When offering a patient beneficial treatment undermines public health.

Sometimes, offering someone beneficial care is likely to thwart the similar or more serious medical needs of more people. For example, when acute shortage is strongly predicted to persist, providing the long period on scarce intensive care that a certain COVID-19 patient needs is sometimes projected to block several future COVID-19 patients from receiving the shorter periods on intensive care that they will need. Expected utility is typically higher if the former is denied intensive care. A tempting initial account of such cases is that consequentialism supports denying care to that patient and nonconsequentialism supports providing that care. This paper argues that the consequentialist case is more complicated than it may initially seem and that nonconsequentialism sides more readily with denial of the beneficial treatment. It also shows that when denying it would directly enhance public health by a lot, either ethical approach would normally recommend denying it. Practical implications are discussed, including how to address conscientious objection to this shared recommendation.

Detecting Mycobacterium tuberculosis Infection in Children Migrating to Australia.

In 2015, Australia updated premigration screening for tuberculosis (TB) disease in children 2-10 years of age to include testing for infection with Mycobacterium tuberculosis and enable detection of latent TB infection (LTBI). We analyzed TB screening results in children <15 years of age during November 2015-June 2017. We found 45,060 child applicants were tested with interferon-gamma release assay (IGRA) (57.7% of tests) or tuberculin skin test (TST) (42.3% of tests). A total of 21 cases of TB were diagnosed: 4 without IGRA or TST, 10 with positive IGRA or TST, and 7 with negative results. LTBI was detected in 3.3% (1,473/44,709) of children, for 30 applicants screened per LTBI case detected. LTBI-associated factors included increasing age, TB contact, origin from a higher TB prevalence region, and testing by TST. Detection of TB and LTBI benefit children, but the updated screening program's effect on TB in Australia is likely to be limited.

The impact of point-of-care hepatitis C testing in needle and syringe exchange programs on linkage to care and treatment uptake among people who inject drugs: An Australian pilot study.

Point-of-care (POC) diagnostics overcome barriers to conventional hepatitis C (HCV) testing in people who inject drugs. This study assessed impact on hepatitis C treatment uptake of POC HCV testing in needle and syringe exchange programs (NSPs). Rapid EC was a single-arm interventional pilot study of HCV POC testing conducted in three inner-city community clinics with NSPs. Twelve months after the POC testing, a retrospective medical record and Pharmaceutical Benefits Scheme audit was performed to determine the number of HCV RNA-positive participants who were prescribed HCV treatment. 70 HCV RNA-positive Rapid EC study participants were included. 44 (63%) were prescribed DAAs; 26 (59%) completed treatment and 15 (34%) had SVR testing, all of whom were cured. Age ≥ 40 years (aOR 3.45, 95% CI 1.10-11.05, p = .03) and secondary school education (aOR 5.8, 95% CI 1.54-21.80, p = .009) had higher likelihood of being prescribed DAAs, whereas homelessness was inversely associated with prescription of DAAs (aOR 0.30, 95% CI 0.09-1.04, p = .057). Median time to receive a DAA script from date of diagnosis was seven days (IQR 0 to 14 days), and time to filling the DAA prescription was 2 days (IQR 0-12 days). In conclusion, provision of POC testing through NSPs was effective for linking new clients to HCV treatment and reduced the time to treatment. Further studies are needed to define the most cost-effective use of POC testing in models of care for people who inject drugs to increase HCV treatment uptake.

Timing of Mycobacterium tuberculosis exposure explains variation in BCG effectiveness: a systematic review and meta-analysis.

RATIONALE: The heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure. METHODS: We updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context. MAIN RESULTS: Of 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings with longer follow-up showed no protection, sometimes with higher case rates in the vaccinated than the controls in the later follow-up period. CONCLUSIONS: The most plausible explanatory hypothesis for these results is that BCG protects against TB that results from exposure shortly after vaccination. However, we found no evidence of protection when exposure occurs later from vaccination, which would be of greater importance in trials in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection observed for many years thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines with repeated exposure to Mycobacterium tuberculosis or other pathogens.

Ethics of selective restriction of liberty in a pandemic.

