Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2 (preprint)

Although vaccines have reduced COVID-19 disease burden, their efficacy in helminth infection endemic areas is not well characterized. We evaluated the impact of infection by Heligmosomoides polygyrus bakeri (Hpb), a murine intestinal hookworm, on the efficacy of an mRNA vaccine targeting the Wuhan-1 spike protein of SARS-CoV-2. Although immunization generated similar B cell responses in Hpb-infected and uninfected mice, polyfunctional CD4+ and CD8+ T cell responses were markedly reduced in Hpb-infected mice. Hpb-infected and mRNA vaccinated mice were protected against the ancestral SARS-CoV-2 strain WA1/2020, but control of lung infection was diminished against an Omicron variant compared to animals immunized without Hpb infection. Helminth mediated suppression of spike-specific CD8+ T cell responses occurred independently of STAT6 signaling, whereas blockade of IL-10 rescued vaccine-induced CD8+ T cell responses. In mice, intestinal helminth infection impairs vaccine induced T cell responses via an IL-10 pathway and compromises protection against antigenically shifted SARS-CoV-2 variants.

Viral Dynamics and Factors Favouring the Duration of Covid-19 Positivity in Cameroon

Background: Evolution evidence of Coronavirus disease 2019 (COVID-19) and viral clearance time remains limited in tropical settings. Understanding this is crucial for public health control measures at community-level. We evaluated the viral dynamics of SARS-CoV-2 infection and factors associated with positivity duration in COVID-19 cases in Cameroon. Method(s): We conducted a prospective cohort-study of SARS-CoV-2 positive cases from the first to third wave (March 2020-October 2021) in Yaounde- Cameroon. RT-PCR was performed on nasopharyngeal swabs. SARS-CoV-2 positivity duration was evaluated from the first to last positive test before a negative result. Epi-info V.7.0 was used for data analyses with p< 0.05 considered statistically significant Results: A total of 282 participants were enrolled. The mean age was 41+/-14 years, with male predominant (62.1%). We had 15.6% symptomatic cases and cough most common (59.09%). The overall median positivity duration was 15[IQR: 9-23] days with 15[ IQR: 13-16] in the first, 17[ IQR: 11-26] in the second and 8[ IQR: 4-12] in the third wave (p= 0.007). Positivity duration was significantly higher in males (16 versus 14 days, p=0.03) and people aged >40 years (15 versus 14 days, p=0.02). Positivity duration was not affected by presence or absence of symptoms (p=0.80). No significant correlation was found with viral load (r=0.03;p=0.61). Considering baseline (24.7+/-7.2Ct) and last viral load (29.3+/-5.9 Ct), the DELTACt (4.6+/-1.3) and positivity duration (15 days) revealed a kinetic in viral decay of 0.3+/-0.087 Ct/day. Conclusion(s): A median positivity duration of 15 days is in accordance with viral clearance around 2 weeks for optimal confinement at community-level. Men and/or the elderly stand at higher risk of prolonged infection. Given the viral decay (0.3 Ct daily), we suggest personalized confinement periods. The variability of positivity duration according to phases could be function of strains which could be a factor of positivity duration.

