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Typhoid fever is endemic in Fiji, with high reported annual incidence. We sought to identify the sources and modes of transmission of typhoid fever in Fiji with the aim to inform disease control. We identified and surveyed patients with blood culture-confirmed typhoid fever from January 2014 through January 2017. For each typhoid fever case we matched two controls by age interval, gender, ethnicity, and residential area. Univariable and multivariable analysis were used to evaluate associations between exposures and risk for typhoid fever. We enrolled 175 patients with typhoid fever and 349 controls. Of the cases, the median (range) age was 29 (2-67) years, 86 (49%) were male, and 84 (48%) lived in a rural area. On multivariable analysis, interrupted water availability (odds ratio [OR] = 2.17; 95% confidence interval [CI] 1.18-4.00), drinking surface water in the last 2 weeks (OR = 3.61; 95% CI 1.44-9.06), eating unwashed produce (OR = 2.69; 95% CI 1.48-4.91), and having an unimproved or damaged sanitation facility (OR = 4.30; 95% CI 1.14-16.21) were significantly associated with typhoid fever. Frequent handwashing after defecating (OR = 0.57; 95% CI 0.35-0.93) and using soap for handwashing (OR = 0.61; 95% CI 0.37-0.95) were independently associated with a lower odds of typhoid fever. Poor sanitation facilities appear to be a major source of Salmonella Typhi in Fiji, with transmission by drinking contaminated surface water and consuming unwashed produce. Improved sanitation facilities and protection of surface water sources and produce from contamination by human feces are likely to contribute to typhoid control in Fiji.

As part of the World Health Organization Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) surveillance in Suva, Fiji, cerebrospinal fluid (CSF) samples from suspected meningitis patients of all ages were examined by traditional methods (culture, Gram stain, and latex agglutination for bacterial antigen) and qPCR for Streptococcus pneumoniae, Neisseria meningitidis , and Haemophilus influenzae . Of 266 samples tested, pathogens were identified in 47 (17.7%). S. pneumoniae was the most common pathogen detected (n = 17) followed by N. meningitidis (n = 13). The use of qPCR significantly increased detection of IB-VPD pathogens (P = 0.0001): of 35 samples that were qPCR positive for S. pneumoniae, N. meningitidis , and H. influenzae , only 10 were culture positive. This was particularly relevant for N. meningitidis , as only 1/13 cases was culture positive. Molecular serotyping by microarray was used to determine pneumococcal serotypes from 9 of 16 (56%) of samples using DNA directly extracted from CSF specimens. Results indicate that qPCR significantly increases detection of S. pneumoniae, N. meningitidis , and H. influenzae in CSF, and that application of molecular diagnostics is a feasible way to enhance local and global surveillance for IB-VPD.

