Complement genes contribute sex-biased vulnerability in diverse disorders.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19.

BACKGROUND: The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation. METHODS: In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed. RESULTS: The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related). CONCLUSIONS: A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

Albumin-ruthenium catalyst conjugate for bio-orthogonal uncaging of alloc group.

The employment of antibodies as a targeted drug delivery vehicle has proven successful which is exemplified by the emergence of antibody-drug conjugates (ADCs). However, ADCs are not without their shortcomings. Improvements may be made to the ADC platform by decoupling the cytotoxic drug from the delivery vehicle and conjugating an organometallic catalyst in its place. The resulting protein-metal catalyst conjugate was designed to uncage the masked cytotoxin administered as a separate entity. Macropinocytosis of albumin by cancerous cells suggests the potential of albumin acting as the tumor-targeting delivery vehicle. Herein reported are the first preparation and demonstration of ruthenium catalysts with cyclopentadienyl and quinoline-based ligands conjugated to albumin. The effective uncaging abilities were demonstrated on allyloxy carbamate (alloc)-protected rhodamine 110 and doxorubicin, providing a promising catalytic scaffold for the advancement of selective drug delivery methods in the future.

Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis.

Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.

Recommendations for culturally safe clinical kidney care for First Nations Australians: a guideline summary.

INTRODUCTION: First Nations Australians display remarkable strength and resilience despite the intergenerational impacts of ongoing colonisation. The continuing disadvantage is evident in the higher incidence, prevalence, morbidity and mortality of chronic kidney disease (CKD) among First Nations Australians. Nationwide community consultation (Kidney Health Australia, Yarning Kidneys, and Lowitja Institute, Catching Some Air) identified priority issues for guideline development. These guidelines uniquely prioritised the knowledge of the community, alongside relevant evidence using an adapted GRADE Evidence to Decision framework to develop specific recommendations for the management of CKD among First Nations Australians. MAIN RECOMMENDATIONS: These guidelines explicitly state that health systems have to measure, monitor and evaluate institutional racism and link it to cultural safety training, as well as increase community and family involvement in clinical care and equitable transport and accommodation. The guidelines recommend earlier CKD screening criteria (age ≥ 18 years) and referral to specialists services with earlier criteria of kidney function (eg, estimated glomerular filtration rate [eGFR], ≤ 45 mL/min/1.73 m2 , and a sustained decrease in eGFR, > 10 mL/min/1.73 m2 per year) compared with the general population. CHANGES IN MANAGEMENT AS RESULT OF THE GUIDELINES: Our recommendations prioritise health care service delivery changes to address institutional racism and ensure meaningful cultural safety training. Earlier detection of CKD and referral to nephrologists for First Nations Australians has been recommended to ensure timely implementation to preserve kidney function given the excess burden of disease. Finally, the importance of community with the recognition of involvement in all aspects and stages of treatment together with increased access to care on Country, particularly in rural and remote locations, including dialysis services.

PICS2: next-generation fine mapping via probabilistic identification of causal SNPs.

SUMMARY: The Probabilistic Identification of Causal SNPs (PICS) algorithm and web application was developed as a fine-mapping tool to determine the likelihood that each single nucleotide polymorphism (SNP) in LD with a reported index SNP is a true causal polymorphism. PICS is notable for its ability to identify candidate causal SNPs within a locus using only the index SNP, which are widely available from published GWAS, whereas other methods require full summary statistics or full genotype data. However, the original PICS web application operates on a single SNP at a time, with slow performance, severely limiting its usability. We have developed a next-generation PICS tool, PICS2, which enables performance of PICS analyses of large batches of index SNPs with much faster performance. Additional updates and extensions include use of LD reference data generated from 1000 Genomes phase 3; annotation of variant consequences; annotation of GTEx eQTL genes and downloadable PICS SNPs from GTEx eQTLs; the option of generating PICS probabilities from experimental summary statistics; and generation of PICS SNPs from all SNPs of the GWAS catalog, automatically updated weekly. These free and easy-to-use resources will enable efficient determination of candidate loci for biological studies to investigate the true causal variants underlying disease processes. AVAILABILITY AND IMPLEMENTATION: PICS2 is available at https://pics2.ucsf.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study.