GENOMIC SURVEILLANCE OF SARS-CoV-2 REVEALS SEVERITY OF DELTA VARIANT IN CAMEROON

Background: At the global level, the dynamics of the COVID-19 pandemic have been driven by several epidemiological waves, determined by the emergence of new SARS-CoV-2 variants from the original viral lineage from Wuhan, China. While the SARS-CoV-2 dynamic has been described globally, there is a lack of data from Sub-Saharan African. Method(s): A laboratory-based survey was conducted in Cameroon, from March 1, 2020 to March 30, 2022, through an assessment of the evolutionary patterns of SARS-CoV-2 lineages across the four COVID-19 waves in the country. Data on full-length sequencing from all four sequencing laboratories were consecutively entered into the GISAID platform. These data were downloaded, and the molecular phylogeny of the SARS-CoV-2 sequences was performed using Nexstrain. The Mann-Whitney U test was used to calculate the correlation between the duration of each outbreak and the number of confirmed cases and between hospitalised cases and CFR, with a p value < 0.05 considered statistically significant. Result(s): A total of 3,881 samples were successfully processed, of which 38.9% (n=1,509) using PCR mutation assay, 41.5% (n=1,612) using targeted sequencing, and 19.6% (n=760) using whole-genome sequencing. The mean age of the study population was 36 years (min-max: 2-86), and 45% were within the age range 26-45. Regarding gender distribution, 50.9% were male, and 49.1% were female. Phylogenetic analysis of the 760 whole-genome sequences generated from March 2020 to March 2022 revealed that the greater proportion of SARS-CoV-2 circulating in Cameroon belonged to the viral sub-lineages of the original strain from Wuhan (74%), 15% Delta variant, 6% Omicron variant, 3% Alpha variant and 2% Beta variant.The pandemic was driven by SARS-CoV-2 lineages of origin in Wave 1 (16 weeks, 2.3% CFR), the Alpha and Beta variants in Wave 2 (21 weeks, 1.6% CFR), Delta variants in Wave 3 (11 weeks, 2.0% CFR), and Omicron variants in Wave 4 (8 weeks, 0.73% CFR), with a declining trend over time (p=0.01208). Conclusion(s): In a nutshell, the SARS-CoV-2 epidemic in Cameroon appears to have been driven by the SARS-CoV-2 lineage of origin in Wave 1, the cointroduction of the Alpha and Beta variants in Wave 2, the Delta variant in Wave 3, and the Omicron variant in Wave 4, with an overall declining trend in the wave duration, confirmed cases and hospitalisations over time.The SARS-CoV-2 lineage of origin and the Delta variant appeared to be the drivers of COVID-19 severity in Cameroon.

Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 omicron infection and related hospital admission among people with substance use disorder in Hong Kong: a matched case-control study.

BACKGROUND: People with substance use disorder have a high risk of SARS-CoV-2 infection and subsequent poor outcomes. Few studies have evaluated COVID-19 vaccine effectiveness among people with substance use disorder. We aimed to estimate the vaccine effectiveness of BNT162b2 (Fosun-BioNTech) and CoronaVac (Sinovac) against SARS-CoV-2 omicron (B.1.1.529) infection and related hospital admission in this population. METHODS: We did a matched case-control study using electronic health databases in Hong Kong. Individuals diagnosed with substance use disorder between Jan 1, 2016, and Jan 1, 2022, were identified. People aged 18 years and older with SARS-CoV-2 infection from Jan 1 to May 31, 2022, and people with COVID-19-related hospital admission from Feb 16 to May 31, 2022, were included as cases and were matched by age, sex, and previous clinical history with controls from all individuals diagnosed with substance use disorder who attended the Hospital Authority health services: up to three controls for SARS-CoV-2 infection and up to ten controls for hospital admission. Conditional logistical regression was used to evaluate the association between vaccination status (ie, one, two, or three doses of BNT162b2 or CoronaVac) and the risk of SARS-CoV-2 infection and COVID-19-related hospital admission, adjusted for baseline comorbidities and medication use. FINDINGS: Among 57 674 individuals with substance use disorder, 9523 people with SARS-CoV-2 infections (mean age 61·00 years, SD 14·90; 8075 [84·8%] males and 1448 [15·2%] females) were identified and matched to 28 217 controls (mean age 60·99 years, 14·67; 24 006 [85·1%] males and 4211 [14·9%] females), and 843 people with COVID-19-related hospital admissions (mean age 70·48 years, SD 14·68; 754 [89·4%] males and 89 [10·6%] females) were identified and matched to 7459 controls (mean age 70·24 years, 13·87; 6837 [91·7%] males and 622 [8·3%] females). Data on ethnicity were not available. We observed significant vaccine effectiveness against SARS-CoV-2 infection for two-dose BNT162b2 vaccination (20·7%, 95% CI 14·0-27·0, p<0·0001) and three-dose vaccination (all BNT162b2 41·5%, 34·4-47·8, p<0·0001; all CoronaVac 13·6%, 5·4-21·0, p=0·0015; BNT162b2 booster after two-dose CoronaVac 31·3%, 19·8-41·1, p<0·0001), but not for one dose of either vaccine or two doses of CoronaVac. Significant vaccine effectiveness against COVID-19-related hospital admission was detected after one dose of BNT162b2 vaccination (35·7%, 3·8-57·1, p=0·032), two-dose vaccination (both BNT162b2 73·3%, 64·3 to 80·0, p<0·0001; both CoronaVac 59·9%, 50·2-67·7, p<0·0001), and three-dose vaccination (all BNT162b2 86·3%, 75·6-92·3, p<0·0001; all CoronaVac 73·5% 61·0-81·9, p<0·0001; BNT162b2 booster after two-dose CoronaVac 83·7%, 64·6-92·5, p<0·0001), but not after one dose of CoronaVac. INTERPRETATION: For both BNT162b2 and CoronaVac, two-dose or three-dose vaccination was protective against COVID-19-related hospital admission and the booster dose provided protection against SARS-CoV-2 infection among people with substance use disorder. Our findings confirm the importance of booster doses in this population during the period dominated by the omicron variant. FUNDING: Health Bureau, the Government of the Hong Kong Special Administrative Region.

