The United States Needs A Better Testing Playbook For Future Public Health Emergencies.

The absence of a comprehensive national playbook for developing and deploying testing has hindered the United States' ability to rapidly suppress recent biological emergencies (for example, the COVID-19 pandemic and outbreaks of mpox). We describe here the Testing Playbook for Biological Emergencies, a national testing playbook we developed. It includes a set of decisions and actions for US officials to take at specific times during infectious disease emergencies to implement testing rapidly and to ensure that available testing meets clinical and public health needs. Although the United States had multiple plans at the federal level for responding to pandemic threats, US leaders were unable to quickly and efficiently operationalize those plans to deploy different types of tests during the COVID-19 pandemic in 2020-21, and again during the US mpox outbreak in 2022. The playbook fills a critical gap by providing the necessary specific and adaptable guidance for decision makers to meet this need.

Valuing adaptive programming: A study of resilience processes and outcomes.

Recent decades have seen a growth in theoretical frameworks focusing on systems, context and the dynamic interplay of multiple variables, stimulating interest in complementary research and programme evaluation methods. With resilience theory now emphasising the complex and dynamic nature of resilience capacities, processes and outcomes, resilience programming stands to benefit from approaches such as design-based research and realist research/evaluation. The aim of this collaborative (researcher/practitioner) study was to explore how such benefits can be achieved when programme theory spans individual, community and institutional outcomes, with a focus on the reciprocal processes involved in effecting change across the social system. The context of the research was a regional (Middle East and North Africa) project operating in contexts with an escalated risk of marginalised young people being drawn into illegal/harmful activity. The project's youth engagement and development approach combined participatory learning, skills training, and collective social action, adapted for diverse localities and during the COVID-19 crisis. Quantitative measures of individual and collective resilience were at the centre of a set of realist analyses evidencing systemic connections in changes to individual, collective and community resilience. Findings demonstrated the value, challenges and limitations of the applied research approach for adaptive, contextualised programming.

Planning For The Next Pandemic: Lab Systems Need Policy Shift To Speed Emerging Infectious Disease Warning And Tracking.

Early detection and ongoing monitoring of infectious diseases depends on diagnostic testing. The US has a large, diverse system of public, academic, and private laboratories that develop new diagnostic tests; perform routine testing; and conduct specialized reference testing, such as genomic sequencing. These laboratories operate under a complex mix of laws and regulations at the federal, state, and local levels. The COVID-19 pandemic exposed major weaknesses in the nation's laboratory system, some of which were seen again during the global mpox outbreak in 2022. In this article we review how the US laboratory system has been designed to detect and monitor emerging infections, describe what gaps were revealed during COVID-19, and propose specific steps that policy makers can take both to strengthen the current system and to prepare the US for the next pandemic.

Using a learning health system to understand the mismatch between medicines supply and actual medicines use among adults with cystic fibrosis.

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply. METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency. RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%. CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.

An investigation into hospital prescribers' knowledge and confidence to provide high-quality, sustainable respiratory care.

The number and range of inhaler combinations and brand names has increased significantly over recent years, making prescribing more complex. Inhalers contribute 3% of the NHS's carbon footprint, therefore appropriate inhaler prescribing, use and disposal could contribute significantly towards the NHS's target of net zero carbon emissions by 2040. We developed a survey to assess prescriber knowledge of inhaled medications, inhalation devices and environmental impacts of inhalers. One-hundred and two secondary care prescribers from one NHS trust responded. Knowledge of the contents and device types of inhalers, and of the environmental impacts of inhalers was lacking. Only 9% of respondents discuss the environmental impact of inhalers with patients and 13% have discussed inhaler disposal with patients, but 46% of respondents expressed that they would educate patients about the environmental impacts of inhalers if they were provided with education and support to do so.

Evaluation of four sampling devices for Burkholderia pseudomallei laboratory aerosol studies.

