Sequence specificity defines the effectiveness of PPMOs targeting Pseudomonas aeruginosa.

Development of new therapeutics against antibiotic resistant pathogenic bacteria is recognized as a priority across the globe. We have reported using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) as species-specific antibiotics. The oligo sequences, 11 bases are designed to be complementary to specific essential genes near the Shine-Dalgarno site and inhibit translation. Here, we analyzed target specificity and the impact of genetic mutations on lead PPMOs targeting the rpsJ or acpP gene of Pseudomonas aeruginosa. Mutants in P. aeruginosa PAO1 were generated with four, two, or one base-pair mutations within the 11-base target sequence of the rpsJ gene. All mutants exhibited increased MICs compared to wild-type PAO1 when treated with the RpsJ PPMO, and the increase in the MICs was proportional to the number of base-pair mutations. Among single base-pair mutants, mutations in the middle of the sequence were more impactful than mutations in 5' or 3' end of the sequence. The increased MICs shown by the rpsJ mutants could be reversed by PPMOs designed to target the mutated rpsJ sequence. BALB/c mice infected intratracheally with mutants demonstrated increased lung burden when treated with RpsJ PPMO compared to wild-type PAO1-infected mice treated with RpsJ PPMO. Treating mice with a PPMOs designed to specifically target the mutant sequence was more effective against these mutant strains. These experiments confirm target specificity of two lead P. aeruginosa PPMOs and illustrate one potential mechanism of resistance that could emerge from an antisense approach.

Systematic Analysis of Mobile Genetic Elements Mediating ß-Lactamase Gene Amplification in Noncarbapenemase-Producing Carbapenem-Resistant Enterobacterales Bloodstream Infections.

Noncarbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE) are increasingly recognized as important contributors to prevalent carbapenem-resistant Enterobacterales (CRE) infections. However, there is limited understanding of mechanisms underlying non-CP-CRE causing invasive disease. Long- and short-read whole-genome sequencing was used to elucidate carbapenem nonsusceptibility determinants in Enterobacterales bloodstream isolates at MD Anderson Cancer Center in Houston, Texas. We investigated carbapenem nonsusceptible Enterobacterales (CNSE) mechanisms (i.e., isolates with carbapenem intermediate resistance phenotypes or greater) through a combination of phylogenetic analysis, antimicrobial resistance gene detection/copy number quantification, porin assessment, and mobile genetic element (MGE) characterization. Most CNSE isolates sequenced were non-CP-CRE (41/79; 51.9%), whereas 25.3% (20/79) were Enterobacterales with intermediate susceptibility to carbapenems (CIE), and 22.8% (18/79) were carbapenemase-producing Enterobacterales (CPE). Statistically significant copy number variants (CNVs) of extended-spectrum ß-lactamase (ESBL) genes (Wilcoxon Test; P-value < 0.001) were present in both non-CP-CR E. coli (median CNV = 2.6×; n = 17) and K. pneumoniae (median CNV = 3.2×, n = 17). All non-CP-CR E. coli and K. pneumoniae had predicted reduced expression of at least one outer membrane porin gene (i.e., ompC/ompF or ompK36/ompK35). Completely resolved CNSE genomes revealed that IS26 and ISEcp1 structures harboring blaCTX-M variants along with other antimicrobial resistance elements were associated with gene amplification, occurring in mostly IncFIB/IncFII plasmid contexts. MGE-mediated ß-lactamase gene amplifications resulted in either tandem arrays, primarily mediated by IS26 translocatable units, or segmental duplication, typically due to ISEcp1 transposition units. Non-CP-CRE strains were the most common cause of CRE bacteremia with carbapenem nonsusceptibility driven by concurrent porin loss and MGE-mediated amplification of blaCTX-M genes. IMPORTANCE Carbapenem-resistant Enterobacterales (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase-producing Enterobacterales (CPE) even though noncarbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies. Thus, carbapenem resistance mechanisms in non-CP-CRE remain poorly characterized. To address this problem, we applied a combination of short- and long-read sequencing technologies to a cohort of CRE bacteremia isolates and used these data to unravel complex mobile genetic element structures mediating ß-lactamase gene amplification. By generating complete genomes of 65 carbapenem nonsusceptible Enterobacterales (CNSE) covering a genetically diverse array of isolates, our findings both generate novel insights into how non-CP-CRE overcome carbapenem treatments and provide researchers scaffolds for characterization of their own non-CP-CRE isolates. Improved recognition of mechanisms driving development of non-CP-CRE could assist with design and implementation of future strategies to mitigate the impact of these increasingly recognized AMR pathogens.

Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement: updated reporting guidance for health economic evaluations.

Health economic evaluations are comparative analyses of alternative courses of action in terms of their costs and consequences. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, published in 2013, was created to ensure health economic evaluations are identifiable, interpretable, and useful for decision making. It was intended as guidance to help authors report accurately which health interventions were being compared and in what context, how the evaluation was undertaken, what the findings were, and other details that may aid readers and reviewers in interpretation and use of the study. The new CHEERS 2022 statement replaces previous CHEERS reporting guidance. It reflects the need for guidance that can be more easily applied to all types of health economic evaluation, new methods and developments in the field, as well as the increased role of stakeholder involvement including patients and the public. It is also broadly applicable to any form of intervention intended to improve the health of individuals or the population, whether simple or complex, and without regard to context (such as health care, public health, education, social care, etc). This summary article presents the new CHEERS 2022 28-item checklist and recommendations for each item. The CHEERS 2022 statement is primarily intended for researchers reporting economic evaluations for peer reviewed journals as well as the peer reviewers and editors assessing them for publication. However, we anticipate familiarity with reporting requirements will be useful for analysts when planning studies. It may also be useful for health technology assessment bodies seeking guidance on reporting, as there is an increasing emphasis on transparency in decision making.

Hormonal correlates of male dominance rank, age, and genital colouration in vervet monkey (Chlorocebus pygerythrus).

Primates are the most colourful members of the Mammalian clade. In vervet monkeys (Chlorocebus pygerythrus), males are characterized by their red penis and blue scrotum. Such colour signals are often used in conspecific communication, and thus could be used to convey signaller condition. We quantified scrotal and penile colour characteristics using digital photographs between May-June 2016 from males in two neighboring groups along the shores of Lake Nabugabo, Uganda. We examined the relationship between fecal hormones, male dominance rank, age (adult vs. immature), and colour. Adult males were higher ranking than immatures, but there were no rank or age differences in fecal hormone levels. Glucocorticoids and androgens were positively correlated in immature, but not adult males. All scrotal characteristics were predicted by age, with adult males having more teal (i.e., less blue, more green) and more luminant scrota. Within adult males, those with higher androgens levels had more saturated blue scrotal colouration and higher-ranking males were more luminant. Penile colouration was also associated with age and rank. High-ranking males had a more saturated red penis, and adult male penile colour was more luminant and bluer than in immature males. Our findings are consistent with previous reports that scrotal colouration advertises sexual or reproductive maturity (i.e., age), but we also find that within adult males, colour also advertises dominance rank and may be mediated by androgen levels. Penile colouration also appears to signal information about male age and dominance rank but does not appear to be mediated by hormones.

The role of the genetic testing industry in patient education of hereditary cancer: An observational study assessing the quality of patient education videos.

OBJECTIVES: Genetic testing (GT) companies have developed patient education videos to supplement or replace pre-test genetic counseling (GC) by certified genetic counselors (CGC). The aim of this study was to assess the quality of these videos compared to the standard of care (SOC). METHODS: Videos from four major GT companies were selected from an internet search identifying pre-test patient education videos. A scoring rubric with 22 questions and 36 total points was devised to assess quality metrics, as described by the National Cancer Institute and National Society of Genetic Counselors. Twenty-two individuals with varying genetics expertise (3 gynecologic oncologists, 3 academic generalists, 4 CGC, a genetics community health worker, 3 cancer care navigators, and 8 medical students) scored each video. Scorers were blinded to others' assessments. RESULTS: Invitae had the highest median score (26/36), followed by Myriad (22/36), Ambry (17.5/36), and Color (15/36). All videos scored highly in explaining DNA basics, cancer development, and hereditary cancer predisposition. All addressed benefits of GT but failed to address potential disadvantages. All scored poorly in explaining medical terms and different GT options. There was variability in addressing patient concerns including cost, privacy, and procedure. CONCLUSIONS: There is significant variation in the content of pre-test patient education videos between GT companies. None of the videos met the SOC for pre-test GC, and none addressed disadvantages of GT, possibly due to a conflict of interest. With improvement in content, accessibility, and use of interactive platforms, these videos may serve as an adjunct to in-person pre-test GC.

