Determinants and Dynamics of SARS-CoV-2 Infection in a Diverse Population: 6-Month Evaluation of a Prospective Cohort Study.

BACKGROUND: We studied risk factors, antibodies, and symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a diverse, ambulatory population. METHODS: A prospective cohort (n = 831) previously undiagnosed with SARS-CoV-2 infection underwent serial testing (SARS-CoV-2 polymerase chain reaction, immunoglobulin G [IgG]) for 6 months. RESULTS: Ninety-three participants (11.2%) tested SARS-CoV-2-positive: 14 (15.1%) asymptomatic, 24 (25.8%) severely symptomatic. Healthcare workers (n = 548) were more likely to become infected (14.2% vs 5.3%; adjusted odds ratio, 2.1; 95% confidence interval, 1.4-3.3) and severely symptomatic (29.5% vs 6.7%). IgG antibodies were detected after 79% of asymptomatic infections, 89% with mild-moderate symptoms, and 96% with severe symptoms. IgG trajectories after asymptomatic infections (slow increases) differed from symptomatic infections (early peaks within 2 months). Most participants (92%) had persistent IgG responses (median 171 days). In multivariable models, IgG titers were positively associated with symptom severity, certain comorbidities, and hospital work. Dyspnea and neurologic changes (including altered smell/taste) lasted ≥ 120 days in ≥ 10% of affected participants. Prolonged symptoms (frequently more severe) corresponded to higher antibody levels. CONCLUSIONS: In a prospective, ethnically diverse cohort, symptom severity correlated with the magnitude and trajectory of IgG production. Symptoms frequently persisted for many months after infection.Clinical Trials Registration. NCT04336215.

The effect of Ramadan fasting during pregnancy on perinatal outcomes: a systematic review and meta-analysis.

BACKGROUND: Although exempt, many pregnant Muslim women partake in the daily fast during daylight hours during the month of Ramadan. In other contexts an impoverished diet during pregnancy impacts on birth weight. The aim of this systematic review was to determine whether Ramadan fasting by pregnant women affects perinatal outcomes. Primary outcomes investigated were perinatal mortality, preterm birth and small for gestational age (SGA) infants. Secondary outcomes investigated were stillbirth, neonatal death, maternal death, hypertensive disorders of pregnancy, gestational diabetes, congenital abnormalities, serious neonatal morbidity, birth weight, preterm birth and placental weight. METHODS: Systematic review and meta-analysis of observational studies and randomised controlled trials was conducted in EMBASE, MEDLINE, CINAHL, Web of Science, Google Scholar, the Health Management Information Consortium and Applied Social Sciences Index and Abstracts. Studies from any year were eligible. Studies reporting predefined perinatal outcomes in pregnancies exposed to Ramadan fasting were included. Cohort studies with no comparator group or that considered fasting outside pregnancy were excluded, as were studies assuming fasting practice based solely upon family name. Quality of included studies was assessed using the ROBINS-I tool for assessing risk of bias in non-randomised studies. Analyses were performed in STATA. RESULTS: From 375 records, 22 studies of 31,374 pregnancies were included, of which 18,920 pregnancies were exposed to Ramadan fasting. Birth weight was reported in 21 studies and was not affected by maternal fasting (standardised mean difference [SMD] 0.03, 95% CI 0.00 to 0.05). Placental weight was significantly lower in fasting mothers (SMD -0.94, 95% CI -0.97 to -0.90), although this observation was dominated by a single large study. No data were presented for perinatal mortality. Ramadan fasting had no effect on preterm delivery (odds ratio 0.99, 95% CI 0.72 to 1.37) based on 5600 pregnancies (1193 exposed to Ramadan fasting). CONCLUSIONS: Ramadan fasting does not adversely affect birth weight although there is insufficient evidence regarding potential effects on other perinatal outcomes. Further studies are needed to accurately determine whether Ramadan fasting is associated with adverse maternal or neonatal outcome.

Clinical characteristics and dose-volume histogram parameters associated with the development of pleural effusions in non-small cell lung cancer patients treated with chemoradiation therapy.

