and biofilm formation by the early oral colonizer
, indicating antibacterial properties of the alloy.
Rationale
In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children.
...Objectives
To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages.
Methods
In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28.
Measurements and main results
Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood.
Conclusions
Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.
Background
Infection with SARS‐CoV‐2 leads to COVID‐19, the course of which is highly variable and depends on numerous patient‐specific risk factors. Patients with tumor diseases are considered to be ...more susceptible to severe COVID‐19; however, they also represent a heterogeneous group of individuals with variable risk. Identifying specific risk factors for a severe course of COVID‐19 in patients with cancer is of great importance.
Methods
Patients diagnosed with solid tumors or hematological malignancies and PCR‐confirmed SARS‐CoV‐2 infection were included into the multicentric ADHOK (Arbeitsgemeinschaft der Hämatologen und Onkologen im Krankenhaus e.V.) coronavirus tumor registry. Detailed information about the patients’ cancer disease, treatment, and laboratory parameters prior to infection, was collected retrospectively. The outcome of the SARS‐CoV‐2 infection was graded according to the WHO.
Results
A total of 195 patients (68% with solid neoplasms and 32% with hematological malignancies) were included in the registry. Overall, the course of the SARS‐CoV‐2 infection varied greatly, as 69% of all patients were either asymptomatic or encountered a mild to moderate course, while 23% of the cohort died from COVID‐19. In multivariable analysis, preinfection laboratory parameters (determined at least 10 days and a median of 21 days before the first documentation of SARS‐CoV‐2 infection) significantly correlated with severe course of the disease. Out of these, the absolute neutrophil count prior to infection showed the strongest association with COVID‐19‐related death.
Conclusion
The course of COVID‐19 in patients with tumor diseases is highly variable. Preinfection laboratory parameters may aid to identify patients at risk for severe COVID‐19 at an early stage prior to infection with the virus.
German Clinical Trials Register identification: DRKS00023012.
The course of SARS‐CoV‐2 infection in tumor patients is highly variable. Subgroups at risk for severe COVID‐19 are yet imprecisely defined. Laboratory parameters prior to infection, particularly pre‐infection neutrophils, may identify patients at risk for death.
Hydroalumination of R-P(H)-C&z.tbd;C-
t
Bu with bulky H-AlCH(SiMe
3
)
2
2
afforded the new P-H functionalized Al/P-based frustrated Lewis pair R-P(H)-C&z.dbd;C(H)-
t
Bu-AlR
2
R = CH(SiMe
3
)
2
; FLP
...7
. A weak adduct of
7
with benzonitrile (
8
) was detected by NMR spectroscopy, but could not be isolated.
tert
-Butyl isocyanide afforded a similar, but isolable adduct (
9
), in which the isocyanide C atom was coordinated to aluminium. The unique reactivity of
7
became evident from its reactions with the heteroatom substituted nitriles PhO-C&z.tbd;N, PhCH
2
S-C&z.tbd;N and H
8
C
4
N-C&z.tbd;N. Hydrophosphination of the C&z.tbd;N triple bonds afforded imines at room temperature which were coordinated to the FLP by Al-N and P-C bonds to yield AlCPCN heterocycles (
10
to
12
). These processes depend on substrate activation by the FLP. Diphenylcyclopropenone and its sulphur derivative reacted with
7
by addition of the P-H bond to a C-C bond of the strained C
3
ring and ring opening to afford the fragment (
Z
)-Ph-C(H)&z.dbd;C(Ph)-C-X-Al (X = O, S). The C-O or C-S groups were coordinated to the FLP to yield AlCPCX heterocycles (
13
and
14
). The thiocarbonyl derived compound
14
contains an internally stabilized phosphenium cation with a localized P&z.dbd;C bond, a trigonal planar coordinated P atom and a short P&z.dbd;C distance (168.9 pm). Insight into formation mechanisms, the structural and energetic properties of FLP
7
and compounds
13
and
14
was gained by quantum chemical DFT calculations.