Association among income loss, financial strain and depressive symptoms during COVID-19: evidence from two longitudinal studies.

BACKGROUND: The COVID-19 pandemic has major ramifications for global health and the economy, with growing concerns about economic recession and implications for mental health. Here we investigated the associations between COVID-19 pandemic-related income loss with financial strain and mental health trajectories over a 1-month course. METHODS: Two independent studies were conducted in the U.S and in Israel at the beginning of the outbreak (March-April 2020, T1; N = 4 171) and at a 1-month follow-up (T2; N = 1 559). Mixed-effects models were applied to assess associations among COVID-19-related income loss, financial strain, and pandemic-related worries about health, with anxiety and depression, controlling for multiple covariates including pre-COVID-19 income. FINDINGS: In both studies, income loss and financial strain were associated with greater depressive symptoms at T1, above and beyond T1 anxiety, worries about health, and pre-COVID-19 income. Worsening of income loss was associated with exacerbation of depression at T2 in both studies. Worsening of subjective financial strain was associated with exacerbation of depression at T2 in one study (US). INTERPRETATION: Income loss and financial strain were uniquely associated with depressive symptoms and the exacerbation of symptoms over time, above and beyond pandemic-related anxiety. Considering the painful dilemma of lockdown versus reopening, with the tradeoff between public health and economic wellbeing, our findings provide evidence that the economic impact of COVID-19 has negative implications for mental health. FUNDING: This study was supported by grants from the National Institute of Mental Health, the US-Israel Binational Science Foundation, Foundation Dora and Kirsh Foundation.

Incidence of respiratory syncytial virus bronchiolitis in hospitalized infants born at 33-36 weeks of gestational age compared with those born at term: a retrospective cohort study.

OBJECTIVE: The aim was to compare incidences of respiratory syncytial virus (RSV) bronchiolitis in late preterm vs. term infants (33-36 vs. >36 weeks of gestational age (WGA)). METHODS: This was a population-based retrospective study including all infants <12 months hospitalized at Soroka medical centre with bronchiolitis between 2004 and 2012. Infants with comorbidities were excluded. RSV bronchiolitis rates were calculated by extrapolating the proportion of positive tests among tested infants. Population denominator for incidence rates was calculated from hospital records. RESULTS: During the study, 374 late preterm and 2948 term infants were hospitalized with bronchiolitis. Out of 229 (61.2%) late preterm infants and 1738 (59%) term infants tested for RSV, 164 (71.6%) and 1266 (72.8%) were positive for RSV respectively. The mean yearly incidences per 1000 children of RSV bronchiolitis hospitalizations of late preterm and term infants were 35.8 ± 13.0 and 19.6 ± 4.1 respectively (p 0.009). During RSV seasons the mean incidence rate ratio between groups was 1.82 (95% CI 1.60-2.08). Duration of hospitalization was 4.8 ± 7.0 and 3.9 ± 4.9 in late preterm and term infants, respectively (p 0.003). CONCLUSIONS: Late preterm-born infants (33-36 WGA) had a higher rate of hospitalization for overall and RSV bronchiolitis during the first year of life compared to those born at term.

Disease burden in offspring is associated with changing paternal demographics in the United States.

BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease. OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States. METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States. RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16 years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5 years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40 years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21 years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17 years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30 years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25 years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort. CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.

Whole-genome sequencing of Staphylococcus epidermidis bloodstream isolates from a prospective clinical trial reveals that complicated bacteraemia is caused by a limited number of closely related sequence types.

