Common Problems in Conveying Oil and Gas Interests.

Abstract Forthcoming

Estimating The Costs And Cost-effectiveness Of Promoting Mammography Screening Among US-based Latinas

Purpose: We characterize the costs and cost-effectiveness of a community health worker (CHW)-based intervention to promote screening mammography among US-based non-adherent Latinas. Methods: The parent study was a randomized controlled trial for 536 Latinas aged 42-74 years old who had sought care within a safety net health center in Western Washington. Participants were block-randomized within clinic to the control arm (usual care) or intervention arm (CHW-led motivational interviewing intervention). We used the perspective of the organization implementing promotional activities to characterize costs and cost-effectiveness. Cost data were categorized as program set-up and maintenance (initial training, booster/annual training) program implementation (administrative activities, intervention delivery); and, overhead/miscellaneous expenses. Cost-effectiveness was calculated as the incremental cost of screening for each additional woman screened between the intervention and control arms. Results: The respective costs per participant for standard care and the intervention arm were $69.96 and$300.99. There were no study arm differences in 1-year QALYs among women who completed a 12-month follow-up survey (intervention= 0.8827, standard care = 0.8841). Most costs pertained to program implementation and administrative activities specifically. The incremental cost per additional woman screened was $2,595.32. Conclusions: Our findings are within the ranges of costs and cost-effectiveness for other CHW programs to promote screening mammography among underserved populations. Our strong study design and focus on non-adherent women provides important strengths to this body of work, especially give implementation and dissemination science efforts regarding CHW-based health promotion for health disparity populations

Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist

<p>Abstract</p> <p>Purpose</p> <p>We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA).</p> <p>Methods</p> <p>Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction.</p> <p>Results</p> <p>In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month.</p> <p>Conclusions</p> <p>Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.</p

¿Oncocercosis en Colombia? Una revaluación del foco de López de Micay

Human onchocerciasis was first described as existing in Colombia in 1965 in a small focus in Lopez de Micay on the Pacific Coast. Subsequent follow-up of the focus 12 years later showed that infection-prevalence had fallen from 15 to 7.5%. Since no patients were reported thereafter, the focus was considered to have been extinguished until 1989, when a child with occular keratitis was referred to the University Hospital in Cali. Onchocerciasis was confirmed by skin,snip examination. In July 1989 a multidisciplinaty team conducted a new survey in the area. Skin biopsies were obtained from 170 individuals. Infection-prevalence detected by skin-snip examination was 4.1% (71170). Ten percent of the surveyed males and 0.9% of the females had detectable microfilariae (mf) in skin. Microfilariae density in skin varied between 0.5 mf per milligram of skin to 47 mflmg and was directly related to the patients' age. Neither palpable subcutaneous nodules nor dermal alterations attributable to the parasite were detected in any of the patients. Occular pathology was found in two patients, consisting of bilateral keratitis and retinal degeneration, respectively. Simuliid activity at the time of the survey was very low and collection was not attempted. We hypothesise that active transmission may be taking place further upstream, where vector activity is greater. An increase in non-immune human settlement in the area is expected, due to the future construction of hydroelectrical plants and related connecting highways. Questions are therefore raised concerning the impact of immigration of naive population to this hypoendemic focus.En 1965 se describió el primer foco de oncocercosis humana en Colombia en López de Micay, en la costa pacífica. Doce años después, una visita de seguimiento mostró que la prevalencia de infección había disminuido del 15 al 7,5%. Ya que no se volvieron a reportar pacientes, se consideró extinguido el foco hasta 1989, cuando un niño con queratitis ocular fue remitido al Hospital Universitario de Cali. Se confirmó el diagnóstico de oncocercosis con una biopsia de piel. En julio de 1989 se hizo una nueva visita al área y se tomaron muestras a 170 personas. La prevalencia de infección detectada por biopsia de piel fue de 4,1% (71170). Se detectaron microfilarias (mf) en piel en 10% de los hombres muestreados y 0,9% de las mujeres. La microfilarodermia varió entre 0,5 mf por miligramo de piel y 47mflmg y estaba directamente relacionada con la edad. No se encontraron nódulos subcutáneos palpables ni alteraciones dérmicas atribuibles al parásito en ningún paciente. Dos pacientes presentaron cambios oculares: queratitis bilateral y degeneración de la retina, respectivamente. Durante la visita, la actividad de los simúlidos fue muy baja y no se intentaron capturas. Es probable que la transmisión ocurra en sitios río arriba, donde la actividad de los vectores es mayor. Con la construcción de vías de acceso y una planta hidroeléctrica se espera un aumento de la población no inmune en el área. Cabe preguntar, cúal será el impacto de esta población susceptible sobre este foco hipoendémico

