Molecular understanding of Ni2+-nitrogen family metal-coordinated hydrogel relaxation times using free energy landscapes.

Incorporating dynamic metal-coordination bonds as cross-links into synthetic materials has become attractive not only to improve self-healing and toughness, but also due to the tunability of metal-coordination bonds. However, a priori determination of bond lifetime of metal-coordination complexes, especially important in the rational design of metal-coordinated materials with prescribed properties, is missing. We report an empirical relationship between the energy landscape of metal-coordination bonds, simulated via metadynamics, and the resulting macroscopic relaxation time in ideal metal-coordinated hydrogels. Importantly, we expand the Arrhenius relationship between the macroscopic hydrogel relaxation time and metal-coordinate bond activation energy to include width and landscape ruggedness identified in the simulated energy landscapes. Using biologically relevant Ni2+-nitrogen coordination complexes as a model case, we demonstrate that the quantitative relationship developed from histidine-Ni2+ and imidazole-Ni2+ complexes can predict the average relaxation times of other Ni2+-nitrogen coordinated networks. We anticipate the quantitative relationship presented here to be a starting point for the development of more sophisticated models that can predict relaxation timescales of materials with programmable viscoelastic properties.

Microscopic dynamics underlying the stress relaxation of arrested soft materials.

Arrested soft materials such as gels and glasses exhibit a slow stress relaxation with a broad distribution of relaxation times in response to linear mechanical perturbations. Although this macroscopic stress relaxation is an essential feature in the application of arrested systems as structural materials, consumer products, foods, and biological materials, the microscopic origins of this relaxation remain poorly understood. Here, we elucidate the microscopic dynamics underlying the stress relaxation of such arrested soft materials under both quiescent and mechanically perturbed conditions through X-ray photon correlation spectroscopy. By studying the dynamics of a model associative gel system that undergoes dynamical arrest in the absence of aging effects, we show that the mean stress relaxation time measured from linear rheometry is directly correlated to the quiescent superdiffusive dynamics of the microscopic clusters, which are governed by a buildup of internal stresses during arrest. We also show that perturbing the system via small mechanical deformations can result in large intermittent fluctuations in the form of avalanches, which give rise to a broad non-Gaussian spectrum of relaxation modes at short times that is observed in stress relaxation measurements. These findings suggest that the linear viscoelastic stress relaxation in arrested soft materials may be governed by nonlinear phenomena involving an interplay of internal stress relaxations and perturbation-induced intermittent avalanches.

Endocrine, cardiac and neuropsychological aspects of adult congenital adrenal hyperplasia.

OBJECTIVE: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. DESIGN, PARTICIPANTS, MEASUREMENTS: Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. RESULTS: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. CONCLUSION: A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits.

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

The TGFß system and TIMP1 and 3 genotypes in Turner syndrome-Relation with aortic congenital malformations.

OBJECTIVE: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk. DESIGN, PATIENTS, PARTICIPANTS AND MEASUREMENTS: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFß), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease. RESULTS: TS participants had lower TGFß1 and TGFß2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFß1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFß1 and TGFß2 levels in TS. CONCLUSION: TGFß and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants.

Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy.

Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to co-administration of ceftriaxone- and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an "unknown" material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 µm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.

Pulmonary function is a strong predictor of 2-year overall survival and non-relapse mortality after allogenic hematopoietic cell transplantation.

OBJECTIVES: The purpose of the study was to assess the validity of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and of pulmonary comorbidity prior to HCT in terms of predicting non-relapse mortality (NRM) and overall survival (OS). METHODS: In this retrospective single-center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low-risk, intermediate-risk, and high-risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT-CI. RESULTS: In univariate analysis, the HCT-CI and the PCS were associated with OS after transplantation when comparing patients in high-risk groups with patients in low-risk groups. Using the PCS, the hazard ratios (HRs) of the 2-year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (p < .001) and 3.27 (p < .001), respectively, whereas the HRs using the HCT-CI were 1.83 (p < .001) and 2.57 (p = .002). The 2-year NRM incidence in the three risk-groups in the entire population was significant using both indexes. In the MAC group, the 2-year NRM was significant using the PCS (p = .003), but not using the HCT-CI (p = .23). CONCLUSIONS: Our study suggest that pulmonary function alone is a strong predictor of 2-year OS and NRM after HCT.

Non-Maxwellian viscoelastic stress relaxations in soft matter.

Viscoelastic stress relaxation is a basic characteristic of soft matter systems such as colloids, gels, and biological networks. Although the Maxwell model of linear viscoelasticity provides a classical description of stress relaxation, it is often not sufficient for capturing the complex relaxation dynamics of soft matter. In this Tutorial, we introduce and discuss the physics of non-Maxwellian linear stress relaxation as observed in soft materials, the ascribed origins of this effect in different systems, and appropriate models that can be used to capture this relaxation behavior. We provide a basic toolkit that can assist the understanding and modeling of the mechanical relaxation of soft materials for diverse applications.

Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.

INTRODUCTION: Donor lymphocyte infusion (DLI) is used to induce remission in patients who relapse after allogeneic stem cell transplantation (allo-HSCT). During the last decade, the hypomethylating agent Azacitidine has been used together with DLI for a synergistic graft-versus-leukemia (GVL) effect. Here we report results of DLI/Azacitidine treatment from a retrospective single-center study. METHODS: 50 AML/MDS patients treated for relapse after allo-HSCT between 2001 and 2020 with DLI at the Department of Hematology, at Rigshospitalet, Copenhagen University Hospital were included for analyses. A subgroup of patients who obtained complete remission (CR) after reinduction chemotherapy, received DLI in combination with low-dose (32 mg/m2) Azacitidine. RESULTS: Overall survival in all patients after DLI treatment was 59% at 2 years and 20% at 5 years. Relapse-free survival in patients in CR prior to DLI was 32% after 2 years and 7% after 5 years. In the DLI+low-dose-Azacitidine group, 5-years relapse-free survival was 40%. CONCLUSION: DLI remains an effective treatment in post-transplant relapse leaving one fifth of patients long-term survivors. Our results support the concomitant use of low-dose Azacitidine in the future use of DLI in order to enhance the GVL effect of donor lymphocytes.

Coordination Stoichiometry Effects on the Binding Hierarchy of Histamine and Imidazole-M2+ Complexes.

Histidine-M2+ coordination bonds are a recognized bond motif in biogenic materials with high hardness and extensibility, which has led to growing interest in their use in soft materials for mechanical function. However, the effect of different metal ions on the stability of the coordination complex remains poorly understood, complicating their implementation in metal-coordinated polymer materials. Herein, rheology experiments and density functional theory calculations are used to characterize the stability of coordination complexes and establish the binding hierarchy of histamine and imidazole with Ni2+ , Cu2+ , and Zn2+ . It is found that the binding hierarchy is driven by the specific affinity of the metal ions to different coordination states, which can be macroscopically tuned by changing the metal-to-ligand stoichiometry of the metal-coordinated network. These findings facilitate the rational selection of metal ions for optimizing the mechanical properties of metal-coordinated materials.

STAT3 is over-activated within CD163pos bone marrow macrophages in both Multiple Myeloma and the benign pre-condition MGUS.

Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163pos TAMs is associated with poor outcome in several human malignancies, including multiple myeloma (MM). Signal transducer and activator of transcription 3 (STAT3) is over-activated in human cancers, and specifically within TAMs activation of STAT3 may induce an immunosuppressive (M2-like) phenotype. Therefore, STAT3-inhibition in TAMs may be a future therapeutic strategy.We investigated TAM markers CD163, CD206, and activated STAT3 (pSTAT3) in patients with MGUS (n = 32) and MM (n = 45), as well as healthy controls (HCs, n = 13).Blood levels of the macrophage biomarkers sCD163 and sCD206, and circulating cytokines, as well as bone marrow mRNA expression of CD163 and CD206, were generally increased in MGUS and MM patients, compared to HCs, but to highly similar levels. By immunohistochemistry, bone marrow levels of pSTAT3 were increased specifically within CD163pos cells in both MGUS and MM patients.In conclusion, macrophage-related inflammatory changes, including activation of STAT3, were present already at the MGUS stage, at similar levels as in MM. Specific increase in pSTAT3 levels within CD163pos cells supports that the CD163 scavenger receptor may be a useful target for future delivery of STAT3-inhibitory drugs to TAMs in MM patients.

Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors.

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.

Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission - results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial.

BACKGROUND: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. METHODS: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. RESULTS: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5. CONCLUSIONS: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. TRIAL REGISTRATION: NCT01208766.

Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group.

OBJECTIVE: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma. METHODS: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 â†’ 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86). RESULTS: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections. CONCLUSION: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity.

Expanding the stoichiometric window for metal cross-linked gel assembly using competition.

