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Abstract Background Knowledge of patient lived experiences of functioning and disability is limited. This study aims to address the gap in the literature by exploring patient lived experiences of functioning and disability following lumbar discectomy. Method A secondary analysis, reported in line with the Standards for Reporting Qualitative Research, was conducted of qualitative data exploring patient journeys following lumbar discectomy surgery (DiscJourn). Adult patients (≥ 16 years) undergoing elective or emergency primary lumbar discectomy were recruited from one National Health Service secondary care centre in the UK. Semi-structured interviews were conducted at 1–3 weeks and 1-year post surgery. Participants who completed both semi-structured interviews were eligible for the secondary analysis. Transcripts from the semi-structured interviews were analysed using interpretative phenomenological analysis (IPA). IPA involved two independent reviewers identifying themes for individual data sets followed by an iterative process involving the wider research team to identify overarching themes that represented the whole date set. Subthemes generated from the IPA were mapped against the International Classification of Functioning, Disability and Health (ICF) framework at the level of chapters, in order to ascertain the ICF’s utility in capturing experiences of functioning and disability. Strategies to enhance trustworthiness of data analysis included blind coding, peer examination and debrief, declaration of pre-conceived beliefs and active reflexivity throughout the study. Results Nine participants met the eligibility criteria and their interview transcripts were analysed. Patient lived experiences of functioning and disability were captured by three overarching themes: Immediate impact following surgery, Multiple roads to recovery over 1 year, and Functioning influenced by personal loci of control. Each theme consisted of three subthemes which were subsequently mapped onto the ICF. Three subthemes mapped to the ICF’s body component, 1 to activity and participation and 3 to environment. Two subthemes themes did not map onto the ICF. Conclusion Findings provide valuable insights into patient experiences of functioning and disability following lumbar discectomy. Convergence in experiences of functioning and disability were identified immediately following surgery. Divergence in such experiences were identified with regards to the roads to recovery over 1 year and the individuals’ locus of control. Findings build on the body of literature exploring patients functioning and disability following discectomy and make recommendations for future research and clinical practice.

Le Dantec virus (LDV), assigned to the species Ledantevirus ledantec, genus Ledantevirus, family Rhabdoviridae has been associated with human disease but has gone undetected since the 1970s. We describe the detection of LDV in a human case of undifferentiated fever in Uganda by metagenomic sequencing and demonstrate a serological response using ELISA and pseudotype neutralisation. By screening 997 individuals sampled in 2016, we show frequent exposure to ledanteviruses with 76% of individuals seropositive in Western Uganda, but lower seroprevalence in other areas. Serological cross-reactivity as measured by pseudotype-based neutralisation was confined to ledanteviruses, indicating population seropositivity may represent either exposure to LDV or related ledanteviruses. We also describe the discovery of a closely related ledantevirus in blood from the synanthropic rodent Mastomys erythroleucus. Ledantevirus infection is common in Uganda but is geographically heterogenous. Further surveys of patients presenting with acute fever are required to determine the contribution of these emerging viruses to febrile illness in Uganda.

Prediction of the potentially devastating impact of landfalling tropical cyclones (TCs) relies substantially on numerical prediction systems. Due to the limited predictability of TCs and the need to express forecast confidence and possible scenarios, it is vital to exploit the benefits of dynamic ensemble forecasts in operational TC forecasts and warnings. RSMCs, TCWCs, and other forecast centers value probabilistic guidance for TCs, but the International Workshop on Tropical Cyclones (IWTC-9) found that the “pull-through” of probabilistic information to operational warnings using those forecasts is slow. IWTC-9 recommendations led to the formation of the WMO/WWRP Tropical Cyclone-Probabilistic Forecast Products (TC-PFP) project, which is also endorsed as a WMO Seamless GDPFS Pilot Project. The main goal of TC-PFP is to coordinate across forecast centers to help identify best practice guidance for probabilistic TC forecasts. TC-PFP is being implemented in 3 phases: Phase 1 (TC formation and position); Phase 2 (TC intensity and structure); and Phase 3 (TC related rainfall and storm surge). This article provides a summary of Phase 1 and reviews the current state of the science of probabilistic forecasting of TC formation and position. There is considerable variability in the nature and interpretation of forecast products based on ensemble information, making it challenging to transfer knowledge of best practices across forecast centers. Communication among forecast centers regarding the effectiveness of different approaches would be helpful for conveying best practices. Close collaboration with experts experienced in communicating complex probabilistic TC information and sharing of best practices between centers would help to ensure effective decisions can be made based on TC forecasts. Finally, forecast centers need timely access to ensemble information that has consistent, user-friendly ensemble information. Greater consistency across forecast centers in data accessibility, probabilistic forecast products, and warnings and their communication to users will produce more reliable information and support improved outcomes.