Liberty-restricting measures have been implemented for centuries to limit the spread of infectious diseases. This article considers if and when it may be ethically acceptable to impose selective liberty-restricting measures in order to reduce the negative impacts of a pandemic by preventing particularly vulnerable groups of the community from contracting the disease. We argue that the commonly accepted explanation-that liberty restrictions may be justified to prevent harm to others when this is the least restrictive option-fails to adequately accommodate the complexity of the issue or the difficult choices that must be made, as illustrated by the COVID-19 pandemic. We introduce a dualist consequentialist approach, weighing utility at both a population and individual level, which may provide a better framework for considering the justification for liberty restrictions. While liberty-restricting measures may be justified on the basis of significant benefits to the population and small costs for overall utility to individuals, the question of whether it is acceptable to discriminate should be considered separately. This is because the consequentialist approach does not adequately account for the value of equality. This value may be protected through the application of an additional proportionality test. An algorithm for making decisions is proposed. Ultimately whether selective liberty-restricting measures are imposed will depend on a range of factors, including how widespread infection is in the community, the level of risk and harm a society is willing to accept, and the efficacy and cost of other mitigation options.

Modelling insights into the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that was declared a pandemic by the World Health Organization on 11th March, 2020. Response to this ongoing pandemic requires extensive collaboration across the scientific community in an attempt to contain its impact and limit further transmission. Mathematical modelling has been at the forefront of these response efforts by: (1) providing initial estimates of the SARS-CoV-2 reproduction rate, R0 (of approximately 2-3); (2) updating these estimates following the implementation of various interventions (with significantly reduced, often sub-critical, transmission rates); (3) assessing the potential for global spread before significant case numbers had been reported internationally; and (4) quantifying the expected disease severity and burden of COVID-19, indicating that the likely true infection rate is often orders of magnitude greater than estimates based on confirmed case counts alone. In this review, we highlight the critical role played by mathematical modelling to understand COVID-19 thus far, the challenges posed by data availability and uncertainty, and the continuing utility of modelling-based approaches to guide decision making and inform the public health response. †Unless otherwise stated, all bracketed error margins correspond to the 95% credible interval (CrI) for reported estimates.

Role of modelling in COVID-19 policy development.

Models have played an important role in policy development to address the COVID-19 outbreak from its emergence in China to the current global pandemic. Early projections of international spread influenced travel restrictions and border closures. Model projections based on the virus's infectiousness demonstrated its pandemic potential, which guided the global response to and prepared countries for increases in hospitalisations and deaths. Tracking the impact of distancing and movement policies and behaviour changes has been critical in evaluating these decisions. Models have provided insights into the epidemiological differences between higher and lower income countries, as well as vulnerable population groups within countries to help design fit-for-purpose policies. Economic evaluation and policies have combined epidemic models and traditional economic models to address the economic consequences of COVID-19, which have informed policy calls for easing restrictions. Social contact and mobility models have allowed evaluation of the pathways to safely relax mobility restrictions and distancing measures. Finally, models can consider future end-game scenarios, including how suppression can be achieved and the impact of different vaccination strategies.

Passport to freedom? Immunity passports for COVID-19.

The COVID-19 pandemic has led a number of countries to introduce restrictive 'lockdown' policies on their citizens in order to control infection spread. Immunity passports have been proposed as a way of easing the harms of such policies, and could be used in conjunction with other strategies for infection control. These passports would permit those who test positive for COVID-19 antibodies to return to some of their normal behaviours, such as travelling more freely and returning to work. The introduction of immunity passports raises a number of practical and ethical challenges. In this paper, we seek to review the challenges relating to various practical considerations, fairness issues, the risk to social cooperation and the impact on people's civil liberties. We make tentative recommendations for the ethical introduction of immunity passports.

Community-based, point-of-care hepatitis C testing: perspectives and preferences of people who inject drugs.

A barrier to hepatitis C treatment for people who inject drugs (PWID) is needing to attend multiple appointments for diagnosis. Point-of-care hepatitis C tests provide results within 20 to 105 minutes and can be offered opportunistically in nonclinical settings such as needle syringe programmes. In this nested qualitative study, we explored the acceptability of point-of-care testing for PWID. PWID attending participating needle syringe programmes were screened using the OraQuick HCV antibody mouth swab (result in 20 minutes); those with a reactive result then underwent venepuncture for a point-of-care RNA test: the Xpert HCV Viral Load (result in 105 minutes). Convenience sampling was used to select participants for a semi-structured interview. A hybrid thematic analysis was performed, guided by Sekhon's "Theoretical Framework of Acceptability." Nineteen participants were interviewed. Three core themes emerged: "people and place," "method of specimen collection," and "rapidity of result return." It was highly acceptable to be offered testing at the needle syringeprogrammes by nurses and community health workers, who were described as competent and nonjudgemental. Most participants reported that even if a finger-stick point-of-care RNA test were an option in the future, they would prefer venepuncture, as the sample could be used for pre-treatment workup and bundled testing. Waiting 20 minutes to receive the antibody test result was acceptable, whereas the 105 minutes required for the RNA result was unacceptable. Offering point-of-care hepatitis C testing at needle syringe programmes is acceptable to PWID, however tests that avoid venepuncture are not necessarily the most attractive to PWID.

Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity.

Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as 'topoisomerase poisoning'. We discovered that two novel fluoroquinolones having aryl functionality at the N-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA complexes, i.e., without poisoning it. Surprisingly, these compounds are more effective in inhibiting the catalytic activities of human and bacterial topoisomerase I. The National Cancer Institute's 60 human tumor cell lines screen revealed significant anti-proliferative activities with 217 and 227 against the majority of 60 cancer cell lines. A proof of concept in vivo efficacy study using an HT-29 xenograft model of human colorectal cancer showed that 217 could inhibit the proliferation of human colorectal cancer cells to a degree comparable to fluorouracil in mice. Although 227 also exhibited anti-proliferative activity, it was not as effective as 217 in this xenograft model. These novel fluoroquinolones may serve as promising lead compounds for the development of new anticancer drugs.

Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase.

Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-1 position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-1 position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II.

Using PDSA cycles to improve oral care compliance.

Oral care has been shown to reduce healthcare-associated pneumonia (HAP) rates, however, compliance with this practice is suboptimal. Using quality improvement PDSA cycles over an 8-week period, we saw improvements in oral care documentation compliance through statistical process control charts; HAP rates did not significantly decrease. Infection prevention leadership should consider regularly incorporating PDSA cycles to improve compliance with evidence-based infection prevention practices.

The Ethics of Selective Mandatory Vaccination for COVID-19.

With evidence of vaccine hesitancy in several jurisdictions, the option of making COVID-19 vaccination mandatory requires consideration. In this paper I argue that it would be ethical to make the COVID-19 vaccination mandatory for older people who are at highest risk of severe disease, but if this were to occur, and while there is limited knowledge of the disease and vaccines, there are not likely to be sufficient grounds to mandate vaccination for those at lower risk. Mandating vaccination for those at high risk of severe disease is justified on the basis of the harm principle, as there is evidence that this would remove the grave public health threat of COVID-19. The risk-benefit profile of vaccination is also more clearly in the interests of those at highest risk, so mandatory vaccination entails a less severe cost to them. Therefore, a selective mandate would create fairness in the distribution of risks. The level of coercion imposed by a mandate would need to be proportionate, and it is likely that multiple approaches will be needed to increase vaccine uptake. However, a selective mandate for COVID-19 vaccines is likely to be an ethical choice and should be considered by policy-makers.

Estimating the long-term effects of mass screening for latent and active tuberculosis in the Marshall Islands.

BACKGROUND: Ambitious population-based screening programmes for latent and active tuberculosis (TB) were implemented in the Republic of the Marshall Islands in 2017 and 2018. METHODS: We used a transmission dynamic model of TB informed by local data to capture the Marshall Islands epidemic's historical dynamics. We then used the model to project the future epidemic trajectory following the active screening interventions, as well as considering a counterfactual scenario with no intervention. We also simulated future scenarios including periodic interventions similar to those previously implemented, to assess their ability to reach the End TB Strategy targets and TB pre-elimination in the Marshall Islands. RESULTS: The screening activities conducted in 2017 and 2018 were estimated to have reduced TB incidence and mortality by around one-third in 2020, and are predicted to achieve the End TB Strategy milestone of 50% incidence reduction by 2025 compared with 2015. Screening interventions had a considerably greater impact when latent TB screening and treatment were included, compared with active case finding alone. Such combined programmes implemented at the national level could achieve TB pre-elimination around 2040 if repeated every 2 years. CONCLUSIONS: Our model suggests that it would be possible to achieve TB pre-elimination by 2040 in the Marshall Islands through frequent repetition of the same interventions as those already implemented in the country. It also highlights the importance of including latent infection testing in active screening activities.

Early epidemiological investigations: World Health Organization UNITY protocols provide a standardized and timely international investigation framework during the COVID-19 pandemic.

BACKGROUND: The declaration of Coronavirus disease 2019 (COVID-19) as a Public Health Emergency of International Concern (PHEIC) on 30 January 2020 required rapid implementation of early investigations to inform appropriate national and global public health actions. METHODS: The suite of existing pandemic preparedness generic epidemiological early investigation protocols was rapidly adapted for COVID-19, branded the 'UNITY studies' and promoted globally for the implementation of standardized and quality studies. Ten protocols were developed investigating household (HH) transmission, the first few cases (FFX), population seroprevalence (SEROPREV), health facilities transmission (n = 2), vaccine effectiveness (n = 2), pregnancy outcomes and transmission, school transmission, and surface contamination. Implementation was supported by WHO and its partners globally, with emphasis to support building surveillance and research capacities in low- and middle-income countries (LMIC). RESULTS: WHO generic protocols were rapidly developed and published on the WHO website, 5/10 protocols within the first 3 months of the response. As of 30 June 2021, 172 investigations were implemented by 97 countries, of which 62 (64%) were LMIC. The majority of countries implemented population seroprevalence (71 countries) and first few cases/household transmission (37 countries) studies. CONCLUSION: The widespread adoption of UNITY protocols across all WHO regions indicates that they addressed subnational and national needs to support local public health decision-making to prevent and control the pandemic.

Tuberculosis in migrants to Australia: Outcomes of a national screening program.

BACKGROUND: Few low-incidence countries are on track to achieve the ambitious target of reaching TB pre-elimination by 2035. Australia is a high-income country with a low burden of TB, which is particularly concentrated in migrant populations. As part of Australia's migration program, permanent, provisional and humanitarian visa applicants are screened for TB, along with some applicants for temporary visas. METHODS: We calculated the prevalence of all forms of active TB and bacteriologically-confirmed TB among onshore and offshore applicants for visas to Australia from July 2014 to June 2017, and investigated associated risk factors using logistic regression. FINDINGS: Visa applicants were predominantly young adults from various Asian countries. Among 2,381,217 applicants, 1263 cases of active TB were diagnosed, including 852 cases of bacteriologically-confirmed TB. Overall TB prevalence was 53.0 per 100,000, corresponding to one TB diagnosis for every 1887 applicants screened. TB rates increased with age and were higher among humanitarian applicants and those previously treated for TB, although most cases occurred in applicants without these risk factors. TB prevalence by country of origin was similar to WHO estimates for some countries, but considerably lower for others. For several highly represented countries of origin, rates appear to have fallen relative to earlier comparable studies. INTERPRETATION: Prevalence of TB among visa applicants to Australia and the consequent risk to the Australian community appear to be declining and remain low. In this context, support for TB control programs overseas and preventive interventions are likely to have the greatest impact on domestic TB burden. FUNDING: No specific funding was received for this study. JMT is a recipient of an Early Career Fellowship from the Australian National Health and Medical Research Council (APP1142638).

Point-of-care hepatitis C testing from needle and syringe programs: An Australian feasibility study.

BACKGROUND: Achieving hepatitis C elimination requires novel approaches to engage people at highest risk of infection into care pathways. Point-of-care-tests may help to overcome some of the barriers preventing people who inject drugs (PWID) accessing testing and progressing to treatment for hepatitis C virus (HCV). We assessed the feasibility and acceptability of HCV point-of-care testing at needle and syringe exchange programs (NSPs) co-located in three community health clinics in Melbourne, Australia. METHODS: NSP clients were offered an oral fluid point-of-care test for HCV antibody by NSP staff. Positive HCV antibody tests were followed by a point-of-care test for HCV RNA alongside standard-of-care laboratory testing for hepatitis C treatment work-up. Participants were offered same-day point-of-care results on site, via phone or text message, or upon return to the service. Participants were scheduled for follow-up review with the study nurse for assessment and linkage to treatment. RESULTS: A total of 174 participants completed HCV antibody point-of-care test; 150 (86%) had a reactive result. Of these, 140 (93%) underwent a HCV RNA point-of-care test and 76 (54%) tested positive; few participants (5%) waited on site for results delivery, but the majority of RNA positive (63%) attended a follow-up visit for treatment work-up (median time to follow-up visit = 11 days; IQR = 7-20 days). The majority of participants reported a preference for point-of-care tests (66%) and supported NSP staff involvement in testing (90%). CONCLUSION: Provision of HCV point-of-care tests, follow-up and linkage to treatment services through NSPs was feasible and acceptable to PWID. Despite few participants waiting to receive same-day results, there was effective linkage to care, suggesting value in further evaluation of this approach.

Historical trends in publications in the International Journal of Epidemiology.

BACKGROUND: This study aimed to provide a detailed insight into the nature of the content published in the International Journal of Epidemiology (IJE) over its history. METHODS: This study reviewed five complete volumes of the IJE at 10-year intervals (1976, 1986, 1996, 2006 and 2016). Information was extracted for 628 articles considered to be most representative of the content of the IJE, with detailed information analysed for 435 articles identified as original research articles. RESULTS: Over time, the number of articles published per issue and per year increased and the number of authors per article increased. Cohort studies were consistently the most common study type. The majority of first authors and two-thirds of the populations studied were from high-income countries, although there was a clear trend over time towards more studies investigating multiple countries. Within original research articles, neoplasms (17%), infectious and parasitic diseases (14%) and diseases of the circulatory system (12%) were the most common disease type studied in original research articles (but the study topics varied between low-income and high-income countries); and socioeconomic factors (17%), environmental factors (15%) and biological factors and behaviours (both 12%) were the most common study factors. The topics of articles generally had good correlation with the global burden of disease, both overall and within geographical regions studied, but mental health and musculoskeletal disorders were notable omissions. CONCLUSIONS: Working to increase publications from low- and middle-income groups, and studies covering areas such as mental health and musculoskeletal disorders, should be considered.

Mre 11 p nuclease activity is dispensable for telomeric rapid deletion.

Telomeric rapid deletion (TRD) is an intrachromatid recombination process that truncates over-elongated telomeres to the genetically determined average telomere length. We have proposed that TRD is initiated by invasion of the 3' G-rich overhang into centromere-proximal telomere sequence, forming an intermediate that leads to excision of the distal telomere tract. TRD efficiency is dependent on Mre 11p and Rad50p, two members of the widely conserved Mre 11p/Rad50p/Xrs2p (MRX) complex. To investigate the role of Mre 11p in TRD, we conducted a structure/function analysis by testing the TRD rate and precision of mutations within known functional domains. We analyzed 12 alleles that disrupt different Mre 11p activities. Surprisingly, mutations in essential residues of the nuclease domain do not inhibit TRD, effectively ruling out nuclease activity as the source of the Mre 11p requirement. Interestingly, loss of Exo1p alone or loss of Exo1p in an Mre 11 nuclease deficient background does not eliminate TRD, suggesting the presence of an additional nuclease. Second, deletion of DNA binding sites A (residues 410--420) and B (residues 644--692) actually enhances the TRD rate. Even deletion of both DNA binding domains does not abrogate TRD, although its kinetics and precision are variable. This suggests altered DNA binding or a conformational defect in the MRX complex may affect the rate of TRD product formation and indicates that the DNA binding sites formally act as repressors of TRD. Remarkably, the H213Y allele (nuclease motif IV) confers an extraordinarily rapid kinetics, with the vast majority of elongated telomeres deleted imprecisely in a single round of subculturing. In striking contrast, the P162S allele that confers dissolution of the complex also exhibits the null phenotype. These data suggest that Mre 11p can act as a positive and negative regulator of TRD in context of the MRX complex that is essential for TRD.