Prevention of respiratory virus transmission by resident memory CD8+ T cells.

An ideal vaccine both attenuates virus growth and disease in infected individuals and reduces the spread of infections in the population, thereby generating herd immunity. Although this strategy has proved successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to respond rapidly to respiratory virus infections2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to the extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8+ T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8+ T cells requires the antiviral cytokine interferon-γ (IFNγ) and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8+ T cells in the respiratory tract can have important roles in protecting the host against viral disease and limiting viral spread throughout the population.

Quantitative Nontarget Analysis of CECs in Environmental Samples Can Be Improved by Considering All Mass Adducts.

Quantitative nontarget analysis (qNTA) for liquid chromatography coupled to high-resolution mass spectrometry enables a more comprehensive assessment of environmental samples. Previous studies have shown that correlations between a compound's ionization efficiency and a range of molecular descriptors can predict the compound's concentration within a factor of 5. In this study, the qNTA approach was further improved by considering all mass adducts instead of only the protonated ion. The model was based on a quantitative structure-property relationship (QSPR), including 216 contaminants of emerging concern (CECs), of which 80 exhibited adduct formation that accounted for >10% of the total peak intensity. When all mass adducts were included, the test set coefficient of determination improved to Q2 = 0.855 compared to Q2 = 0.670 when only the protonated ions were considered (test set median RF error factor 1.6). The inclusion of all adducts was also important to transfer the RF QSPR model reliably. It was assumed that RF variations are sequence-dependent; therefore, a second QSPR model for the prediction of the transferability factor was built for each sequence. For validation, samples were analyzed up to two years apart. The median prediction fold change was 1.74 for analytical standards (63 compounds) and 2.4 for enriched wastewater effluent samples (41 compounds), with 80% of the compounds predicted within a fold change of 2.4 and 3.3, respectively. The model was also validated on a second instrument, where 80% of the 26 compounds in wastewater effluent were predicted within a factor of 3.8.

Systemic infection in aged mice causes upregulation of crystallin alpha A in the RPE/choroid.

Aging changes the responsiveness of our immune defense, and this decline in immune reactivity plays an important role in the increased susceptibility to infections that marks progressing age. Aging is also the most pronounced risk factor for development of age-related macular degeneration (AMD), a disease that is characterized by dysfunctional retinal pigment epithelial (RPE) cells and loss of central vision. We have previously shown that acute systemic viral infection has a large impact on the retina in young mice, leading to upregulation of chemokines in the RPE/choroid (RPE/c) and influx of CD8 T cells in the neuroretina. In this study, we sought to investigate the impact of systemic infection on the RPE/c in aged mice to evaluate whether infection in old age could play a role in the pathogenesis of AMD. We found that systemic infection in mice led to upregulation of genes from the crystallin family in the RPE/c from aged mice, but not in the RPE/c from young mice. Crystallin alpha A (CRYAA) was the most upregulated gene, and increased amounts of CRYAA protein were also detected in the aged RPE/c. Increased CRYAA gene and protein expression has previously been found in drusen and choroid from AMD patients, and this protein has also been linked to neovascularization. Since both drusen and neovascularization are important hallmarks of advanced AMD, it is interesting to speculate if upregulation of crystallins in response to infection in old age could be relevant for the pathogenesis of AMD.

Pulmonary diffusing capacity for carbon monoxide and nitric oxide after COVID-19: A prospective cohort study (the SECURe study).

