The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further ...randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empiric treatment, response to treatment, new antibiotics or new forms of antibiotic administration and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent.The European Respiratory Society launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine and the European Society of Clinical Microbiology and Infectious Diseases, were invited to participate and appointed their representatives. The Latin American Thoracic Association was also invited.A total of 15 experts and two methodologists made up the panel. Three experts from the USA were also invited (Michael S. Niederman, Marin Kollef and Richard Wunderink).Applying the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, the panel selected seven PICO (population–intervention–comparison–outcome) questions that generated a series of recommendations for HAP/VAP diagnosis, treatment and prevention.
PURPOSE OF REVIEWMeningococcal disease is a severe consequence of infection with Neisseria meningitidis, a pathobiont of the pharynx. This organism is panmitic so virulent clones transformed with new ...genetic material can emerge and cause severe outbreaks. The key to sustainable prevention is to restrict carriage of disease-causing strains and thus reduce the chances of transmission between human hosts.
RECENT FINDINGSMeningococcal population biology has changed recently with emergence of virulent strains linked to a number of sublineages of clonal complex 11. These strains have variously expressed the capsular material of serogroups C and W and caused severe disease in various countries. Glycoconjugate vaccines including quadrivalent (ACWY) and now pentavalent (ACWYX) vaccines are highly immunogenic and prevent disease and carriage due to their respective serogroups. For NmB, new vaccines (4CMenB and MenB-FHbp) containing conserved outer membranes proteins have been deployed and are immunogenic and protective at population level, but clones exist which do not express cognate antigens. In contrast to glycoconjugate vaccines they may not have potent carriage-reducing activity. Mass chemoprophylaxis is gaining credence as an alternative strategy is effective, but has significant shortcomings in sustainability.
SUMMARYMeningococcal disease is well defined genomically for epidemiological purposes. There is potential for unpredictable emergence of clones that may have reduced susceptibility even to modern vaccines, and continued surveillance and vigilance is necessary. However, tremendous strides have been made in recent years.
Artificial intelligence (AI), machine learning and deep learning (including generative AI) are increasingly being investigated in the context of research and management of human infection.
We ...summarise recent and potential future applications of AI and its relevance to clinical infection practice.
1617 PubMed results were screened, with priority given to clinical trials, systematic reviews and meta-analyses. This narrative review focusses on studies using prospectively collected real-world data with clinical validation, and on research with translational potential, such as novel drug discovery and microbiome-based interventions.
There is some evidence of clinical utility of AI applied to laboratory diagnostics (e.g. digital culture plate reading, malaria diagnosis, antimicrobial resistance profiling), clinical imaging analysis (e.g. pulmonary tuberculosis diagnosis), clinical decision support tools (e.g. sepsis prediction, antimicrobial prescribing) and public health outbreak management (e.g. COVID-19). Most studies to date lack any real-world validation or clinical utility metrics. Significant heterogeneity in study design and reporting limits comparability. Many practical and ethical issues exist, including algorithm transparency and risk of bias.
Interest in and development of AI-based tools for infection research and management are undoubtedly gaining pace, although the real-world clinical utility to date appears much more modest.
•Artificial intelligence (AI) algorithms have been applied to clinical and laboratory diagnostics, public health surveillance, and drug discovery.•Most AI algorithms to date relating to human infection lack real-world validation or assessment of clinical utility.•Ongoing issues such as methodological heterogeneity, algorithm transparency, and risk of bias must be addressed.
BACKGROUND:Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein–coupled apelin receptor, despite lack of sequence similarity to the established ligand ...apelin. Our aim was to investigate the receptor pharmacology, expression pattern, and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model.
METHODS:In silico docking analysis, competition binding experiments, and downstream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and Pyrapelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- and Sugen/hypoxia-exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the monocrotaline rat model.
RESULTS:ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. ELA activated G-protein– and β-arrestin–dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats.
CONCLUSIONS:These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans.
