Predictors of Preterm Birth in New Mexico: outcomes from 377,770 pregnancies over fifteen years

Background: Preterm birth (PTB) is a significant health problem both in New Mexico and nationally. It accounts for significant infant morbidity and mortality and it poses an economic burden to both individuals and the state. The goal of this study is to elucidate maternal risk factors for PTB in New Mexico, a poor state with a unique ethnic background. By doing this we hope to be able to identify women at increased risk and invite further study into targeted interventions among these high risk populations. Methods: This was a cross-sectional analysis of 377,770 singleton live births in the state of New Mexico from 1991-2005. The medical risk factors tracked were pulmonary, renal, cardiac, diabetes, eclampsia, oligo/polyhydramnios, hypertensive disorders, cervical incompetence, previous preterm delivery, tocolysis and isoimmunization. Gestational age of less than 37 weeks was defined as PTB. Multiple gestations and congenital anomalies were excluded. The Kotelchuck Index was used as a measure for level of prenatal care described as inadequate, intermediate, adequate, and intensive. Multivariate logistic regression was conducted using SAS 9.1 statistical software. Results: Of the live births analyzed, 28,036 of these were preterm (7.4%). Overall the PTB rate has risen from 1991-2005 at a rate of 0.18 percent per year. This was statistically significant (p = \u3c0.00004). Among patients with medical risk factors, PTB rate had a direct inverse relationship with an intensive level of prenatal care. High risk patients with intensive care were less likely to have a PTB delivery with an odds ratio of 0.74 than similar patients with low levels of care. The nadir for risk of PTB is among women aged 25-29 with significant increases in risk among women \u3c15 and \u3e40 years of age. Other risk factors are unmarried status, education less than high school,tobacco/alcohol use, Black, Asian, and White Hispanic ethnicity and the presence of one or more medical risk factors. Statistically significant protective factors for PTB are age 25-29, education surpassing high school, and Native American race. Counties with rising adjusted PTB rates are Chaves, Dona Ana, Grant, Hidalgo, Lea, Lincoln, McKinley, Mora, Otero, Rio Arriba, San Juan and San Miguel. Counties with decreasing PTB rates are Sandoval and Santa Fe counties. Conclusion: Even adjusted for known risk factors PTB is still a significant problem in New Mexico. A lack of prenatal care was a significant predictor of PTB in high risk patients. Other predictors include the known risk factors of age \u3c15 and \u3e40, single, tobacco/alcohol use, being of low socioeconomic status and White Hispanic, Asian and Black ethnicities. Interestingly, Native American patients have a lower PTB rate compared to other groups, even though this group is traditionally one of low socioeconomic status in New Mexico

An exploratory study of the variables impacting preterm birth rates in New Mexico

BACKGROUND: Preterm birth (PTB) is a substantial health problem that accounts for significant infant morbidity and mortality and poses an economic burden to both individuals and the state of residence. The goal of this study was to identify maternal risk factors for PTB in New Mexico, a poor state with a unique ethnic background, in order to identify populations at increased risk that would benefit from intervention. METHODS: This was a cross-sectional retrospective exploratory analysis of 377,770 singleton live births in the state of New Mexico from 1991-2005. Gestational age of less than 37 weeks was defined as PTB. The Kotelchuck Index was used as a measure for level of prenatal care described as inadequate, intermediate, adequate, and intensive. RESULTS: Of the live births analyzed, 28,036 of these were preterm (7.4%). Overall the PTB rate rose at a rate of 0.18% per year from 1991-2005. Among patients with medical risk factors, the absence of prenatal care was associated with higher odds for PTB as compared to adequate prenatal care. Other risk factors were unmarried status, education less than high school, tobacco/alcohol use, black, Asian, and white Hispanic ethnicity, and the presence of one or more medical risk factors. Statistically significant protective factors for PTB were age 25-29, education surpassing high school, and Native American race. CONCLUSIONS: This study identified several factors that correlate with increased PTB in New Mexico, in particular ethnicity and level of prenatal care. The finding that Native American patients have a lower PTB rate compared to other groups, even though this group is traditionally one of low socioeconomic status in New Mexico, signifies that other factors yet to be identified affect PTB

Monocyte response to SARS-CoV-2 protein ORF8 is associated with severe COVID-19 infection in patients with chronic lymphocytic leukemia

The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would be associated with subsequent severe COVID-19. We tested ORF8 ex vivo on peripheral blood mononuclear cells (PBMCs) from 26 anonymous healthy blood donors and measured intracellular cytokine/chemokine levels in monocytes by flow cytometry. The % monocytes staining positive in the sample and change in mean fluorescence intensity (ΔMFI) after ORF8 were used to calculate the adjusted MFI for each cytokine. We then tested pre-COVID-19 PBMC samples from 60 CLL patients who subsequently developed COVID-19 infection. Severe COVID-19 was defined as hospitalization due to COVID-19. In the 26 normal donor samples, the adjusted MFI for interleukin (IL)-1β, IL-6, IL-8, and CCL-2 were significantly different with ORF8 stimulation vs controls. We next analyzed monocytes from pre-COVID-19 PBMC samples from 60 CLL patients. The adjusted MFI to ORF8 stimulation of monocyte intracellular IL-1β was associated with severe COVID-19 and a reactive ORF8 monocyte response was defined as an IL- 1β adjusted MFI ≥ 0.18 (sensitivity 67%, specificity 75%). The median time to hospitalization after infection in CLL patients with a reactive ORF8 response was 12 days versus not reached for patients with a non-reactive ORF8 response with a hazard ratio of 7.7 (95% CI: 2.4-132, p=0.005). These results provide new insight on the monocyte inflammatory response to virus with implications in a broad range of disorders involving monocytes

