A Framework for Building Technological Learning: Evidence from the New Zealand Dairy Industry

One aspect of the process of technology adoption is technological learning (TL), the way farmers gather information and turn it into knowledge. In a study of the New Zealand dairy industry, researchers examined the factors that affect TL. Findings suggest that the speed with which farmers engage in TL is influenced by the efficiency of the innovation system, the maturity of the farm system, and the individual characteristics of the farmer. The article presents a model demonstrating how these three sets of factors may affect TL that can be used by Extension agents to help them develop a strategy for engaging farmers in TL

Intolerance of uncertainty predicts altered threat expectancy ratings during reinstatement

Intolerance of uncertainty (IU) is a transdiagnostic risk factor for psychiatric disorders, and plays an important role in fear and threat learning under uncertainty. The ‘reinstatement of fear/threat’ is an understudied phenomenon thought to represent clinical symptom relapse. Reinstatement of conditioned responding can be captured in the laboratory by presenting unsignaled presentations of an aversive unconditional stimulus. The present study investigated IU as a predictor of reinstatement effects, such that individuals higher in IU, relative to lower IU, would show larger reinstatement. Sixty-two participants completed the Intolerance of Uncertainty Scale and provided threat expectancy ratings (i.e. certainty of receiving a shock) during a differential threat conditioning and extinction paradigm with reinstatement. Findings suggested a differential increase in threat expectancy ratings to both the threat and safety cue following reinstatement, although this effect was small and did not survive follow-up tests. Nevertheless, IU was a significant predictor of reinstatement to the threat cue but not the safety cue, although this effect was not in the expected direction. Specifically, higher IU was associated with reduced threat expectancy ratings post-reinstatement. These findings provide support for the limited literature demonstrating an important role for IU in reinstatement effects and should be investigated further

The Extent of User Involvement in the Design of Self-tracking Technology for Bipolar Disorder: Literature Review

Background: Self-monitoring applications for bipolar disorder are increasing in numbers. The involvement of users has been informed by it's long history in Human-Computer Interaction (HCI) research and is becoming a core concern for designers working in this space. The application of models of involvement, such as user-centred design (UCD), is becoming standardised to optimise the reach, adoption and sustained use of this type of technology.Objective: This paper aims to examine the current ways in which users are involved in the design and evaluation of self-monitoring apps for BD by investigating 3 specific questions: are users involved in the design and evaluation of technology? If so, how does this happen? And what are the best practice ingredients regarding the design of mental health technology?Methods: We reviewed the available literature on self-tracking technology for BD and make an overall assessment of the level of user involvement in design. The findings were reviewed by an expert panel, including an individual with lived experience of BD, to form best practice ingredients for the design of mental health technology. This combines the existing practices of patient and public involvement and HCI to evolve from the generic guidelines of user-centered design and to those that are tailored toward mental health technology.Results: For the first question, it was found that out of the 11 novel smartphone apps included in this review, 4 (36%) self-monitoring apps were classified as having no mention of user involvement in design, 1 (9%) self-monitoring app was classified as having low user involvement, 4 (36%) self-monitoring apps were classified as having medium user involvement, and 2 (18%) self-monitoring apps were classified as having high user involvement. For the second question, it was found that despite the presence of extant approaches for the involvement of the user in the process of design and evaluation, there is large variability in whether the user is involved, how they are involved, and to what extent there is a reported emphasis on the voice of the user, which is the ultimate aim of such design approaches. For the third question, it is recommended that users are involved in all stages of design with the ultimate goal of empowering and creating empathy for the user

Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study)

Abstract Background Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson’s Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed. Methods The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology – Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures. Trial registration ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939 Protocol Version: 04-FEB-2021, Version 9.0

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

High Intolerance of Uncertainty Predicts Reduced Reinstatement of Threat Expectancy to Danger but not Safety Cues

Background. Intolerance of uncertainty (IU) is a transdiagnostic risk factor for an array of psychiatric disorders, and plays an important role in fear and threat learning. In concert, the ‘reinstatement of fear/threat’ is an understudied phenomenon thought to represent clinical symptom relapse, and occurs when unsignaled presentations of an aversive unconditional stimulus introduce uncertainty related to previously conditioned associations, leading to reinstatement of conditioned responding. The present study investigated IU as a predictor of reinstatement effects, such that individuals higher in IU would show larger reinstatement than those low in IU. Methods. Analyses were conducted on data from 62 participants who completed the Intolerance of Uncertainty Scale and provided threat expectancy ratings (i.e. certainty of receiving a shock) during a differential threat conditioning and extinction paradigm with reinstatement. Results. Findings suggested a differential increase in threat expectancy ratings to both the threat and safety cue following reinstatement, although this effect was small and did not survive follow-up tests. Nevertheless, IU was a significant predictor of reinstatement to the threat cue but not the safety cue, although this effect was not in the expected direction. Specifically, higher IU was associated with reduced threat expectancy (i.e., certainty of receiving a shock) ratings post-reinstatement. Conclusions. These findings provide support for the limited literature demonstrating an important role for IU in reinstatement effects and should be investigated further