title: Discontinuation of isolation for persons with COVID-19: Is 10 days really safe?

abstract:
BackgroundThe detection of SARS-CoV-2 RNA by real-time polymerase chain reaction (PCR) in respiratory samples from COVID-19 patients is not a direct indication of the presence of viable viruses. The isolation of SARS-CoV-2 in cell culture system however, can acts as surrogate marker of infectiousness. Cell culture based studies performed mostly with hospitalized and moderate/severe COVID-19 claims that no replication competent virus is found after 9 days of the symptoms onset in respiratory samples. Therefore, it is now recommended 10 days isolation before patient discharge.

MethodsWe cell-cultured 29 SARS-COV-2 RT-PCR positive respiratory samples at the 10th day after the illness in Vero E6 cells. After two passages, cytopathic effect and cycle threshold (CT) lower than the obtained in the original sample were used to determine positivity.

FindingsWe found viable particles in (7/29) 24% of samples tested. The positivity in cell culture was strongly associated (p<0.0001) to the low cycle thresholds in clinical samples (Ct <21).

ConclusionThis data adds important knowledge to the current protocols for de-isolation of patients with non-hospitalized mild COVID-19.


title: Persistent COVID-19 symptoms minimally impact the development of SARS-CoV-2 specific cellular immunity

abstract: SARS-CoV-2 represents an unprecedented public health challenge with many unknowns remaining regarding the factors that impact viral pathogenicity and the development of immunity after infection. While the majority of SARS-CoV-2 infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, a significant number of individuals experienced prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, especially within the cellular immune compartment. However, it is unclear if persistent mild-to-moderate COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed the development of SARS-CoV-2 specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms, or symptoms persisting for 18 days or more. We observed that the duration of COVID-19 symptoms minimally impacts the magnitude, antigen specificity, and transcriptional profile of SARS-CoV-2 specific cellular immunity within both the CD4+ and CD8+ T cell compartments. Furthermore, we observed that reactivity against the structural N protein from SARS-CoV-2 in convalescent COVID-19 patients correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide additional insight into the complex processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses.

category: infectious diseases


title: A mathematical model to estimate percentage secondary infections from margin of error of diagnostic sensitivity: Useful tool for regulatory agencies to assess the risk of propagation due to false negative outcome of diagnostics

abstract: False negative outcome of a diagnosis is one the major reasons for the dissemination of the diseases with high risk of propagation. Diagnostic sensitivity and the margin of error determine the false negative outcome of the diagnosis. A mathematical model had been developed to estimate the mean % secondary infections based on the margin of error of diagnostic sensitivity, % prevalence and R0 value. This model recommends a diagnostic test with diagnostic sensitivity [≥] 96% and at least 92% lower bound limit of the 95% CI or [≤] 4% margin of error for a highly infectious diseases like COVID-19 to curb the secondary transmission of the infection due to false negative cases. Positive relationship was found between mean % secondary infection and margin of error of sensitivity suggesting greater the margin of error of a diagnostic test sensitivity, higher the number of secondary infections in a population due to false negative cases. Negative correlation was found between number of COVID-19 test kits (>90% sensitivity) with regulatory approval and margin of error (R= -0.92, p=0.023) suggesting lesser the margin of error of a diagnostic test, higher the chances of getting approved by the regulatory agencies. However, there are no specific regulatory standards available for margin of error of the diagnostic sensitivity of COVID-19 diagnostic tests. Highly infectious disease such as COVID-19, certainly need specific regulatory standards on margin of error or 95% CI of the diagnostic sensitivity to curb the dissemination of the disease due to false negative cases and our model can be used to set the standards such as sensitivity, margin of error or lower bound limit of 95% CI.


title: MOATAI-VIR - an AI algorithm that predicts severe adverse events and molecular features for COVID-19's complications

abstract: Following SARS-CoV-2 infection, some COVID-19 patients experience severe adverse events caused by pathogenic host responses. To treat these complications, their underlying etiology must be identified. Thus, a novel AI-based methodology, MOATAI-VIR, which predicts disease-protein-pathway relationships for 22 clinical manifestations attributed to COVID-19 was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure associated risk genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. Three uncharacterized manifestation categories are found: neoplasms, mental and behavioral disorders, and congenital malformations, deformations, and chromosomal abnormalities. The prevalence of neoplasms suggests a possible association between COVID-19 and cancer, whether by shared molecular mechanisms between oncogenesis and viral replication, or perhaps, SARS-CoV-2 is an oncovirus. To assess the molecular basis of each manifestation, the proteins shared across each group of comorbidities were prioritized and subject to global pathway analysis. From these most frequent pathways, the molecular features associated with hallmark COVID-19 phenotypes, such as loss of sense of smell/taste, unusual neurological symptoms, cytokine storm, and blood clots were explored. Results of MOATAI-VIR are available for academic users at: http://pwp.gatech.edu/cssb/MOATAI-VIR/.


title: Retinol Depletion in Severe COVID-19

abstract:
Background and PurposeVitamin A is depleted during infections. Vitamin A has been used successfully in measles, RSV and AIDS patients and is an effective vaccine adjuvant. In this study, low retinol levels were found in patients with severe COVID-19. Retinoid signaling impairment in COVID-19 disrupts Type-I interferon synthesis.

Material and MethodTwo groups were formed in the study. The patient group consisted of 27 (Group 1) severe COVID-19 patients hospitalized in the intensive care unit with respiratory failure, and the control group consisted of 23 (Group 2) patients without COVID-19 symptoms. Serum retinol levels were analyzed by ELIZA and HPLC in both groups.

FindingsRetinol levels were found to be significantly lower in the patient group (P <0.001). There was no difference in retinol between two different age groups in the patient group (P> 0.05). There was no significant difference in retinol between men and women (P> 0.05). Comorbidity did not affect serum retinol levels (P >0.05).

ConclusionSerum retinol levels were low in patients with severe COVID-19. Drugs preventing retinol excretion were not stopped in the patient group. Some patients took vitamin A externally. Despite this, retinol was low in COVID-19 patients. Retinol depletion impairs Type-I interferon synthesis by impairing retinoid signaling. Retinoid signaling may be the main pathogenetic disorder in COVID-19. This pathogenesis can serve as a guide for adjuvants, drug targets, and candidate drugs. Retinol, retinoic acid derivatives, and some CYP450 inhibitors may work on COVID-19.


title: Sensitive extraction-free SARS-CoV-2 RNA virus detection using a novel RNA preparation method

abstract: Current conventional detection of SARS-CoV-2 involves collection of a patient sample with a nasopharyngeal swab, storage of the swab during transport in a viral transport medium, extraction of RNA, and quantitative reverse transcription PCR (RT-qPCR). We developed a simplified and novel preparation method using a Chelex resin that obviates RNA extraction during viral testing. Direct detection RT-qPCR and digital-droplet PCR was compared to the current conventional method with RNA extraction for simulated samples and patient specimens. The heat-treatment in the presence of Chelex markedly improved detection sensitivity as compared to heat alone, and lack of RNA extraction shortens the overall diagnostic workflow. Furthermore, the initial sample heating step inactivates SARS-CoV-2 infectivity, thus improving workflow safety. This fast RNA preparation and detection method is versatile for a variety of samples, safe for testing personnel, and suitable for standard clinical collection and testing on high throughput platforms.


title: Differential Cytokine Signatures of SARS-CoV-2 and Influenza Infection Highlight Key Differences in Pathobiology

abstract:
BackgroundSeveral inflammatory cytokines are upregulated in severe COVID-19. We compared cytokines in COVID-19 versus influenza in order to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease.

MethodsThirty-seven cytokines and chemokines were measured in plasma from 145 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was utilized to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was utilized to identify cytokines that mediate the effect of BMI on disease severity.

ResultsIL-18, IL-1{beta}, IL-6, and TNF- were significantly increased in COVID-19 versus influenza patients while GM-CSF, IFN-{gamma}, IFN-{lambda}1, IL-10, IL-15, and MCP-2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF- were elevated in severe COVID-19, but not severe influenza. Random forest analysis identified high IL-6 and low IFN-{lambda}1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity.

ConclusionsThese findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.

SummarySevere COVID-19 is marked by dysregulated inflammation and is associated with elevated BMI. By comparing cytokines and chemokines in patients with either COVID-19 or influenza, we identified distinct inflammatory pathways and a cytokine mediator of the effect of BMI.


title: Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2

abstract: Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list.


title: Diagnostic accuracy of PanbioTM rapid antigen tests on oropharyngeal swabs for detection of SARS-CoV-2

abstract:
BackgroundAntigen-detecting rapid diagnostic tests (Ag-RDTs) for the detection of SARS-CoV-2 offer new opportunities for testing in the context of the COVID-19 pandemic. Nasopharyngeal swabs (NPS) are the reference sample type, but oropharyngeal swabs (OPS) may be a more acceptable sample type in some patients.

MethodsWe conducted a prospective study in a single screening center to assess the diagnostic performance of the Panbio COVID-19 Ag Rapid Test (Abbott) on OPS compared with reverse-transcription quantitative PCR (RT-qPCR) using NPS.

Results402 outpatients were enrolled in a COVID-19 screening center, of whom 168 (41.8%) had a positive RT-qPCR test. The oropharyngeal Ag-RDT sensitivity compared to nasopharyngeal RT-qPCR was 81% (95%CI: 74.2-86.6). Two false positives were noted out of the 234 RT-qPCR negative individuals, which resulted in a specificity of 99.1% (95%CI: 96.9-99.9) for the Ag-RDT.

