A higher incidence of thromboembolic disorders in COVID-19 has been reported by many clinicians worldwide.Selected studies found in PubMed that reported thromboembolic events were included for meta-analysis using weighted fixed and random effects. Data from 19 articles on cohort studies in patients diagnosed with COVID-19 and thromboembolic events, including thrombosis and embolism were included in this review.The likelihood for developing thromboembolic disorders in hospitalized COVID-19 patients was 0.28 (95% CI 0.21–0.36).This study further validates the increased risk of VTE in COVID-19 patients when compared to healthy, non-hospitalized people, and hospitalized patients. These findings will be useful to researchers and medical practitioners caring for COVID-19 patients. Some viral infections manifest clinically with hemorrhage and coagulation syndromes. These may run the spectrum of mild skin hemorrhages to disseminated intravascular coagulation. Dengue, endemic in the Caribbean and in Asia, may present as skin rashes and petechiae in its mild form, but may be also associated with hemorrhagic shock syndromes in severe cases. Viral hemorrhagic fevers, like Ebola, Marburg, Lassa fever, Rift Valley fever and Crimean Congo fever, named after geographic locations where they were first discovered or are most prevalent, trigger hemorrhages of varying degrees of severity, some associated with high morbidity and mortality. Some patients with cytomegalovirus and parvovirus B19 may develop clotting abnormalities, like thrombosis. Viral respiratory tract infections are known to increase the risk of deep venous thrombosis and possibly pulmonary embolism [Reports on coronaviruses did not appear in the literature until the 1960’s. Early documented cases of coronaviruses  were reported to produce only mild upper respiratory infections in immunocompromised patients. In 2003, the sudden appearance of the highly pathogenic Severe Acute Respiratory Syndrome (SARS-CoV) in Asia spread to more than two dozen countries worldwide before disappearing in mid-2003. SARS was followed in 2012 by another highly pathogenic coronavirus, the Middle East Respiratory Syndrome coronavirus (MERS CoV) . MERS, aSARS-CoV-2, the etiologic agent of COVID-19, is a highly infectious coronavirus responsible for the current global pandemic. As of March 29, 2021, it has claimed more than 2.7 million lives and infected 127 million people globally since it was first reported in December 2019 . VasculaSeveral factors lead to the hypercoagulability state in patients with severe cases of COVID-19: circulatory stasis from immobility (common to intensive care patients), acute inflammatory reaction overdrive with increases in acute phase proteins  and elevated clotting factors, increased Von Willebrand Factor (vWF) activity, neutrophilia, and increase in Neutrophil Extracellular traps (NETs) . ReportsSeveral reports of the thromboembolic consequences of COVID-19 have recently been published. The aim of this study is to determine the incidence of thromboembolic events in hospitalized COVID-19 patients.This study followed PRISMA guidelines for conducting meta-analysis . PubMed 2) [2 and Tau [Data were analyzed using StatDirect 3 (StatsDirect Ltd) and Rstudio, Version 1.2.5033 . Proportions were transformed using the Freeman-Tukey double arcsine method  and were2)  and by t and Tau . While tThe total pooled COVID-19 patient population was 2554. The forest plot of results of the analysis in 2) was large, 93.6% (95% CI 91.3%−95.3%). A random effects analysis was used instead to generate the forest plot which gave an inverse variance value of 0.28 (95% CI 0.21–0.36). The pooled estimates of the odds ratios from the random effect meta-regression analyses for effect of four variables of interest on developing VTE  were not significant.Pooled proportion of VTE using the fixed effect method was 0.22, but the heterogeneity measure of studies  of COVID-19 patients will develop venous thromboembolic events, a higher incidence than in the general population, hospitalized ICU and non-ICU patients. Two reports of cohort studies , 28 thatHospitalization increases the risk for VTE. In a review based on the 2003 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project (HCUP by the American College of Chest Physicians (ACCP) showed the risk for developing VTE among surgical patients classified as low, moderate, high, and very high were 44%, 15%, 24%, and 17% respectively . Among mICU patients are predisposed to developing thromboembolism from all elements of Virchow’s triad. Two more papers in this review provide evidence that ICU patients with COVID-19 are at greater risk to VTE. Lodigiani, et al reported that in 388 COVID-19 patients, thromboembolic events occurred in 27.6% of ICU patients but only 6.6% general ward patients . AsymptoSeveral societies and organizations have advanced recommendations, guidelines, and consensus statements regarding anticoagulation and COVID-19 patients. The American Society of Hematology (ASH) suggests using prophylactic-intensity over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19–related critical illness who do not have suspected or confirmed VTE . The AmeThe entire population of 2554 patients were considered as a cohort of patients diagnosed with COVID-19 and the individual study effects of anticoagulation or specific anticoagulant use was not accounted for except to note that the majority of patients in this study (93.5%) were given some type of anticoagulant, variously described as prophylactic, intermediate, or therapeutic. Each study was weighted to account for its number of patients.2 inconsistency value, therefore, a random effects model with pooled proportion (= 0.28) was adopted to account for the heterogeneity of the 19 studies reviewed. Also, between-study heterogeneity was large, and tests of bias were statistically significant indicating a “small sample” bias across the 19 studies.The differences between studies were large with a 94% IIn order to explore the association between patient characteristics and VTE development, a meta-regression was used. Since a fixed effects meta-regression model does not account for high heterogeneity across different studies, a random-effect meta-regression analysis was adopted although the meta-regression results for the effects of age, gender, thromboprophylaxis and ICU admission did not attain statistical significance. Possible intercorrelation between thromboprophylaxis and other variables could exist - not controlling for such intercorrelations could yield misleading information. For example, patients given thromboprophylaxis might have greater medical burdens that those without and thus they are more vulnerable to VTE.2 = 94%) also indicates a sample bias.The literature search was limited only to PubMed because of the unprecedented increase in COVID-19 publications. The 19 studies reviewed came from several countries and were very heterogeneous. Additionally, the effects of international variations in patient populations, testing strategies, thrombosis prophylactic measures, diagnostic test quality and availability, access to care and treatment strategies, as well as variability in outcome reporting for COVID-19, might also be a limitation. However, the adoption of the random effect approach instead of fixed effect approach might compensate for the diversity. These issues influence the reported diagnosed cases, casualties, and, in turn case-fatality rates. The incidence reported in this study might change as more cohort studies are reported and clinicians learn more about COVID-19 and its management. Publication bias brought about by publications analyzed in this review depend on a large extent on what their authors might consider as significant or perceive as important - these factors are beyond the control of this review. This study may have failed to include all relevant studies which might affect the estimated incidence. With COVID-19 now a worldwide pandemic, non-English publications may have also been missed (language bias). The large heterogeneity (IThis study provides more evidence that COVID-19 increases the risk of VTE. Although the majority of the reports did not have a control group, a comparison with historical groups of patients in the general community, hospitalized patients, and ICU patients showed a significant difference between the incidence of thromboembolism in COVID-19 patients. Vulnerable patients, such as the elderly, and those with other chronic comorbid conditions have greater risk of hospitalizations and, even critical care unit admissions, which will further predispose them to even greater risk of thromboembolism. The consensus among experts supports anticoagulation in all hospitalized COVID-19 patients. The findings of this study might be potentially useful to medical practitioners who care for COVID-19 patients who are at higher risk of developing thromboembolic events.