Research on the adaptations talkers make to different communication conditions during interactive conversations has primarily focused on speech signals. We extended this type of investigation to two other important communicative signals, i.e., partner-directed gaze and iconic co-speech hand gestures with the aim of determining if the adaptations made by older adults differ from younger adults across communication conditions. We recruited 57 pairs of participants, comprising 57 primary talkers and 57 secondary ones. Primary talkers consisted of three groups: 19 older adults with mild Hearing Loss (older adult-HL); 17 older adults with Normal Hearing (older adult-NH); and 21 younger adults. The DiapixUK “spot the difference” conversation-based task was used to elicit conversions in participant pairs. One easy (No Barrier: NB) and three difficult communication conditions were tested. The three conditions consisted of two in which the primary talker could hear clearly, but the secondary talkers could not, due to multi-talker babble noise (BAB1) or a less familiar hearing loss simulation (HLS), and a condition in which both the primary and secondary talkers heard each other in babble noise (BAB2). For primary talkers, we measured mean number of partner-directed gazes; mean total gaze duration; and the mean number of co-speech hand gestures. We found a robust effects of communication condition that interacted with participant group. Effects of age were found for both gaze and gesture in BAB1, i.e., older adult-NH looked and gestured less than younger adults did when the secondary talker experienced babble noise. For hearing status, a difference in gaze between older adult-NH and older adult-HL was found for the BAB1 condition; for gesture this difference was significant in all three difficult communication conditions (older adult-HL gazed and gestured more). We propose the age effect may be due to a decline in older adult’s attention to cues signaling how well a conversation is progressing. To explain the hearing status effect, we suggest that older adult’s attentional decline is offset by hearing loss because these participants have learned to pay greater attention to visual cues for understanding speech.

Abstract Plant-based animal product alternatives are increasingly promoted to achieve more sustainable diets. Here, we use a global economic land use model to assess the food system-wide impacts of a global dietary shift towards these alternatives. We find a substantial reduction in the global environmental impacts by 2050 if globally 50% of the main animal products (pork, chicken, beef and milk) are substituted—net reduction of forest and natural land is almost fully halted and agriculture and land use GHG emissions decline by 31% in 2050 compared to 2020. If spared agricultural land within forest ecosystems is restored to forest, climate benefits could double, reaching 92% of the previously estimated land sector mitigation potential. Furthermore, the restored area could contribute to 13-25% of the estimated global land restoration needs under target 2 from the Kunming Montreal Global Biodiversity Framework by 2030, and future declines in ecosystem integrity by 2050 would be more than halved. The distribution of these impacts varies across regions—the main impacts on agricultural input use are in China and on environmental outcomes in Sub-Saharan Africa and South America. While beef replacement provides the largest impacts, substituting multiple products is synergistic.

ABSTRACTWe phylogenetically compared sequences of the zoonotic Lassa virus (LASV) obtained from Mastomys rodents in seven localities across the highly endemic Edo and Ondo States within Nigeria. Sequencing 1641 nt from the S segment of the virus genome, we resolved clades within lineage II that were either limited to Ebudin and Okhuesan in Edo state (2g-beta) or along Owo-Okeluse-Ifon in Ondo state (2g-gamma). We also found clades within Ekpoma, a relatively large cosmopolitan town in Edo state, that extended into other localities within Edo (2g-alpha) and Ondo (2g-delta). LASV variants from M. natalensis within Ebudin and Ekpoma in Edo State (dated approximately 1961) were more ancient compared to those from Ondo state (approximately 1977), suggesting a broadly east-west virus migration across south-western Nigeria; a pattern not always consistent with LASV sequences derived from humans in the same localities. Additionally, in Ebudin and Ekpoma, LASV sequences between M. natalensis and M. erythroleucus were interspersed on the phylogenetic tree, but those from M. erythroleucus were estimated to emerge more recently (approximately 2005). Overall, our results show that LASV amplification in certain localities (reaching a prevalence as high as 76% in Okeluse), anthropogenically-aided spread of rodent-borne variants amidst the larger towns (involving communal accommodation such as student hostels), and virus-exchange between syntopic M. natalensis and M. erythroleucus rodents (as the latter, a savanna species, encroaches southward into the degraded forest) pose perpetual zoonotic hazard across the Edo-Ondo Lassa fever belt, threatening to accelerate the dissemination of the virus into non endemic areas.