OBJECTIVES: The significance of isolating Staphylococus epidermidis from a blood culture is highly heterogeneous, ranging from contamination to an indication of a serious infection. Herein we sought to determine whether there is a relationship between S. epidermidis genotype and clinical severity of bacteraemia. METHODS: S. epidermidis bacteraemias from a prospective, multicentre trial at 15 centres in the United States and one in Spain were classified as simple (including possible contamination), uncomplicated, and complicated. Whole-genome sequencing (WGS) was performed on 161 S. epidermidis isolates, and clinical outcomes were correlated with genotypic information. RESULTS: A total of 49 S. epidermidis sequence types (STs) were identified. Although strains of all 49 STs were isolated from patients with either simple or uncomplicated infection, all strains causing complicated infections were derived from five STs: ST2, ST5, ST7, ST16, and ST32. ST2 and ST5 isolates were significantly more likely to cause uncomplicated and complicated bloodstream infections compared to simple bacteraemia (odds ratio 2.0, 95%CI 1.1-3.9, p 0.04). By multivariate regression analysis, having an ST2 or ST5 S. epidermidis bacteraemia was an independent predictor of complicated bloodstream infection (odds ratio 3.7, 95%CI 1.2-11.0, p 0.02). ST2/ST5 strains carried larger numbers of antimicrobial resistance determinants compared to non-ST2/ST5 isolates (6.34 ± 1.5 versus 4.4 ± 2.5, p < 0.001). CONCLUSION: S. epidermidis bacteraemia was caused by a genetically heterogeneous group of organisms, but only a limited number of STs-particularly multidrug-resistant ST2 and ST5 strains-caused complicated infections.

From biology to behavior: a cross-disciplinary seminar series surrounding added sugar and low-calorie sweetener consumption.

INTRODUCTION: This report presents a synopsis of a three-part, cross-sector, seminar series held at the George Washington University (GWU) in Washington, DC from February-April, 2018. The overarching goal of the seminar series was to provide a neutral forum for diverse stakeholders to discuss and critically evaluate approaches to address added sugar intake, with a key focus on the role of low-calorie sweeteners (LCS). METHODS: During three seminars, twelve speakers from academic institutions, federal agencies, non-profit organizations, and the food and beverage industries participated in six interactive panel discussions to address: 1) Do Farm Bill Policies Impact Population Sugar Intake? 2) What is the Impact of Sugar-sweetened Beverage (SSB) Taxes on Health and Business? 3) Is Sugar Addictive? 4) Product Reformulation Efforts: Progress, Challenges, and Concerns? 5) Low-calorie Sweeteners: Helpful or Harmful, and 6) Are Novel Sweeteners a Plausible Solution? Discussion of each topic involved brief 15-minute presentations from the speakers, which were followed by a 25-minute panel discussion moderated by GWU faculty members and addressed questions generated by the audience. Sessions were designed to represent opposing views and stimulate meaningful debate. Given the provocative nature of the seminar series, attendee questions were gathered anonymously using Pigeonhole™, an interactive, online, question and answer platform. RESULTS: This report summarizes each presentation and recapitulates key perspectives offered by the speakers and moderators. CONCLUSIONS: The seminar series set the foundation for robust cross-sector dialogue necessary to inform meaningful future research, and ultimately, effective policies for lowering added sugar intakes.

Evolutionarily distinct amphibians are disproportionately lost from human-modified ecosystems.

Humans continue to alter terrestrial ecosystems, but our understanding of how biodiversity responds is still limited. Anthropogenic habitat conversion has been associated with the loss of evolutionarily distinct bird species at local scales, but whether this evolutionary pattern holds across other clades is unknown. We collate a global dataset on amphibian assemblages in intact forests and nearby human-modified sites to assess whether evolutionary history influences susceptibility to land conversion. We found that evolutionarily distinct amphibian species are disproportionately lost when forested habitats are converted to alternative land-uses. We tested the hypothesis that grassland-associated amphibian lineages have both higher diversification and are pre-adapted to human landscapes, but found only weak evidence supporting this. The loss of evolutionarily distinct amphibians with land conversion suggests that preserving remnant forests will be vital if we aim to preserve the amphibian tree of life in the face of mounting anthropogenic pressures.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Mother-to-child transmission of extended-spectrum-beta-lactamase-producing Enterobacteriaceae.