BACKGROUND: To investigate descriptive characteristics and dose metric (DM) parameters associated with development of pleural effusions (PlEf) in non-small cell lung cancer (NSCLC) treated with definitive chemoradiation therapy (CRT). MATERIALS AND METHODS: We retrospectively assessed treatment records and follow-up imaging of 66 NSCLC patients to identify PlEf formation after CRT. PlEf association between mean heart dose (MHD), mean lung dose (MLD), heart V5-V60 (HV), and lung V5-V60 (LV) were evaluated using Cox Proportional Hazard Models. RESULTS: A total of 52% (34 of 66 patients) of our population developed PlEf and the actuarial rates at 6 months, 12 months, and 18 months were 7%, 30%, and 42%, respectively. Median time to diagnosis was five months (range 0.06-27 months). The majority of PlEfs were grade one (67%) and developed at a median of four (0.06-13) months, followed by grade two (15%) at a median 11 (5-12) months, and grade three (18%) at a median of 11 (3-27) months. On multivariate analysis, increasing HV5-HV50, LV5-LV50, MHD, and MLD were associated with greater risk of PlEf. Higher grade PlEf was also associated with higher doses of radiation to the heart, while lung DM parameters were not significantly associated with higher PlEf grades. At five-months post-CRT, MHD of 25 Gy was associated with a 100% chance of grade one PlEf, an 82% risk of grade two PlEf, and a 19% risk of grade three PlEf. CONCLUSIONS: Post-CRT PlEf is common in NSCLC with the majority being grade one. Increasing heart and lung irradiation was associated with increased risk of PlEf. Increasing heart irradiation also correlated with development of increasing grades of PlEf. The impact of potential cardiopulmonary toxicity and resultant PlEfs after CRT requires additional study.

Recurrent Fevers, Dysautonomia, and Dehydration in a Patient With Lesch-Nyhan Syndrome.

Lesch-Nyhan syndrome (LNS) is a disease characterized by a reduced ability to recycle purines, leading to increased de novo purine synthesis and uric acid production. Patients classically present with an array of hyperuricemic, neurologic, and behavioral symptoms. In this report, we describe a 26-year-old male with a history of LNS and recurrent fevers of unknown origin who presented to the emergency department (ED) with a fever, hypotension, and hypernatremia. We suspect that our patient's presentation was caused by autonomic instability in the setting of LNS leading to excessive free water loss. This report highlights a rare but life-threatening manifestation of LNS.

Clinical and CSF single-cell profiling of post-COVID-19 cognitive impairment.

Natural history and mechanisms for persistent cognitive symptoms ("brain fog") following acute and often mild COVID-19 are unknown. In a large prospective cohort of people who underwent testing a median of 9 months after acute COVID-19 in the New York City/New Jersey area, we found that cognitive dysfunction is common; is not influenced by mood, fatigue, or sleepiness; and is correlated with MRI changes in very few people. In a subgroup that underwent cerebrospinal fluid analysis, there are no changes related to Alzheimer's disease or neurodegeneration. Single-cell gene expression analysis in the cerebrospinal fluid shows findings consistent with monocyte recruitment, chemokine signaling, cellular stress, and suppressed interferon response-especially in myeloid cells. Longitudinal analysis shows slow recovery accompanied by key alterations in inflammatory genes and increased protein levels of CXCL8, CCL3L1, and sTREM2. These findings suggest that the prognosis for brain fog following COVID-19 correlates with myeloid-related chemokine and interferon-responsive genes.

Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation.