Paul Little and colleagues call for better promotion of simple measures that can help reduce the spread and severity of infection among those living with people who have covid-19
In children, SARS-CoV-2 infection is usually asymptomatic or causes a mild illness of short duration. Persistent illness has been reported; however, its prevalence and characteristics are unclear. We ...aimed to determine illness duration and characteristics in symptomatic UK school-aged children tested for SARS-CoV-2 using data from the COVID Symptom Study, one of the largest UK citizen participatory epidemiological studies to date.
In this prospective cohort study, data from UK school-aged children (age 5–17 years) were reported by an adult proxy. Participants were voluntary, and used a mobile application (app) launched jointly by Zoe Limited and King's College London. Illness duration and symptom prevalence, duration, and burden were analysed for children testing positive for SARS-CoV-2 for whom illness duration could be determined, and were assessed overall and for younger (age 5–11 years) and older (age 12–17 years) groups. Children with longer than 1 week between symptomatic reports on the app were excluded from analysis. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed.
258 790 children aged 5–17 years were reported by an adult proxy between March 24, 2020, and Feb 22, 2021, of whom 75 529 had valid test results for SARS-CoV-2. 1734 children (588 younger and 1146 older children) had a positive SARS-CoV-2 test result and calculable illness duration within the study timeframe (illness onset between Sept 1, 2020, and Jan 24, 2021). The most common symptoms were headache (1079 62·2% of 1734 children), and fatigue (954 55·0% of 1734 children). Median illness duration was 6 days (IQR 3–11) versus 3 days (2–7) in children testing negative, and was positively associated with age (Spearman's rank-order rs 0·19, p<0·0001). Median illness duration was longer for older children (7 days, IQR 3–12) than younger children (5 days, 2–9). 77 (4·4%) of 1734 children had illness duration of at least 28 days, more commonly in older than younger children (59 5·1% of 1146 older children vs 18 3·1% of 588 younger children; p=0·046). The commonest symptoms experienced by these children during the first 4 weeks of illness were fatigue (65 84·4% of 77), headache (60 77·9% of 77), and anosmia (60 77·9% of 77); however, after day 28 the symptom burden was low (median 2 symptoms, IQR 1–4) compared with the first week of illness (median 6 symptoms, 4–8). Only 25 (1·8%) of 1379 children experienced symptoms for at least 56 days. Few children (15 children, 0·9%) in the negatively tested cohort had symptoms for at least 28 days; however, these children experienced greater symptom burden throughout their illness (9 symptoms, IQR 7·7–11·0 vs 8, 6–9) and after day 28 (5 symptoms, IQR 1·5–6·5 vs 2, 1–4) than did children who tested positive for SARS-CoV-2.
Although COVID-19 in children is usually of short duration with low symptom burden, some children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate.
Zoe Limited, UK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation, and Alzheimer's Society.
Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 ...human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID
of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237 ; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study's primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log
copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2-4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70-80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome.
Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) ...kill bacteria.
To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung.
We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing.
Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for ≥12 h) overwhelmed initial killing, and a second, late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of
and
in wild-type mice but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced
in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during
lung infection.
Mcl-1 upregulation prevents macrophage apoptosis-associated killing and establishes that apoptosis-associated killing is required to allow AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.
IntroductionPregnant women have been historically excluded from interventional research. While recent efforts have been made to improve their involvement, there remains a disparity in the evidence ...base for treatments available to pregnant women compared with the non-pregnant population. A significant barrier to the enrolment of pregnant women within research is risk perception and a poor understanding of decision-making in this population.ObjectiveAssess the risk perception and influences on decision-making in pregnant women, when considering whether to enrol in a hypothetical interventional research study.DesignSemistructured interviews were undertaken, and thematic analysis was undertaken of participant responses.ParticipantsTwelve pregnant women were enrolled from an antenatal outpatient clinic.ResultsParticipants were unanimously positive about enrolling in the proposed hypothetical interventional study. Risk perception was influenced by potential risks to their fetus and their previous experiences of healthcare and research. Participants found the uncertainty in quantifying risk for new research interventions challenging. They were motivated to enrol in research by altruism and found less invasive research interventions more tolerable.ConclusionIt is vital to understand how pregnant women balance the perceived risks and benefits of interventional research. This may help clinicians and scientists better communicate risk to pregnant women and address the ongoing under-representation of pregnant women in interventional research.
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