Enhanced surveillance of tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis (Tdap) vaccines in pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 2011–2015

BackgroundIn October 2011, the Advisory Committee on Immunization Practices (ACIP) issued updated recommendations that all pregnant women routinely receive a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine.ObjectivesWe characterized reports to the Vaccine Adverse Event Reporting System (VAERS) in pregnant women who received Tdap after this updated recommendation (2011–2015) and compared the pattern of adverse events (AEs) with the period before the updated recommendation (2005–2010).MethodsWe searched the VAERS database for reports of AEs in pregnant women who received Tdap vaccine after the routine recommendation (11/01/2011–6/30/2015) and compared it to published data before the routine Tdap recommendation (01/01/2005–06/30/2010). We conducted clinical review of reports and available medical records. The clinical pattern of reports in the post-recommendation period was compared with the pattern before the routine Tdap recommendation.ResultsWe found 392 reports of Tdap vaccination after the routine recommendation. One neonatal death but no maternal deaths were reported. No maternal or neonatal deaths were reported before the recommendation. We observed an increase in proportion of reports for stillbirths (1.5–2.8%) and injection site reactions/arm pain (4.5–11.9%) after the recommendation compared to the period before the routine recommendation for Tdap during pregnancy. We noted a decrease in reports of spontaneous abortion (16.7–1%). After the 2011 Tdap recommendation, in most reports, vaccination (79%) occurred during the third trimester compared to 4% before the 2011 Tdap recommendation. Twenty-six reports of repeat Tdap were received in VAERS; 13 did not report an AE. One medical facility accounted for 27% of all submitted reports.ConclusionsNo new or unexpected vaccine AEs were noted among pregnant women who received Tdap after routine recommendations for maternal Tdap vaccination. Changes in reporting patterns would be expected, given the broader use of Tdap in pregnant women in the third trimester.     

Adverse childhood experiences,inflammation, and depressive symptoms in later life: a prospective cohort study

BackgroundExposure to adverse childhood experiences (ACEs) has been associated with both inflammation and depression. However, little research has examined the potential mediational role of inflammation in the link between ACEs and depression using longitudinal data. Therefore, we investigated the direct and indirect effects of ACEs on inflammation, depression, and their change trajectories over time.MethodsWe used data from the English Longitudinal Study of Ageing. Four ACE categories were assessed retrospectively at wave 3 (2006–07): abuse (physical or sexual abuse or physical assault), family dysfunction (parent arguments, parent mental illness or substance abuse, or parent separation or divorce), poor parent–child bonding (maternal or paternal), and loss of an attachment figure (separation from mother for >6 months, parent death, foster care or adoption, or institutionalisation). A cumulative ACE score was calculated representing the total number of ACEs experienced by the participants. Concentration of C-reactive protein (CRP), an inflammatory marker, was measured at waves 2 (2004–05), 4 (2008–09), and 6 (2012–13). Depressive symptoms were ascertained using the 8-item Centre for Epidemiological Studies Depression Scale from waves 6 to 8 (2016–17). The longitudinal direct and indirect effects of ACEs were estimated using parallel process latent growth curve modelling. All analyses were adjusted for relevant confounders. Missing data were estimated using multiple imputation.ResultsAmong the study sample (N=4382; mean age 70 years; 56% female), 24% of participants reported one ACE and 13% had two or three ACEs. The percentage of participants with three or more depressive symptoms was 21% at baseline. Greater cumulative exposure to ACEs was associated with increased CRP concentration (β=0·042, p=0·010) and depressive symptoms (β=0·164, p<0·0001) at baseline and predicted a steeper increase in these outcomes throughout the study (β_CRP=0·074, p=0·011; β_Depression=0·338, p<0·0001). However, indirect effects of ACEs on depression mediated by CRP were not observed, with only weak associations between CRP and depressive symptoms (β_iDepression=0·032, p=0·173; β_sDepression=0·067, p=0·240). Sensitivity analyses using only somatic depressive symptoms as the outcome revealed a positive association between CRP and somatic symptoms at baseline (β_iDepression=0·068, p=0·008), although the indirect effects remained non-significant in this model.InterpretationBiological mechanisms other than inflammation might underlie the relationship between ACEs and depression. Psychosocial interventions to reduce the negative effects of ACEs on children's development could help to reduce the risk of depression and of other medical conditions linked to inflammation.FundingEconomic and Social Research Council–Biotechnology and Biological Sciences Research Council Soc-B Centre for Doctoral Training (ES/P000347/1).     

