Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence

APC Activation Restores Functional CD4+CD25+ Regulatory T Cells in NOD Mice that Can Prevent Diabetes Development

BACKGROUND: Defects in APC and regulatory cells are associated with diabetes development in NOD mice. We have shown previously that NOD APC are not effective at stimulating CD4(+)CD25(+) regulatory cell function in vitro. We hypothesize that failure of NOD APC to properly activate CD4(+)CD25(+) regulatory cells in vivo could compromise their ability to control pathogenic cells, and activation of NOD APC could restore this defect, thereby preventing disease. METHODOLOGY/PRINCIPAL FINDINGS: To test these hypotheses, we used the well-documented ability of complete Freund's adjuvant (CFA), an APC activator, to prevent disease in NOD mice. Phenotype and function of CD4(+)CD25(+) regulatory cells from untreated and CFA-treated NOD mice were determined by FACS, and in vitro and in vivo assays. APC from these mice were also evaluated for their ability to activate regulatory cells in vitro. We have found that sick NOD CD4(+)CD25(+) cells expressed Foxp3 at the same percentages, but decreased levels per cell, compared to young NOD or non-NOD controls. Treatment with CFA increased Foxp3 expression in NOD cells, and also increased the percentages of CD4(+)CD25(+)Foxp3(+) cells infiltrating the pancreas compared to untreated NOD mice. Moreover, CD4(+)CD25(+) cells from pancreatic LN of CFA-treated, but not untreated, NOD mice transferred protection from diabetes. Finally, APC isolated from CFA-treated mice increased Foxp3 and granzyme B expression as well as regulatory function by NOD CD4(+)CD25(+) cells in vitro compared to APC from untreated NOD mice. CONCLUSIONS/SIGNIFICANCE: These data suggest that regulatory T cell function and ability to control pathogenic cells can be enhanced in NOD mice by activating NOD APC

Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT

Prior mucosal exposure to heterologous cells alters the pathogenesis of cell-associated mucosal feline immunodeficiency virus challenge

<p>Abstract</p> <p>Background</p> <p>Several lines of research suggest that exposure to cellular material can alter the susceptibility to infection by HIV-1. Because sexual contact often includes exposure to cellular material, we hypothesized that repeated mucosal exposure to heterologous cells would induce an immune response that would alter the susceptibility to mucosal infection. Using the feline immunodeficiency virus (FIV) model of HIV-1 mucosal transmission, the cervicovaginal mucosa was exposed once weekly for 12 weeks to 5,000 heterologous cells or media (control) and then cats were vaginally challenged with cell-associated or cell-free FIV.</p> <p>Results</p> <p>Exposure to heterologous cells decreased the percentage of lymphocytes in the mucosal and systemic lymph nodes (LN) expressing L-selectin as well as the percentage of CD4+ CD25+ T cells. These shifts were associated with enhanced ex-vivo proliferative responses to heterologous cells. Following mucosal challenge with cell-associated, but not cell-free, FIV, proviral burden was reduced by 64% in cats previously exposed to heterologous cells as compared to media exposed controls.</p> <p>Conclusions</p> <p>The pathogenesis and/or the threshold for mucosal infection by infected cells (but not cell-free virus) can be modulated by mucosal exposure to uninfected heterologous cells.</p

Results of the COVID-19 mental health international for the general population (COMET-G) study.

INTRODUCTION: There are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study. MATERIAL AND METHODS: During the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively. STATISTICAL ANALYSIS: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables. RESULTS: Probable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed. CONCLUSIONS: The final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them

Ketamine in the Prehospital Environment: A National Survey of Paramedics in the United States.

AbstractBackgroundUse of ketamine in the prehospital setting may be advantageous due to its potent analgesic and sedative properties and favorable risk profile. Use in the military setting has demonstrated both efficacy and safety for pain relief. The purpose of this study was to assess ketamine training, use, and perceptions in the civilian setting among nationally certified paramedics (NRPs) in the United States.MethodsA cross-sectional survey of NRPs was performed. The electronic questionnaire assessed paramedic training, authorization, use, and perceptions of ketamine. Included in the analysis were completed surveys of paramedics who held one or more state paramedic credentials, indicated “patient care provider” as their primary role, and worked in non-military settings. Descriptive statistics were calculated.ResultsA total of 14,739 responses were obtained (response rate=23%), of which 10,737 (73%) met inclusion criteria and constituted the study cohort. Over one-half (53%) of paramedics reported learning about ketamine during their initial paramedic training. Meanwhile, 42% reported seeking ketamine-related education on their own. Of all respondents, only 33% (3,421/10,737) were authorized by protocol to use ketamine. Most commonly authorized uses included pain management (55%), rapid sequence intubation (RSI; 72%), and chemical restraint/sedation (72%). One-third of authorized providers (1,107/3,350) had never administered ketamine, with another 32% (1,070/3,350) having administered ketamine less than five times in their career. Ketamine was perceived to be safe and effective as the vast majority reported that they were comfortable with the use of ketamine (94%) and would, in similar situations (95%), use it again.ConclusionThis was the first large, national survey to assess ketamine training, use, and perceptions among paramedics in the civilian prehospital setting. While training related to ketamine use was commonly reported among paramedics, few were authorized to administer the drug by their agency’s protocols. Of those authorized to use ketamine, most paramedics had limited experience administering the drug. Future research is needed to determine why the prevalence of ketamine use is low and to assess the safety and efficacy of ketamine use in the prehospital setting.BucklandDM, CroweRP, CashRE, GondekS, MalusoP, SirajuddinS, SmithER, DangerfieldP, ShapiroG, WankaC, PanchalAR, SaraniB. Ketamine in the prehospital environment: a national survey of paramedics in the United States. Prehosp Disaster Med. 2018;33(1):23–28.</jats:sec

Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence