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The ongoing COVID-19 pandemic is a major public health crisis. Despite the development and deployment of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic persists. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the spike protein. Although these differences in spike are important in terms of transmission and vaccine responses, these variants possess mutations in the other parts of their genome that may also affect pathogenesis. Of particular interest to us are the mutations present in the accessory genes, which have been shown to contribute to pathogenesis in the host through interference with innate immune signaling, among other effects on host machinery. To examine the effects of accessory protein mutations and other nonspike mutations on SARS-CoV-2 pathogenesis, we synthesized both viruses possessing deletions in the accessory genes as well as viruses where the WA-1 spike is replaced by each variant spike gene in a SARS-CoV-2/WA-1 infectious clone. We then characterized the in vitro and in vivo replication of these viruses and compared them to both WA-1 and the full variant viruses. Our work has revealed that the accessory proteins contribute to SARS-CoV-2 pathogenesis and the nonspike mutations in variants can contribute to replication of SARS-CoV-2 and pathogenesis in the host. This work suggests that while spike mutations may enhance receptor binding and entry into cells, mutations in accessory proteins may alter clinical disease presentation.

Surface rheology becomes important for droplets with adsorbed proteins, solid particulates, lipids, or polymers, and understanding how surface rheology alters basic droplet processes like coalescence provides insight into the processing of dispersions in industrial and biological systems. In this work, we model the approach of two equal-size deformable droplets under an axisymmetric, biaxial extensional flow in the Stokes flow limit. We explore how the viscosity contrast between the drop and suspending fluid alters the film drainage behaviour when interfacial viscosity is present. For a clean droplet at a fixed capillary number, the drainage time is observed to be independent of the viscosity ratio (λ) for λ≤O(1), while the drainage increases linearly with the viscosity ratio for λ≥O(1). Surface viscosity increases the drainage time by causing the thin film between the droplets to flatten and widen, and shifts the viscosity ratio at which the aforementioned scaling behaviour changes to larger values. The drainage time is increased more significantly at lower viscosity ratio values than higher values. In the second half of the paper, we examine how surface viscosity alters film drainage when the surfactant can be soluble. We examine the kinetically controlled adsorption/desorption limit. We find that surfactant solubility abolishes surface tension gradients and increases the prominence of surface viscosity effects, the effects of which are quantified for Boussinesq numbers Bq∼O(0.1).

Hairy Cell Leukemia (HCL) is a rare chronic B-cell lymphoproliferative neoplasm typically presenting with splenomegaly and pancytopenia. This case report discusses the atypical presentation of HCL in a 29-year-old male who exhibited isolated thrombocytopenia without classical symptoms leading to initial misdiagnosis as dengue delayed recognition until immunophenotyping revealed monotypic B cell markers characteristic of HCL. This case underscores the challenges in diagnosing atypical HCL emphasizing the importance of vigilance, detailed morphological assessment and advanced diagnostic tools for early detection and contributes to awareness of non-classical HCL presentations.

The need for classification systems for cardiovascular disease (CVD) that is population-specific is important towards understanding the clinical disease and diagnostics associated with the disease. This paper presents the form and validation results of this classification system. The survey data used was captured from 778 participants, 526 persons with no prior CVD, and 252 who reported prior CVD. Binomial logistic regression and Discriminant analysis were utilised to develop classification models. This classification system provided a general measure of severity of disease by utilising scores estimated from two algorithms developed from 13 routine physiologic measurements, along with demographic information of age and ethnicity, , and previous health status. For each model, specific score ranges were identified, which gave the best classification for those with a prior CVD incident (higher scores) and for others labelled as non-CVD (lower scores). The two classification models (Logistic Regression Model and Discriminant Analysis Model) developed had high area under the receiver-operating characteristic (AUROC) values (98% & 99%) and sensitivity (86 and 90%), which improved discrimination between Non-CVD and CVD participants and, more importantly, correctly classified a greater proportion of CVD participants. New to this type of research was the estimation and detailed evaluation of a range of scores, labelled non-differentiating, which fell in the middle of the spectrum and which contained the higher-end scores for the non-CVD individuals and the lower-end scores for CVD patients, all of whom were incorrectly classified, based on their prior history. The classification system of scores is able to differentiate the CVD status of individuals, with good predictability, and could assist physicians with recommending different treatment plans. The two models in this classification system each individually outperformed the three established models in terms of the strength of their correct classifications of individuals with or without prior reported CVD incidents. More importantly, they have smaller non-differentiating ranges than the three known models and, in that range, the two new models have lower CVD/non-CVD ratios suggesting they are more likely to misclassify non-CVD individuals compared to CVD patients, which is a more benign misclassification. Further, when used in combination, the two models increased the sensitivity, in classifying individuals of different ethnicities, beyond that of either one used independently or of any of the three standard European/North American models. These efforts will be instrumental in advancing personalised CVD management strategies and improving health outcomes across diverse populations.