Close contacts of coronavirus disease (COVID-19) patients are at high risk for severe acute respiratory syndrome 2 (SARS-CoV-2) infection. We assessed the seroprevalence of SARS-CoV-2–specific antibodies among quarantined close contacts of COVID-19 patients in the Faroe Islands. We invited quarantined close contacts of COVID-19 index patients identified during March 3–April 22, 2020, to participate in this study; 584 (81%) contacts consented and underwent serologic testing. Among the 584 participants, 32 (5.5%) were seropositive for total antibody against SARS-CoV-2. Household and young or elderly contacts had higher risk for seropositivity than other contacts. We found a secondary attack rate of 19.2%. Seroprevalence among close contacts was almost 10-fold higher than among the general population of the Faroe Islands. Regularly testing household close contacts of COVID-19 patients might help track the transmission of SARS-CoV-2. Reverse transcription PCR (RT-PCR) is a standard tool for diagnosing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, different testing strategies might cause wide variation in the number of identified subclinical and asymptomatic cases, which could remain undetected (Since the identification of the first imported case of coronavirus disease (COVID-19) in the Faroe Islands on March 3, 2020, the territory has complied with World Health Organization recommendations to use an active suppression strategy focusing on testing and isolating patients and their close contacts. Accordingly, all close contacts of COVID-19 patients in the Faroe Islands were advised to quarantine for 2 weeks  during March 3–April 22, 2020. No local transmission occurred for the next 104 days, April 23–August 3, 2020 , which communicated with all close contacts and requested that contacts quarantine for 14 days from the time of exposure. Close contacts of COVID-19 patients during the 48 hours before symptom onset, or of asymptomatic persons during the All infected persons were asked to avoid contact with other persons in their household and to use separate bathrooms. Close contacts also were asked to self-quarantine and to avoid contact with other members of the household. Most patients and close contacts could successfully self-quarantine, except for those in households with small children. When patients or contacts were unable to adequately separate from household members, hotel rooms were offered free of charge by the government.During their quarantine periods, close contacts were interviewed by telephone to monitor potential onset of symptoms , according to the manufacturer’s instructions.Participants gave informed consent to provide a blood sample and answer a short questionnaire. The questionnaire asked about demographic information, smoking habits, and medical history, as well as their experience in quarantine. For example, the questionnaire inquired whether participants had been tested by RT-PCR, whether they had experienced symptoms during quarantine, if other members of the household had also been quarantined, and whether they knew the identity of the infected person with whom they had contact. We used these data to classify all participants as household, workplace, or other  contacts. In total, 82 (14%) participants could not be classified on the basis of available data. We collected blood samples and administered questionnaires mainly during May 27–July 14, 2020; we also collected data from 3 participants earlier in May 2020 and 4 participants later in August and September 2020. No local cases were diagnosed in the Faroes during April 23–August 3, 2020. We telephoned seropositive participants about their results and asked them to recall symptoms experienced during the quarantine, which we registered alongside data from the telephone interviews conducted during quarantine. Parents responded on behalf of children <18 years of age. We used serum samples to determine patient serologic status by the commercially available Wantai SARS-CoV-2 Ab ELISA kit  for the analysis.We estimated the crude seroprevalence by dividing the total number of seropositive cases by the total number of close contacts. We calculated categorical variables as percentages and continuous variables as means and SDs. We estimated 95% CIs for crude prevalence using exact binomial models. We adjusted for test performance as reported by independent evaluation  persons, comprised of 17 women and 15 men who had not previously tested positive by RT-PCR, were seropositive for total antibody against SARS-CoV-2. After adjustment for test sensitivity and specificity, we calculated the prevalence of SARS-CoV-2–specific antibodies as 5.3% (95% CI 3.5%–7.5%). A total of 43.8% of the seropositive close contacts retrospectively reported symptoms, mainly fever, running nose, and loss of taste or smell. Most seropositive participants were in the youngest age group  . Among sAccording to the multivariable logistic regression analysis, type of contact (p<0.01) and age group (p = 0.02) were significantly associated with seropositivity. The risk for seropositivity was significantly higher for household contacts compared with other contacts . We did not find a statistically significant difference for workplace contacts compared with other contacts (p = 0.8). Overall, age was significantly associated with seropositivity (p = 0.02). Most age groups had lower aORs than the youngest age group (0–9 years), although these associations were statistically significant only for the 35–49-year  and 50–66-year  age groups. Participants >67 years of age had an increased aOR compared with the youngest age group; however, this association was not statistically significant . In this study, we identified 32 secondary SARS-CoV-2 infections by later serologic assay in addition to the 132 identified through initial RT-PCR, indicating a secondary attack rate of 19.2%. Most (67.5%) seropositive persons had been in quarantine with their families. In total, 65% of seropositive persons were infected by household members; when including noncohabitating close family members, this total rose to 71%. The other persons were infected by extended family, workplace, or social contacts. We identified 3 sibling pairs, 2 sets of spouses, and 3 parent–child pairs among the seropositive persons.In this retrospective cohort study of close contacts of COVID-19 patients, we found a 5.5% seropositivity rate among contacts who were not previously identified as positive by RT-PCR. Seroprevalence was highest among household contacts. We found the highest seropositivity rate among children who were infected by their parents. The risk for seropositivity among household contacts was 5-fold that of the risk posed by other close contacts, probably because household members might have closer and more prolonged interactions than work or social contacts. In total, 56% of secondary infections were asymptomatic.https://corona.fo]). Our results for close contacts of patients with confirmed COVID-19 are in accordance with the seroprevalence study  seroprevalence among those who had unspecified contact with a COVID-19 patient  who had reported symptoms. The sensitivity of RT-PCR is dependent on multiple factors, primarily the presence of viral RNA on the test swab, which can vary by swabbing technique and whether viral RNA is present at the anatomic site of the test. Therefore, the timing of testing in relation to infection onset is critical. Among participants who underwent RT-PCR, most were tested during the early stage of quarantine, probably before symptom onset, and thus perhaps also before infection onset , which might explain their negative RT-PCR results . In addiThe major strengths of this study are its nationwide nature, in which all close contacts of confirmed COVID-19 patients from the first wave in the Faroe Islands were directly contacted, and the high participation rate. As a result, the likelihood of selection bias is low. Because the Faroe Islands eliminated COVID-19 for 104 days after the last patient in this wave was identified, there was little risk for exposure from sources other than the index cases. One limitation of our study is that contacts were asked retrospectively about symptoms during quarantine, introducing the possibility for recall bias. The risk for bias is especially relevant for children, whose questionnaires were answered by parents. However, because most index cases occurred in a family member, parents were probably vigilant for potential symptoms in children. Another limitation might be the classification of participants as household, workplace, or other contacts. Because this classification was based on whether participants knew the identity of the index patient, this measure might be imprecise. However, we were able to classify most participants into 3 groups on the basis of available information. We found that the primary exposure route is within families, and we believe this information is valuable, even if the data might be flawed. Finally, RT-PCR was not routinely conducted for quarantined persons. Because symptomatic persons were probably prioritized for RT-PCR, this selection might have introduced bias.In conclusion, our study found that seroprevalence among close contacts of COVID-19 patients is higher than that among the general population. Close contacts, especially household members, of COVID-19 patients are at higher risk for infection. Thus, routinely testing household contacts of COVID-19 patients, regardless of symptoms, might improve detection of SARS-CoV-2 infection. Our results also indicate that close contacts should maintain quarantine even if they receive negative RT-PCR results early in quarantine.


Mounting evidence suggests the safety and efficacy of medical marijuana (MM) in treating chronic ailments, including chronic pain, epilepsy, and anorexia. Despite incremental use of medical and recreational cannabinoids, current limited evidence shows generalized unpreparedness of medical providers to discuss or recommend these substances to their patients. Herein, the present study aims to examine internal medicine residents’ knowledge of marijuana and their attitude towards its medical use.This is a descriptive cross-sectional study. A survey with 12 standardized queries was created and distributed among the internal medicine residents from Mount Sinai Morningside-West (MSMW) program from July 2020 to December 2020. Participants included preliminary and categorical residents from post-graduate years one to three. The survey consisted of self-assessment of residents’ knowledge on the indication, contraindication, adverse effects of MM.Eighty-six (59%) out of 145 residents completed the questionnaire. Despite most trainees (70%) having considered certifying the use of MM for their patients, over 90% reported none to little knowledge on its use. Approximately 80% of the surveyed residents expressed willingness to receive an appropriate educational curriculum.To the best of our knowledge, this is the first study that indicated a critical lack of medical marijuana-related knowledge in surveyed internal medicine residents. In a population with growing cannabis consumption, physician training on the indication, toxicity, and drug interaction of cannabinoids is warranted. Mounting studies suggest the therapeutic efficacy of cannabis and its derivatives, tetrahydrocannabinol (THC) and cannabidiol (CBD), in debilitating conditions such as chemotherapy-induced nausea, anorexia, epilepsy, multiple sclerosis, and amyotrophic lateral sclerosis –3. MoreoIn this descriptive cross-sectional study, IM residents from Mount Sinai Morningside-West (MSMW) program were surveyed from July 2020 to December 2020. The data was collected for a medical education-based needs assessment survey. All trainees from the post-graduate year (PGY) one to three were eligible and included preliminary and categorical residents. An anonymous online questionnaire with 12 standardized queries was created using SurveyMonkey® and distributed via Microsoft® Teams, institutional emails, and smartphone messaging applications. The survey consisted of demographics questions, as well as five-point scale questions about trainees’ self-assessment on MM use, and their stance on MM education during residency training. The full questionnaire is available in Table MSMW IM residency is an ACGME-accredited program affiliated to Mount Sinai Icahn School of Medicine . This is one of the largest academic programs in the United States and is composed of a preliminary internship of 20 trainees and a categorical residency with 125 residents. Approximately 74% of the in-training physicians are international medical graduates.Eighty-six (59%) out of 145 residents completed the questionnaire, of which 39 (45%) and 47 (55%) were female and male, respectively. 80 (93%) were aged 25 to 34 years. Of participants who chose to disclose their ethnicity, 29 (34%) self-identified as Caucasian, whereas 15 (17%) were Hispanic. PGY-1 trainees had the highest participation rate of 42%, followed by 32% in PGY-2and 26% in PGY-3.n=60, 70%) of trainees had considered certifying medical cannabinoids for their patients, only six (7%) residents felt they had an adequate amount of knowledge . Eighty-five (99%) expressed none to some familiarity with marijuana dosing, whereas only four (5%) reported substantial knowledge on different formulations of medical cannabinoid products. Of notable significance, 71 (83%) participants were unsure where to find pertinent information, and 79 (92%) agreed on the necessity of implementing medical education on this substance  [P=0.0378) [N=1997, 55%), only 4.6% reported ongoing severe pain. Concomitant opioid use was decreased and stopped respectively in 10 and 36% of patients.Accumulating evidence suggests the safety and efficacy of MM in the treatment of both chronic non-cancerous pain and cancer-related pain. A systematic review with thirty-six trials assessed the efficacy of different MM formulations  to treat non-cancer neuropathic and non-neuropathic pain. In the sixteen evaluable trials, prolonged cannabinoid treatment (two to eight weeks), as opposed to placebo, was associated with a significantly greater reduction in pain  certification exam . MedicalOur survey results were based on a single-institution experience from an academic center located in New York. A significant percentage of surveyed trainees obtained their medical degrees from outside countries. Nevertheless, the present study emphasizes the lack of formal education on medical cannabis during IM residency training and not before it. Albeit the survey participation was limited, we believe the results were relevant as they show a general trend towards a lack of knowledge on medical cannabis and point to the necessity of a formal educational curriculum.The study is a descriptive cross-sectional study at a single institution and may not be extendible to residencies or IM programs across the country. Additionally, our study seeks the residents to self-rate their knowledge and attitude regarding MM use.The consumption of medical and nonmedical cannabis is growing. Our study highlighted a needs assessment for MM education at our institution, with the results recognizing the resident's self-awareness about their lack of knowledge. Frontline providers like in-training residents should be familiarized with MM. Analogous studies, if done in other programs across the country, may yield similar results resulting in a more extensive discussion about the need for curriculum development.Our study “Medical Marijuana Knowledge and Attitudes amongst Internal Medicine Residents” did not consist of any experimental protocols. In this descriptive cross-sectional study, IM residents from Mount Sinai Morningside-West (MSMW) program voluntarily responded to the distributed survey. All methods were carried out in accordance with relevant guidelines and regulations. The IRB determined that the proposed activity is not research involving human subjects as defined by DHHS and FDA regulations. The data set presented is the secondary use of information collected for purposes other than research . The holder of any identifiable data would never share those identifiers, nor could data be linked to any identifiable information. For that reason, the Federal Regulations did not apply, including obtaining consent. Accordingly, the IRB determined this project to be Not Human Subjects (NHSR) research.