Importance Pneumococcal nasopharyngeal carriage is a prerequisite for pneumococcal disease. The main transmission route is from toddlers, who commonly carry pneumococci. However, neonatal pneumococcal disease case reports suggest that vertical pneumococcal transmission may also occur. Objective To describe and compare pneumococcal nasopharyngeal carriage and density by infant mode of delivery in young Fijian infants. Design, Setting, and Participants Annual cross-sectional surveys were performed in Suva, Fiji, before the introduction of 10-valent pneumococcal conjugate vaccine (PCV10), from September 14 to December 20, 2012, and after PCV10 was introduced, from July 11 to November 19, 2013; July 15 to December 9, 2014; and August 13 to November 19, 2015. Caregivers of 2006 infants aged 5 to 8 weeks participated in the surveys. Statistical analysis was performed from May 24, 2018, to August 12, 2019. Exposures Caregivers provided data on infant mode of delivery and demographics via interviewer-led survey. Main Outcomes and Measures Pneumococci in swab samples were detected and quantified bylytA quantitative polymerase chain reaction with molecular serotyping by microarray. Pneumococci were categorized as PCV10 or non-PCV10 serotypes. Results Of the 2006 infants (976 girls and 1030 boys; mean [SD] age, 6.1 [0.02] weeks]), 1742 (86.8%) were born vaginally and 264 were born by cesarean delivery. Infants delivered vaginally, compared with those born by cesarean delivery, had a higher prevalence of overall pneumococcal nasopharyngeal carriage (470 of 1722 [27.3%; 95% CI, 25.2%-29.4%] vs 47 of 260 [18.1%; 95% CI, 13.6%-23.3%];P = .002), PCV10 carriage (113 of 1698 [6.7%; 95% CI, 5.5%-7.9%] vs 8 of 256 [3.1%; 95% CI, 1.4%-6.1%];P = .03), and non-PCV10 carriage (355 of 1698 [20.9%; 95% CI, 19.0%-22.9%] vs 38 of 256 [14.8%; 95% CI, 10.7%-19.8%];P = .02), and had higher median densities of overall pneumococci (4.9 log10genome equivalents [GE]/mL [interquartile range, 4.8-5.0 log10GE/mL] vs 4.5 log10GE/mL [interquartile range, 4.1-4.6 log10GE/mL];P = .01) and non-PCV10 pneumococci (4.9 log10GE/mL [interquartile range, 4.7-5.0 log10GE/mL] vs 4.4 log10GE/mL [interquartile range, 4.0-4.7 log10GE/mL];P = .01). Vaginal delivery was associated with overall (adjusted odds ratio, 1.57 [95% CI, 1.10-2.23];P = .01) and non-PCV10 (adjusted odds ratio, 1.49 [95% CI, 1.01-2.20];P = .04]) pneumococcal nasopharyngeal carriage. Vaginal delivery was not associated with PCV10 carriage (adjusted odds ratio, 1.67 [95% CI, 0.80-3.51];P = .17). After adjustment, vaginal delivery was not associated with density. Conclusions and Relevance Pneumococcal nasopharyngeal carriage prevalence and density were higher in infants delivered vaginally compared with those delivered by cesarean birth. After adjustment, vaginal delivery was associated with pneumococcal carriage. Differences in carriage by mode of delivery may be due to differential exposure to the vaginal microbiota during delivery and the effect of intrapartum antibiotics during cesarean delivery on the infant microbiome. Our findings also raise the hypothesis that vertical transmission may contribute to pneumococcal acquisition.

Background Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), disproportionately impact the Aboriginal and Torres Strait Islander population of Australia. Aboriginal Community Controlled Health Services (ACCHSs) are primary care services, established to provide healthcare in culturally safe environments for Aboriginal people. There is little information about the respiratory services for people with chronic respiratory diseases provided by ACCHSs. Aim To describe current provision of respiratory services of ACCHSs based in New South Wales (NSW), with a focus on identifying barriers and facilitators to providing pulmonary rehabilitation. Methods A researcher-administered survey was conducted via Zoom plus a follow-up email to collect client and health workforce data. Participants were NSW-based ACCHSs, members of the Aboriginal Health and Medical Research Council (AH&MRC). Exclusions were ACCHSs that only delivered drug and alcohol rehabilitation, housing or employment services. The survey collected information related to client numbers, smoking history, COPD diagnoses, health workforce, and respiratory services with a focus on pulmonary rehabilitation programs. Results Forty-one ACCHSs were invited to participate and 18 (44%) completed the survey. Most provided respiratory care, although variation existed in service scope and delivery. The main respiratory services provided were smoking cessation (100%), spirometry (89%) and respiratory clinics (33%). Most ACCHSs (78%), reported some access to respiratory physicians. No ACCHSs provided pulmonary rehabilitation. Main barriers included staff shortages, lack of staff training, financial constraints and lack of space. Several ACCHSs expressed interest in providing a pulmonary rehabilitation program, if appropriate resourcing was available. Ten ACCHS (56%) reported that Aboriginal clients would not access mainstream public health services for pulmonary rehabilitation. Barriers to accessing these externally available pulmonary rehabilitation programs included transportation issues, cultural considerations and geographical location. Conclusions ACCHSs are delivering respiratory services for Aboriginal people living with chronic respiratory diseases within constrained infrastructure and resources. Additional funding is required to improve access to best practice care for Aboriginal people living with COPD including culturally safe, evidence-based and accessible pulmonary rehabilitation programs.

