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The COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells, and TMPRSS2 inhibitors are being developed for COVID-19 therapy. However, the SARS-CoV-2 Omicron variant, which currently dominates the pandemic, prefers the endo/lysosomal cysteine protease cathepsin L over TMPRSS2 for cell entry, raising doubts as to whether TMPRSS2 inhibitors would be suitable for the treatment of patients infected with the Omicron variant. Nevertheless, the contribution of TMPRSS2 to the spread of SARS-CoV-2 in the infected host is largely unclear. In this study, we show that the loss of TMPRSS2 strongly reduced the replication of the Beta variant in the nose, trachea and lung of C57BL/6 mice, and protected the animals from weight loss and disease. The infection of mice with the Omicron variant did not cause disease, as expected, but again, TMPRSS2 was essential for efficient viral spread in the upper and lower respiratory tract. These results identify the key role of TMPRSS2 in SARS-CoV-2 Beta and Omicron infection, and highlight TMPRSS2 as an attractive target for antiviral intervention.

Eustachian tube disorders can lead to chronic otitis media with consecutive conductive hearing loss. To improve treatment and to develop new types of implants such as stents, an adequate experimental animal model is required. As the middle ear of sheep is known to be comparable to the human middle ear, the dimensions of the Eustachian tube in two strains of sheep were investigated. The Eustachian tube and middle ear of half heads of heathland and blackface sheep were filled with silicone rubber, blended with barium sulfate to induce X-ray visibility. Images were taken by digital volume tomography. The tubes were segmented, and a three-dimensional model of every Eustachian tube was generated. The lengths, diameters and shapes were determined. Additionally, the feasibility of endoscopic stent implantation and fixation was tested in cadaver experiments. The length of the tube between ostium pharyngeum and the isthmus and the diameters were comparable to published values for the human tube. The tube was easily accessible through the nose, and then stents could be implanted and fixed at the isthmus. The sheep appears to be a promising model for testing new stent treatments for middle ear ventilation disorders.

Background Untreated chronic otitis media severely impairs quality of life in affected individuals. Local destruction of the middle ear and subsequent loss of hearing are common sequelae, and currently available treatments provide limited relief. Therefore, the objectives of this study were to evaluate the feasibility of the insertion of a coronary stent from the nasopharynx into the Eustachian tube in-vivo in sheep and to make an initial assessment of its positional stability, tolerance by the animal, and possible tissue reactions. Methods Bilateral implantation of bare metal cobalt-chrome coronary stents of two sizes was performed endoscopically in three healthy blackface sheep using a nasopharyngeal approach. The postoperative observation period was three months. Results Stent implantation into the Eustachian tube was feasible with no intra- or post-operative complications. Health status of the sheep was unaffected. All stents preserved their cylindrical shape. All shorter stents remained in position and ventilated the middle ear even when partially filled with secretion or tissue. One of the long stents became dislocated toward the nasopharynx. Both of the others remained fixed at the isthmus but appeared to be blocked by tissue or secretion. Tissue overgrowth on top of the struts of all stents resulted in closure of the tissue-lumen interface. Conclusion Stenting of the Eustachian tube was successfully transferred from cadaver studies to an in-vivo application without complications. The stent was well tolerated, the middle ears were ventilated, and clearance of the auditory tube appeared possible. For fixation, it seems to be sufficient to place it only in the cartilaginous part of the Eustachian tube.

The COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells and TMPRSS2 inhibitors are being developed for COVID-19 therapy. However, the SARS-CoV-2 Omicron variant, which currently dominates the pandemic, prefers the endo/lysosomal cysteine protease cathepsin L over TMPRSS2 for cell entry, raising doubts whether TMPRSS2 inhibitors would be suitable for treatment of patients infected with the Omicron variant. Nevertheless, the contribution of TMPRSS2 to spread of SARS-CoV-2 in the infected host is largely unclear. Here, we show that loss of TMPRSS2 strongly reduced the replication of the Beta variant in nose, trachea and lung of C57BL mice and protected the animals from weight loss and disease. Infection of mice with the Omicron variant did not cause disease, as expected, but again TMPRSS2 was essential for ef-ficient viral spread in the upper and lower respiratory tract. These results identify a key role of TMPRSS2 in SARS-CoV-2 Beta and Omicron infection and highlight TMPRSS2 as an attractive target for antiviral intervention.Competing Interest StatementThe authors have declared no competing interest.