Sensitive point-of-care screening tests are urgently needed to identify individuals at highest risk of tuberculosis. We prospectively tested performance of host-blood transcriptomic tuberculosis signatures.Adults without suspicion of tuberculosis were recruited from five endemic South African communities. Eight parsimonious host-blood transcriptomic tuberculosis signatures were measured by microfluidic RT-qPCR at enrolment. Upper respiratory swab specimens were tested with a multiplex bacterial-viral RT-qPCR panel in a subset of participants. Diagnostic and prognostic performance for microbiologically confirmed prevalent and incident pulmonary tuberculosis was tested in all participants at baseline and during active surveillance through 15 months follow-up, respectively.p < 0.05) in participants with viral respiratory infections or detectable HIV viraemia than those without.Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2923 and 861 were enroled. There were 61 HIV-uninfected  and 10 HIV-infected  tuberculosis cases at baseline. Parsimonious signature diagnostic performance was superior among symptomatic (AUCs 0.85–0.98) as compared to asymptomatic (AUCs 0.61–0.78) HIV-uninfected participants. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident tuberculosis . Among HIV-uninfected individuals, prognostic performance for incident tuberculosis occurring within 6–12 months was higher relative to 15 months. 1000 HIV-uninfected participants were tested for respiratory microorganisms and 413 HIV-infected for HIV plasma viral load; 7/8 signature scores were higher  signatures could be used to find active cases of TB. Whilst most of the signatures met WHO Target Product Profile criteria for a triage test to diagnose symptomatic TB; most signatures did not meet the criteria for asymptomatic TB. Delays in tuberculosis (TB) diagnosis result in increased disease severity, risk of death, and infection of further individuals. The presence of symptoms is typically used to find  people with TB. However, about half of individuals with TB are asymptomatic. We evaluated blood samples from individuals living in areas with high incidence of TB to see whether there were changes in components of the blood following infection with TB. Markers were identified that diagnosed TB in symptomatic adults, but were not as accurate to detect TB in those without symptoms. Most markers tested were able to accurately predict progression to TB within 6 months in HIV-uninfected individuals. These markers in the blood could enable the screening of symptomatic adults and predict TB risk, thus enabling targeting of therapy. TB prevalence surveys in Africa and Asia demonstrate that approximately 50% of TB cases are asymptomatic , highlighting a major blind spot in the symptom-dependent case-finding strategies, which may perpetuate Mycobacterium tuberculosis (Mtb) transmission5. Currently available triage tests and passive case-finding strategies for symptomatic  disease are thus inadequate to find these missing cases among people who do seek healthcare. Effective active case-finding tools for screening of asymptomatic individuals in the community are urgently needed for earlier detection, further microbiological testing, and treatment, in order to interrupt the spread of Mtb.An estimated 2.9 million people with tuberculosis (TB) disease went undiagnosed or unreported in 20196 is one such approach for rapid and cheap mass screening, particularly in resource-constrained settings. Mobile sputum Xpert MTB/RIF screening also performs well as a community-based case-finding strategy, but requires considerable resources and is dependent on availability of a sputum sample7. Tests for detection of Mtb-exposed individuals at high risk of progression to TB disease, particularly in high burden settings, are also urgently needed to guide TB preventive therapy (TPT). Interferon-γ release assays (IGRAs) and tuberculin skin testing lack specificity in endemic settings due to high rates of prior Mtb exposure, which result in both overtreatment of those unlikely to progress to disease and missed incipient cases8. IGRAs are also laborious, and require laboratory facilities and skilled technicians.Computer-aided detection for automated interpretation of digital chest radiographs10. Diagnostic and prognostic performance of RISK11 as a PCR-based screening test was prospectively validated in HIV-uninfected adults11 and people living with HIV (PLHIV)12. This signature is not ideal for further development due to its large size (48 primer-probe assays). Fortunately, several refined, parsimonious diagnostic and prognostic transcriptomic signatures, which are more amenable to translation to point-of-care testing, have been developed16. However, most transcriptomic signature discovery and validation studies use a case-control design with stringent exclusion criteria, resulting in spectrum bias and best-case discriminative performance, which is not reproducible in prospective studies in heterogenous real-world settings. Transcriptomic signatures are predominantly measured by microarray or RNA-sequencing, techniques which are not suitable for use at the point of care. Current PCR methods are also laborious and require a laboratory and skilled operators. However, the successful development of the fingerstick blood-based Cepheid Xpert-MTB-Host Response (HR)-Prototype cartridge system19 clearly demonstrates proof-of-concept that a near-point-of-care platform can be implemented. There are also few studies which have performed unbiased head-to-head comparisons of signature performance15 and none for active case-finding in a community setting. It is therefore not clear which, if any, signatures offer potential in this context and should be advanced along the developmental pipeline into a near-point-of-care platform.We previously developed a predictive correlate of risk signature, RISK11, for diagnosis of TB disease and for identification of individuals at high risk of progression to active TB disease21. As an exploratory aim, we also explored the effect of HIV and upper respiratory tract microorganisms on transcriptomic signature scores.In this paper we report the results of a multicentre observational study, which prospectively tested the performance of eight parsimonious host-blood TB interferon-stimulated gene (ISG) signatures measured by microfluidic real-time quantitative PCR (RT-qPCR), for diagnosing prevalent pulmonary TB and predicting progression to incident TB disease, in a predominantly asymptomatic community cohort of HIV-uninfected and HIV-infected South African adults. As secondary aims, we compared signature diagnostic performance in symptomatic and asymptomatic participants, and benchmarked parsimonious signature accuracy against RISK11 and the World Health Organization (WHO) Target Product Profile (TPP) criteria for triage and prognostic TB testsWe found that diagnostic performance of the parsimonious signatures was superior among symptomatic as compared to asymptomatic participants; While none of the signatures met WHO triage test TPP criteria to diagnose subclinical TB, several signatures met or approached the criteria for diagnosing clinical TB. Most signatures had a good prognostic performance for incident TB occurring within 6 months of testing. Signature scores for most signatures were higher in the HIV-infected participants with detectable HIV plasma viral load, or HIV-uninfected participants with upper respiratory tract viruses, but not bacteria, as compared to those with undetectable HIV viral load or no respiratory viruses, respectively. Accordingly, most signatures were unable to differentiate individuals with TB from those with those with viral upper respiratory tract infection. Parsimonious TB transcriptomic signatures hold promise for triage of symptomatic adults seeking care, screening of ART clinic attendees, and prediction of short-term risk of TB for initiation of targeted preventive therapy. However, ISG induction from common viral infections results in poor specificity which is problematic for community active case-finding efforts in endemic settings, where there is a high burden of undiagnosed subclinical disease.22.In this diagnostic and prognostic accuracy study, we evaluated parsimonious blood-based host transcriptomic signature performance in four South African cohorts  and institutional human research ethics committees at each participating site. Written informed consent was obtained from all participants and all experiments conformed to the principles set out in the WMA Declaration of Helsinki and the US Department of Health and Human Services Belmont Report.23. Briefly, adults aged ≥18 years with newly diagnosed pulmonary TB confirmed by sputum Xpert MTB/RIF  and/or liquid mycobacterial culture  were enroled at primary healthcare clinics in Worcester and Masiphumelele, South Africa. Healthy, asymptomatic community controls were recruited from the same areas. HIV infection was diagnosed with the Determine HIV1/2 test . All participants provided written, informed consent and the protocols were approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (HREC 126/2006 and 288/2008).The CTBC case-control study was previously described12. Briefly, healthy adult volunteers without clinical suspicion of TB, residing in five TB endemic communities in South Africa , were recruited through word-of-mouth, house-to-house visits, and liaison with non-governmental organisations. Recruitment did not target symptomatic individuals seeking healthcare or other high-risk groups. Eligible participants aged 18–59 years were without comorbidities (except for HIV) and did not have known TB disease, or household exposure to individuals with multi-drug resistant TB, within the prior three years. The RISK11 signature was measured at enrolment, and a pre-specified score threshold of 60% was used to differentiate RISK11-positive from RISK11-negative participants. The HIV-uninfected CORTIS-01 population was enriched for participants at high risk of TB disease through enrolment of all eligible RISK11-positive individuals, and randomisation of RISK11-negative participants to enrolment or non-enrolment at a 1:7–9 ratio. RISK11-positive participants were randomised to receive TPT  or no intervention; RISK11-negative participants were randomised to no intervention or excluded from the study. In the CORTIS-HR observational study, PLHIV were enroled irrespective of RISK11 status and referred for standard of care antiretroviral and isoniazid preventive therapy.The CORTIS-01 clinical trial in HIV-uninfected individuals and CORTIS-HR observational study in PLHIV have previously been describedAll CORTIS participants provided two spontaneously expectorated sputum samples, if able to, at enrolment and at the end of study visits. End of study visits were performed at month 15 of follow-up or at an earlier timepoint for withdrawn participants. Both samples collected at enrolment from HIV-uninfected participants (CORTIS-01) were tested for Mtb using Xpert MTB/RIF, and from HIV-infected participants (CORTIS-HR) using Xpert MTB/RIF and MGIT culture. The two samples collected at the end of study visit were tested using Xpert MTB/RIF or Xpert Ultra (Cepheid), and MGIT culture. In addition, symptom-triggered TB investigations  were performed at six routine study visits through 15 months follow-up. TB symptoms included at least one of: persistent unexplained cough, night sweats, fever, or weight loss for 2 weeks or more, or any haemoptysis. Participants diagnosed with microbiologically-confirmed TB were withdrawn from the study and referred for curative treatment.24. Briefly, HIV-uninfected participants were consecutively enroled in this sub-study irrespective of CORTIS-01 enrolment, or signs and symptoms of upper respiratory tract infections. Paired nasopharyngeal and oropharyngeal