Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNSTCRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNSTCRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.

Code status communication training in postgraduate oncology programs: a needs assessment.

Background: Discussions with patients with cancer about cardiopulmonary resuscitation directives (code status) are often led by residents. This study was carried out in Canada to identify current educational practices and gaps in training for this communication skill. Methods: Canadian medical and radiation oncology residents and program directors (pds) were surveyed about teaching practices, satisfaction with current education, and barriers to teaching code status discussion skills. Relative frequencies of categorical and ordinal responses were calculated. Results: Between November 2016 and February 2017, 95 (58.6%) of 162 residents and 17 (63%) of 27 pds completed surveys. Only 54.1% and 48.3% of medical and radiation oncology residents, respectively, had received any code status communication training before entering an oncology program. While 41% of residents expected to receive formal teaching on this topic during residency, 47.1% of pds endorsed inclusion of this topic in curricula. Only 20% of residents reported receiving formal evaluation of this skill while 41.2% of pds indicated that evaluations are provided. The importance of this communication skill in oncology was strongly supported. Among residents, 88% desired more training, and 82.3% of pds identified the need for new educational resources. Lack of time, resources, and evaluation tools were among the most commonly identified barriers to teaching. Conclusions: Oncology residency pds and trainees feel that code status communication is important, but teaching and evaluation of this skill are limited. Barriers to teaching and skill-building have been identified. Further work is underway to develop novel educational resources for code status communication training.

Implementing changes to a residency program curriculum before competency-based medical education: a survey of Canadian medical oncology program directors.

Background: Postgraduate medical education is undergoing a paradigm shift in many universities worldwide, transitioning from a time-based model to competency-based medical education (cbme). Residency programs might have to alter clinical rotations, educational curricula, assessment methods, and faculty involvement in preparation for cbme, a process not yet characterized in the literature. Methods: We surveyed Canadian medical oncology program directors on planned or newly implemented residency program changes in preparation for cbme. Results: Prior to implementing cbme, all program directors changed at least 1 clinical rotation, most commonly making hematology/oncology (74%) entirely outpatient and eliminating radiation oncology (64%). Introductory rotations were altered to focus on common tumour sites, and later rotations were changed to increase learner autonomy. Most program directors planned to enhance resident learning with electronic teaching modules (79%), new training experiences (71%), and academic half-day changes (50%). Most program directors (64%) planned to change assessment methods to be entirely based on entrustable professional activities. All programs had developed a competence committee to review learner progress, and most (86%) had integrated academic coaches. Conclusions: Transitioning to cbme led to major structural and curricular changes within medical oncology training programs. Identifying these commonly implemented changes could help other programs transition to cbme.

Oncologists and medical assistance in dying: where do we stand? Results of a national survey of Canadian oncologists.

Background: In June 2016, when the Parliament of Canada passed Bill C-14, the country joined the small number of jurisdictions that have legalized medical assistance in dying (maid). Since legalization, nearly 7000 Canadians have received maid, most of whom (65%) had an underlying diagnosis of cancer. Although Bill C-14 specifies the need for government oversight and monitoring of maid, the government-collected data to date have tracked patient characteristics, rather than clinician encounters and beliefs. We aimed to understand the views of Canadian oncologists 2 years after the legalization of maid. Methods: We developed and administered an online survey to medical and radiation oncologists to understand their exposure to maid, self-perceived knowledge, willingness to participate, and perception of the role of oncologists in introducing maid as an end-of-life care option. We used complete sampling through the Canadian Association of Medical Oncologists and the Canadian Association of Radiation Oncology membership e-mail lists. The survey was sent to 691 physicians: 366 radiation oncologists and 325 medical oncologists. Data were collected during March-June 2018. Results are presented using descriptive statistics and univariate or multivariate analysis. Results: The survey attracted 224 responses (response rate: 32.4%). Of the responding oncologists, 70% have been approached by patients requesting maid. Oncologists were of mixed confidence in their knowledge of the eligibility criteria. Oncologists were most willing to engage in maid with an assessment for eligibility, and yet most refer to specialized teams for assessments. In terms of introducing maid as an end-of-life option, slightly more than half the responding physicians (52.8%) would initiate a conversation about maid with a patient under certain circumstances, most commonly the absence of viable therapeutic options, coupled with unmanageable patient distress. Conclusions: In this first national survey of Canadian oncologists about maid, we found that most respondents encounter patient requests for maid, are confident in their knowledge about eligibility, and are willing to act as assessors of eligibility. Many oncologists believe that, under some circumstances, it is appropriate to present maid as a therapeutic option at the end of life. That finding warrants further deliberation by national or regional bodies for the development of consensus guidelines to ensure equitable access to maid for patients who wish to pursue it.

