Differences in nasal immunoglobulin A responses to influenza vaccine strains after live attenuated influenza vaccine (LAIV) immunization in children.

Different vaccine strains included in the live attenuated influenza vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a Phase IV open-label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunization. There was a significant increase in nasal immunoglobulin (Ig)A to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting that the response is multi-factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine; the reasons for this require further investigation.

The impact of timing of maternal influenza immunization on infant antibody levels at birth.

Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunization is a potent tool to protect both these at-risk groups. While the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunized in the second trimester of pregnancy had the highest antibody titres compared to children immunized in the third trimester. The aim of the current study was to investigate how the timing of maternal influenza immunization impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both immunoglobulin (Ig)G-binding enzyme-linked immunosorbent assay (ELISA) and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunization was performed less than 4 weeks before birth. These studies confirm that immunization during pregnancy increases the antibody titre in infants. Importantly, antibody levels in cord blood were significantly higher when the mother was vaccinated in either trimesters 2 or 3, although titres were significantly lower if the mother was immunized less than 4 weeks before birth. Based on these data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available.

An evaluation of the implementation of a parent-led, games-based physical activity intervention: the Active Play at Home quasi-randomized trial.

Trial Registration: NCT02058342. Registered 6 February 2014 retrospectively registered.

Comprehensive molecular screening strategy of OCLN in band-like calcification with simplified gyration and polymicrogyria.

Occludin (OCLN) is an important component of the tight junction complex, providing apical intercellular connections between adjacent cells in endothelial and epithelial tissue. In 2010 O'Driscoll et al reported mutations in OCLN to cause band-like calcification with simplified gyration and polymicrogyria (BLC-PMG). BLC-PMG is a rare autosomal recessive syndrome, characterized by early onset seizures, progressive microcephaly, severe developmental delay and deep cortical gray matter and basal ganglia calcification with symmetrical, predominantly fronto-parietal, polymicrogyria. Here we report 4 additional cases of BLC-PMG with novel OCLN mutations, and provide a summary of the published mutational spectrum. More generally, we describe a comprehensive molecular screening strategy taking into account the technical challenges associated with the genetic architecture of OCLN, which include the presence of a pseudo-gene and copy number variants.

Nutrient exports from watersheds with varying septic system densities in the North Carolina Piedmont.

Septic systems (SSs) have been shown to be a significant source of nitrogen and phosphorus to nutrient-sensitive coastal surface and groundwaters. However, few published studies have quantified the effects of SSs on nutrient inputs to water supply watersheds in the Piedmont region of the USA. This region consists of rolling hills at the surface underlain by clayey soils. There are nearly 1 million SSs in this region, which accounts for approximately 50% of all SSs in North Carolina. The goal of this study was to determine if significant differences in nutrient concentrations and exports exist between Piedmont watersheds with different densities of SSs. Water quality was assessed in watersheds with SSs (n = 11) and a sewer and a forested watershed, which were designated as controls. Stream flow and environmental readings were recorded and water samples were collected from the watersheds from January 2015-December 2016. Additional samples were collected from sand filter watersheds in April 2015-March 2016 to compare to septic and control watersheds. Samples were analyzed for total dissolved nitrogen (TDN) and orthophosphate (PO4-P). Results indicated that watersheds served by a high-density (HD) of SSs (4.9 kg-N yr-1 ha-1; 0.2 kg-P yr-1 ha-1) exported more than double the median masses of TDN and PO4-P, respectively, relative to low-density (1.0 kg-N yr-1 ha-1; <0.1 kg-P yr-1 ha-1) and control watersheds (1.4 kg-N yr-1 ha-1; <0.1 kg-P yr-1 ha-1) during baseflow. Isotopic analysis indicated that wastewater was the most likely source of nitrate-N in HD watersheds. In all other watersheds, isotopic results suggested non-wastewater sources as the dominant nitrate-N provider. These findings indicated that SS density was a significant factor in the delivery of septic-derived nutrients to these nutrient-sensitive, water supply watersheds of the North Carolina Piedmont.

Increase in migraine diagnoses and guideline-concordant treatment in veterans, 2004-2012.