Complications associated with energy-based devices during thyroidectomy from 2010-2020.

Objective: Harmonic Focus (Ethicon, Johnson and Johnson, Cincinnati, OH, USA), LigaSure Small Jaw (Medtronic, Covidien Products, Minneapolis, MN, USA), and Thunderbeat Open Fine Jaw (Olympus, Japan) are electrosurgical instruments used widely in head and neck surgery. The study aims to compare device malfunctions, adverse events to patients, operative injuries, and interventions related to Harmonic, LigaSure, and Thunderbeat use during thyroidectomy. Methods: The US Food and Drug Administration's Manufacture and User Facility Device Experience (MAUDE) database was queried for adverse events associated with Harmonic, LigaSure, and Thunderbeat from January 2005 to August 2020. Data were extracted from reports pertaining to thyroidectomy. Results: Of the 620 adverse events extracted, 394 (63.5%) involved Harmonic, 134 (21.6%) LigaSure, and 92 (14.8%) Thunderbeat. The reported device malfunctions most frequently associated with Harmonic was damage to the blade (110 (27.9%)), LigaSure was inappropriate function (47 (43.1%)), Thunderbeat was damage to the tissue or Teflon pad (27 (30.7%)), respectively. Burn injury and incomplete hemostasis were the most commonly reported adverse events. The operative injury reported most frequently when using Harmonic and LigaSure was burn injury. No operator injuries were reported with Thunderbeat use. Conclusion: The most frequently reported device malfunctions were damage to the blade, inappropriate function, and damage to the tissue or Teflon pad. The most frequently reported adverse events to patients was a burn injury and incomplete hemostasis. Interventions aimed at improving physician education may help reduce adverse events attributed to improper use.

Machine Learning in Cardiology: A Potential Real-World Solution in Low- and Middle-Income Countries.

Artificial intelligence (AI) and machine learning (ML) is a promising field of cardiovascular medicine. Many AI tools have been shown to be efficacious with a high level of accuracy. Yet, their use in real life is not well established. In the era of health technology and data science, it is crucial to consider how these tools could improve healthcare delivery. This is particularly important in countries with limited resources, such as low- and middle-income countries (LMICs). LMICs have many barriers in the care continuum of cardiovascular diseases (CVD), and big portion of these barriers come from scarcity of resources, mainly financial and human power constraints. AI/ML could potentially improve healthcare delivery if appropriately applied in these countries. Expectedly, the current literature lacks original articles about AI/ML originating from these countries. It is important to start early with a stepwise approach to understand the obstacles these countries face in order to develop AI/ML-based solutions. This could be detrimental to many patients' lives, in addition to other expected advantages in other sectors, including the economy sector. In this report, we aim to review what is known about AI/ML in cardiovascular medicine, and to discuss how it could benefit LMICs.