Sub-segmental pulmonary embolism in three academic teaching hospitals: a review of management and outcomes.

BACKGROUND: The availability of computed tomography pulmonary angiography (CTPA) has led to an increase in the diagnosis of sub-segmental pulmonary embolism (SSPE). Current clinical practice guidelines do not make any treatment distinctions for SSPE, though the benefits of anticoagulation for SSPE have not been established. OBJECTIVES: To review the frequency of pulmonary embolism and sub-segmental pulmonary embolism identified through CTPA as well as their management. METHODS: Cross-sectional review of the charts of 2213 patients who underwent CTPA in three Hamilton teaching hospitals from 2009 to 2011. In-depth review of the charts of patients with SSPE was undertaken to determine the frequency with which patients received anticoagulation therapy for SSPE, as well as bleeding complications and recurrent thrombosis. RESULTS: A total of 2216 CTPAs were reviewed. The frequency of PE was 24.8% (n = 550). The most frequent filling defect was SSPE in 82 patients (3.9% of total scans and 15.0% of identified PEs). In 55 of these 82 SSPEs, an alternative diagnosis to PE was identified on CT to explain the patients' symptoms. Approximately 52.4% (n = 43) received anticoagulation for SSPE. Major life-threatening bleeding complications occurred in two of the 43 who received anticoagulation for SSPE. There was no documented recurrent thrombosis in any patients with SSPE, with or without anticoagulation. SUMMARY/CONCLUSIONS: A substantial proportion of patients received anticoagulation for SSPE (52%) and two developed life-threatening bleeding complications. Randomized controlled trial data are needed to further investigate the risks and benefits of anticoagulation in patients with SSPE.

Using social network analysis to examine the decision-making process on new vaccine introduction in Nigeria.

The decision-making process to introduce new vaccines into national immunization programmes is often complex, involving many stakeholders who provide technical information, mobilize finance, implement programmes and garner political support. Stakeholders may have different levels of interest, knowledge and motivations to introduce new vaccines. Lack of consensus on the priority, public health value or feasibility of adding a new vaccine can delay policy decisions. Efforts to support country-level decision-making have largely focused on establishing global policies and equipping policy makers with the information to support decision-making on new vaccine introduction (NVI). Less attention has been given to understanding the interactions of policy actors and how the distribution of influence affects the policy process and decision-making. Social network analysis (SNA) is a social science technique concerned with explaining social phenomena using the structural and relational features of the network of actors involved. This approach can be used to identify how information is exchanged and who is included or excluded from the process. For this SNA of vaccine decision-making in Nigeria, we interviewed federal and state-level government officials, officers of bilateral and multilateral partner organizations, and other stakeholders such as health providers and the media. Using data culled from those interviews, we performed an SNA in order to map formal and informal relationships and the distribution of influence among vaccine decision-makers, as well as to explore linkages and pathways to stakeholders who can influence critical decisions in the policy process. Our findings indicate a relatively robust engagement of key stakeholders in Nigeria. We hypothesized that economic stakeholders and implementers would be important to ensure sustainable financing and strengthen programme implementation, but some economic and implementation stakeholders did not appear centrally on the map; this may suggest a need to strengthen the decision-making processes by engaging these stakeholders more centrally and earlier.

Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. FINDINGS: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. INTERPRETATION: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

Functional antibody activity elicited by fractional doses of Haemophilus influenzae type b conjugate vaccine (polyribosylribitol phosphate-tetanus toxoid conjugate).

