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Respiratory infectious diseases are mainly caused by viruses or bacteria that often interact with one another. Although their presence is a prerequisite for subsequent infections, viruses and bacteria may be present in the nasopharynx without causing any respiratory symptoms. The upper respiratory tract hosts a vast range of commensals and potential pathogenic bacteria, which form a complex microbial community. This community is assumed to be constantly subject to synergistic and competitive interspecies interactions. Disturbances in the equilibrium, for instance due to the acquisition of new bacteria or viruses, may lead to overgrowth and invasion. A better understanding of the dynamics between commensals and pathogens in the upper respiratory tract may provide better insight into the pathogenesis of respiratory diseases. Here we review the current knowledge regarding specific bacterial-bacterial and viral-bacterial interactions that occur in the upper respiratory niche, and discuss mechanisms by which these interactions might be mediated. Finally, we propose a theoretical model to summarize and illustrate these mechanisms.

The early-life microbiome appears to be affected by mode of delivery, but this effect may depend on intrapartum antibiotic exposure. Here, we assess the effect of delivery mode on gut microbiota, independent of intrapartum antibiotics, by postponing routine antibiotic administration to mothers until after cord clamping in 74 vaginally delivered and 46 caesarean section born infants. The microbiota differs between caesarean section born and vaginally delivered infants over the first year of life, showing enrichment of Bifidobacterium spp., and reduction of Enterococcus and Klebsiella spp. in vaginally delivered infants. The microbiota composition at one week of life is associated with the number of respiratory infections over the first year. The taxa driving this association are more abundant in caesarean section born children, providing a possible link between mode of delivery and susceptibility to infectious outcomes. Here, in a cohort of infants unexposed to maternal antibiotics, the authors analyse the gut microbiome development of children born naturally and by caesarean section, finding a higher abundance of known pathogens in the latter group, and an association between these bacteria and a higher incidence of respiratory infections in the first year of life.

Breastfeeding elicits significant protection against respiratory tract infections in infancy. Modulation of respiratory microbiota might be part of the natural mechanisms of protection against respiratory diseases induced by breastfeeding. To study the association between breastfeeding and nasopharyngeal microbial communities, including all cultivable and noncultivable bacteria. In this observational study, we analyzed the microbiota of infants that had received exclusive breastfeeding (n = 101) and exclusive formula feeding (n = 101) at age 6 weeks and 6 months by 16S-based GS-FLX-titanium-pyrosequencing. At 6 weeks of age the overall bacterial community composition was significantly different between breastfed and formula-fed children (nonmetric multidimensional scaling, P = 0.001). Breastfed children showed increased presence and abundance of the lactic acid bacterium Dolosigranulum (relative effect size [RES], 2.61; P = 0.005) and Corynebacterium (RES, 1.98; P = 0.039) and decreased abundance of Staphylococcus (RES, 0.48; P 0.03) and anaerobic bacteria, such as Prevotella (RES, 0.25; P < 0.001) and Veillonella (RES, 0.33; P < 0.001). Predominance (>50% of the microbial profile) of Corynebacterium and Dolosigranulum was observed in 45 (44.6%) breastfed infants compared with 19 (18.8%) formula-fed infants (relative risk, 2.37; P = 0.006). Dolosigranulum abundance was inversely associated with consecutive symptoms of wheezing and number of mild respiratory tract infections experienced. At 6 months of age associations between breastfeeding and nasopharyngeal microbiota composition had disappeared. Our data suggest a strong association between breastfeeding and microbial community composition in the upper respiratory tract of 6-week-old infants. Observed differences in microbial community profile may contribute to the protective effect of breastfeeding on respiratory infections and wheezing in early infancy. Clinical trial registered with www.clinicaltrials.gov (NCT 00189020).

Background Obesity changes a patient’s pharmacokinetics and pharmacotherapeutic advices should be personalized to ensure proper treatment. Currently, implementations of advices regarding the obese population are lacking and weight and body mass index (BMI) are rarely monitored. The Maasstad Hospital built a clinical decision support system (CDSS) for pharmacists, based on current Dutch guidelines, to supply therapeutic advices for (morbidly) obese patients based on patient characteristics. In this study we evaluated whether patients receiving inadequate pharmacotherapy are indeed identified via this CDSS and to which extent irrelevant alerts are generated. Moreover, it is investigated to which extent pharmacists carry on the generated advices and to which extent physicians act upon these. Methods The research concerned a retrospective observational study performed at the Maasstad Hospital in Rotterdam, the Netherlands between January 2021 and august 2021. The drugs included were dalteparin, apixaban, dabigatran, edoxaban, rivaroxaban, vancomycin and ciprofloxacin. Dispensing data, patient characteristics and CDSS processing were collected. Dispensing data was included when the patient’s weight or BMI could potentially lead to dose adjustments via the CDSS. The CDSS was evaluated for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Additionally, excess alerts, defined as irrelevant alerts on the moment of assessment, of the CDSS and adherence to the CDSS were investigated. Results 1218 alerts over 3735 drug dispenses were generated. 568 alerts (46.6%) resulted in a pharmacotherapeutic advice by the pharmacist to the physician. In most cases, the sensitivity, specificity, PPV and NPV were 100.0% with varying 95% CIs. For some drugs technical adjustments were needed, including the initially incorrect BMI setting of vancomycin within the CDSS, resulting in a high excess alerts of 56.9%. Dabigatran had a NPV of 22.2% 95% CI [6.3–54.7] and a sensitivity of 56.3% 95% CI [33.2–76.9]. Overall excess alerts varied from 22.2% to 56.9%. Depending on the drug, the advices resulted in 6.9–100.0% real pharmacotherapy adjustments in practise. Conclusion The (morbid) obesity CDSS functions as expected and identifies the (morbidly) obese patients with inadequate pharmacotherapy. The adherence of physicians and the follow-up in practise varies widely and requires further investigation. Trial registration Non-WMO research W21.218.