The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically naïve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.

Abstract Background Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses. Method We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms. Results Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination. Conclusions These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort.

RationalePatient satisfaction is a complex construct consisting of human and system attributes. Patient satisfaction can afford insight into patient experience, itself a key component of evaluating healthcare quality. Internationally, advanced physiotherapy practice (APP) extends across clinical fields and is characterised as a higher level of practice with a high degree of autonomy and complex decision making. Patient satisfaction with APP appears positive. While evidence synthesis of patient satisfaction with APP exists, no systematic review has synthesised evidence across clinical fields. Therefore, the objectives of this systematic review are 1) to evaluate patient satisfaction with APP internationally, and 2) to evaluate human and system attributes of patient satisfaction with APP.Materials and methodsA systematic mixed studies review using a parallel-results convergent synthesis design will be conducted. Searches of Medline, Embase, Web of Science, CINAHL, Cochrane, PEDro and grey literature databases will be conducted from inception to 18/7/2023. Studies of APP (World Physiotherapy definition) whereby practitioners a) have advanced clinical and analytical skills that influence service improvement and provide clinical leadership, b) have post-registration masters level specialisation (or equivalence), c) deliver safe, competent care to patients with complex needs and d) may use particular occupational titles; that measure patient satisfaction across all clinical fields and countries will be included. Two reviewers will screen studies, extract data, assess methodological quality of included studies (mixed methods appraisal tool), and contribute to data synthesis. Quantitative data will undergo narrative synthesis (textual descriptions) and qualitative data thematic synthesis (analytical themes). Integration of data syntheses will inform discussion.ImplicationsThis systematic review will provide insight into patient satisfaction with APP internationally, exploring attributes that influence satisfaction. This will aid design, implementation, or improvement of APP and facilitate the delivery of patient-centred, high-quality healthcare. Lastly, this review will inform future methodologically robust research investigating APP patient satisfaction and experience.

ObjectivesThe SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this.MethodsIn this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death.ResultsOur cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants).ConclusionsThe Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.

Current HCV nucleic acid-based diagnosis is largely performed in centralised laboratories. Here, the authors present a pan-genotypic RNA assay, based on reverse transcriptase loop mediated isothermal amplification and develop a low-cost prototype paper-based lateral flow device for point-of-care use, providing a visually read result within 40 min.

Rhabdoviridae is a large viral family, with members infecting a diverse range of hosts including, vertebrate species, arthropods, and plants. The predominant human pathogen within the family is Rabies lyssavirus, the main cause of human rabies. While rabies is itself a neglected disease, there are other, less well studied, rhabdoviruses known to cause human infection. The increasing application of next-generation sequencing technology to clinical samples has led to the detection of several novel or rarely detected rhabdoviruses associated with febrile illness. Many of these viruses have been detected in low- and middle-income countries where the extent of human infection and the burden of disease remain largely unquantified. This review describes the rhabdoviruses other than Rabies lyssavirus that have been associated with human infection. The discovery of the Bas Congo virus and Ekpoma virus is discussed, as is the re-emergence of species such as Le Dantec virus, which has recently been detected in Africa 40 years after its initial isolation. Chandipura virus and the lyssaviruses that are known to cause human rabies are also described. Given their association with human disease, the viruses described in this review should be prioritised for further study.

This study examined whether visual speech provides speech-rhythm information that perceivers can use in speech perception. This was tested by using speech that naturally varied in the familiarity of its rhythm. Thirty Australian English L1 listeners performed a speech perception in noise task with English sentences produced by three speakers: an English L1 speaker (familiar rhythm); an experienced English L2 speaker who had a weak foreign accent (familiar rhythm), and an inexperienced English L2 speaker who had a strong foreign accent (unfamiliar speech rhythm). The spoken sentences were presented in three conditions: Audio-Only (AO), Audio-Visual with mouth covered (AVm), and Audio-Visual (AV). Speech was best recognized in the AV condition regardless of the degree of foreign accent. However, speech recognition in AVm was better than AO for the speech with no foreign accent and with a weak accent, but not for the speech with a strong accent. A follow-up experiment was conducted that only used the speech with a strong foreign accent, under more audible conditions. The results also showed no difference between the AVm and AO conditions, indicating the null effect was not due to a floor effect. We propose that speech rhythm is conveyed by the motion of the jaw opening and closing, and perceivers use this information to better perceive speech in noise.

