Accelerated development of immunity following transplantation of maternal marrow stem cells into infants with severe combined immunodeficiency and transplacentally acquired lymphoid chimerism.

Transplacentally acquired lymphoid chimerism was detected in two infants with severe combined immunodeficiency (SCID) by two-colour cytofluorographic studies. These cells had no demonstrable function in studies in vitro. Following T cell-depleted maternal bone marrow stem cell transplantation, evidence of T cell function was detected 20 and 50 days later, and transient B cell function was detected 50 days later. These immune functions appeared much sooner than the 90-120 days usually required for T cell function and the 2-2.5 years for B cell function to develop after haplo-identical stem cell transplants into SCID infants without transplacental engraftment. The presence of maternal lymphoid chimerism did not interfere with haplo-identical marrow cell engraftment, even though no pre-transplant immunosuppression was given. This observation suggests that the transplanted maternal marrow stem cell in some way conferred reactivity on the engrafted but apparently non-functional mature T cells that had entered the fetal circulation transplacentally.     

Impact of active antibody‐mediated rejection treatment on donor‐specific antibodies in pediatric kidney transplant recipients

AMR is a major cause of graft loss after kidney transplantation. We evaluated a retrospective cohort of 13 pediatric kidney transplant patients diagnosed with active AMR. All 13 patients were treated with plasmapheresis (PP), IVIg, and rituximab. Anti‐HLA DSAs were measured at the time of transplantation, AMR diagnosis, 30 days post‐rejection treatment, 90 days post‐rejection treatment, and 24 ± 12 months post‐AMR. A total of 68 DSAs were identified from 13 patients at the time of active AMR diagnosis. The primary objective of this study was to differentiate treatment response rates between class I and class II anti‐HLA DSA post‐AMR treatment. Overall, DSAs were significantly reduced at 30 days, and the reduction was sustained at 90 days post‐treatment, even for class II anti‐HLA and strongly positive DSAs. A significant difference between class I and class II anti‐HLA DSA was observed at 30 days; however, between class significance was lost at 90‐day follow‐up due to continued class II anti‐HLA DSA treatment response. Low DSA strength was predictive of treatment response. eGFR demonstrated significant improvement 90 days after AMR diagnosis compared to the initial value at the time of AMR, and the effect was sustained for 12 months. These results suggest that the AMR treatment is effective in pediatric kidney transplant recipients with an early diagnosis of active AMR across both class I and class II anti‐HLA DSAs.     

Outcomes following rescue cerclage in twin pregnancies*

Objective: Our aim was to compare perinatal outcomes in twin pregnancies complicated by premature asymptomatic cervical dilatation treated with rescue cerclage and expectant management.

Methods: A retrospective cohort study was conducted at a single tertiary referral center between 2003 and 2014 and included all women with twins found to have a dilated cervix with intact membranes before 25-week gestation. Pregnancy outcomes were compared between women with rescue cerclage and those managed expectantly. A total of 36 women were eligible for the study, 27 (75.0%) of whom had a rescue cerclage compared to 9 (25.0%) women managed expectantly. Student’s t-test was used to compare continuous variables between the groups and the chi-square and Fisher’s exact tests were used for categorical variables as appropriate. Statistical analysis was performed with the SPSS v21.0 software (IBM Corp; Armonk, NY). Differences were considered significant when the p value was less than .05.

Results: Among the 27 women with a rescue cerclage, the mean gestational age at time of cerclage insertion was 21.5?±?2.6 weeks. The intervention and control groups were similar with respect to the degree of cervical dilatation at presentation (2.6?±?1.3 versus 3.0?±?1.5?cm, p?=?.5). Women in the cerclage group gave birth at a more advanced gestation (28.9?±?6.1 versus 24.2?±?2.6?weeks, respectively, p?=?.03) and were less likely to give birth at <34 and <28?weeks (66.7 versus 100.0%, p?=?.046, and 59.3 versus 100.0%, p?=?.02, respectively). The mean latency from the placement of cerclage to delivery was 7.3?±?5.5 weeks. Similar findings were observed when analysis was limited to women with cervical dilatation of ≤3?cm at presentation.

