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Background Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested “Armed” OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T cells after treatment however, CAdVEC was still able to induce clinical responses even given at a 100-fold lower dose.Methods To address the mechanisms of CAdTrio-mediated antitumor effect in patients, we analyzed patients’ samples using Enzyme-linked immunosorbent spot (ELISpot) to measure T-cell specificity and quantitative polymerase chain reaction (qPCR) to measure CAdVEC viral genome copies at tumor sites. We then evaluated potential mechanisms of CAdVEC efficacy in vitro using live-cell imaging. Based on those results, we developed a new CAdVEC additionally expressing a T-cell engager molecule targeting CD44v6 to redirect tumor-infiltrating irrelevant T cells against cancer stem cell populations (CAdTetra) for further improvement of local CAdVEC treatment. We tested its efficacy against different cancer types both in vitro and in vivo including Ad pre-immunized humanized mice.Results We found that HDAd-infected cells escape Ad-specific T-cell recognition with enhanced tumor-specific T-cell activity through immunomodulatory transgenes. Since CAdVEC treatment initially amplified Ad-specific T cells in patients, we re-direct these virus-specific T cells to target tumor cells by additionally expressing CD44v6.BiTE from CAdTetra. CAdTetra significantly controlled tumor growth, repolarizing local and systemic responses against cancer cells in both immunologically “hot” and “cold” tumor models and also induced immunologic memory against rechallenged tumors.Conclusions Our results indicate that CAdTetra effectively induces adaptive T-cell responses against cancer cells by using tumor-infiltrating irrelevant T cells.

This study details a genomics-based approach for the early detection of mosquito-borne pathogens, marked by Uruguay's first ever complete genomic sequencing of Dengue Virus type I genotypes I and V. This pioneering effort has facilitated the prompt identification of these genotypes within the country, enabling Uruguayan public health authorities to develop timely and effective response strategies. Further integrated into this approach is a climate-driven suitability measure, closely associated with Dengue case reports and indicative of the local climate's role in the virus's transmission in the country within the changing climate context. The detection of multiple DENV-1 genotypes co-circulating in Uruguay underscores the necessity for proactive surveillance, particularly at borders, to prevent the introduction and dissemination of novel viral strains within the country and the region. This approach aids in facilitating prompt public health responses and intervention strategies, which are crucial in mitigating the impact of dengue outbreaks.

Systemic delivery of oncolytic and immunomodulatory adenoviruses may be required for optimal effects on human malignancies. Mesenchymal stromal cells (MSCs) can serve as delivery systems for cancer therapeutics due to their ability to transport and shield these agents while homing to tumors. We now use MSCs to deliver a clinically validated binary oncolytic and helper-dependent adenovirus combination (CAdVEC) to tumor cells. We show successful oncolysis and helper-dependent virus function in tumor cells even in the presence of plasma from adenovirus-seropositive donors. In both two- and three-dimensional cultures, CAdVEC function is eliminated even at high dilutions of seropositive plasma but is well sustained when CAdVEC is delivered by MSCs. These results provide a robust in vitro model to measure oncolytic and helper-dependent virus spread and demonstrate a beneficial role of using MSCs for systemic delivery of CAdVEC even in the presence of a neutralizing humoral response.

Abstract Background Cholera is newly emergent in Papua New Guinea but may soon become endemic. Identifying the risk factors for cholera provides evidence for targeted prevention and control measures. Methods We conducted a hospital-based case–control study to identify cholera risk factors. Using stool culture as the standard, we evaluated a cholera point of care test in the field. Results 176 participants were recruited: 54 cases and 122 controls. Independent risk factors for cholera were: being over 20 years of age (aOR 2.5; 95%CI 1.1, 5.4), defecating in the open air (or river) (aOR 4.5; 95% CI 1.4, 14.4) and knowing someone who travelled to a cholera affected area (aOR 4.1; 95%CI 1.6, 10.7); while the availability of soap for handwashing at home was protective (aOR 0.41; 95%CI 0.19, 0.87). Those reporting access to a piped water distribution system in the home were twice as likely to report the availability of soap for handwashing. The sensitivity and specificity of the rapid test were 72% (95% CI 47–90) and 71% (95%CI 44–90%). Conclusions Improving population access to the piped water distribution system and sanitation will likely reduce transmission by enabling enhanced hygiene and limiting the contamination of water sources. The One step V. cholerae O1/O139 Antigen Test is of limited utility for clinical decision making in a hospital setting with access to traditional laboratory methods. Settlement dwellers and mobile populations of all age groups should be targeted for interventions in Papua New Guinea.