Previous field and laboratory studies investigating airborne Burkholderia pseudomallei have used a variety of different aerosol samplers to detect and quantify concentrations of the bacteria in aerosols. However, the performance of aerosol samplers can vary in their ability to preserve the viability of collected microorganisms, depending on the resistance of the organisms to impaction, desiccation, or other stresses associated with the sampling process. Consequently, sampler selection is critical to maximizing the probability of detecting viable microorganisms in collected air samples in field studies and for accurate determination of aerosol concentrations in laboratory studies. To inform such decisions, the present study assessed the performance of four laboratory aerosol samplers, specifically the all-glass impinger (AGI), gelatin filter, midget impinger, and Mercer cascade impactor, for collecting aerosols containing B. pseudomallei generated from suspensions in two types of culture media. The results suggest that the relative performance of the sampling devices is dependent on the suspension medium utilized for aerosolization. Performance across the four samplers was similar for aerosols generated from suspensions supplemented with 4% glycerol. However, for aerosols generated from suspensions without glycerol, use of the filter sampler or an impactor resulted in significantly lower estimates of the viable aerosol concentration than those obtained with either the AGI or midget impinger. These results demonstrate that sampler selection has the potential to affect estimation of doses in inhalational animal models of melioidosis, as well as the likelihood of detection of viable B. pseudomallei in the environment, and will be useful to inform design of future laboratory and field studies.

Influence of aerodynamic particle size on botulinum neurotoxin potency in mice.

OBJECTIVE: For many agents, the aerodynamic particle size can affect both the virulence and disease course in animal models. Botulinum neurotoxins (BoNTs), which are widely known as potential bioterrorism agents, have been shown to be toxic via multiple routes of exposure, including small particle inhalation (1-3 µm MMAD). However, the impact of larger particle sizes on the potency of BoNT has not been previously reported. In this study, we compared the potency of BoNT in small and large particle aerosols. MATERIALS AND METHODS: Outbred mice (ICR (CD-1®)) were exposed to BoNT-containing aerosols with differing mass median aerodynamic diameters (MMADs) of 1.1, 4.9, and 7.6 microns. The effects of bioaerosol sampler and inhalation exposure modality were studied. RESULTS AND DISCUSSION: Collecting aerosolized BoNT onto gelatin filters or into liquid impingers resulted in equivalent estimates of aerosol concentration. Nose-only and whole-body inhalation exposure resulted in nearly identical estimates of the median lethal dose (LD50). The LD50 for inhaled BoNT increased approximately 50-fold when the median aerodynamic particle size was increased from 1.1 to 4.9 µm, from 139 (95% CI: 111-185) to 7324 (95% CI: 4287-10 891) mouse intraperitoneal median lethal doses (MIPLD50). These results demonstrate the importance of aerodynamic particle size and regional deposition patterns with regards to BoNT inhalational toxicity. CONCLUSIONS: These data will be useful for medical countermeasure development, as well as biodefense preparedness modeling by demonstrating that the estimates of dose and toxicity of an inhaled aerosol containing BoNT can be significantly affected by a range of factors.

Neutralizing Antibody Responses in COVID-19 Convalescent Sera.

Passive transfer of antibodies from COVID-19 convalescent patients is being used as an experimental treatment for eligible patients with SARS-CoV-2 infections. The United States Food and Drug Administration's (FDA) guidelines for convalescent plasma initially recommended target antibody titers of 160. We evaluated SARS-CoV-2 neutralizing antibodies in sera from recovered COVID-19 patients using plaque reduction neutralization tests (PRNT) at moderate (PRNT50) and high (PRNT90) stringency thresholds. We found that neutralizing activity significantly increased with time post symptom onset (PSO), reaching a peak at 31-35 days PSO. At this point, the number of sera having neutralizing titers of at least 160 was approximately 93% (PRNT50) and approximately 54% (PRNT90). Sera with high SARS-CoV-2 antibody levels (>960 enzyme-linked immunosorbent assay titers) showed maximal activity, but not all high-titer sera contained neutralizing antibody at FDA recommended levels, particularly at high stringency. These results underscore the value of serum characterization for neutralization activity.

Childhood eye cancer from a parental perspective: The lived experience of parents with children who have had retinoblastoma.