flocked swabs  were collected and stored in Primestore buffer  at −80 °C, and viral and bacterial nucleic acid was later extracted  and quantified using a multiplex RT-qPCR assay kit  on the CFX96 Touch System lightcycler platform , according to the manufacturer’s instructions. Participants co-enroled into the CORTIS-01 trial were investigated for TB at baseline; those only enroled into the Respiratory Pathobionts cohort were not investigated for TB  at enrolment in all cohorts, frozen at −20 °C, and shipped to the South African Tuberculosis Vaccine Initiative (SATVI) Cape Town laboratory. For the CTBC study, RNA was manually extracted with the PAXgene blood RNA kit (Qiagen) according to the manufacturer’s instructions, stored at −80 °C, and later used for transcriptomic analysis. For the other cohorts, RNA was extracted using a high-throughput, standardised, and reproducible fully automated procedure on the Freedom EVO 150 robotic platform  with the Maxwell SimplyRNA kit . One aliquot of RNA was used immediately for cDNA synthesis and measurement of the RISK11 signature, and a second aliquot was stored at −80 °C, and later used to measure the panel of parsimonious transcriptomic signatures.25, Maertzdorf426 , Penn-Nicholson6 23, Suliman4 27, Roe128 (BATF2 only), Roe329, Sweeney330, and Thompson531 —to a microfluidic RT-qPCR platform using TaqMan primer-probe assays for quantification of transcripts, and signature scores were calculated as previously reported , and availability of target sequences for custom primer-probe design or predesigned TaqMan assay.We translated measurement of eight parsimonious TB transcriptomic signatures—Francisco2Following cDNA synthesis with EpiScript reverse transcriptase , genes of interest Tables  were pre11. The Roe1 and Roe3 signatures scores were calculated from the same Fluidigm 96.96 gene expression chip assay panels as the RISK11 signature . An assay passed qualification if at least one segment within a dilution series met the following three criteria: (1) strong correlation (Pearson r2 ≥ 0.99), (2) linear slope (regression coefficient between 3.1–3.6), and (3) efficient amplification ([101/slope – 1] = 90–110%). All new primer-probe assays passed qualification with efficient linear amplification  with quality control filters that assessed the integrity and reproducibility of each chip. The following parameters were applied for extracting Ct values: Linear (Derivative) baseline correction, Quality Threshold of 0.3, and Auto  for Ct Threshold Method using Fluidigm Biomark software version 4.5.1. Chips with marked deviation in internal positive control sample primer-probe assay Ct values or RISK6 signature score from historical runs, with detection in the no-template (water) control or no-reverse-transcriptase (to detect amplification of genomic DNA) control in primer-probes spanning exon-exon junctions, or with more than 20% failed reactions for a particular primer-probe assay, were repeated. Individual samples with more than 20% failed primer-probe reactions were classified as failed and no signature scores were computed. If less than 20% of primer-probe reactions failed for an individual sample, signature scores were computed where possible and signatures with missing primer-probe raw Ct values were deemed failed for that sample. Samples and primer-probe assays were run in singlet, and failed signature results for individual samples were assumed to follow a random distribution, thus not repeated, and excluded from analysis.For the CTBC study and Respiratory Pathobionts sub-study, TB disease was defined by a single sputum sample positive for Mtb on either Xpert MTB/RIF and/or liquid culture at enrolment. The coprimary protocol-specified endpoints in the CORTIS studies were baseline prevalent TB disease and incident disease through 15 months follow-up confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or MGIT culture, on two or more separate sputum samples collected within any 30-day period. The secondary endpoint was microbiologically confirmed TB disease on at least one sputum sample. All Xpert Ultra trace positive results were excluded from the analysis because of the risk of false positives.All primary and secondary analyses for the CORTIS-01 and CORTIS-HR sub-studies were pre-specified in the statistical analysis plan, but not in the original parent study protocols. CTBC and Respiratory Pathobionts sub-study analyses were exploratory. All statistical analyses were done in R , version 3.6.1. Sample sizes for this sub-study were not pre-specified, but were based on the accumulated enrolment of the CTBC and CORTIS parent studies. Performance of the signatures was evaluated on their ability to diagnose prevalent TB disease at baseline and predict progression to incident TB disease through 15-month follow-up. For all analyses, HIV-infected (CORTIS-HR) and HIV-uninfected (CORTIS-01) participants were considered independently. Diagnostic performance at baseline was assessed in all participants enroled in the CORTIS studies with available PAXgene samples. Thereafter, participants meeting the primary prevalent TB endpoint definition, participants who did not attend further follow-up visits, and participants randomised to the RISK11-positive 3HP group (CORTIS-01 only) were excluded from the primary endpoint prognostic performance analysis. Participants were followed for up to 15 months; those who discontinued follow-up prior to 15 months and did not meet the primary endpoint definition were censored at their final study visit or last negative sputum sample collection but included in the prognostic analysis.Due to enrichment of RISK11-positive individuals in the CORTIS-01 enroled population, analyses of signature performance required participant weighting to obtain estimates applicable to the screened population, effectively upweighting RISK11-negative participants in the CORTIS-01 analyses (i.e. inverse probability weighting). Enrolment in the CORTIS-HR study and Respiratory Pathobionts sub-study were independent of RISK11 status; analyses for these cohorts are not weighted.34 in R. Signature performance (AUC) between HIV-infected and HIV-uninfected participants in the CTBC study was compared using methods described by DeLong et al.35. Prognostic performance metrics through 15 months follow-up in CORTIS-HR were calculated by use of non-parametric methods for time-dependent ROC curve analysis from survival data using the R survAM.estimate function in the survAccuracyMeasures package36 in R. Binary weighted ROC analysis was performed in the CORTIS-01 cohort to evaluate both diagnostic and prognostic performance. In a post-hoc analysis, prognostic performance in CORTIS-01 was qualitatively compared between 6, 12, and 15 months of follow-up for the primary endpoint by use of identical methods.For evaluation of diagnostic performance in the CTBC, CORTIS-HR, and Respiratory Pathobionts studies, area under the receiver operating characteristic (ROC) curve (AUC) was generated using the pROC packagec) as follows: √[(1 − Sensitivityc)2 + (1 − Specificityc)2]37. Signature diagnostic and prognostic accuracy was also benchmarked against the minimal and optimal WHO TPP for a community-based TB triage or referral test20 and the minimal and optimal WHO TPP for an incipient TB test, to predict progression to TB disease21, respectively.There were no pre-defined score thresholds for the parsimonious signatures; optimal signature score thresholds were calculated using the minimum Euclidean distance to 100% sensitivity and specificity, i.e. the point closest to the top-left of the ROC curve, calculated for each cut-point , and negative predictive value (NPV) at each threshold were calculated using binary endpoint indicators and standard formulae. Estimates of PPV and NPV were computed based on the observed incidence of TB in the enroled study population. The 95% CIs on diagnostic and prognostic performance estimates were calculated with a non-parametric percentile bootstrap with 10,000 resamplesU test and corrected for multiple comparisons by use of the Benjamini–Hochberg Procedure39. Spearman’s rank coefficient was used to report correlation between signature scores; only samples with all assays passing were include in the correlation matrices; and Roe1 and Roe3 signatures were multiplied by −1 to obtain a positive correlation for all signatures. An alpha of <0.05 was considered significant in all analyses.Signature score distribution was described using median and interquartile range. Differences between groups were calculated using the Mann–Whitney Transcriptomic signature scores were measured by laboratory personnel who were blinded to participant TB status. Participants and study staff responsible for TB screening were blinded to transcriptomic signature scores. The statistical analysis team had access to clinical and demographic data (including TB status), but were blinded to signature scores, to allow data cleaning and preparation of analysis scripts prior to database lock. Signature scores and TB microbiology results were maintained in different files, which were only integrated after the study database had been cleaned and locked, and group allocations unblinded in CORTIS-01.The funders of this sub-study had no role in protocol development, study design, data collection, data analysis, data interpretation, or writing of the report.25, Maertzdorf426 (DIAG4), Penn-Nicholson6 (RISK6)23, Suliman4 (RISK4)27, Roe128 (BATF2), Roe329, Sweeney330, and Thompson531 (RESPONSE5)—to a microfluidic RT-qPCR platform using TaqMan primer-probe assays for quantification of transcripts  to 0.97   for RISK11 (p = 0.027), Francisco2 (p = 0.0095), and Sweeney3 (p = 0.021)  and in all enroled HIV-infected CORTIS-HR participants who had baseline RNA samples available 857/861 (99.5%). RISK11 performance in these cohorts was previously reported12, but is included here for comparison without a pre-specified score threshold. The parsimonious transcriptomic signature assay panel  TB, and successively lower in participants with asymptomatic  and incident TB (participants who progressed to TB disease), and symptomatic and asymptomatic participants without TB  in the HIV-uninfected cohort through 15 months follow-up  transcriptomic signature scores than those with supressed HIV plasma viral load (<100 copies/mL). The exception was Thompson5, the only signature that does not include ISGs31, which was not affected by viral load  between those with and without TB symptoms  had significantly higher  in participants with any viral pathobiont, or both viral and bacterial pathobionts, compared to those with only bacterial, or no pathobionts, with the exception of Thompson5  commonly colonise the respiratory tract of healthy individuals, hence we are unable to determine the effect of pathogenic bacteria on signature scores. Thompson5 was the only signature for which no differences in scores were observed between participants with viral, bacterial, or no pathobionts, and subsequently was not able to differentiate between these groups , or mixed viral and bacterial pathobionts (n = 33), had prevalent TB. The presence of bacterial upper respiratory pathobionts did not significantly affect TB diagnostic performance. Transcriptomic signatures differentiated between participants with prevalent TB and those with no pathobionts detected, with AUCs between 0.63 and 0.79, and between participants with prevalent TB and those with other bacterial pathobionts with AUCs ranging from 0.60 to 0.81  of participants were co-enroled into the Respiratory Pathobionts sub-study and CORTIS-01 and consequently investigated for TB  may spontaneously control the infection and thus not progress to disease41, resulting in reduced specificity. In this regard, we suggest that the 2-year predictive window for a prognostic test proposed in the WHO