Faster detection of asymptomatic COVID-19 cases among care home staff in England through the combination of SARS-CoV-2 testing technologies.

To detect SARS-CoV-2 amongst asymptomatic care home staff in England, a dual-technology weekly testing regime was introduced on 23 December 2020. A lateral flow device (LFD) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) test were taken on the same day (day 0) and a midweek LFD test was taken three to four days later. We evaluated the effectiveness of using dual-technology to detect SARS-CoV-2 between December 2020 to April 2021. Viral concentrations derived from qRT-PCR were used to determine the probable stage of infection and likely level of infectiousness. Day 0 PCR detected 1,493 cases of COVID-19, of which 53% were in the early stages of infection with little to no risk of transmission. Day 0 LFD detected 83% of cases that were highly likely to be infectious. On average, LFD results were received 46.3 h earlier than PCR, enabling removal of likely infectious staff from the workplace quicker than by weekly PCR alone. Demonstrating the rapidity of LFDs to detect highly infectious cases could be combined with the ability of PCR to detect cases in the very early stages of infection. In practice, asymptomatic care home staff were removed from the workplace earlier, breaking potential chains of transmission.

Effect of a Technology-Integrated Curriculum on Sugary Drink and Snack Intake of Elementary-Aged Youth Experiencing Low Income.

OBJECTIVE: To describe the results of a technology-integrated intervention on sugar-sweetened beverage (SSB) and energy-dense snack intake with third graders experiencing low income. DESIGN: A 2 × 2 quasi-randomized cluster-block, parallel-group experimental research design. SETTING: Low-income schools in Rhode Island. PARTICIPANTS: Two-hundred seventeen intervention and 242 control third-grade students in low-income (89.6% and 88.2% free/reduced meals, respectively), ethnically and racially diverse (63% Hispanic/20% Black and 62% Hispanic/18% Black, respectively) schools. INTERVENTION(S): A 13-week in-school program held once per week for 1 hour. The hands-on, technology-integrated program used a modified version of the Body Quest: Food of the Warrior curriculum. MAIN OUTCOME MEASURE(S): Intake of SSB and energy-dense snacks, both salty and sweet snacks, using baseline (week 1) and postassessment (week 13) previous day self-recall. ANALYSIS: Generalized mixed modeling with nesting. RESULTS: Intervention students significantly reduced their SSB intake by 38% (0.5 times/d; F[1, 540] = 4.26; P = 0.04) and salty snack intake by 58% (0.8 times/d; F[1, 534] = 6.58, P < 0.01) from baseline to postassessment as compared with the control students. CONCLUSIONS AND IMPLICATIONS: Findings suggest a technology-integrated curriculum is effective in decreasing SSB and salty snacks in elementary-aged students of low-income, minoritized populations. Improved dietary habits can potentially influence other facets of students' lives.

Real world utilisation of doravirine among people living with human immunodeficiency virus in England (DRIVE-REAL).

BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor recommended for the treatment of virologically suppressed and treatment naïve people living with HIV. The DRIVE-REAL study aimed to describe the characteristics, treatment patterns, and virological outcomes of doravirine users in a real-world cohort in the UK. METHODS: A retrospective, observational, multi-centre chart review was conducted for 300 adults living with HIV initiating doravirine-containing antiretroviral therapy. RESULTS: At baseline 83% of individuals were male, 45% aged ≥50 years, 65% white ethnicity. Median time since HIV diagnosis was 12 years. 96% were antiretroviral therapy-experienced, 87% had a HIV viral load <50 copies/ml, and 15% had resistance to at least one antiretroviral drug. 66% had comorbidities, most commonly depression (26%), and 70% were taking at least one co-medication. At six months, 94% (n = 283/300) were still receiving doravirine. Viral load data were available for n = 266/300 individuals and 95% (n = 253/266) had viral load <50 copies/ml. CONCLUSIONS: Individuals initiating doravirine in this cohort are predominantly treatment-experienced white middle-aged males, with a high frequency of comorbidities and co-medication. The majority of individuals at 6 months remained on doravirine and maintained or achieved HIV viral suppression. This study provides epidemiologic characteristics that can inform clinical care and subsequent hypothesis-testing studies.

Quality of Life and Treatment-Related Side Effects in Patients With HR+/HER2- Advanced Breast Cancer: Findings From a Multicountry Survey.

