Despite antibiotics, antifungals and haematopoietic growth factors, infections remain a major threat to neutropenic patients. To determine the role of granulocyte transfusions (GTs) in anti-infective ...therapy during neutropenia, GT administration was randomized in 74 adults with haematological or malignant diseases, febrile neutropenia and pulmonary or soft-tissue infiltrates after conventional or high-dose chemotherapy, a majority of them after allo-SCT (n=39). Neutrophil reconstitution was equal in the treatment and control arm. GT toxicity was minimal. The probability of 28-day survival after randomization was >80% in both groups, and no effect of GT on survival until day 100 could be detected in patients with fungal (n=55), bacterial or unknown infection (n=17) and various levels of neutropenia (ANC <500 vs >500 x 10(6)/l). These findings can be attributed primarily to procedural obstacles, such as long delay from randomization to first GT, low cell content and slow sequence of GT, difficulties in randomizing a safe and potentially life-saving treatment in severely endangered individuals, and a large proportion of rapidly recovering patients in both arms. The requirement of another trial in a more specific patient population with daily transfusions of sufficient numbers of granulocytes to support or refute the empirically acknowledged benefits of GT is discussed.
We describe a laser–plasma platform for photon–photon collision experiments to measure fundamental quantum electrodynamic processes. As an example we describe using this platform to attempt to ...observe the linear Breit–Wheeler process. The platform has been developed using the Gemini laser facility at the Rutherford Appleton Laboratory. A laser Wakefield accelerator and a bremsstrahlung convertor are used to generate a collimated beam of photons with energies of hundreds of MeV, that collide with keV x-ray photons generated by a laser heated plasma target. To detect the pairs generated by the photon–photon collisions, a magnetic transport system has been developed which directs the pairs onto scintillation-based and hybrid silicon pixel single particle detectors (SPDs). We present commissioning results from an experimental campaign using this laser–plasma platform for photon–photon physics, demonstrating successful generation of both photon sources, characterisation of the magnetic transport system and calibration of the SPDs, and discuss the feasibility of this platform for the observation of the Breit–Wheeler process. The design of the platform will also serve as the basis for the investigation of strong-field quantum electrodynamic processes such as the nonlinear Breit–Wheeler and the Trident process, or eventually, photon–photon scattering.
Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic ...lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.
...the outcome of HSCT in patients with syndromes with predominant autoimmunity is unclear, given that target antigens of autoimmune reactions remain unchanged, and both autoimmunity and inflammation ...can persist because of disease-causing factors extrinsic to the hematopoietic and immune system. ...the need for immunosuppressive treatment decreased, and most patients were off immunoglobulin replacement after HSCT (Fig 1, D and E). The risk of LRBA-related lymphoma or immunosuppression-associated malignancy would be anticipated to be substantially reduced or abolished in HSCT survivors, as well as the future risk of infections, compared with patients undergoing continuous treatment with CTLA4-Ig, sirolimus, or other immunosuppression. ...based on the present results, we would proceed to HSCT if a suitable donor was present. ...among the small cohort of 12 LRBA-deficient patients who underwent transplantation from heterozygous LRBA mutation carriers (n = 6) or LRBA wild-type (n = 1) or unrelated donors (n = 5), no correlation between residual or recurring LRBA-related symptoms and donor LRBA status was detected, arguing against a dose effect of LRBA.2,6 Lastly, these data indicate that any alluded LRBA-dependent effects outside the (transplanted) hematopoietic/immune tissues play no or only an inferior role with regard to outcome and remission.
Abstract Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαβ+CD4−CD8− double negative T cells and impaired T cell apoptosis are hallmarks ...of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.
Marine dissolved organic matter (DOM) contains one of the largest exchangeable organic carbon pools on Earth. Riverine input represents an important source of DOM to the oceans, yet much remains to ...be learned about the fate of the DOM linking terrestrial to oceanic carbon cycles through rivers at the global scale. Here we use ultrahigh‐resolution mass spectrometry to identify 184 molecular formulae that are indicators of riverine inputs (referred to as t‐Peaks) and to track their distribution in the deep North Atlantic and North Pacific Oceans. The t‐Peaks were found to be enriched in the Amazon River, to be highly correlated with known tracers of terrigenous input, and to be observed in all samples from four different rivers characterized by vastly different landscapes and vegetation coverage spanning equatorial (Amazon and Congo), subtropical (Altamaha), and Arctic (Kolyma) regions. Their distribution reveals that terrigenous organic matter is injected into the deep ocean by the global meridional overturning circulation, indicating that a fraction of the terrigenous DOM introduced by rivers contributes to the DOM pool observed in the deep ocean and to the storage of terrigenous organic carbon. This novel molecular approach can be used to further constrain the transfer of DOM from land to sea, especially considering that Fourier transform ion cyclotron resonance mass spectrometer analysis is becoming increasingly frequent in studies characterizing the molecular composition of DOM in lakes, rivers, and the ocean.
Key Points
184 molecular formulae indicative of riverine inputs (t‐Peaks) have been identified
t‐Peaks are correlated with tracers of terrigenous input and observed in multiple rivers worldwide
t‐Peaks revealed injection of terrigenous DOM into deep ocean by meridional overturning circulation
BACKGROUND AND PURPOSE—In patients who present with acute ischemic stroke while on treatment with non–vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the ...eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke.
METHODS—Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012–2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored.
RESULTS—In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%–44% 95% confidence interval 1%–69%). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients.
CONCLUSIONS—NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01850797.
We report on scaling, rotation, and channeling behavior of helical and skyrmion spin textures in thin films of Te-doped Cu
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Topologically nontrivial spin textures such as vortices, ...skyrmions, and monopoles are promising candidates as information carriers for future quantum information science. Their controlled manipulation including creation and annihilation remains an important challenge toward practical applications and further exploration of their emergent phenomena. Here, we report controlled evolution of the helical and skyrmion phases in thin films of multiferroic Te-doped Cu
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as a function of material thickness, dopant, temperature, and magnetic field using in situ Lorentz phase microscopy. We report two previously unknown phenomena in chiral spin textures in multiferroic Cu
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: anisotropic scaling and channeling with a fixed-Q state. The skyrmion channeling effectively suppresses the recently reported second skyrmion phase formation at low temperature. Our study provides a viable way toward controlled manipulation of skyrmion lattices, envisaging chirality-controlled skyrmion flow circuits and enabling precise measurement of emergent electromagnetic induction and topological Hall effects in skyrmion lattices.
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