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Plasmodium knowlesi can adapt to infect Duffy-negative Erythrocytes.
Get PDFPlasmodium knowlesi, a zoonotic malaria species, has become a significant public health concern in Southeast Asia. In regions such as Malaysia and southern Thailand, P. knowlesi incidence has risen, even as other human malaria parasites are nearing elimination. Like its close relative Plasmodium vivax, P. knowlesi relies on Duffy-Antigen Receptor for Chemokine (DARC) as a key receptor for erythrocyte invasion. Only Duffy-positive individuals are thought to be susceptible to clinical infection. Here, we reveal that P. knowlesi possesses greater invasion plasticity than previously recognized. This parasite can bypass the need for DARC, as shown by its in vitro adaptation to invade and replicate in Duffy-negative (Fy-) erythrocytes. This adaptation is stable and independent of DARC binding, enabling the adapted parasite line to be maintained in Fy-erythrocytes and to resist inhibition by a-DARC antibodies. Genomic analysis identified a genomic recombination event between the parasite's dbpα and dbpγ genes, resulting in a new chimeric gene dbpαγ. Using CRISPR-Cas9 targeted reversion, we were able to demonstrate that dbpαγ is essential for invasion of Fy- erythrocytes. These findings shed new light on the invasion plasticity of P. knowlesi, with implications for its potential spread beyond Southeast Asia and for understanding the complex host-cell specificity and atypical invasion pathways seen in P. vivax
Location of In-Hospital Cardiac Arrest: An Updated Analysis of Epidemiology, Emergency Response, and Outcomes.
Get PDFOBJECTIVES: In the United States, in-hospital cardiac arrest (IHCA) affects about 290,000 adults per year. This study provides an updated and expanded analysis of the epidemiology, resuscitative response, and outcomes following IHCA in various hospital locations. DESIGN: This observational cohort study used the prospectively collected nationwide Get With The Guidelines-Resuscitation (GWTG-R) registry. SETTING: GWTG-R registry. PATIENTS: All adult patients with an index cardiac arrest in the emergency department (ED), ICU, or ward (telemetry or nontelemetry) between 2010 and 2021 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 235,560 IHCA events were included, of which 53.4% (n = 125,798) occurred in the ICU, 14.0% (n = 32,862) in the ED, 16.0% (n = 37,780) on telemetry wards, and 16.6% (n = 39,120) on nontelemetry wards. Shockable initial rhythms were identified in 15.9% (n = 37,465) of IHCAs, with the highest prevalence in monitored locations. Adjusted for confounding factors, a survival rate of 21.2% (95% CI, 20.6-21.9%) was found in the ICU, 22.2% (95% CI, 21.4-23.1%) in the ED, 23.0% (95% CI, 22.3-23.7%) on telemetry wards, and 19.2% (95% CI, 18.4-20.0%) on nontelemetry wards. CONCLUSIONS: Survival after IHCA is low and varies based on the hospital location of the IHCA. Patients with IHCA on nontelemetry wards have the lowest probability of in-hospital survival after IHCA
Invisible girls, visible harms: health, well-being, and safety among child domestic workers in Myanmar
Get PDFGlobally, an estimated 17.2 million children work as child domestic workers (CDWs), with nearly 3.7 million exposed to hazardous working conditions. Despite their prevalence, CDWs remain a hidden and hard-to-reach population. This study examines the hidden voices of CDWs in Myanmar, exploring their working conditions, experiences of abuse and isolation and the impact of being away from families on their well-being. In 2023, we conducted in-depth interviews with 33 former CDWs in Myanmar. All interviews were audio-recorded, transcribed, translated from Burmese to English, and analysed using thematic analysis. Our study reveals most CDWs entered domestic work out of economic necessity, feeling obligated to help ease their families’ financial hardships. They endured long hours in hazardous conditions, often facing abuse and unfair compensation. They were also restricted from communicating with family and friends, leaving them isolated for extended periods. Despite these adversities, most participants chose to remain in their jobs, prioritizing their families over their own hardships. Even in the face of abuse, the findings illuminate the deep sense of duty and connection young CDWs feel toward their biological families. This study underscores the urgent need for policies and parental engagement to protect CDWs safety and healthy child development
Performance of the Self-Controlled Case Series for Drug Safety Signal Detection: A Multi-Database Study.