A P-H functionalized FLP reacted with RX-C&z.tbd;N by hydrophosphination. Ring opening by treatment with cyclopropenthione resulted in P&z.dbd;C bond formation.
Serum lipase activities above the threefold upper reference limit indicate acute pancreatitis. We investigated whether high lipase activity-within the reference range and in the absence of ...pancreatitis-are associated with genetic single nucleotide polymorphisms (SNP), and whether these identified SNPs are also associated with clinical pancreatitis.
Genome-wide association studies (GWAS) on phenotypes 'serum lipase activity' and 'high serum lipase activity' were conducted including 3966 German volunteers from the population-based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genome-wide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients.
Initial discovery GWAS detected SNPs within or near genes encoding the ABO blood group specifying transferases A/B (ABO), Fucosyltransferase-2 (FUT2), and Chymotrypsinogen-B2 (CTRB2), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR=1.49; p=0.012) and ABO blood-type-B (OR=2.48; p=7.29×10(-8)) with high lipase activity levels. In pancreatitis patients, significant associations were found for FUT-2 non-secretor status (OR=1.53; p=8.56×10(-4)) and ABO-B (OR=1.69, p=1.0×10(-4)) with chronic pancreatitis, but not with acute pancreatitis. Conversely, carriers of blood group O were less frequently affected by chronic pancreatitis (OR=0.62; p=1.22×10(-05)) and less likely to have high lipase activity levels (OR=0.59; p=8.14×10(-05)).
These are the first results indicating that ABO blood type-B as well as FUT2 non-secretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects.
Comprehensive studies investigated the role of T cells in asthma leading to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B ...cells to this chronic inflammatory disease. In this study, we investigated the contribution of various B cell populations to specific clinical features in asthma.
In the All Age Asthma Cohort (ALLIANCE) a subgroup of 154 adult asthma patients and 28 healthy controls were included for B cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B cells
association studies and multivariate linear models.
Patients with severe asthma showed decreased immature B cell populations while memory B cells were significantly increased compared to both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of immunoglobulin A positive (IgA
) memory B cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA
memory B cells, particularly in patients with mild to moderate asthma. Additionally, IgA
memory B cells significantly correlated with clinical features of SAD such as exacerbations.
With this study we demonstrate for the first time a significant association of increased IgA
memory B cells with asthma and SAD, pointing towards future options for B cell-directed strategies in preventing and treating asthma.
Abstract
Background and Aims
Antibody-mediated rejection (AMR) is among the most common causes for kidney transplant loss. The histological diagnosis is hampered by significant intra- and ...interobserver variability. Training a deep learning classifier for the recognition of AMR on glomerular transections as the most decisive compartment could establish a reliable and perfectly reproducible diagnostic method.
Method
We identified 48 biopsies with AMR (all positive for donor-specific antibody) and 38 biopsies without AMR according to Banff 2017 from our archive. Photographs were taken from all non-globally sclerosed glomeruli on two PAS-stained level sections, yielding a total of 1,655 images as a training set. 1,503 images could be labeled by three experienced nephropathologists conclusively as AMR or non-AMR in a blinded fashion. We trained a DenseNet-121 classifier (pre-trained on ImageNet) with basic online augmentation. In addition, we implemented StyPath++, a data augmentation algorithm that leverages a style transfer mechanism, addressing significant domain shifts in histopathology. Each sample was assigned a consensus label generated by the pathologists.
Results
Five-fold cross validation schemes produced a weighted glomerular level performance of 88.1%, exceeding the baseline performance by 5%. The improved generalization ability of the StyPath++ augmented model shows that it is possible to construct reliable glomerular classification algorithms with scarce datasets.
Conclusion
We created a deep learning classifier with excellent performance and reproducibility for the diagnosis of AMR on glomerular transections. We plan to expand the training set, including challenging cases of differential diagnoses like glomerulonephritis or other glomerulopathies. We are also interested in external clinicopathological datasets to further validate our results.
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