In Vivo Gene Essentiality and Metabolism in Bordetella pertussis

Bordetella pertussis is the causative agent of whooping cough, a serious respiratory illness affecting children and adults, associated with prolonged cough and potential mortality. Whooping cough has reemerged in recent years, emphasizing a need for increased knowledge of basic mechanisms of B. pertussis growth and pathogenicity. While previous studies have provided insight into in vitro gene essentiality of this organism, very little is known about in vivo gene essentiality, a critical gap in knowledge, since B. pertussis has no previously identified environmental reservoir and is isolated from human respiratory tract samples. We hypothesize that the metabolic capabilities of B. pertussis are especially tailored to the respiratory tract and that many of the genes involved in B. pertussis metabolism would be required to establish infection in vivo. In this study, we generated a diverse library of transposon mutants and then used it to probe gene essentiality in vivo in a murine model of infection. Using the CON-ARTIST pipeline, 117 genes were identified as conditionally essential at 1 day postinfection, and 169 genes were identified as conditionally essential at 3 days postinfection. Most of the identified genes were associated with metabolism, and we utilized two existing genome-scale metabolic network reconstructions to probe the effects of individual essential genes on biomass synthesis. This analysis suggested a critical role for glucose metabolism and lipooligosaccharide biosynthesis in vivo. This is the first genome-wide evaluation of in vivo gene essentiality in B. pertussis and provides tools for future exploration. IMPORTANCE Our study describes the first in vivo transposon sequencing (Tn-seq) analysis of B. pertussis and identifies genes predicted to be essential for in vivo growth in a murine model of intranasal infection, generating key resources for future investigations into B. pertussis pathogenesis and vaccine design

Safety and immunogenicity of ChAdOx1 85A prime followed by MVA85A boost compared with BCG revaccination among Ugandan adolescents who received BCG at birth: a randomised, open-label trial

Background BCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A–MVA85A compared with BCG revaccination among Ugandan adolescents. Methods After ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12–17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-γ ELISpot response to antigen 85A (day 63 [geometric mean] and days 0–224 [area under the curve; AUC). Findings Six adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A–MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A–MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A–MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-γ ELISpot responses peaked on day 63 in the ChAdOx1 85A–MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30·59 [95% CI 17·46–53·59], p<0·0001, day 63; AUC mean difference 57 091 [95% CI 40 524–73 658], p<0·0001, days 0–224). Interpretation The ChAdOx1 85A–MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines. Funding UK Research and Innovations and Medical Research Council. Translations For the Swahili and Luganda translations of the abstract see Supplementary Materials section

Educational sessions in pharmacovigilance: What do the doctors think?

Background: The aim of this study was to determine physicians"opinion regarding pharmacovigilance feedback sessions. A survey was conducted in a teaching hospital, and the physicians who attended the sessions were invited to participate by filling out a structured questionnaire. All sessions included a review of adverse drug reactions identified at the hospital and information on pharmacovigilance issues (news on warnings released by regulatory agencies or drug toxicity problems identified by recently published studies in medical journals). The survey questions were related to the interest, satisfaction, and belief in the utility of the sessions. A Likert scale (0-10 points) was used to assess physicians" opinions. Findings: A total of 159 physicians attended the sessions and 115 (72.3%) participated in the survey. The mean (SD) age was 38.9 (12.1) years, and 72 (62.6%) were men. The mean (SD) scores of interest, satisfaction with the information provided, and belief in the utility of these sessions were 7.52 (1.61), 7.58 (1.46), and 8.05 (1.38) respectively. Significant differences were observed among physicians according to medical category and speciality in terms of interest, satisfaction, and belief in the utility of those sessions. Conclusions: Educational activities for physicians, such as feedback sessions, can be integrated into the pharmacovigilance activities. Doctors who attend the sessions are interested in and satisfied with the information provided and consider the sessions to be useful. Additional studies on the development and effectiveness of educational activities in pharmacovigilance are necessary

Assessment of pre-clinical liver models based on their ability to predict the liver-tropism of AAV vectors

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver