Very young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We ...conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population.
A total of 80 children aged 2.0-5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy.
There were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70-180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204).
Use of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.
We recently reported that use of an "advanced" hybrid closed-loop system reduced hyperglycemia without increasing hypoglycemia compared to a first-generation system. The aim of this analysis was to ...evaluate whether this improved performance was specifically related to better mealtime glycemic control.
We conducted a secondary analysis of postprandial glycemic control in an open-label, multinational, randomized crossover trial of 112 participants with type 1 diabetes, aged 14-29, of the Medtronic MiniMed™ 670G hybrid closed-loop system (670G) versus the Medtronic advanced hybrid closed-loop (AHCL) system, for 12 weeks each. We compared glycemic and insulin delivery metrics over a 3 h horizon across all meals to assess system performance and outcomes.
Overall meal size and premeal insulin on board were similar during run-in and between 670G and AHCL arms. Compared with 670G arm, premeal, peak, and mean glucose levels were numerically lower in the AHCL arm (167 ± 23, 231 ± 23, and 177 ± 20 mg/dL vs. 175 ± 23, 235 ± 23, and 180 ± 19 mg/dL, respectively), with a trend to lower hyperglycemia level 2 in AHCL arm. Adjusting for premeal glucose level, all postmeal outcomes between 670G and AHCL were statistically similar. Prandial insulin delivery also was similar in both treatment arms (21 ± 9 vs. 23 ± 10 U), with a shift in basal/bolus ratio from 28%/71% in 670G arm to 20%/80% in AHCL arm.
Reduced hyperglycemia with AHCL compared to 670G was not related to early postprandial glycemic excursions after adjusting for premeal glucose level (<3 h after meal), but likely to later (>3 h) postprandial or overnight improvements. Further refinements to mealtime bolus algorithms and strategies may more optimally control prandial glycemic excursions.
Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively ...has been referred to as Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and non-human primates (NHPs). In macaques, fetal CZS outcomes from maternal ZIKV infection range from none to significant. In the present study we develop the olive baboon (Papio anubis), as a model for vertical transfer of ZIKV during pregnancy. Four mid-gestation, timed-pregnant baboons were inoculated with the French Polynesian ZIKV isolate (104 ffu). This study specifically focused on the acute phase of vertical transfer. Dams were terminated at 7 days post infection (dpi; n = 1), 14 dpi (n = 2) and 21 dpi (n = 1). All dams exhibited mild to moderate rash and conjunctivitis. Viremia peaked at 5-7 dpi with only one of three dams remaining mildly viremic at 14 dpi. An anti-ZIKV IgM response was observed by 14 dpi in all three dams studied to this stage, and two dams developed a neutralizing IgG response by either 14 dpi or 21 dpi, the latter included transfer of the IgG to the fetus (cord blood). A systemic inflammatory response (increased IL2, IL6, IL7, IL15, IL16) was observed in three of four dams. Vertical transfer of ZIKV to the placenta was observed in three pregnancies (n = 2 at 14 dpi and n = 1 at 21 dpi) and ZIKV was detected in fetal tissues in two pregnancies: one associated with fetal death at ~14 dpi, and the other in a viable fetus at 21 dpi. ZIKV RNA was detected in the fetal cerebral cortex and other tissues of both of these fetuses. In the fetus studied at 21 dpi with vertical transfer of virus to the CNS, the frontal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, disorganized migration of immature neurons to the cortical layers, and signs of pathology in immature oligodendrocytes. In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL6 expression. Of interest, in one fetus examined at 14 dpi without detection of ZIKV RNA in brain and other fetal tissues, increased neuroinflammation (IL6 and microglia) was observed in the cortex. Although the placenta of the 14 dpi dam with fetal death showed considerable pathology, only minor pathology was noted in the other three placentas. ZIKV was detected immunohistochemically in two placentas (14 dpi) and one placenta at 21 dpi but not at 7 dpi. This is the first study to examine the early events of vertical transfer of ZIKV in a NHP infected at mid-gestation. The baboon thus represents an additional NHP as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus with devastating outcomes seen recently in the Americas due to the association of maternal ZIKV infection with fetal microcephaly and other ...fetal malformations not previously associated with flavivirus infections. Here, we have developed the olive baboon (
) as a nonhuman primate (NHP) translational model for the study of ZIKV pathogenesis and associated disease outcomes to contrast and compare with humans and other major NHPs, such as macaques. Following subcutaneous inoculation of adult male and nonpregnant female baboons, viremia was detected at 3 and 4 days postinfection (dpi) with the concordant presentation of a visible rash and conjunctivitis, similar to human ZIKV infection. Furthermore, virus was detected in the mucosa and cerebrospinal fluid. A robust ZIKV-specific IgM and IgG antibody response was also observed in all the animals. These data show striking similarity between humans and the olive baboon following infection with ZIKV, suggesting our model is a suitable translational NHP model to study ZIKV pathogenesis and potential therapeutics.