BACKGROUND: Preterm infants are at high risk for extended-spectrum-beta-lactamase-producing Enterobacteriaceae (ESBL-E) sepsis and neonatal intensive care unit (NICU) outbreaks. Maternal colonization with ESBL-E may be precursory to mother-to-child transmission. However, there is no consensus regarding surveillance of pregnant women for ESBL-E colonization. AIM: To identify pairs of mothers and infants harbouring same-strain ESBL-E colonization and to determine whether maternal transmission may play a role in increasing ESBL-E carriage in preterm infants. METHODS: This was a one-year analysis from an ongoing, prospective ESBL-E surveillance of mothers of premature infants and their offspring. Mother-infant pairs colonized with the same bacteria underwent strain analysis using pulsed-field gel electrophoresis (PFGE). Clinical parameters were collected from the hospital computerized records. FINDINGS: Between January 2015 and January 2016, 313/409 (76.5%) mothers and all 478 (100%) infants were screened for ESBL-E colonization; carriage rates were 21.5% and 14.8%, respectively. Four (5.6%) colonized infants developed late-onset sepsis and two (2.8%) died. Twenty-five mother-infant pairs colonized with the same bacterial strain were identified; a subgroup of 10 pairs of isolates underwent PFGE, and 70% displayed an identical PFGE fingerprint. No similarities were found between isolates recovered from unrelated neonates and mothers. ESBL-E colonization was found significantly earlier in infants of mothers colonized at birth (P<0.001) compared with infants of non-colonized mothers. CONCLUSIONS: ESBL-E carriage rates in mothers and NICU infants with non-negligible maternal-neonatal ESBL-E transmission in the study region indicate that maternal colonization surveillance and/or further infection control interventions should be considered.

Local recurrence after 'standard' abdominoperineal resection: do we really need ELAPE?

Introduction Low rectal cancers requiring abdominoperineal resection tend to have a worse prognosis than higher tumours, which may be treated by anterior resection. One of the reasons for this may be inadequate local surgery, in particular the narrow waist of the resection specimen of a standard abdominoperineal resection may be associated with a high positive circumferential resection margin. The extralevator abdominoperineal excision (ELAPE) aims to improve the R0 resection rate but carries significant morbidity. We examined our own results of standard abdominoperineal resection to assess the need for a change of policy. Methods We operformed a retrospective analysis of consecutive standard abdominoperineal resections for rectal cancer in a single centre from June 2002 to December 2011. Results A total of 102 patients underwent standard abdominoperineal resection with curative intent; 19 had no preoperative treatment, 42 had short course radiotherapy, 9 had long course radiotherapy and 32 had neoadjuvant chemotherapy followed by long course chemoradiotherapy. In 17/102(16.6%), there was a positive circumferential resection margin. Over a median follow up of 32 months, 20 patients developed recurrence of any type. Local recurrence occurred in five patients (two of which also had distant recurrence), of whom two had a positive circumferential resection margin (P = 0.10). Actuarial two-year local only recurrence was 3.4% and any recurrence was 17.7%. Overall five-year cancer specific survival was 77%. Conclusions In this series we found low rates of local recurrence after standard abdominoperineal resection even with a circumferential margin rate positivity of 16.6%.Performing an ELAPE in selected cases may improve these results further but is not necessarily required for all patients.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). METHODS: This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. RESULTS: From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. CONCLUSIONS: This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.

Coping strategies, satisfaction with life, and quality of life in Crohn's disease: A gender perspective using structural equation modeling analysis.

OBJECTIVE: To identify coping strategies and socio-demographics impacting satisfaction with life and quality of life in Crohn's disease (CD). METHODS: 402 patients completed the Patient Harvey-Bradshaw Index, Brief COPE Inventory, Satisfaction with Life Scale (SWLS), Short Inflammatory Bowel Disease Questionnaire (SIBDQ). We performed structural equation modeling (SEM) of mediators of quality of life and satisfaction with life. RESULTS: The cohort comprised: men 39.3%, women 60.1%; P-HBI 4.75 and 5.74 (p = 0.01). In inactive CD (P-HBI≤4), both genders had SWLS score 23.8; men had SIBDQ score 57.4, women 52.6 (p = 0.001); women reported more use of emotion-focused, problem-focused and dysfunctional coping than men. In active CD, SWLS and SIBDQ scores were reduced, without gender differences; men and women used coping strategies equally. A SEM model (all patients) had a very good fit (X2(6) = 6.68, p = 0.351, X2/df = 1.114, SRMR = 0.045, RMSEA = 0.023, CFI = 0.965). In direct paths, economic status impacted SWLS (ß = 0.39) and SIBDQ (ß = 0.12), number of children impacted SWLS (ß = 0.10), emotion-focused coping impacted SWLS (ß = 0.11), dysfunctional coping impacted SWLS (ß = -0.25). In an indirect path, economic status impacted dysfunctional coping (ß = -0.26), dysfunctional coping impacted SIBDQ (ß = -0.36). A model split by gender and disease activity showed that in active CD economic status impacted SIBDQ in men (ß = 0.43) more than women (ß = 0.26); emotional coping impacted SWLS in women (ß = 0.36) more than men (ß = 0.14). CONCLUSIONS: Gender differences in coping and the impacts of economic status and emotion-focused coping vary with activity of CD. Psychological treatment in the clinic setting might improve satisfaction with life and quality of life in CD patients.