Use of mammalian museum specimens to test hypotheses about the geographic expansion of Lyme disease in the southeastern United States

Lyme disease, caused primarily in North America by the bacterium Borrelia burgdorferi sensu stricto, is the most frequently reported vector-borne disease in North America and its geographic extent is increasing in all directions from foci in the northeastern and north central United States. Several southeastern states, including Virginia and North Carolina, have experienced large increases in Lyme disease incidence in the past two decades, with the biggest changes in incidence occurring in the western portion of each state. We tested the hypothesis that B. burgdorferi s.s. was present in western Virginia and North Carolina Peromyscus leucopus populations prior to the recent emergence of Lyme disease. Specifically, we examined archived P. leucopus museum specimens, sampled between 1900 and 2000, for B. burgdorferi s.s. DNA. After confirming viability of DNA extracted from ear punch biopsies from P. leucopus study skins collected between 1945 and 2000 in 19 Virginia counties and 17 North Carolina counties, we used qPCR of two species-specific loci to test for the presence of B. burgdorferi s.s. DNA. Ten mice, all collected from the Eastern Shore of Virginia in 1989, tested positive for presence of B. burgdorferi; all of the remaining 344 specimens were B. burgdorferi-negative. Our results suggest that B. burgdorferi s.s was not common in western Virginia or North Carolina prior to the emergence of Lyme disease cases in the past two decades. Rather, the emergence of Lyme disease in this region has likely been driven by the relatively recent expansion of B. burgdorferi s.s. in southward-moving ticks and reservoir hosts in the mountainous counties of these two states.     

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

BackgroundFamily history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.ObjectiveTo detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.Design, setting, and participantsA two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.Outcome measurements and statistical analysisFrequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.Results and limitationsEleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.ConclusionsOur approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.Patient summaryMultiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.     

Correlation between mutated genes and forearm deformity in patients with multiple osteochondroma

BackgroundsExostosin-1 (EXT1) and exostosin-2 (EXT2) cause multiple osteochondromas (MO). In this study, we investigated the correlation between forearm deformity and mutant EXTs in Japanese families with MO.MethodsWe evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. Of these, 28 patients were selected and underwent radiography for their forearms since they had gross forearm deformities. We measured the radial articular angle (RAA), ulna variance (UV), carpal slip (CS), and percentage of radial bowing (%RB) to compare between patients with mutant EXT1 or EXT2 and those with missense or other mutations using Student's t-test.ResultsTwenty-two (78.6%) and 6 (11.4%) out of 28 patients had mutations in EXT1 and EXT2, respectively. Nine (32.1%) and 19 (67.9%) of the 28 patients had missense and other mutations, respectively. The mean age of patients with EXT1 and EXT2 were 25.9 ± 20.3 and 33.5 ± 25.4 years, respectively and those with missense mutation and other mutations were 28.7 ± 27.0 and 24.6 ± 17.0 years, respectively. There were no significant differences in RAA, UV, and RB between patients harbouring mutant EXT1 or EXT2 (RAA, 40.1 ± 8.7 and 31.5 ± 13.9°; UV, ?2.7 ± 5.7 and ?3.1 ± 3.7 mm; %RB, 8.6 ± 1.5 and 8.3 ± 2.0%). CS was significantly greater in patients with mutant EXT1 than that in those with mutant EXT2 (EXT1, 44.1 ± 16.8%; EXT2, 18.6 ± 14.0%). There were no significant differences in RAA, UV, CS and %RB between patients with missense and other mutations.ConclusionsPatients with mutant EXT1 displayed greater CS than patients with mutant EXT2, indicating that patients with MO harbouring EXT1 mutations sustain more severe ulnar drift deformities than those with EXT2 mutations.