A Hierarchical Framework for Assessing Transmission Causality of Respiratory Viruses

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing, and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for present and future pandemics of viral respiratory pathogens. We review the history of causality assessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierarchy of evidence to integrate clinical, epidemiologic, molecular, and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency, and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.     

Assessment of functioning in Dutch primary care: Development study of a consultation tool for patients with chronic conditions and multimorbidity

BackgroundIn primary care, a shift from a disease‐oriented approach for patients with multimorbidity towards a more person‐centred approach is needed.AimTo transform a self‐report questionnaire for patients with chronic conditions in primary care, the Primary Care Functioning Scale (PCFS), into an understandable, visually attractive and feasible consultation tool for patients and health care providers. The consultation tool consists of a web‐based version of the PCFS, which is filled in by the patient and is processed to a feedback report that summarizes and visualizes the main findings. The feedback report can be discussed with the patient to facilitate a more person‐centred conversation for patients with chronic conditions and multimorbidity in general practice.Design and SettingIn this qualitative study, we developed the consultation tool by using design thinking in a participatory developmental process.MethodsIn the first phase, we constructed five different feedback report templates to summarize and display the results of a completed PCFS questionnaire in a series of two expert meetings with patients and general practitioners (GPs). In the second phase, we performed an exploratory qualitative interview study involving dyads of patients with chronic conditions and their practice nurses. In an iterative process, we explored their experiences with the consultation tool.ResultsPatients, as well as GPs, preferred a clear manner of presenting the results of the questionnaire in a feedback report. In 18 interviews with patients and practice nurses during three different interview rounds, we adjusted the feedback report and consultation tool based on the input from patients and practice nurses. After the final interview round, patients and practice nurses consented that the consultation tool was useful for having a more in‐depth consultation about functioning and patients'' preferences when integrated into the regularly scheduled consultations.ConclusionWe were able to develop an understandable and feasible consultation tool that is applicable in already existing chronic disease management programmes in general practice in the Netherlands.Patient or Public ContributionTo increase the understandability and feasibility of the consultation tool, we collaborated with end‐users and actively involved patients, GPs and practice nurses in a participatory development process.     

Invasive Pneumococcal Disease and Long-Term Mortality Rates in Adults,Alberta, Canada

The relationship between increased short-term mortality rates after invasive pneumococcal disease (IPD) has been frequently studied. However, the relationship between IPD and long-term mortality rates is unknown. IPD patients in Alberta, Canada, had clinical data collected that were linked to administrative databases. We used Cox proportional hazards modeling, and the primary outcome was time to all-cause deaths. First IPD events were identified in 4,522 patients, who had a median follow-up of 3.2 years (interquartile range 0.8‒9.1 years). Overall all-cause mortality rates were consistently higher among cases than controls at 30 days (adjusted hazard ratio [aHR] 3.75, 95% CI 3.29–4.28), 30‒90 days (aHR 1.56, 95% CI 1.27‒1.93), and >90 days (aHR 1.43, 95% CI 1.33–1.54). IPD increases risk for short, intermediate, and long-term mortality rates regardless of age, sex, or concurrent conditions. These findings can help clinicians focus on postdischarge patient plans to limit long-term effects after acute IPD infection.     

Kinetics of the SARS-CoV-2 Antibody Avidity Response Following Infection and Vaccination

Serological assays capable of measuring antibody responses induced by previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been critical tools in the response to the COVID-19 pandemic. In this study, we use bead-based multiplex assays to measure IgG and IgA antibodies and IgG avidity to five SARS-CoV-2 antigens (Spike (S), receptor-binding domain (RBD), Nucleocapsid (N), S subunit 2, and Membrane-Envelope fusion (ME)). These assays were performed in several cohorts of healthcare workers and nursing home residents, who were followed for up to eleven months after SARS-CoV-2 infection or up to six months after vaccination. Our results show distinct kinetic patterns of antibody quantity (IgG and IgA) and avidity. While IgG and IgA antibody levels waned over time, with IgA antibody levels waning more rapidly, avidity increased with time after infection or vaccination. These contrasting kinetic patterns allow for the estimation of time since previous SARS-CoV-2 infection. Including avidity measurements in addition to antibody levels in a classification algorithm for estimating time since infection led to a substantial improvement in accuracy, from 62% to 78%. The inclusion of antibody avidity in panels of serological assays can yield valuable information for improving serosurveillance during SARS-CoV-2 epidemics.     