BACKGROUND: Quality of life (QOL) is a critical factor in decision-making for advanced breast cancer (ABC). There is a need to improve how QOL and treatment-related side effects (SEs) that impact it are clinically assessed. We examined healthcare professionals' (HCPs') and patients' perspectives on the importance of QOL discussions and the impact of SEs on QOL in clinical settings. PATIENTS AND METHODS: A cross-sectional online survey was conducted (7/2020-5/2021) among oncologists, nurses, and patients with HR+/HER2- ABC in 7 countries. RESULTS: The survey was completed by 502 HCPs and 467 patients. Overall, 88% of oncologists and 49% of patients recalled QOL discussions at follow-up. In the first- through fourth-line (1L, 2L, 3L, and 4L) settings, respectively, 48%, 57%, 79%, and 85% of oncologists reported QOL was very important; 73% and 45% of patients receiving 1L and 2L treatment and 40% receiving 3L+ treatment indicated QOL was important. Patients reported that insomnia, anxiety, back pain, fatigue, diarrhea, hot flashes, low sexual interest, and loss of appetite had a moderate/severe impact on QOL. Of patients experiencing certain SEs, ≥64% did not discuss them with HCPs until there was a moderate/severe impact on QOL. In patients receiving a CDK4/6 inhibitor, SEs, including insomnia, diarrhea, back pain, and fatigue, had a moderate/severe impact on QOL. CONCLUSIONS: This survey discovered disconnects between HCPs and patients with ABC on the importance of QOL discussions and the impact of SEs on QOL. These data support the use of ABC-specific QOL questionnaires that closely monitor SEs impacting QOL.

Obesity-related complications, healthcare resource use and weight loss strategies in six European countries: the RESOURCE survey.

BACKGROUND: Obesity-related complications (ORCs), such as type 2 diabetes (T2D) and cardiovascular disease, contribute considerably to the clinical and economic impacts of obesity. To obtain a holistic overview of health and weight management attempts for people with obesity in Europe, we designed the cross-sectional RESOURCE survey to collect data on comorbidities, healthcare resource use (HCRU) and weight loss strategies from people with obesity in France, Germany, Italy, Spain, Sweden and the UK. METHODS: Adults (≥18 years old) with self-reported body mass index (BMI) ≥30 kg/m2 who reported interacting with primary or secondary healthcare services in the past 12 months, but had not been pregnant during this time, were recruited from an existing consumer research panel. All data were self-reported via an online survey (May-June 2021). Weight changes over the past year were calculated from participants' estimated weights. RESULTS: Of the 1850 participants in the survey, 26.3% reported that they had ≥3 ORCs from a set of 15 conditions of interest. The most frequently reported ORCs were hypertension (39.3% of participants), dyslipidaemia (22.8%) and T2D (17.5%). Participants in obesity class III (BMI 40 to <70 kg/m2) were more likely to report multiple ORCs than those in lower obesity classes. The presence of multiple ORCs was linked to various types of HCRU, including a significantly increased chance of reporting hospitalization in the past year. Most participants (78.6%) had attempted to lose weight in the past year, but of those who also reported estimated weight changes, 73.4% had not experienced clinically meaningful weight loss of ≥5%. CONCLUSIONS: ORCs are common in people with obesity, and are linked to increased HCRU. Together with the low reported success rate of weight loss attempts, this highlights an unmet need in Europe for enhanced weight management support for people with obesity.

Caregivers of patients with malignant pleural mesothelioma: who provides care, what care do they provide and what burden do they experience?

PURPOSE: There are limited data on the impact of caregiving for patients with malignant pleural mesothelioma (MPM) on the caregiver. We aimed to identify the demographic characteristics of these caregivers, the caregiving activities they perform and how caregiving burden impacts their work productivity and overall activity. METHODS: This cross-sectional study collected data from caregivers of patients with MPM across France, Italy, Spain and the United Kingdom January-June 2019. Caregiver demographics, daily caregiving tasks and the impact of caregiving on physical health was collected via questionnaire. The Zarit Burden Interview (ZBI) was used to assess caregiver burden and the Work Productivity and Activity Impairment questionnaire (WPAI) assessed impairment at work and during daily activities. Analyses were descriptive. RESULTS: Overall, 291 caregivers provided data. Caregivers were mostly female (83%), living with the patient (82%) and their partner/spouse (71%). Caregivers provided over five hours of daily emotional/physical support to patients. ZBI scores indicated 74% of caregivers were at risk of developing depression. Employed caregivers had missed 12% of work in the past seven days, with considerable presenteeism (25%) and overall work impairment (33%) observed. Overall, the mean activity impairment was 40%. CONCLUSION: Caregivers provide essential care for those with MPM. We show caregiving for patients with MPM involves a range of burdensome tasks that impact caregivers' emotional health and work reflected in ZBI and WPAI scores. Innovations in the management of MPM must account for how caregivers may be impacted and can be supported to carry out this important role.

Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein.

Sero-surveillance can monitor and project disease burden and risk. However, SARS-CoV-2 antibody test results can produce false positive results, limiting their efficacy as a sero-surveillance tool. False positive SARS-CoV-2 antibody results are associated with malaria exposure, and understanding this association is essential to interpret sero-surveillance results from malaria-endemic countries. Here, pre-pandemic samples from eight malaria endemic and non-endemic countries and four continents were tested by ELISA to measure SARS-CoV-2 Spike S1 subunit reactivity. Individuals with acute malaria infection generated substantial SARS-CoV-2 reactivity. Cross-reactivity was not associated with reactivity to other human coronaviruses or other SARS-CoV-2 proteins, as measured by peptide and protein arrays. ELISAs with deglycosylated and desialated Spike S1 subunits revealed that cross-reactive antibodies target sialic acid on N-linked glycans of the Spike protein. The functional activity of cross-reactive antibodies measured by neutralization assays showed that cross-reactive antibodies did not neutralize SARS-CoV-2 in vitro. Since routine use of glycosylated or sialated assays could result in false positive SARS-CoV-2 antibody results in malaria endemic regions, which could overestimate exposure and population-level immunity, we explored methods to increase specificity by reducing cross-reactivity. Overestimating population-level exposure to SARS-CoV-2 could lead to underestimates of risk of continued COVID-19 transmission in sub-Saharan Africa.

Skill and self-knowledge: empirical refutation of the dual-burden account of the Dunning-Kruger effect.

For many intellectual tasks, the people with the least skill overestimate themselves the most, a pattern popularly known as the Dunning-Kruger effect (DKE). The dominant account of this effect depends on the idea that assessing the quality of one's performance (metacognition) requires the same mental resources as task performance itself (cognition). Unskilled people are said to suffer a dual burden: they lack the cognitive resources to perform well, and this deprives them of metacognitive insight into their failings. In this Registered Report, we applied recently developed methods for the measurement of metacognition to a matrix reasoning task, to test the dual-burden account. Metacognitive sensitivity (information exploited by metacognition) tracked performance closely, so less information was exploited by the metacognitive judgements of poor performers; but metacognitive efficiency (quality of metacognitive processing itself) was unrelated to performance. Metacognitive bias (overall tendency towards high or low confidence) was positively associated with performance, so poor performers were appropriately less confident-not more confident-than good performers. Crucially, these metacognitive factors did not cause the DKE pattern, which was driven overwhelmingly by performance scores. These results refute the dual-burden account and suggest that the classic DKE is a statistical regression artefact that tells us nothing much about metacognition.

Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.

The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.

Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential.

Claspin is an adaptor protein required for ATR-dependent phosphorylation of CHK1 during S-phase following DNA replication stress. Claspin expression is highly variable in cancer, with low levels frequently correlating with poor patient survival. To learn more about the biological consequences of reduced Claspin expression and its effects on tumorigenesis, we investigated mice with a heterozygous knockout of the Clspn gene. Claspin haploinsufficiency resulted in reduced female fertility and a maternally inherited defect in oocyte meiosis I cell cycle progression. Furthermore, aged Clspn+/- mice developed spontaneous lymphoid hyperplasia and increased susceptibility to non-alcoholic fatty liver disease. Importantly, we demonstrate a tumour suppressor role for Claspin. Reduced Claspin levels result in increased liver damage and tumourigenesis in the DEN model of hepatocellular carcinoma. These data reveal that Clspn haploinsufficiency has widespread unanticipated biological effects and establishes the importance of Claspin as a regulatory node controlling tumorigenesis and multiple disease aetiologies.

Malignant pleural mesothelioma: treatment patterns and humanistic burden of disease in Europe.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive and rare tumour with poor prognosis. Most patients are diagnosed with advanced disease and there is a paucity of data on the humanistic burden of MPM in terms of impact on health-related quality of life (HRQoL) and activity. This study examined real-world treatment patterns and humanistic disease burden of MPM in Europe. METHODS: Physicians abstracted demographic/clinical characteristics and treatment data from MPM-patient medical records; MPM patients self-completed a questionnaire including symptoms, 3-level-EQ-5D questionnaire and Visual Analogue Scale (VAS), Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso), and Work Productivity and Activity Impairment (WPAI) questionnaire. RESULTS: Physicians (n = 171) abstracted data of 1390 patients; 767/1390 patients self-completed questionnaires. Patients were elderly with advanced, unresectable MPM. Treatment patterns followed guidelines with most (81%) patients receiving platinum+antifolate chemotherapy at first line (1 L). Maintenance treatment use was high (51.1%) despite no recommended maintenance therapies. Symptom burden was high and health states and HRQoL were poor at 1; declining further with progression. Overall mean (SD): LCSS-Average Symptom Burden Index score was 48.8 (19.3; n = 758); EQ-5D Utility Index score was 0.510 (0.349; n = 763); EQ-5D VAS score was 54.2 (20.3;n = 766); LCSS-3-Item Global Index score was 143.2 (64.5; n = 762); LCSS-normal activities score was 51.9 (24.6;n = 765); WPAI-activity impairment was 56.0% (23.2%; n = 737). CONCLUSION: The humanistic burden of MPM is high, despite treatments being prescribed as per available guidance. Treatments that delay progression and provide palliation of symptoms are most likely to improve/maintain HRQoL.

Longitudinal Immune Profiling of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection in a Solid Organ Transplant Recipient.

BACKGROUND: The underlying immunologic deficiencies enabling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for coronavirus disease 2019 (COVID-19). METHODS: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigations were performed on samples from the primary and secondary infections. RESULTS: Whole viral genome sequencing and phylogenetic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection. CONCLUSIONS: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naive CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients.

Kynurenic acid may underlie sex-specific immune responses to COVID-19.

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.

Real-world analysis of patient characteristics, treatment outcomes, and healthcare resource utilization across Europe in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation who received lenalidomide- or bortezomib-based regimens.

We aimed to compare real-world outcomes, resource use, and costs for patients with newly diagnosed multiple myeloma (NDMM) treated with continuous first-line (1 L) lenalidomide or fixed bortezomib in Europe. We performed a multicenter, retrospective, observational chart review of transplant-ineligible NDMM patients across 7 countries. Of 453 eligible patients, 220 received 1 L lenalidomide-based regimens; 105 (47.7%) received second-line (2 L) treatment, of which 50 (47.6%) received 2 L bortezomib. 233 patients received 1 L bortezomib-based regimens; 142 (60.9%) had 2 L treatment, of which 104 (73.2%) received 2 L lenalidomide. Patients receiving 1 L lenalidomide-based regimens had better progression-free survival than patients receiving 1 L bortezomib-based regimens (p = .002) and a longer time to 2 L or third-line treatment (both p < .05). Total treatment-associated monthly costs for patients receiving 1 L lenalidomide-based regimens (n = 171, €2,268.55) were significantly greater than for 1 L bortezomib-based regimens (n = 188, €1,724.77) (p < .001) over the follow-up period (median, 38.7 months).

Delayed production of neutralizing antibodies correlates with fatal COVID-19.

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.

Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.

The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal-transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection 7 months after primary infection. To elucidate the immunological mechanisms responsible for reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses that was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we identified the development of neutralizing antibodies and humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation.

Plasmodium infection induces cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein.

Individuals with acute malaria infection generated high levels of antibodies that cross-react with the SARS-CoV-2 Spike protein. Cross-reactive antibodies specifically recognized the sialic acid moiety on N-linked glycans of the Spike protein and do not neutralize in vitro SARS-CoV-2. Sero-surveillance is critical for monitoring and projecting disease burden and risk during the pandemic; however, routine use of Spike protein-based assays may overestimate SARS-CoV-2 exposure and population-level immunity in malaria-endemic countries.