For cycle threshold values [≤] 26.7 ([≥] 1E6 SARS-CoV-2 genomes copies/mL, a presumed cut-off for infectious virus), 96.3% sensitivity (95%CI: 90.7-99.0%) was obtained with the Ag-RDT using OPS.

InterpretationBased on our findings, the diagnostic performance of the Panbio Covid-19 RDT with OPS samples meet the criteria required by the WHO for Ag-RDTs (sensitivity[≥]80% and specificity [≥]97%).


title: Under what circumstances could vaccination offset the harm from a more transmissible variant of SARS-COV-2 in NYC? Trade-offs regarding prioritization and speed of vaccination.

abstract:
IntroductionNew York City (NYC) was a global epicenter of COVID-19. Vaccines against COVID-19 became available in December 2020 with limited supply, resulting in the need for policies regarding prioritization. The next month, SARS-CoV-2 variants were detected that were more transmissible but still vaccine-susceptible, raising scrutiny of these policies. In particular, prioritization of higher-risk people could prevent more deaths per dose of vaccine administered but could also delay herd immunity if the prioritization introduced bottlenecks that lowered vaccination speed (the number of doses that could be delivered per day). We used mathematical modeling to examine the trade-off between prioritization and the vaccination speed.

MethodsA stochastic, discrete-time susceptible-exposed-infected-recovered (SEIR) model with age- and comorbidity-adjusted COVID-19 outcomes (infections, hospitalizations, and deaths by July 1, 2021) was used to examine the trade-off between vaccination speed and whether or not vaccination was prioritized to individuals age 65+ and "essential workers," defined as including first responders and healthcare, transit, education, and public safety workers. The model was calibrated to COVID-19 hospital admissions, hospital census, ICU census, and deaths in NYC. Vaccination speed was assumed to be 10,000 doses per day starting December 15th, 2020 targeting healthcare workers and nursing home populations, and to subsequently expand at alternative starting times and speeds. We compared COVID-outcomes across alternative expansion starting times (January 15th, January 21st, or February 1st) and speeds (20,000, 30,000, 50,000, 100,000, 150,000, or 200,000 doses per day for the first dose), as well as alternative prioritization options ("yes" versus "no" prioritization of essential workers and people age 65+). Model projections were produced with and without considering the emergence of a SARS-COV-2 variant with 56% greater transmissibility over January and February, 2021.

ResultsIn the absence of a COVID-19 vaccine, the emergence of the more transmissible variant would triple the peak in infections, hospitalizations, and deaths and more than double cumulative infections, hospitalizations, and deaths. To offset the harm from the more transmissible variant would require reaching a vaccination speed of at least 100,000 doses per day by January 15th or 150,000 per day by January 21st. Prioritizing people ages 65+ and essential workers increased the number of lives saved per vaccine dose delivered: with the emergence of a more transmissible variant, 8,000 deaths could be averted by delivering 115,000 doses per day without prioritization or 71,000 doses per day with prioritization. If prioritization were to cause a bottleneck in vaccination speed, more lives would be saved with prioritization only if the bottleneck reduced vaccination speed by less than one-third of the maximum vaccine delivery capacity. These trade-offs between vaccination speed and prioritization were robust over a wide range of delivery capacity.

ConclusionsThe emergence of a more transmissible variant of SARS-CoV-2 has the potential to triple the 2021 epidemic peak and more than double the 2021 COVID-19 burden in NYC. Vaccination could only offset the harm of the more transmissible variant if high speed were achieved in mid-to late January. Prioritization of COVID-19 vaccines to higher-risk populations saves more lives only if it does not create an excessive vaccine delivery bottleneck.


title: Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study

abstract:
ObjectivesTo investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.

DesignTwo-sample Mendelian randomization study.

SettingSummary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analyzed results of genome-wide analyses in the COVID-19 Host Genetics Initiative.

Participants17,965 COVID-19 cases including 11,085 laboratory or physician confirmed cases, 7,885 hospitalized cases, and 4,336 severe respiratory cases, and 1,370,547 controls, primarily of European ancestry.

ExposuresGenetically predicted variation in serum vitamin D status, based on genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency.

Main outcome measuresSusceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalization.

ResultsMendelian randomization analysis, powered to detect moderate effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as proxies for serum vitamin D concentration, the odds ratio for a standard deviation increase in serum vitamin D was 1.04 (95% confidence interval 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84-1.31) for hospitalized COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative, and 1.44 (0.75 to 2.78) for hospitalized COVID-19 versus non-hospitalized COVID-19. Results were similar in analyses that used all SNPs with genome-wide significant associations with serum vitamin D (i.e., including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency.

ConclusionsThese findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects, nor do they preclude potential causal effects of acute responses to therapeutic doses of vitamin D. Future directions include extension of this work to non-European ancestry populations, and high-risk populations, for example persons with comorbid disease.


title: Identification of B.1.346 lineage of SARS-CoV-2 in Japan: Genomic evidence of re-entry of Clade 20C

abstract:
ObjectivesWhole SARS-CoV-2 genome sequencing from COVID-19 patients is useful for infection control and regional trends evaluation. We report a lineage data collected from hospitals in the Kanto region of Japan.

MethodsWe performed whole genome sequencing in specimens of 198 COVID-19 patients at 13 collaborating hospitals in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions underwent to differentiate and classify the viral lineages.

ResultsMore than 90% of the strains belonged to Clade 20B and two lineages (B.1.1.284 and B.1.1.214) have been detected predominantly in the Kanto region. However, one sample from a COVID-19 patient in November 2020, belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in western United States. The patient had no history of overseas travel and no contact with anyone who had travelled abroad, suggesting that this strain appeared likely to have been imported from western United States, across the strict quarantine barrier.

ConclusionB.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region and B.1.346 of clade 20C in one patient was probably imported from western United States. These results illustrate that a decentralized network of hospitals can be significantly advantageous for monitoring regional molecular epidemiologic trends.

Highlights{middle dot} Whole SARS-CoV-2 genome sequencing is useful for infection control
{middle dot} B.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region
{middle dot} B.1.346 of Clade 20C was detected in one COVID-19 patient in November
{middle dot} Molecular genomic data sharing provides benefits to public health against COVID-19


title: Aerosol emission from the respiratory tract: an analysis of relative risks from oxygen delivery systems

abstract:
BackgroundRisk of aerosolisation of SARS-CoV-2 directly informs organisation of acute healthcare and PPE guidance. Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are widely used modes of oxygen delivery and respiratory support for patients with severe COVID-19, with both considered as high risk aerosol generating procedures. However, there are limited high quality experimental data characterising aerosolisation during oxygen delivery and respiratory support.

MethodsHealthy volunteers were recruited to breathe, speak, and cough in ultra-clean, laminar flow theatres followed by using oxygen and respiratory support systems. Aerosol emission was measured using two discrete methodologies, simultaneously. Hospitalised patients with COVID-19 were also recruited and had aerosol emissions measured during breathing, speaking, and coughing.

FindingsIn healthy volunteers (n = 25 subjects; 531 measures), CPAP (with exhalation port filter) produced less aerosols than breathing, speaking and coughing (even with large >50L/m facemask leaks). HFNO did emit aerosols, but the majority of these particles were generated from the HFNO machine, not the patient. HFNO-generated particles were small (<1m), passing from the machine through the patient and to the detector without coalescence with respiratory aerosol, thereby unlikely to carry viral particles. Coughing was associated with the highest aerosol emissions with a peak concentration at least 10 times greater the mean concentration generated from speaking or breathing. Hospitalised patients with COVID-19 (n = 8 subjects; 56 measures) had similar size distributions to healthy volunteers.

InterpretationIn healthy volunteers, CPAP is associated with less aerosol emission than breathing, speaking or coughing. Aerosol emission from the respiratory tract does not appear to be increased by HFNO. Although direct comparisons are complex, cough appears to generate significant aerosols in a size range compatible with airborne transmission of SARS-CoV-2. As a consequence, the risk of SARS-CoV-2 aerosolisation is likely to be high in all areas where patients with Covid-19 are coughing. Guidance on personal protective equipment policy should reflect these updated risks.

FundingNIHR-UKRI Rapid COVID call (COV003), Wellcome Trust GW4-CAT Doctoral Training Scheme (FH), MRC CARP Fellowship(JD, MR/T005114/1). Natural Environment Research Council grant (BB, NE/P018459/1)

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPubMed was searched from inception until 10/1/21 using the terms  aerosol, and variations of  non-invasive positive pressure ventilation and  high-flow nasal oxygen therapy. Studies were included if they measured aerosol generated from volunteers or patients receiving non-invasive positive pressure ventilation (NIV) or high flow nasal oxygen therapy (HFNO), or provided experimental evidence on a simulated human setting. One study was identified (Gaeckle et al, 2020) which measured aerosol emission with one methodology (APS) but was limited by high background concentration of aerosol and a low number of participants (n = 10).

Added value of this studyThis study used multiple methodologies to measure aerosol emission from the respiratory tract before and during CPAP and high-flow nasal oxygen, in an ultra-clean, laminar flow theatre with near-zero background aerosol and recruited patients with COVID-19 to ensure similar aerosol distributions. We conclude that there is negligible aerosol generation with CPAP, that aerosol emission from HFNO is from the machine and not the patient, coughing emits aerosols consistent with airborne transmission of SARS CoV2 and that healthy volunteers are a reasonable proxy for COVID-19 patients.

