Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.

ABSTRACT: High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

The procoagulant potential before and after surgery for endometriosis and its association with disease severity.

OBJECTIVES: Previous studies have suggested that endometriosis is associated with increased hypercoagulable state. We aimed to determine the procoagulant potential among women with endometriosis before and after surgery. METHODS: A prospective longitudinal study performed during 2020-2021 at a university hospital. Women undergoing laparoscopic surgery for endometriosis served as the study group. Blood samples were taken preoperatively and 3 months after surgery. The degree of hypercoagulability was assessed by thrombin generation, a global marker of the activation of the coagulation system, expressed as the endogenous thrombin potential (ETP). Healthy volunteers, without any medical condition or medications use, matched for age and weight of the study group, served as a control group. RESULTS: Thirty women with histologically-proven endometriosis and thirty healthy control subjects were enrolled in this study. Median preoperative ETP was significantly higher in women with moderate-to-severe endometriosis (3313 [interquartile range, IQR 3067-3632] nM) as compared to those with minimal-to-mild disease (2368 [IQR 1850-2621] nM) and the control group (2451 [2096-2617] nM) ( P  < 0.001 for both comparisons). Following surgery, the ETP significantly decreased in those with moderate-to-severe endometriosis (postoperative: 2368 vs. preoperative: 3313 nM, P  < 0.001) and was comparable to the ETP in the control group ( P  = 0.35). In multivariate analysis, moderate-to-severe endometriosis was the only independent predictor of the preoperative ETP level ( P  < 0.001), with a direct positive correlation between disease revised American Society for Reproductive Medicine severity score and the preoperative ETP level ( rs  = 0.67; P  < 0.0001). CONCLUSION: Moderate-to-severe endometriosis is associated with enhanced hypercoagulable state, which decreases significantly after surgery. Disease severity was independently associated with the degree of hypercoagulability.

Differential prognosis of single and multiple TP53 abnormalities in high-count MBL and untreated CLL.

TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction >10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured.

Kinetics of Maternally Derived Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies in Infants in Relation to the Timing of Antenatal Vaccination.

BACKGROUND: SARS-CoV-2 infection during early infancy can result in severe disease. We evaluated the durability of maternally-derived anti-SARS-CoV-2 antibodies in infants and its relation to antenatal vaccination timing. METHODS: Sera were prospectively collected at birth and 3 months after delivery from mother-infant pairs following antenatal BNT162b2 vaccination. SARS-CoV-2 receptor binding domain (RBD)-specific IgG levels and neutralizing activity were evaluated. RESULTS: 56 mother-infant pairs were included: 15 (26.8%) were vaccinated in the first trimester, 16 (28.6%) in the second trimester, and 25 (44.6%) in the third trimester.At the time of delivery, all neonates were positive for anti-RBD-specific IgG with a median concentration of 4046 [IQR 2446-7896] AU/mL, with the highest concentration found after third trimester vaccination (median 6763 [IQR 3857-12561] AU/mL). At 3 months after delivery, anti RBD-specific IgG levels in infants significantly waned with a median concentration of 545 [IQR 344-810] AU/mL (P < .001). The half-life of anti-RBD-specific IgG was 66 days among mothers and 30 days among infants. While at the time of delivery, all neonates had detectable neutralizing activity regardless of gestational age at vaccination, at 3-months of age, a higher proportion of infants born to mothers vaccinated in third trimester had persistent neutralizing activity as compared to those born to mothers vaccinated in second trimester. CONCLUSIONS: Maternal vaccination leads to efficient transplacental antibody transfer, with persistent anti-SARS-CoV-2 antibodies detected at 3 months of age in all infants. The observed effect of antenatal immunization timing on the kinetics of maternally-derived antibodies may have implications for SARS-CoV-2 vaccination strategies.

Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis.

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

The inherited genetic contribution and polygenic risk score for risk of CLL and MBL: a narrative review.

Chronic lymphocytic leukemia (CLL) is a neoplasm of B-cells in the blood and monoclonal B-cell lymphocytosis (MBL) is a precursor state to CLL. This narrative review provides an overview of the genetic studies that identified 43 common variants associated with risk of CLL among individuals of European ancestry. Emerging studies found that ∼50% of these variants are associated with MBL risk. Moreover, the polygenic risk score (PRS) calculated from these CLL variants has been shown to be a robust predictor for both CLL and MBL risk among European ancestry individuals but a weak predictor among African ancestry individuals. By summarizing these genetic studies, we conclude that additional studies are needed in other race/ethnic populations to identify race-specific susceptibility variants, that functional studies are needed to validate the biological mechanisms of the variants, and that the clinical utility of the PRS is limited until preventive strategies for CLL are developed.

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

Progression and survival of MBL: a screening study of 10 139 individuals.

Monoclonal B-cell lymphocytosis (MBL) is a common hematological premalignant condition that is understudied in screening cohorts. MBL can be classified into low-count (LC) and high-count (HC) types based on the size of the B-cell clone. Using the Mayo Clinic Biobank, we screened for MBL and evaluated its association with future hematologic malignancy and overall survival (OS). We had a two-stage study design including discovery and validation cohorts. We screened for MBL using an eight-color flow-cytometry assay. Medical records were abstracted for hematological cancers and death. We used Cox regression to evaluate associations and estimate hazard ratios and 95% confidence intervals (CIs), adjusting for age and sex. We identified 1712 (17%) individuals with MBL (95% LC-MBL), and the median follow-up time for OS was 34.4 months with 621 individuals who died. We did not observe an association with OS among individuals with LC-MBL (P = .78) but did among HC-MBL (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). Among the discovery cohort with a median of 10.0 years follow-up, 31 individuals developed hematological cancers with two-thirds being lymphoid malignancies. MBL was associated with 3.6-fold risk of hematological cancer compared to controls (95% CI, 1.7-7.7; P < .001) and 7.7-fold increased risk for lymphoid malignancies (95% CI:3.1-19.2; P < .001). LC-MBL was associated with 4.3-fold risk of lymphoid malignancies (95% CI, 1.4-12.7; P = .009); HC-MBL had a 74-fold increased risk (95% CI, 22-246; P < .001). In this large screening cohort, we observed similar survival among individuals with and without LC-MBL, yet individuals with LC-MBL have a fourfold increased risk of lymphoid malignancies. Accumulating evidence indicates that there are clinical consequences to LC-MBL, a condition that affects 8 to 10 million adults in the United States.

Maternal and Neonatal Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant Neutralization After Antenatal Messenger RNA Vaccination.

We evaluated the neutralization efficiency against SARS-CoV-2 Omicron variant in maternal and cord blood sera after antenatal BNT162b2 vaccination. Neutralizing antibodies against Omicron were lacking at the time of delivery after 2-dose vaccination. A third booster dose was essential in building neutralizing antibody capacity against Omicron among mothers and neonates.

Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmsted County, Minnesota.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m2 < 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0-25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05-4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68-4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50-4.42, P = 0.001), and abnormal free light chain ratio (FLCr) (HR = 3.39, CI:1.98-5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68-0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06-11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57-3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLCr. This association may be stronger among females.

Prevalence of heavy chain MGUS by race and family history risk groups using a high-sensitivity screening method.

Mass-spectrometry (MS) assays detect lower levels of monoclonal proteins and result in earlier detection of monoclonal gammopathy of undetermined significance (MGUS). We examined heavy chain MGUS prevalence using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS among 3 risk groups, ages 50 or older: 327 African Americans (AA) and 1223 European Americans (EA) from a clinical biobank and 1093 unaffected first-degree relatives (FDR) of patients with hematologic disorders. Age- and sex-adjusted prevalence rates were directly standardized to 2010 United States population. Prevalence ratios were estimated for comparisons of AA and FDR to the EA group using the Poisson distribution. Results were also compared with population-based prevalence using conventional gel-based methods. Risk groups had similar sex and age distributions. MALDI-TOF MGUS prevalence was higher in the AA (16.5% [95% confidence interval (CI), 12.2%, 20.8%]) and FDR (18.3% [95% CI, 16.6%, 21.6%]) than in EA (10.8% [95% CI, 8.8%, 12.7%]), translating to prevalence ratios of 1.73 (95% CI, 1.31, 2.29) and 1.90 (95% CI, 1.55, 2.34), respectively. MALDI-TOF EA prevalence was over threefold higher than conventional estimates but showed similar age trends. Thus, the MALDI-TOF assay found greater numbers with MGUS but similar relative differences by race, family history, and age as prior studies.