This article explores male and female academics' perceptions of what it means to be both a parent and an academic and the relations between them. Based on an Interpretative Phenomenological Analysis of interviews with 35 academics from a university in England, findings suggest that the way in which academics experience being both a parent and an academic depends upon how they understand the meaning of each of these two roles and what they are trying to achieve within them. These meanings and experiences also appear to differ by gender. Ways in which higher education can offer more targeted and specific support to academic mothers in particular are discussed.

Abstract Protease inhibitors, as part of highly active anti-retroviral therapy (HAART), have significantly increased the lifespan of human immunodeficiency virus (HIV) infected patients. Several deleterious side effects including dyslipidemia and lipodystrophy, however, have been observed with HAART. Women are at a higher risk of developing adipose tissue alterations and these alterations have different characteristics as compared to men. We have previously demonstrated that in mice the HIV protease inhibitor, ritonavir, caused a reduction in weight gain in females, but had no effect on male mice. In the present study, we examined the potential causes of this difference in weight gain. Low-density lipoprotein receptor (LDL-R) null mice or wild-type C57BL/6 mice, were administered 15 μg/ml ritonavir or vehicle (0.01% ethanol) in the drinking water for 6 weeks. The percent of total body weight gained during the treatment period was measured and confirmed that female LDL-R gained significantly less weight with ritonavir treatment than males. In wild type mice, however, there was no effect of ritonavir treatment in either sex. Despite the weight loss in LDL-R null mice, ritonavir increased food intake, but no difference was observed in gonadal fat weight. Serum leptin levels were significantly lower in females. Ritonavir further suppressed leptin levels in (p < 0.05). Ritonavir did not alter serum adiponectin levels in either gender. To determine the source of these differences, female mice were ovariectomized remove the gonadal sex hormones. Ovariectomy prevented the weight loss induced by ritonavir (p < 0.05). Furthermore, leptin levels were no longer suppressed by ritonavir (p < 0.05). This study demonstrates that gonadal factors in females influence the hormonal control of weight gain changes induced by HIV protease inhibitors in an environment of elevated cholesterol.

This study examines the epidemiological and genomic characteristics, along with the transmission dynamics, of SARS-CoV-2 within prison units I and II in Campo Grande, Mato Grosso do Sul, Brazil. Conducted between May and October 2022, it reveals how the virus spreads in the confined settings of prisons, emphasizing the roles of overcrowded cells, frequent transfers, and limited healthcare access. The research involved 1927 participants (83.93% of the total prison population) and utilized nasopharyngeal swabs and RT-qPCR testing for detection. Contact tracing monitored exposure within cells. Out of 2108 samples, 66 positive cases were identified (3.13%), mostly asymptomatic (77.27%), with the majority aged 21–29 and varying vaccination statuses. Next-generation sequencing generated 28 whole genome sequences, identifying the Omicron variant (subtypes BA.2 and BA.5) with 99% average coverage. Additionally, the study seeks to determine the relationship between immunization levels and the incidence of SARS-CoV-2 cases within this enclosed population. The findings underscore the necessity of comprehensive control strategies in prisons, including rigorous screening, isolation protocols, vaccination, epidemiological monitoring, and genomic surveillance to mitigate disease transmission and protect both the incarcerated population and the broader community.

