A simple model of COVID-19 explains disease severity and the effect of treatments.

Considerable effort has been made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue by focusing on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation, identifying the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and reveal conditions that can increase the likelihood of desired clinical outcome from treatment administration. In particular, the analysis suggest that antivirals need to be administered early during infection to have an impact on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.

Methods to capture proteomic and metabolomic signatures from cerebrospinal fluid and serum of healthy individuals.

Discovery of reliable signatures for the empirical diagnosis of neurological diseases-both infectious and non-infectious-remains unrealized. One of the primary challenges encountered in such studies is the lack of a comprehensive database representative of a signature background that exists in healthy individuals, and against which an aberrant event can be assessed. For neurological insults and injuries, it is important to understand the normal profile in the neuronal (cerebrospinal fluid) and systemic fluids (e.g., blood). Here, we present the first comparative multi-omic human database of signatures derived from a population of 30 individuals (15 males, 15 females, 23-74 years) of serum and cerebrospinal fluid. In addition to empirical signatures, we also assigned common pathways between serum and CSF. Together, our findings provide a cohort against which aberrant signature profiles in individuals with neurological injuries/disease can be assessed-providing a pathway for comprehensive diagnostics and therapeutics discovery.

Estimating the reproductive number R0 of SARS-CoV-2 in the United States and eight European countries and implications for vaccination.

SARS-CoV-2 rapidly spread from a regional outbreak to a global pandemic in just a few months. Global research efforts have focused on developing effective vaccines against COVID-19. However, some of the basic epidemiological parameters, such as the exponential epidemic growth rate and the basic reproductive number, R0, across geographic areas are still not well quantified. Here, we developed and fit a mathematical model to case and death count data collected from the United States and eight European countries during the early epidemic period before broad control measures were implemented. Results show that the early epidemic grew exponentially at rates between 0.18 and 0.29/day (epidemic doubling times between 2.4 and 3.9 days). We found that for such rapid epidemic growth, high levels of intervention efforts are necessary, no matter the goal is mitigation or containment. We discuss the current estimates of the mean serial interval, and argue that existing evidence suggests that the interval is between 6 and 8 days in the absence of active isolation efforts. Using parameters consistent with this range, we estimated the median R0 value to be 5.8 (confidence interval: 4.7-7.3) in the United States and between 3.6 and 6.1 in the eight European countries. We further analyze how vaccination schedules depend on R0, the duration of protective immunity to SARS-CoV-2, and show that individual-level heterogeneity in vaccine induced immunity can significantly affect vaccination schedules.

Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure.

Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop-PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed-Effects Modeling (NONMEM) and R software. A total of 281 white patients were included to develop the Pop-PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7-22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF.

Fast spread of COVID-19 in Europe and the US suggests the necessity of early, strong and comprehensive interventions.

The COVID-19 pandemic caused more than 800,000 infections and 40,000 deaths by the end of March 2020. However, some of the basic epidemiological parameters, such as the exponential epidemic growth rate and R0 are debated. We developed an inference approach to control for confounding factors in data collection, such as underreporting and changes in surveillance intensities, and fitted a mathematical model to infection and death count data collected from eight European countries and the US. In all countries, the early epidemic grew exponentially at rates between 0.19-0.29/day (epidemic doubling times between 2.4-3.7 days). This suggests a highly infectious virus with an R0 likely between 4.0 and 7.1. We show that similar levels of intervention efforts are needed, no matter the goal is mitigation or containment. Early, strong and comprehensive intervention efforts to achieve greater than 74-86% reduction in transmission are necessary.

High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2.

Severe acute respiratory syndrome coronavirus 2 is the causative agent of the ongoing coronavirus disease pandemic. Initial estimates of the early dynamics of the outbreak in Wuhan, China, suggested a doubling time of the number of infected persons of 6-7 days and a basic reproductive number (R0) of 2.2-2.7. We collected extensive individual case reports across China and estimated key epidemiologic parameters, including the incubation period (4.2 days). We then designed 2 mathematical modeling approaches to infer the outbreak dynamics in Wuhan by using high-resolution domestic travel and infection data. Results show that the doubling time early in the epidemic in Wuhan was 2.3-3.3 days. Assuming a serial interval of 6-9 days, we calculated a median R0 value of 5.7 (95% CI 3.8-8.9). We further show that active surveillance, contact tracing, quarantine, and early strong social distancing efforts are needed to stop transmission of the virus.

Nanoparticle heterogeneity: an emerging structural parameter influencing particle fate in biological media?

Drug nanocarriers' surface chemistry is often presumed to be uniform. For instance, the polymer surface coverage and distribution of ligands on nanoparticles are described with averaged values obtained from quantification techniques based on particle populations. However, these averaged values may conceal heterogeneities at different levels, either because of the presence of particle sub-populations or because of surface inhomogeneities, such as patchy surfaces on individual particles. The characterization and quantification of chemical surface heterogeneities are tedious tasks, which are rather limited by the currently available instruments and research protocols. However, heterogeneities may contribute to some non-linear effects observed during the nanoformulation optimization process, cause problems related to nanocarrier production scale-up and correlate with unexpected biological outcomes. On the other hand, heterogeneities, while usually unintended and detrimental to nanocarrier performance, may, in some cases, be sought as adjustable properties that provide NPs with unique functionality. In this review, results and processes related to this issue are compiled, and perspectives and possible analytical developments are discussed.

Exploring an alternative explanation for the second phase of viral decay: Infection of short-lived cells in a drug-limited compartment during HAART.

Most HIV-infected patients who initiate combination antiretroviral therapy experience a viral load decline in several phases. These phases are characterized by different rates of viral load decay that decrease when transitioning from one phase to the next. There is no consensus as to the origin of these phases. One hypothesis put forward is that short- and long-lived infected cells are responsible for the first and second phases of decay, respectively. However, significant differences in drug concentrations are observed in monocytes from various tissues, suggesting the first two phases of decay in viral loads could instead be attributed to short-lived cells being differently exposed to drugs. Compared to a well-exposed compartment, new cell infection can be expected in a compartment with limited drug exposure, thus leading to a slower viral load decay with potential virologic failure and drug resistance. In the current study, the latter hypothesis was investigated using a model of viral kinetics. Empirical datasets were involved in model elaboration and parameter estimation. In particular, susceptibility assay data was used for an in vitro to in vivo extrapolation based on the expected drug concentrations inside physiological compartments. Results from numerical experiments of the short-term evolution of viral loads can reproduce the first two phases of viral decay when allowing new short-lived cell infections in an unidentified drug-limited compartment. Model long-term predictions are however less consistent with clinical observations. For the hypothesis to hold, efavirenz, tenofovir and emtricitabine drug exposure in the drug-limited compartment would have to be very low compared to exposure in peripheral blood. This would lead to significant long-term viral growth and the frequent development of resistant strains, a prediction not supported by clinical observations. This suggests that the existence of a drug-limited anatomical compartment is unlikely, by itself, to explain the second phase of viral load decay.

Therapeutic drug monitoring in treatment-experienced HIV-infected patients receiving darunavir-based salvage regimens: A case series.

Therapeutic drug monitoring (TDM) constitutes a compelling approach for the optimization of antiretroviral therapy in treatment-experienced HIV-1 patients. While various inhibitory indices have been proposed to predict virologic outcome, there is a lack of consensus on the clinical value of TDM. Here, we report the comparative results of TDM in 14 HIV-1-infected patients who had previously received at least two different PI-based regimens and who initiated darunavir (DRV)-based salvage therapy. Pharmacokinetic/pharmacodynamics (PK/PD) parameters were calculated for each subject. Seventy-nine percent of subjects had a viral load <50 copies/mL at 48 weeks. The only subject with two consecutive viral loads >50 copies/mL at the end of the study period was the patient with the lowest instantaneous inhibitory potential (IIP). The sample size was insufficient to show an association between any of the PK/PD parameters and virologic response. Based on our observations, we suggest that the utility of IIP for antiretroviral combinations for the prediction of virologic outcome in HIV-1 drug-experienced patients should be studied further.