ZIKV was first identified in 1947 in a sentinel rhesus monkey in Uganda and subsequently spread to Southeast Asia. Until 2007, only a small number of cases were reported, and ZIKV infection was relatively minor until the South Pacific and Brazilian outbreaks, where more severe outcomes were reported. Here, we present the baboon as a nonhuman primate model for contrast and comparison with other published animal models of ZIKV, such as the mouse and macaque species. Baboons breed year round and are not currently a primary nonhuman primate species used in biomedical research, making them more readily available for studies other than human immunodeficiency virus studies, which many macaque species are designated for. This, taken together with the similarities baboons have with humans, such as immunology, reproduction, genetics, and size, makes the baboon an attractive NHP model for ZIKV studies in comparison to other nonhuman primates.
Zika virus (ZIKV) infection is now firmly linked to congenital Zika syndrome (CZS), including fetal microcephaly. While
species of mosquito are the primary vector for ZIKV, sexual transmission of ...ZIKV is a significant route of infection. ZIKV has been documented in human, mouse, and nonhuman primate (NHP) semen. It is critical to establish NHP models of the vertical transfer of ZIKV that recapitulate human pathogenesis. We hypothesized that vaginal deposition of ZIKV-infected baboon semen would lead to maternal infection and vertical transfer in the olive baboon (
). Epidemiological studies suggest an increased rate of CZS in the Americas compared to the original link to CZS in French Polynesia; therefore, we also compared the French Polynesian (FP) ZIKV isolate to the Puerto Rican (PR) isolate. Timed-pregnant baboons (
= 6) were inoculated via vaginal deposition of baboon semen containing 10
focus-forming units (FFU) of ZIKV (
= 3 for FP isolate H/PF/2013;
= 3 for PR isolate PRVABC59) at midgestation (86 to 95 days of gestation dG; term, 183 dG) on day 0 (all dams) and then at 7-day intervals through 3 weeks. Maternal blood, saliva, and cervicovaginal wash (CVW) samples were obtained. Animals were euthanized at 28 days (
= 5) or 39 days (
= 1) after the initial inoculation, and maternal/fetal tissues were collected. Viremia was achieved in 3/3 FP ZIKV-infected dams and 2/3 PR ZIKV-infected dams. ZIKV RNA was detected in CVW samples of 5/6 dams. ZIKV RNA was detected in lymph nodes but not the ovaries, uterus, cervix, or vagina in FP isolate-infected dams. ZIKV RNA was detected in lymph nodes (3/3), uterus (2/3), and vagina (2/3) in PR isolate-infected dams. Placenta, amniotic fluid, and fetal tissues were ZIKV RNA negative in the FP isolate-infected dams, whereas 2/3 PR isolate-infected dam placentas were ZIKV RNA positive. We conclude that ZIKV-infected semen is a means of ZIKV transmission during pregnancy in primates. The PR isolate appeared more capable of widespread dissemination to tissues, including reproductive tissues and placenta, than the FP isolate.
