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Diabetes mellitus (DM) is thought to be associated with poor outcomes in cervicofacial infections (CFI), yet little is known about the prevalence of DM in these cases. Stress hyperglycaemia (SHG), a normal physiological response to inflammation, is distinct from DM, though they overlap and may be conflated. We aimed to establish the prevalence of DM and SHG in CFI, and to determine the effect of each on severity of disease and outcome measures. The Maxillofacial Surgery Trainee Research Collaborative (MTReC) carried out an audit of all patients with CFI admitted to 25 hospitals between May and October 2017. To the best of our knowledge this created the largest prospective database on CFI, with information collected on presentation, source of infection, biological data, and outcomes. We recorded 1002 admissions, of which 78 (7.8%) had DM. Random blood glucose was measured on admission in 401 patients (40%), of which 45 (11%) displayed SHG. Patients diagnosed with DM were more likely to have infections arising from a salivary source (13% vs 4%, p0.00), more returns to theatre (9% vs 2%, p0.00), and a longer hospital stay (median (range) 2 (0-34) vs 1 (0-139) day, p=0.01) than non-DM patients. In contrast, patients with SHG had more severe disease (multiple fascial spaces involved in 59% vs 19%, p=0.01, and systemic inflammatory response syndrome present in 66% vs 45% p=0.03), but did not have significantly more returns to theatre (2% vs 3%, p=0.91) or longer stays in hospital (median (range) 1 (0-63) vs 1 (0-6), p=0.55) than normoglycaemic patients. The prevalence of DM in our cohort was only marginally higher than in the general population, despite previous retrospective case reviews suggesting a significantly higher prevalence. SHG was not associated with poor outcomes in our cohort, but is likely to be associated with a small increased risk of subsequent diagnosis of DM, which can be quantified using a calculator tool. On discharge, it is important to give appropriate advice about diet, lifestyle, exercise, and weight loss to all patients with CFI.

Idiopathic pulmonary fibrosis (IPF) is a poorly understood, progressive lethal lung disease with no known cure. In addition to alveolar epithelial cell (AEC) injury and excessive deposition of extracellular matrix proteins, chronic inflammation is a hallmark of IPF. Literature suggests that the persistent inflammation seen in IPF primarily consists of monocytes and macrophages. Recent work demonstrates that monocyte-derived alveolar macrophages (moAMs) drive lung fibrosis, but further characterization of critical moAM cell attributes is necessary. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an important epidermal growth factor receptor ligand that has essential roles in angiogenesis, wound healing, keratinocyte migration, and epithelial-mesenchymal transition. Our past work has shown HB-EGF is a primary marker of profibrotic M2 macrophages, and this study seeks to characterize myeloid-derived HB-EGF and its primary mechanism of action in bleomycin-induced lung fibrosis using

Legionella pneumophila are host-adapted bacteria that infect and reproduce primarily in amoeboid protists. Using similar infection mechanisms, they infect human macrophages, and cause Legionnaires’ disease, an atypical pneumonia, and the milder Pontiac fever. We hypothesized that, despite the similarities in infection mechanisms, the hosts are different enough that there exist high-selective value mutations that would dramatically increase the fitness of Legionella inside the human host. By comparing a large number of isolates from independent infections, we identified two genes, mutated in three unrelated patients, despite the short duration of the incubation period (2–14 days). One is a gene coding for an outer membrane protein (OMP) belonging to the OmpP1/FadL family. The other is a gene coding for an EAL-domain-containing protein involved in cyclic-di-GMP regulation, which in turn modulates flagellar activity. The clinical strain, carrying the mutated EAL-domain-containing homologue, grows faster in macrophages than the wild-type strain, and thus appears to be better adapted to the human host. As human-to-human transmission is very rare, fixation of these mutations into the population and spread into the environment is unlikely. Therefore, parallel evolution – here mutations in the same genes observed in independent human infections – could point to adaptations to the accidental human host. These results suggest that despite the ability of L. pneumophila to infect, replicate in and exit from macrophages, its human-specific adaptations are unlikely to be fixed in the population.

Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Streptococcus suis is a leading cause of bacterial meningitis in South-East Asia, with frequent zoonotic transfer to humans associated with close contact with pigs. A small number of invasive lineages are responsible for endemic infection in the swine industry, causing considerable global economic losses. A lack of surveillance and a rising trend in clinical treatment failure has raised concerns of growing antimicrobial resistance (AMR) among invasive S. suis . Gene flow between healthy and disease isolates is poorly understood and, in this study, we sample and sequence a collection of isolates predominantly from healthy pigs in Chiang Mai province, Northern Thailand. Pangenome characterization identified extensive genetic diversity and frequent AMR carriage in isolates from healthy pigs. Multiple AMR genes were identified, conferring resistance to aminoglycosides, lincosamides, tetracycline and macrolides. All isolates were non-susceptible to three or more different antimicrobial classes, and 75 % of non-serotype 2 isolates were non-susceptible to six or more classes (compared to 37.5 % of serotype 2 isolates). AMR genes were found on integrative and conjugative elements previously observed in other species, suggesting a mobile gene pool that can be accessed by invasive disease isolates. This article contains data hosted by Microreact.