Oral microbes form a complex and dynamic biofilm community, which is subjected to daily host and environmental challenges. Dysbiosis of the oral biofilm is correlated with local and distal infections and postulating a baseline for the healthy core oral microbiota provides an opportunity to examine such shifts during the onset and recurrence of disease. Here we quantified the daily, weekly, and monthly variability of the oral microbiome by sequencing the largest oral microbiota time-series to date, covering multiple oral sites in ten healthy individuals. Temporal dynamics of salivary, dental, and tongue consortia were examined by high-throughput 16S rRNA gene sequencing over 90 days, with four individuals sampled additionally 1 year later. Distinct communities were observed between dental, tongue, and salivary samples, with high levels of similarity observed between the tongue and salivary communities. Twenty-six core OTUs that classified within Streptococcus, Fusobacterium, Haemophilus, Neisseria, Prevotella , and Rothia genera were present in ≥95% samples and accounted for ~65% of the total sequence data. Phylogenetic diversity varied from person to person, but remained relatively stable within individuals over time compared to inter-individual variation. In contrast, the composition of rare microorganisms was highly variable over time, within most individuals. Using machine learning, an individual's oral microbial assemblage could be correctly assigned to them with 88–97% accuracy, depending on the sample site; 83% of samples taken a year after initial sampling could be confidently traced back to the source subject. Peering into the mouth: Bacterial turnover in plaque and saliva A study of bacteria in the mouth reveals insights into their diversity, stability, and variability among people and over time. By tracking daily, weekly, and monthly fluctuations of plaque and salivary bacteria in ten healthy volunteers, Dilani Senadheera at the Faculty of Dentistry, University of Toronto and co-researchers in Canada reveal significant differences in the “microbiome” present in dental, tongue and saliva samples over time. They found considerable variation in these communities between individuals, sufficient to identify a person with “bacterial fingerprints” using plaque or saliva even after 1 year. The researchers reveal a “core community” that spans different persons, oral sites, and time, suggesting some level of stability. This study is useful to understand the diversity and community drifts in different oral sites over time, which is important when plaque and saliva are used for bacterial analysis in diagnostic, risk-prediction, and forensic applications.

Inflammation is thought to play a pivotal role in the onset of term and some forms of preterm labour. Although, we recently found that myometrial inflammation is a consequence rather than a cause of term labour, there are several other reproductive tissues, including amnion, choriodecidua parietalis and decidua basalis, where the inflammatory stimulus to labour may occur. To investigate this, we have obtained amnion, choriodecidual parietalis and decidua basalis samples from women at various stages of pregnancy and spontaneous labour. The inflammatory cytokine profile in each tissue was determine by Bio-Plex Pro® cytokine multiplex assays and quantitative RT-PCR. Active motif assay was used to study transcription activation in the choriodecidua parietalis. Quantitative RT-PCR was use to study the pro-labour genes ( PGHS-2 , PGDH , OTR and CX43 ) in all of the tissues at the onset of labour and oxytocin (OT) mRNA expression in the choriodecidual parietalis and decidua basalis. Statistical significance was ascribed to a P value <0.05. In the amnion and choriodecidua parietalis, the mRNA levels of various cytokines decreased from preterm no labour to term no labour samples, but the protein levels were unchanged. The choriodecidua parietalis showed increase in the protein levels of IL-1β and IL-6 in the term early labour samples. In the amnion and decidua basalis, the protein levels of several cytokines rose in term established labour. The multiples of the median derived from the 19-plex cytokine assay were greater in term early labour and term established labour samples from the choriodecidua parietalis, but only in term established labour for myometrium. These data suggest that the inflammatory stimulus to labour may begin in the choriodecidua parietalis, but the absence of any change in prolabour factor mRNA levels suggests that the cytokines may act on the myometrium where we observed changes in transcription factor activation and increases in prolabour gene expression in earlier studies.

We previously reported that at term pregnancy, a decline in myometrial protein kinase A (PKA) activity leads to an exchange protein activated by cyclic AMP (Epac1)-dependent increase in oxytocin receptor (OTR) expression, promoting the onset of labour. Here, we studied the changes in the cyclic adenosine monophosphate (cAMP) effector system present in different phenotypes of preterm labour (PTL). Myometrial biopsies obtained from women with phenotypically distinct forms of PTL and the levels of PKA and OTR were examined. Although we found similar changes in the cAMP effector pathway in all forms of PTL, only in the case of twin PTL (T-PTL) was myometrial OTR levels increased in association with these results. Although there were several changes in the mRNA levels of components of the cAMP synthetic pathway, the total myometrial cAMP levels did not change with the onset of any subtype of PTL. With regards to the expression of cAMP-responsive genes, we found that the mRNA levels of 4 of the 5 cAMP-down-regulated genes were increased in T-PTL, similar to our findings in term labour. These data signify that although changes in the cAMP effector system were common to all forms of PTL, only in T-PTL were OTR levels increased. Similarly, the mRNA levels of cAMP-repressed genes were only increased in T-PTL supporting the concept that the decline in PKA levels influences myometrial function driving the onset of T-PTL.