BACKGROUND: Patients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear. OBJECTIVE: To determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID. DESIGN: Prospective observational cohort study. SETTING: Two U.S. CID referral centers. PARTICIPANTS: Volunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination. MEASUREMENTS: Anti-SARS-CoV-2 spike (S) IgG+ binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination. RESULTS: Most of the 133 participants with CID (88.7%) and all 53 immunocompetent participants developed antibodies in response to mRNA-based SARS-CoV-2 vaccination, although some with CID developed numerically lower titers of anti-S IgG. Anti-S IgG antibody titers after vaccination were lower in participants with CID receiving glucocorticoids (n = 17) than in those not receiving them; the geometric mean of anti-S IgG antibodies was 357 (95% CI, 96 to 1324) for participants receiving prednisone versus 2190 (CI, 1598 to 3002) for those not receiving it. Anti-S IgG antibody titers were also lower in those receiving B-cell depletion therapy (BCDT) (n = 10). Measures of immunogenicity differed numerically between those who were and those who were not receiving antimetabolites (n = 48), tumor necrosis factor inhibitors (n = 39), and Janus kinase inhibitors (n = 11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies. LIMITATIONS: Small sample that lacked demographic diversity, and residual confounding. CONCLUSION: Compared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study. PRIMARY FUNDING SOURCE: The Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

The new world of philanthropy: How changing financial behavior, public policies, and COVID-19 affect nonprofit fundraising and marketing.

Evolving financial behavior, an unpredictable public policy atmosphere, and an unparalleled global pandemic have collaborated to disrupt nonprofit fundraising. The COVID-19 pandemic alone exacerbated consumer demands for nonprofit services while curtailing nonprofit organizations' ability to fundraise. Without fundraising, nonprofit organizations cannot achieve their mission or support their causes, leading to a precarious situation for societal well-being. Meanwhile, consumers are changing their financial behaviors, with younger generations often going cashless. At the same time, governments continue to change policies that affect nonprofit organizations. In keeping with the transformative consumer research movement, the present study provides a conceptual framework for the state of nonprofit fundraising amid the challenges associated with changes in financial behavior and public policy, coupled with the effects of the global pandemic. Marketing strategies for fundraising success are presented to aid nonprofits going forward and serve societal interests.

Predicting Clinical Practice Change: An Evaluation of Trainings on Sexually Transmitted Disease Knowledge, Diagnosis, and Treatment.

BACKGROUND: Sexually transmitted disease clinical training for working professionals requires substantial time and resources. Understanding the predictors of change in worksite practices and barriers to change will allow educators, learners, and clinical leadership to aid in ensuring learned practices are implemented and barriers are addressed. METHODS: Data for this analysis come from the first standardized national evaluation of a Centers for Disease Control and Prevention-funded clinical prevention training network, including precourse registration and responses to immediate postcourse (1-3 days) and 90-day postcourse evaluations from 187 courses. Univariate statistics describe the trainees and their workplace. Bivariate statistics describe their intention to change and actual change stratified by functional role and employment setting. Logistic regression identified predictors of self-reported changes in practice. RESULTS: The strongest predictors for practice change included an intention to change and attendance at a training lasting 4 hours or more. Functional role was a weaker predictor of change in practice; employment setting did not predict change. More than half of the trainees (65.9%; n = 912) stated their intention to make a change in their practice immediately after training. At 90 days after a course, 62.4% (n = 863) reported making a practice change. Trainees that took courses lasting 4 hours or more reported making a change more often (70%) compared with trainees from shorter courses (53%). We also report on trainees' barriers to practice change. CONCLUSIONS: Results suggest that longer trainings may result in more practice change than shorter trainings, recruitment of trainees should focus on those more likely to make a change in their practice, and future trainings should focus on organizational capacity building and assessing change at the organizational level.

Use of belatacept as alternative graft vs host disease prophylaxis in pediatric allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immunosuppressive prophylaxis is usually given to decrease the development of acute graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Belatacept is a Cytotoxic T-lymphocyte-associated protein 4, blocking agent, an immunosuppressive agent used for organ rejection prevention in adult renal transplant recipients. METHODS: We describe two children in whom belatacept was successfully used for GvHD prophylaxis. Case 1 was noncompliant with prior immunosuppressive therapy for aplastic anemia, and Case 2 developed severe thrombotic microangiopathy (TMA) precluding the use of calcineurin inhibitors (CNI) or mTOR inhibitors. RESULTS AND CONCLUSION: Belatacept was found to be a safe alternative in preventing GvHD in 2 patients in whom traditional prophylactic therapies were not possible to use.

Vitamin D has no impact on outcomes after HSCT in children-A retrospective study.