framework21 be revisited. Transient viral infections may also increase false positivity24. Low sensitivity may reflect the high burden of population Mtb exposure and rate of new infections in this endemic setting.This waning accuracy mirrors the finding of a short prognostic window after signature testing in the meta-analysis by Gupta et al.15. Most signatures were able to differentiate between those who would progress to TB disease (progressors) through 15 months follow-up and non-progressors in the HIV-infected cohort, and the Roe1 signature met the minimal WHO TPP benchmark for a prognostic test21. The greater prognostic window of the signatures measured at baseline in PLHIV may reflect prevalent TB cases missed at study enrolment (possibly due to paucibacillary sputum), but detected further along the disease spectrum during follow-up. At each study visit, participants underwent symptom screening with symptom-guided TB investigations which would have missed asymptomatic disease at earlier timepoints. However, all participants provided sputum samples for TB investigation at the end-of-study visits, which may also explain the bulk of disease diagnosed at the month 15 visit. Most of the incident TB cases in the HIV-infected cohort were detected after 12 months follow-up; this may be due to the appearance of symptoms late in the disease course in immunosuppressed individuals, and as a result, incident TB cases may have been missed by symptom screening at earlier visits. It is also conceivable that the better performance in PLHIV is driven by ART-naïve individuals who have increased risk of TB disease, but also have elevated signature scores (or lower for Roe1 and Roe3) due to their higher HIV plasma viral loads. However, 74% (142/193) of ART-naïve participants started ART during the study  for all transcriptomic biomarkers in the CORTIS studies make these good rule-out tests, however low PPV (<6%), reflective of low TB prevalence and incidence in this community setting, make these inadequate rule-in tests. Performance of most signatures is promising for triage of symptomatic adults seeking care and PLHIV attending ART clinic, to rule-out active disease and guide further investigation (e.g. sputum Xpert Ultra or radiography), and for short-term (6–12 months) prognosis of TB disease risk for targeted preventive therapy in those without disease. Recent studies of 3HP have shown limited duration of efficacy (9 months) for biomarker-guided preventive therapy in HIV-uninfected adults in South Africa12. However, we would note that these benchmarks were not intended for TB screening in a healthy community setting, but rather “to test persons with any symptoms or risk factors suggestive of TB who are seeking care”20, and thus the bar may have been too high for a strategy that seeks to find subclinical TB cases. Currently, chest radiography is the only sufficiently accurate screening tool in widespread use for detecting asymptomatic subclinical disease5. Portable molecular screening has also been proposed as a possible universal screening tool for active case-finding7, but this remains unaffordable in most settings. Given the recently recognised burden of asymptomatic TB in endemic settings and lack of affordable and accessible active case-finding tools to detect early and subclinical disease in community settings, we would propose that a new consensus framework for the development of screening tests for asymptomatic TB is urgently needed. Such a framework should also provide clear definitions of contentious concepts of asymptomatic incipient and subclinical TB49. We have previously demonstrated a sequential inflammatory TB disease process50. The trend of increasing signature scores from individuals without TB disease, through early or incipient , subclinical, and clinical TB disease observed in this study  or multinomial (multiple outcomes or covariates) modelling approaches to TB signature discovery may help to mitigate the effect of exogenous factors on signature performance45.The correlation between most signatures (with the exception of Thompson5), and fact that no individual signature was significantly superior for diagnosis or prognosis, indicates they likely measure the same or similar biological pathways. Our study would suggest that performance of ISG dominant transcriptomic host-response signatures may be approaching an apex and that further signature discovery using similar conventional methodology and study designs is unlikely to deliver better diagnostic tools. What could be done differently? First, we would argue the necessity for recruiting larger heterogenous unselected prospective discovery cohorts, with TB cases representing a spectrum from subclinical through clinical disease at prevalence rates that reflect the real epidemic, rather than carefully-curated case-control studies with uniform and highly enriched TB cases and homogenous healthy controls or inappropriate other diseases. In this study, all signatures performed superbly in the CTBC case-control cohort, but performance dipped substantially in the real-world CORTIS studies. Second, we have shown that parsimonious signatures perform at least as well as non-reduced signatures such as RISK11; early translation of parsimonious signatures to near point-of-care technology, such as RT-qPCR, would allow more rapid advancement along the developmental pipeline. Third, few studies have incorporated clinical features  into predictive host-response models, which may prove low-hanging fruit for improving signature performance19. The large proportion of asymptomatic prevalent TB cases is a feature unique to this cohort, and may prove valuable for future biomarker discovery. Recruitment was restricted to South Africa, limiting generalisability of the results to other contexts; there is a need for similar large prospective diagnostic validation cohorts in other TB endemic regions.A major strength of this study was the prospective recruitment of large community cohorts of unselected adults from multiple sites reflecting distinct patterns of Mtb exposure and rates of TB disease in an endemic setting. Despite intensive community active case-finding with enrichment of the HIV-uninfected study population for individuals at greatest risk of TB disease, sputum sample collection from all enroled participants at enrolment and end-of-study visits, and symptom-triggered investigation during follow-up, there were relatively few prevalent and incident TB cases, reducing the precision of sensitivity and PPV estimates. We also did not investigate participants for extra-pulmonary TB, potentially missing cases amongst PLHIV. Another limitation was the high Suliman4 failure rate, resulting in less precise performance estimates for this signature. Since we put together our signature panel in 2017, numerous new TB transcriptomic signatures have been discovered, including several in cohorts with symptomatic controls with other diseases. It is possible that other parsimonious signatures, or derivatives of larger signatures, may measure other aspects of the immune response to TB which are less affected by viral infection (as demonstrated by Thompson5), and may have greater diagnostic or prognostic utility, than the predominantly ISG signatures included in this study. We also acknowledge that primer sequences selected for RT-qPCR may not be equivalent to those used for microarray or in the Cepheid Xpert MTB Host Response prototype cartridge19, would bring these signatures from the laboratory bench to the clinic bedside.Several parsimonious TB transcriptomic signatures hold promise for triage of symptomatic adults seeking care, screening of ART clinic attendees and other high-risk groups for further investigation, and prediction of short-term risk of TB for initiation of targeted preventive therapy. Point-of-care RT-qPCR testing platforms currently under development and in field implementation studiesFurther information on research design is available in the Supplementary InformationSupplementary Data 1Description of Additional Supplementary FilesPeer Review FileReporting Summary


Early extensive surgery is a cornerstone in treatment of diffuse low-grade gliomas (DLGGs), and an additional survival benefit has been demonstrated from early radiochemotherapy in selected “high-risk” patients. Still, there are a number of controversies related to DLGG management. The objective of this multicenter population-based cohort study was to explore potential variations in diagnostic work-up and treatment between treating centers in 2 Scandinavian countries with similar public health care systems.Patients screened for inclusion underwent primary surgery of a histopathologically verified diffuse WHO grade II glioma in the time period 2012 through 2017. Clinical and radiological data were collected from medical records and locally conducted research projects, whereupon differences between countries and inter-hospital variations were explored.A total of 642 patients were included , and annual age-standardized incidence rates were 0.9 and 0.8 per 100 000 in Norway and Sweden, respectively. Considerable inter-hospital variations were observed in preoperative work-up, tumor diagnostics, surgical strategies, techniques for intraoperative guidance, as well as choice and timing of adjuvant therapy.Despite geographical population-based case selection, similar health care organizations, and existing guidelines, there were considerable variations in DLGG management. While some can be attributed to differences in clinical implementation of current scientific knowledge, some of the observed inter-hospital variations reflect controversies related to diagnostics and treatment. Quantification of these disparities renders possible identification of treatment patterns associated with better or worse outcomes and may thus represent a step toward more uniform evidence-based care. In the present retrospective multicenter population-based cohort study in a single-payer universal health care setting, we sought to explore possible variations in diagnostics and treatment strategies of DLGG across centers in 2 Scandinavian countries.The study is part of a collaborative Scandinavian multicenter project including all 11 neurosurgical departments performing glioma surgery in Norway and Sweden. Included centers appear from author affiliations. The Scandinavian tax-funded universal coverage public health care system, with geographical-based referral to regional neurosurgical centers, limits the possibility for referral bias. Since there are no competing private alternatives, insurance policies do not influence the management, and the study population thus represents a practically unselected population-based series. Regional tumor board meetings and discussion in multidisciplinary teams are endeavored in both countries, and national standardized clinical pathways for diagnostics, treatment, and follow-up on suspicion of a brain tumor were developed and implemented during the study period. All departments aim for tissue diagnostics upon radiological suspicion of a DLGG.13 Three centers did not register data in 2017. Incidence rates and temporal trends were therefore calculated for the time period 2012-2016.Patients screened for inclusion were adults 18 years or older who underwent primary surgery (biopsy or resection) of a histopathologically verified supratentorial diffuse WHO grade II glioma in the time period from 2012 through 2017. Tumors were classified according to the 2007 or 2016 WHO classification system.14Clinical and radiological data were retrieved from medical records at the respective institutions or collected as part of research projects conducted locally. Data were collected between August 2018 and September 2019, and study variables were filled out in electronic case report forms (CRF). The CRF covered patient