Implications of all the available evidenceCPAP and HFNO should not be considered high risk aerosol generating procedures, based on our study and that of Gaeckle et al. Recorded aerosol emission from HFNO stems from the machine. Cough remains a significant aerosol risk. PPE guidance should be updated to ensure medical staff are protected with appropriate PPE in situations when patients with suspected or proven COVID-19 are likely to cough.


title: Impact of public sentiments on the transmission of COVID-19 across a geographical gradient

abstract: COVID-19 is a respiratory disease caused by a recently discovered, novel coronavirus, SARS-COV2. The disease has led to over 81 million confirmed cases of COVID-19, with close to 2 million deaths. In the current social climate, the risk of COVID-19 infection is driven by individual and public perception of risk and sentiments. A number of factors influences public perception, including an individuals belief system, prior knowledge about a disease and information about a disease. In this paper, we develop a model for COVID-19 using a system of ordinary differential equations following the natural history of the infection. The model uniquely incorporates social behavioral aspects such as quarantine and quarantine violation. The model is further driven by peoples sentiments (positive and negative) which accounts for the influence of disinformation. Peoples sentiments were obtained by parsing through and analyzing COVID-19 related tweets from Twitter, a social media platform across six countries. Our results show that our model incorporating public sentiments is able to capture the trend in the trajectory of the epidemic curve of the reported cases. Furthermore, our results show that positive public sentiments reduce disease burden in the community. Our results also show that quarantine violation and early discharge of the infected population amplifies the disease burden on the community. Hence, it is important to account for public sentiment and individual social behavior in epidemic models developed to study diseases like COVID-19.


title: Testing out of quarantine

abstract: Since SARS-CoV-2 emerged, a 14-day quarantine has been recommended based on COVID-19"s incubation period. Using an RT-PCR or rapid antigen test to "test out" of quarantine is a frequently proposed strategy to shorten duration without increasing risk. We calculated the probability that infected individuals test negative for SARS-CoV-2 on a particular day post-infection and remain symptom free for some period of time. We estimate that an infected individual has a 20.1% chance (95% CI 9.8-32.6) of testing RT-PCR negative on day five post-infection and remaining asymptomatic until day seven. We also show that the added information a test provides decreases as we move further from the test date, hence a less sensitive test that returns rapid results is often preferable to a more sensitive test with a delay.


title: Predicting Prognosis in COVID-19 Patients using Machine Learning and Readily Available Clinical Data

abstract:
RationalePrognostic tools for aiding in the treatment of hospitalized COVID-19 patients could help improve outcome by identifying patients at higher or lower risk of severe disease.

ObjectivesThe study objective was to develop models to stratify patients by risk of severe outcomes during COVID-19 hospitalization using readily available information at hospital admission.

MethodsHierarchical ensemble classification models were trained on a set of 229 patients hospitalized with COVID-19 to predict severe outcomes, including ICU admission, development of ARDS, or intubation, using easily attainable attributes including basic patient characteristics, vital signs at admission, and basic lab results collected at time of presentation. Each test stratifies patients into groups of increasing risk. An additional cohort of 330 patients was used for blinded, independent validation. Shapley value analysis evaluated which attributes contributed most to the models predictions of risk.

Measurements and Main ResultsTest performance was assessed using precision (positive predictive value) and recall (sensitivity) of the final risk groups. All test cut-offs were fixed prior to blinded validation. In both development and validation, the tests achieved precision in the lowest risk groups near or above 0.9. The proportion of patients with severe outcomes significantly increased across increasing risk groups. While the importance of attributes varied by test and patient, CRP, LDH, and D-dimer were often found to be important in the assignment of risk label.

ConclusionsRisk of severe outcomes for patients hospitalized with COVID-19 infection can be assessed using machine learning-based models based on attributes routinely collected at hospital admission.

category: intensive care and critical care medicine


title: "This is really like waiting for war and this is not good" - Intertwining between pandemic experiences, and the development of professional action of healthcare professionals in critical care at the beginning of the COVID-19 pandemic in Germany: a qualitative study

abstract:
Healthcare professionals (HCPs) are facing remarkable challenges in their daily work since the outbreak of the COVID-19 pandemic. Being well prepared is crucial for dealing with such a pandemic. The aim of our study was to explore HCPs subjective perspectives on their professional action and coping strategies in critical care during the preparation and coping phase after the outbreak of the COVID-19 pandemic in Germany.

Together with HCPs working in critical care, we collaboratively designed an interview study based on an ethnomethodological approach. We performed semi-structured qualitative interviews via telephone or video call and analysed the data based on grounded theory.

Our research interest was focused on HCPs (qualified nurses, physicians, medical students) working in critical care during the first wave of the COVID-19 pandemic in Germany between April and July 2020.

Our sample consisted of 39 HCPs (19 nurses, 17 physicians, three medical students, 18/39 female) from ten German federal states. All participants were involved in the acute care of COVID-19 infected patients in hospitals and had a mean professional experience of 14.8{+/-}10.1 years, 15 participants held a management position (e.g. senior physician or head nurse). We recruited participants via personal contacts and snowballing.

Initial and focused coding resulted in seven categories: Creating structural measures, handling operational changes, dealing with personal protective equipment, building up knowledge and skills, managing information, perceiving peer support and experiencing emotions.

Professional action and subjectively perceived preparedness (professional and emotional) interacted with each other. Their interrelation was not static, but rather dynamic and ambiguous according to the situation. The findings of our study can be beneficial in developing guidelines, policy interventions or personnel and work practice strategies.


title: Performance of Heart Failure Clinical Prediction Models: A Systematic External Validation Study

abstract:
BackgroundMost heart failure (HF) clinical prediction models (CPMs) have not been externally validated.

MethodsWe performed a systematic review to identify CPMs predicting outcomes in HF, stratified by acute and chronic HF CPMs. External validations were performed using individual patient data from 8 large HF trials (1 acute, 7 chronic). CPM discrimination (c-statistic, % relative change in c-statistic), calibration (calibration slope, Harrells E, E90), and net benefit were evaluated for each CPM with and without recalibration.

ResultsOf 135 HF CPMs screened, 24 (18%) were compatible with the population, predictors and outcomes to the trials and 42 external validations were performed (14 acute HF, 28 chronic HF). The median derivation c-statistic of acute HF CPMs was 0.76 (IQR, 0.75, 0.8), validation c-statistic was 0.67 (0.65, 0.68) and model-based c-statistic was 0.68 (0.66, 0.76), Hence, most of the apparent decrement in model performance was due to narrower case-mix in the validation cohort compared with the development cohort. The median derivation c-statistic for chronic HF CPMs was 0.76 (0.74, 0.8), validation c-statistic 0.61 (0.6, 0.63) and model-based c-statistic 0.68 (0.62, 0.71), suggesting that the decrement in model performance was only partially due to case-mix heterogeneity. Calibration was generally poor - median E (standardized by outcome rate) was 0.5 (0.4, 2.2) for acute HF CPMs and 0.5 (0.3, 0.7) for chronic HF CPMs. Updating the intercept alone led to a significant improvement in calibration in acute HF CPMs, but not in chronic HF CPMs. Net benefit analysis showed potential for harm in using CPMs when the decision threshold was not near the overall outcome rate but this improved with model recalibration.

ConclusionsOnly a small minority of published CPMs contained variables and outcomes that were compatible with the clinical trial datasets. For acute HF CPMs, discrimination is largely preserved after adjusting for case-mix; however, the risk of net harm is substantial without model recalibration for both acute and chronic HF CPMs.

category: cardiovascular medicine


title: Paclitaxel-Coated or Uncoated Devices: Significant Differences in Patient Populations and Mortality Led to Study Incomparability

abstract: The SWEDEPAD trial reported an unplanned interim analysis to show no difference in the mortality rate between the paclitaxel-coated and uncoated groups (Nordanstig et al., 2020), which contradicts the long-term risk of paclitaxel-coated devices claimed by a meta-analysis (Katsanos et al., 2018). However, there existed significant differences in mortality rates between the SWEDEPAD trial and the trials included in the meta-analysis, which were caused by significant differences in the patient populations. As a result, the SWEDEPAD trial and meta-analysis results are not directly comparable. An updated meta-analysis including the SWEDPEPAD trial and all studies in the meta-analysis (Katsanos et al., 2018) shows marginal differences in mortality rates between the paclitaxel-coated and control groups at two years with Bayesian relative risk (RR) 1.39 (95% credible interval (CrI) [1.01, 2.39]) and frequentist RR 1.16 (95% confidence interval (CI) [0.99, 1.36]) and differences in mortality rates during the entire follow-up period with Bayesian RR 1.29 (95% CrI [1.01, 1.72]) and frequentist RR 1.13 (95% CI [0.99, 1.28]) under random-effects models. Given the relatively short follow-up thus far in the SWEDEPAD trial (with a mean follow-up of 2.49 years) and the paclitaxel-coated risk being long-term (e.g., 4 or 5 years), the interim results on the risk of paclitaxel-coated devices reported by the SWEDEPAD trial warrant further investigation.


title: Accuracy of four lateral flow immunoassays for anti SARS-CoV-2 antibodies: a head-to-head comparative study

abstract:
BackgroundSARS-CoV-2 antibody tests are used for population surveillance and might have a future role in individual risk assessment. Lateral flow immunoassays (LFIAs) can deliver results rapidly and at scale, but have widely varying accuracy.

MethodsIn a laboratory setting, we performed head-to-head comparisons of four LFIAs: the Rapid Test Consortiums AbC-19 Rapid Test, OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, and Biomerica COVID-19 IgG/IgM Rapid Test. We analysed blood samples from 2,847 key workers and 1,995 pre-pandemic blood donors with all four devices.

FindingsWe observed a clear trade-off between sensitivity and specificity: the IgG band of the SureScreen device and the AbC-19 device had higher specificities but OrientGene and Biomerica higher sensitivities. Based on analysis of pre-pandemic samples, SureScreen IgG band had the highest specificity (98.9%, 95% confidence interval 98.3 to 99.3%), which translated to the highest positive predictive value across any pre-test probability: for example, 95.1% (95%CI 92.6, 96.8%) at 20% pre-test probability. All four devices showed higher sensitivity at higher antibody concentrations ("spectrum effects"), but the extent of this varied by device.

InterpretationThe estimates of sensitivity and specificity can be used to adjust for test error rates when using these devices to estimate the prevalence of antibody. If tests were used to determine whether an individual has SARS-CoV-2 antibodies, in an example scenario in which 20% of individuals have antibodies we estimate around 5% of positive results on the most specific device would be false positives.

FundingPublic Health England.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched for evidence on the accuracy of the four devices compared in this study: OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, Biomerica COVID-19 IgG/IgM Rapid Test and the UK Rapid Test Consortiums AbC-19 Rapid Test. We searched Ovid MEDLINE (In-Process & Other Non-Indexed Citations and Daily), PubMed, MedRxiv/BioRxiv and Google Scholar from January 2020 to 16th January 2021. Search terms included device names AND ((SARS-CoV-2) OR (covid)). Of 303 records assessed, data were extracted from 24 studies: 18 reporting on the accuracy of the OrientGene device, 7 SureScreen, 2 AbC-19 and 1 Biomerica. Only three studies compared the accuracy of two or more of the four devices. With the exception of our previous report on the accuracy of the AbC-19 device, which the current manuscript builds upon, sample size ranged from 7 to 684. For details, see Supplementary Materials.

The largest study compared OrientGene, SureScreen and Biomerica. SureScreen was estimated to have the highest specificity (99.8%, 95% CI 98.9 to 100%) and OrientGene the highest sensitivity (92.6%), but with uncertainty about the latter result due to small sample sizes. The other two comparative studies were small (n = 65, n = 67) and therefore provide very uncertain results.

We previously observed spectrum effects for the AbC-19 device, such that sensitivity is upwardly biased if estimated only from PCR-confirmed cases. The vast majority of previous studies estimated sensitivity in this way.

Added value of this studyWe performed a large scale (n = 4,842), head-to-head laboratory-based evaluation and comparison of four lateral flow devices, which were selected for evaluation by the UK Department of Health and Social Cares New Tests Advisory Group, on the basis of a survey of test and performance data available. We evaluated the performance of diagnosis based on both IgG and IgM bands, and the IgG band alone. We found a clear trade-off between sensitivity and specificity across devices, with the SureScreen and AbC-19 devices being more specific and OrientGene and Biomerica more sensitive. Based on analysis of 1,995 pre-pandemic blood samples, we are 99% confident that SureScreen (IgG band reading) has the highest specificity of the four devices (98.9%, 95% CI 98.3, 99.3%).

We found evidence that all four devices have reduced sensitivity at lower antibody indices, i.e. spectrum effects. However, the extent of this varies by device and appears to be less for other devices than for AbC-19.

Our estimates of sensitivity and specificity are likely to be higher than would be observed in real use of these devices, as they were based on majority readings of three trained laboratory personnel.

Implications of all the available evidenceWhen used in epidemiological studies of antibody prevalence, the estimates of sensitivity and specificity provided in this study can be used to adjust for test errors. Increased precision in error rates will translate to increased precision in seroprevalence estimates. If lateral flow devices were used for individual risk assessment, devices with maximum specificity would be preferable. However, if, for an example, 20% of the tested population had antibodies, we estimate that around 1 in 20 positive results on the most specific device would be incorrect.

category: epidemiology


title: COVID-19 Hospitalizations in Five California Hospitals

abstract:
STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSCharacterization of a diverse cohort hospitalized with COVID-19 in a health care system in California is needed to further understand the impact of SARS-CoV-2 and improve patient outcomes.

ObjectivesTo investigate the characteristics of patients hospitalized with COVID-19 and assess factors associated with poor outcomes.

DesignPatient-level retrospective cohort study

SettingUniversity of California five academic hospitals.

ParticipantsPatients [≥]18 years old with a confirmed test result for SAR-CoV-2 virus hospitalized at five UC hospitals.

ExposureConfirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive results on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring hospital admission.

Main Outcomes and MeasuresAdmission to the intensive care unit, death during hospitalization, and the composite of both outcomes.

ResultsOutcomes were assessed for 4,730 patients who were discharged or died during a hospitalization. A total of 846 patients were treated at UC Davis, 1,564 UC Irvine, 1,283 UC Los Angeles, 471 UC San Diego, and 566 UC San Francisco. More than 20% of patients were [≥]75 years of age (75-84: 12.3%, [≥]85: 10.5%), male (56.5%), Hispanic/Latino (45.7%), and Asian (10.3%). The most common comorbidities were hypertension (35.2%), cardiac disease (33.3%), and diabetes (24.0%). The ICU admission rate was 25.2% (1194/4730), with 7.0% (329/4730) in-hospital mortality. Among patients admitted to the ICU, 18.8% (225/1194) died; 2.9% (104/3536) died without ICU admission. The rate of the composite outcome (ICU admission and/or death) was 27.4% (1,298/4,730). While controlling for comorbidities, patients of age 75-84 (OR 1.47, 95% CI: 1.11-1.93) and 85-59 (OR 1.39, 95% CI: 1.04-1.87) were more likely to experience a composite outcome than 18-34 year-olds. Males (OR 1.39, 95% CI: 1.21-1.59), and patients identifying as Hispanic/Latino (OR 1.35, 95% CI: 1.14-1.61), and Asian (OR 1.43, 95% CI: 1.23-1.82), were also more likely to experience a composite outcome than White. Patients with 5 or more comorbidities were exceedingly likely to experience a composite outcome (OR 2.74, 95% CI: 2.32-3.25).

ConclusionsMales, older patients, those with pre-existing comorbidities, and those identifying as Hispanic/Latino or Asian experienced an increased risk of ICU admission and/or death.

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are the characteristics and outcomes of patients with SARS-CoV-2 infection hospitalized at five UC Health medical centers in California?

FindingsIn this retrospective case series of 4,730 patients requiring hospitalization for COVID-19 in UC Healths five medical centers, male (OR 1.41, 95% CI: 1.23-1.61), Hispanic/Latino (OR 1.35, 95% CI: 1.14-1.61), and Asian (OR 1.43, 95% CI: 1.12-1.82) were more likely to be admitted to the ICU and/or die after adjustment for age and comorbidity. ICU admission and/or death was more likely among older individuals and greater numbers of pre-existing conditions.

MeaningThis study describes the experience of a large, diverse cohort of patients with COVID-19 hospitalized in five hospitals in California between December 14, 2019 and January 6, 2021.


title: Strategies for vaccination against SARS-CoV-2 to efficiently bring R<1

abstract: With limited availability of vaccines, an efficient use of the limited supply of vaccines in order to achieve herd immunity will be an important tool to combat the wide-spread prevalence of COVID-19. Here, we compare a selection of strategies for vaccine distribution, including a novel targeted vaccination approach (EHR) that provides a noticeable increase in vaccine impact on disease spread compared to age-prioritized and random selection vaccination schemes. Using high-fidelity individual-based computer simulations with Oslo, Norway as an example, we find that for a community reproductive number in a setting where the base pre-vaccination reproduction number R = 2.1 without population immunity, the EHR method reaches herd immunity at 48% of the population vaccinated with 90% efficiency, whereas the common age-prioritized approach needs 89%, and a population-wide random selection approach requires 61%. We find that age-based strategies have a substantially weaker impact on epidemic spread and struggle to achieve herd immunity under the majority of conditions. Furthermore, the vaccination of minors is essential to achieving herd immunity, even for ideal vaccines providing 100% protection.


title: Comparing the impact of vaccination strategies on spread of COVID-19, including a novel household-targeted vaccination strategy


title: COVID-19 spread and Weather in U.S. states: a cross-correlative study on summer-autumn 2020.

abstract: An effect of weather on sars-cov-2 transmission is regularly proposed as a putative cause of unexplained fluctuations of covid-19 new cases, but clear data supporting this hypothesis remains to be presented. Here I measured longitudinal time-series correlations between outdoor temperature, humidity and covid-19 reproduction number (Rt) in the 50 U.S. states (+DC). In order to mitigate the confounding influence of varying social restriction measures, the analysis spans a 5-month period during summer and autumn 2020 when restrictions were comparatively lower and more stable. I used a cross-covariance approach to account for a variable delay between infection and case report. For a delay near 11 days, most U.S. states exhibited a negative correlation between outdoor temperature and Rt, as well as between absolute humidity and Rt (mean r = -0.35). In 21 states, the correlation was strong (r < -0.5). Individual state data are presented, and associations between cold and/or dry weather episodes and short-term new case surges are proposed. After identifying potential confounding factors, I discuss 3 possible causal mechanisms that could explain a correlation between outdoor weather and indoor disease transmission: behavioral adaptations to cold weather, respiratory tract temperature, and the importing of outdoor absolute humidity to indoor spaces.