Many patients exhibit persistently reduced pulmonary diffusing capacity after coronavirus disease 2019 (COVID-19). In this study, dual test gas diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) metrics and their relationship to disease severity and physical performance were examined in patients who previously had COVID-19. An initial cohort of 148 patients diagnosed with COVID-19 of all severities between March 2020 and March 2021 had a DL,CO,NO measurement performed using the single-breath method at 5.7 months follow-up. All patients with at least one abnormal DL,CO,NO metric (n = 87) were revaluated at 12.5 months follow-up. The DL,CO,NO was used to provide the pulmonary diffusing capacity for nitric oxide (DL,NO), the pulmonary diffusing capacity for carbon monoxide (DL,CO,5s), the alveolar-capillary membrane diffusing capacity and the pulmonary capillary blood volume. At both 5.7 and 12.5 months, physical performance was assessed using a 30 s sit-to-stand test and the 6 min walk test. Approximately 60% of patients exhibited a severity-dependent decline in at least one DL,CO,NO metric at 5.7 months follow-up. At 12.5 months, both DL,NO and DL,CO,5s had returned towards normal but still remained abnormal in two-thirds of the patients. Concurrently, improvements in physical performance were observed, but with no apparent relationship to any DL,CO,NO metric. The severity-dependent decline in DL,NO and DL,CO observed at 5.7 months after COVID-19 appears to be reduced consistently at 12.5 months follow-up in the majority of patients, despite marked improvements in physical performance.

Physical capacity in children and adolescents with newly diagnosed cancer: A systematic review and meta-analysis.

OBJECTIVE: To review the body of evidence on cardiorespiratory fitness, muscle strength, and physical performance in children with newly diagnosed cancer, five databases (MEDLINE, Embase, CINAHL, CENTRAL, and Web of Science) were searched on December 19, 2022. METHODS: Thirteen studies, embodying 594 participants within 1 month of cancer diagnosis and 3674 healthy controls were included. Eighteen different outcomes on cardiorespiratory fitness (n = 2), muscle strength (n = 5), physical performance (n = 10), and adverse events (n = 1) were analyzed. RESULTS: Fifteen out of 17 outcomes on physical capacity showed severe impairments compared with healthy controls. Where possible, random-effects meta-analysis was conducted to synthesize the results. No adverse events were reported related to testing. CONCLUSION: Children with cancer have impaired cardiorespiratory fitness, muscle strength, and physical performance within the first month after diagnosis. However, the evidence is based on a small number of studies with large clinical heterogeneity, limiting the certainty of evidence.

ICP-MS As a Contributing Tool to Nontarget Screening (NTS) Analysis for Environmental Monitoring.

Due to the increasing number of chemicals released into the environment, nontarget screening (NTS) analysis is a necessary tool for providing comprehensive chemical analysis of environmental pollutants. However, NTS workflows encounter challenges in detecting both known and unknown pollutants with common chromatography high-resolution mass spectrometry (HRMS) methods. Identification of unknowns is hindered by limited elemental composition information, and quantification without identical reference standards is prone to errors. To address these issues, we propose the use of inductively coupled plasma mass spectrometry (ICP-MS) as an element-specific detector. ICP-MS can enhance the confidence of compound identification and improve quantification in NTS due to its element-specific response and unambiguous chemical composition information. Additionally, mass balance calculations for individual elements (F, Br, Cl, etc.) enable assessment of total recovery of those elements and evaluation of NTS workflows. Despite its benefits, implementing ICP-MS in NTS analysis and environmental regulation requires overcoming certain shortcomings and challenges, which are discussed herein.

Persistent Antigen Harbored by Alveolar Macrophages Enhances the Maintenance of Lung-Resident Memory CD8+ T Cells.

Lung tissue-resident memory T cells are crucial mediators of cellular immunity against respiratory viruses; however, their gradual decline hinders the development of T cell-based vaccines against respiratory pathogens. Recently, studies using adenovirus (Ad)-based vaccine vectors have shown that the number of protective lung-resident CD8+ TRMs can be maintained long term. In this article, we show that immunization of mice with a replication-deficient Ad serotype 5 expressing influenza (A/Puerto Rico/8/34) nucleoprotein (AdNP) generates a long-lived lung TRM pool that is transcriptionally indistinct from those generated during a primary influenza infection. In addition, we demonstrate that CD4+ T cells contribute to the long-term maintenance of AdNP-induced CD8+ TRMs. Using a lineage tracing approach, we identify alveolar macrophages as a cell source of persistent NP Ag after immunization with AdNP. Importantly, depletion of alveolar macrophages after AdNP immunization resulted in significantly reduced numbers of NP-specific CD8+ TRMs in the lungs and airways. Combined, our results provide further insight to the mechanisms governing the enhanced longevity of Ag-specific CD8+ lung TRMs observed after immunization with recombinant Ad.