The Effect of Gestational Age at BNT162b2 mRNA Vaccination on Maternal and Neonatal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Levels.

BACKGROUND: Coronavirus disease 2019 (COVID-19) during pregnancy and early infancy can result in severe disease. Evaluating the effect of gestational age at the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on maternal antibody levels and transplacental antibody transfer has important implications for maternal care and vaccination strategies. METHODS: Maternal and cord blood sera were collected from mother-newborn dyads (n = 402), following term delivery after antenatal 2-dose SARS-CoV-2 BNT162b2 mRNA vaccination. SARS-CoV-2 spike protein (S) and receptor binding domain (RBD)-specific IgG levels were evaluated in the samples collected. RESULTS: Median anti-S and anti-RBD-specific IgG levels in maternal sera at the time of delivery were lowest following first-trimester vaccination (n = 90; anti-S IgG: 76 AU/mL; anti-RBD-specific IgG: 478 AU/mL), intermediate in those vaccinated in the second trimester (n = 124; anti-S IgG: 126 AU/mL; anti-RBD-specific IgG: 1263 AU/mL), and highest after third-trimester vaccination (n = 188; anti-S IgG: 240 AU/mL; anti-RBD-specific IgG: 5855 AU/mL). Antibody levels in neonatal sera followed a similar pattern and were lowest following antenatal vaccination in the first trimester (anti-S IgG: 126 AU/mL; anti-RBD-specific IgG: 1140 AU/mL). In a subgroup of parturients vaccinated in the first trimester (n = 30), a third booster dose was associated with significantly higher maternal and neonatal antibody levels. CONCLUSIONS: These results suggest a considerable antibody waning throughout pregnancy in those vaccinated at early gestation. The observed boosting effect of a third vaccine dose hints at its potential benefit in those who completed the 2-dose vaccine series at early pregnancy or before conception. The impact of antenatal immunization timing on SARS-CoV-2 transplacental antibody transfer may influence neonatal seroprotection.

Duration of the second stage of labour and risk of subsequent spontaneous preterm birth.

OBJECTIVES: To determine the risk of spontaneous preterm birth (sPTB) associated with the length of second stage of labour in the first term delivery. DESIGN: Retrospective cohort study. SETTING: University hospital. POPULATION: Women with first two consecutive singleton births and the first birth at term. Those who did not reach the second stage of labour in the first delivery were excluded. METHODS: Charts from 2007 to 2019 were reviewed. MAIN OUTCOME MEASURES: Rate of sPTB (<37 weeks of gestation) in the second delivery. RESULTS: Of 13 958 women who met study inclusion criteria, 1464 (10.5%) parturients had a prolonged second stage (≥180 min) in their first term delivery. The rate of sPTB in the second delivery was similar in those with and without a prolonged second stage in first delivery (2.8% versus 2.8%; adjusted odds ratio [aOR] 1.35, 95% CI 0.96-1.90). After adjustment for mode of delivery, prolonged second stage was also not associated with subsequent sPTB in those who delivered by spontaneous and operative vaginal delivery. Those delivered by second-stage caesarean section in the first delivery had a higher risk of sPTB in the second delivery (25/526, 4.8%; aOR 2.66, 95% CI 1.71-4.12; p < 0.001), with a more pronounced risk in those with second-stage caesarean following a prolonged second stage of labour (15/259, 5.8%; aOR 3.40, 95% CI 1.94-5.94; p < 0.001). CONCLUSION: Second-stage duration in a first term vaginal delivery is not associated with subsequent sPTB. The risk of sPTB is increased following second-stage caesarean section, particularly if performed after a prolonged second stage. TWEETABLE ABSTRACT: Second-stage caesarean delivery, particularly after prolonged second stage, increases the risk of preterm birth.