This article explores STEM (science, technology, engineering and mathematics) student associations of assessment with individual achievement, becoming part of a discipline or profession, or developing an orientation towards society. This perspective is based in Frankfurt School critical theory, which argues for the inter-relation between individual and social wellbeing. From a critical theory perspective, education should facilitate movement from a conception of the individual as autonomous towards the individual as a member of society: this is the foundation of social justice. We consider this philosophical position against the empirical experiences of students to explore the extent to which their engagement with assessment has helped shape a sense of interconnectedness between themselves and others in society. We describe a longitudinal and comparative study among chemistry and chemical engineering undergraduate students at universities in England, South Africa and the USA. The study finds that only a very small number of students display any orientation to society when discussing assessment. This is surprising because there are a number of socially-related assessment tasks within the curricula. More may be required to achieve a higher education oriented to social justice than simply the deliberate inclusion of socially-related activities in the curriculum or as assessment tasks.

The emergence and continued geographic expansion of arboviruses and the growing number of infected people have highlighted the need to develop and improve multiplex methods for rapid and specific detection of pathogens. Sequencing technologies are promising tools that can help in the laboratory diagnosis of conditions that share common symptoms, such as pathologies caused by emerging arboviruses. In this study, we integrated nanopore sequencing and the advantages of reverse transcription polymerase chain reaction (RT-PCR) to develop a multiplex RT-PCR protocol for the detection of Chikungunya virus (CHIKV) and several orthoflaviviruses (such as dengue (Orthoflavivirus dengue), Zika (Orthoflavivirus zikaense), yellow fever (Orthoflavivirus flavi), and West Nile (Orthoflavivirus nilense) viruses) in a single reaction, which provides data for sequence-based differentiation of arbovirus lineages.

In 2012, the World Health Assembly (WHA) endorsed the Global Vaccine Action Plan (GVAP), (1) with the objective of eliminating measles (2) in 5 of the 6 WHO regions by [...]

Since its discovery in early 1916, dengue fever, a common vector-borne illness in Brazil, has resulted in extensive urban outbreaks and poses a serious threat to the public’s health. Understanding the dynamics of Dengue Virus (DENV) serotypes circulating in different regions of Brazil is essential for implementing effective disease control and prevention measures. In response to this urgent need, we conducted an on-site training program in genomic surveillance in collaboration with the Central Laboratory of Health and the Secretary of Health of the Mato Grosso do Sul state. This initiative resulted in the generation of 177 DENV genome sequences collected between May 2021 and May 2022, a period during which over 11,391 dengue fever cases were reported in the state. Through this approach, we were able to identify the co-circulation of two different dengue serotypes (DENV1 and DENV2) as well as the existence of diverse viral lineages within each genotype, suggesting that multiple introduction events of different viral strains occurred in the region. By integrating epidemiological data, our findings unveiled temporal fluctuations in the relative abundance of different serotypes throughout various epidemic seasons, highlighting the complex and changing dynamics of DENV transmission throughout time. These findings demonstrate the value of ongoing surveillance activities in tracking viral transmission patterns, monitoring viral evolution, and informing public health actions.

Genomic surveillance has emerged as a crucial tool in monitoring and understanding the dynamics of viral variants during the COVID-19 pandemic. In the Midwest region of Brazil, Mato Grosso do Sul has faced a significant burden from the SARS-CoV-2 epidemic, with a total of 613,000 confirmed cases as of June 2023. In collaboration with the Central Public Health Laboratory in the capital city of Campo Grande, we conducted a portable whole-genome sequencing and phylodynamic analysis to investigate the circulation of the Omicron variant in the region. The study aimed to uncover the genomic landscape and provide valuable insights into the prevalence and transmission patterns of this highly transmissible variant. Our findings revealed an increase in the number of cases within the region during 2022, followed by a gradual decline as a result of the successful impact of the vaccination program together with the capacity of this unpredictable and very transmissible variant to quickly affect the proportion of susceptible population. Genomic data indicated multiple introduction events, suggesting that human mobility played a differential role in the variant’s dispersion dynamics throughout the state. These findings emphasize the significance of implementing public health interventions to mitigate further spread and highlight the powerful role of genomic monitoring in promptly tracking and uncovering the circulation of viral strains. Together those results underscore the importance of proactive surveillance, rapid genomic sequencing, and data sharing to facilitate timely public health responses.