OBJECTIVES: This study aimed to explore the lived experience of parents with children who have had retinoblastoma. METHODS: The study adopted a qualitative approach using the data collection method of written accounts. Eleven parents were recruited via snowball sampling from across the UK. Parents were asked to retrospectively produce a written account of their experiences. These narrative autobiographical accounts were analysed using thematic analysis. RESULTS: Data analysis elicited three themes: waiting and misdiagnosis; emotional rollercoaster; and support needs. Parents described experiencing prolonged periods of waiting from referral to clinical investigations and the implementation of a treatment plan. Difficulties in obtaining an accurate diagnosis for their child elicited anxiety for parents. Emotions were described in terms of a rollercoaster with highs and lows and times of despair, anger, relief, and hope. Experiences of personal support varied and had lasting impacts on relationships. However, the support from other parents with a child with retinoblastoma was perceived to be instrumental in facilitating coping. CONCLUSIONS: The findings show parental experiences were characterised by numerous difficulties and suggest a need for greater awareness of childhood eye cancer. This research highlights the importance of psychological and social support for parents of a child with retinoblastoma.

Pathogen Genomics in Public Health.

Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease. This momentum is likely to continue, given the ongoing development in sequencing and sequencing-related technologies.

Simultaneous detection of genotype and phenotype enables rapid and accurate antibiotic susceptibility determination.

Multidrug resistant organisms are a serious threat to human health1,2. Fast, accurate antibiotic susceptibility testing (AST) is a critical need in addressing escalating antibiotic resistance, since delays in identifying multidrug resistant organisms increase mortality3,4 and use of broad-spectrum antibiotics, further selecting for resistant organisms. Yet current growth-based AST assays, such as broth microdilution5, require several days before informing key clinical decisions. Rapid AST would transform the care of patients with infection while ensuring that our antibiotic arsenal is deployed as efficiently as possible. Growth-based assays are fundamentally constrained in speed by doubling time of the pathogen, and genotypic assays are limited by the ever-growing diversity and complexity of bacterial antibiotic resistance mechanisms. Here we describe a rapid assay for combined genotypic and phenotypic AST through RNA detection, GoPhAST-R, that classifies strains with 94-99% accuracy by coupling machine learning analysis of early antibiotic-induced transcriptional changes with simultaneous detection of key genetic resistance determinants to increase accuracy of resistance detection, facilitate molecular epidemiology and enable early detection of emerging resistance mechanisms. This two-pronged approach provides phenotypic AST 24-36 h faster than standard workflows, with <4 h assay time on a pilot instrument for hybridization-based multiplexed RNA detection implemented directly from positive blood cultures.

Using our understanding of time to increase self-efficacy towards goal achievement.

This paper reports two studies that uniquely explore how time perspective (TP) predicts general self-efficacy (GSE) towards goal achievement. In Study 1, participants (N = 162) identified a goal they wished to achieve within the near future then completed questionnaires. For those who achieved their goal, the 'past positive' and 'future' TPs were found to positively predict GSE, whereas 'present fatalism' negatively predicted GSE. Study 2 explored whether accessing time related information that may not normally be used to determine GSE via a writing intervention can promote both near and distant-future goal achievement. Participants (N = 139) were randomly assigned to one of four writing conditions and results reveal that GSE towards goal achievement can increase with a focus on both a 'positive past' with a projective positive 'future' TP. Thus, focusing on particular TPs may function to enhance (or prevent) goal achievement.

Comprehensive Whole-Genome Sequencing and Reporting of Drug Resistance Profiles on Clinical Cases of Mycobacterium tuberculosis in New York State.