Vaccination History and Risk of Lymphoma and Its Major Subtypes.

BACKGROUND: Vaccinations have been hypothesized to play a role in lymphoma etiology, but there are few studies, mixed results, and limited data on lymphoma subtypes. Herein, we investigate the association of vaccinations with risk of major lymphoma subtypes. METHODS: We studied 2,461 lymphoma cases and 2,253 controls enrolled from 2002 to 2014. Participants self-reported history of vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza. Polytomous logistic regression was used to estimate OR and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS: After multivariable adjustment, vaccination against influenza was inversely associated with lymphoma (OR = 0.82; 95% CI, 0.66-1.02), which was stronger for last vaccination 1+ years before enrollment (OR = 0.71; 95% CI, 0.56-0.91) and for >5 influenza vaccinations (OR = 0.56; 95% CI, 0.46-0.68). Ever vaccination against hepatitis A (OR = 0.81; 95% CI, 0.66-1.00) but not hepatitis B (OR = 0.97; 95% CI, 0.81-1.18) was associated with lymphoma risk, although more recent vaccinations were inversely associated with lymphoma risk for both hepatitis A (<6 years before enrollment, OR = 0.56; 95% CI, 0.40-0.77) and hepatitis B (<9 years before enrollment, OR = 0.72; 95% CI, 0.55-0.93). Ever vaccination against yellow fever was inversely associated with risk (OR = 0.73; 95% CI, 0.55-0.96), and this did not vary by time since last vaccination. Although there was no overall statistical evidence for heterogeneity of vaccination history by lymphoma subtype, the only statistically significant inverse associations were observed for influenza and yellow fever vaccinations with diffuse large B-cell and follicular lymphoma. CONCLUSIONS: Selected vaccinations were inversely associated with lymphoma risk, with time since last vaccination relevant for some of these vaccines. IMPACT: Vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza are unlikely to increase lymphoma risk.

Trial of labor after cesarean in primiparous women with fetal macrosomia.

KEY MESSAGE: Spontaneous labor onset, epidural anesthesia and prior cesarean for non-arrest disorders are strong predictors of successful vaginal birth after cesarean in women delivering a macrosomic fetus. PURPOSE: Lower rates of successful vaginal birth after cesarean in association with increasing birthweight were previously reported. We aimed to determine the factors associated with successful trial of labor after cesarean (TOLAC) among primiparous women with fetal macrosomia. METHODS: A retrospective cohort study conducted during 2005-2019 at two university hospitals, including all primiparous women delivering a singleton fetus weighing ≥ 4000 g, after cesarean delivery at their first delivery. A multivariate analysis was performed to evaluate the characteristics associated with TOLAC success (primary outcome). RESULTS: Of 551 primiparous women who met the inclusion criteria, 50.1% (n = 276) attempted a TOLAC and 174 (63.0%) successfully delivered vaginally. In a multivariate analysis, spontaneous onset of labor (aOR [95% CI] 3.68 (2.05, 6.61), P < 0.001), epidural anesthesia (aOR [95% CI] 2.38 (1.35, 4.20), P = 0.003) and history of cesarean delivery due to non-arrest disorder (aOR [95% CI] 2.25 (1.32, 3.85), P = 0.003) were the only independent factors associated with TOLAC success. Successful TOLAC was achieved in 82.0% (82/100) in the presence of all three favorable factors, 61.3% (65/106) in the presence of two factors and 38.6% (27/70) in the presence of one or less of these three factors (P < 0.001). CONCLUSION: Spontaneous onset of labor, epidural anesthesia and prior cesarean delivery due to non-arrest disorders were independently associated with higher vaginal birth after cesarean rate among women with fetal macrosomia, with an overall favorable success rate in the presence of these factors. These findings should be implemented in patient counseling in those contemplating a vaginal birth in this setting.