title: Estimated SARS-CoV-2 Seroprevalence in Healthy Children and Those with Chronic Illnesses in The Washington Metropolitan Area as of October 2020

abstract: The estimated SARS-CoV-2 seroprevalence in children was found to be 9.46% for the Washington Metropolitan area. Hispanic/Latinx individuals were found to have higher odds of seropositivity. While chronic medical conditions were not associated with having antibodies, previous fever and body aches were predictive symptoms.


title: Understanding soaring coronavirus cases and the effect of contagion policies in the UK

abstract: The number of new daily SARS-CoV-2 infections is frantically rising in almost every country of the EU. The phenomenological explanation offered is a new mutation of the virus, first identified in the UK. We use publicly available data in combination with a controlled SIR model, which captures the effects of preventive measures on the active cases, to show that the current wave of infections is consistent with a single transmission rate. This suggests that the new SARS-CoV-2 variant is as transmissible as previous strains. Our findings indicate that the relaxation of preventive measures is closely related with the ongoing surge in cases. We simulate the effects of new restrictions and vaccination campaigns in 2021, demonstrating that lockdown policies are not fully effective to flatten the curve. For effective mitigation, it is critical that the public keeps on high alert until vaccination reaches a critical threshold.


title: Impact of the Clinical Trials Act on noncommercial clinical research in Japan: An interrupted time-series analysis

abstract:
BackgroundThe number of new noncommercial clinical studies conducted in Japan declined within the first year of the implementation of the Clinical Trials Act (CTA) on April 1, 2018. This study aimed to examine the impact of the CTAs enforcement on the number of new noncommercial clinical studies registered in the Japanese Clinical Trial Registry.

MethodsAn interrupted time-series design was used in the analysis, which was conducted for the period of April 2015 to March 2019. We collected data for trials registered in the Clinical Trial Registry, managed by the University Hospital Medical Information Network.

ResultsIn total, 35,811 studies were registered in the registry; of these, 16,455 fulfilled the eligibility criteria. The difference in the trend of monthly number of new trials after CTA enforcement decreased significantly by 15.0 trials (95% CI, -18.7 to -11.3), and the level decreased by 40.8 (95% CI, -68.2 to -13.3) from the pre-enforcement to the post-enforcement period. Multigroup analyses indicated that the act exerted a significant effect on the trend of new clinical trials, particularly those with smaller sample sizes, interventional study designs, and nonprofit funding sponsors.

ConclusionsThe number of Japanese noncommercial clinical studies declined significantly following implementation of the CTA. It is necessary to establish a system to promote clinical studies in Japan while ensuring transparency and safety.


title: Integrating primary care and social services for older adults with multimorbidity: A qualitative study

abstract:
BackgroundGrowing demand from an ageing population, chronic preventable disease and multimorbidity has resulted in complex health and social care needs requiring more integrated services. Integrating primary care with social services could more efficiently utilise resources, and improve experiences for patients, their families and carers. There is limited evidence on progress including key barriers and drivers of integration to inform large-scale national change.

AimTo elicit stakeholder views on drivers and barriers of integrated primary care and social services. and highlight opportunities for successful implementation.

Design and settingA qualitative interview study.

MethodSemi-structured interviews with maximum variation sampling to capture stakeholder views across services and professions.

ResultsThirty-seven interviews were conducted across England including GPs, nurses, social care staff, commissioners, local government, voluntary and private sectors, patients and carers. Drivers of integration included groups of like-minded individuals supported by good leadership, expanded interface roles to bridge gaps between systems and co-location of services. Barriers included structural and interdisciplinary tension between professions, organisational self-interest and challenges in record-sharing.

ConclusionsDrivers and barriers to integration identified in other contexts are also present in primary care and social services. Benefits of integration are unlikely to be realised if these are not addressed in the design and execution of new initiatives. Efforts should go beyond local and professional level change to include wider systems and policy-level initiatives. This will support a more systems-wide approach to integrated care reform, which is necessary to meet the complex and growing needs of an ageing multimorbid population.

category: primary care research


title: Developing Functional Network Connectivity of the Dorsal Anterior Cingulate Cortex Mediates Externalizing Psychopathology in Adolescents with Child Neglect

abstract: Childhood adversity in form of child abuse and neglect is associated with elevated risk for psychopathologies. We investigated whether development of functional brain networks important for executive function (EF) could serve as potential mediators of this association. We analyzed data of 475 adolescents, a subsample of the multisite longitudinal NCANDA (National Consortium on Alcohol and Neurodevelopment in Adolescence) cohort with completed measures of childhood trauma, resting-state functional brain connectivity data, and internalizing/externalizing psychopathological syndrome data at baseline and follow-up years 1-4. Using parallel process latent growth models, we found that childhood adversity was associated with increased risk for externalizing/internalizing behaviors. We specifically investigated whether functional connectivity of the dorsal anterior cingulate cortex (dACC) to brain regions within the cingulo-opercular (CO) network, a well-known EF network that underlies control of attention and self-regulation, mediates the association between adversity and psychopathological behaviors. We found that childhood adversity, specifically neglect was negatively associated with functional connectivity of the dACC within the CO network, and that this connectivity mediated the association between child neglect and externalizing behaviors. Our study advances a mechanistic understanding of how childhood adversity may impact the development of psychopathology, highlighting the relevance of dACC functional networks particularly for externalizing psychopathology.

category: psychiatry and clinical psychology


title: Impact of COVID-19 restrictions on the postpartum experience of women living in Eastern Canada: A mixed method cohort study

abstract:
ObjectivesTo (1) compare changes in self-efficacy, social support, postpartum anxiety and postpartum depression in Canadian women collected before (Cohort 1) and during the COVID-19 pandemic (Cohort 2); (2) explore the women felt related to having a newborn during the pandemic; and (3) explore ways that women coped.

MethodsPrior to the pandemic (October 1, 2019-January 1, 2020), an online survey was conducted with women had given birth within the past six months in one of the three Eastern Canadian Maritime provinces (Cohort 1). A second, similar survey was conducted between August 1, 2020 and October 31, 2020 (Cohort 2) during a period of provincial pandemic response to COVID-19.

ResultsFor Cohort 1, 561 women completed the survey and 331 women in Cohort 2. Cohorts were similar in terms of age of women, parity, and age of newborn. There were no significant differences for self-efficacy, social support, postpartum anxiety, and depression between the cohorts. Difficulties that women reported as a result of COVID-19 restrictions included lack of support from family and friends, fear of COVID-19 exposure, feeling isolated and uncertain, negative impact on perinatal care experience, and hospital restrictions. Having support from partners and families, in-person/virtual support, as well as self-care and the low prevalence of COVID-19 during the summer of 2020 helped women cope.

ConclusionWhile there was no significant difference in pre-pandemic and during pandemic psychosocial outcomes, there were still challenges and negative impacts that women identified. Consideration of vulnerable populations is important when making public health recommendations.

What is already known on this subject?Previous work has shown the importance of social support in the postpartum transition in developing parenting self-efficacy and decreasing postpartum anxiety and depression. However, during the COVID-19 pandemic, womens mental health, particularly during the perinatal period, has seen an increases in rates of postpartum anxiety and depression.

What this study adds?This study is able to compare self-efficacy, social support, postpartum anxiety and depression between two cohorts of postpartum women living in Eastern Canada - pre-COVID-19 pandemic and during. While there was no significant difference in pre-pandemic and during pandemic psychosocial outcomes, there were still challenges and negative impacts that women identified.

category: public and global health


title: Radiomics Analysis of Clinical Myocardial Perfusion Stress SPECT Images to Identify Coronary Artery Calcification

abstract:
PurposeMyocardial perfusion stress SPECT (MPSS) is an established diagnostic test for patients suspected with coronary artery disease (CAD). Meanwhile, coronary artery calcification (CAC) scoring obtained from diagnostic CT is a highly specific test, offering incremental diagnostic information in identifying patients with significant CAD yet normal MPSS scans. However, after decades of wide utilization of MPSS, CAC is not commonly reimbursed (e.g. by the CMS), nor widely deployed in community settings. We aimed to perform radiomics analysis of normal MPSS scans to investigate the potential to predict the CAC score.

MethodsWe collected data from 428 patients with normal (non-ischemic) MPSS (99mTc-Sestamibi; consensus reading). A nuclear medicine physician verified iteratively reconstructed images (attenuation-corrected) to be free from fixed perfusion defects and artifactual attenuation. 3D images were automatically segmented into 4 regions of interest (ROIs), including myocardium and 3 vascular segments (LAD-LCX-RCA). We used our software package, standardized environment for radiomics analysis (SERA), to extract 487 radiomic features in compliance with the image biomarker standardization initiative (IBSI). Isotropic cubic voxels were discretized using fixed bin-number discretization (8 schemes). We first performed blind-to-outcome feature selection focusing on a priori usefulness, dynamic range, and redundancy of features. Subsequently, we performed univariate and multivariate machine learning analyses to predict CAC scores from i) selected radiomic features, ii) 10 clinical features, iii) combined radiomics + clinical features. Univariate analysis invoked Spearman correlation with Benjamini-Hotchberg false-discovery correction. The multivariate analysis incorporated stepwise linear regression, where we randomly selected a 15% test set and divided the other 85% of data into 70% training and 30% validation sets. Training started from a constant (intercept) model, iteratively adding/removing features (stepwise regression), invoking Akaike information criterion (AIC) to discourage overfitting. Validation was run similarly, except that the training output model was used as the initial model. We randomized training/validation sets 20 times, selecting the best model using log-likelihood for evaluation in the test set. Assessment in the test set was performed thoroughly by running the entire operation 50 times, subsequently employing Fishers method to verify the significance of independent tests.