Background Despite the high incidence of chronic obstructive pulmonary disease (COPD) in Aboriginal communities in Australia, Aboriginal Health Workers (AHWs) have limited knowledge about effective management. Aim To evaluate an online education program, co-designed with AHWs and exercise physiologists (EPs) or physiotherapists (PTs), to increase knowledge about COPD and its management. Methods AHWs and EPs from four Aboriginal Community Controlled Health Services (ACCHS) were recruited. An Aboriginal researcher and a physiotherapist experienced in COPD management and pulmonary rehabilitation (PR) delivered seven online education sessions. These sessions used co-design principles and an Aboriginal pedagogy framework ‘8 Ways of learning’, which incorporates Aboriginal protocols and perspectives to realign teaching techniques and strengthen learning outcomes. Topics covered were: How the lungs work; What is COPD; Medications and how to use inhalers and COPD Action Plans; Why exercise is important; Managing breathlessness; Healthy eating; Managing anxiety and depression. After each session, AHWs with support from EPs, co-designed education ‘yarning’ resources using Aboriginal ways of learning to ensure topics were culturally safe for the local Aboriginal community and practiced delivering this at the following session. At the end of the program participants completed an anonymous online survey (5-point Likert scale) to assess satisfaction, and a semi-structured interview about their experience of the online education. Results Of the 12 participants, 11 completed the survey (7 AHWs, 4 EPs). Most (90%) participants strongly agreed or agreed that the online sessions increased knowledge and skills they needed to support Aboriginal patients with COPD. All (100%) participants felt: their cultural perspectives and opinions were valued and that they were encouraged to include cultural knowledge. Most (91%) reported that delivering their own co-designed yarning scripts during the online sessions improved their understanding of the topics. Eleven participants completed semi-structured interviews about participating in online education to co-design Aboriginal ‘yarning’ resources. Themes identified were: revealing the Aboriginal lung health landscape; participating in online learning; structuring the online education sessions; co-designing with the facilitators. Conclusions Online education using co-design and 8 Ways of learning was rated highly by AHWs and EPs for improving COPD knowledge and valuing cultural perspectives. The use of co-design principles supported the cultural adaptation of COPD resources for Aboriginal people with COPD. Trial registration PROSPERO (registration number: CRD42019111405).

The introduction of rotavirus vaccine (RVV), pneumococcal conjugate vaccine (PCV) and human papillomavirus vaccine (HPVV) has been slow in Pacific Island Countries, particularly among middle-income countries. To assist decision-making on the simultaneous introduction of these three vaccines, cost-effectiveness and budget impact evaluations were undertaken in Samoa, Tonga, Tuvalu and Vanuatu, using locally relevant data. A proportionate outcomes model was used to evaluate vaccine introduction in each country from a health systems perspective, using country-specific data supplemented with regional and global estimates. A 10-year vaccination program was modelled from 2021, with costs and outcomes (disability-adjusted life years [DALYs]) summed over a life-time horizon and discounted at 3%. Vaccine dose costs were based on Pan American Health Organization (PAHO) Revolving Fund prices, with lower-priced products also explored. Introduction of all three vaccines in all countries could prevent over 1,000 deaths over the lifetimes of the vaccinated cohorts. The cost per DALY averted at PAHO Revolving Fund prices ranged from 42% to 73% of the per capita gross domestic product (GDP) in each country, and 15% to 58% for lower-priced vaccines. The budget impact ranged from 359% (Samoa) to 1,368% (Vanuatu) of the 2019 vaccine budgets, and 149% (Samoa) to 775% (Vanuatu) for lower-priced vaccines. Cost-effectiveness results were most sensitive to disease burden, discount rate, vaccine efficacy, and program costs. A limitation of our study is the reliance on data from Fiji to inform disease burden, as availability of country-specific data was limited. With development partner support, introduction of HPVV, PCV and RVV may represent good value for money in Samoa, Tonga, Tuvalu and Vanuatu, depending on willingness to pay thresholds. However, inclusion of these three vaccines will place considerable burden on immunisation budgets. Financial sustainability requires increases in immunisation budgets and negotiation of affordable vaccine prices. This analysis provides evidence of the benefit of introducing new vaccines, but shows the importance of affordable pricing to ensure sustainability for small Pacific Island countries.