Zika virus remains a worldwide health threat, with outbreaks still occurring in the Americas. While mosquitos are the primary vector for the spread of the virus, sexual transmission of Zika virus is also a significant means of infection, especially in terms of passage from an infected to an uninfected partner. While sexual transmission has been documented in humans, and male-to-female transmission has been reported in mice, ours is the first study in nonhuman primates to demonstrate infection via vaginal deposition of Zika virus-infected semen. The latter is important since a recent publication indicated that human semen inhibited, in a laboratory setting, Zika virus infection of reproductive tissues. We also found that compared to the French Polynesian isolate, the Puerto Rican Zika virus isolate led to greater spread throughout the body, particularly in reproductive tissues. The American isolates of Zika virus appear to have acquired mutations that increase their efficacy.
The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete 'road map' of gene-expression and regulatory networks in all immune ...cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the development of the three-dimensional vertebrate body plan, the left-right axis is linked to the dorsoventral and anterioposterior axes. In humans, altered left-right development results in ...severe cardiovascular and visceral abnormalities in individuals and in conjoined twins. Although zygotically transcribed genes that are asymmetrically expressed have been identified, the mechanism by which left-right asymmetries are established during embryogenesis is unknown. Here we show that the Xenopus maternal gene Vg1, a member of the TGF-beta family of cell-signalling molecules which are implicated in dorsoanterior development, initiates left-right axis formation. Altered expression of Vg1 on the right side of 16-cell embryos or disruption of endogenous Vg1 signalling on the left side randomizes cardiac and visceral left-right orientation and alters expression of Xnr-1, a nodal-related molecular marker for left-right development. Furthermore, the orientation of the left-right axis in conjoined twins is dependent upon which cell-signalling molecule initiated twin formation and on whether the secondary axis is on the left or right side of the primary embryonic axis, implicating a molecular pathway leading to the formation of conjoined twins.
T and B lymphocytes are developmentally and functionally related cells of the immune system, representing the two major branches of adaptive immunity. Although originating from a common precursor, ...they play very different roles: T cells contribute to and drive cell-mediated immunity, whereas B cells secrete Abs. Because of their functional importance and well-characterized differentiation pathways, T and B lymphocytes are ideal cell types with which to understand how functional differences are encoded at the transcriptional level. Although there has been a great deal of interest in defining regulatory factors that distinguish T and B cells, a truly genomewide view of the transcriptional differences between these two cells types has not yet been taken. To obtain a more global perspective of the transcriptional differences underlying T and B cells, we exploited the statistical power of combinatorial profiling on different microarray platforms, and the breadth of the Immunological Genome Project gene expression database, to generate robust differential signatures. We find that differential expression in T and B cells is pervasive, with the majority of transcripts showing statistically significant differences. These distinguishing characteristics are acquired gradually, through all stages of B and T differentiation. In contrast, very few T versus B signature genes are uniquely expressed in these lineages, but are shared throughout immune cells.
Chytridiomycosis is a globally emerging disease of amphibians and the leading cause of population declines and extirpations at species-diverse montane sites in Central America. We continued long-term ...monitoring efforts for the presence of the fungal pathogen
Batrachochytrium dendrobatidis
(
Bd
) and for amphibian populations at two sites in western Panama, and we began monitoring at three new sites to the east. Population declines associated with chytridiomycosis emergence were detected at Altos de Campana National Park. We also detected
Bd
in three species east of the Panama Canal at Soberanía National Park, and prevalence data suggests that
Bd
may be enzootic in the lowlands of the park. However, no infected frogs were found further east at Tortí (prevalence <7.5% with 95% confidence). Our results suggest that Panama’s diverse and not fully described amphibian communities east of the canal are at risk. Precise predictions of future disease emergence events are not possible until factors underlying disease emergence, such as dispersal, are understood. However, if the fungal pathogen spreads in a pattern consistent with previous disease events in Panama, then detection of
Bd
at Tortí and other areas east of the Panama Canal is imminent. Therefore, development of new management strategies and increased precautions for tourism, recreation, and biology are urgently needed.
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