Cervicofacial infections carry significant morbidity. Patients present on a broad spectrum of severity, with some requiring outpatient management and others admission to higher level care. Recognition of risk factors is helpful in decision making regarding the need for admission to higher level care. Prospective data were captured on 1002 patients in 25 centres across 17 regions of the United Kingdom (UK) by the Maxillofacial Trainee Research Collaborative (MTReC). Patients admitted to critical care were compared with those who received ward-level care. Multivariate and receiver operating characteristic curve analyses were used to identify predictors for critical care admission. Our results show that the best predictor for critical care admission is the presence of three or more features of airway compromise (AUC 0.779), followed by C-reactive protein (CRP)100 mg/L (OR 2.70; 95% CI 1.59 to 4.58; p 0.005), submandibular space involvement (OR 3.82; 95% CI 1.870 to 7.81; p = 0.003), white cell count (WCC)12 × 10

Background Lung cancer risk prediction models do not routinely incorporate imaging metrics available on low-dose CT (LDCT) imaging of the chest ordered for lung cancer screening. Research Question What is the association between quantitative emphysema measured on LDCT imaging and lung cancer incidence and mortality, all-cause mortality, and airflow obstruction in individuals who currently or formerly smoked and are undergoing lung cancer screening? Study Design and Methods In 7,262 participants in the CT arm of the National Lung Screening Trial, percent low attenuation area (%LAA) was defined as the percentage of lung volume with voxels less than –950 Hounsfield units on the baseline examination. Multivariable Cox proportional hazards models, adjusting for competing risks where appropriate, were built to test for association between %LAA and lung cancer incidence, lung cancer mortality, and all-cause mortality with censoring at 6 years. In addition, multivariable logistic regression models were built to test the cross-sectional association between %LAA and airflow obstruction on spirometry, which was available in 2,700 participants. Results The median %LAA was 0.8% (interquartile range, 0.2%-2.7%). Every 1% increase in %LAA was independently associated with higher hazards of lung cancer incidence (hazard ratio [HR], 1.02; 95% CI, 1.01-1.03; P = .004), lung cancer mortality (HR, 1.02; 95% CI, 1.00-1.05; P = .045), and all-cause mortality (HR, 1.01; 95% CI, 1.00-1.03; P = .042). Among participants with spirometry, 892 had airflow obstruction. The likelihood of airflow obstruction increased with every 1% increase in %LAA (odds ratio, 1.07; 95% CI, 1.06-1.09; P 65 years. Interpretation Quantitative emphysema measured on LDCT imaging of the chest can be leveraged to improve lung cancer risk prediction and help diagnose COPD in individuals who currently or formerly smoked and are undergoing lung cancer screening.

Legionella pneumophila are host-adapted bacteria that infect and reproduce primarily in amoeboid protists. Using similar infection mechanisms, they infect human macrophages, and cause Legionnaires’ disease, an atypical pneumonia, and the milder Pontiac fever. We hypothesized that, despite these similarities, the hosts are different enough so that there exist high-selective value mutations that would dramatically increase the fitness of Legionella inside the human host. By comparing a large number of isolates from independent infections, we identified two genes, mutated in three unrelated patients, despite the short duration of the incubation period (2-14 days). One is a gene coding for an outer membrane protein (OMP) belonging to the OmpP1/FadL family. The clinical strain, carrying the mutated OMP homolog, grows faster in macrophages than the wild type strain, and thus appears to be better adapted to the human host. The other is a gene coding for a protein involved in cyclic-di-GMP regulation, which in turn modulates flagellar activity. As human-to-human transmission is very rare, fixation of these mutations into the population and spread into the environment is unlikely. Therefore, convergent evolution – here mutations in the same genes observed in independent human infections – could point to adaptations to the accidental human host. These results suggest that despite its ability to infect, replicate, and disperse from amoebae, L. pneumophila is not well adapted to the human host.Impact statementLegionella pneumophila is primarily infecting amoeboid protists, but occasionally infects human lung macrophages, causing Legionnaires’ disease, an atypical pneumonia. By comparing 171 isolates from patients to their probable environmental source, we identified 119 mutations that presumably occurred in-patient. Among these, several mutations occurred in the gene. In particular, two genes were mutated thrice, significantly more often than expected by chance alone, and are likely to represent adaptations to the human host. We experimentally show that, for one mutation at least, the mutated strain grows faster in human macrophages than in amoebae. By specifically investigating in-patient mutations, we were able to identify two genes that might be involved in human host-specific adaptations of L. pneumophila. This result suggests that L. pneumophila is not particularly well adapted to the human host, as mutations get fixed in-patient, during the short course of an infection (2-14 days), indicating a very high selective value.Data SummaryThe sequencing data generated in this study are available in the NCBI database under the BioProject accession number: PRJEB52976.