Self-reported versus health administrative data: implications for assessing chronic illness burden in populations. A cross-sectional study.

BACKGROUND: Various data sources may be used to document the presence of chronic medical conditions. This study examined the agreement between self-reported and health administrative data. METHODS: A randomly selected cohort of participants aged 25-75 years recruited by telephone from the general population of Quebec reported on the presence of 1 or more chronic conditions from a candidate list of 12 conditions: diabetes, hypertension, thyroid disorder, any cardiac disease, cancer diagnosis in the previous 5 years (including melanoma but excluding other skin cancers), asthma, osteoarthritis, rheumatoid arthritis or lupus, osteoporosis, chronic obstructive pulmonary disease, intestinal disease and hypercholesterolemia. We also used health administrative data from Quebec's universal health insurance provider to identify participants' chronic conditions. Unique identifiers allowed linkage of both data sources to the individual participant. The frequencies of the 12 conditions and the prevalence of multimorbidity (≥ 2, ≥ 3 and ≥ 4 conditions) were analyzed for each data source. RESULTS: We analyzed data for 1177 participants (mean age 53 [standard deviation 12.4] yr; 684 women [58.1%]). We found low (but varied) agreement between the 2 data sources, with the poorest agreement for hypercholesterolemia (κ = 0.04 [95% confidence interval (CI) 0.01 to 0.07]) and the best for diabetes (κ = 0.82 [95% CI 0.76 to 0.88]). Prevalence estimates of multimorbidity obtained with health administrative data were lower than those obtained with self-reported data regardless of the operational definition used. Most participants with multimorbidity were identified by self-report. INTERPRETATION: We argue for the use of self-reported chronic conditions in the study of multimorbidity, as health administrative data based on the billing system in Quebec seem to underestimate the prevalence of many chronic conditions, which results in biased estimates of multimorbidity.

Personal Characteristics and Experience of Primary Care Predicting Frequent Use of Emergency Department: A Prospective Cohort Study.

OBJECTIVE: A small number of patients frequently using the emergency department (ED) account for a disproportionate amount of the total ED workload and are considered using this service inappropriately. The aim of this study was to identify prospectively personal characteristics and experience of organizational and relational dimensions of primary care that predict frequent use of ED. METHODS: This study was conducted among parallel cohorts of the general population and primary care patients (N = 1,769). The measures were at baseline (T1), 12 (T2) and 24 months (T3): self-administered questionnaire on current health, health behaviours and primary care experience in the previous year. Use of medical services was confirmed using administrative databases. Mixed effect logistic regression modeling identified characteristics predicting frequent ED utilization. RESULTS: A higher likelihood of frequent ED utilization was predicted by lower socioeconomic status, higher disease burden, lower perceived organizational accessibility, higher number of reported healthcare coordination problems and not having a complete annual check-up, above and beyond adjustment for all independent variables. CONCLUSIONS: Personal characteristics such as low socioeconomic status and high disease burden as well as experience of organizational dimensions of primary care such as low accessibility, high healthcare coordination problems and low comprehensiveness of care are prospectively associated with frequent ED utilization. Interventions developed to prevent inappropriate ED visits, such as case management for example, should tailor low socioeconomic status and patients with high disease burden and should aim to improve experience of primary care regarding accessibility, coordination and comprehensiveness.

Feasibility and acceptability of a delirium prevention program for cognitively impaired long term care residents: a participatory approach.

In this participatory action research study, researchers conducted a total of 3 implementation cycles to evaluate the feasibility and acceptability of a new delirium prevention program (DPP) for cognitively impaired residents in long term care (LTC) settings. Researchers interviewed 95 health care staff to obtain feedback on their use of the DPP and then modified the DPP and tested the changes in the next implementation cycle. Our results indicated that the DPP was feasible and that health care staff would accept it under certain conditions. We found there were 4 keys to successful implementation of the DPP: support for the program from both the administration and the users; effective clinician leadership to ensure proper delivery of the DPP (format, content and values) and its appropriate adaptation to the LTC facility's internal culture and policies; a sense of ownership among the DPP users; and, last, practical hands-on training as well as theoretical training for staff.