Background and aim Health administrators, policy makers, and educators have attempted to increase guideline adherence of migraine medications while reducing inappropriate use of opioid- and barbiturate-containing medications. We evaluated the burden of migraine and proportion of guideline-concordant care in a large, national health care system over time. Methods We conducted a time-series study using data from the Veterans Health Administration (VHA) electronic health record. Veterans with migraines were identified by ICD-9 code (346.X). Prescriptions and comorbid conditions were evaluated before and after migraine diagnosis. Chi-square tests and logistic regression were performed. Results A total of 57,064 veterans were diagnosed with migraine headache (5.3%), with women significantly more likely diagnosed (11.6% vs. 4.4%, p < 0.0001). The number of veterans diagnosed with migraine has significantly increased over the years. By 2012, triptans were prescribed to 43% of people with migraine, with no difference by gender. However, triptan prescriptions increased from 2004 to 2012 in men, but not women, veterans. Preventive medicines showed a significant increase with the year of migraine diagnosis, after controlling for age, sex, race, and for comorbidities treated with medications used for migraine prevention. Conclusions The burden of migraines is increasing within the VHA, with a corresponding increase in the delivery of guideline-concordant acute and prophylactic migraine-specific medication.

Hearing optimisation in neurofibromatosis type 2: A systematic review.

BACKGROUND: It is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient group. OBJECTIVES: The aim of this systematic review was to review the current literature regarding hearing outcomes of treatments for vestibular schwannomas in neurofibromatosis type 2 including conservative and medical management, radiotherapy, hearing preservation surgery and auditory implantation in order to determine the most effective way of preserving or rehabilitating hearing. SEARCH STRATEGY: A MESH search in PubMed using search terms (('Neurofibromatosis 2' [Mesh]) AND 'Neuroma, Acoustic'[Mesh]) AND 'Hearing Loss' [Mesh] was performed. A search using keywords was also performed. Studies with adequate hearing outcome data were included. With the exception of the cochlear implant studies (cohort size was very small), case studies were excluded. EVALUATION METHOD: The GRADE system was used to assess quality of publication. Formal statistical analysis of data was not performed because of very heterogenous data reporting. RESULTS: Conservative management offers the best chance of hearing preservation in stable tumours. The use of bevacizumab probably improves the likelihood of hearing preservation in growing tumours in the short term and is probably more effective than hearing preservation surgery and radiotherapy in preserving hearing. Of the hearing preservation interventions, hearing preservation surgery probably offers better hearing preservation rates than radiotherapy for small tumours but recurrence rates for hearing preservation surgery were high. For patients with profound hearing loss, cochlear implantation provides significantly better auditory outcomes than auditory brainstem implantation. Patients with untreated stable tumours are likely to achieve the best outcomes from cochlear implantation. Those who have had their tumours treated with surgery or radiotherapy do not gain as much benefit from cochlear implantation than those with untreated tumours. CONCLUSIONS: This review summarises the current literature related to hearing preservation/rehabilitation in patients with NF2. Whilst it provides indicative data, the quality of the data was low and should be interpreted with care. It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision-making is determined by many factors, not just the need to preserve hearing.

Novel mutation in the fumarate hydratase gene in a patient with Reed syndrome.

Reed syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma caused by mutations in the fumarate hydratase gene. Dermatologic evaluation is often the first or only opportunity to discover the diagnosis of Reed syndrome in affected patients, which may prove to be life-saving. We present a 40-year-old woman with history of large uterine leiomyomas who presented with a two-year history of a pruritic papular eruption on the left neck refractory to topical corticosteroids. After histopathologic examination and genetic work-up, the patient was found to have a novel mutation in the fumarate hydratase gene and was subsequently diagnosed with Reed syndrome.

Meteorological influences on nitrogen dynamics of a coastal onsite wastewater treatment system.

On-site wastewater treatment systems (OWTS) can contribute nitrogen (N) to coastal waters. In coastal areas with shallow groundwater, OWTS are likely affected by meteorological events. However, the meteorological influences on temporal variability of N exports from OWTS are not well documented. Hydrogeological characterization and seasonal monitoring of wastewater and groundwater quality were conducted at a residence adjacent to the Pamlico River Estuary, North Carolina, during a 2-yr field study (October 2009-2011). Rainfall was elevated during the first study year, relative to the annual mean. In the second year, drought was followed by extreme precipitation from Hurricane Irene. Recent meteorological conditions influenced N speciation and concentrations in groundwater. Groundwater total dissolved nitrogen (TDN) beneath the OWTS drainfield was dominated by nitrate during the drought; during wetter periods, ammonium and organic N were common. Effective precipitation (precipitation [P] minus evapotranspiration [ET]) affected OWTS TDN exports because of its influence on groundwater recharge and discharge. Groundwater nitrate-N concentrations beneath the drainfield were typically higher than 10 mg/L when total biweekly precipitation was less than evapotranspiration (precipitation deficit: P < ET). Overall, groundwater TDN concentrations were elevated above background concentrations at distances >15 m downgradient of the drainfield. Although OWTS nitrate inputs caused elevated groundwater nitrate concentrations between the drainfield and the estuary, the majority of nitrate was attenuated via denitrification between the OWTS and 48 m to the estuary. However, DON originating from the OWTS was mobile and contributed to elevated TDN concentrations along the groundwater flowpath to the estuary.