Introduction Achievement of universal health coverage (UHC) and the sustainable development goals are currently unattainable in the fragile state of Papua New Guinea. (1) Total health expenditure as a percentage [...], In the context of declining economic growth, now exacerbated by the coronavirus disease 2019 pandemic, Papua New Guinea is increasing the efficiency of its health systems to overcome difficulties in reaching global health and development targets. Before 2015, the national health information system was fragmented, underfunded, of limited utility and accessed infrequently by health authorities. We built an electronic system that integrated mobile technologies and geographic information system data sets of every house, village and health facility in the country. We piloted the system in 184 health facilities across five provinces between 2015 and 2016. By the end of 2020, the system's mobile tablets were rolled out to 473 facilities in 13 provinces, while the online platform was available in health authorities of all 22 provinces, including church health services. Fractured data siloes of legacy health programmes have been integrated and a platform for civil registration systems established. We discuss how mobile technologies and geographic information systems have transformed health information systems in Papua New Guinea over the past 6 years by increasing the timeliness, completeness, quality, accessibility, flexibility, acceptability and utility of national health data. To achieve this transformation, we highlight the importance of considering the benefits of mobile tools and using rich geographic information systems data sets for health workers in primary care in addition to the needs of public health authorities. Dans un contexte de declin de la croissance economique, exacerbe par la pandemie de maladie a coronavirus, la Papouasie-Nouvelle-Guinee a decide d'augmenter l'efficacite de ses systemes sanitaires afin de surmonter les difficultes a atteindre les objectifs globaux en matiere de sante et de developpement. Avant 2015, le systeme d'information sanitaire national etait fragmente, sous-finance, peu utile et rarement consulte par les autorites sanitaires. Nous avons donc concu un systeme electronique integrant des technologies mobiles et des ensembles de donnees geographiques provenant de chaque menage, de chaque village et de chaque etablissement de soins du pays. Entre 2015 et 2016, nous avons pilote le systeme dans 184 etablissements de soins repartis sur cinq provinces. Fin 2020, les tablettes mobiles du systeme ont ete distribuees dans 473 etablissements de 13 provinces, tandis que les autorites sanitaires des 22 provinces du pays, y compris les services sanitaires confessionnels, ont pu acceder a la plateforme en ligne. Les silos de donnees fragmentees des programmes de sante anterieurs y ont ete incorpores et une plateforme destinee aux registres d'etat civil a ete creee. Le present document se penche sur la maniere dont les technologies d'information mobiles et geographiques ont transforme les systemes d'information sanitaire en Papouasie-Nouvelle-Guinee ces six dernieres annees en ameliorant la ponctualite, l'exhaustivite, la qualite, l'accessibilite, la flexibilite, la recevabilite et l'utilite des donnees nationales sur la sante. Pour realiser cette transformation, il est a nos yeux essentiel de tenir compte des avantages que representent les outils mobiles, et de tirer profit des vastes ensembles de donnees geographiques non seulement pour les travailleurs des soins de sante primaires, mais aussi pour les besoins des autorites de sante publique. En el contexto de un crecimiento economico en declive, agravado ahora por la pandemia de la enfermedad por coronavirus, Papua Nueva Guinea esta aumentando la eficiencia de sus sistemas sanitarios para superar las dificultades para alcanzar los objetivos globales de salud y desarrollo. Antes de 2015, el sistema nacional de informacion sanitaria estaba fragmentado, carecia de fondos suficientes, su utilidad era limitada y las autoridades sanitarias accedian a el con poca frecuencia. Construimos un sistema electronico que integraba tecnologias moviles y conjuntos de datos del sistema de informacion geografica de cada casa, pueblo y centro de salud del pais. Entre 2015 y 2016 pusimos a prueba el sistema en 184 centros de salud de cinco provincias. A finales de 2020, las tabletas moviles del sistema se implementaron en 473 centros de 13 provincias, mientras que la plataforma en linea estaba disponible en las autoridades sanitarias de las 22 provincias, incluidos los servicios de salud de las iglesias. Se han integrado los silos de datos fracturados de los programas sanitarios heredados y se ha establecido una plataforma para los sistemas de registro civil. Exponemos como las tecnologias moviles y los sistemas de informacion geografica han transformado los sistemas de informacion sanitaria en Papua Nueva Guinea en los ultimos seis anos, aumentando la puntualidad, la exhaustividad, la calidad, la accesibilidad, la flexibilidad, la aceptabilidad y la utilidad de los datos sanitarios nacionales. Para lograr esta transformacion, destacamos la importancia de tener en cuenta los beneficios de las herramientas moviles y de utilizar conjuntos de datos ricos en sistemas de informacion geografica para los trabajadores sanitarios de la atencion primaria, ademas de las necesidades de las autoridades sanitarias publicas.