Timing of SARS-CoV-2 vaccination during the third trimester of pregnancy and transplacental antibody transfer: a prospective cohort study.

OBJECTIVE: We aimed to assess the impact of early versus late third-trimester maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on transplacental transfer and neonatal levels of SARS-CoV-2 antibodies. METHODS: Maternal and cord blood sera were collected following term delivery after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination, with the first vaccine dose administered between 27 and 36 weeks of gestation. SARS-CoV-2 spike protein (S) and receptor-binding domain (RBD) -specific, IgG levels and neutralizing potency were evaluated in maternal and cord blood samples. RESULTS: The study cohort consisted of 171 parturients-median age 31 years (interquartile range (IQR) 27-35 years); median gestational age 39+5 weeks (IQR 38+5-40+4 weeks)-83 (48.5%) were immunized in early thrird-trimester (first dose at 27-31 weeks) and 88 (51.5%) were immunized in late third trimester (first dose at 32-36 weeks). All mother-infant paired sera were positive for anti S- and anti-RBD-specific IgG. Anti-RBD-specific IgG concentrations in neonatal sera were higher following early versus late third-trimester vaccination (median 9620 AU/mL (IQR 5131-15332 AU/mL) versus 6697 AU/mL (IQR 3157-14731 AU/mL), p 0.02), and were positively correlated with increasing time since vaccination (r = 0.26; p 0.001). Median antibody placental transfer ratios were increased following early versus late third-trimester immunization (anti-S ratio: 1.3 (IQR 1.1-1.6) versus 0.9 (IQR 0.6-1.1); anti-RBD-specific ratio: 2.3 (IQR 1.7-3.0) versus 0.7 (IQR 0.5-1.2), p < 0.001). Neutralizing antibodies placental transfer ratio was greater following early versus late third-trimester immunization (median 1.9 (IQR 1.7-2.5) versus 0.8 (IQR 0.5-1.1), p < 0.001), and was positively associated with longer duration from vaccination (r = 0.77; p < 0.001). CONCLUSIONS: Early compared with late third-trimester maternal SARS-CoV-2 immunization enhanced transplacental antibody transfer and increased neonatal neutralizing antibody levels. Our findings highlight that vaccination of pregnant women early in the third trimester may enhance neonatal seroprotection.

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10-29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10-63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10-5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Is real-time dynamic cervical shortening predictive of preterm birth?- A case control study.

OBJECTIVES: We aimed to assess the risk of preterm birth in those with real-time dynamic cervical shortening. METHODS: A retrospective matched case-control study. The study group comprised all women with dynamic cervical shortening (≥4 mm) noted from 24 to 34 weeks of gestation during 2010-2017 at a university hospital. Two control groups of women were established by matching the minimal and maximal cervical length measured, as well as age, parity, gestational age, history of spontaneous preterm birth, symptoms of preterm labor, and delivery year. RESULTS: Data from 339 women were analyzed, 113 with dynamic cervical shortening comprised the study group, and two groups with 113 women each, matched for the minimal and maximal cervical lengths measured comprised the control groups. Rates of spontaneous preterm birth rate at <37 weeks (32.7% vs. 15.9%; OR [95% CI]: 2.60 (1.36, 4.87), p = .004) and <35 weeks (15.9% vs. 5.3%; OR [95% CI]: 3.38 (1.29, 8.86), p = .013) were significantly higher among those with dynamic cervix than among the control group matched for the maximal cervical length, and comparable to the control group matched for the minimal cervical length. The negative predictive values of cervical length for preterm birth occurrence at various cutoff values were lower in those with dynamic cervix. CONCLUSIONS: The minimal cervical length measured should be used to guide patient management when dynamic cervix is noted. In the setting of dynamic cervical change, the value of cervical length as a negative predictor of preterm birth is limited.