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BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Background Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population especially when the population affected is undefined. Methods We evaluated the utility of CDC COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), COVID-19 Case Surveillance System (CCSS), and 2020 U.S. Census data to determine demographic representation in the four stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at U.S. ACTT sites, with the respective 95% confidence intervals, to the reference data in forest plots. Results U.S. ACTT sites enrolled 3,509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic or Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with U.S. Census and CCSS. The proportion of participants ages 65 years was either similar or lower than COVID-NET and higher than CCSS and U.S. Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions While surveillance data of hospitalized cases may not be available early in an outbreak, it is a better comparator than U.S. Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

BackgroundCorticosteroids confer a survival benefit in individuals hospitalized with coronavirus disease 2019 (COVID-19) who require oxygen. This meta-analysis seeks to determine the duration of corticosteroids needed to optimize this mortality benefit.MethodsElectronic databases were searched to 9 March 2022, for studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. We estimated the effect of corticosteroids on mortality by random-effects meta-analyses. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment while adjusting for the severity of disease, age, duration of symptoms, and proportion of control group given steroids.ResultsWe identified 27 eligible studies consisting of 13 404 hospitalized COVID-19 patients. Seven randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy (risk ratio [RR], 0.71 [95% confidence interval {CI}, .58–.87]). Pooled analysis of 18 studies showed the greatest survival benefit for a treatment duration up to 6 days (RR, 0.54 [95% CI, .39–.74]). Survival benefit was 0.65 (95% CI, .51–.83) up to 7 days, and no additional survival benefit was observed beyond 7 days of treatment (RR, 0.64 [95% CI, .44–.93]). The survival benefit was not confounded by severity of disease, age, duration of symptoms, or proportion of control group given steroids.ConclusionsIn this meta-analysis, optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with >7 days of treatment.

Background Corticosteroids confer a survival benefit in hospitalized COVID-19 patients requiring oxygen, but optimal treatment duration remains uncertain. The goal of this meta-analysis is to determine the optimal duration of corticosteroids in the treatment of severe COVID-19. Figure:The effect of systemic steroids on mortality stratified by the duration of treatment in days. The greatest survival benefit was observed for the treatment duration of up to 6 days (A). No survival benefit was observed beyond 7 days of treatment (B). Methods Electronic databases (MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, the World Health Organization Global Literature on Coronavirus Disease, CoronaCentral, and Web of Science) and trial registries were searched to March 9, 2022, for randomized controlled trials and observational cohort studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. Risk of bias was assessed using the Cochrane Risk of Bias tool (randomized controlled trials) or the Newcastle-Ottawa Scale (observational studies). We estimated the effect of corticosteroids on mortality by random-effects meta-analyses using the generic inverse variance method. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment. Results We identified 28 eligible studies consisting of 13,404 hospitalized COVID-19 patients. Median age was 62 years (interquartile range: 59 – 67), and 65% were male. Eight randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy (risk ratio, 0.75; 95% CI: 0.64; 0.87). Pooled analysis of 19 studies showed the greatest survival benefit for a treatment duration up to 6 days (risk ratio, 0.54; 95% CI, 0.39; 0.74). Survival benefit was 0.68 (95% CI, 0.57; 0.82) up to 7 days, and no survival benefit was observed beyond 7 days of treatment (risk ratio, 0.71; 95% C: 0.51; 1.01). Conclusion In this meta-analysis, the optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with > 7 days of treatment. Future analyses should stratify survival benefit by baseline disease severity to see if subgroups of patients derive greater benefit from longer courses of steroids. Disclosures All Authors: No reported disclosures.

This post hoc analysis of the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) shows a treatment effect of remdesivir (RDV) on progression to invasive mechanical ventilation (IMV) or death. Additionally, we create a risk profile that better predicts progression than baseline oxygen requirement alone. The highest risk group derives the greatest treatment effect from RDV.

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

Therapeutics for hospitalized COVID-19 patients were identified through a robust research response with several lessons learned: clinical trial data should guide therapeutic use, results should not be extrapolated between disease stages, and robust studies should be designed to give clinically relevant data. These lessons should be applied to the outpatient research response.