Background Progesterone is known to maintain uterine quiescence as pregnancy advances. Recently, its efficacy in preventing preterm birth has been questioned prompting a search for an alternative treatment option. Cyclic AMP has been shown invitro to act in synergy with progesterone to maintain uterine quiescence. Methods We undertook an open label randomised feasibility study to test the hypothesis that the addition of aminophylline to the standard of care (SoC) is acceptable and can be tolerated in pregnant women at high risk of spontaneous preterm labour (sPTL). Women at high risk of sPTL, who met the inclusion criteria were invited to participate and randomised to receive the SoC (progesterone alone, n  = 33) or treatment with the SoC and aminophylline ( n  = 37). The main outcome measure was to assess the how many women at high-risk of sPTL tolerated and continued to take aminophylline. Data were analysed using Graphpad Prism 8.0c (Graphpad Software, San Diego, CA, USA). Results We found that of the addition of aminophylline was well tolerated in 30 of the 33 (91%) of women who continued in the combined arm, without any additional adverse maternal or fetal outcomes. 58% of eligible women agreed to participate in the study. The compliance rate was high at 99.42% +-0.82%. 67% of the women completed the post study questionnaire and all stated their willingness to take aminophylline if it were offered routinely for the prevention of sPTL. Conclusions The addition of aminophylline to the SoC is acceptable to women at high-risk of sPTL confirming that a randomised trial of aminophylline to reduce preterm delivery in women at high-risk of PTL is feasible. Trial registration Clinical trial gov NCT03152942. Date of full registration: 15/5/2017. https://clinicaltrials.gov/ct2/show/NCT03152942?cond=NCT03152942%26;draw=2%26;rank=1 .

With the onset of COVID-19, the development of ex vivo laboratory models became an urgent priority to study host-pathogen interactions in response to the pandemic. In this study, we aimed to establish an ex vivo mucosal tissue explant challenge model for studying SARS-CoV-2 infection and replication. Nasal or oral tissue samples were collected from eligible participants and explants generated from the tissue were infected with various SARS-CoV-2 strains, including IC19 (lineage B.1.13), Beta (lineage B.1.351) and Delta (lineage B.1.617.2). A qRT-PCR assay used to measure viral replication in the tissue explants over a 15-day period, demonstrated no replication for any viral strains tested. Based on this, the ex vivo challenge protocol was modified by reducing the viral infection time and duration of sampling. Despite these changes, viral infectivity of the nasal and oral mucosa was not improved. Since 67% of the enrolled participants were already vaccinated against SARS-CoV-2, it is possible that neutralizing antibodies in explant tissue may have prevented the establishment of infection. However, we were unable to optimize plaque assays aimed at titrating the virus in supernatants from both infected and uninfected tissue, due to limited volume of culture supernatant available at the various collection time points. Currently, the reasons for the inability of these mucosal tissue samples to support replication of SARS-CoV-2 ex vivo remains unclear and requires further investigation.

In this study, we perform boundary-integral simulations to investigate the role of interfacial viscosity in the deformation and breakup of a single droplet suspended in an axisymmetric extensional flow under the Stokes flow regime. We model the insoluble surfactant monolayer using the Boussinesq–Scriven constitutive relationship for a Newtonian interface. We compare the deformation and breakup results from our boundary-element simulations with results from small deformation perturbation theories. We observe that the surface shear/dilational viscosity increases/decreases the critical capillary number beyond which the droplet becomes unstable and breaks apart by reducing/increasing the droplet deformation at a given capillary number compared with a clean droplet. We present the relative importance of surface shear and dilational viscosity on droplet stability based on their measured values reported in experimental studies on surfactants, lipid bilayers and proteins. In the second half of the paper, we incorporate the effect of surfactant transport by solving the time-dependent convection–diffusion equation and consider a nonlinear equation of state (Langmuir adsorption isotherm) to correlate the interfacial tension with the changes in surfactant concentration. We explore the coupled influence of pressure-dependent surface viscosity and Marangoni stresses on droplet deformation and breakup. In the case of a droplet with pressure-dependent surface shear viscosity, we find that a droplet with pressure-thinning/thickening surfactant is less/more deformed than a droplet with pressure-independent surfactant. We conclude by discussing the combined impact of surface viscosity and surfactant transport on the relaxation of an initially extended droplet in a quiescent external fluid.