Impact of PCV7/PCV13 introduction on invasive pneumococcal disease (IPD) in young children: Comparison between meningitis and non-meningitis IPD.

BACKGROUND: The worldwide introduction of pneumococcal conjugate vaccines (PCV) into National Immunization Programs resulted in rapid and substantial reduction of invasive pneumococcal disease (IPD) rates in children. However, the reduction of meningitis vs. non-meningitis IPD (nm-IPD) was not yet fully elucidated. We compared 7-valent and 13-valent PCV (PCV7 and PCV13) impact on pneumococcal-meningitis vs. nm-IPD in Israeli children <5years. METHODS: We conducted an ongoing nationwide, prospective, population-based, active surveillance. PCV7 and PCV13 were implemented in Israel in July 2009 and November 2010, respectively. All pneumococcal isolates (blood and/or CSF) from IPD episodes in children <5years from July 2000 through June 2015 were included. Extrapolation for missing serotypes (34.7% of all isolates) was conducted. RESULTS: 4163 IPD cases were identified; 3739nm-IPD (89.8%) and 424 meningitis (10.2%). During the pre-PCV period (2000-2008), children <12months constituted 52.1% and 33.7% of meningitis and nm-IPD, respectively (p<0.001). The respective proportions of non-PCV13 serotypes (non-VT) were 18.2% vs. 10.1%, (p<0.001). Comparing the last study year (2014-2015) to the mean of pre-PCV period, meningitis incidence in children <5years decreased non-significantly by 27%, while nm-IPD decreased significantly by 69%. Dynamic rates of meningitis and nm-IPD caused by PCV13 serotypes were similar, with 93% and 95% overall reductions, respectively. However, non-VT increased in meningitis relatively to nm-IPD, mainly in children <24months. Serotype 12F rose sharply and significantly since 2009-2010 through 2014-2015 (28.6% of all non-VT meningitis in children <24m). CONCLUSIONS: The overall impact of PCV7/PCV13 in children <5years in Israel was less prominent in meningitis than in nm-IPD. This could be attributed to the younger age of children with meningitis and differences in causative serotypes between the two groups, as the decline of the incidence of meningitis and nm-IPD caused by vaccine-serotypes is similar. Continuous monitoring of meningitis and nm-IPD is warranted.

Merkel Cell Carcinoma: rising incidence in the East of England.

BACKGROUND: Merkel Cell Carcinoma (MCC) is an infrequent but highly aggressive skin cancer. Five-year survival rates are poor, as there are high rates of metastases at primary diagnoses. Recurrences are also common. There is controversy about actual incidence rates which vary considerably between developed countries with majority populations of fair skin types. OBJECTIVES: We report the age-standardized incidence rates of MCC for both males and females from the East of England, and use linear regression analyses to estimate numbers of cases for 2020 and 2025 to aid healthcare planning and allocation of resources. METHODS: All cases of MCC diagnosed histopathologically between 1st January 2004 and 31st December 2013 were extracted from the databases of the Eastern Office, National Cancer Registration Service, Public Health England, and the Pathology department of the Norfolk and Norwich University Hospital, which serves as the tertiary referral centre for the region. Age-standardization incidence rate calculations (ASIs) and linear regression analyses were performed. RESULTS: The ASIs for males and females were 0.70 and 1.08 per 100 000 person-years respectively. The total age-adjusted incidence rate was therefore 1.78 per 100 000 person-years. The ratio of female: male disease was 3:2. The total number of cases for this region over the time period studied was 73. There has been a threefold increase over this period. Estimated cases for this region are 17 in 2020, and 22 in 2025. Estimated UK cases for 2020 are 920, and 1134 in 2025. CONCLUSIONS: MCC is increasing steadily in the East of England, and has risen threefold over the last 10 years and is similar to the highest reported rates from Western Australia. These data are 12-fold higher than previous UK estimates, and suggest that the incidence rate is also rising in other regions of the UK.

Dog bites - are vets missing an educational opportunity?

Veterinary surgeons have a key role to play in tackling the public health problem of dog bites, say CHRISTOPHER MANNION: and DANIELLE GREENBERG: , who argue that a multiprofessional approach to the problem is needed.