Is new tech a pain in the neck? The impact of introducing new technologies in home-care on neck pain: a prospective study.

BACKGROUND: Home healthcare services are increasingly utilizing novel technologies to enhance quality and efficiency of caregiving, to reduce workloads and compensate for expected labor shortages in the future due to ageing populations. However, rapid, ongoing implementation of new technologies may demand considerable adaptation for employees. The objective of this study was to prospectively examine associations of newly introduced work technologies with neck pain complaints. METHODS: With a nationally representative prospective sample of home-care workers in Norway (N = 887), we estimated effects of 1) introducing new technologies and 2) the appraised quality of training during implementation on neck pain eight months after. RESULTS: A majority of employees reported new technologies having been introduced the previous 12 months (73.8%). This was not by itself associated with neck pain. However, perceived high quality of training was associated with less subsequent neck pain, also after adjustment for job demands and job control. The strongest effect was seen for "very good" versus "very poor" quality training (OR 0.35, 95% CI 0.17,0.71, in the fully adjusted model). Cross-lagged path analyses ruled out potential reverse causation stemming from the influence of pain on needs for or appraisals of training. CONCLUSION: The present findings suggest the introduction of new work technologies has a significant impact on home-care workers' health, depending on the quality of training during implementation. This highlights the need to include training programs in risk assessments when implementing new technologies.

The potential of structured active play for social and personal development in preschoolers during cancer treatment: A qualitative RePlay study.

AIM: To explore the potential of a structured active play intervention to promote social and personal development in preschoolers during cancer treatment. DESIGN: A hermeneutic-phenomenological inspired explorative study. METHODS: Participant observations were conducted on 15 consecutively sampled children (aged 1-5 years) from April 2021 to April 2022. Observations were written as narrative scenic descriptions from field notes and were analysed inspired by hermeneutic-phenomenological analysis and using a thematic analysis structure. RESULTS: Observations were carried out during 67 group or individual structured active play sessions, resulting in 129 scenic descriptions. Observations of the children's emotional, verbal and bodily expressions and social interactions resulted in three main themes: (1) wanting to play, (2) gaining confidence in movement and (3) being part of a group. The findings showed how children, irrespective of age and the severity of their illness, wanted to play and expressed joy of movement. The children's daily physical state fluctuated and influenced their motivation to participate as well as their confidence in their physical abilities. Through structured active play and with support from their parents and healthcare professionals, the children had successful movement experiences and regained confidence in movement, supporting their personal development. Playing together with other children and accompanied by their parents, healthcare professionals supported the children's opportunities to practice social skills, such as turn-taking, waiting and taking charge. Familiarity, recognizability and fun were key motivational components for the children. CONCLUSION: Participating in structured active play during treatment has the potential to promote personal and social development in preschoolers with cancer. Parents play a crucial role in supporting the participation of their children. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The healthcare system and healthcare professionals should provide opportunities for preschoolers with cancer and other illnesses to participate in structured active play. IMPACT: What problem did the study address? Cancer treatment affects the development of preschoolers' gross motor-, personal and social skills-essential skills in childhood development. This study aimed to explore the potential for social and personal development through structured active play. What were the main findings? This study found that preschoolers want to play, and participating in structured active play can support their personal and social development through regained confidence in movement and becoming part of a group. Where and on whom will the research have an impact? The research impacts healthcare professionals working with preschoolers in the healthcare system. Creating opportunities for preschoolers to participate in structured active play throughout treatment can promote personal and social development. REPORTING METHOD: The study adheres to relevant EQUATOR guidelines and is reported according to the Standards for Reporting Qualitative Research (SRQR) checklist. PATIENT OR PUBLIC CONTRIBUTION: Participants in this study were preschoolers with cancer and their parents. No public or patient involvement in the design of this study. TRIAL AND PROTOCOL REGISTRATION: ClinicalTrials.gov: NCT04672681. Registered on December 17, 2020. https://clinicaltrials.gov/ct2/show/NCT04672681.

Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice.

