Risk of infection with ferric derisomaltose compared to standard of care in patients with heart failure and iron deficiency in the uk: a prespecified analysis of the ironman trial

IntroductionRecent results from the IRONMAN trial add to previous data and demonstrate that correction of iron deficiency in patients with heart failure, with high dose IV iron can improve quality of life, and reduce the risk of heart failure hospitalisation (by around 25% in meta-analysis). Yet there are theoretical risks that IV iron administration may increase the risk from bacterial infection. A meta-analysis in 2021 (across many clinical indications) suggested an excess risk of infections with IV iron but noted most trials did not pre-specify infection as an end point, with risk of reporting bias. To answer this important question hospitalisation for infection or death due to infection were pre-specified safety endpoints in IRONMAN.MethodsIRONMAN was a prospective, randomised open-label, blinded endpoint (PROBE) event-driven trial of IV ferric derisomaltose (FDI) and usual care versus usual care alone in patients with heart failure (LVEF ≤45% ) and iron deficiency (ferritin <100 µg/L and/or TSAT <20%, provided ferritin ≤400 µg/L). Patients were enrolled if they had a current or recent hospitalisation for heart failure or elevated natriuretic peptide plasma concentration. Every four months, IV iron was administered if either ferritin was <100 µg/L or TSAT was <25% (provided ferritin ≤400 µg/L). All hospitalisations and deaths were adjudicated blindly. Given that a large part of the trial was conducted during the COVID-19 pandemic, we also evaluated COVID-19 related SAEs.Results1137 patients (26.4% women) with median (IQR) age 73 (63 to 79) years were recruited by the Ironman Study Group between Aug 2016 and Oct 2021 across 70 UK sites. Median (IQR) follow-up was 2·7 (1·8 to 3·6) years. 97% of patients consented to record linkage to national databases of deaths and hospital discharge summaries, thereby ensuring investigators were aware of all potential events. There were a similar number of hospitalisations due to infection for those assigned to ferric derisomaltose (175) and usual care (213) (p = 0.16) and infection related death (34 and 28, respectively, p = 0.43). When considering first events of hospitalisation for infection or infection death there were 120 (21.1%) events for those randomised to IV FDI and 146 (25.7%) for the usual care arm (figure). There were fewer patients with COVID related SAEs in those randomised to IV FDI (12) as compared with usual care (30), HR (95% CI) 0.40 (0.20, 0.78). p=0.007. For deaths attributed to COVID-19, 4 were seen in the IV FDI arm and 8 in the usual care arm: HR 0.51 (0.15, 1.68) p=0.27.ConclusionsThere was no excess risk of infection related hospitalisation or death in patients receiving IV ferric derisomaltose. Fewer COVID-19 related SAEs were seen in patients receiving IV FDI. Given that iron plays an important role in the T and B cell response to vaccination, further analysis needs to be done in this area.Conflict of InterestHonorarium for education from Pharmocosmos

Risk aversion and COVID-19 vaccine hesitancy.

We here investigate the role of risk aversion in COVID-19 vaccine hesitancy. The theoretical effect is ambiguous, as both COVID-19 infection and vaccination side-effects involve probabilistic elements. In large-scale data covering five European countries, we find that vaccine hesitancy falls with risk aversion, so that COVID-19 infection is perceived as involving greater risk than is vaccination.

SARS-CoV-2 coinfections with variant genomic lineages identified by multiplex fragment analysis.

Immunocompromised patients can experience prolonged SARS-CoV-2 infections in the setting of a lack of protectivity immunity despite vaccination. As circulating SARS-CoV-2 strains become more heterogeneous, concomitant infection with multiple SARS-CoV-2 variants has become an increasing concern. Immunocompromised patient populations represent potential reservoirs for the emergence of novel SARS-CoV-2 variants through mutagenic change or coinfection followed by recombinatory events. Identification of SARS-CoV-2 coinfections is challenging using traditional next generation sequencing pipelines; however, targeted genotyping approaches can facilitate detection. Here we describe five COVID-19 cases caused by coinfection with different SARS-CoV-2 variants (Delta/Omicron BA.1 and Omicron BA.1/BA.2) as identified by multiplex fragment analysis.

The impact of COVID-19 lockdown stringency on loneliness in five European countries.

RATIONALE: The coronavirus pandemic has forced governments to implement a variety of different dynamic lockdown-stringency strategies in the last two years. Extensive lockdown periods could have potential unintended consequences on mental health, at least for at-risk groups. OBJECTIVE: We present novel evidence on the heterogeneous direct and indirect effects of lockdown-stringency measures on individuals' perception of social isolation (i.e. loneliness) using panel data from five European countries (Germany, France, Spain, Italy and Sweden), which tracks changes in both in-person and remote social interactions between May 2020 and March 2021. METHOD: We combine data from the COME-HERE panel survey (University of Luxembourg) and the Oxford COVID-19 Government Response Tracker (OxCGRT). We implement a dynamic mixture model in order to estimate the loneliness sub-population classes based on the severity of loneliness, as well as the evolution of social interactions. RESULTS: While loneliness is remarkably persistent over time, we find substantial heterogeneity across individuals, identifying four latent groups by loneliness severity. Group membership probability varies with age, gender, education and cohabitation status. Moreover, we note significant differences in the impact of social interactions on loneliness by degree of severity. Older people are less likely to feel lonely, but were more affected by lockdown measures, partly due to a reduction in face-to-face interactions. On the contrary, the younger, especially those living alone, report high levels of loneliness that are largely unaffected by changes in the pandemic after lockdown measures were initially implemented. CONCLUSIONS: Understanding the heterogeneity in loneliness is key for the identification of at-risk populations that can be severely affected by extended lockdown measures. As part of public-health crisis-response systems, it is critical to develop support measures for older individuals living alone, as well as promoting continuous remote communication for individuals more likely to experience high levels of loneliness.

Gender, loneliness and happiness during COVID-19.

We analyse a measure of loneliness from a representative sample of German individuals interviewed in both 2017 and at the beginning of the COVID-19 pandemic in 2020. Both men and women felt lonelier during the COVID-19 pandemic than they did in 2017. The pandemic more than doubled the gender loneliness gap: women were lonelier than men in 2017, and the 2017-2020 rise in loneliness was far larger for women. This rise is mirrored in life-satisfaction scores. Men's life satisfaction changed only little between 2017 and 2020; yet that of women fell dramatically, and sufficiently so to produce a female penalty in life satisfaction. We estimate that almost all of this female penalty is explained by the disproportionate rise in loneliness for women during the COVID-19 pandemic.

SARS-CoV-2 coinfections with variant genomic lineages identified by multiplex fragment analysis

Immunocompromised patients can experience prolonged SARS-CoV-2 infections in the setting of a lack of protectivity immunity despite vaccination. As circulating SARS-CoV-2 strains become more heterogeneous, concomitant infection with multiple SARS-CoV-2 variants has become an increasing concern. Immunocompromised patient populations represent potential reservoirs for the emergence of novel SARS-CoV-2 variants through mutagenic change or coinfection followed by recombinatory events. Identification of SARS-CoV-2 coinfections is challenging using traditional next generation sequencing pipelines;however, targeted genotyping approaches can facilitate detection. Here we describe five COVID-19 cases caused by coinfection with different SARS-CoV-2 variants (Delta/Omicron BA.1 and Omicron BA.1/BA.2) as identified by multiplex fragment analysis.

Building International Capacity for Citizen Scientist Engagement in Mosquito Surveillance and Mitigation: The GLOBE Program's GLOBE Observer Mosquito Habitat Mapper.

The GLOBE Program's GLOBE Observer Mosquito Habitat Mapper is a no-cost citizen scientist data collection tool compatible with Android and iOS devices. Available in 14 languages and 126 countries, it supports mosquito vector surveillance, mitigation, and education by interested individuals and as part of participatory community surveillance programs. For low-resource communities where mosquito control services are inadequate, the Mosquito Habitat Mapper supports local health action, empowerment, and environmental justice. The tangible benefits to human health supported by the Mosquito Habitat Mapper have encouraged its wide adoption, with more than 32,000 observations submitted from 84 countries. The Mosquito Habitat Mapper surveillance and data collection tool is complemented by an open database, a map visualization interface, data processing and analysis tools, and a supporting education and outreach campaign. The mobile app tool and associated research and education assets can be rapidly deployed in the event of a pandemic or local disease outbreak, contributing to global readiness and resilience in the face of mosquito-borne disease. Here, we describe the app, the Mosquito Habitat Mapper information system, examples of Mosquito Habitat Mapper deployment in scientific research, and the outreach campaign that supports volunteer training and STEM education of students worldwide.

Overstimulation of the ergoreflex-A possible mechanism to explain symptoms in long COVID.

Long COVID refers to a multitude of symptoms that persist long after SARS-CoV-2 infection. Fatigue and breathlessness are the most common symptoms of long COVID across a range of studies. They are also cardinal symptoms of chronic heart failure (CHF). In this review, we propose that fatigue and breathlessness in patients with long COVID may be explained by skeletal muscle abnormalities, in a manner similar to patients with CHF. The ergoreflex is a cardiorespiratory reflex activated by exercise, which couples ventilation and cardiovascular function to exercise intensity. At least part of the symptomatology of CHF is related to abnormal skeletal muscle and an enhanced ergoreflex, resulting in heightened sympathetic, vasoconstrictor and ventilator drives. Similarly, SARS-CoV-2 infection results in a hyperinflammatory and hypercatabolic state. This leads to reduction in skeletal muscle mass and altered function. We postulate that the ergoreflex is chronically overstimulated, resulting in fatigue and breathlessness. Exercise training preserves muscle mass and function as well as reduces ergoreflex activation; therefore may have a role in improving symptoms associated with long COVID. Should the ergoreflex be proven to be an important pathophysiological mechanism of long COVID, tailored exercise interventions should be trialed with the aim of improving both symptoms and perhaps outcomes in patients with long COVID.