Vitamin D not only plays an important role in bone metabolism but is also involved in multiple immune-mediated processes in the body which may be adversely affected in those with low levels. Most pediatric studies evaluating the association of vitamin D in patients undergoing allogeneic HSCT are single-center studies. We present the results of retrospective study at 5 centers across the United States in pediatric patients undergoing allogeneic HSCT. (VDD) and (VDI) were defined by vitamin D levels of <20 ng/ml and 21-30 ng/ml, respectively. The mean vitamin D levels pre-HSCT, day +30, and +100 were suggestive of VDI, but normalized thereafter. We compared the transplant characteristics and outcomes in 233 patients with VDD and VDI and those with normal levels and found no statistical difference in neutrophil or platelet engraftment, infections (viral, bacterial, or fungal) post-HSCT, length of hospital stay during HSCT, graft failure, acute or chronic GvHD, survival at day +100 and 1 year, or relapse of primary malignancy. We conclude that VDI or deficiency does not affect any of the common transplant variables after allogeneic HSCT in children. There is a need of a large multicenter prospective study to evaluate its role further.

Total Synthesis of Laucysteinamide A, a Monomeric Congener of Somocystinamide A.

Laucysteinamide A (4) is a marine natural product isolated from the cyanobacterium Caldora penicillata and contains structural motifs found in promising cancer drug leads. The first total synthesis of 4 and its analogues was achieved, which also enabled a concise formal synthesis of somocystinamide A (3), a dimeric congener of 4 that previously showed extremely potent antiproliferative activities. This work provides further insights on structure-activity relationships in this class of natural products.

Impact of Medical Blog Reading and Information Presentation on Readers' Preventative Health Intentions: Mixed Methods, Multistudy Investigation.

BACKGROUND: Medical blogs have become valuable information sources for patients and caregivers. Most research has focused on patients' creation of blogs as therapy. But we know less about how these blogs affect their readers and what format of information influences readers to take preventative health actions. OBJECTIVE: This study aimed to identify how reading patient medical blogs influences readers' perceived health risk and their intentions to engage in preventative health actions. Further, we aimed to examine the format of the medical blog and the reader's response. METHODS: We surveyed 99 university participants and a general-population, online panel of 167 participants. Both studies randomly assigned participants to conditions and measured blog evaluation, intentions for preventative health action, and evaluation of health risk and beliefs, and allowed open-ended comments. The second study used a different sample and added a control condition. A third study used a convenience sample of blog readers to evaluate the link between reading medical blogs and taking preventative health action. RESULTS: Across 3 studies, participants indicated a desire to take future preventative health action after reading patient blogs. Studies 1 and 2 used experimental scenario-based designs, while Study 3 employed a qualitative design with real blog readers. The 2 experimental studies showed that the type of blog impacted intentions to engage in future preventative health actions (Study 1: F2,96=6.08, P=.003; Study 2: F3,166=2.59, P=.06), with a statistical blog being most effective in both studies and a personal narrative blog showing similar effectiveness in Study 2, contrary to some prior research. The readers' perceptions of their own health risk did not impact the relationship between the blog type and health intentions. In contrast, in one study, participants' judgments about the barriers they might face to accessing care improved the fit of the model (F2,95=13.57, P<.001). In Study 3's sample of medical blog readers, 53% (24/45) reported taking preventative health action after reading a health blog, including performing a self-check, asking a doctor about their health risk, or requesting a screening test. Additionally, these readers expressed that they read the blogs to follow the author (patient) and to learn general health information. All studies demonstrated the blogs were somewhat sad and emotional but also informative and well-written. They noted that the blogs made them appreciate life more and motivated them to consider taking some action regarding their health. CONCLUSIONS: Reading patient blogs influences intentions to take future health actions. However, blog formats show different efficacy, and the readers' disease risk perceptions do not. Physicians, medical practitioners, and health organizations may find it useful to curate or promote selected medical blogs to influence patient behavior.

Osmotherapy for malignant cerebral edema in a phase 2 prospective, double blind, randomized, placebo-controlled study of IV glibenclamide.

BACKGROUND/OBJECTIVE: Malignant edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo. METHODS: GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by "osmolar load". Radiographic edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a. RESULTS: Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27-55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146-211] mL v. 139 [112-170] mL; P=0.046). Adjudicated malignant edema (75% v. 16%; P<0.001) was more common in the osmotherapy treated group. There were no differences in the proportion of patients receiving osmotherapy or the median total osmolar load between treatment arms. Most patients (76%) had a decrease in consciousness (NIHSS item 1A ≥1) on the day they began receiving osmotherapy. CONCLUSIONS: In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined.

Automated Calculation of Alberta Stroke Program Early CT Score: Validation in Patients With Large Hemispheric Infarct.