Rosewell Shaw et al. show that a previously developed immunotherapy strategy, coupling oncolytic adenoviral immunotherapy with clinically tested HER2-specific CAR T-cells, is effective against pancreatic ductal adenocarcinoma (PDAC). This combination therapy produces a curative response in both PDAC xenografts and humanized mouse models.

Despite the wealth of literature on academic work, roles and identities, the meaning of being an academic often does not go beyond such pre-defined and separate roles of teacher, researcher, academic, professional and manager. Consequently, our understanding of academic work is limited. This article explores the holistic meaning of being an academic and considers how this relates to gender. Based on interviews with 35 academics from a single United Kingdom (UK) institution, we argue that what it means to be an academic, goes beyond these pre-defined and separate roles; and that other aspects, such as academic freedom, intellectual stimulation, and a sense of a calling play different roles in different constructions of being an academic. Gender is also found to be an important factor in the different ways of defining academic work. These findings have implications for our understanding of career trajectories of male and female academics.

Smallpox was declared eradicated in 1980, with known seed stock retained in two high security Biosafety Level 4 laboratories in the United States and Russia. Experts agree the likelihood of theft from these laboratories is low, and that synthetic creation of smallpox is a theoretical possibility. Until 2017 it was believed that synthetic smallpox was technically too complex a task to be a serious threat. However, in 2017, Canadian scientists synthesised a closely related orthopoxvirus, horsepox, using mail order DNA and $100,000. Simultaneously, terrorist groups have declared intent to conduct biological attacks. In this context an exercise was held on August 16th 2018, with international and cross-sectoral stakeholders to review preparedness for a bioterrorism attack in the Asia-Pacific region and globally. The exercise was conducted by The National Health and Medical Research Council (NHMRC) Centre for Research Excellence, Integrated Systems for Epidemic Response, with contextual input from the Ministry of Health and Medical Services Fiji. The scenario involved a deliberate release in Fiji, followed by a larger release in a more populous Asian country. Mathematical modelling was used to underpin epidemic projections under different conditions. The exercise alternated between clinical, public health, emergency and societal responses, with participants making real-time decisions on cross-sectoral response across the region and the world. Key weak points which are influential in determining the final size and impact of the epidemic were identified (based on mathematical modelling of transmission in Fiji and globally). We identified potential gaps in preparedness for smallpox and factors which influence the severity of a smallpox epidemic. This included identifying which determinants of epidemic size are potentially within our control, and which are not. Influential factors within our control include: preventing an attack through intelligence, law enforcement and legislation; speed of diagnosis; speed and completeness of case finding and case isolation; speed and security of vaccination response, including stockpiling; speed and completeness of contact tracing; protecting critical infrastructure and business continuity; non-pharmaceutical interventions (social distancing, PPE, border control); protecting first responders; operational support and logistics; social mobilisation and risk communication. Based on discussion at the workshop between diverse stakeholders, recommendations were made to guide improved prevention, mitigation and rapid response, thus providing a holistic, cross-sectoral framework for prevention of a worst-case scenario smallpox pandemic.