In chronic obstructive pulmonary disease (COPD) functional small airways disease (fSAD) has been identified as a transitional state between healthy lung and irremediable emphysema. Topological analysis of the CT-based parametric response map (PRM) spatially quantifies distribution and arrangement of fSAD and emphysema. We present a cross sectional analysis of topological PRM (tPRM) in 8,972 participants from the COPDGene study, covering a complete spectrum of COPD severity. We aimed to evaluate tPRM dynamics with respect to GOLD and test association of tPRM with pulmonary function using Spearman correlation and stepwise linear regression. Baseline CT and clinical data were included, and tPRM was computed as whole lung averages summarizing disease volume density, surface area, curvature and perforation (measured by Ⲭ). Strong correlation (ρ = -0.74, p < 0.001) was determined between degree of perforation in healthy lung (ⲬNorm) and fSAD regions (ⲬfSAD), transposing from predominantly healthy lung perforated with fSAD (GOLD 2, ⲬNorm = -0.84, ⲬfSAD = 0.47) to fSAD perforated with healthy lung (GOLD 4, ⲬNorm = 0.39, ⲬfSAD = -0.36). tPRM significantly (p < 0.05) contributed to regression modelling of FEV1/FVC (R2 = 0.71), where surface area of emphysema had the most notable effect (β = -0.49, p < 0.01). Thus, tPRM provided insight into topology of fSAD and emphysema in COPD and associated statistically with clinical lung function measures.

Longitudinal biomarker data are often collected in studies, providing important information regarding the probability of an outcome of interest occurring at a future time. With many new and evolving technologies for biomarker discovery, the number of biomarker measurements available for analysis of disease progression has increased dramatically. A large amount of data provides a more complete picture of a patient's disease progression, potentially allowing us to make more accurate and reliable predictions, but the magnitude of available data introduces challenges to most statistical analysts. Existing approaches suffer immensely from the curse of dimensionality. In this article, we propose methods for making dynamic risk predictions using repeatedly measured biomarkers of a large dimension, including cases when the number of biomarkers is close to the sample size. The proposed methods are computationally simple, yet sufficiently flexible to capture complex relationships between longitudinal biomarkers and potentially censored events times. The proposed approaches are evaluated by extensive simulation studies and are further illustrated by an application to a data set from the Nephrotic Syndrome Study Network.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Nitrogen transport from agriculture production fields raises the specter of environmental degradation of freshwater resources. Our objectives were to document and evaluate nitrate-N, ammonium-N, phosphorus and other nutrients emanating from a 40-ha controlled subsurface irrigation drainage technology coupled in series with a denitrification bioreactor. The intent of the denitrification bioreactor is to create an environment for anoxic microbial populations to support denitrification. We monitored the tile-drainage effluent and denitrification bioreactor water chemistry under a corn-soybean rotation to estimate the nutrient concentrations and the competence of the denitrification bioreactor to foster denitrification. Nitrate-N bearing tile drainage effluents ranged from less than 1.5 to 109 mg NO3- -N/L, with the nitrate concentration differences attributed primarily to the: 1) timing of nitrogen fertilization for corn, 2) soil mineralization and residue decomposition, and 3) intense rainfall events. The denitrification bioreactor was highly effective in reducing drainage water nitrate-N concentrations providing the rate of water flow through the denitrification bioreactor permitted sufficient time for equilibrium to be attained for the nitrate reduction reactions. The nitrate-N concentrations entering the denitrification bioreactor ranged from 0.4 to 103 mg NO3- -N/L in 2018, whereas the outlet nitrate concentrations typically ranged from 0.3 to 5.2 mg NO3- -N/L in 2018. Nitrate tile-drainage effluent concentrations in 2019 were marginal, given soybeans obtain nitrogen from biological nitrogen fixation. Nutrient uptake by corn reduced the soil nitrate leaching pool and created nitrogen-bearing biomass, features important for formulating best management practices.

Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6). Topological metrics were determined from each PRM classification and compared to structural and biological markers determined from microCT and histopathology of lung core samples. Whole-lung measurements of PRM-defined functional small airways disease (fSAD), which serves as a readout of BOS, were significantly elevated in BOS versus RAS patients (p = 0.01). At the core-level, PRM-defined parenchymal disease, a potential readout of RAS, was found to correlate to neutrophil and collagen I levels (p < 0.05). We demonstrate the relationship of structural and biological markers to the CT-based distribution and arrangement of PRM-derived readouts of BOS and RAS. ispartof: CELLS vol:11 issue:4 ispartof: location:Switzerland status: published

RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas

Cervicofacial infection (CFI) is a frequently encountered presentation to Oral and Maxillofacial Departments (OMFS). The United Kingdom has recently seen cessation of all routine community dental treatment due to the Coronavirus (COVID-19) pandemic and consequently an initial modification of treatment received in secondary care. Subsequent airway difficulties and the need for level 2 High Dependency Unit (HDU) or level 3 Intensive Care Unit (ICU) is a concern to surgeons and anaesthetists alike. The availability of skilled staff and appropriate facilities can be variable. It is imperative to understand the resource implications of CFI with respect to airway management and critical care utilisation. Adequate provision is fundamental for optimal care. A national, multicentre, trainee-led audit was carried out across 17 hospitals in the UK from May to September 2017. Information recorded included demographic features, presentation, airway management, medical and surgical treatment, and steroid administration. One thousand and two presentations (1002) were recorded. Forty-five percent were female, with a mean (range) age of 37.5 years (0-94). Regarding surgical airway management, 63.4% had a standard intubation (oral 42%, nasal 21.4%). Awake fibreoptic intubation (AFOI) was performed in 28% and surgical airway required in 0.9%. Impending airway compromise at the time of presentation was 1.7%. Following surgical incision and drainage, 96.1% of patients returned to a general ward, 2.7% to Level 3, and 1.1% to Level 2 care. The return to theatre was 2.8%, and 0.7% required reintubation. There was an association between corticosteroid administration and duration of intubation. Those who received steroids were more likely to remain intubated postoperatively (p = 0.006), require a higher level of postoperative care (p lt; 0.001), and require a return to theatre (p = 0.019). Postoperatively, patients who received steroids were less likely to be extubated at the close of the procedure. Intubated patients who received multiple steroid doses postoperatively were extubated with less frequency those that received a single dose. To our knowledge, this dataset is the largest ever recorded for CFI. Our results showed a high requirement for advanced airway management in this cohort. The requirement for surgical airway was low, but the significance of this situation should not be underestimated. The relatively frequent need for care at levels 2 or 3 within this cohort also placed a significant demand on already overburdened resources. Knowledge of care requirements for these patients will inform resource planning.

Background: The optimal polymyxin B dosage needed to achieve an efficacy target of 50-100 mg·h/L when treating multi-drug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. Methods: This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50-100 mg every 12 hours. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents, B1 and B2, were quantified using Liquid Chromatography Mass Spectrometry (LC-MS). Population PK (NONMEM® software) analysis was performed using pooled polymyxin B1+B2 concentrations. Results: Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21-57 years) and 58.0kg (range 38.3-70.4kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution, 2.09 L/hr and 12.7 L, respectively, corresponding to a 4.1 hour mean half-life (t1/2). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 hours was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients; acute kidney injury events in two patients. These events resolved within 2-4 days after discontinuing polymyxin B. Conclusions: Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.

SummaryStreptococcus suis is a leading cause of bacterial meningitis in SE Asia, with frequent zoonotic transfer to humans associated with close contact with pigs. A small number of invasive lineages are responsible for endemic infection in the swine industry causing considerable global economic losses. A lack of surveillance and a rising trend in clinical treatment failure has raised concerns of growing antimicrobial resistance (AMR) among invasive S. suis. The source-sink dynamics between healthy and disease isolates is poorly understood and, in this study, we sample and sequence a collection of isolates predominantly from healthy pigs in Chiang Mai province, Northern Thailand. Pangenome comparisons with a selection of invasive serotype 2 isolates identified increased genetic diversity and more frequent AMR carriage in isolates from healthy pigs. Multiple antimicrobial resistance genes were identified conferring resistance to aminoglycosides, lincosamides, tetracycline and macrolides. All isolates were non-susceptinle to three or more different antimicrobial classes, and 75% of non-serotype 2 isolates were non-susceptible to 6 or more classes (compared to 37.5% of serotype 2 isolates). Antimicrobial resistance genes were found on integrative and conjugative elements (ICE) previously observed in other species, suggesting mobile gene pool which can be accessed by invasive disease isolates.Significance statementThe zoonotic pathogen Streptococcus suis causes respiratory disease in pigs and is among the most common causative agents of human clinical bacterial meningitis in SE Asia. We collected isolates from farmed healthy pigs in Northern Thailand, representing a source population from which invasive isolates have recently emerged – linked to the pork production industry. Pangenome characterisation of the isolates revealed a reservoir of genetic diversity and antimicrobial resistance suggesting that One Health approaches may be beneficial in tackling the increase in antimicrobial resistance.