Return on investment in electronic health records in primary care practices: a mixed-methods study.

BACKGROUND: The use of electronic health records (EHR) in clinical settings is considered pivotal to a patient-centered health care delivery system. However, uncertainty in cost recovery from EHR investments remains a significant concern in primary care practices. OBJECTIVE: Guided by the question of "When implemented in primary care practices, what will be the return on investment (ROI) from an EHR implementation?", the objectives of this study are two-fold: (1) to assess ROI from EHR in primary care practices and (2) to identify principal factors affecting the realization of positive ROI from EHR. We used a break-even point, that is, the time required to achieve cost recovery from an EHR investment, as an ROI indicator of an EHR investment. METHODS: Given the complexity exhibited by most EHR implementation projects, this study adopted a retrospective mixed-method research approach, particularly a multiphase study design approach. For this study, data were collected from community-based primary care clinics using EHR systems. RESULTS: We collected data from 17 primary care clinics using EHR systems. Our data show that the sampled primary care clinics recovered their EHR investments within an average period of 10 months (95% CI 6.2-17.4 months), seeing more patients with an average increase of 27% in the active-patients-to-clinician-FTE (full time equivalent) ratio and an average increase of 10% in the active-patients-to-clinical-support-staff-FTE ratio after an EHR implementation. Our analysis suggests, with a 95% confidence level, that the increase in the number of active patients (P=.006), the increase in the active-patients-to-clinician-FTE ratio (P<.001), and the increase in the clinic net revenue (P<.001) are positively associated with the EHR implementation, likely contributing substantially to an average break-even point of 10 months. CONCLUSIONS: We found that primary care clinics can realize a positive ROI with EHR. Our analysis of the variances in the time required to achieve cost recovery from EHR investments suggests that a positive ROI does not appear automatically upon implementing an EHR and that a clinic's ability to leverage EHR for process changes seems to play a role. Policies that provide support to help primary care practices successfully make EHR-enabled changes, such as support of clinic workflow optimization with an EHR system, could facilitate the realization of positive ROI from EHR in primary care practices.

Peritraumatic distress but not dissociation predicts posttraumatic stress disorder in the elderly.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms include re-experiencing, avoidance, and hyperarousal after a particularly intense event. In view of the aging of the population, increased clinical knowledge is required for better understanding of PTSD in the elderly. Extending previous research in this field in adults and children, the aim of our study was to assess the utility of peri-traumatic dissociation and distress as a predictor of PTSD in the elderly. METHODS: A prospective longitudinal study was conducted in a consecutive cohort of subjects aged 65 years and over admitted to emergency departments after a physical assault or a road traffic accident. Peri-traumatic responses of distress and of dissociation were measured. One, 6, and 12 months after trauma exposure, PTSD symptoms and diagnosis were assessed using both a dimensional and a semistructured interview. RESULTS: Thirty-nine male and female participants with an average age of 72.4 years were recruited. Mixed model regression analyses did not detect a significant effect of age, sex, nor time. Significant associations were detected between peri-traumatic distress and the self-report PTSD Checklist (p = 0.008), as well as the Clinician-administered PTSD scale (p = 0.03). No association was detected between peri-traumatic dissociation and PTSD. CONCLUSIONS: Peri-traumatic distress predicts PTSD symptoms and diagnosis in the elderly, thereby suggesting its systematic evaluation at the emergency department would be a worthwhile thing to do.

Trauma reactivation under the influence of propranolol: an examination of clinical predictors.