In sharp contrast to viruses such as measles, in which a single exposure generates long-lasting immunity, individuals are repeatedly exposed to influenza viruses throughout their lifetime without developing broad and durable protection against infection. As a consequence, substantial worldwide

BACKGROUND The Pfizer-BioNTech COVID-19 vaccine uses a novel messenger RNA technology to elicit a protective immune response. Short-term physiologic responses to the vaccine have not been studied using wearable devices. OBJECTIVE We aim to characterize physiologic changes in response to COVID-19 vaccination in a small cohort of participants using a wearable device (WHOOP Strap 3.0). This is a proof of concept for using consumer-grade wearable devices to monitor response to COVID-19 vaccines. METHODS In this prospective observational study, physiologic data from 19 internal medicine residents at a single institution that received both doses of the Pfizer-BioNTech COVID-19 vaccine was collected using the WHOOP Strap 3.0. The primary outcomes were percent change from baseline in heart rate variability (HRV), resting heart rate (RHR), and respiratory rate (RR). Secondary outcomes were percent change from baseline in total, rapid eye movement, and deep sleep. Exploratory outcomes included local and systemic reactogenicity following each dose and prophylactic analgesic use. RESULTS In 19 individuals (mean age 28.8, SD 2.2 years; n=10, 53% female), HRV was decreased on day 1 following administration of the first vaccine dose (mean –13.44%, SD 13.62%) and second vaccine dose (mean –9.25%, SD 22.6%). RHR and RR showed no change from baseline after either vaccine dose. Sleep duration was increased up to 4 days post vaccination, after an initial decrease on day 1. Increased sleep duration prior to vaccination was associated with a greater change in HRV. Local and systemic reactogenicity was more severe after dose two. CONCLUSIONS This is the first observational study of the physiologic response to any of the novel COVID-19 vaccines as measured using wearable devices. Using this relatively small healthy cohort, we provide evidence that HRV decreases in response to both vaccine doses, with no significant changes in RHR or RR. Sleep duration initially decreased following each dose with a subsequent increase thereafter. Future studies with a larger sample size and comparison to other inflammatory and immune biomarkers such as antibody response will be needed to determine the true utility of this type of continuous wearable monitoring in regards to vaccine responses. Our data raises the possibility that increased sleep prior to vaccination may impact physiologic responses and may be a modifiable way to increase vaccine response. These results may inform future studies using wearables for monitoring vaccine responses. CLINICALTRIAL ClinicalTrials.gov NCT04304703; https://www.clinicaltrials.gov/ct2/show/NCT04304703

A priority for the National Institute of Allergy and Infectious Diseases is development of a universal influenza vaccine providing durable protection against multiple influenza strains. NIAID will use this strategic plan as a foundation for future investments in influenza research.

Development of a universal influenza vaccine is a research priority for the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. To facilitate this goal, we convened a workshop in Rockville, Maryland to identify knowledge gaps in influenza research and develop strategies to fill them.

Background The Pfizer-BioNTech COVID-19 vaccine uses a novel messenger RNA technology to elicit a protective immune response. Short-term physiologic responses to the vaccine have not been studied using wearable devices. Objective We aim to characterize physiologic changes in response to COVID-19 vaccination in a small cohort of participants using a wearable device (WHOOP Strap 3.0). This is a proof of concept for using consumer-grade wearable devices to monitor response to COVID-19 vaccines. Methods In this prospective observational study, physiologic data from 19 internal medicine residents at a single institution that received both doses of the Pfizer-BioNTech COVID-19 vaccine was collected using the WHOOP Strap 3.0. The primary outcomes were percent change from baseline in heart rate variability (HRV), resting heart rate (RHR), and respiratory rate (RR). Secondary outcomes were percent change from baseline in total, rapid eye movement, and deep sleep. Exploratory outcomes included local and systemic reactogenicity following each dose and prophylactic analgesic use. Results In 19 individuals (mean age 28.8, SD 2.2 years; n=10, 53% female), HRV was decreased on day 1 following administration of the first vaccine dose (mean –13.44%, SD 13.62%) and second vaccine dose (mean –9.25%, SD 22.6%). RHR and RR showed no change from baseline after either vaccine dose. Sleep duration was increased up to 4 days post vaccination, after an initial decrease on day 1. Increased sleep duration prior to vaccination was associated with a greater change in HRV. Local and systemic reactogenicity was more severe after dose two. Conclusions This is the first observational study of the physiologic response to any of the novel COVID-19 vaccines as measured using wearable devices. Using this relatively small healthy cohort, we provide evidence that HRV decreases in response to both vaccine doses, with no significant changes in RHR or RR. Sleep duration initially decreased following each dose with a subsequent increase thereafter. Future studies with a larger sample size and comparison to other inflammatory and immune biomarkers such as antibody response will be needed to determine the true utility of this type of continuous wearable monitoring in regards to vaccine responses. Our data raises the possibility that increased sleep prior to vaccination may impact physiologic responses and may be a modifiable way to increase vaccine response. These results may inform future studies using wearables for monitoring vaccine responses. Trial Registration ClinicalTrials.gov NCT04304703; https://www.clinicaltrials.gov/ct2/show/NCT04304703