Whole-genome sequencing (WGS) is a newer alternative for tuberculosis (TB) diagnostics and is capable of providing rapid drug resistance profiles while performing species identification and capturing the data necessary for genotyping. Our laboratory developed and validated a comprehensive and sensitive WGS assay to characterize Mycobacterium tuberculosis and other M. tuberculosis complex (MTBC) strains, composed of a novel DNA extraction, optimized library preparation, paired-end WGS, and an in-house-developed bioinformatics pipeline. This new assay was assessed using 608 MTBC isolates, with 146 isolates during the validation portion of this study and 462 samples received prospectively. In February 2016, this assay was implemented to test all clinical cases of MTBC in New York State, including isolates and early positive Bactec mycobacterial growth indicator tube (MGIT) 960 cultures from primary specimens. Since the inception of the assay, we have assessed the accuracy of identification of MTBC strains to the species level, concordance with culture-based drug susceptibility testing (DST), and turnaround time. Species identification by WGS was determined to be 99% accurate. Concordance between drug resistance profiles generated by WGS and culture-based DST methods was 96% for eight drugs, with an average resistance-predictive value of 93% and susceptible-predictive value of 96%. This single comprehensive WGS assay has replaced seven molecular assays and has resulted in resistance profiles being reported to physicians an average of 9 days sooner than with culture-based DST for first-line drugs and 32 days sooner for second-line drugs.

A Large Community Outbreak of Legionnaires' Disease Associated With a Cooling Tower in New York City, 2015.

OBJECTIVES: Infections caused by Legionella are the leading cause of waterborne disease outbreaks in the United States. We investigated a large outbreak of Legionnaires' disease in New York City in summer 2015 to characterize patients, risk factors for mortality, and environmental exposures. METHODS: We defined cases as patients with pneumonia and laboratory evidence of Legionella infection from July 2 through August 3, 2015, and with a history of residing in or visiting 1 of several South Bronx neighborhoods of New York City. We describe the epidemiologic, environmental, and laboratory investigation that identified the source of the outbreak. RESULTS: We identified 138 patients with outbreak-related Legionnaires' disease, 16 of whom died. The median age of patients was 55. A total of 107 patients had a chronic health condition, including 43 with diabetes, 40 with alcoholism, and 24 with HIV infection. We tested 55 cooling towers for Legionella, and 2 had a strain indistinguishable by pulsed-field gel electrophoresis from 26 patient isolates. Whole-genome sequencing and epidemiologic evidence implicated 1 cooling tower as the source of the outbreak. CONCLUSIONS: A large outbreak of Legionnaires' disease caused by a cooling tower occurred in a medically vulnerable community. The outbreak prompted enactment of a new city law on the operation and maintenance of cooling towers. Ongoing surveillance and evaluation of cooling tower process controls will determine if the new law reduces the incidence of Legionnaires' disease in New York City.

Zika Virus Testing Considerations: Lessons Learned from the First 80 Real-Time Reverse Transcription-PCR-Positive Cases Diagnosed in New York State.

The performance and interpretation of laboratory tests for Zika virus (ZKV) continue to be evaluated. Serology is cross-reactive, laborious, and frequently difficult to interpret, and serum was initially solely recommended for molecular diagnosis. ZKV testing was initiated in January 2016 in New York State for symptomatic patients, pregnant women, their infants, and patients with Guillain-Barré syndrome who had traveled to areas with ZKV transmission. Subsequently, eligibility was expanded to pregnant women with sexual partners with similar travel histories. Serum and urine collected within 4 weeks of symptom onset or within 6 weeks of travel were tested with real-time reverse transcription-PCR (RT-PCR) assays targeting the ZKV envelope and NS2B genes. In this review of lessons learned from the first 80 positive cases in NYS, ZKV RNA was detected in urine only in 50 patients, in serum only in 19 patients, and in both samples concurrently in 11 patients, with average viral loads in urine a log higher than those in serum. Among 93 positive samples from the 80 patients, 41 were positive on both gene assays, 52 were positive on the envelope only, and none were positive on the NS2B only. Of the 80 infected patients, test results for 74 (93%) would have defined their infection status as not detected or equivocal if the requirement for positive results from two assay targets (two-target-positive requirement) in the initial federal guidance to public health laboratories was enforced, if urine was not tested, or if the extended eligibility time for molecular testing was not implemented. These changes facilitated more extensive molecular diagnosis of ZKV, reducing reliance on time-consuming and potentially inconclusive serology.

Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918.

The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized.