Immunisation and the law : slippery slope to a healthy society

The immunisation of children against communicable diseases is a crucial public health intervention with both individual and collective outcomes. Current New Zealand immunisation policy prioritises parental autonomy, but has not succeeded in actively targeting all of the factors that prevent parents from ever making informed immunisation decisions. Consequently, our coverage rates are unsatisfactory both in absolute (by reference to the goal of 'population immunity') and relative terms. In order to have a realistic chance of meeting the Ministry of Health's optimistic coverage targets, it is necessary to consider whether New Zealand's comparatively weak immunisation law could be strengthened to eliminate the phenomenon of 'passive' non-immunisation without fatally undermining the decision-making capacity of parents. If this is not possible, then either the goal of population immunity or the prioritisation of individual choice must be abandoned. Of the three options for law reform explored by this paper, two are thought to be unworkable because they would, or should, be perceived as failing to achieve the delicate balance between individual freedom and public good. These are, first, a universal mandatory immunisation requirement, which may be justifiable in principle but would almost certainly encounter prohibitive public opposition; and, secondly, a targeted law that would require beneficiaries to make active decisions about immunisation, and (it is submitted) represents an unwarranted misuse of the vulnerability of those dependent upon taxpayer support. The reform option recommended is more moderate and more equitable. Creating a legal presumption in favour of immunisation, at the point of entry into primary school, would shift New Zealand from its current paradigm of 'informed consent' - whereby parents must actively opt in to immunisation - to a United States-style model that required parents who wished to opt out of immunisation to undergo a 'informed refusal' process. The stringency of this process would depend upon the degree to which policy-makers were satisfied that only those parents whose deeply held convictions prevented them from being open to persuasion were attempting to invoke it. Unless the size of the anti-immunisation lobby significantly increases, it is suggested that an informed refusal requirement could successfully tackle the problem of passive non-immunisation, thereby discharging the State's responsibility to further the interest of all New Zealanders in achieving and maintaining population immunity levels

The IASLC Lung Cancer Staging Project: A Renewed Call to Participation

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

International audienceAbstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 )

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Placing changes in the microbiome in the context of the American Gut. We accumulated samples over sequencing runs to demonstrate the structural consistency in the data. We demonstrate that while the ICU dataset (https://www.ncbi.nlm.nih.gov/pubmed/27602409) falls within the American Gut samples, they do not fall close to most samples at any of the body sites. We then highlight samples from the United Kingdom, Australia, the United States and other countries to show that nationality does not overcome the variation in body site. We then highlight the utility of the American Gut in meta-analysis by reproducing results from (https://www.ncbi.nlm.nih.gov/pubmed/20668239) and (https://www.ncbi.nlm.nih.gov/pubmed/23861384), using the AGP dataset as the context for dynamic microbiome changes instead of the HMP dataset. We show rapid, complete recovery of C. diff patients following fecal material transplantation and also contextualized the change in an infant gut over time until it settles into an adult state. This demonstrates the power of the American Gut dataset, both as a cohesive study and as a context for other investigations

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The SEPP (Mirarab et al Pac Symp Biocomput 2012) fragment insertion tree used for phylogenetic analyses

American Gut Project fecal sOTU counts table

The Deblur sOTU counts table for the fecal samples used in the American Gut Project manuscript. The samples were trimmed to a common read length of 125nt, and processed by Deblur (Amir et al mSystems 2017). Blooms were removed (Amir et al mSystems 2017) and any sample with fewer than 1250 sequences was omitted. This table is not rarefied,

Unweighted UniFrac distances

The unweighted UniFrac distance (Lozupone and Knight AEM 2005) matrix of the 9511 fecal samples used in the American Gut paper. UniFrac was computed using Striped UniFrac (https://github.com/biocore/unifrac). Prior to execution of UniFrac, Deblur (Amir et al mSystems 2017) was run on the samples, all bloom sOTUs were removed (Amir et al mSystems 2017), and samples were rarefied to a depth of 1250 reads (Weiss et al Microbiome 2017). For the phylogeny, fragments were inserted using SEPP (Mirarab et al Pac Symp Biocomput 2012) into the Greengenes 13_5 99% OTU tree (McDonald et al ISME 2012)