ResultsUnsupervised feature selection significantly reduced 8x487 features to 56. In univariate analysis, no feature survived FDR to directly correlate with CAC scores. Applying Fishers method to the multivariate regression results demonstrated combining radiomics with the clinical features to enhance the significance of the prediction model across all cardiac segments. The median absolute Pearsons coefficient values / p-values for the three feature-pools (radiomics, clinical, combined) were: (0.15, 0.38, 0.41)/(0.1, 0.001, 0.0006) for myocardium, (0.24, 0.35, 0.41)/(0.05, 0.004, 0.0007) for LAD, (0.07, 0.24, 0.28)/(0.4, 0.06, 0.02), for LCX, and (0.06, 0.16, 0.24)/(0.4, 0.2, 0.05) for RCA, demonstrating consistently enhanced correlation and significance for combined radiomics and clinical features across all cardiac segments.

ConclusionsOur standardized and statistically robust multivariate analysis demonstrated significant prediction of the CAC score for all cardiac segments when combining MPSS radiomic features with clinical features, suggesting radiomics analysis can add diagnostic or prognostic value to standard MPSS for wide clinical usage.

category: radiology and imaging


title: IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality

abstract: Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy are umbrella terms for a number of pathologically distinct diseases involving disabling, immune-mediated injury to peripheral nerves. Current treatments involve non-specific immunomodulation. Prospective identification of patients with specific disease mechanisms should increasingly inform the use of more targeted disease modifying therapies and may lead to improved outcomes. In this cohort study, we tested serum for antibodies directed against nodal/paranodal protein antigens. The clinical characteristics of antibody positive and seronegative patients were then compared. Eight patients with IgG1-subclass antibodies directed against both isoforms of the nodal/paranodal cell-adhesion molecule neurofascin were identified. All developed rapidly progressive tetraplegia. Cranial nerve deficits (100% versus 26%), autonomic dysfunction (75% versus 13%) and respiratory involvement (88% versus 14%) were more common than in seronegative patients. The response to intravenous immunoglobulin, steroids and/or plasmapheresis was poor. Four patients received the B-cell-depleting therapy rituximab. After several weeks, these patients began to show progressive functional improvements, became seronegative, and were ultimately discharged home. Four patients who did not receive rituximab did not improve and died following the development of infectious complications and/or withdrawal of intensive care support. IgG1 panneurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically-classified patient group.

category: neurology


title: Dysgraphic features in motor neuron disease: a review

abstract:
BackgroundMotor neuron disease (MND) patients can show oral language deficits mimicking those of frontotemporal degenerations (FTD). Although dysgraphic features have been also reported within the MND-FTD continuum, their characteristics and clinical relevance are still largely unexplored.

AimsTo profile writing disorders in MND patients can help further define their cognitive semiology and thus conveys relevant clinical entailments. Therefore, this study aimed at reviewing evidence of writing impairment in MND patients. This review was implemented and reported by consulting Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Qualitative/quantitative measures of writing abilities in MND patients was the primary outcome. Both group studies and case reports/series were taken into consideration. Twenty-four contributions were included out of an initial N=83. Potential biases in generalizing results were qualitatively controlled for by extracting background, disease-related, neuropsychological and neuroanatomofunctional secondary outcomes.

Main ContributionFifteen studies assessed writing abilities in Japaneses patients, whereas the remaining eight in western patients. Central dysgraphic features were reported in both neuropsychologically-impaired and -unimpaired MND patients. Phonetic/phonological paragraphias and morpho-syntactic errors were frequently reported. Although FTD was frequently co-occurent, neither cognitive nor language impairment fully accounted for writing impairment in some patients. By contrast, evidence of peripheral dysgraphia was scarce. Patients displaying writing deficits often presented with bulbar signs and perisylvian cortices involvement (including Exners area and the left angular gyrus). Writing deficits proved to be associated with abnormalities in executive functioning and its neural substrates. Writing-to-dictation tasks as well as writing samples assessment proved to be useful to detect writing errors.

ConclusionsDysgraphic features in MND patients might be due to dysfunctions of the graphemic buffer - and possibly the phonological route. The lexico-semantic route appeared to be less involved. However, a mixed peripheral/central involvement cannot be ruled out. In this population, executive/attentive deficits are likely to contribute to writing errors as well. Writing deficits might thus be specific of MND patients cognitive/language impairment profile. The evaluation of writing abilities via writing-to-dictation/narrative writing tasks may be useful when assessing cognition/language in both neuropsychological-impaired and -unimpaired MND patients - especially when severe dysarthria/anarthria is present and prevents clinicians from assessing oral language.


title: Language impairment in motor neuron disease phenotypes different from classical amyotrophic lateral sclerosis: a review

abstract:
BackgroundUp to 35-40% of patients with amyotrophic lateral sclerosis (ALS) present with language deficits falling within the spectrum of frontotemporal degeneration (FTD). It is currently debated whether frontotemporal involvement occurs or not in motor neuron disease (MND) phenotypes that differ from classical ALS (i.e., both non-ALS MNDs and non-classical ALS endo-phenotypes) - this stance being supported by the notion of a common pathology underlying MNDs. To investigate whether language dysfunctions also occur in patients with different-from-classical-ALS MNDs can; a) help determine whether the MND-FTD continuum could be broadened at a neuropsychological level; b) convey relevant entailments to cognitive diagnostics in these populations.

AimsThe present study thus aimed at reviewing evidence regarding language impairment in different-from-classical-ALS MND patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were consulted to implement and report the present review. Studies were included if a) language was quantitatively assessed b) in patients diagnosed with different-from-classical-ALS MND phenotypes. Studies assessing demented patients only were excluded. From an original N=1117 contributions, N=20 group studies were finally included. Secondary outcomes were taken into account for qualitatively assessing potential biases in generalizing results.

Main contributionStudies were divided into those assessing predominant-upper vs. - lower MND patients (UMND/LMND). Language dysfunctions appeared to be more prevalent and severe in UMND patients. Language screeners were able to detect language deficits in both groups. Lexical-semantic deficits appeared to be highly prevalent in both groups and a selective difficulty in action-vs. object-naming was systematically detected. Morpho-syntactic deficits were seldom reported in both groups. Phonological deficits and central dysgraphic features were found in UMND patients only.

ConclusionPatients with different-from-classical-ALS MND phenotypes display language deficits similar to those of classical ALS patients (as far as both prevalence and type are concerned) and thus could be validly included in the MND-FTD continuum at a neuropsychological level. A greater cortical involvement might account for language deficits being more severe in UMND patients. Consistently with guidelines for cognitive assessment in ALS patients, action-naming tasks might represent a valid and sensitive tool for assessing language in UMND/LMND patients too.


title: CSF Aβ38 levels are associated with Alzheimer-related decline: implications for γ-secretase modulators

abstract:
ObjectiveShorter A{beta} species might modulate disease progression in Alzheimers disease (AD). Here we studied whether A{beta}38 levels in cerebrospinal fluid (CSF) are associated with risk of developing AD dementia and cognitive decline.

MethodsCSF A{beta}38 levels were measured in 656 individuals across two clinical cohorts - the Swedish BioFINDER study and the Alzheimers Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline A{beta}38 levels and risk of AD dementia in AD-biomarker positive individuals (AD+; determined by CSF P-tau/A{beta}42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed effects models were used to evaluate the association between baseline A{beta}38 levels and cognitive decline as measured by MMSE in AD+ participants with SCD, MCI or AD dementia.

ResultsIn the BioFINDER cohort, high A{beta}38 levels were associated with slower decline in MMSE ({beta} = 0.30 points / sd., P = 0.001) and with lower risk of conversion. To AD dementia (HR = 0.83 per sd., P = 0.03). In the ADNI cohort, higher A{beta}38 levels were associated with less decline in MMSE ({beta} = 0.27, P = 0.01), but not risk of conversion to AD dementia (P = 0.66). A{beta}38 levels in both cohorts remained significantly associated with both outcomes when adjusted for CSF P-tau levels and remained associated with cognition when adjusted for CSF A{beta}42 levels.

ConclusionsHigher CSF A{beta}38 levels are associated with lower risk of AD-related changes in two independent clinical cohorts. These findings may have implications for {gamma}-secretase modulators as potential disease-altering therapy.


title: A gene expression platform to predict benefit from adjuvant external beam radiation in resected non-small cell lung cancer

abstract:
BackgroundWe hypothesized that the radiosensitivity index (RSI), would classify non-small cell lung cancer (NSCLC) patients into radioresistant (RR) or radiosensitive (RS).

MethodsWe identified resected pathologic stage III NSCLC. For the radiation group (RT) group, at least 45 Gy of external beam radiation was required. mRNA was extracted from primary tumor. The predefined cut-point was the median RSI with a primary endpoint of local control. Similar criteria were then applied to two extramural datasets (E1; E2) with progression free survival as the primary endpoint.