Abstract Background Solomon Islands is one of the least developed countries in the world. Recognising that timely detection of outbreaks is needed to enable early and effective response to disease outbreaks, the Solomon Islands government introduced a simple syndromic surveillance system in 2011. We conducted the first evaluation of the system and the first exploration of a national experience within the broader multi-country Pacific Syndromic Surveillance System to determine if it is meeting its objectives and to identify opportunities for improvement. Methods We used a multi-method approach involving retrospective data collection and statistical analysis, modelling, qualitative research and observational methods. Results We found that the system was well accepted, highly relied upon and designed to account for contextual limitations. We found the syndromic algorithm used to identify outbreaks was moderately sensitive, detecting 11.8% (IQR: 6.3–25.0%), 21.3% (IQR: 10.3–36.8%), 27.5% (IQR: 12.8–52.3%) and 40.5% (IQR: 13.5–65.7%) of outbreaks that caused small, moderate, large and very large increases in case presentations to health facilities, respectively. The false alert rate was 10.8% (IQR: 4.8–24.5%). Rural coverage of the system was poor. Limited workforce, surveillance resourcing and other ‘upstream’ health system factors constrained performance. Conclusions The system has made a significant contribution to public health security in Solomon Islands, but remains insufficiently sensitive to detect small-moderate sized outbreaks and hence should not be relied upon as a stand-alone surveillance strategy. Rather, the system should sit within a complementary suite of early warning surveillance activities including event-based, in-patient- and laboratory-based surveillance methods. Future investments need to find a balance between actions to address the technical and systems issues that constrain performance while maintaining simplicity and hence sustainability.

Background The Community Mine Continuation Agreement Middle (CMCA) and South Fly Health Program (the Health Program) is a partnership for improving health service delivery in remote Papua New Guinea (PNG). The Health Program is delivered by a private contractor working in partnership with existing health service providers to improve service delivery using existing government systems, where possible, and aligns with national policies, plans and strategies. A midline evaluation was conducted to determine changes in health service delivery since commencement of the Health Program. Methods A mixed methods evaluation was undertaken mid-way through implementation of the Health Program, including a pre/post analysis of health service delivery indicators, semi-structured interviews with health workers and assessment of health facility equipment and infrastructure. Results Improvements in many of the long-term expected outcomes of the Health Program were observed when compared to the pre-program period. The number of outpatient visits per person per year and number of outreach clinics per 1000 children under 5 years increased by 15% and 189% respectively (P < .001). Increases in vaccination coverage for infants aged P < .001) and 75% for 1st dose Sabin (P < .001), 30% for 3rd dose pentavalent (P < .001) and 26% for measles vaccination (P < .001). Family planning coverage remained at similar levels (increasing 5%, P = .095) and antenatal care coverage increased by 26% (P < .001). Supervised deliveries coverage declined by 32% (P < .001), a continuation of the pre-Program trend. The proportion of facilities with standard equipment items, transport and lighting increased. Health worker training, in particular obstetric training, was most commonly cited by health workers as leading to improved services. Conclusion Following implementation, substantial improvements in health service delivery indicators were observed in the Health Program area as compared with pre-program period and the stagnating or declining national performance. This model could be considered for similar contexts where existing health service providers require external assistance to provide basic health services to the community.

Abstract Background Intelligence generated by a surveillance system is dependent on the quality of data that are collected. We investigated the knowledge, attitudes and practices of nurses responsible for outbreak early warning surveillance data collection in Solomon Islands to identify factors that influence their ability to perform surveillance-related tasks with rigour. Methods We interviewed 12 purposively selected surveillance nurses and conducted inductive analysis on resulting data. Results Interviewees were knowledgeable and willing to contribute to the surveillance system. Constraining factors included the perception that surveillance was less important than patient care and could be ‘deferred’ during busy periods and wide variability in the application of case definitions. Motivating factors were frequent in-clinic training, formal recognition for good performance, incentives and designation of a focal point. Nurses held mixed views about the effect of mobile technologies on surveillance practice. Conclusions This study identified several challenges to consistent and accurate data collection and reporting. Engagement of different parts of the health system, including human resources and health facilities’ management, is needed to address these challenges.