Search

Background: Intellectual conflicts of interest (COI), like financial COI, may threaten the validity and trustworthiness of clinical practice guidelines (CPGs). However, comparatively little is known about intellectual COI in CPGs. This study sought to estimate the prevalence of intellectual COI and corresponding management strategies among cardiology and pulmonology CPGs. Methods: We conducted a retrospective document review of CPGs published by cardiology or pulmonology professional societies from the United States, Canada, or Europe from 2018 to 2019 available via the Emergency Care Research Institute, Guidelines International Network, or Medscape databases. We assessed the percentage of authors with an intellectual COI, defined as i) authorship on a study reviewed by the CPG, ii) authorship of a prior editorial related to a CPG recommendation, or iii) authorship of a prior related CPG. Management strategies assessed included use of GRADE methodology, inclusion of a methodologist, and recusals due to intellectual COI. Outcomes were assessed overall and compared between cardiology and pulmonology CPGs. Results: Among the 39 CPGs identified (14 cardiology, 25 pulmonology), there were a total of 737 authors, of whom 473 (64%) had at least one intellectual COI. Among all CPGs, a median of 67% (Interquartile Range 50%-76%) of authors had at least one intellectual COI, and COI was more prevalent among cardiology compared with pulmonology CPGs (84% vs 57%, p<0.001). There was variable use of management strategies among the CPGs, including use of GRADE methodology (64% of CPGs), inclusion of a methodologist (49%), and recusals due to intellectual COI (0%). Conclusion: Intellectual conflicts of interest appear to be highly prevalent and under-reported among cardiology and pulmonology CPGs, which may threaten their validity. Greater attention to and improved management of intellectual COI by CPG-producing organizations is needed. [ABSTRACT FROM AUTHOR]

Objective: Macmoondongtang has been used as a traditional medicine to treat pulmonary disease in Korea. However, the mechanism underlying its therapeutic effect has yet to be reported. In the present study, the role of macmoondongtang as a respiratory medicine, especially as an anti-asthmatic agent, has been attributed to the down-regulation of interleukin (IL)-4 and tumor necrosis factor (TNF)-α. Materials & methods: BALB/c mice were divided into five groups: control, asthma-induced control, dexamethasone treatment, treatment with 150 mg/kg macmoondongtang, and treatment with 1500 mg/kg macmoondongtang. To evaluate the anti-asthmatic effect of macmoondongtang, we investigated its suppressive or inhibitory effects against typical asthmatic changes such as differential cell count in bronchioalveolar fluid (BALF), serum IgE levels, lung morphology, expression of Th1/Th2 cell transcription factors such as T-bet and GATA-3, and Th1-/Th2-/Th17-related cytokines such as interferon (IFN)-γ, IL-12p40, IL-4, -5, -13, TNF-α, and IL-6. The active ingredients in macmoondongtang were further analyzed. Results: Macmoondongtang treatment down-regulated serum IgE level, a very important marker of hyper-responsiveness. It reversed typical morphological changes such as mucous hypersecretion, lung epithelial cell hyperplasia, and inflammatory cell infiltration near bronchioalveolar space and veins. Macmoondongtang significantly decreased neutrophil count in BALF, as well as reduced T-bet, IFN-γ, and TNF-α expression in the lung. It also showed a dose-dependent control of inflammatory cells in BALF, controlled the expression of IL-12, IL-4, and IL-5 genes in the lung, and the protein expression of IL12p40, GATA-3, IL-4, IL-5, and IL-13. The component analysis revealed glycyrrhizin and liquiritin as the active ingredients. Conclusions: Macmoondongtang treatment alleviates asthma symptoms and modulate the Th1-/Th2- related cytokines. Glycyrrhizin and liquiritin could be the major the active therapeutic components. [ABSTRACT FROM AUTHOR]

The aim of our study was to compare early and long-term outcome of patients undergoing either on-pump or off-pump coronary artery bypass grafting with special focus on impairment of renal function. Five hundred ninety-three consecutive patients undergoing coronary artery bypass grafting were retrospectively analyzed. They were assigned either to on-pump (n = 281) or to off-pump (n = 312) group. Early and long-term outcomes were analyzed with special focus on renal function. Basic demographics and preoperative characteristics did not differ between groups (p>0.05) as well as postoperative renal parameters (p>0.05). Postoperative odds ratios (OR) of off-pump group in comparison to on-pump group were higher without reaching significance in terms of incidence of gastrointestinal complications and pneumonia (OR = 2.23 and 1.61, respectively) as well as hazard ratios (HR) on long-term follow-up for mortality and incidence of myocardial infarction (HR = 1.50 and 2.29, respectively). Kaplan-Meier estimation analysis also revealed similar results for both groups in terms of mid- and long-term survival (Breslow p = 0.062 and Log-Rank p = 0.064, respectively) and for incidence of myocardial infarction (Breslow p = 0.102 and Log-Rank p = 0.103, respectively). Our study suggests that use or not use of coronary artery bypass did not influence postoperative renal function. Odds of early outcomes were similar in both groups as well as incidence of myocardial infarction and mortality in long-term follow-up. [ABSTRACT FROM AUTHOR]