An Investigation on the Impact of COVID-19 Pandemic on New Zealand's Knitwear Manufacturing Sector

Knitwear producers in New Zealand are looking for ways to deal with the uncertainties that have arisen due to the COVID-19 pandemic. This research considers the impact of the pandemic and its effects on the development and long-term survival of the knitwear sector. An anonymous online survey was undertaken among New Zealand's established knitwear manufacturers, with seven taking up the survey. The respondent companies accounted for around half of the total workforce employed in the country's knitwear sector. The data were analysed using both quantitative and qualitative methods. A SWOT analysis was conducted to place the sector in a global context, identifying necessary measures for future strategic planning. The findings revealed that the supply chain has been disrupted, some businesses have stalled, and the cost of obtaining raw materials has skyrocketed. Due to the impact of the pandemic on the tourism industry, revenues have fallen. As COVID-19 is an ongoing challenge, knitwear manufacturers need to rearrange their supply chains to increase local suppliers and explore new and innovative ways to engage with domestic customers.

Patient hesitancy in perioperative clinical trial enrollment during the COVID-19 pandemic.

The COVID-19 pandemic has caused tremendous disruptions to non-COVID-19 clinical research. However, there has been little investigation on how patients themselves have responded to clinical trial recruitment during the COVID-19 pandemic. To investigate the effect of the COVID-19 pandemic on rates of patient consent to enrollment into non-COVID-19 clinical trials, we carried out a cross-sectional study using data from the Nitric Oxide/Acute Kidney Injury (NO/AKI) and Minimizing ICU Neurological Dysfunction with Dexmedetomidine-Induced Sleep (MINDDS) trials. All patients eligible for the NO/AKI or MINDDS trials who came to the hospital for cardiac surgery and were approached to gain consent to enrollment were included in the current study. We defined "Before COVID-19" as the time between the start of the relevant clinical trial and the date when efforts toward that clinical trial were deescalated by the hospital due to COVID-19. We defined "During COVID-19" as the time between trial de-escalation and trial completion. 5,015 patients were screened for eligibility. 3,851 were excluded, and 1,434 were approached to gain consent to enrollment. The rate of consent to enrollment was 64% in the "Before COVID-19" group and 45% in the "During COVID-19" group (n = 1,334, P<0.001) (RR = 0.70, 95% CI 0.62 to 0.80, P<0.001). Thus, we found that rates of consent to enrollment into the NO/AKI and MINDDS trials dropped significantly with the onset of the COVID-19 pandemic. Patient demographic and socioeconomic status data collected from electronic medical records and patient survey data did not shed light on possible explanations for this observed drop, indicating that there were likely other factors at play that were not directly measured in the current study. Increased patient hesitancy to enroll in clinical trials can have detrimental effects on clinical science, patient health, and patient healthcare experience, so understanding and addressing this issue during the COVID-19 pandemic is crucial.

Perspectives on nonmedical switching and the COVID-19 pandemic: a narrative review.