Get PDFBACKGROUND: Differences in performance of the Self-Controlled Case Series (SCCS) for signal detection have been reported across different databases. However, there has been limited comparative analysis of performance and it remains unknown whether combinations of databases could enable more effective signal detection.
OBJECTIVES: This study aims to compare the performance of the SCCS for signal detection across several data sources, and to determine whether combinations of databases can improve SCCS performance.
METHODS: We applied the SCCS to macrolides and fluoroquinolone antibiotics, in four databases: Merative MarketScan Commercial Claims and Medicare, the Clinical Practice Research Datalink (CPRD) Aurum and the Système National des Données de Santé. We developed a reference set of 104 positive controls and 58 negative controls, using a taxonomy framework to ensure the selected drug outcome pairs are theoretically well suited to the SCCS design. The observation period lasted 2 years, with a 30-day risk-window after each dispensing. Diagnostic performance was measured using sensitivity, specificity and area under the receiver operating curve (AUC) with respect to the product labels, both for individual and combinations of databases.
RESULTS: The sensitivity of the SCCS ranged from 0.57-0.89 across individual databases, and the specificity from 0.43-0.77 when limited to drug-outcome pairs sufficiently powered. The combination of all databases achieved the maximum sensitivity of 0.89 (0.41 specificity) for the full reference set, and a sensitivity of 1 (0.35 specificity) for drug outcome pairs with enough power. Whilst AUCs ranged from 0.66 to 0.71 across individual databases, the highest performing combination was CPRD plus MarketScan Commercial Claims (0.76 AUC).
CONCLUSIONS: Using a carefully designed reference set of drug-outcome pairs well suited to the study design, the SCCS performance varied substantially by database due to differences in population, reporting, healthcare and coding systems and prescribing patterns. Multi-database studies showed increased performance of SCCS for signal detection
Circus arts shine a spotlight on antimicrobial resistance in Cambodia.
Get PDFBACKGROUND: In Cambodia, limited conceptual understanding of antimicrobials and the wide availability of over-the-counter medications increases antimicrobial resistance (AMR) threats. Community-based campaigns are critical to foster fundamental concepts of antimicrobials, their appropriate use and potential consequences of AMR.
METHODS: A circus-based drama on AMR was co-designed with a non-profit arts school and local youth groups, in coordination with two provincial health authorities.
RESULTS: Events held across three venues were attended by >1200 people and the accompanying social media campaign received >0.5 million views.
CONCLUSIONS: Following the success of the campaign, the circus drama's key messages are being developed into educational materials for school children nationwide
Social, environmental and policy contexts affecting the feasibility and acceptability of improving household flooring for better health in rural Kenya.
Get PDFBACKGROUND: Homes with unimproved floors (earth, sand, or clay) are associated with increased risks of soil-transmitted parasites and enteric infections, leading to higher morbidity and reduced quality of life. This study explored the enablers and barriers to adopting improved flooring (sealed, washable, and durable) in three culturally diverse regions of Kenya - Narok, Bungoma, and Kwale - to mitigate disease burdens. METHODS: Between August 2021 and July 2022, we conducted 24 focus group discussions with homeowners, stratified by age, gender, and floor type. Additionally, 28 key informant interviews with local government officials, microfinance representatives, and masonry trainers in Kwale and Bungoma provided contextual insights. Transcribed data underwent thematic analysis. RESULTS: In the study areas, most homes were constructed by residents themselves using traditional techniques and locally sourced materials. Despite awareness of the health risks, unimproved floors remained widespread. In Bungoma and Kwale, financial constraints and competing household priorities were primary barriers to flooring improvements, while in Narok, cultural identity contributed strongly to the rejection of changes in traditional houses. Key enablers included perceived health benefits and social status, while feasibility depended on the affordability and availability of materials and skilled labour. Strengthening the role of local artisans and leveraging their social influence were seen as effective strategies to shift perceptions on cost and feasibility. Improved collaboration between health and built-environment sectors could enhance community trust and support environmental disease management. CONCLUSION: Communities in Kwale and Bungoma were more receptive to improved flooring, while cultural practices and preferences in Narok posed significant adoption challenges. For receptive communities, affordable flooring technologies are critical to overcoming financial barriers, while behaviour change initiatives should address cultural and perceptual concerns. However, clinical evidence on locally generated health benefits is needed to support policy decisions and budget allocations for flooring interventions
Evaluation of rotavirus, pneumococcal conjugate and human papillomavirus vaccination in four Pacific island countries: A cost-effectiveness modelling study.