Parental and other factors associated with hydroxyurea use for pediatric sickle cell disease.

BACKGROUND: Hydroxyurea (HU) is highly effective treatment for sickle cell disease (SCD). While pediatric use of HU is accepted clinical practice, barriers to use may impede its potential benefit. PROCEDURE: A survey of parents of children ages 5-17 years with SCD was performed across five institutions to assess factors associated with HU use. RESULTS: Of the 173 parent responses, 65 (38%) had children currently taking HU. Among parents of children not taking HU, the most commonly cited reasons were that their hematology provider had not offered it, their child was not sufficiently symptomatic and concerns about potential side effects. Even parents of HU users reported widespread concern about effectiveness, long-term safety, and off-label use. In bivariate analyses, children's ages, parental demographics such as education level, or travel time to their hematology provider were not correlated with HU use. Bivariate analysis and multivariate logistic regression revealed three significant factors associated with current HU use: better parental knowledge about its major therapeutic effects (P < 0.001), sickle genotype (P = 0.005), and institution of clinical care (P = 0.04). CONCLUSIONS: Pervasive concerns about HU safety exist, even among parents of current users. Varying knowledge among parents appears to be independent of their demographics, and is associated with HU use. Inter-institutional variability in parental knowledge and drug uptake highlights potentially potent site-specific influences on likelihood of HU use. Overall, these survey data underscore the need for strategies to bolster parental understanding about benefits of HU and address concerns about its safety.

Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts.

Islet transplantation is a promising treatment for diabetes but long-term success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes.

Heritable and inducible genetic interference by double-stranded RNA encoded by transgenes.

Double-stranded RNA interference (RNAi) is an effective method for disrupting expression of specific genes in Caenorhabditis elegans and other organisms. Applications of this reverse-genetics tool, however, are somewhat restricted in nematodes because introduced dsRNA is not stably inherited. Another difficulty is that RNAi disruption of late-acting genes has been generally less consistent than that of embryonically expressed genes, perhaps because the concentration of dsRNA becomes lower as cellular division proceeds or as developmental time advances. In particular, some neuronally expressed genes appear refractory to dsRNA-mediated interference. We sought to extend the applicability of RNAi by in vivo expression of heritable inverted-repeat (IR) genes. We assayed the efficacy of in vivo-driven RNAi in three situations for which heritable, inducible RNAi would be advantageous: (i) production of large numbers of animals deficient for gene activities required for viability or reproduction; (ii) generation of large populations of phenocopy mutants for biochemical analysis; and (iii) effective gene inactivation in the nervous system. We report that heritable IR genes confer potent and specific gene inactivation for each of these applications. We suggest that a similar strategy might be used to test for dsRNA interference effects in higher organisms in which it is feasible to construct transgenic animals, but impossible to directly or transiently introduce high concentrations of dsRNA.

Onsite wastewater system nitrogen contributions to groundwater in coastal North Carolina.

The objective of the study described in this article was to evaluate the nitrogen contributions from two onsite wastewater systems (sites 1 and 2) to groundwater and adjacent surface waters in coastal Beaufort County, North Carolina. Groundwater levels and water quality parameters including total nitrogen, nitrogen species, temperature, and pH were monitored from October 2009 to May 2010. Nitrogen was also tested in groundwater from deeper irrigation or drinking water wells from the two sites and six additional neighboring residences. Mean total nitrogen concentrations in groundwater beneath onsite wastewater systems 1 and 2 were 34.3 +/- 16.7 mg/L and 12.2 +/- 2.9 mg/L, respectively, and significantly higher than background groundwater concentrations (< 1 mg/L). Groundwater in the deeper wells appeared not to be influenced by the onsite systems. Groundwater nitrogen concentrations typically decreased with distance down-gradient from the systems, but were still elevated relative to background conditions more than 15 m from the systems and near the estuary. This was a pioneering effort to better understand the link of onsite systems, the fate of nitrogen in the environment, and public health.