Background and Purpose- We compared the Alberta Stroke Program Early CT Score (ASPECTS), calculated using a machine learning-based automatic software tool, RAPID ASPECTS, as well as the median score from 4 experienced readers, with the diffusion-weighted imaging (DWI) ASPECTS obtained following the baseline computed tomography (CT) in patients with large hemispheric infarcts. Methods- CT and magnetic resonance imaging scans from the GAMES-RP study, which enrolled patients with large hemispheric infarctions (82-300 mL) documented on DWI-magnetic resonance imaging, were evaluated by blinded experienced readers to determine both CT and DWI ASPECTS. The CT scans were also evaluated by an automated software program (RAPID ASPECTS). Using the DWI ASPECTS as a reference standard, the median CT ASPECTS of the clinicians and the automated score were compared using the interclass correlation coefficient. Results- The median CT ASPECTS for the clinicians was 5 (interquartile range, 4-7), for RAPID ASPECTS 3 (interquartile range, 1-6), and for DWI ASPECTS 3 (2-4). Median error for RAPID ASPECTS was 1 (interquartile range, -1 to 3) versus 3 (interquartile range, 1-4) for clinicians (P<0.001). The automated score had a higher level of agreement with the median of the DWI ASPECTS, both for the full scale and when dichotomized at <6 versus 6 or more (difference in intraclass correlation coefficient, P=0.001). Conclusions- RAPID ASPECTS was more accurate than experienced clinicians in identifying early evidence of brain ischemia as documented by DWI.

Role of the IL-12/IL-35 balance in patients with Sjögren syndrome.

BACKGROUND: An interferon signature is involved in the pathogenesis of primary Sjögren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of TH1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene (IL12A), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35. OBJECTIVE: We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies. METHODS: The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively. RESULTS: We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele (P = .016). Serum levels of IL-12p70 were greater in patients than control subjects (P = .0001), especially in patients with more active disease (P = .05); conversely, IL-35 levels were decreased in patients (P = .0001), especially in patients with more active disease (P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS. CONCLUSION: Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.

Don't give US pink ribbons and skinny girls: Breast cancer survivors' evaluations of cancer advertising.

Breast cancer related promotions, advertising, and pink ribbons are now ubiquitous in October, yet comparatively little is known about how this advertising impacts breast cancer survivors specifically. The present research uses an embodied knowledge perspective to explore the impact of cancer advertising on female breast cancer survivors. Five focus groups were conducted with 42 participants, and the discussions were analyzed to find common themes. The survivors expressed a desire for cancer advertising to be representative, informative (particularly regarding detection and treatment options), hopeful, and transparent about the organization's motivation and support. Implications and recommendations are also discussed.

Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke.

BACKGROUND AND PURPOSE: Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke. METHODS: We tested the efficacy of acute (1.5 hours) or delayed (1-3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7-14 weeks) and aged mice (20-22 months) of both sexes, as well as adult marmosets of either sex. RESULTS: We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke. CONCLUSIONS: Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.

Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. METHODS: Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). RESULTS: We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10-5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10-3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10-7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10-5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. CONCLUSIONS: The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

70% Ethanol for Decontamination of Central Venous Lines Exposed to Calcineurin Inhibitors.

BACKGROUND: Tacrolimus, commonly used for graft versus host disease prophylaxis is usually administered via a dedicated central venous line (CVL) and trough levels drawn from the unexposed lumen. Being an oil-based medication, it may be adsorbed to the inner lumen of the CVL and result in falsely high levels drawn from an inadvertently exposed lumen. There is no treatment for decontamination of such CVLs, and natural decay occurs over months before the CVL can be used to draw reliable trough levels. OBJECTIVE: The primary objective of the study was to estimate the effectiveness of 70% ethanol locks for decontaminating CVLs exposed to tacrolimus. METHODS: We studied the efficacy of 70% ethanol lock in decontaminating CVLs exposed to tacrolimus in patients during transplant. Trough tacrolimus levels were drawn from the exposed and unexposed (control) lumens at 8:00 am, followed by a 2-mL 70% ethanol lock instilled for a 2-hour dwell into the exposed (intervention) lumen. Trough tacrolimus levels were again drawn from both lumens at 8:00 pm and levels compared for efficacy. RESULTS: All 20 sets showed a high 8 am trough level in the exposed intervention arm (median = 30 ng/mL), significantly greater ( P < 0.0001) than that in the control arm (median = 9.05 ng/mL), and were contaminated. After the 2-hour ethanol lock, 65% of the lumens were decontaminated. The difference between the control and intervention arms was no longer found to be statistically significant ( P = 0.0826). CONCLUSION: A 2-hour 70% ethanol lock is effective for decontamination of CVLs exposed to tacrolimus.