Background: Pancreatic islets are heavily vascularized in vivo yet lose this vasculature after only a few days in culture. Determining how to maintain islet vascularity in culture could lead to better outcomes in transplanting this tissue for the treatment of type 1 diabetes as well as provide insight into the complex communication between beta-cells and endothelial cells (ECs). We previously showed that islet ECs die in part due to limited diffusion of serum albumin into the tissue. We now aim to determine the impact of hypoxia on islet vascularization. Methods: We induced hypoxia in cultured mouse islets using the hypoxia mimetic cobalt chloride (100 μM CoCl2). We measured the impact on islet metabolism (two-photon NAD(P)H and Rh123 imaging) and function (insulin secretion and survival). We also measured the impact on hypoxia related transcripts (HIF-1α, VEGF-A, PDK-1, LDHA, COX4) and confirmed increased VEGF-A expression and secretion. Finally, we measured the vascularization of islets in static and flowing culture using PECAM-1 immunofluorescence. Results: CoCl2 did not induce significant changes in beta cell metabolism (NAD(P)H and Rh123), insulin secretion, and survival. Consistent with hypoxia induction, CoCl2 stimulated HIF-1α, PDK-1, and LDHA transcripts and also stimulated VEGF expression and secretion. We observed a modest switch to the less oxidative isoform of COX4 (isoform 1 to 2) and this switch was noted in the glucose-stimulated cytoplasmic NAD(P)H responses. EC morphology and survival were greater in CoCl2 treated islets compared to exogenous VEGF-A in both static (dish) and microfluidic flow culture. Conclusions: Hypoxia induction using CoCl2 had a positive effect on islet EC morphology and survival with limited impact on beta-cell metabolism, function, and survival. The EC response appears to be due to endogenous production and secretion of angiogenic factors (e.g. VEGF-A), and mechanistically independent from survival induced by serum albumin. [ABSTRACT FROM AUTHOR]

H3N2 canine influenza viruses are prevalent in Asian and North American countries. During circulation of the viruses in dogs, these viruses are occasionally transmitted to cats. If this canine virus causes an epidemic in cats too, sporadic infections may occur in humans because of the close contact between these companion animals and humans, possibly triggering an emergence of mutant viruses with a pandemic potential. In this study, we aimed to gain an insight into the mutations responsible for inter-species transmission of H3N2 virus from dogs to cats. We found that feline CRFK cell-adapted viruses acquired several mutations in multiple genome segments. Among them, HA1-K299R, HA2-T107I, NA-L35R, and M2-W41C mutations individually increased virus growth in CRFK cells. With a combination of these mutations, virus growth further increased not only in CRFK cells but also in other feline fcwf-4 cells. Both HA1-K299R and HA2-T107I mutations increased thermal resistance of the viruses. In addition, HA2-T107I increased the pH requirement for membrane fusion. These findings suggest that the mutations, especially the two HA mutations, identified in this study, might be responsible for adaptation of H3N2 canine influenza viruses in cats. [ABSTRACT FROM AUTHOR]

Hypoxia and angiogenesis are critical components in the progression of solid cancer, including gastric cancers (GCs). miR-382 has been identified as a hypoxia-induced miR (hypoxamiR), but the clinical significance in GCs has not been identified yet. To explore the clinical and prognostic importance of miR-382 in GCs, the surgical specimens of 398 patients with GCs in KNU hospital in Korea, the total of 183 patients was randomly selected using simple sampling methods and big data with 446 GCs and 45 normal tissues from the data portal () were analysed. Expression of miR-382 as well as miR-210, as a positive control hypoxamiR by qRT-PCR in histologically malignant region of GCs showed significantly positive correlation (R = 0.516, p<0.001). High miR-210 and miR-382 expression was significantly correlated with unfavorable prognosis including advanced GCs (AGC), higher T category, N category, pathologic TNM stage, lymphovascular invasion, venous invasion, and perinueral invasion, respectively (all p<0.05). In univariate analysis, high miR-210 expression was significantly associated with worse overall survival (OS) (p = 0.036) but not high miR-382. In paired 60 gastric normal and cancer tissues, miR-382 expression in cancer tissues was significantly higher than normal counterpart (p = 0.003), but not miR-210 expression. However, by increasing the patient number from the big data analysis, miR-210 as well as miR-382 expression in tumor tissues was significantly higher than the normal tissues. Our results suggest that miR-382, as novel hypoxamiR, can be a prognostic marker for advanced GCs and might be correlated with metastatic potential. miR-382 might play important roles in the aggressiveness, progression and prognosis of GCs. In addition, miR-382 give a predictive marker for progression of GCs compared to the normal or preneoplastic lesion. [ABSTRACT FROM AUTHOR]

Sepsis can be caused by malaria infection, but little is known about the utility of the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) and SOFA score in malaria. We conducted a prospective observational study from March 2013 to February 2017 to examine adults admitted with community-acquired infection in a tertiary-care hospital in Ubon Ratchathani, Northeast Thailand (Ubon-sepsis). Subjects were classified as having sepsis if they had a modified SOFA score ≥2 within 24 hours of admission. Serum was stored and later tested for malaria parasites using a nested PCR assay. Presence of severe malaria was defined using modified World Health Organization criteria. Of 4,989 patients enrolled, 153 patients (3%) were PCR positive for either Plasmodium falciparum (74 [48%]), P. vivax (69 [45%]), or both organisms (10 [7%]). Of 153 malaria patients, 80 were severe malaria patients presenting with sepsis, 70 were non-severe malaria patients presenting with sepsis, and three were non-severe malaria patients presenting without sepsis. The modified SOFA score (median 5; IQR 4–6; range 1–18) was strongly correlated with malaria severity determined by the number of World Health Organization severity criteria satisfied by the patient (Spearman’s rho = 0.61, p<0.001). Of 80 severe malaria patients, 2 (2.5%), 11 (14%), 62 (77.5%) and 5 (6%), presented with qSOFA scores of 0, 1, 2 and 3, respectively. Twenty eight-day mortality was 1.3% (2/153). In conclusion, qSOFA and SOFA can serve as markers of disease severity in adults with malarial sepsis. Patients presenting with a qSOFA score of 1 may also require careful evaluation for sepsis; including diagnosis of cause of infection, initiation of medical intervention, and consideration for referral as appropriate. [ABSTRACT FROM AUTHOR]

Background: People with advanced cancer experience multiple symptoms during their illness trajectory, which can fluctuate in intensity. Aim: To describe the course of self-reported quality of life, emotional functioning, physical functioning and symptom intensity over time in cancer patients receiving palliative care. Design: Longitudinal study with monthly assessments, using the EORTC QLQ-C15-PAL. Data were analysed (1) prospectively, from baseline to ≥8-month follow-up; and (2) retrospectively, by taking death as index date and comparing results from three cross-sectional subsamples at different stages of illness (time to death ≥6, 5–3 and 2–0 months). Linear mixed models were calculated. Setting/participants: A total of 1739 patients (mean age 66, 50% male) from 30 palliative care centers in 12 countries were included. Results: In prospective analyses, quality of life, functioning and symptoms–except nausea/vomiting–remained generally stable over time. In retrospective analyses, patients 2–0 months before death reported significantly lower quality of life and physical functioning scores than those 5–3 months before death, who in turn scored lower than those ≥6 months before death, suggesting progressive decline. Emotional functioning remained initially unchanged, but decreased in the last months. Pain, fatigue and appetite loss showed a stable increase in intensity towards death. Dyspnea, insomnia and constipation increased from 5–3 to 2–0 months before death. Nausea/vomiting only increased when comparing those ≥6 months before death with those 2–0 months before death. Conclusion: While the prospective approach showed predominantly stable patterns for quality of life, functioning and symptom severity throughout study duration, retrospective analyses indicated that deterioration was already apparent before the terminal phase and accelerated close to death. Our findings support the importance of early symptom identification and treatment in this population, and highlight the need for further studies to explore what characterizes those with either lower or higher symptom burden at different time points towards death. [ABSTRACT FROM AUTHOR]

Background: Understanding the cardiorespiratory factors related to the increase in oxygen consumption () during exercise is essential for improving cardiorespiratory fitness in individuals with stroke. However, cardiorespiratory factors related to the increase in during exercise in these individuals have not been examined using multivariate analysis. This study aimed to identify cardiorespiratory factors related to the increase in during a graded exercise in terms of respiratory function, cardiac function, and the ability of skeletal muscles to extract oxygen. Methods: Eighteen individuals with stroke (aged 60.1 ± 9.4 years, 67.1 ± 30.8 days poststroke) underwent a graded exercise test for the assessment of cardiorespiratory response to exercise. The increases in from rest to first threshold and that from rest to peak exercise were measured as a dependent variable. The increases in respiratory rate, tidal volume, minute ventilation, heart rate, stroke volume, cardiac output, and arterial-venous oxygen difference from rest to first threshold and those from rest to peak exercise were measured as the independent variables. Results: From rest to first threshold, the increases in arterial-venous oxygen difference (β = 0.711) and cardiac output (β = 0.572) were significant independent variables for the increase in (adjusted R2 = 0.877 p < 0.001). Similarly, from rest to peak exercise, the increases in arterial-venous oxygen difference (β = 0.665) and cardiac output (β = 0.636) were significant factors related to the increase in (adjusted R2 = 0.923, p < 0.001). Conclusion: Our results suggest that the ability of skeletal muscle to extract oxygen is a major cardiorespiratory factor related to the increase in during exercise testing in individuals with stroke. For improved cardiorespiratory fitness in individuals with stroke, the amount of functional muscle mass during exercise may need to be increased. [ABSTRACT FROM AUTHOR]