Gender differences in PTSD severity and pain outcomes: baseline results from the LAMP trial.

Background: Post-traumatic stress disorder (PTSD) and chronic pain are highly prevalent comorbid conditions. Veterans dually burdened by PTSD and chronic pain experience more severe outcomes compared to either disorder alone. Few studies have enrolled enough women Veterans to test gender differences in pain outcomes [catastrophizing, intensity, interference] by the severity of PTSD. Aim: Examine gender differences in the association between PTSD symptoms and pain outcomes among Veterans enrolled in a chronic pain clinical trial. Methods: Participants were 421 men and 386 women Veterans with chronic pain who provided complete data on PTSD symptoms and pain outcomes. We used hierarchical linear regression models to examine gender differences in pain outcomes by PTSD symptoms. Results: Adjusted multivariable models indicated that PTSD symptoms were associated with higher levels of pain catastrophizing (0.57, 95% CI [0.51, 0.63]), pain intensity (0.30, 95% CI [0.24, 0.37]), and pain interference (0.46, 95% CI [0.39, 0.52]). No evidence suggesting differences in this association were found in either the crude or adjusted models (all interaction p-values<0.05). Conclusion: These findings may reflect the underlying mutual maintenance of these conditions whereby the sensation of pain could trigger PTSD symptoms, particularly if the trauma and pain are associated with the same event. Clinical implications and opportunities testing relevant treatments that may benefit both chronic pain and PTSD are discussed.

Overwhelming support among urban Irish COPD patients for lung cancer screening by low-dose CT scan.

PURPOSE: The National Lung Screening Trial (NLST) has renewed interest in low-dose computed tomography (LDCT) screening for lung cancer. Smokers may be less receptive toward LDCT screening, however, compared with never smokers. The views of patients with COPD, a particularly high-risk group, toward LDCT screening for lung cancer are currently unknown. We therefore evaluated attitudes of patients with COPD toward LDCT screening for lung cancer. METHODS: Interviews with Irish patients with COPD who satisfied NLST eligibility criteria were conducted in clinical settings using a questionnaire based on that of a comparable study of U.S. current/former smokers of unspecified disease status. RESULTS: A total of 142 subjects had a mean age of 65.09 ± 6.07 years (46.4 % were male, mean pack years 54.5 ± 33.3, mean FEV1 59.16 ± 23 %); 97.8 % had an identifiable usual source of healthcare. Compared with data from a U.S. cohort of current/former smokers, a higher proportion of Irish COPD smokers: believed that they were at risk for lung cancer (63.6 vs. 15.7 %); believed that early detection improved chances of survival (90 vs. 51.2 ); were willing to consider LDCT screening (97.9 vs. 78.6 %); were willing to pay for a LDCT scan (68.6 vs. 36.2 %); and were willing to accept treatment recommendations arising (95.7 vs. 56.2 %; p < 0.0001 for all comparisons). CONCLUSIONS: Urban Irish smokers with COPD who would be eligible for LDCT screening are almost universally in favor of being screened and treated for screening-detected lung cancers. This readily accessible high-risk population should be actively targeted in future screening programs.

The protected antimicrobial process in a University Teaching Hospital: a qualitative interview study exploring the knowledge, attitudes, and experiences of healthcare professionals.

Background The protected or restricted supply of certain antimicrobials such as linezolid, caspofungin, aztreonam, in the acute hospital setting is an important element of Antimicrobial Stewardship (AMS) programmes to address the growing problem of antimicrobial resistance. This process involves submitting an application for use to be reviewed typically by a Consultant Microbiologist, Infectious Disease Consultant or Antimicrobial Pharmacist. Aim To investigate healthcare professionals' knowledge, experiences, and attitudes towards the protected/restricted antimicrobials process in order to identify possible methods of optimisation and improvement. Method Semi-structured interviews with stakeholders involved in the protected/restricted antimicrobial prescribing, dispensing and administration process were conducted in September-October 2019 in a 350-bed voluntary, general, acute hospital in Ireland. Interviews were analysed by the Framework method and mapped to the Theoretical Domains Framework (TDF). Results Interviews were conducted with 8 Doctors, 4 Pharmacists and 3 Nurses. TDF domains identified included: 'Knowledge'; 'Social/professional role and identity'; 'Social influences'; 'Memory, attention and decision processes'; 'Beliefs about consequences'; 'Environmental contexts and resources'. The relationship between prescribers and the AMS Team was reported as a facilitator of the process, whereas the inconsistency of the filing and versions of forms on the wards were seen as challenges. Conclusion The results of this study have shown that the existing protected/restricted antimicrobial process is a multi-disciplinary effort with barriers that require attention in order to make future improvements. Standardization of the form across all wards, an electronic version of the form, and structured education around AMS were suggested to optimize the process.