Differential requirement for Hoxa9 in the development and differentiation of B, NK, and DC-lineage cells from Flt3+ multipotential progenitors

<p>Abstract</p> <p>Hoxa9 is a homeodomain transcription factor important for the generation of Flt3+hiIL-7R- lymphoid biased-multipotential progenitors, Flt3+IL-7R+ common lymphoid progenitors (CLPs), and B cell precursors (BCP) in bone marrow (BM). In addition to B-cell, Flt3+IL-7R+ CLPs possess NK and DC developmental potentials, although DCs arise from Flt3+IL-7R- myeloid progenitors as well. In this study, we investigated the requirement for Hoxa9, from Flt3+ or Flt3- progenitor subsets, in the development of NK and DC lineage cells in BM. Flt3+IL-7R+Ly6D- CLPs and their Flt3+IL-7R+Ly6D+ B lineage-restricted progeny (BLP) were significantly reduced in <it>hoxa9−/−</it> mice. Interestingly, the reduction in Flt3+IL-7R+ CLPs in <it>hoxa9−/−</it> mice had no impact on the generation of NK precursor (NKP) subsets, the differentiation of NKP into mature NK cells, or NK homeostasis. Similarly, percentages and numbers of common dendritic progenitors (CDP), as well as their plasmacytoid or conventional dendritic cell progeny in <it>hoxa9−/−</it> mice were comparable to wildtype. These findings reveal distinct requirements for Hoxa9 or Hoxa9/Flt3 molecular circuits in regulation of B versus NK and DC development in BM.</p

Comparison of the blood immune repertoire with clinical features in chronic lymphocytic leukemia patients treated with chemoimmunotherapy or ibrutinib.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD19+ CD5+ clonal B lymphocytes in the blood, bone marrow, and peripheral lymphoid organs. Treatment options for patients range from historical chemoimmunotherapy (CIT) to small molecule inhibitors targeting pro-survival pathways in leukemic B cells, such as the Brutons tyrosine kinase inhibitor ibrutinib (IBR). Using biobanked blood samples obtained pre-therapy and at standard response evaluation timepoints, we performed an in-depth evaluation of the blood innate and adaptive immune compartments between pentostatin-based CIT and IBR and looked for correlations with clinical sequelae. CD4+ conventional T cells and CD8+ cytotoxic T cells responded similarly to CIT and IBR, although exhaustion status differed. Both treatments dramatically increased the prevalence and functional status of monocyte, dendritic cell, and natural killer cell subsets. As expected, both regimens reduced clonal B cell levels however, we observed no substantial recovery of normal B cells. Although improvements in most immune subsets were observed with CIT and IBR at response evaluation, both patient groups remained susceptible to infections and secondary malignancies during the study

Separation of plasmacytoid dendritic cells from B-cell-biased lymphoid progenitor (BLP) and Pre-pro B cells using PDCA-1.

B-cell-biased lymphoid progenitors (BLPs) and Pre-pro B cells lie at a critical juncture between B cell specification and commitment. However, both of these populations are heterogenous, which hampers investigation into the molecular changes that occur as lymphoid progenitors commit to the B cell lineage. Here, we demonstrate that there are PDCA-1(+)Siglec H(+) plasmacytoid dendritic cells (pDCs) that co-purify with BLPs and Pre-pro B cells, which express little or no CD11c or Ly6C. Removal of PDCA-1(+) pDCs separates B cell progenitors that express high levels of a Rag1-GFP reporter from Rag1-GFP(low/neg) pDCs within the BLP and Pre-pro B populations. Analysis of Flt3-ligand knockout and IL-7Rα knockout mice revealed that there is a block in B cell development at the all-lymphoid progenitor (ALP) stage, as the majority of cells within the BLP or Pre-pro B gates were PDCA-1(+) pDCs. Thus, removal of PDCA-1(+) pDCs is critical for analysis of BLP and Pre-pro B cell populations. Analysis of B cell potential within the B220(+)CD19(-) fraction demonstrated that AA4.1(+)Ly6D(+)PDCA-1(-) Pre-pro B cells gave rise to CD19(+) B cells at high frequency, while PDCA-1(+) pDCs in this fraction did not. Interestingly, the presence of PDCA-1(+) pDCs within CLPs may help to explain the conflicting results regarding the origin of these cells

Chronic lymphocytic leukemia B-cell-derived TNFα impairs bone marrow myelopoiesis.

TNFα is implicated in chronic lymphocytic leukemia (CLL) immunosuppression and disease progression. TNFα is constitutively produced by CLL B cells and is a negative regulator of bone marrow (BM) myelopoiesis. Here, we show that co-culture of CLL B cells with purified normal human hematopoietic stem and progenitor cells (HSPCs) directly altered protein levels of the myeloid and erythroid cell fate determinants PU.1 and GATA-2 at the single-cell level within transitional HSPC subsets, mimicking ex&nbsp;vivo expression patterns. Physical separation of CLL cells from control HSPCs or neutralizing TNFα abrogated upregulation of PU.1, yet restoration of GATA-2 required TNFα neutralization, suggesting both cell contact and soluble-factor-mediated regulation. We further show that CLL patient BM myeloid progenitors are diminished in frequency and function, an effect recapitulated by chronic exposure of control HSPCs to low-dose TNFα. These findings implicate CLL B-cell-derived TNFα in impaired BM myelopoiesis