We evaluated the functional activities of antibodies, serum bactericidal activity (SBA), and immunoglobulin G (IgG) antibody avidity indices, using sodium thiocyanate (NaSCN) elution, elicited after vaccination with fractional doses of the Haemophilus influenzae type b conjugate (polyribosylribitol phosphate [PRP] conjugated to tetanus toxoid [PRP-T]) vaccine. A cohort of 600 infants from the Dominican Republic were randomized to receive one of three regimens of the PRP-T vaccine at ages 2, 4, and 6 months: full doses (10 microg of PRP antigen), one-half doses (5.0 microg), and one-third doses (3.3 microg) (J. Fernandez et al., Am. J. Trop. Med. Hyg. 62:485-490, 2000). Sixty serum samples, collected at age 7 months, with > or =2.0 microg of anti-PRP IgG per ml were randomly selected for avidity determinations. Geometric mean IgG concentrations were 13, 14, and 17 microg/ml for infants who received the full-dose (n = 19), one-half-dose (n = 19), and one-third-dose (n = 22) regimens, respectively. SBA geometric mean titers (1/dilution) were 85.0, 82.0, and 76.1 in sera from infants receiving the full-, one-half-, and one-third-dose regimens, respectively. Avidity indices (mean +/- standard error weighted average of NaSCN molar concentration x serum dilution factor) were 71.9 +/- 9.4, 123.6 +/- 26.8, and 150.9 +/- 24.9 for the full-, one-half-, and one-third-dose regimens, respectively. Upon comparison, the only significant difference (P = 0.024) found was a greater avidity index for sera from infants receiving the one-third-dose regimen than for sera from infants receiving the the full-dose regimen. We conclude that fractional doses elicit similar functional antibody activities in infants with > or = 2 microg of anti-PRP IgG per ml, corresponding to 89, 90, and 97% of infants receiving three doses of either the full concentration or one-half or one-third of the labeled concentration, respectively. This approach offers an alternative strategy for the prevention of H. influenzae type b disease in countries with limited resources.

Physician control of pediatric antimicrobial use in Beijing, China, and its rural environs.

BACKGROUND: Antibiotic resistance is recognized as an increasing problem in China. It is widely believed that because antibiotics are available without a prescription, changing physician prescribing behaviors will not decrease inappropriate usage. This study identified the sources of antibiotics and the important influence that physicians have on antibiotic use by children in one region of China. METHODS: Trained medical professionals surveyed parents of children attending several kindergartens in urban Beijing and rural Gu'An, Hebei County. Parents completed a questionnaire concerning the children's recent illnesses, care-seeking patterns and antibiotic use. The team also observed hospital- and non-hospital-based pharmacy purchases of antibiotics for children, assessed the proportion accompanied by a prescription and then interviewed parents about factors influencing those purchases. RESULTS: Of 241 urban and 143 rural kindergarten parents, 76 to 82% usually obtained children's antibiotics from a hospital pharmacy (with a prescription). For 84% the first source of care was usually a physician (primarily western medicine, sometimes traditional Chinese medicine). Only 5% of antibiotics were obtained from independent vendors without prior physician consultation. Among 229 observed antibiotic purchases 72% occurred at hospital-based facilities, even after longer observation times at nonhospital pharmacies. Prescriptions accompanied all hospital-based antibiotic purchases, contrasting with 18% of nonhospital transactions (P < 0.001). Together 86% of parents self-reported that the observed purchase stemmed from a doctor's recommendation. CONCLUSIONS: Doctors directly and indirectly controlled the majority of antibiotic usage for childhood illnesses in Beijing and Gu'An (Hebei County). Physician education and implementation of treatment guidelines might substantially reduce inappropriate antimicrobial usage and help prevent antimicrobial resistance in this region.

Evaluation of Binax NOW, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients.

In our evaluation of a new assay for the detection of pneumococcal antigen in urine (Binax NOW; Binax), the test result was no more likely to be positive among 88 children with radiographically confirmed pneumonia than among 198 control subjects; however, it was significantly more likely to be positive among children who were nasopharyngeal carriers of pneumococci. This test is not likely to be useful for distinguishing children with pneumococcal pneumonia from those who are merely colonized.

Prevention of Haemophilus influenzae type b colonization by vaccination: correlation with serum anti-capsular IgG concentration.