Get PDFBACKGROUND: 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.
METHODS AND FINDINGS: 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.
CONCLUSIONS: 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
Surface visualisation of bacterial biofilms using neutral atom microscopy.
Get PDFThe scanning helium microscope (SHeM) is a new technology that uses a beam of neutral helium atoms to image surfaces non-destructively and with extreme surface sensitivity. Here, we present the application of the SHeM to image bacterial biofilms. We demonstrate that the SHeM uniquely and natively visualises the surface of the extracellular polymeric substance matrix in the absence of contrast agents and dyes and without inducing radiative damage
Mucosal immune responses to Bordetella pertussis in Gambian infants after maternal and primary vaccination: an immunological substudy of a single-centre, randomised, controlled, double-blind, phase 4 trial.
Get PDFBACKGROUND: Mucosal protection against pertussis depends on antibodies and the activation of mucosal-resident memory T cells, both of which are differentially induced by acellular pertussis and whole-cell pertussis vaccines. We aimed to investigate the effect of primary vaccination with these two vaccine types on pertussis-specific mucosal immunity in infants after their mothers received an acellular pertussis-containing vaccine (tetanus-diphtheria-acellular pertussis-inactivated poliovirus; Tdap-IPV) or a tetanus-toxoid (TT)-only vaccine during pregnancy.
METHODS: This immunological substudy was embedded within the Gambian Pertussis Study (GaPs), a single-centre, randomised, controlled, double-blind, phase 4 trial conducted in The Gambia. In GaPs, healthy, pregnant participants aged 18-40 years were randomly assigned (1:1) to receive a pertussis-containing (Tdap-IPV) vaccine or a TT-only vaccine at 28-34 weeks' gestation, and their infants were randomly assigned (1:1) to receive a primary immunisation series comprising either a diphtheria-tetanus-whole-cell pertussis (DTwP) vaccine or a diphtheria-tetanus-acellular pertussis (DTaP) vaccine at the ages of 8, 12, and 16 weeks. Nasosorption devices were used to collect nasal mucosal lining fluid (MLF) from infants at the ages of 8, 16, 17, and 20 weeks, and 9 months. The immunological substudy was conducted in a subset of infants in the GaPs trial for whom MLF and paired cord blood and serum samples were available; outcomes were the concentrations of nasal anti-B pertussis IgG and IgA and anti-pertussis toxin IgG, before and after the DTaP or DTwP primary immunisation series at the ages of 8 weeks, 20 weeks, and 9 months, and the concentrations of nasal T-cell-associated cytokines at age 17 weeks. This study is registered with ClinicalTrials.gov, NCT03606096.