Antibody-mediated rejection (AMR) following renal transplantation is less responsive to conventional anti-rejection therapies. Plasmapheresis (PP), intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG) and rituximab deplete immature B-cells but not mature plasma cells. The proteasome inhibitor bortezomib has activity against mature plasma cell, the source of damaging donor-specific antibody (DSA).We present the successful use of bortezomib in 2 patients who developed AMR following kidney transplantation. The first patient was a 54-year-old white female who received living-unrelated kidney transplantation from her husband. She developed severe AMR early after transplantation with rising DSA titers consistent with an anamnestic immune response by memory cells to the donor antigens. Renal function deteriorated despite treatment with pulse methylprednisolone (MP), PP and IVIg. After initiation of therapy with bortezomib, DSA titers became negative and serum creatinine returned to baseline with histological resolution of AMR. The second patient was a 19-year-old white male who received deceased donor kidney transplantation and developed AMR within 2 weeks, refractory to therapy with pulse MP, PP and IVIg with rising DSA. Bortezomib use resulted in disappearance of DSA and renal function improvement. Both patients tolerated the treatment well with stable renal function at last follow-up. The novel mechanisms of action and preliminary results with bortezomib are encouraging, but require larger studies and longer follow-up.

Screening for Social Risk Factors in the ICU During the Pandemic.

Due to limitations in data collected through electronic health records, the social risk factors (SRFs) that predate severe illness and restrict access to critical care services are poorly understood. OBJECTIVES: This study explored the feasibility and utility of directly eliciting SRFs in the ICU by implementing a screening program. DESIGN SETTING AND PARTICIPANTS: Five hundred sixty-six critically ill patients at the medical ICU of Robert Wood Johnson University Hospital from July 1, 2019, to September 31, 2021, were interviewed for SRFs using an adapted version of the American Academy of Family Physicians' Social Needs Screening Tool. MAIN OUTCOMES AND MEASURES: For each SRFs, we compared basic demographic factors, proxies of socioeconomic status, and severity score between those with and without the SRFs through chi-square tests and Wilcoxon rank-sum tests. Furthermore, we determined the prevalence of SRFs overall, before, and during the COVID-19 pandemic. RESULTS: Of critically ill patients, 39.58% reported at least one SRF. Age, zip-code matched median household income, and insurance type differed depending on the SRFs. Notably, patients with SRFs were admitted with a lower average severity score, indicating reduced risk in mortality. Since March 2020, the prevalence of SRFs in the ICU overall fell from 54.47% to 35.44%. Conversely, the proportion of patients unable to afford healthcare increased statistically significantly from 7.32% to 18.06%. CONCLUSIONS AND RELEVANCE: Screening for SRFs in the ICU detected the presence of disproportionally low-risk patients whose access to critical care services became restricted throughout the pandemic.

MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study.

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure. Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results: tPA was associated with significant PaO2/FiO2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO2/FiO2 ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration. Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population.

The age pattern of the male-to-female ratio in mortality from COVID-19 mirrors that of cardiovascular disease in the general population.

Males are at a higher risk of dying from COVID-19 than females. Older age and cardiovascular disease are also associated with COVID-19 mortality. To better understand how age and sex interact in contributing to COVID-19 mortality, we stratified the male-to-female (sex) ratios in mortality by age group. We then compared the age-stratified sex ratios with those of cardiovascular mortality and cancer mortality in the general population. Data were obtained from official government sources in the US and five European countries: Italy, Spain, France, Germany, and the Netherlands. The sex ratio of deaths from COVID-19 exceeded one throughout adult life, increasing up to a peak in midlife, and declining markedly in later life. This pattern was also observed for the sex ratio of deaths from cardiovascular disease, but not cancer, in the general populations of the US and European countries. Therefore, the sex ratios of deaths from COVID-19 and from cardiovascular disease share similar patterns across the adult life course. The underlying mechanisms are poorly understood and warrant further investigation.

Physiologic Improvement in Respiratory Acidosis Using Extracorporeal Co2 Removal With Hemolung Respiratory Assist System in the Management of Severe Respiratory Failure From Coronavirus Disease 2019.

OBJECTIVES: About 15% of hospitalized coronavirus disease 2019 patients require ICU admission, and most (80%) of these require invasive mechanical ventilation. Lung-protective ventilation in coronavirus disease 2019 acute respiratory failure may result in severe respiratory acidosis without significant hypoxemia. Low-flow extracorporeal Co2 removal can facilitate lung-protective ventilation and avoid the adverse effects of severe respiratory acidosis. The objective was to evaluate the efficacy of extracorporeal Co2 removal using the Hemolung Respiratory Assist System in correcting severe respiratory acidosis in mechanically ventilated coronavirus disease 2019 patients with severe acute respiratory failure. DESIGN: Retrospective cohort analysis of patients with coronavirus disease 2019 mechanically ventilated with severe hypercapnia and respiratory acidosis and treated with low-flow extracorporeal Co2 removal. SETTING: Eight tertiary ICUs in the United States. PATIENTS: Adult patients supported with the Hemolung Respiratory Assist System from March 1, to September 30, 2020. INTERVENTIONS: Extracorporeal Co2 removal with Hemolung Respiratory Assist System under a Food and Drug Administration emergency use authorization for coronavirus disease 2019. MEASUREMENTS AND MAIN RESULTS: The primary outcome was improvement in pH and Paco2 from baseline. Secondary outcomes included survival to decannulation, mortality, time on ventilator, and adverse events. Thirty-one patients were treated with Hemolung Respiratory Assist System with significant improvement in pH and Pco2 in this cohort. Two patients experienced complications that prevented treatment. Of the 29 treated patients, 58% survived to 48 hours post treatment and 38% to hospital discharge. No difference in age or comorbidities were noted between survivors and nonsurvivors. There was significant improvement in pH (7.24 ± 0.12 to 7.35 ± 0.07; p < 0.0001) and Paco2 (79 ± 23 to 58 ± 14; p < 0.0001) from baseline to 24 hours. CONCLUSIONS: In this retrospective case series of 29 patients, we have demonstrated efficacy of extracorporeal Co2 removal using the Hemolung Respiratory Assist System to improve respiratory acidosis in patients with severe hypercapnic respiratory failure due to coronavirus disease 2019.

Vaccination boosts protective responses and counters SARS-CoV-2-induced pathogenic memory B cells.

Much is to be learned about the interface between immune responses to SARS-CoV-2 infection and vaccination. We monitored immune responses specific to SARS-CoV-2 Spike Receptor-Binding-Domain (RBD) in convalescent individuals for eight months after infection diagnosis and following vaccination. Over time, neutralizing antibody responses, which are predominantly RBD specific, generally decreased, while RBD-specific memory B cells persisted. RBD-specific antibody and B cell responses to vaccination were more vigorous than those elicited by infection in the same subjects or by vaccination in infection-naïve comparators. Notably, the frequencies of double negative B memory cells, which are dysfunctional and potentially pathogenic, increased in the convalescent subjects over time. Unexpectedly, this effect was reversed by vaccination. Our work identifies a novel aspect of immune dysfunction in mild/moderate COVID-19, supports the practice of offering SARS-CoV-2 vaccination regardless of infection history, and provides a potential mechanistic explanation for the vaccination-induced reduction of "Long-COVID" symptoms.

Highly versatile antibody binding assay for the detection of SARS-CoV-2 infection.

Monitoring the burden and spread of infection with the new coronavirus SARS-CoV-2, whether within small communities or in large geographical settings, is of paramount importance for public health purposes. Serology, which detects the host antibody response to the infection, is the most appropriate tool for this task, since virus-derived markers are most reliably detected during the acute phase of infection. Here we show that our ELISA protocol, which is based on antibody binding to the Receptor Binding Domain (RBD) of the S1 subunit of the viral Spike protein expressed as a novel fusion protein, detects antibody responses to SARS-CoV-2 infection and COVID-19 vaccination. We also show that our ELISA is accurate and versatile. It compares favorably with commercial assays widely used in clinical practice to determine exposure to SARS-CoV-2. Moreover, our protocol accommodates use of various blood- and non-blood-derived biospecimens, such as breast milk, as well as dried blood obtained with microsampling cartridges that are appropriate for remote collection. As a result, our RBD-based ELISA protocols are well suited for seroepidemiology and other large-scale studies requiring parsimonious sample collection outside of healthcare settings.

Highly versatile antibody binding assay for the detection of SARS-CoV-2 infection and vaccination.

Monitoring the burden and spread of infection with the new coronavirus SARS-CoV-2, whether within small communities or in large geographical settings, is of paramount importance for public health purposes. Serology, which detects the host antibody response to the infection, is the most appropriate tool for this task, since virus-derived markers are most reliably detected during the acute phase of infection. Here we show that our ELISA protocol, which is based on antibody binding to the Receptor Binding Domain (RBD) of the S1 subunit of the viral Spike protein expressed as a novel fusion protein, detects antibody responses to SARS-CoV-2 infection and vaccination. We also show that our ELISA is accurate and versatile. It compares favorably with commercial assays widely used in clinical practice to determine exposure to SARS-CoV-2. Moreover, our protocol accommodates use of various blood- and non-blood-derived biospecimens, such as breast milk, as well as dried blood obtained with microsampling cartridges that are appropriate for remote collection. As a result, our RBD-based ELISA protocols are well suited for seroepidemiology and other large-scale studies requiring parsimonious sample collection outside of healthcare settings.

Associations of Stay-at-Home Order and Face-Masking Recommendation with Trends in Daily New Cases and Deaths of Laboratory-Confirmed COVID-19 in the United States.

BACKGROUND AND OBJECTIVES: Public health interventions have reduced coronavirus disease 2019 (COVID-19) transmission in several countries, but their impacts on COVID-19 epidemics in the USA are unclear. We examined associations of stay-at-home order (SAHO) and face-masking recommendation with COVID-19 epidemics in the USA. METHODS: In this quasi-experimental interrupted time-series study, we modeled temporal trends in daily new cases and deaths of laboratory-confirmed COVID-19 cases, and COVID-19 time-varying reproduction numbers in the USA between March 1 and April 20, 2020. In addition, we conducted simulation analyses. RESULTS: The number of residents under SAHO increased since March 19 and plateaued at 290,829,980 (88.6% of the U.S. population) on April 7. Trends in COVID-19 time-varying reproduction numbers peaked on March 23, further reduced on April 3, and fell below/around 1.0 on April 13. Early-implementation and early-lift of SAHO would reduce and increase COVID-19 epidemics, respectively. Multivariable piecewise log-linear regression revealed the states' neighboring relationship with New York was linked to COVID-19 daily new cases and deaths. There were two turning points in daily new-case trend, being March 28 (slope-changes = -0.09) and April 3 (slope-changes = -0.09), which appeared to be associated with implementation of SAHO on March 28 (affecting 48.5% of the US population in 22 states and District of Columbia), and face-masking recommendation on April 3, respectively. There were also two turning points in daily new-death trend, being April 9 (slope-changes = -0.06) and April 19 (slope-changes = -0.90). CONCLUSIONS: We identified two turning points of COVID-19 daily new cases or deaths in the USA, which seem to be linked to implementation of SAHO and the Center for Disease Control's face-masking recommendation.

Observational study of the use of recombinant tissue-type plasminogen activator in COVID-19 shows a decrease in physiological dead space.

#COVID19-induced ARDS is partly explained by the presence of microthrombi, motivating the use of thrombolytics. This study shows that thrombolytics decrease dead space ventilation in COVID-19 ARDS patients. https://bit.ly/2GdM44a.

Trends and Prediction in Daily New Cases and Deaths of COVID-19 in the United States: An Internet Search-Interest Based Model.