Concentrations of serum anti-Haemophilus influenzae type b (anti-Hib) capsular polysaccharide (CPS) >/=0.15 and >/=1.0 microgram/mL are widely used as surrogates for protection against invasive Hib disease. However, the relationship between serum anti-Hib CPS following immunization and protection against colonization is not known, making it difficult to evaluate new Hib vaccines or combination vaccines. In the Dominican Republic, nasopharyngeal swabs were collected from 546 9-month-old infants who had received Hib conjugate vaccine at ages 2, 4, and 6 months and from 600 unvaccinated infants of the same age. The prevalence of Hib colonization was lower among vaccinated infants than among unvaccinated infants (0.9% vs. 2.3%). Among vaccinated infants, protection against colonization was significantly correlated with anti-Hib CPS concentrations >/=5 microgram/mL 1 month following the third dose of vaccine. These results suggest that the concentration of serum anti-Hib CPS needed for protection against colonization is greater than that needed for protection for invasive disease.

Toward elimination of Haemophilus influenzae type B carriage and disease among high-risk American Indian children.

OBJECTIVES: This report describes the epidemiology of Haemophilus influenzae type b (Hib) invasive disease and oropharyngeal colonization among Navajo and White Mountain Apache children younger than 7 years in an era of widespread immunization. METHODS: We conducted active surveillance for invasive H influenzae disease from 1992 to 1999 and an oropharyngeal carriage study from 1997 to 1999. The predominant vaccine used was PedvaxHib. RESULTS: The average annual incidence of invasive Hib disease among children younger than 24 months was 22 cases per 100,000. Of 381 children younger than 7 years, only 1 (0.3%; 95% confidence interval = 0.0%, 1.3%) was colonized with Hib; 370 (97%) had received 2 or more doses of Hib conjugate vaccine. CONCLUSIONS: Among Navajo and White Mountain Apache children, Hib conjugate vaccines have led to a sustained reduction in invasive Hib disease and a reduction in oropharyngeal Hib carriage. The disease incidence among children younger than 24 months remains 20 times higher than in the general US population. Hib elimination will require additional characterization of colonization and disease in these high-risk populations.

Experience with the prevention of invasive Haemophilus influenzae type b disease by vaccination in Alaska: the impact of persistent oropharyngeal carriage.

OBJECTIVES: To report the epidemiology of invasive Haemophilus influenzae type b (Hib) disease in high-risk Alaska Native infants before and after universal infant Hib vaccination and evaluate an increase in invasive Hib disease in 1996 after changing Hib vaccine type. STUDY DESIGN: Statewide laboratory surveillance for invasive Hib disease has been conducted since 1980. Three cross-sectional Hib carriage studies were conducted in 1997 and 1998. RESULTS: The invasive Hib disease rate in Alaska Natives decreased from 332 cases per 100,000 children <5 years old in 1980-1991 to 17:100,000 in 1992-1995 but increased primarily in rural areas to 57.9:100,000 after a switch in Hib vaccine types. Carriage studies in 5 rural Alaska Native villages showed oropharyngeal Hib carriage as high as 9.3% in children aged 1 to 5 years; in contrast, carriage in urban Alaska Native children was <1%. CONCLUSIONS: Although Hib disease has decreased in Alaska, the rate of Hib disease and carriage in rural Alaska Natives did not decrease to the same extent as in non-Natives and urban Alaska Natives. Use of polyribosylribitol phosphate-outer-membrane protein conjugate vaccine for the first vaccine dose is critical to disease control in this population with continued transmission in infants <6 months of age. The ability to eliminate Hib carriage and disease may be affected by population characteristics, vaccination coverage, and Hib vaccine type used. This may pose a challenge to global elimination of Hib.

Haemophilus influenzae type b and Streptococcus pneumoniae as causes of pneumonia among children in Beijing, China.

To determine if Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae could be identified more often from the nasopharynx of patients with pneumonia than from control patients, we obtained nasopharyngeal swab specimens from 96 patients with chest x-ray-confirmed pneumonia and 214 age-matched control patients with diarrhea or dermatitis from the outpatient department at Beijing Children's Hospital. Pneumonia patients were more likely to be colonized with Hib and S. pneumoniae than control patients, even after the data were adjusted for possible confounding factors such as day-care attendance, the presence of other children in the household, and recent antibiotic use. In China, where blood cultures from pneumonia patients are rarely positive, the results of these nasopharyngeal cultures provide supporting evidence for the role of Hib and S. pneumoniae as causes of childhood pneumonia.

Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study.