ResultsMedian follow-up from diagnosis was 23.5 months (range: 4.8-169.6 months). RSI was associated with time to local failure in the RT group with a two-year rate of local control of 80% and 56% between RS and RR groups, respectively p=0.02. RSI was the only variable found to be significant on Cox local control analysis (HR 2.9; 95% CI: 1.2-8.2; p=0.02). There was no significance of RSI in predicting local control in patients not receiving RT, p=0.48. A cox regression model between receipt of radiotherapy and RSI combining E1 and E2 showed that the interaction term was significant for PFS (3.7; 95% CI 1.4-10; p=0.009). A summary measure combining E1 and E2 showed statistical significance for PFS between RR and RS patients treated with radiotherapy (HR 2.7l; 95% CI 1.3-5.6; p=0.007) but not in patients not treated with radiotherapy (HR 0.94; 95% CI 0.5-1.78; p=0.86).

ConclusionsRSI appears to be predictive for benefit from adjuvant radiation. Prospective validation is required.

category: oncology


title: Cohort-based association study of germline genetic variants with acute and chronic health complications of childhood cancer and its treatment: Genetic risks for childhood cancer complications Switzerland (GECCOS) study protocol

abstract:
BackgroundChildhood cancer and its treatment may lead to many acute and chronic health complications. Related impairment in quality of life, excess in deaths, and accumulated health care costs are relevant. There is a wide inter-individual variability in the type and severity of health complications. Genetic variations are suggested to contribute to individual susceptibility. So far, only few genetic variants have been used to risk-stratify treatment and follow-up care. This study platform aims to identify germline genetic variants associated with acute and late complications of childhood cancer.

MethodsThe Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. It includes patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Pediatric Biobank for Research in Hematology and Oncology (BaHOP), Geneva, host of the Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS). BISKIDS is a national biobank for the collection of germline DNA in childhood cancer patients and survivors.

GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study (SCCSS), which contains health-related data of survivors. Phenotypic data consist of objective measurements, health conditions diagnosed by physicians, second primary neoplasms, self-reported and health-related information from participants. Germline genetic samples and sequencing data have been collected in BISKIDS. We will perform gene panel sequencing, whole-exome sequencing, or whole-genome sequencing depending on the research questions. We will perform association analyses to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models.

DiscussionGECCOS will serve as an overarching platform to enable genotype-phenotype association analyses on complications associated with childhood cancer and its treatments. Knowledge of germline genetic variants associated with childhood cancer-associated health conditions will help to further individualize cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects, for personalized cancer care.

Trial registrationClinicaltrials.gov: NCT04702321

category: genetic and genomic medicine


title: Prognosis and hematological findings in patients with COVID-19 in an Amazonian population of Peru

abstract:
ObjectiveThis study examined the laboratory results of COVID-19 patients from a hospital in the Peruvian Amazon and their clinical prognosis.

MethodsAn analytical cross-sectional study was carried out whose purpose was to identify the laboratory tests of patients with COVID-19 and mortality in a hospital in Ucayali, Peru during the period from March 13 to May 9, 2020, selecting a total of 127 with Covid-19. Mean and the standard deviation was described for age, leukocytes, neutrophils, platelets, RDW-SD; median and interquartile range for the variables lymphocyte, RN / L, fibrinogen, CRP, D-dimer, DHL, hematocrit, monocytes, eosinophils.

ResultsNo differences were observed in this population regarding death and sex (OR: 1.31; 95% CI 0.92 to 1.87), however, it was observed that, for each one-year increase, the probability of death increased by 4% (PR: 1.04, 95% CI 1.03 to 1.05). The IRR (Incidence Risk Ratio) analysis for the numerical variables showed results strongly associated with hematological values such as Leukocytes (scaled by 2500 units) (IRR: 1.08, 95% CI 1.03 to 1.13), neutrophils (scaled by 2500 units) (IRR: 1.08; 95% CI 1.03 to 1.13), on the contrary, it is observed that the increase of 1000 units in lymphocytes, the probability of dying decreased by 48% (IRR: 0.52; 95% CI 0.38 to 071).

ConclusionParameters such as leukocytes and neutrophils were statistically much higher in patients who died.

category: hematology


title: Immuno-fibrotic drivers of impaired lung function in post-COVID-19 syndrome

abstract:
IntroductionSubjects recovering from COVID-19 frequently experience persistent respiratory ailments; however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.

MethodsWe performed a prospective cohort study of subjects with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.

ResultsSixty-one subjects were enrolled across two academic medical centers at a median of 9 weeks (interquartile range 6-10) after COVID-19 illness: n=13 subjects (21%) mild/non-hospitalized, n=30 (49%) hospitalized/non-critical, and n=18 subjects (30%) hospitalized/intensive care ("ICU"). Fifty-three subjects (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P<0.05), but did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered subjects by past COVID-19 severity. Lipocalin 2 (LCN2), matrix metalloproteinase-7 (MMP-7), and hepatocyte growth factor (HGF) identified by the model were significantly higher in the ICU group (P<0.05) and inversely correlated with FVC and DLCO (P<0.05), and were confirmed in a separate validation cohort (n=53).

ConclusionsSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.

FundingThe study was funded in part by the NHLBI (K08HL130557 to BDK and R01HL142818 to HJC), the DeLuca Foundation Award (AP), a donation from Jack Levin to the Benign Hematology Program at Yale, and Divisional/Departmental funds from Duke University.


title: Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC)


title: Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine

abstract: An important question is arising as COVID-19 vaccines are getting rolled out: Should individuals who already had a SARS-CoV-2 infection receive one or two shots of the currently authorized mRNA vaccines. In this short report, we show that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naive individuals after the second dose. We also show that the reactogenicity is significantly higher in individuals who have been infected with SARS-CoV-2 in the past. Changing the policy to give these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses.

category: allergy and immunology


title: Mortality Risk and Temporal Patterns of Atrial Fibrillation in the Nationwide Registry

abstract: Aims Persistent and permanent atrial fibrillation (AF) often occurs in the presence of multiple comorbidities and is linked to adverse clinical outcomes. It is unclear whether the sustained pattern of AF itself is prognostic or if it is confounded by underlying comorbidities. Here, we tested the association between the temporal patterns of AF and the risks of ischemic stroke and all-cause mortality. Methods and Results In a prospective multicenter cohort, 3046 non-valvular AF patients were consecutively enrolled and followed for adverse outcomes of all-cause mortality and ischemic stroke. The risks of both outcomes were adjusted for underlying comorbidities, and compared between the patterns of AF. At baseline, the patients were classified as paroxysmal (N=963, 31.6%), persistent (N=604, 19.8%), and permanent AF (N=1479, 45.6%) according to the standard definition. Anticoagulants were administered in 75% of all patients and 83% of those with CHA2DS2-VASc score [≥]2 in males or [≥]3 in females . During a mean follow up of 26 (SD 10.5) months, all-cause mortality occurred less in paroxysmal AF (2.5 per 100 patient-years) than in persistent AF (4.4 per 100 patient-years; adjusted hazard ratio [HR] 0.66, 95% CI, 0.46-0.96; P = .029) and permanent AF (4.1 per 100 patient-years; adjusted HR 0.71, 95% CI, 0.52-0.98; P = .036). The risk of ischemic stroke was similar across all patterns of AF. Conclusions In this multicenter nationwide registry of AF patients, persistent and permanent AF was associated with higher all-cause mortality than paroxysmal AF, independent of baseline comorbidities.


title: Using time use diaries to track changing behavior across successive stages of COVID-19 social restrictions

abstract: How did people change their behavior over the different phases of the UK COVID-19 restrictions, and how did these changes affect their risk of being exposed to infection? Time use diary surveys are unique in providing a complete chronicle of daily behavior; 24-hour continuous records of the populations activities, their social context and their location. We present results from four such surveys, collected in real time from representative UK samples, both before, and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of substantial changes in the UK populations behavior relating to activities, locations and social context. We assign different levels of risk to combinations of activities, locations and copresence, to compare risk-related behavior across successive  lockdowns. We find evidence that during the second lockdown (November 2020) there was an increase in high-risk behaviors relative to the first (starting March 2020). This increase is shown to be associated with more paid work time in the workplace. At a time when capacity is still limited both in respect of immunization and track-trace technology, governments must continue to rely on changes in peoples daily behaviors to contain the spread of COVID-19 and similar viruses. Time use diary information of this type, collected in real time across the course of the COVID-19 pandemic, can provide policy-makers with information to assess and quantify changes in daily behaviors, and the impact they are likely to have on overall behavioral-associated risks.


title: Minimizing loss of life in Covid-19 in a 100 day period in the U.S.A. by age-tailored dosing and distribution of a limited vaccine supply

abstract:
BackgroundWe aimed at minimizing loss of lives in the Covid-19 pandemic in the USA by identifying optimal vaccination strategies during a 100-day period with limited vaccine supplies. While lethality is highest in the elderly, transmission and case numbers are highest in the younger. A strategy of first vaccinating the elderly is widely used, thought to protect the vulnerable, elderly best. Despite lower immunogenicity in the elderly, mRNA vaccines retain high efficacy, implying that in the younger, reduced vaccine doses might suffice, thereby increasing vaccination counts with a given vaccine supply.