A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans.

Similar to mammalian excitotoxic cell death, necrotic-like cell death (NCD) in Caenorhabditis elegans can be initiated by hyperactive ion channels. Here we investigate the requirements for genes that execute and regulate programmed cell death (PCD) in necrotic-like neuronal death caused by a toxic MEC-4 channel. Neither the kinetics of necrosis onset nor the total number of necrotic corpses generated is altered by any C. elegans mutation known to block PCD, which provides genetic evidence that the activating mechanisms for NCD and apoptotic cell death are distinct. In contrast, all previously reported ced genes required for phagocytotic removal of apoptotic corpses, as well as ced-12, a new engulfment gene we have identified, are required for efficient elimination of corpses generated by distinct necrosis-inducing stimuli. Our results show that a common set of genes acts to eliminate cell corpses irrespective of the mode of cell death, and provide the first identification of the C. elegans genes that are required for orderly removal of necrotic cells. As phagocytotic mechanisms seem to be conserved from nematodes to humans, our findings indicate that injured necrotic cells in higher organisms might also be eliminated before lysis through a controlled process of corpse removal, a hypothesis that has significant therapeutic implications.

Evaluation of on-site wastewater system Escherichia coli contributions to shallow groundwater in coastal North Carolina.

The study goal was to determine if on-site wastewater systems (OSWWS) installed in coastal areas were effective at reducing indicator bacteria densities before discharge to groundwater. Groundwater Escherichia coli (E. coli) densities and groundwater levels adjacent to 16 OSWWS in three different soil groups (sand, sandy loam, and sandy clay loam) were monitored and compared to background groundwater conditions on four occasions between March 2007 and February 2008 in coastal North Carolina. Groundwater beneath OSWWS had significantly (p≤0.05) lower densities of E. coli than septic tank effluent, but significantly higher densities of E. coli than background conditions for each soil type. Twenty three percent of all groundwater samples near OSWWS had E. coli densities that exceeded the EPA freshwater contact standards (single sample 235 cfu/100 mL) for surface waters. Groundwater E. coli densities near OSWWS were highest during shallow water table periods. The results indicate that increasing the required vertical separation distance from drainfield trenches to seasonal high water table could improve shallow groundwater quality.

High-Resolution Differentiation of Enteric Bacteria in Premature Infant Fecal Microbiomes Using a Novel rRNA Amplicon.

Identifying and tracking microbial strains as microbiomes evolve are major challenges in the field of microbiome research. We utilized a new sequencing kit that combines DNA extraction with PCR amplification of a large region of the rRNA operon and downstream bioinformatic data analysis. Longitudinal microbiome samples of coadmitted twins from two different neonatal intensive care units (NICUs) were analyzed using an ∼2,500-base amplicon that spans the 16S and 23S rRNA genes and mapped to a new, custom 16S-23S rRNA database. Amplicon sequence variants (ASVs) inferred using DADA2 provided sufficient resolution for the differentiation of rRNA variants from closely related but not previously sequenced Klebsiella, Escherichia coli, and Enterobacter strains, among the first bacteria colonizing the gut of these infants after admission to the NICU. Distinct ASV groups (fingerprints) were monitored between coadmitted twins over time, demonstrating the potential to track the source and spread of both commensals and pathogens. The high-resolution taxonomy obtained from long amplicon sequencing enables the tracking of strains temporally and spatially as microbiomes are established in infants in the hospital environment.IMPORTANCE Achieving strain-level resolution is a major obstacle for source tracking and temporal studies of microbiomes. In this study, we describe a novel deep-sequencing approach that provides species- and strain-level resolution of the neonatal microbiome. Using Klebsiella, E. coli, and Enterobacter as examples, we could monitor their temporal dynamics after antibiotic treatment and in pairs of twins. The strain-level resolution, combined with the greater sequencing depth and decreased cost per read of PacBio Sequel 2, enables this advantageous source- and strain-tracking analysis method to be implemented widely across more complex microbiomes.