Selecting features for BCI control based on a covert spatial attention paradigm

Covert attention to spatial locations in the visual field is a relatively new control signal for brain–computer interfaces. Previous EEG research has shown that trials can be classified by thresholding based on left and right hemisphere alpha power in covert spatial attention paradigms. We reexamine the covert attention paradigm based on MEG measurements for fifteen subjects. It is shown that classification performance can be improved by applying sparse logistic regression in order to select a subset of the sensors specific to each subject as the basis for classification. Furthermore, insight is gained into how classification performance changes as a function of the length of the attention period and as a function of the number of trials. Classification performance steadily increases as the length of the attention period over which is averaged is increased, although this does not necessarily translate into higher bit rates. Good classification performance using early components of the attention period may be related to evoked response. With regard to the number of used trials, classification performance became maximal after 150 samples had been obtained, requiring a training time of approximately eleven minutes under the current experimental paradigm.     

Passive expiratory flow-volume curve is not an accurate method to measure the respiratory time constant in rabbits

BACKGROUND: In mechanically ventilated patients, inspiration is forced by an externally applied positive pressure whereas expiration remains passive and depends on the time constant of the total respiratory system (tau), which constitutes an important determinant of mechanical ventilation. The end-inspiratory occlusion technique is one of the easiest methods to obtain tau values in ventilated patients, especially infants, but its accuracy is not well established. The aim of this study was to compare in anesthetized, paralyzed rabbits tau values given by the end-inspiratory occlusion technique (tau(rs)) to tau values obtained by references methods for measurements (i.e. the product of static lung compliance by airway resistance: tau(ref)) during carbachol-induced bronchospasm eliciting marked modifications of the respiratory mechanics. METHODS: Comparisons were made in the basal state and after carbachol-induced bronchoconstriction in seven New Zealand adult rabbits. This procedure resulted in a wide range of expiratory time constants. A pneumotachograph was used to measure expiratory flow and volume before and after end-inspiratory occlusion. The slope of the flow volume curve gave tau(rs). Then tau(rs) was compared with tau(ref) (which ranged from 0.30 to 1.96 s). RESULTS: Statistical analysis revealed a weak correlation between the two methods, and a size-dependent bias of tau(rs) measurements. CONCLUSIONS: The end-inspiratory occlusion technique leads to a systemic bias in measurements of respiratory time constant, especially when the resistance of the respiratory system is elevated.     

Acid–base physiology: new concepts

The traditional approach to acid–base physiology is based on the Henderson–Hasselbalch equation which is derived from the ${\text{CO}}_2/{{\text{HCO}}_3}^{?}$ buffer system. However, it is becoming increasingly recognized that this is an incomplete analysis as it focuses on only one of the six reactions involving H⁺ and can lead to the incorrect assumption that CO₂ and ${{\text{HCO}}_3}^{?}$ are independently adjusted factors that ultimately determine pH. In 1983, Stewart, a Canadian physiologist, proposed that a fuller understanding of acid–base physiology required consideration of biological fluids as a complex dynamic system, taking into account the interactions of all the chemical species involved. He showed that the true independent variables controlling the pH of any given fluid compartment are: the difference in the concentration of ‘strong ions’; the total concentration of ‘weak acid’; and the PCO₂. Importantly, H⁺ and ${{\text{HCO}}_3}^{?}$ are dependent variables and it is incorrect to think of them as being specifically regulated to manipulate pH. This review will discuss the importance of pH homeostasis and highlight the implications of the Stewart approach in our understanding of acid–base control mechanisms and disorders. In particular, the true mechanisms by which the kidney regulates plasma pH will be discussed, emphasizing key misconceptions that have been propagated as a result of the traditional approach.     

Testing for rational bubbles in a coexplosive vector autoregression

Summary Asset bubbles can be described through the rational bubble solution of the standard stock price model linking stock prices and dividends. We show how the hypothesis of a rational bubble can be tested in the context of a bivariate coexplosive vector autoregression. The methodology is illustrated using US stock prices and dividends for the period 1974–2000.     

A benefit/risk approach towards selecting appropriate pharmaceutical dosage forms - An application for paediatric dosage form selection

The design and selection of new pharmaceutical dosage forms involves the careful consideration and balancing of a quality target product profile against technical challenges and development feasibility. Paediatric dosage forms present particular complexity due to the diverse patient population, patient compliance challenges and safety considerations of this vulnerable population. This paper presents a structured framework for assessing the comparative benefits and risks of different pharmaceutical design options against pre-determined criteria relating to (1) efficacy, (2) safety and (3) patient access. This benefit/risk framework has then been applied to three hypothetical, but realistic, scenarios for paediatric dosage forms in order to explore its utility in guiding dosage form design and formulation selection. The approach allows a rigorous, systematic and qualitative assessment of the merits and disadvantages of each dosage form option and helps identify mitigating strategies to modify risk. The application of a weighting and scoring system to the criteria depending on the specific case could further refine the analysis and aid decision-making. In this paper, one case study is scored for illustrative purposes. However, it is acknowledged that in real development scenarios, the generation of actual data considering the very specific situation for the patient/product/developer would come into play to drive decisions on the most appropriate dosage form strategy.