The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma. Personalized cancer vaccine trials Neoantigens have long been considered optimal targets for anti-tumour vaccines, and recent mutation coding and prediction techniques have aimed to streamline their identification and selection. Two papers in this issue report results from personalized neoantigen vaccine trials in patients with cancer. Catherine Wu and colleagues report the results of a phase I trial of a personalized cancer vaccine that targets up to 20 patient neoantigens. The vaccine was safe and induced tumour-antigen-specific immune responses. Four out of six patients treated showed no recurrence at 25 months, and progressing patients responded to further therapy with checkpoint inhibitor. Ugur Sahin and colleagues report the first-in-human application of a personalized neoantigen vaccine in patients with melanoma. Their vaccination strategy includes sequencing and computational identification of neoantigens from patients, and design and manufacture of a poly-antigen RNA vaccine for treatment. In 13 patients, the vaccine boosted immunity against some of the selected tumour antigens from the individual patients, and two patients showed infiltration of tumour-reactive T cells. These results suggest that personalized vaccines could be refined and tailored to provide clinical benefit as cancer immunotherapies. T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations 1 , 2 . Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.

In this article, we examine the role of errors in data-driven research and assess the extent to which a lack of a constructive error culture has been addressed across various research fields. Motivated by recurring calls in the research data management community for clearer guidance, it presents examples of how scientific communities have addressed problems related to ‘flawed research’—a term we use to describe research acts that lead to wrong and unreliable results. Furthermore, it highlights observations on how error culture in science can positively impact the research process. We demonstrate that error culture both benefits from suitable infrastructures and depends on their support to spread. This creates a reciprocal relationship between error culture, transparency and open science. Consequently, we argue that errors themselves do not hinder the progress of scientific knowledge. Instead, it is the way they are subsequently dealt with that poses a challenge. Moreover, data sharing and open science practices can be fostered by developing an error culture in each disciplinary context.

Background Musculoskeletal pain conditions are the largest contributors to disability and healthcare burden globally. Exercise interventions improve physical function and quality of life in individuals with musculoskeletal pain, yet optimal exercise prescription variables (e.g. duration, frequency, intensity) are unclear. Objective We aimed to examine evidence gaps, methodological quality and exercise prescription recommendations in systematic reviews of exercise for musculoskeletal pain. Methods In our prospectively registered umbrella review, PubMed, SPORTDiscus, Cochrane Database of Systematic Reviews, EMBASE, and CINAHL were searched from inception to 14 February 2023. Backward citation tracking was performed. We included peer-reviewed, English language, systematic reviews and meta-analyses of randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that compared exercise with conservative treatment, placebo or other exercise interventions in adults with musculoskeletal pain. Data were extracted from the following groups of reviews based on their reporting of exercise prescription data and analysis of the relationship between prescription variables and outcomes: (1) those that did not report any exercise prescription data, (2) those that reported exercise prescription data but did not perform a quantitative analysis and (3) those that performed a quantitative analysis of the relationship between exercise prescription variables and outcomes. Outcome measures were physical function, pain, mental health, adverse effects and adherence to treatment. AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) was used to assess methodological quality. Results From 6757 records, 274 systematic reviews were included. 6.6% of reviews did not report any exercise prescription data, and only 10.9% quantitatively analyzed the relationship between prescription variables and the outcome(s). The overall methodological quality was critically low in 85% of reviews. Conclusion High methodological quality evidence is lacking for optimal exercise training prescription variables in individuals with musculoskeletal pain. To better inform practice and evidence gaps, future systematic reviews should (1) identify optimum exercise prescription variables, for example, via dose–response (network) meta-analysis, (2) perform high-quality reviews per AMSTAR-2 criteria and (3) include outcomes of mental health, adverse events and exercise adherence. PROSPERO registration number CRD42021287440 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021287440 ).

Rewilding initiatives are increasing in number across Europe and the UK in response to a growing awareness of substantial nature depletion, despite a lack of policy, guidance and legislation. Ongoing transformations of UK environmental policies offer a ‘policy window’ in which rewilding could become established as a key strategy for nature recovery. Here, we present the results of discussion sessions held as part of a British Ecological Society Policy Training workshop. A total of 46 participants, academics, practitioners and young people interested in rewilding attended. Our discussion focused on three pre‐determined thematic discussion sessions: (1) barriers to rewilding and trade‐offs; (2) species reintroductions; (3) facilitating rewilding in policy. Using thematic analysis, four emerging cross‐cutting themes were identified from our workshop discussions: (a) environmental stewardship & public engagement, (b) cross‐policy approaches, (c) incentivising rewilding and (d) an evidence base for rewilding. Policy Implications. Given the UK's considerable biodiversity loss, restoring ecosystem processes and function on a large scale is increasingly urgent, and operationalising rewilding through supportive environmental policy structures should be a key priority for government. Read the free Plain Language Summary for this article on the Journal blog. Read the free Plain Language Summary for this article on the Journal blog.