MethodsUsing published immunogenicity data of the Moderna mRNA-1273 vaccine, we examined the value of personalized-dose vaccination strategies, using a modeling approach incorporating age-related vaccine immunogenicity, social contact patterns, population structure, Covid-19 case and death rates in the USA in late January 2021. An increase if the number of persons that can be vaccinated and a potential reduction of the individual protective efficacy was accounted for.

ResultsAge-personalized dosing strategies reduced cases faster, shortening the pandemic, reducing the delay to reaching <100000 cases/day from 64 to 30 days and avoiding 25000 deaths within 100 days in the USA. In an "elderly first" vaccination strategy, mortality is higher even in the elderly. Findings were robust with transmission blocking efficacies of reduced dose vaccination between 30% to 90%, and with a vaccine supply from 1 to 3 million full dose vaccinations per day.

ConclusionRapid reduction of Covid-19 case and death rate in the USA in 100 days with a limited vaccine supply is best achieved when personalized, age-tailored dosing for highly effective vaccines is used, according to this vaccination strategy model parameterized to U.S. demographics, Covid-19 transmission and vaccine characteristics. Protecting the vulnerable is most effectively achieved by personalized-dose vaccination of all population segments, while an "elderly first" approach costs more lives, even in the elderly.


title: Minimizing loss of life in Covid-19 in a 100 day period in the U.S.A. by personalize-dose vaccination and distribution of a limited vaccine supply


title: Minimizing loss of life in Covid-19 in a 100 day period in the U.S.A. by personalized-dose vaccination and distribution of a limited vaccine supply


title: Minimizing loss of life in Covid-19 in a 100 day period in the U.S.A. by personalized-dose vaccination and distribution of a limited vaccine supply - a vaccination strategy model


title: Emergence of first strains of Sars-CoV-2 lineage B.1.1.7 in Romania

abstract: United Kingdom reported the emergence of a new and highly transmissible SARS-CoV-2 variant B.1.1.7. that rapidly spread to other contries. The impact of this new mutation that occurs in the S protein, on infectivity, virulence and current vaccine effectiveness is still under evaluation. We have identified the first cases of the B.1.1.7 variant in samples collected from Romanian patients, of which one was traced to the UK region where the new variant was originally sequenced. Mutations in the Nsp3 protein, N844S and D455N and L15F in Orf3a were also detected, indicating common ancestry with UK strains as well as remote connections with strains from Nagasaki, Japan. These results indicate, for the first time, the presence and characteristics of the new variant B.1.1.7 in Romania and underscore the need for increased genomic sequencing in confirmed COVID-19 patients.


title: Emergence of universality in the transmission dynamics of COVID-19

abstract: The complexities involved in modeling the transmission dynamics of COVID-19 has been a major roadblock in achieving predictability in the spread and containment of the disease. In addition to understanding the modes of transmission, the effectiveness of the mitigation methods also needs to be built into any effective model for making such predictions. We show that such complexities can be circumvented by appealing to scaling principles which lead to the emergence of universality in the transmission dynamics of the disease. The ensuing data collapse renders the transmission dynamics largely independent of geopolitical variations, the effectiveness of various mitigation strategies, population demographics, etc. We propose a simple two-parameter model--the Blue Sky model--and show that one class of transmission dynamics can be explained by a solution that lives at the edge of a blue sky bifurcation. In addition, the data collapse leads to an enhanced degree of predictability in the disease spread for several geographical scales which can also be realized in a model-independent manner as we show using a deep neural network. The methodology adopted in this work can potentially be applied to the transmission of other infectious diseases and new universality classes may be found. The predictability in transmission dynamics and the simplicity of our methodology can help in building policies for exit strategies and mitigation methods during a pandemic.


title: A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses

abstract: IntroThe molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree (Supplemental Table-1) and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.


title: Who should be first in line for the COVID-19 vaccine? Surveys in 13 countries of the publics preferences for prioritisation

abstract: How does the public want a COVID-19 vaccine to be allocated? We conducted a conjoint experiment asking 15,536 adults in 13 countries to evaluate 248,576 profiles of potential vaccine recipients that varied randomly on five attributes. Our sample includes diverse countries from all continents. The results suggest that in addition to giving priority to health workers and to those at high risk, the public favours giving priority to a broad range of key workers and to those on lower incomes. These preferences are similar across respondents of different education levels, incomes, and political ideologies, as well as across most surveyed countries. The public favoured COVID-19 vaccines being allocated solely via government programs, but were highly polarized in some developed countries on whether taking a vaccine should be mandatory. There is a consensus among the public on many aspects of COVID-19 vaccination which needs to be taken into account when developing and communicating roll-out strategies.

category: health economics


title: Molecular epidemiology of SARS-CoV-2 in Greece reveals low rates of onward virus transmission after lifting of travel restrictions based on risk assessment during summer 2020

abstract: Molecular epidemiology has provided an additive value to traditional public health tools by identifying SARS-CoV-2 clusters, or providing evidence that clusters based on virus sequences and contact tracing are highly concordant. Our aim was to infer the levels of virus importation and to estimate the impact of public health measures related to travel restrictions to local transmission in Greece. Our phylogenetic and phylogeographic analyses included 389 SARS-CoV-2 sequences collected during the first 7 months of the pandemic in Greece and a random collection in 5 replicates of 3,000 sequences sampled globally, as well as the best hits to our dataset identified by BLAST. Phylogenetic analyses revealed the presence of 70 genetically distinct viruses identified as independent introductions into Greece. The proportion of imported strains was 41%, 11.5%, and 8.8% during the three periods of sampling, namely, March (no travel restrictions), April to June (strict travel restrictions), and July to September (lifting of travel restrictions based on a thorough risk assessment), respectively. These findings reveal low levels of onward transmission from imported cases during summer and underscore the importance of targeted public health measures that can increase the safety of international travel during a pandemic.


title: Dynamics of SARS-CoV-2-specific antibodies during and after COVID19: Lessons from a biobank in Argentina

abstract:
BackgroundBiobanks are instrumental for accelerating research. Early in SARS-CoV-2 pandemic, the Argentinean Biobank of Infectious Diseases (BBEI) initiated the COVID19 collection and started its characterization.

MethodsBlood samples from subjects with confirmed SARS-CoV-2 infection either admitted to health institutions or outpatients, were enrolled. Highly exposed seronegative individuals, were also enrolled. Longitudinal samples were obtained in a subset of donors, including persons who donated plasma for therapeutic purposes (plasma donors). SARS-CoV-2-specific IgM and IgG levels, IgG titers and IgG viral neutralization capacity were determined.

FindingsOut of 825 donors, 57.1% were females and median age was 41 years (IQR 32-53 years). Donors were segregated as acute or convalescent donors, and mild versus moderate/severe disease donors. Seventy-eight percent showed seroconversion to SARS-CoV-2 specific antibodies. Specific IgM and IgG showed comparable positivity rates in acute donors. IgM detectability rate declined in convalescent donors while IgG detectability remained elevated in early (74,8%) and late (83%) convalescent donors. Among donors with follow-up samples, IgG levels seemed to decline more rapidly in plasma donors. IgG levels were higher with age, disease severity, number of symptoms, and was more durable in moderate/severe disease donors. Levels and titers of anti-spike/RBD IgG strongly correlated with neutralization activity against WT virus.

InterpretationThe BBEI-COVID19 collection served a dual role in this SARS-CoV-2 global crisis. First, it feed researchers and developers transferring samples and data to fuel research projects. Second, it generated highly needed local data to understand and frame the regional dynamics of the infection.

FundingThis work was supported by a grant from the Agencia Nacional de Promocion de la Investigacion, el Desarrollo Tecnologico y la Innovacion (Agencia I+D+i) from Argentina through an extraordinary funding opportunity to improve the national response to COVID19 (Proyecto COVID N{degrees} 11, IP 285).


title: Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9

abstract:
BACKGROUNDDefective proteasome activities due to genetic mutations lead to an autoinflammatory disease, termed as proteasome-associated autoinflammatory syndromes (PRAAS). In PRAAS relapsing inflammations and progressive wasting are common, but immunodeficiency has not been reported.

METHODSWe studied two unrelated Japanese infants with PRAAS-like manifestations. We have also generated and analyzed the mice carrying the candidate mutation found in the patients.

RESULTSBoth patients showed neonatal-onset skin rash, myositis and basal ganglia calcification, similar to PRAAS patients. Meanwhile, they manifested distinct phenotypes, including pulmonary hypertension and immunodeficiency without lipoatrophy. We identified a novel de novo heterozygous missense mutation, G156D, in a proteasome subunit gene, PSMB9, encoding {beta}1i, in the two patients. Maturation and activity of the immunoproteasome were impaired, but ubiquitin accumulation was hardly detected not only in patient-derived cells and samples but also in Psmb9G156D/+ mice. As an immunodeficient phenotype, one patient showed decrease of B cells and increase of monocytes, while the other patient showed decrease of CD8 T cells. The proteasome defects and immunodeficient phenotypes were recapitulated in Psmb9G156D/+ mice.

CONCLUSIONSThe PSMB9 G156D is a unique mutation in proteasome subunits in causing defects by its heterozygosity, affecting two {beta} rings interaction and leading to immunodeficiency. The mutant mice are the first mice model for analyzing proteasome dysfunctions in PRAAS. We here propose the term, proteasome-associated autoinflammation and immunodeficiency disease (PRAID), as an umbrella name for our cases, PRAAS with immunodeficiency, as well as PRAAS described so far.