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.

Abstract Background Past research indicates that when younger adults are engaged in a visual working memory task, they are less distracted by novel auditory stimuli than when engaged in a visual task that does not require working memory. The current study aimed to determine whether working memory affords the same protection to older adults. Method We examined behavioral and EEG responses in 16 younger and 16 older adults to distractor sounds when the listeners performed two visual tasks; one that required working memory (W1) and the other that did not (W0). Auditory distractors were presented in an oddball paradigm, participants were exposed to either standard tones (600 Hz: 80%) or various novel environmental sounds (20%). Results It was found that: 1) when presented with novel vs standard sounds, older adults had faster correct response times in the W1 visual task than in the W0 task, indicating that they were less distracted by the novel sound; there was no difference in error rates. Younger adults did not show a task effect for correct response times but made slightly more errors when a novel sound was presented in the W1 task compared to the W0 task. 2) In older adults (but not the younger adults), the amplitude of N1 was smaller in the W1 condition compared to the W0 condition. 3) The working memory manipulation had no effect on MMN amplitude in older adults. 4) For the W1 compared to W0 task, the amplitude of P3a was attenuated for the older adults but not for the younger adults. Conclusions These results suggest that during the working memory manipulation older adults were able to engage working memory to reduce the processing of task-irrelevant sounds.

The ability to recognise emotion from faces or voices appears to decline with advancing age. However, some studies have shown that emotion recognition of auditory-visual (AV) expressions is largely unaffected by age, i.e., older adults get a larger benefit from AV presentation than younger adults resulting in similar AV recognition levels. An issue with these studies is that they used well-recognised emotional expressions that are unlikely to generalise to real-life settings. To examine if an AV emotion recognition benefit generalizes across well and less well recognised stimuli, we conducted an emotion recognition study using expressions that had clear or unclear emotion information for both modalities, or clear visual, but unclear auditory information. Older (n = 30) and younger (n = 30) participants were tested on stimuli of anger, happiness, sadness, surprise, and disgust (expressed in spoken sentences) in auditory-only (AO), visual-only (VO), or AV format. Participants were required to respond by choosing one of 5 emotion options. Younger adults were more accurate in recognising emotions than older adults except for clear VO expressions. Younger adults showed an AV benefit even when unimodal recognition was poor. No such AV benefit was found for older adults; indeed, AV was worse than VO recognition when AO recognition was poor. Analyses of confusion responses indicated that older adults generated more confusion responses that were common between AO and VO conditions, than younger adults. We propose that older adults' poorer AV performance may be due to a combination of weak auditory emotion recognition and response uncertainty that resulted in a higher cognitive load.

The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 replication. Utilizing a three-dimensional (3D) air-liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.

Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.

The rapid spread of COVID-19 and disruption of normal supply chains has resulted in severe shortages of personal protective equipment (PPE), particularly devices with few suppliers such as powered air-purifying respirators (PAPRs). A scarcity of information describing design and performance criteria for PAPRs represents a substantial barrier to mitigating shortages. We sought to apply open-source product development (OSPD) to PAPRs to enable alternative sources of supply and further innovation. We describe the design, prototyping, validation, and user testing of locally manufactured, modular, PAPR components, including filter cartridges and blower units, developed by the Greater Boston Pandemic Fabrication Team (PanFab). Two designs, one with a fully custom-made filter and blower unit housing, and the other with commercially available variants (the “Custom” and “Commercial” designs, respectively) were developed; the components in the Custom design are interchangeable with those in Commercial design, although the form factor differs. The engineering performance of the prototypes was measured and safety validated using National Institutes for Occupational Safety and Health (NIOSH)-equivalent tests on apparatus available under pandemic conditions at university laboratories. Feedback was obtained from four individuals; two clinicians working in ambulatory clinical care and two research technical staff for whom PAPR use is standard occupational PPE; these individuals were asked to compare PanFab prototypes to commercial PAPRs from the perspective of usability and suggest areas for improvement. Respondents rated the PanFab Custom PAPR a 4 to 5 on a 5 Likert-scale 1) as compared to current PPE options, 2) for the sense of security with use in a clinical setting, and 3) for comfort compared to standard, commercially available PAPRs. The three other versions of the designs (with a Commercial blower unit, filter, or both) performed favorably, with survey responses consisting of scores ranging from 3 to 5. Engineering testing and clinical feedback demonstrate that the PanFab designs represent favorable alternatives to traditional PAPRs in terms of user comfort, mobility, and sense of security. A nonrestrictive license promotes innovation in respiratory protection for current and future medical emergencies.