BACKGROUND: Early-onset group B streptococcal (GBS) prevention efforts are based on targeted use of intrapartum antibiotic prophylaxis (IAP); applicability of these prevention efforts to infections caused by other organisms is not clear. METHODS: Multicenter surveillance during 1995 to 1996 for culture-confirmed, early-onset sepsis in an aggregate of 52 406 births; matched case-control study of risk factors for GBS and other sepsis. RESULTS: Early-onset disease occurred in 188 infants (3.5 cases per 1000 live births). GBS (1.4 cases per 1000 births) and Escherichia coli (0.6 cases per 1000 births) caused most infections. GBS sepsis less often occurred in preterm deliveries compared with other sepsis. Compared with gestation-matched controls without documented sepsis, GBS disease was associated with intrapartum fever (matched OR, 4.1; CI, 1.2-13.4) and frequent vaginal exams (matched OR, 2.9; CI, 1.1-8. 0). An obstetric risk factor-preterm delivery, intrapartum fever, or membrane rupture >/=18 hours-was found in 49% of GBS cases and 79% of other sepsis. IAP had an adjusted efficacy of 68.2% against any early-onset sepsis. Ampicillin resistance was evident in 69% of E coli infections. No deaths occurred among susceptible E coli infections, whereas 41% of ampicillin-resistant E coli infections were fatal. Ninety-one percent of infants who developed ampicillin-resistant E coli infections were preterm, and 59% of these infants were born to mothers who had received IAP. CONCLUSIONS: Either prenatal GBS screening or a risk-based strategy could potentially prevent a substantial portion of GBS cases. Sepsis caused by other organisms is more often a disease of prematurity. IAP seemed efficacious against early-onset sepsis. However, the severity of ampicillin-resistant E coli sepsis and its occurrence after maternal antibiotics suggest caution regarding use of ampicillin instead of penicillin for GBS prophylaxis.

Population-based surveillance for bacterial meningitis in the Dominican Republic: implications for control by vaccination.

Quantifying the local burden of disease is an important step towards the introduction of new vaccines, such as Haemophilus influenzae type b (Hib) conjugate vaccine. We adapted a generic protocol developed by the World Health Organization for population-based surveillance of bacterial meningitis. All hospitals that admit paediatric patients with meningitis in the National District, Dominican Republic were included in the system and standard laboratory methods were used. The system identified 111 cases of confirmed bacterial meningitis. Hib was the leading cause of bacterial meningitis, followed by group B streptococcus, S. pneumoniae, and N. meningitidis. Unlike hospital-based case series, this population-based system was able to calculate incidence rates. The incidence of Hib meningitis was 13 cases per 100,000 children < 5 years old. The data from this study were used by the Ministry of Health to support the introduction of routine Hib vaccination and will be used to monitor its effectiveness.

Randomized trial of the immunogenicity of fractional dose regimens of PRP-T Haemophilus influenzae type b conjugate vaccine.

To assess the immunogenicity of more economical regimens of Haemophilus influenzae type b (Hib) conjugate vaccine, a randomized trial of fractional doses of polyribosylribitol phosphate-tetanus toxoid (PRP-T) Hib vaccine was undertaken in the Dominican Republic. Six hundred children were assigned to one of six regimens with PRP-T vaccine: full-dose, half-dose, and one-third-dose of Hib vaccine given separately or combined with diphtheria, tetanus, and pertussis (DTP) vaccine at ages 2, 4, and 6 months. Regimens that elicited antibody levels > 1.0 microg/mL in >70% of children and < or = 0.15 microg/mL in > 90% of children were considered acceptable. At 1 month post Dose 3, all regimens met the criteria for acceptable response. Among those who received Hib as a separate injection, geometric mean concentrations of anti-PRP bodies (GMCs) at age 1 month post Dose 3 were 11.2, 11.9, and 16.3 in the full, half, and one-third dose groups, respectively. Among those who received Hib and DTP combined, the GMCs were 6.4, 5.2, and 5.7 in the full-, half-, and one-third-dose groups respectively.

Effectiveness of pneumococcal polysaccharide vaccine for preschool-age children with chronic disease.

To estimate the effectiveness of pneumococcal polysaccharide vaccine, we serotyped isolates submitted to the Pneumococcal Sentinel Surveillance System from 1984 to 1996 from 48 vaccinated and 125 unvaccinated children 2 to 5 years of age. Effectiveness against invasive disease caused by serotypes included in the vaccine was 63%. Effectiveness against serotypes in the polysaccharide vaccine but not in a proposed seven-valent protein conjugate vaccine was 94%.