Polymer networks with dynamic cross-links have generated widespread interest as tunable and responsive viscoelastic materials. However, narrow stoichiometric limits in cross-link compositions are typically imposed in the assembly of these materials to prevent excess free cross-linker from dissolving the resulting polymer networks. Here we demonstrate how the presence of molecular competition allows for vast expansion of the previously limited range of cross-linker concentrations that result in robust network assembly. Specifically, we use metal-coordinate cross-linked gels to verify that stoichiometric excessive metal ion cross-linker concentrations can still result in robust gelation when in the presence of free ion competing ligands, and we offer a theoretical framework to describe the coupled dynamic equilibria that result in this effect. We believe the insights presented here can be generally applied to advance engineering of the broadening class of polymer materials with dynamic cross-links.

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

Validation of the UK myeloma research alliance risk profile, a new clinical prediction model for outcome in patients with newly diagnosed multiple myeloma not eligible for autologous stem cell transplantation; a population-based study from the Danish national multiple myeloma registry.

In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk-groups with an observed hazard ratio of 2.91 for early death in high-risk versus low-risk patients.

Functional immune reconstitution early after allogeneic haematopoietic cell transplantation: A comparison of pre- and post-transplantation cytokine responses in stimulated whole blood.

We aimed to use a novel standardized whole-blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day -21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat-killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra- and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon-γ, interleukin (IL)-12p40, IL-10, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A and tumour necrosis factor-α using a multiplex Luminex assay. Pre-HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post-HCT cytokine responses were higher and less intercorrelated than pre-HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat-killed Candida albicans stimuli, we identified a cluster of patients in whom post-HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections.

Maternal health and pregnancy outcome in diagnosed and undiagnosed Marfan syndrome: A registry-based study.

In Marfan syndrome (MFS), pregnancy is considered as high risk due to the deficiency of fibrillin in the connective tissue and increased risk of aortic dissection. The objective was to demonstrate the consequences on maternal health, in women with diagnosed and undiagnosed MFS at the time of pregnancy and childbirth. By using national health care registries, we identified all pregnancy related outcomes, from women with MFS (n = 183) and an age-matched background population (n = 18,300). We found 91 pregnancies during follow-up. Significantly fewer women with MFS gave birth, compared to the background population. No women with known MFS had a pregnancy related aortic dissection but complications related to the cervix were increased (HR:19.8 [95% CI:2.2-177.5]). Fifty women with MFS were undiagnosed at the time of their first pregnancy and/or childbirth. Among these, there were more birth canal related complications HR:27.2 (95% CI: 2.3-315.0), preeclampsia (HR:2.25 [95% CI: 1.11-4.60]), fetal deaths (HR:12.3 [95% CI: 1.51-99.8]), and all delivery-related dissections came from this subgroup. In conclusion, undiagnosed women with MFS experienced more pregnancy and childbirth related complications including fetal death, birth canal issues, preeclampsia, and aortic disease, which emphasizes the need for an early MFS diagnosis and special care during pregnancy and childbirth.

Vitamin E and acute graft-versus-host disease after myeloablative allogeneic hematopoietic cell transplantation.

OBJECTIVES: Vitamin E has antioxidant and immunomodulatory effects that might influence the development of acute graft-versus-host disease (GvHD). We investigated the association between plasma vitamin E levels and acute GvHD. METHODS: We studied 115 adults who underwent myeloablative allogeneic hematopoietic cell transplantation between July 2015 and August 2018. Vitamin E was measured by high-performance liquid chromatography in stored plasma samples obtained pre-transplantation at day -23 (±15 days) and post-transplantation at day +28 (±3 days). RESULTS: Pre-transplantation vitamin E levels were inversely associated with grade II-IV acute GvHD (hazard ratio 0.68 per 10 µmol/L increase, 95% confidence interval [CI]: 0.47-0.98). The association remained after adjustment for known prognostic factors for acute GvHD. Patients with levels below the median had a cumulative incidence of grade II-IV acute GvHD of 46% (CI: 33-59%) versus 21% (CI: 10-32%) in patients with levels above the median. No clear association with non-relapse mortality, relapse, or chronic GvHD was found. Post-transplantation vitamin E levels (measured in 72 [63%] patients) were correlated with pre-transplantation levels (ρ = .31) but were not associated with subsequent grade II-IV acute GvHD. CONCLUSIONS: High pre-transplantation vitamin E levels were associated with less acute GvHD.