Background MEDI8852 is a novel monoclonal antibody (mAb) that neutralizes both group I and group II influenza A viruses (IAVs) in vitro. We evaluated whether MEDI8852 was effective for prophylaxis and therapy against representative group I (H5N1) and group II (H7N9) pandemic IAVs in mice and ferrets and could be used to block transmission of influenza H1N1pdm09 in ferrets, compared to an irrelevant control mAb R347 and oseltamivir. Methods MEDI8852 was administered to mice and ferrets by intraperitoneal injection at varying doses, 24 hours prior to intranasal infection with H5N1 and H7N9 viruses for prophylaxis, and 24, 48, and 72 hours post-infection for treatment. A comparison with oseltamivir alone and combination of MEDI8852 and oseltamivir was included in some studies. Survival, weight loss, and viral titers were assessed over a 14-day study period. For the transmission study, naive respiratory contact ferrets received MEDI8852 or R347 prior to exposure to ferrets infected with an H1N1pdm09 virus. Results MEDI8852 was effective for prophylaxis and treatment of H7N9 and H5N1 infection in mice, with a clear dose-dependent response and treatment with MEDI8852 24, 48, or 72 hours postinfection was superior to oseltamivir for H5N1. MEDI8852 alone was effective treatment for lethal H5N1 infection in ferrets compared to oseltamivir and R347, and MEDI8852 plus oseltamivir was better than oseltamivir alone. MEDI8852 or oseltamivir alone early in infection was equally effective for H7N9 infection in ferrets while the combination yielded similar protection when treatment was delayed. MEDI8852 was able to protect naive ferrets from airborne transmission of H1N1pdm09. Conclusions MEDI8852, alone or with oseltamivir, shows promise for prophylaxis or therapy of group I and II IAVs with pandemic potential. Additionally, MEDI8852 blocked influenza transmission in ferrets, a unique finding among influenza-specific mAbs.

Chasing Seasonal Influenza As we prepare for a potentially severe influenza season, we must consider whether our current vaccines can be improved and whether longer-term, transformative vaccine approaches are needed to minimize influenza-related morbidity and mortality.

Measles in 2019 — Going Backward Recent increases in measles cases in the United States mirror patterns in other countries that had previously eliminated the virus. This resurgence is all the more frustrating since the disease is entirely preventable through vaccination.

Sylvatic transmission cycles of yellow fever continue to occur in endemic tropical regions. If the outbreak in Brazil leads to urban spread, U.S. clinicians should adopt a high index of suspicion for the disease, particularly in travelers returning from affected areas.

Tickborne Diseases The burden of tickborne diseases is growing substantially and seems likely to continue to do so. Prevention and management are hampered by suboptimal diagnostics, lack of treatment options for emerging viruses, and a paucity of vaccines.

Adaptation to the acidic microenvironment, and adherence to mucosal epithelium, are essential for persistent colonization of the human stomach by Helicobacter pylori. The expression of SabA, an adhesin implicated in the ability of H. pylori to adhere to the host gastric epithelium, can be modulated by phase variation via slipped-strand mispairing in repetitive nucleotide tracts located in both the promoter region and the coding region. This study demonstrates the occurrence of phase variation at the sabA locus within individual strains of H. pylori, and among multiple isolates from a single patient. In addition, transcription of sabA is repressed by the acid-responsive ArsRS two-component signal transduction system in vitro. Our results demonstrate that isogenic inactivation of the arsS (jhp0151/HP0165) histidine kinase locus results in a 10-fold SabA-dependent increase in adherence to gastric epithelial cells in strain J99 (contains an in-frame sabA allele), but not in strain 26695 (out-of-frame sabA allele). The combination of transcriptional regulation of the sabA locus by the ArsRS two-component signal-transduction system and the generation of subpopulations harbouring alternate sabA alleles by slipped-strand mispairing during chromosomal replication could permit H. pylori to rapidly adapt to varying microenvironments or host immune responses. As a pathogen with a paucity of regulatory proteins, this dual regulation indicates that SabA expression is a tightly regulated process in H. pylori infection.