characteristics, preoperative work-up, tumor data, and a detailed description of primary surgical care and adjuvant treatment regimens, as well as surgical approach at disease progression and recurrence. Dates of radiological diagnosis, primary surgery, and re-operation were also registered. An overview of the collected variables can be found in P ≤ .05. Holm’s sequential Bonferroni procedure was conducted to counteract family-wise error rate associated with multiple testing, and all reported P values are adjusted. Normality was explored using the Shapiro-Wilk test and by visual assessment of Q-Q plots, while distributional shapes were assessed by visual inspection of boxplots. Central tendencies are presented as mean (±SD) or median (range) for normally distributed and skewed data, respectively. Chi-square test, Fisher’s exact test, and Fisher-Freeman-Halton exact test were conducted for hypothesis testing in contingency tables. For r × c contingency tables, omnibus testing was supplemented with analyses of adjusted standardized residuals. Mann-Whitney U test and Kruskal-Wallis test were conducted for exploration of differences between groups on a continuous or ordinal dependent variable. Cochran-Armitage test of linear trends in proportions was conducted for investigation of temporal trends.Statistical analyses were performed in IBM SPSS Statistics version 27.0  and R version 3.6.3. All tests were 2-sided and statistical significance level was set at 15Population estimates were obtained from Statistics Norway and Statistics Sweden. Annual age-standardized incidence rates were calculated by adjusting the crude incidence rates relative to the European standard population 2011-2030 projection, as recommended in the Eurostat revision guidelines from 2013.Funnel plots were generated for exploration of inter-hospital variations in important key aspects of clinical management plotted against case volume. Unadjusted funnel plots were generated with observed proportion at each center plotted against case volume, with the observed overall proportion set as the target outcome for Y. The funnel control limits for identifying potential outliers were obtained at 95% and 99% prediction limits based on the Binomial distribution of proportions. Further, multivariable logistic regression modeling was used to risk-adjust outcome variations between centers based on preselected clinical factors. Resection rates within 6 months from radiological diagnosis were adjusted for patient age, Karnofsky performance status (KPS) score, and year of surgery. Rates of early postoperative RT plus PCV were adjusted for age, KPS score, year of surgery, and primary surgical intervention . Predicted probabilities of the event for each patient treated at each center were calculated and summarized to render expected count at each center. Adjusted ratio at each center was calculated by dividing the observed number of cases by the predicted number of cases at each center, ie, the observed-to-expected ratio. For the adjusted funnel plots, control limits for identifying potential outliers were obtained at 95% and 99% prediction limits based on the Poisson distribution.Data collection and transfer of patient data across treatment centers were approved by the Regional Committee for Medical and Health Research Ethics in Central Norway (REC reference 2017/1780) and by the regional committee of Western Sweden (EPN reference 705/17). The need for informed consent was waived by the committees.Patient characteristics including symptom burden at radiological diagnosis and an overview of the presurgical work-up with range between treating centers are presented in P < .02).Epileptic seizures were the most frequent onset symptom (60%), followed by headaches and/or other symptoms related to increased intracranial pressure (ICP) (24%). Seventy-one tumors (11%) were incidentally discovered when neuroimaging was carried out for unrelated symptoms or disease. An overview of different aspects of clinical management at the individual treating centers is displayed in IDH-mutant tumors were significantly younger than patients diagnosed with IDH-wildtype tumors, with median age of 41 (18-77) years vs 54 (18-80) years at the time of primary surgery (P < .02). Further, 68% of centrally located tumors were IDH-wildtype, while only 8% were IDH-mutant (P < .02). However, mutational status of IDH was not assessed in 24% of tumors with central tumor location. An overview of histopathological diagnoses at primary surgery and molecular genetic status within each histopathological subtype is presented in As seen in P = 1.00). Watch-and-scan was not associated with tumor location or presumed eloquence but was advocated more frequently in asymptomatic patients with incidental DLGGs than in symptomatic patients, 44% (0%-64% across centers) vs 14% (0%-26%) of cases (P < .02). Further, patients in the watch-and-scan group had smaller tumors than patients who received upfront primary surgery, with median largest diameter measuring 30 (3-110) mm against 46 (10-110) mm, respectively (P < .02). Median duration of the watch-and-scan period calculated from the first MRI examination with DLGG suspect findings to primary surgery was 35.1 months (median 13.6-66.3 months across centers), and tumor growth was documented prior to surgery in 72% of patients during the watch-and-scan period.Surgical strategies are outlined in P < .02). Moreover, resection rates were significantly lower in patients with centrally located tumors  when compared to other tumor locations  (P < .02).Three hundred and forty-seven patients  were resected within 3 months from radiological diagnosis, and 422 patients  underwent resection within 6 months from radiological diagnosis. Elapsed time from radiological diagnosis to surgery was missing in 2 cases. For resection rates within 6 months, variability in expected range is displayed between centers when plotted against case volume  and expeP < .02). While awake surgery and mapping asleep were performed at all 6 Swedish centers, these techniques were utilized at 2 and 3 centers in Norway, respectively.While neuronavigation based on preoperative MRI was extensively used at all treating centers , availability and choice of other tools and techniques for intraoperative guidance and surgical decision-making varied between centers . IntraopIDH and 1p/19q. As seen in P = .02). Further details on adjuvant therapy following primary surgery are available in Combined early adjuvant RT and chemotherapy (CHT) was administered in 154 patients , and this fraction was evenly distributed across histopathological subtypes and mutational status of 8 Further, in spite of an increasing time trend, the use of early adjuvant RT + PCV was limited to a small minority of patients, and with diverging practices between treating centers. However, landmark studies were published in the study period, and time to clinical implementation of newly acquired scientific evidence and subsequent practice changes may vary. Although differences in tumor classification and implementation of molecular markers are concerning, much of the variation can be attributed to the fact that patients were included in the transitional phase between the 2007 and 2016 WHO classification. The different use of techniques intending to spare functions and guiding surgical resection is likely to reflect the low evidence for most adjuncts and lack of well-conducted comparative studies. Altogether, many of the observed variations highlight major controversies associated with treatment of DLGGs and demonstrate that management of this heterogenous patient group still differs across treating centers, even in countries with universal coverage public health care where patients are treated free of charge, and where insurance policies do not influence the management. Some of the observed variations may presumably also reflect variability in clinical assessments and interpretation of the current evidence base and emphasize the need for high-level evidence to fill knowledge gaps.The objective of this multicenter study was to explore variations in DLGG management across all treating centers in 2 Scandinavian countries with similarly structured public health care systems. Surprisingly, no declining time trend was observed in watch-and-scan during the 5-year period, despite convincing evidence in favor of early resection.1–3 Since the incidence of intracranial tumors is associated with the number of MRI scans carried out,17 local differences in the availability and use of MRI may influence DLGG incidence. Small fluctuations in diagnosis-specific incidence rates may also be caused by the often notoriously difficult diagnostic distinction between WHO grade II and III gliomas. Further, pronounced intra-tumoral heterogeneity implies a risk of tissue sampling bias. Consequently, under- and overgrading is not uncommon in studies exploring the concordance between histopathological diagnoses established from stereotactic biopsies compared to specimens obtained from open resections.18Age-standardized incidence rates in the present study approximated 1/100 000 person-years which is comparable to incidence rates reported in the literature.19 However, patients were included in the transitional phase between the 2007 and 2016 WHO classification, and clinical implementation of IDH and 1p/19q in glioma diagnostics was widely varying across centers. The second cIMPACT-NOW  update from 2018 opened for refraining from direct 1p/19q testing in IDH-mutant DLGGs with unambiguous astrocytic phenotype, given strong p53 immunopositivity and/or definite loss of nuclear expression of ATRX .20 Since the CRF solely contained questions regarding mutational status of IDH and 1p/19q, data on assessments of ATRX and TP53 were not available.The risk of erroneous glioma subtyping is reduced by incorporation of molecular markers that reflect genetic alterations occurring early and homogenously in tumorigenesis.21 Yet, despite an increasing temporal trend, neuropsychological assessments were only performed to a small extent at most centers. In similarity with findings from an online survey on DLGG imaging practice among members of the European Low-Grade Glioma Network (ELGGN) with data from 24 European countries,22 there were pronounced variations in the application of advanced imaging techniques in preoperative work-up between treating centers, which may partly be attributed to the fact that most techniques are supported by limited evidence.23 Clinical utilization of amino acid PET may further be restricted by demanding logistics and high costs, because many of the included treating centers cannot produce their own tracers.Because subtle symptoms and deficits can be difficult to detect anamnestically and by standard neurological examination, there is a consensus that neuropsychological testing should ideally be an integral part of clinical preoperative work-up in DLGG patients.8 Because the progressive infiltrative nature of the disease and treatment-induced adverse effects both contribute to morbidity in DLGG patients, clinical decision-making is often challenging. The optimal treatment strategy in asymptomatic patients with small DLGG suspect lesions is debatable, especially in equivocal cases where benign lesions  cannot be ruled out, when located in highly eloquent regions, or in older or very comorbid patients. Still, DLGGs always grow and there is a risk of malignant transformation at any time point. Thus, deferring treatment until demonstrated radiological growth or symptom onset is not a risk-free strategy. In a survey study within the ELGGN from 2015 including 21 European centers, 48% and 81% of respondents favored watch-and-scan as the preferred initial strategy in resectable and unresectable tumors, respectively, in all patients or depending on risk factors.24 However, most survey