OBJECTIVE: A prophylactic vaccine is needed to control the HCV epidemic, with genotypes 1-3 causing >80% of worldwide infections. Vaccine development is hampered by HCV heterogeneity, viral escape including protection of conserved neutralising epitopes and suboptimal efficacy of HCV cell culture systems. We developed cell culture-based inactivated genotype 1-3 HCV vaccine candidates to present natively folded envelope proteins to elicit neutralising antibodies. DESIGN: High-yield genotype 1a, 2a and 3a HCV were developed by serial passage of TNcc, J6cc and DBN3acc in Huh7.5 cells and engineering of acquired mutations detected by next-generation sequencing. Neutralising epitope exposure was determined in cell-based neutralisation assays using human monoclonal antibodies AR3A and AR4A, and polyclonal antibody C211. BALB/c mice were immunised with processed and inactivated genotype 1a, 2a or 3a viruses using AddaVax, a homologue of the licenced adjuvant MF-59. Purified mouse and patient serum IgG were assayed for neutralisation capacity; mouse IgG and immune-sera were assayed for E1/E2 binding. RESULTS: Compared with the original viruses, high-yield viruses had up to ~1000 fold increased infectivity titres (peak titres: 6-7 log10 focus-forming units (FFU)/mL) and up to ~2470 fold increased exposure of conserved neutralising epitopes. Vaccine-induced IgG broadly neutralised genotype 1-6 HCV (EC50: 30-193 µg/mL; mean 71 µg/mL), compared favourably with IgG from chronically infected patients, and bound genotype 1-3 E1/E2; immune-sera endpoint titres reached up to 32 000. CONCLUSION: High-yield genotype 1-3 HCV could be developed as basis for inactivated vaccine candidates inducing broadly neutralising antibodies in mice supporting further preclinical development.

Supercritical Fluid Chromatography Coupled to High-Resolution Mass Spectrometry Reveals Persistent Mobile Organic Compounds with Unknown Toxicity in Wastewater Effluents.

Broad screening approaches for monitoring wastewater are normally based on reversed-phase liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS). This method is not sufficient for the very polar micropollutants, neglected in the past due to a lack of suitable analytical methods. In this study, we used supercritical fluid chromatography (SFC) to detect very polar and yet-undetected micropollutants in wastewater effluents. We tentatively identified 85 compounds, whereas 18 have only rarely been detected and 11 have not previously been detected in wastewater effluents such as 17α-hydroxypregnenolone, a likely transformation product (TP) of steroids, and 1H-indole-3-carboxamide, a likely TP from new synthetic cannabinoids. Suspect screening of 25 effluent wastewater samples from 8 wastewater treatment plants revealed several distinct potential pollution sources such as a pharmaceutical company and a golf court. The analysis of the same samples with LC-HRMS showed clearly how SFC increases the ionization efficiency for low-molecular-weight micropollutants (m/z < 300 Da) by a factor 2 to 87 times, which significantly improved the mass spectra for identifying very polar compounds. In order to assess which micropollutants might be of environmental concern, literature and toxicological databases were screened. There was a lack of available hazard and bio-activity data for regulatory-relevant in vitro and in vivo assays for >50% of the micropollutants. Especially, 70% of the data were lacking for the whole organism (in vivo) tests.

Source-Supported Suspect Screening (4S) of Phytotoxins in Terrestrial and Aquatic Environments: A Field Study of Lupinus angustifolius L. (Blue Lupin).

Phytotoxins (PTs) are bioactive secondary metabolites produced by plants. More recently, they have been recognized as important aquatic micropollutants. Despite that, only a few PTs have been detected and reported in terrestrial and aquatic environments, while their source and leaching pathways remain largely unclear. Herein, we established a novel approach named source-supported suspect screening (4S) to discover PTs in different environments, investigate their environmental occurrences, identify their sources, and initiate discussions on their leaching mechanisms. The 4S-approach was demonstrated on a five-month Lupinus angustifolius L. (L. angustifolius) crop field experiment, where plant, topsoil, drainage water, and surface water were sampled and analyzed. As a result, 72 PTs (flavonoids and alkaloids) were identified at high confidence, with 10 PTs fully confirmed. Fifty-three PTs detected in soil or water were linked to L. angustifolius, among which 26 PTs were coherently detected in all three environmental compartments. The occurrence and abundance of PTs in terrestrial soil and aquatic environments were influenced by the plant growth stage and precipitation. Soil served as an intermedium when PTs leached from L. angustifolius to the drainage water, while the degree of retardation and eventual occurrence in the aquatic environment depended on both PTs and soil physico-chemical properties.