FINDINGS: This substudy included 160 infants enrolled in the main GaPs trial between Feb 13, 2019, and May 17, 2021. At age 8 weeks, before primary vaccination, infants born to mothers who had received the Tdap-IPV vaccine in pregnancy had higher concentrations of maternally derived nasal anti-pertussis toxin IgG (geometric mean ratio 3·84 [95% CI 3·22-4·59]; p<0·0001) and anti-B pertussis IgG (6·45 [5·94-7·01]; p<0·0001), but not IgA, than infants whose mothers received the TT vaccine in pregnancy. After primary vaccination, both groups of infants who received the DTwP vaccine had significantly higher geometric mean concentrations (GMCs) of nasal anti-B pertussis IgG than infants who received the DTaP vaccine (5·42 arbitrary units [AU] per mL [95% CI 3·79-7·75], p=0·0036 for the TT-DTwP group and 4·40 AU/mL [2·99-6·45], p=0·024 for the Tdap-IPV-DTwP group vs 2·16 AU/mL [1·40-3·32] for the Tdap-IPV-DTaP group). Furthermore, DTaP-vaccinated infants born to mothers who had received the Tdap-IPV vaccine in pregnancy had the lowest anti-B pertussis IgG concentrations, even those who had low concentrations of maternally derived antibodies pre-vaccination. Similarly, compared with TT immunisation, Tdap-IPV immunisation in pregnancy was associated with lower nasal anti-pertussis toxin IgG responses in infants after completion of both DTwP and DTaP primary immunisation series at age 20 weeks, although this blunting was more pronounced after DTwP vaccination (GMC 0·016 international units [IU] per mL [0·011-0·025] for the Tdap-IPV-DTwP group vs 0·073 IU/mL [0·044-0·120] for the TT-DTwP group [p=0·0002] and 0·021 IU/mL [0·014-0·032] for the Tdap-IPV-DTaP group vs 0·058 IU/mL [0·041-0·081] for the TT-DTaP group [p=0·0016]). Broad nasal T-cell-associated cytokine responses were observed after primary vaccination in DTwP-vaccinated but not DTaP-vaccinated infants, with no clear impact of the vaccine given in pregnancy.
INTERPRETATION: Tdap-IPV vaccination during pregnancy induces antibodies that are transferred across the placenta to reach the upper airway mucosa of the infant and could contribute to local protection. Although maternally derived antibodies modulate pertussis toxin-specific IgG responses to primary vaccination in the infant, those who received the DTwP vaccine consistently generated higher mucosal IgG to whole-cell B pertussis and showed stronger local cellular activation than those who received the DTaP vaccine, corroborating DTwP-specific mucosal effects identified from animal studies. Taken together, these findings provide mechanistic support for the established early-life protection conferred by immunisation during pregnancy and demonstrate the broader mucosal immunity elicited by DTwP vaccination, informing policy discussions on antenatal vaccination programmes and infant pertussis vaccination schedules. FUNDING: The Innovative Medicines Initiative 2 Joint Undertaking, Horizon 2020, European Federation of Pharmaceutical Industries and Associations, Gates Foundation, Wellcome Trust, and BactiVac
Stakeholder perceptions of political and economic factors influencing vaccination in two States with a high burden of zero-dose children in Nigeria.
No full textGlobally, an estimated 22.7 million children are unimmunized or 'zero-dose' (ZD), with 3.1 million in Nigeria. The political and economic environment plays a critical role in influencing the number of ZD and under-immunized children. We explored stakeholder perceptions of the political and economic context of vaccination services in Kano and Lagos States, two Nigerian States with a high number of ZD children. We conducted stakeholder mapping, followed by key informant interviews with 84 State, local, and community informants responsible for or influential in immunization. Transcripts were analyzed using a reflective thematic framework approach. We describe the multi-level network of domestic and international actors characterizing Nigeria's immunization policymaking and implementation landscape. Respondents perceived a strong and mutual political commitment by all actors involved in routine immunization. The pivotal role of local influencers further reinforced this commitment, from traditional to religious leaders, to improving uptake in challenging settings. Knowledge of national policies, and thus, perception of their adequacy in addressing under-immunization, was weakest among participants working at the local and community levels. Other reported barriers to policy implementation included bureaucratic delays in fund disbursement, outdated policies, slow dissemination of policies to local levels, and inadequate policy provisions for funding and staffing at the local level. To enhance equitable immunization coverage in Kano and Lagos, our findings suggest a need for meaningful engagement of community actors in policy development, timely policy revisions, and the establishment of mechanisms for expediting fund disbursements and addressing funding shortfalls at the local levels