High rates of potentially pathogenic bacteria and respiratory viruses can be detected in the upper respiratory tract of healthy children. Investigating presence of and associations between these pathogens in healthy individuals is still a rather unexplored field of research, but may have implications for interpreting findings during disease. We selected 986 nasopharyngeal samples from 433 6- to 24-month-old healthy children that had participated in a randomized controlled trial. We determined the presence of 20 common respiratory viruses using real-time PCR. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus were identified by conventional culture methods. Information on risk factors was obtained by questionnaires. We performed multivariate logistic regression analyses followed by partial correlation analysis to identify the overall pattern of associations. S. pneumoniae colonization was positively associated with the presence of H. influenzae (adjusted odds ratio 1.60, 95% confidence interval 1.18-2.16), M. catarrhalis (1.78, 1.29-2.47), human rhinoviruses (1.63, 1.19-2.22) and enteroviruses (1.97, 1.26-3.10), and negatively associated with S. aureus presence (0.59, 0.35-0.98). H. influenzae was positively associated with human rhinoviruses (1.63, 1.22-2.18) and respiratory syncytial viruses (2.78, 1.06-7.28). M. catarrhalis colonization was positively associated with coronaviruses (1.99, 1.01-3.93) and adenoviruses (3.69, 1.29-10.56), and negatively with S. aureus carriage (0.42, 0.25-0.69). We observed a strong positive association between S. aureus and influenza viruses (4.87, 1.59-14.89). In addition, human rhinoviruses and enteroviruses were positively correlated (2.40, 1.66-3.47), as were enteroviruses and human bocavirus, WU polyomavirus, parainfluenza viruses, and human parechovirus. A negative association was observed between human rhinoviruses and coronaviruses. Our data revealed high viral and bacterial prevalence rates and distinct bacterial-bacterial, viral-bacterial and viral-viral associations in healthy children, hinting towards the complexity and potential dynamics of microbial communities in the upper respiratory tract. This warrants careful consideration when associating microbial presence with specific respiratory diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Upper extremity deep vein thrombosis (UEDVT) accounts for 5% of all deep vein thromboses (DVTs). UEDVT may be complicated by post thrombotic syndrome and pulmonary embolism, and early recognition and prompt start of anticoagulant treatment are key. Primary UEDVT, also known as Paget-von Schrötter syndrome, is associated with repeated or sudden physical activity of the upper arm and venous outflow obstruction due to anatomical variations. Secondary UEDVT is often associated with malignancy or use of intravenous devices, such as central venous catheters or pacemaker leads. Although the diagnosis and treatment of UEDVT have many similarities with DVT of the lower extremities, knowledge of specific aspects regarding UEDVT is important to guide optimal management. In this review, we will discuss the epidemiology, diagnosis, and treatment of UEDVT based on the current literature.

Neutrophil released peptidyl arginine deiminase 4 (PAD4) converts arginine residues on plasma proteins into citrulline. Here, we developed an assay to quantify citrullinated fibrinogen. We employed a biotin‐conjugated phenylglyoxal (biotin‐phenylglyoxal (PG)) compound that selectively labels citrulline. Patient samples were derived from a multicenter prospective cohort study that aimed to identify cancer patients at high risk for venous thromboembolism (VTE). Our data show that cancer patients have higher (median 2‐fold increased) citrullinated fibrinogen levels when compared to normal human plasma and a cohort of healthy donors. Our results show that citrullination of fibrinogen is a common posttranslational modification in patients with cancer. Citrullination is a post‐translational modification of arginine. Recent research has shown that citrullination can affect the activity of coagulation factors like fibrinogen. Quantitative analysis of citrullinated fibrinogen showed that cancer patients who are at increased risk of developing venous thromboembolism have significantly increased levels of circulating citrullinated fibrinogen compared to healthy controls. This finding is indicative of widespread plasma protein citrullination in cancer patients.

Carriage of Streptococcus pneumoniae in adults is rarely detected by the gold standard culture method. With molecular tests of high sensitivity now available, we analysed upper respiratory tract samples collected during autumn/winter 2012/2013 from parents of PCV7-vaccinated infants and from childless adults, directly comparing culture and qPCR-based S. pneumoniae detection. As compared to the gold standard of testing nasopharyngeal swabs, qPCR-based analysis of oral samples significantly improved detection of pneumococcal carriage (5% versus 20%, p  < 0.0001) with higher carriage rates in parents compared to childless adults (34% versus 7%; p  < 0.001). Molecular methods also increased the number of serotype-carriage events detected with higher carriage frequencies of serotypes 3 and 7A/F and lower of serotypes 6C/D and 15A/B/C in parents compared to their infant children. We provide evidence that culture-based methods severely underestimate adult carriage rates and for the superiority of testing oral samples over nasopharyngeal swabs. The substantial circulation of pneumococci in parents is however, not representative for the entire adult population. While age-associated differences in serotype carriage suggests reservoirs outside infants as potential sources of vaccine-serotypes contributing to weakening of vaccine herd effects, we find no evidence for reservoirs in adults contributing to serotype replacement in carriage.