Ultra-high-performance supercritical fluid chromatography-mass spectrometry for the analysis of organic contaminants in sediments.

A nontarget screening method was developed based on D-optimal designs for ultra-high performance supercritical fluid chromatography with positive and negative electrospray ionization mode mass spectrometry. A mixture of organic contaminants such as pesticides, steroids, surfactants, phenolic and fatty acids, and polycyclic aromatic hydrocarbon derivatives, was used for the optimization. An aprotic mixture of dichloromethane and acetone [3:1] performed overall best as the injection solvent. The highest peak capacities (n) were accomplished at the shallowest gradient (1%B/min), ammonium formate (n = 378 in negative ionization mode), or ammonium acetate (n = 327 in positive ionization mode) in methanol as the modifier. Capillary voltage, make-up solvent flow rate, water, and additive concentration were the most significant factors for improving peak intensity: higher peak intensities were obtained at lower additive concentrations (5mM ammonium formate), and with 5% water in positive ionization mode. Conversely, water had detrimental effects in negative ionization mode. The optimized method was used to quantify organic contaminants in 17 freshwater sediment samples from Copenhagen, Denmark. Out of 50 monitored contaminants, 35 were detected in at least one sample. Further, the method has a potential for target and nontarget screening analysis of organic contaminants in solid matrices.

Functional and cognitive rehabilitation interventions during intensive care admission: A protocol for a systematic integrative review.

BACKGROUND: Long-term cognitive impairment occurs in up to 60% of intensive care unit (ICU) survivors. Early use of functional and cognitive rehabilitation interventions, while patients are still in ICU, may reduce cognitive decline. We aim to describe the functional and cognitive interventions used during the ICU stay, the healthcare professionals providing interventions, and the potential impact on functional and cognitive rehabilitation. METHOD: In this integrative systematic review, we will include empirical qualitative, quantitative, mixed- and multiple-methods studies assessing the use of functional and cognitive rehabilitation provided in ICU. We will identify studies in relevant electronic databases from 2012 to 2022, which will be screened for eligibility by at least two reviewers. Literature reported as narrative reviews and editorials will be excluded. We will assess the impact of interventions evaluating a cognitive and functional function, quality of life, and all-cause mortality at 6-12 months after ICU discharge. The Revised Cochrane risk-of-bias Tool will be used for assessing risk of bias in clinical trials. For observational studies, we will use the National Institutes of Health Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. Furthermore, we will use the critical appraisal skills programme for qualitative studies and the mixed methods appraisal tool for mixed methods studies. We will construct four matrices, including results describing which ICU patients and healthcare professionals were engaged in rehabilitation, which interventions were included in early rehabilitation in ICU, the potential impact on patient outcomes of rehabilitation interventions provided in ICU and a narrative synthesis of themes. A summary of the main results will be reported using modified GRADE methodology. IMPACT: This integrative review will inform the feasibility randomised clinical trial testing the development of a complex intervention targeting functional and cognitive rehabilitation for patients in ICU.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

The contribution of office design to the appraisal of job control: A longitudinal study.

The appraisal of control over work intensity and decisions at the workplace is a well-established determinant of health and well-being among employees. Building on job design theories, the overarching aim of this study was to determine office layout as a predictor of perceived job control. Specifically, we investigated between-group differences in control by contrasting employees in cellular offices with employees in shared/open offices, as well as effects on control among employees transitioning from one office design to another. This is a longitudinal study with three survey points across 48 months comprising 3,415 Norwegian office employees. Data were analyzed with latent growth curve analyses, adjusted for gender, age, leadership responsibility, and teleworking. Employees in cellular offices reported significantly higher control over work intensity and control over decisions when compared with employees in shared/open workspaces. Transitioning from a shared/open workspace to a cellular office led to a significant increase in perceived control regarding work intensity. As the experience of control may buffer the negative impact of job demands, organizations that rely on shared or open office solutions may benefit from identifying tools that can contribute to enhancing their employees' perceived control.

Inactivated whole hepatitis C virus vaccine employing a licensed adjuvant elicits cross-genotype neutralizing antibodies in mice.

BACKGROUND & AIMS: A prophylactic vaccine is required to eliminate HCV as a global public health threat. We developed whole virus inactivated HCV vaccine candidates employing a licensed adjuvant. Further, we investigated the effects of HCV envelope protein modifications (to increase neutralization epitope exposure) on immunogenicity. METHODS: Whole virus vaccine antigen was produced in Huh7.5 hepatoma cells, processed using a multistep protocol and formulated with adjuvant (MF-59 analogue AddaVax or aluminium hydroxide). We investigated the capacity of IgG purified from the serum of immunized BALB/c mice to neutralize genotype 1-6 HCV (by virus neutralization assays) and to bind homologous envelope proteins (by ELISA). Viruses used for immunizations were (i) HCV5aHi with strain SA13 envelope proteins and modification of an O-linked glycosylation site in E2 (T385P), (ii) HCV5aHi(T385) with reversion of T385P to T385, featuring the original E2 sequence determined in vivo and (iii) HCV5aHi(ΔHVR1) with deletion of HVR1. For these viruses, epitope exposure was investigated using human monoclonal (AR3A and AR4A) and polyclonal (C211 and H06) antibodies in neutralization assays. RESULTS: Processed HCV5aHi formulated with AddaVax induced antibodies that efficiently bound homologous envelope proteins and broadly neutralized cultured genotype 1-6 HCV, with half maximal inhibitory concentrations of between 14 and 192 µg/ml (mean of 36 µg/ml against the homologous virus). Vaccination with aluminium hydroxide was less immunogenic. Compared to HCV5aHi(T385) with the original E2 sequence, HCV5aHi with a modified glycosylation site and HCV5aHi(ΔHVR1) without HVR1 showed increased neutralization epitope exposure but similar immunogenicity. CONCLUSION: Using an adjuvant suitable for human use, we developed inactivated whole HCV vaccine candidates that induced broadly neutralizing antibodies, which warrant investigation in further pre-clinical studies. LAY SUMMARY: A vaccine against hepatitis C virus (HCV) is needed to prevent the estimated 2 million new infections and 400,000 deaths caused by this virus each year. We developed inactivated whole HCV vaccine candidates using adjuvants licensed for human use, which, following immunization of mice, induced antibodies that efficiently neutralized all HCV genotypes with recognized epidemiological importance. HCV variants with modified envelope proteins exhibited similar immunogenicity as the virus with the original envelope proteins.

Tapering of TNF inhibitors in axial spondyloarthritis in routine care - 2-year clinical and MRI outcomes and predictors of successful tapering.

OBJECTIVES: In a 2-year follow-up study of patients with axial spondyloarthritis (axSpA) in clinical remission who tapered TNF inhibitor (TNFi) treatment according to a clinical guideline, we aimed to investigate the proportion who successfully tapered/discontinued therapy and baseline predictors thereof. The proportion regaining clinical remission after flare and the progression on MRI/radiography were also assessed. METHODS: One-hundred-and-nine patients (78 [72%]/31 [28%] receiving standard and reduced dose, respectively) in clinical remission (BASDAI < 40, physician global score < 40) and no signs of disease activity the previous year tapered TNFi as follows: to two-thirds of standard dose at baseline, half at week 16, one-third at week 32 and discontinuation at week 48. Patients experiencing clinical, BASDAI or MRI flare (predefined criteria) stopped tapering and escalated to previous dose. Prediction analyses were performed by multivariable regression. RESULTS: One hundred and six patients (97%) completed 2 years' follow-up; 55 patients (52%) had successfully tapered: 23 (22%) receiving two-thirds, 15 (14%) half, 16 (15%) one-third dose and 1 (1%) discontinued. In patients at standard dose at baseline (n = 78), lower physician global score was the only independent predictor of successful tapering (odds ratio [OR] = 0.79 [95% CI: 0.64, 0.93]; P = 0.003). In the entire patient group lower physician global score (OR = 0.86 [0.75, 0.98]; P = 0.017), lower Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Erosion score (OR = 0.78 [0.57, 0.98]; P = 0.029) and current smoker (OR = 3.28 [1.15, 10.57]; P = 0.026) were independent predictors of successful tapering. At 2 years, 97% of patients were in clinical remission. Minimal changes in imaging findings were observed. CONCLUSION: After 2 years following a clinical guideline, 52% of patients with axSpA in clinical remission had successfully tapered TNFi, only 1% discontinued. Baseline physician global score was an independent predictor of successful tapering.