OBJECTIVES: Nonmedical switching (NMS) is a change in a patient's treatment regimen for reasons other than lack of efficacy, intolerance, adverse effects, or poor adherence. We describe the impact of NMS on patients, health care workers, and health systems, focusing on NMS to in-class biologic alternatives in US patients with chronic, immune-mediated rheumatic and dermatologic conditions. Additionally, we evaluate the ways in which the COVID-19 pandemic may exacerbate the physical, psychological, and economic impacts of NMS. STUDY DESIGN: Narrative review. METHODS: We performed a search of MEDLINE's PubMed database from October 2015 to October 2020, with a repeat search in October 2021. Search terms included relevant keywords pertaining to NMS, biologics, and disease areas. Results were supplemented by a search of key congress abstracts from 2015 to 2021 and a targeted internet search. RESULTS: NMS increases medication abandonment, errors, and adverse effects, and it can lead to longer patient visits, increased follow-up visits, additional laboratory tests and procedures, and greater overall health care resource utilization (HCRU). The increased HCRU associated with NMS increases patients' financial burden due to additional co-pays and out-of-pocket costs. CONCLUSIONS: The decision to switch treatments should result from shared decision-making between health care providers (HCPs) and patients to achieve the best clinical outcomes and optimal HCRU. The issues related to NMS may be compounded by the financial and psychosocial stress on HCPs and patients created by the COVID-19 pandemic. HCPs should advocate for continuous patient treatment and be familiar with continuity of care legislation, appeals processes, and manufacturer assistance programs.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

Evaluation of a Virtual Training to Enhance Public Health Capacity for COVID-19 Infection Prevention and Control in Nursing Homes.

CONTEXT: Between April 2020 and May 2021, the Centers for Disease Control and Prevention (CDC) awarded more than $40 billion to health departments nationwide for COVID-19 prevention and response activities. One of the identified priorities for this investment was improving infection prevention and control (IPC) in nursing homes. PROGRAM: CDC developed a virtual course to train new and less experienced public health staff in core healthcare IPC principles and in the application of CDC COVID-19 healthcare IPC guidance for nursing homes. IMPLEMENTATION: From October 2020 to August 2021, the CDC led training sessions for 12 cohorts of public health staff using pretraining reading materials, case-based scenarios, didactic presentations, peer-learning opportunities, and subject matter expert-led discussions. Multiple electronic assessments were distributed to learners over time to measure changes in self-reported knowledge and confidence and to collect feedback on the course. Participating public health programs were also assessed to measure overall course impact. EVALUATION: Among 182 enrolled learners, 94% completed the training. Most learners were infection preventionists (42%) or epidemiologists (38%), had less than 1 year of experience in their health department role (75%), and had less than 1 year of subject matter experience (54%). After training, learners reported increased knowledge and confidence in applying the CDC COVID-19 healthcare IPC guidance for nursing homes (≥81%) with the greatest increase in performing COVID-19 IPC consultations and assessments (87%). The majority of participating programs agreed that the course provided an overall benefit (88%) and reduced training burden (72%). DISCUSSION: The CDC's virtual course was effective in increasing public health capacity for COVID-19 healthcare IPC in nursing homes and provides a possible model to increase IPC capacity for other infectious diseases and other healthcare settings. Future virtual healthcare IPC courses could be enhanced by tailoring materials to health department needs, reinforcing training through applied learning experiences, and supporting mechanisms to retain trained staff.

Perspectives on Nonmedical Switching and the COVID-19 Pandemic: A Narrative Review

Objectives: Nonmedical switching (NMS) is a change in a patient's treatment regimen for reasons other than lack of efficacy, intolerance, adverse effects, or poor adherence. We describe the impact of NMS on patients, health care workers, and health systems, focusing on NMS to in-class biologic alternatives in US patients with chronic, immune-mediated rheumatic and dermatologic conditions. Additionally, we evaluate the ways in which the COVID-19 pandemic may exacerbate the physical, psychological, and economic impacts of NMS. Study Design: Narrative review. Methods: We performed a search of MEDLINE's PubMed database from October 2015 to October 2020, with a repeat search in October 2021. Search terms included relevant keywords pertaining to NMS, biologics, and disease areas. Results were supplemented by a search of key congress s from 2015 to 2021 and a targeted internet search. Results: NMS increases medication abandonment, errors, and adverse effects, and it can lead to longer patient visits, increased follow-up visits, additional laboratory tests and procedures, and greater overall health care resource utilization (HCRU). The increased HCRU associated with NMS increases patients' financial burden due to additional co-pays and out-of-pocket costs. Conclusions: The decision to switch treatments should result from shared decision-making between health care providers (HCPs) and patients to achieve the best clinical outcomes and optimal HCRU. The issues related to NMS may be compounded by the financial and psychosocial stress on HCPs and patients created by the COVID-19 pandemic. HCPs should advocate for continuous patient treatment and be familiar with continuity of care legislation, appeals processes, and manufacturer assistance programs.