Background Strong evidence exists for the benefits of pulmonary rehabilitation (PR) for people with chronic obstructive pulmonary disease (COPD), however the availability of culturally safe PR for Aboriginal and Torres Strait Islander (Indigenous) Peoples is limited. The study aims to determine whether PR can be implemented within Aboriginal Community Controlled Health Services (ACCHS) to improve outcomes for Indigenous people with COPD. Methods Multi-centre cohort study using participatory action research guided by the Knowledge-to-Action Framework. ACCHS supportive of enhancing services for chronic lung disease will be recruited. Aboriginal Health Workers (AHW) and the exercise physiologist (EP) or physiotherapist (PT) within these ACCHS will attend a workshop aimed at increasing knowledge and skills related to management of COPD and the provision of PR. Indigenous people with COPD will be invited to attend an 8-week, twice weekly, supervised PR program. Outcomes: AHW, EP/PT knowledge, skills and confidence in the assessment and management of COPD will be measured before and immediately after the BE WELL workshop and at 3, 6 and 12 months using a survey. PR participant measures will be exercise capacity (6-minute walk test (6MWT), health-related quality of life and health status at commencement and completion of an 8-week PR program. Secondary outcomes will include: number, length and cost of hospitalisations for a COPD exacerbation in 12-months prior and 12-months post PR; local contextual factors influencing implementation of PR; specific respiratory services provided by ACCHS to manage COPD prior to project commencement and at project completion. Repeated measures ANOVA will be used to evaluate changes in knowledge and confidence over time of AHWs and EP/PTs. Paired t-tests will be used to evaluate change in patient outcomes from pre- to post-PR. Number of hospital admissions in the 12 months before and after the PR will be compared using unpaired t-tests. Discussion Pulmonary rehabilitation is an essential component of best-practice management of COPD and is recommended in COPD guidelines. Indigenous peoples have limited access to culturally safe PR programs. This study will evaluate whether PR can be implemented within ACCHS and improve outcomes for Indigenous people with COPD. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001337369, Registered 2nd September 2017 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373585&isClinicalTrial=False

Objectives The increasing success of Chimeric Antigen Receptor (CAR) T cell therapy in haematological malignancies is reinvigorating its application in many other cancer types and with renewed focus on its application to solid tumors. We present a novel CAR against glioblastoma, an aggressive, malignant glioma, with a dismal survival rate for which treatment options have remained unchanged for over a decade. Methods We use the human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a novel single‐chain variable fragment (scFv) that recognises epidermal growth factor receptor mutant variant III (EGFRvIII), a common and tumor‐specific mutation found in glioblastoma. We use both in vitro functional assays and an in vivo orthotopic xenograft model of glioblastoma to examine the function of our novel CAR, called GCT02, targeted using murine CAR T cells. Results Our EGFRvIII‐specific scFv was found to be of much higher affinity than reported comparators reverse‐engineered from monoclonal antibodies. Despite the higher affinity, GCT02 CAR T cells kill equivalently but secrete lower amounts of cytokine. In addition, GCT02‐CAR T cells also mediate rapid and complete tumor elimination in vivo. Conclusion We present a novel EGFRvIII‐specific CAR, with effective antitumor functions both in in vitro and in a xenograft model of human glioblastoma. We have made novel chimeric antigen receptor T (CART) cells specific for glioblastoma, a devastating brain tumor with poor survival. This receptor is of extremely high affinity, and the CAR T cells can completely clear brain tumors in mice.

Vanessa Wong and colleagues report whole-genome sequencing of 1,832 Salmonella enterica serovar Typhi isolates from 63 endemic countries. They identify mutations that define the multidrug resistant (MDR) H58 lineage and report numerous inter- and intracontinental transmissions of this lineage as well as an ongoing MDR typhoid epidemic in Africa. The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi ( S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

Objectives In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from older patients are inherently more differentiated, but we hypothesised that specific activation protocols could be used to limit CAR T cell differentiation during manufacturing, particularly in older patients. Methods We used PBMCs from young (20–30 years old) and older (60+ years old) healthy donors to generate CAR T cells using two activation protocols: soluble anti‐(α) CD3 monoclonal antibody (mAb) vs immune complexes of αCD3 and αCD28 mAbs. Products were assessed for yield, function and differentiation, which was used as a measure of CAR T cell quality. T cells in PBMCs were assessed for CD28 expression and correlative analyses were performed. Results Older samples generated fewer, more differentiated CAR T cells than young samples, and the αCD3/CD28 mAb protocol exacerbated this, further reducing yield and quality. CD28 expression by T cells correlated with CAR T cell differentiation, but T cell differentiation in PBMC starting material was a stronger correlate of CAR T cell differentiation. Conclusions Choice of activation protocol can substantially impact on the yield and quality of CAR T cells during manufacturing. This is a key consideration for older patients whose samples already generate a poorer yield and lower quality of CAR T cells. It is unclear whether specific T cell activation protocols are more or less effective for CAR T cell therapy in older patients. Our study demonstrates that specific activation protocols (anti‐CD3/28 mAb complexes) can exacerbate low yield and advanced differentiation already seen in older patients and generate a poorer quality CAR T cell product.