Parents' perceptions of their children's physical activity during the COVID-19 pandemic.

BACKGROUND: COVID-19 has drastically changed the everyday lives of children, including limiting interactions with peers, loss of regularly organized activities, and closure of schools and recreational facilities. While COVID-19 protocols are in place to reduce viral transmission, they have affected children's access to physical activity opportunities. The purpose of this study was to understand how COVID-19 has affected children's engagement in physical activity and to identify strategies that can support children's return to physical activity programming in public places. METHODS: Parents of past participants in the Grade 5 ACT-i-Pass Program in London, Ontario, Canada were invited to participate in a semi-structured interview online (in November and December 2020) via Microsoft Teams. The script was comprised of questions about their child's physical activity levels (before, current, and anticipated following COVID-19), lifestyle changes due to COVID-19, and what service providers can do to assist children's return to public programming. Interviews were transcribed in Microsoft Teams, reviewed by a member of the research team, and analyzed in NVivo 12 using thematic analysis. RESULTS: Twenty-seven parents participated in an interview. Four themes and two subthemes were identified during analysis: (1) modifications to everyday life (a. activity options available and b. altered social environment), (2) safety in public spaces, (3) accessibility of activities, and (4) utilizing outdoor spaces. CONCLUSIONS: COVID-19 protocols have decreased children's physical activity levels due to the loss of their regular activities, recreational spaces, and peer support. Implementing facility and activity-specific health protocols, providing outdoor activity options, and offering a variety of activity types, times, and locations are three strategies recommended by parents to help facilitate their children's return to public recreational places. Due to the negative consequences of physical inactivity on children's health and well-being, service providers need to implement programming and safety protocols that support children's engagement in physical activity throughout the remainder of, and the years following, the COVID-19 pandemic.

Characteristics associated with COVID-19 vaccine hesitancy.

Understanding what lies behind actual COVID-19 vaccine hesitancy is fundamental to help policy makers increase vaccination rates and reach herd immunity. We use June 2021 data from the COME-HERE survey to explore the predictors of actual vaccine hesitancy in France, Germany, Italy, Luxembourg, Spain and Sweden. We estimate a linear-probability model with a rich set of covariates and address issues of common-method variance. 13% of our sample say they do not plan to be vaccinated. Post-Secondary education, home-ownership, having an underlying health condition, and one standard-deviation higher age or income are all associated with lower vaccine hesitancy of 2-4.5% points. Conservative-leaning political attitudes and a one standard-deviation lower degree of confidence in the government increase this probability by 3 and 6% points respectively. Vaccine hesitancy in Spain and Sweden is significantly lower than in the other countries.

Multiplex Fragment Analysis for Flexible Detection of All SARS-CoV-2 Variants of Concern.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge, and effective tracking requires rapid return of results. Surveillance of variants is typically performed by whole genome sequencing (WGS), which can be financially prohibitive and requires specialized equipment and bioinformatic expertise. Genotyping approaches are rapid methods for monitoring SARS-CoV-2 variants but require continuous adaptation. Fragment analysis may represent an approach for improved SARS-CoV-2 variant detection. METHODS: A multiplex fragment analysis approach (CoVarScan) was validated using PCR targeting variants by size and fluorescent color. Eight SARS-CoV-2 mutational hot spots in variants of concern (VOCs) were targeted. Three primer pairs (recurrently deleted region [RDR] 1, RDR2, and RDR3-4) flank RDRs in the S-gene. Three allele-specific primers target recurrent spike receptor binding domain mutants. Lastly, 2 primer pairs target recurrent deletions or insertions in ORF1A and ORF8. Fragments were resolved and analyzed by capillary electrophoresis (ABI 3730XL), and mutational signatures were compared to WGS results. RESULTS: We validated CoVarScan using 3544 clinical respiratory specimens. The assay exhibited 96% sensitivity and 99% specificity compared to WGS. The limit of detection for the core targets (RDR1, RDR2, and ORF1A) was 5 copies/reaction. Variants were identified in 95% of samples with cycle threshold (CT) <30 and 75% of samples with a CT 34 to 35. Assay design was frozen April 2021, but all subsequent VOCs have been detected including Delta (n = 2820), Mu, (n = 6), Lambda (n = 6), and Omicron (n = 309). Genotyping results are available in as little as 4 h. CONCLUSIONS: Multiplex fragment analysis is adaptable and rapid and has similar accuracy to WGS to classify SARS-CoV-2 variants.

Correction to: the Fall in Income Inequality during COVID-19 in Four European Countries.

[This corrects the article DOI: 10.1007/s10888-021-09499-2.].

Mainstreaming Urban Agriculture: Opportunities and Barriers to Upscaling City Farming

Urban Agriculture (UA), i.e., the production of crops or rearing of livestock in cities, is growing in popularity. Upscaled UA is increasingly gaining support from policy makers, funders, local authorities and other key actors across the globe. Radical forms of the concept, in the form of edible rooftops, urban farms and high-tech growing projects, are becoming more commonplace in our cityscapes;enabling production on a level not witnessed previously. With the mainstreaming of large-scale UA comes the potential to further the social, environmental and economic value of the practice, through job creation, biodiversity enhancement, the creation of short food supply chains and other benefits. Yet, despite this growth, there are barriers to upscaling city farming. Evidence suggests that a core issue surrounds urban soil contamination and hesitation with regards to crops in the city. This paper uses a qualitative approach to explore the UK’s largest urban farm and a spectrum of other UA sites to illustrate such barriers. We reveal how public hesitation, financial barriers and soil quality prevent development. We reflect on the breadth of the issue and call for a more pragmatic approach to these barriers. In doing so, we propose a path forward for enabling UA at scale.

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

AIMS: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect. METHODS AND RESULTS: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041). CONCLUSION: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

The fall in income inequality during COVID-19 in four European countries.

We here use panel data from the COME-HERE survey to track income inequality during COVID-19 in France, Germany, Italy, and Spain. Relative inequality in equivalent household disposable income among individuals changed in a hump-shaped way between January 2020 and January 2021, with an initial rise from January to May 2020 being more than reversed by September 2020. Absolute inequality also fell over this period. Due to the pandemic some households lost more than others, and government compensation schemes were targeted towards the poorest, implying that on average income differences decreased. Generalized Lorenz domination reveals that these distributive changes reduced welfare in Italy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10888-021-09499-2.

Parents' Report of Canadian Elementary School Children's Physical Activity and Screen Time during the COVID-19 Pandemic: A Longitudinal Study.

COVID-19 public health protocols have altered children's daily routines, limiting their physical activity opportunities. The purpose of this study was to examine how the COVID-19 pandemic affected children's (ages 10-12 years) physical activity and screen time, and to explore the impact of gender, socioeconomic status (SES), and public health constraints (i.e., facility use and social interaction) on the changes in children's health behaviors. Online surveys were disseminated to parents at two time points: before COVID-19 (May 2019 to February 2020) and during COVID-19 (November to December 2020). Wilcoxon signed-rank tests were used to assess changes in physical activity and screen time, and for subgroup analyses. Parents (n = 95) reported declines in children's physical activity (Z = -2.53, p = 0.01, d = 0.18), and increases in weekday (Z = -4.61, p < 0.01, d = 0.33) and weekend screen time (Z = -3.79, p < 0.01, d = 0.27). Significant changes in physical activity and screen time behaviors were identified between gender, SES, and facility use groups. All social interaction groups underwent significant changes in screen time. Overall, COVID-19 protocols have negatively influenced children's physical activity and screen time. Due to the negative consequences of inactivity and excessive screen time, resources must be made available to support families during the pandemic.

Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48.

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.

Computational fluid dynamics modeling of cough transport in an aircraft cabin

To characterize the transport of respiratory pathogens during commercial air travel, Computational Fluid Dynamics simulations were performed to track particles expelled by coughing by a passenger assigned to different seats on a Boeing 737 aircraft. Simulation data were post-processed to calculate the amounts of particles inhaled by nearby passengers. Different airflow rates were used, as well as different initial conditions to account for random fluctuations of the flow field. Overall, 80% of the particles were removed from the cabin in 1.3–2.6 min, depending on conditions, and 95% of the particles were removed in 2.4–4.6 min. Reducing airflow increased particle dispersion throughout the cabin but did not increase the highest exposure of nearby passengers. The highest exposure was 0.3% of the nonvolatile mass expelled by the cough, and the median exposure for seats within 3 feet of the cough discharge was 0.1%, which was in line with recent experimental testing.

COVID-19 compliance behaviors of older people: The role of cognitive and non-cognitive skills.

This paper examines the empirical relationship between individuals' cognitive and non-cognitive abilities and COVID-19 compliance behaviors using cross-country data from the Survey of Health, Ageing and Retirement in Europe (SHARE). We find that both cognitive and non-cognitive skills predict responsible health behaviors during the COVID-19 crisis. Episodic memory is the most important cognitive skill, while conscientiousness and neuroticism are the most significant personality traits. There is also some evidence of a role for an internal locus of control in compliance.