Direct-acting antivirals (DAAs) have revolutionised the treatment of Hepatitis C virus (HCV), allowing the World Health Organisation (WHO) to set a target of eliminating HCV by 2030. In this study we aimed to investigate glecaprevir and pibrentasvir (GP) treatment outcomes in a cohort of patients with genotype 2a infection. Methods: Clinical data and plasma samples were collected in NHS Greater Glasgow & Clyde. Next generation whole genome sequencing and replicon assays were carried out at the MRC-University of Glasgow Centre for Virus Research. Results: 132 cases infected with genotype 2a HCV were identified. The SVR rate for this group was 91% (112/123) following treatment with GP. An NS5A polymorphism, L31M, was detected in all cases of g2a infection, and L31M+R353K in individuals that failed treatment. The results showed that R353K was present in 90% of individuals in the Glasgow genotype 2a phylogenetic cluster but in less than 5% of all HCV subtype 2a published sequences. In vitro efficacy of pibrentasvir against sub-genomic replicon constructs containing these mutations showed a 2-fold increase in IC50 compared to wildtype. Conclusion: This study describes a cluster of HCV genotype 2a infection associated with a lower-than-expected SVR rate following GP treatment in association with the NS5A mutations L31M+R353K.

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.

The global energy system is undergoing a major transition, and in energy planning and decision-making across governments, industry and academia, models play a crucial role. Because of their policy relevance and contested nature, the transparency and open availability of energy models and data are of particular importance. Here we provide a practical how-to guide based on the collective experience of members of the Open Energy Modelling Initiative (Openmod). We discuss key steps to consider when opening code and data, including determining intellectual property ownership, choosing a licence and appropriate modelling languages, distributing code and data, and providing support and building communities. After illustrating these decisions with examples and lessons learned from the community, we conclude that even though individual researchers' choices are important, institutional changes are still also necessary for more openness and transparency in energy research. Keywords: Open source, Open data, Energy modelling

Abstract: Management of venous thromboembolism (VTE) remains challenging in patients with hematologic malignancy who undergo hematopoietic cell transplantation (HCT) due to prolonged thrombocytopenia. This study aims to (1) determine the incidence of VTE recurrence and bleeding during autologous HCT, (2) assess the impact of continuing vs temporarily withholding anticoagulation during thrombocytopenia, and (3) explore the impact of platelet threshold among other variables on the risk of bleeding. We performed this observational study in adults with lymphoma and myeloma who underwent autologous HCT between 2006 and 2015. We selected patients with index VTE prior to HCT and assigned them to different cohorts based on antithrombotic management at the onset of thrombocytopenia. Primary outcomes included VTE recurrence and major bleeding by 30 days after HCT. Secondary outcomes included platelet and red blood cell transfusions, time to engraftment, and overall survival. Of the 1631 patients who underwent autologous HCT, 204 patients (12.5%) had preceding index VTE events, and among them, 132 patients continued and 72 patients temporarily withheld anticoagulation during thrombocytopenia. There were no significant differences in VTE recurrence (1.5% vs 1.4%) or major bleeding (3.8% vs 4.2%) between 2 groups by 30 days. The number of platelet transfusions was significantly higher in the first group. Baseline elevated bilirubin, creatinine, and prothrombin time were independently associated with increased risk in major bleeding, whereas neither platelet threshold nor average platelet count was predictive. Our findings suggest that for many patients undergoing autologous HCT, temporarily withholding anticoagulation during thrombocytopenia may offer the best risk-benefit tradeoff among available options.

Biogas is expected to contribute 10% of the total renewable energy use in Europe in 2030. This expectation largely depends on the use of several biomass byproducts and wastes as feedstocks. However, the current development of a biobased economy requires biomass sources for multiple purposes. If alternative applications also use biogas feedstocks, it becomes doubtful whether they will be available for biogas production. To explore this issue, this paper aims to provide an overview of potential alternative uses of different biogas feedstocks being researched in literature. We conducted a literature review using the machine learning technique “co-occurrence analysis of terms”. This technique reads thousands of abstracts from literature and records when pairs of biogas feedstock-application are co-mentioned. These pairs are assumed to represent the use of a feedstock for an application. We reviewed 109 biogas feedstocks and 217 biomass applications, revealing 1053 connections between them in nearly 55,000 scientific articles. Our results provide two insights. First, a large share of the biomass streams presently considered in the biogas estimates have many alternative uses, which likely limit their contribution to future biogas production. Second, there are streams not being considered in present estimates for biogas production although they have the proper characteristics.