VisualEars: How an immersive art exhibit impacts mood during the COVID-19 pandemic.

This paper explores the positive impact of viewing a virtual art exhibit on mood during the COVID-19 Pandemic. During global lockdowns, depression, anxiety, and the burden of other mental illnesses have increased even among prior psychiatrically healthy individuals. Art and music-based interventions have shown to be effective clinical interventions in individuals with mental illness. The VisualEars project explored whether a virtual activity involving vision and auditory stimuli could improve positive and negative affect. Eight musical pieces were selected, and 28 visual artists from around the world visualized two musical pieces. A total of 56 works of art were created and hung in eight 3D virtual rooms. Visitors were randomly selected to either view the art exhibit without music (non-immersive) or view the art exhibit while listening to music (immersive). Visitors were asked to complete a positive and negative affect schedule (PANAS) in three languages (English, French, and Farsi) pre and post their virtual visit. A total of 160 participants completed baseline PANAS, 58 of which completed the follow-up PANAS. Linear mixed-effects models found that older participants had lower negative affect scores overall (b = -0.3, p = 0.003), while male participants had lower positive affect scores overall (b = -0.27, p = 0.02). Following the virtual exhibit participants of both conditions had higher positive (b = 0.17, p = 0.03), and lower negative affect scores (b = -0.19, p = 0.007). We found that the virtual art exhibit increased positive affect and decreased negative affect in participants, suggesting an overall improvement in mood attributable to the virtual exhibit. This suggests that virtual exhibits may serve as a beneficial and accessible intervention to improve mood during a pandemic.

Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19.

BACKGROUND: Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. METHODS AND FINDINGS: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and 58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had changed by -0.57 log10 (95% CI -1.21 to 0.07, p = 0.08) and in the lopinavir-ritonavir+placebo arm by -0.18 log10 (95% CI -0.82 to 0.46, p = 0.58) compared to the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p = 0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p = 0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. The major limitation was that the study population was relatively young and healthy compared to those most affected by the COVID-19 pandemic. CONCLUSIONS: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. TRIAL REGISTRATION: Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68.

Development of a colorectal cancer screening intervention for Alaska Native people during a pandemic year.

Objectives: Alaska Native (AN) people experience twice the rate of colorectal cancer (CRC) as US Whites. There is a need for increased screening and early detection. We describe the development and implementation of a randomized controlled trial of the multi-target stool DNA test (mt-sDNA; Cologuard® Exact Sciences, Madison WI) to increase CRC screening among AN people. Methods: A total of 32 rural/remote AN communities were randomized to a varied intensity intervention (patient navigation vs mailed health education) compared to 14 communities receiving usual opportunistic care. Outcome measures include screening completion and method used (mt-sDNA vs colonoscopy). Health care provider interviews and AN patient focus groups will be used to assess patient-, provider-, and system-level CRC screening promoters and barriers. Results: The study began in April 2020 during the COVID-19 pandemic, resulting in a number of challenges and study adaptations. These included difficulty finding laboratory space, lack of timely mail service due to flight reductions across the state, and travel restrictions that led to postponement of in-person focus groups. Videoconferencing platforms for Tribal engagement replaced face-to-face interactions. After an extensive search, a laboratory with space available was identified and the preprocessing laboratory established. Study staff will work closely with patients to monitor mail service to get mt-sDNA kits sent on time. We are also exploring the use of videoconferencing platforms as alternatives to in-person focus groups. Conclusions: Despite the challenges encountered during the COVID-19 pandemic, we successfully initiated the intervention and established the first mt-sDNA preprocessing laboratory in Alaska.