Benefits of cardiac rehabilitation following acute coronary syndrome for patients with and without diabetes: a systematic review and meta-analysis.

AIM: The benefits of cardiac rehabilitation (CR) after acute coronary syndrome (ACS) are well established. However, the relative benefit of CR in those with comorbidities, including diabetes, is not well understood. This systematic review and meta-analysis examined the benefit of CR on exercise capacity and secondary outcomes in ACS patients with a co-diagnosis of diabetes compared to those without. METHODS: Five databases were searched in May 2021 for randomised controlled trials (RCTs) and observational studies reporting CR outcomes in ACS patients with and without diabetes. The primary outcome of this study was exercise capacity expressed as metabolic equivalents (METs) at the end of CR and ≥ 12-month follow-up. Secondary outcomes included health-related quality of life, cardiovascular- and diabetes-related outcomes, lifestyle-related outcomes, psychological wellbeing, and return to work. If relevant/possible, studies were pooled using random-effects meta-analysis. RESULTS: A total of 28 studies were included, of which 20 reported exercise capacity and 18 reported secondary outcomes. Overall, the studies were judged to have a high risk of bias. Meta-analysis of exercise capacity was undertaken based on 18 studies (no RCTs) including 15,288 patients, of whom 3369 had diabetes. This analysis showed a statistically significant smaller difference in the change in METs in ACS patients with diabetes (standardised mean difference (SMD) from baseline to end of CR: - 0.15 (95% CI: - 0.24 to - 0.06); SMD at the ≥ 12-month follow-up: - 0.16 (95% CI: - 0.23 to - 0.10, four studies)). CONCLUSION: The benefit of CR on exercise capacity in ACS patients was lower in those with diabetes than in those without diabetes. Given the small magnitude of this difference and the substantial heterogeneity in the results of the study caused by diverse study designs and methodologies, further research is needed to confirm our findings. Future work should seek to eliminate bias in observational studies and evaluate CR based on comprehensive outcomes.

The relationship between telework from home and employee health: a systematic review.

BACKGROUND: Globalization and technological progress have made telework arrangements such as telework from home (TWFH) well-established in modern economies. TWFH was rapidly and widely implemented to reduce virus spread during the Coronavirus disease (COVID-19) pandemic, and will probably be widespread also post-pandemic. How such work arrangements affect employee health is largely unknown. Main objective of this review was to assess the evidence on the relationship between TWFH and employee health. METHODS: We conducted electronic searches in MEDLINE, Embase, Amed, PsycINFO, PubMed, and Scopus for peer-reviewed, original research with quantitative design published from January 2010 to February 2021. Our aim was to assess the evidence for associations between TWFH and health-related outcomes in employed office workers. Risk of bias in each study was evaluated by the Newcastle-Ottawa Scale and the collected body of evidence was evaluated using the the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included 14 relevant studies (22,919 participants) reporting on 28 outcomes, which were sorted into six outcome categories (general health, pain, well-being, stress, exhaustion & burnout, and satisfaction with overall life & leisure). Few studies, with many having suboptimal designs and/or other methodological issues, investigating a limited number of outcomes, resulted in the body of evidence for the detected outcome categories being GRADED either as low or very low. CONCLUSIONS: The consisting evidence on the relationship between TWFH and employee health is scarce. The non-existence of studies on many relevant and important health outcomes indicates a vast knowledge gap that is crucial to fill when determining how to implement TWFH in the future working life. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO registration ID # CRD42021233796 .