A growing body of evidence shows that brain oscillations track speech. This mechanism is thought to maximise processing efficiency by allocating resources to important speech information, effectively parsing speech into units of appropriate granularity for further decoding. However, some aspects of this mechanism remain unclear. First, while periodicity is an intrinsic property of this physiological mechanism, speech is only quasi-periodic, so it is not clear whether periodicity would present an advantage in processing. Second, it is still a matter of debate which aspect of speech triggers or maintains cortical entrainment, from bottom-up cues such as fluctuations of the amplitude envelope of speech to higher level linguistic cues such as syntactic structure. We present data from a behavioural experiment assessing the effect of isochronous retiming of speech on speech perception in noise. Two types of anchor points were defined for retiming speech, namely syllable onsets and amplitude envelope peaks. For each anchor point type, retiming was implemented at two hierarchical levels, a slow time scale around 2.5 Hz and a fast time scale around 4 Hz. Results show that while any temporal distortion resulted in reduced speech intelligibility, isochronous speech anchored to P-centers (approximated by stressed syllable vowel onsets) was significantly more intelligible than a matched anisochronous retiming, suggesting a facilitative role of periodicity defined on linguistically motivated units in processing speech in noise.

Biological invasions are a challenge to conservation and constitute a threat to biodiversity worldwide. The Italian wall lizard Podarcis sicula has been widely introduced, and seems capable of adapting to most of the regions where it is established and to impact on native biota. Here we construct a phylogenetic framework to assess the origin of the introduced populations in the United Kingdom, Greece and Turkey comparing cytochrome-b gene sequences of lizards from five locations to published sequences from the native range and other non-native locations. The results support an origin from central Italy for the United Kingdom population, from the Adriatic region for the Greek population and from Calabria for the population from Turkey. These results emphasise the multiple-source pattern of introduction of this species identified in previous studies. The improvement in the knowledge of the origin and pathways by which invaders arrive in new areas, as well as the monitoring of their populations, are crucial for successful strategies to deal with exotic species.

Auditory selective attention enables task-relevant auditory events to be enhanced and irrelevant ones suppressed. In the present study we used a frequency tagging paradigm to investigate the effects of attention on auditory steady state responses (ASSR). The ASSR was elicited by simultaneously presenting two different streams of white noise, amplitude modulated at either 16 and 23.5 Hz or 32.5 and 40 Hz. The two different frequencies were presented to each ear and participants were instructed to selectively attend to one ear or the other (confirmed by behavioral evidence). The results revealed that modulation of ASSR by selective attention depended on the modulation frequencies used and whether the activation was contralateral or ipsilateral. Attention enhanced the ASSR for contralateral activation from either ear for 16 Hz and suppressed the ASSR for ipsilateral activation for 16 Hz and 23.5 Hz. For modulation frequencies of 32.5 or 40 Hz attention did not affect the ASSR. We propose that the pattern of enhancement and inhibition may be due to binaural suppressive effects on ipsilateral stimulation and the dominance of contralateral hemisphere during dichotic listening. In addition to the influence of cortical processing asymmetries, these results may also reflect a bias towards inhibitory ipsilateral and excitatory contralateral activation present at the level of inferior colliculus. That the effect of attention was clearest for the lower modulation frequencies suggests that such effects are likely mediated by cortical brain structures or by those in close proximity to cortex.

Background Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells.Design and Methods We retrospectively analyzed data from 2162 hematopoietic cell transplant recipients to examine the effect of these factors on overall cytopenias occurring after 28 days in hematopoietic cell transplantation.Results Advanced age of the patient, recipient cytomegalovirus seropositivity, unrelated donor status, human leukocyte antigen mismatch and lower doses of transplanted CD34+ cells (≤ 6.4×106/kg) significantly increased the risk of cytopenias after day 28. Non-myeloablative hematopoietic cell transplantation had protective effects on anemia and thrombocytopenia after day 28 (adjusted odds ratio 0.76, probability value of 0.05 and adjusted odds ratio 0.31, probability value of