respondents stated an average duration of watch-and-scan of 6 months or less when advocated. By comparison, median duration of watch-and-scan ranged between 13.6 and 66.3 months across treating centers in the present cohort.Surprisingly, watch-and-scan was pursued in 1 out of 6 patients in this cohort, with greater variability than expected across treating centers and 1 significant outlier. Further, there was no significant declining time trend, despite that studies supporting early resection were published in the study period.25Surgical treatment was also awaited in some patients in the upfront primary resection group without any records of structured monitoring with MRI or cause of delay. In some cases, physicians may have chosen to await surgery due to comorbidity, without watch-and-scan being advocated as a deliberate strategy. Further, in ambiguous cases where other differential diagnoses were initially considered more likely, this may have caused delayed referrals and/or a decision to await surgery until supplementary diagnostic radiological work-up had been carried out or volumetric growth had been demonstrated.IDH-wildtype gliomas had a predilection site for central brain regions and more frequently affected an older patient group than IDH-mutant gliomas.26 Aggressive biological behavior combined with an often more unfavorable tumor location is believed to partly explain the negative prognostic and predictive significance of age. Nevertheless, age-dependent variations in treatment strategies can also be caused by a certain element of therapeutic nihilism.28One-fifth were biopsied only in the study period, and resection rates were lower in older adults with centrally located tumors. As previously reported, 9–11 In the present cohort, the use of early RT + PCV was limited to a small minority of patients, albeit an increasing temporal trend was observed during the study period. Besides delay to clinical implementation, divergent practices between centers may also be partly attributed to variations in patient selection, since the definition of “high-risk” DLGG remains disputable29 and due to possible case-mix variations.Due to the risk of long-term toxicity, early adjuvant radiochemotherapy is usually reserved for patients with an unfavorable prognostic profile and presumed high risk of early malignant transformation. Results from the Radiation Therapy Oncology Group (RTOG) 9802 trial that demonstrated significantly prolonged OS in selected “high-risk” patients treated with combined adjuvant RT + PCV as compared to early RT alone were published in the study period.24 Correspondingly, TMZ was largely preferred over PCV at some centers in the present study. Because no trials to date have compared these chemotherapeutic regimens directly, the use of TMZ instead of PCV has less evidence base and remains controversial.31 An ongoing randomized phase III trial (NCT00887146) with estimated primary completion in 2025 is aiming to evaluate RT plus PCV vs RT with concomitant and adjuvant TMZ in patients with newly diagnosed 1p/19q co-deleted “high-risk” DLGGs and anaplastic gliomas.32TMZ has some advantages in terms of administration method and toxicity profile, and in a survey study within the ELGGN from 2015, 76% of the included centers reported a preference for TMZ as first-line treatment over PCV.The retrospective study design and assessment of patient characteristics and clinical variables from non-standardized documentation in medical records are the main limitations of the study, and some data were thus incomplete or missing. Since the objective was to study variations in clinical practice, we refrained from attempting to homogenize data or imaging by performing central review. Three centers that accounted for 30% of the total case volume between 2012 and 2016 did not register data in 2017. Temporal trends and incidence rates were therefore calculated for 2012-2016. Despite existing guidelines, individual patient selection and treatment strategies will to some extent rely on subjective assessment. Besides, regional differences in organization and sub-specialization may contribute to variations in clinical management. Even though all treating centers advocate tissue diagnostics when a DLGG is radiologically suspected and this cohort for all practical purposes is an unselected population-based series, not all patients are fit enough for neurosurgical interventions at an acceptable risk/benefit ratio. Because the study exclusively includes patients who underwent surgery in the study period, a small number of patients may have been excluded due to inoperability. This selection effect is not random, as conservative treatment is more likely to be pursued in older comorbid patients with impaired functional status. Tumor growth was documented prior to surgery in the majority of patients followed by watch-and-scan. However, individual cases that may have undergone malignant transformation during the watch-and-scan period would thus no longer meet the inclusion criteria at the time of tissue diagnosis, and transformation rates may have been higher in patients harboring tumors with a more aggressive molecular biological profile. Consequently, the frequency of watch-and-scan may have been underestimated in this study. Moreover, the generalizability of findings to countries with differently structured health care systems is probably limited. However, one can speculate that the observed inter-hospital variations will be even greater in a setting without universal coverage public health care, where patient populations assumedly are more inhomogeneous and the resources more unevenly distributed.We describe the current pattern of care of DLGGs across treating centers in Norway and Sweden. Despite uniform public health care systems, geographical catchment regions that ensure population-based case selection, and existing national and international treatment guidelines, there were substantial differences in preoperative work-up, surgical strategies, and adjuvant treatment regimens across centers. Some of the observed disparities reflect controversies in DLGG management and highlight aspects where the knowledge base is deficient. Systematic registration of data can help improve negative outliers and enable future benchmark studies that evaluate progress over time and will make it possible to identify patterns associated with better or worse treatment results, including surgical resection grades, neurological outcomes, and survival. National or regional tumor boards might be a way to provide more homogenous and evidence-based care.npab054_suppl_Supplementary_TablesClick here for additional data file.


Active surveillance (AS) has evolved as an alternative to radical treatment for potentially indolent prostate cancer. However, current selection criteria for entering AS are suboptimal, and a significant percentage of patients discontinue AS because of disease reclassification. Hence, there is an unmet need for novel biomarkers for the accurate identification of high-risk PCa and the unequivocal classification of indolent disease. Circulating biomarkers, including microRNAs identified through liquid biopsies, represent a valuable approach to improve on currently available clinicopathological risk-stratification tools. In an attempt to identify specific microRNA signatures as potential circulating biomarkers, the authors performed an unprecedented analysis of the global microRNA profile in plasma samples from AS patients and identified and validated a three-microRNA signature able to predict patient reclassification. The addition of the three-microRNA signature was able to improve the performance of currently available clinicopathological variables, thus showing potential for the refinement of AS patients’ selection.miR-511-5p, miR-598-3p and miR-199a-5p) was found to predict reclassification in all patient cohorts . Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only . Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS.Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts . A three-miRNA signature ( Prostate cancer (PCa) is the third most common malignancy and the fifth cause of cancer death in men worldwide , with thActive surveillance (AS) has emerged as an alternative strategy in selected men with favorable-risk disease . It consThe efficacy and safety of AS have been assessed in several long-term prospective AS cohorts, showing a 15-year cancer-specific mortality ranging from 0.2 to 5%  − Ctreference [Within each set of data , the following preprocessing steps were applied: (eference . For dateference . TRS dateference . The pre2 (RQ), and upgrading was assessed by resorting to the nonparametric Kruskal–Wallis test and to the logistic regression model. miRNAs showing at least one instance of significance in univariate fashion were then combined in multivariate fashion . According to the required number of events per variable (EPV) [S), and its 95% CI was computed according to the bias-corrected and accelerated bootstrap method (95% CIBCa) [S ≥ 0.75) was considered as relevant [In the TRS, the association between miRNA levels, on logarithmic scale logle (EPV) , standarle (EPV)  was usedle (EPV) . The bes% CIBCa) ; only sirelevant . Variablrelevant . The nonrelevant  was usedAll statistical analyses were carried out with the SAS  and R software by adopting a significance alpha level of 5%.Circulating miRNA profiles were assessed in plasma samples prospectively collected from 386 PCa patients at inclusion in AS programs at INT from 2009 to 2018. let-7c-5p, miR-126-3p, miR-26b-5p and miR-379-5p) were selected to be used for data normalization to control intersample variability in the TRS cohort. A list of 17 miRNAs differentially expressed in plasma samples from upgrading compared to indolent patients was identified by univariate analysis  + (−0.5848 × expression of miR-598-3p) + (−0.3441 × expression of miR-199a-5p) + (−4.020). The ROC curves of the miRNA model are depicted in By opportunely combining the candidate miRNAs in a multivariate fashion, 31 promising signatures, with a statistically significant performance and a high multivariate detection rate , were identified in the TRS and validated in the TES by applying the same regression coefficients B. Among The performance of the available clinicopathological variables  was then evaluated in the overall case series. As reported in p = 0.658) from that of the three-miRNA model in the overall cohort . However, its performance was significantly improved (p = 0.007) when the miRNA score was included , with the AUC value increasing to 0.76 (95% CI: 0.68–0.84)  was not substantially different (68–0.84) A. The diFor the explorative purpose to illustrate the potential usefulness of the signatures, we pursued a further analysis by estimating the performance indexes after dichotomization of the linear predictor according to the Youden index based cutoff values. We obtained 80% (95% CI: 65–90%) sensitivity, 50% (95% CI: 43–57%) specificity, 23% (95% CI: 19–43%) positive predictive value (PPV) and 93% (95% CI: 86–95%) negative predictive value (NPV) for the three-miRNA signature. An appreciable increment was observed for specificity , PPV  and NPV  by jointly considering the clinicopathological variables with the miRNA-signature, while a similar sensitivity value was retained .miR-511-5p, miR-598-3p and miR-199a-5p) signature associated with disease upgrading, which was shown to provide risk refinement to standard clinicopathological features.In this study, we performed an unprecedented analysis of the circulating miRNome in plasma samples from three independent cohorts of low-risk PCa patients followed in AS protocols at INT in the search for biomarkers to improve the prediction of disease reclassification. We trained, tested and validated a three-miRNA  score significantly