Conclusions: In asymptomatic women with twin pregnancies and cervical dilatation before 25?weeks of gestation, rescue cerclage can prolong pregnancy and improve perinatal outcomes when compared to expectant management.     

A rapid method for the inactivation of virus infectivity prior to assay for interferons

Virus infectivity in samples of culture medium or suspensions of animal tissue which are required for interferon assay can be rapidly and conveniently inactivated by overnight incubation with beta-propiolactone (BPL). As BPL hydrolyses spontaneously samples can be assayed with no further treatment. BPL does not affect the interfering activity of alpha, beta or gamma mouse interferons.     

Mathematical modelling of the growth processes in the developing chick wing bud

This paper illustrates how a simple geometric model resembling the shape of the chick wing bud at an early growth stage can be mathematically expanded to simulate subsequent growth characteristics of the developing bud. The model was tested against several sets of experimental data and gave an acceptable representation of growth over the range considered. Representing growth patterns in this form enables the determination of differential growth characteristics in different parts of the bud and provides boundary constraints which will play an important part in the eventual evaluation of internal growth mechanisms.     

Uses of cell free fetal DNA in maternal circulation

For over a decade, researchers have focused their attention on the development of non-invasive prenatal diagnosis tests based on cell-free fetal DNA circulating in maternal blood. With the possibility of earlier and safer testing, non-invasive prenatal diagnosis has the potential to bring many positive benefits to prenatal diagnosis. Non-invasive prenatal diagnosis for fetal sex determination for women who are carriers of sex-linked conditions is now firmly established in clinical practice. Other non-invasive prenatal diagnosis-based tests are set to follow, as future applications, such?as the detection of single-gene disorders and chromosomal abnormalities, are now well within reach. Here, we review recent developments in non-invasive prenatal diagnosis for genetic conditions and chromosomal abnormalities, and provide an overview of research into ethical concerns, social issues and stakeholder view points.     

Risk factors for meningococcal disease in students in grades 9-12

BACKGROUND: Meningococcal disease is a serious problem in adolescents, including high school students. Universal immunization of adolescents with meningococcal conjugate vaccine was recently recommended. We studied risk factors for meningococcal disease in students in grades 9-12. METHODS: This was a matched case-control study using surveillance for meningococcal disease in students in grades 9-12 in sites throughout the United States. For each case-patient, up to 4 controls were selected from the home room classroom. All subjects answered an extensive questionnaire. Logistic regression was performed to identify risk factors associated with meningococcal disease. Meningococcal isolates were characterized. RESULTS: Of 69 eligible patients, 49 (71%) were enrolled and had at least 1 control. Isolates were available for 59 (86%) cases. Attending at least 1 barbeque or picnic [matched odds ratio (MOR): 0.26, P value = 0.003] or school dance (MOR: 0.30, P = 0.04) were independently associated with decreased risk of meningococcal disease. Male gender (MOR: 2.94, P = 0.009), upper respiratory infection symptoms (MOR: 2.43, P = 0.04), marijuana use (MOR: 4.21, P = 0.009), and nightclub/disco attendance (MOR: 3.30, P = 0.04) were associated with increased risk. Among 54 students not from Oregon (where serogroup B strains predominate) with available serogroup, 38 (73.1%) cases were potentially vaccine preventable: 18 (34.6%) serogroup C, 19 (36.5%) serogroup Y, and 1 (1.9%) serogroup W-135. CONCLUSIONS: Certain behaviors increase the risk of meningococcal infection, whereas others are associated with decreased risk. Most meningococcal disease in high school students can be prevented if recommendations on use of meningococcal conjugate vaccine are implemented.     

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.     

Cellular therapy: Immune‐related complications

The advent of chimeric antigen receptor T (CAR‐T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized “living therapy” is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR‐T. The overwhelming release of cytokines and chemokines by activated CAR‐T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. Tocilizumab, an anti‐IL6 receptor antibody, was recently FDA approved for treatment of CRS after CAR‐T based on its ability to mitigate CRS in many patients. Unfortunately, some patients are refractory and additional therapies are needed. Patients treated with CAR‐T can also develop neurotoxicity and, as the biology is poorly understood, current therapeutic interventions are limited to supportive care. Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR‐T‐related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR‐T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR‐T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.