BACKGROUND AND OBJECTIVES: The daily incidence and deaths of coronavirus disease 2019 (COVID-19) in the USA are poorly understood. Internet search interest was found to be correlated with COVID-19 daily incidence in China, but has not yet been applied to the USA. Therefore, we examined the association of internet search-interest with COVID-19 daily incidence and deaths in the USA. METHODS: We extracted COVID-19 daily new cases and deaths in the USA from two population-based datasets, namely 1-point-3-acres.com and the Johns Hopkins COVID-19 data repository. The internet search-interest of COVID-19-related terms was obtained using Google Trends. The Pearson correlation test and general linear model were used to examine correlations and predict trends, respectively. RESULTS: There were 636,282 new cases and,325 deaths of COVID-19 in the USA from March 1 to April 15, 2020, with a crude mortality of 4.45%. The daily new cases peaked at 35,098 cases on April 10, 2020 and the daily deaths peaked at 2,494 on April 15, 2020. The search interest of COVID, "COVID pneumonia" and "COVID heart" were correlated with COVID-19 daily incidence, with 12 or 14 days of delay (Pearson's r = 0.978, 0.978 and 0.979, respectively) and deaths with 19 days of delay (Pearson's r = 0.963, 0.958 and 0.970, respectively). The 7-day follow-up with prospectively collected data showed no significant correlations of the observed data with the predicted daily new cases or daily deaths, using search interest of COVID, COVID heart, and COVID pneumonia. CONCLUSIONS: Search terms related to COVID-19 are highly correlated with the COVID-19 daily new cases and deaths in the USA.

Trends and prediction in daily incidence and deaths of COVID-19 in the United States: a search-interest based model.

Background and Objectives: The coronavirus disease 2019 (COVID-19) infected more than 586,000 patients in the U.S. However, its daily incidence and deaths in the U.S. are poorly understood. Internet search interest was found correlated with COVID-19 daily incidence in China, but not yet applied to the U.S. Therefore, we examined the association of internet search-interest with COVID-19 daily incidence and deaths in the U.S. Methods: We extracted the COVDI-19 daily incidence and death data in the U.S. from two population-based datasets. The search interest of COVID-19 related terms was obtained using Google Trends. Pearson correlation test and general linear model were used to examine correlations and predict future trends, respectively. Results: There were 555,245 new cases and 22,019 deaths of COVID-19 reported in the U.S. from March 1 to April 12, 2020. The search interest of COVID, "COVID pneumonia," and "COVID heart" were correlated with COVDI-19 daily incidence with ~12-day of delay (Pearson's r=0.978, 0.978 and 0.979, respectively) and deaths with 19-day of delay (Pearson's r=0.963, 0.958 and 0.970, respectively). The COVID-19 daily incidence and deaths appeared to both peak on April 10. The 4-day follow-up with prospectively collected data showed moderate to good accuracies for predicting new cases (Pearson's r=-0.641 to -0.833) and poor to good accuracies for daily new deaths (Pearson's r=0.365 to 0.935). Conclusions: Search terms related to COVID-19 are highly correlated with the trends in COVID-19 daily incidence and deaths in the U.S. The prediction-models based on the search interest trend reached moderate to good accuracies.

Associations of stay-at-home order and face-masking recommendation with trends in daily new cases and deaths of laboratory-confirmed COVID-19 in the United States.

BACKGROUND AND OBJECTIVES: Public health interventions were associated with reduction in coronavirus disease 2019 (COVID-19) transmission in China, but their impacts on COVID-19 epidemiology in other countries are unclear. We examined the associations of stay-at-home order (SAHO) and face-masking recommendation with epidemiology of laboratory-confirmed COVID-19 in the United States. METHODS: In this quasi-experimental study, we modeled the temporal trends in daily new cases and deaths of COVID-19, and COVID-19 time-varying reproduction numbers (Rt) in the United States between March 1 and April 20, 2020, and conducted simulation studies. RESULTS: The number and proportion of U.S. residents under SAHO increased between March 19 and April 7, and plateaued at 29,0829,980 and 88.6%, respectively. Trends in COVID-19 daily cases and Rt reduced after March 23 (P<0.001) and further reduced on April 3 (P<0.001), which was associated with implementation of SAHO by 10 states on March 23, and face-masking recommendation on April 3, respectively. The estimates of Rt eventually fell below/around 1.0 on April 13. Similar turning points were identified in the trends of daily deaths with a lag time. Early implementation and early-removal of SAHO would be associated with significantly reduced and increased daily new cases and deaths, respectively.