predicted reclassification (defined as upgrading or PSA doubling time <3 years or MRI progression) and also conferred additive predictive value to PSA [miR-24, miR-30c and CRIP3 gene methylation, significantly predicted patient reclassification. Another report investigated circulating miRNAs in PCa patients potentially eligible for AS but who underwent radical prostatectomy [miR-19, miR-345 and miR-519c-5p could help identify patients showing upgrading of the disease in the surgical specimen compared to the initial biopsy [The only previous study looking at blood miRNAs in the AS setting pursued a targeted approach by analyzing the expression of nine miRNAs,  cohorts . It was e to PSA . In a fue to PSA  reportedatectomy . The autl biopsy .miR-223, miR-24 and miR-375 [Circulating miRNAs are promising biomarkers in oncology but have not yet been implemented in the clinical practice given the lack of concordance across the studies, as can be easily inferred by the variable results obtained in AS or AS-eligible patients, which failed to identify common miRNAs. In this context, in our AS cohorts, we were not able to find any significant correlation between  miR-375 —neither  miR-375 , have bePTEN deletion or MYC amplification [Thus far, a relevant fraction of patients enrolled in AS drop out of the protocol due to upgrading at the time of a repeated biopsy . Though fication .PCA3, assessed on baseline samples improved the accuracy of predicting reclassification at the first surveillance biopsy but did not provide further value over clinical variables on subsequent biopsies [Based on the assumption that circulating miRNAs carry information coming from all tumor foci present in the prostate gland, they could complement the intrinsically limited information obtained through bioptic sampling. Ideally, they could be suitable for repeated measurements, in addition to or in place of repeated biopsies, to monitor disease status during AS. Indeed, in our study, we found that the three-miRNA signature on plasma samples collected at the baseline is significantly associated with upgrading at the first repeated biopsy. However, due to the unavailability of tissue samples for the majority of patients, we could not investigate whether such a predictive value is maintained on subsequent biopsies. In this context, other circulating biomarkers, such as PHI and biopsies ,9.PCA3 [An AS program’s success is critically dependent on selecting patients who are predicted to have clinically insignificant cancer. Methods to improve selection tools are an active research area. Many researchers found that some clinicopathological features  were associated with upgrading in AS . HoweverPCA3  in the ACoupling of our three-miRNA signature with selected clinicopathological variables, however, led to a statistically significant, although modest (6%), improvement in the discrimination of aggressive cancer, underlining possible complementary information coming from the miRNome. PSA density (<0.15 ng/mL) and the number of positive cores (≤2) at diagnosis are already used in international guidelines to discriminate very low-risk vs. low-risk patients . Some ASThe addition of a biomarker that is biopsy-independent, as is the miRNA signature, could help to refine the classification of patients into subgroups, such as those having a “decreased risk” of misclassification at diagnosis  and those having an “increased risk” of misclassification . This improved knowledge of the single patient risk could help in counseling patients about treatment choice and personalized monitoring intensity during AS. To more precisely define its possible clinical utility for risk estimation, the three-miRNA signature should be investigated in contemporary AS protocols together with mpMRI, which was not routinely available in the great majority of patients at the time of this study.miR-199a-5p. Consistent with the downregulation observed in plasma samples from upgrading patients, it was reported that miR-199a-5p is under-expressed in PCa clinical specimens and acts as an oncosuppressor, since its reconstitution in PCa models decreased cell proliferation, motility and tumor angiogenesis and increased apoptosis by directly targeting HIF-1α [miR-511-5p was reported tofunction as a tumor suppressor in colorectal cancer by directly targeting GPR116 [miR-598-3p was found to be downregulated in serum samples from breast cancer patients compared to healthy individuals [Information concerning the biological functions in PCa of miRNAs included in the signature is only available for g HIF-1α . As regag GPR116 , while mividuals .ad hoc studies.Overall, we identified and validated a plasma miRNA signature significantly associated with disease upgrading at the first repeated biopsy in three mono-institutional independent cohorts of AS patients. When combined with selected clinicopathological criteria, the miRNA signature enhanced their predictive value. However, it should be considered that any formal evaluation of the clinical utility of the signature depends on cutoff selection, which needs to be validated in As the main limitation of the study is the absence of mpMRI data, the clinical utility of the signature as a novel biomarker to improve patient selection needs to be further validated in other cohorts of AS patients together with mpMRI.We trained, tested and validated a plasma miRNA signature significantly associated with disease upgrading at the first repeated biopsy in three mono-institutional independent cohorts of AS patients. When combined with clinicopathological parameters, the miRNA signature enhanced their predictive value. The clinical utility of the signature as a novel biomarker to improve patient selection should be further validated in contemporary AS protocols together with mpMRI.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has important implications for gravid patients as they are more likely to experience severe complications of pregnancy such as multisystem inflammatory syndrome if infected with coronavirus disease 2019 (COVID-19). Due to normal physiological adaptations of pregnancy, COVID-19 may strain an already stressed respiratory system, making delivery a viable treatment option. We present a case of a gravid patient infected with COVID-19 pneumonia who delivered vaginally in the intensive care unit (ICU) at our hospital. Further research into clinical progress and management of pregnancy complicated by COVID-19 is necessary. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19), along with other coronaviruses, can cause a spectrum of disease manifestations ranging from the common cold to pneumonia to severe acute respiratory syndrome (SARS). This disease has important implications for gravid patients . First, A 34-year-old female G2P0010 at 33 4/7 weeks of gestation presented to the emergency department with a chief complaint of fever, chills, runny nose, and watery eyes for four days and subsequently tested positive for COVID-19. She denied receiving the COVID-19 vaccine. The patient denied sick contacts as she was only exposed to her live-in partner who was asymptomatic at the time. She denied cough, shortness of breath, chest pain, nausea, vomiting, diarrhea, constipation, contractions, leakage of fluid, and vaginal bleeding. She endorsed good fetal movement. Her past medical history was notable for uterine fibroids, but her family medical history was non-contributory. Her only medication was prenatal vitamins. Her physical examination was within normal limits, and initial lab values were significant for transaminitis, with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) three to four times the upper limit of normal, believed to be COVID-related.2 supplementation and O2 requirements steadily increased as her respiratory status worsened. On day four of inpatient management, she received a COVID-19 convalescent plasma (CCP) infusion. On day five, she developed shortness of breath, tachypnea, and desaturated to 84% oxygen on room air. The patient developed a compensated respiratory alkalosis and was transferred to the ICU where she received 5 L O2 via high-flow nasal cannula. She started a five-day course of remdesivir and a 10-day course of dexamethasone.She was admitted to the labor and delivery floor for observation and supportive treatment where she spiked fevers but remained hemodynamically stable for four days. Fetal assessment was reassuring with reactive nonstress test (NST) and normal biophysical profile (BPP), performed daily. She required OOn day nine in the ICU at 34 6/7 weeks of gestation, she was induced for maternal benefit with Cervidil (dinoprostone) 10 mg and Cook cervical ripening balloon  due to worsening respiratory status. After artificial membrane rupture, we performed a shortened second stage of labor with vacuum-assisted vaginal delivery in the ICU. The appearance, pulse, grimace, activity, and respiration (APGAR) scores were nine and nine at one and five minutes, respectively, and the baby weighed 4 pounds 14 ounces. The estimated blood loss was 200 mL and a second-degree laceration was repaired. Neonate was transferred to the newborn intensive care unit (NICU) and underwent routine preterm neonate testing and care. The patient tolerated delivery well. She received routine postpartum care as her pain was controlled, she ambulated and tolerated oral fluids and nutrition, and passed flatus. She continued to be managed in the ICU from a respiratory standpoint.2 nasal cannula (NC) on postpartum day seven with O2 saturation between 96% and 98%. Her transaminitis resolved. On postpartum day 11, 22 days after initially presenting to the emergency department, she was discharged home with oxygen supplementation.Her respiratory status steadily improved, and she was transferred to the floor on 2 L OPregnancy is associated with respiratory and immunological adaptations as the fetus develops. Total body oxygen consumption increases by approximately 20% as compared to non-pregnant levels with a significant increase in minute ventilation and resulting in compensated respiratory alkalosis . PregnanCOVID-19 is known to target the respiratory system, and respiratory distress is a common complication in pregnant women. For gravid patients with comorbidities, the risk of acute respiratory distress in the presence of COVID-19 infection is even greater . Due to Maternal and fetal status ultimately determine the timing and method of delivery in the critically ill patient in accordance with obstetrical guidelines. This patient was induced for vaginal delivery due to the viable fetal gestational age and the significantly decreased physiological stress of vaginal delivery as compared to operative delivery . While dThis case highlights the importance of not only treating COVID-19 in pregnant women but also infection prevention. Pregnant women should strive to mitigate exposure risk and be fully vaccinated against COVID-19. Clinical trials have demonstrated no serious adverse effects after vaccination in pregnant women . The CenThe effects of SARS-CoV-2 virus during pregnancy have important implications and require further research. Current literature shows that infection with COVID-19 leads to increased maternal complications as compared to pregnant women without COVID-19 infection. COVID-19 infection has been shown to cause serious complications in pregnancy and the postpartum period, especially in patients that already have underlying risk factors. It is vital for pregnant women who are infected with COVID-19 to undergo careful monitoring for both maternal and fetal complications. Our case highlights how inducing preterm birth can provide maternal benefit for a woman experiencing respiratory complications of COVID-19. There is a need for more research detailing clinical progress and management of pregnancy complicated by COVID-19 infection.