BACKGROUND: In two recent studies conducted by our group, a treatment combining propranolol with a brief reactivation session subsequently reduced posttraumatic stress disorder (PTSD) symptom severity and diagnosis, as well as reducing psychophysiological responses during trauma-related script-driven imagery. One likely explanation for those results is that memory reconsolidation was blocked by propranolol. OBJECTIVE: We explored the influence of various predictors on treatment outcome (i.e., PTSD severity), and whether the treated individuals improved in other important domains of functioning associated with PTSD. METHOD: Thirty-three patients with longstanding PTSD participated in a 6-week open-label trial consisting of actively recalling one's trauma under the influence of propranolol, once a week. RESULTS: Treated patients reported a better quality of life, less comorbid depressive symptoms, less negative emotions in their daily life and during trauma recollections. Women were also found to improve more than men. Type of trauma (childhood vs. adulthood), time elapsed since trauma, borderline personality traits, depressive symptoms severity, Axis I comorbidity, and age did not influence treatment outcome. CONCLUSION: These results must await publication of a randomized-controlled trial to further delineate effectiveness with this novel treatment approach.

Factors predicting patient use of the emergency department: a retrospective cohort study.

BACKGROUND: Many studies have shown the tendency for people without a regular care provider or primary physician to make greater use of emergency departments. We sought to determine the effects of three aspects of care provided by primary physicians (physician specialty, continuity of care and comprehensiveness of care) on their patients' use of the emergency department. METHODS: Using provincial administrative databases, we created a cohort of 367,315 adults aged 18 years and older. Participants were residents of urban areas of Quebec. Affiliation with a primary physician, the specialty of this physician (i.e., family physician v. specialist), continuity of care (as measured using the Usual Provider Continuity index) and comprehensiveness of care (i.e., number of complete annual examinations) were measured among participants (n = 311,701) who had visited a physician three or more times during a two-year baseline period. We used multivariable negative binomial regression to investigate the relationships between measures of care and the number of visits to emergency departments during a 12-month follow-up period. RESULTS: Among participants under 65 years of age, emergency department use was higher for those not affiliated than for those affiliated with a family physician (incidence rate ratio [IRR] 1.11, 95% confidence interval [CI] 1.05-1.16) or a specialist (IRR 1.10, 95% CI 1.04-1.17). Among patients aged 65 years and older, having a specialist primary physician, as opposed to a family physician, predicted increased use of the emergency department (IRR 1.13, 95% CI 1.09-1.17). Greater continuity of care with a family physician predicted less use of the emergency department only among participants who made 25 or more visits to a physician during the baseline period. Greater continuity of care with a specialist predicted less use of the emergency department overall, particularly among participants with intermediate numbers of multimorbidities and admissions to hospital. Greater comprehensiveness of care by family physicians predicted less use of the emergency department. INTERPRETATION: Efforts to increase the proportion of adults affiliated with a family physician should target older adults, people who visit physicians more frequently and people with multiple comorbidities and admissions to hospital.

Emergency department visits and primary care among adults with chronic conditions.

BACKGROUND: An emergency department (ED) visit may be a marker for limited access to primary medical care, particularly among those with ambulatory care sensitive chronic conditions (ACSCC). OBJECTIVES: In a population with universal health insurance, to examine the relationships between primary care characteristics and location of last general physician (GP) contact (in an ED vs. elsewhere) among those with and without an ACSCC. RESEARCH DESIGN: A cross-sectional survey using data from 2 cycles of the Canadian Community Health Survey carried out in 2003 and 2005. SUBJECTS: The study sample comprised Québec residents aged ≥18 who reported at least one GP contact during the previous 12 months, and were not hospitalized (n = 33,491). MEASURES: The primary outcome was place of last GP contact: in an ED versus elsewhere. Independent variables included the following: lack of a regular physician, perceived unmet healthcare needs, perceived availability of health care, number of contacts with doctors and nurses, and diagnosis of an ACSCC (hypertension, heart disease, chronic respiratory disease, diabetes). RESULTS: Using multiple logistic regression, with adjustment for sociodemographic, health status, and health services variables, lack of a regular GP and perceptions of unmet needs were associated with last GP contact in an ED; there was no interaction with ACSCC or other chronic conditions. CONCLUSIONS: Primary care characteristics associated with GP contact in an ED rather than another site reflect individual characteristics (affiliation with a primary GP and perceived needs) rather than the geographic availability of healthcare, both among those with and without chronic conditions.