Mycoplasma hyorhinis (MHR) and Mycoplasma hyosynoviae (MHS) are common opportunistic pathogens in the upper respiratory tract and tonsils of swine. The identification of the specific species involved in clinical cases using conventional diagnostic methods is challenging. Therefore, a recombinant chimeric polypeptide based on the seven known variable lipoproteins (A-G) specific of MHR and a cocktail of surface proteins detergent-extracted from MHS cultures were generated and their suitability as antemortem biomarkers for serodiagnosis of MHR- and MHS-infection were evaluated by ELISA. M. hyorhinis and MHS ELISA performance, evaluated using serum samples collected over a 56-day observation period from pigs inoculated with MHR, MHS, M. hyopneumoniae, M. flocculare, or Friis medium, varied by assay, targeted antibody isotype, and cutoffs. The progressions of MHR and MHS clinical diseases were evaluated in relation to the kinetics of the isotype-specific antibody response in serum and bacterial shedding in oral fluids during the observation period. In pigs inoculated with MHR, bacterial DNA was detected in one or more of the 5 pens at all sampling points throughout the study, IgA was first detected at DPI 7, one week before the first clinical signs, with both IgA and IgG detected in all samples collected after DPI 14. The peak of MHS shedding (DPI 8) coincided with the onset of the clinical signs, with both IgA and IgG detected in all serum samples collected ≥ DPI 14. This study demonstrated, under experimental conditions, that both ELISAs were suitable for early detection of specific antibodies against MHR or MHS. The diagnostic performance of the MHR and MHS ELISAs varied depending on the selected cutoff and the antibody isotype evaluated. The high diagnostic and analytical specificity of the ELISAs was particularly remarkable. This study also provides insights into the infection dynamics of MHR-associated disease and MHS-associated arthritis not previously described. [ABSTRACT FROM AUTHOR]

Two novel and related pathogenic variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene were structurally and functionally characterized. These alterations have not been previously described in literature. Two patients with diagnosis of Cystic Fibrosis (CF) based on the presence of one mutated allele, p.Phe508del, pathological sweat test and clinical symptoms were studied. To complete the genotypes of both patients, an extensive genetic and functional analysis of the CFTR gene was performed. Extensive genetic characterization confirmed the presence of p.Phe508del pathogenic variant and revealed, in both patients, the presence of an insertion of part of intron 10 in intron 9 of the CFTR gene, within the (TG)m repeat, with a variable poly-T stretch. The molecular lesions resulted to be very similar in both patients, with only a difference in the number of T in the poly-T stretch. The functional characterization at RNA level revealed a complete anomalous splicing, without exon 10, from the allele with the insertion of both patients. Consequently, the alleles with the insertions are expected not to contribute to the formation of a functional CFTR protein. Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene. This also allowed the completion of the genetic characterization of both patients. [ABSTRACT FROM AUTHOR]

Introduction: Use of tobacco and its products are the single most preventable cause of death in the world. The objective of this study was to determine the prevalence of current tobacco use and identify associated factors among Rwandans aged 15–34 years. Methods: This study involved secondary analysis of existing data from the nationally representative WHO STEPwise approach to Surveillance of non-communicable diseases (STEPS) conducted in 2013 to explore the prevalence of tobacco use and its associated factors in Rwanda. Data of 3,900 youth participants (15–34 years old) who had been selected using multistage cluster sampling during the survey was analyzed. The prevalence of current smoking along with socio-demographic characteristics of the sample were determined and multivariable logistic regression was employed to identify independent factors associated with current tobacco use. Results: The prevalence (weighted) of current tobacco use (all forms) was 8% (95%CI: 7.08–9.01). The prevalence was found to be significantly higher among males, young adults aged 24–34, youth with primary school education or less, those from Southern province, people with income (work in public, private organizations and self-employed) and young married adults. However, geographical location i.e. urban (7%) and rural (8%) settings did not affect prevalence of tobacco use. Factors that were found to be associated with current tobacco use through the multivariate analysis included being male, aged 25 years and above, having an income, and residing in Eastern, Kigali City and Southern Province compared to Western province. Conclusion: The association between smoking and socio-demographic characteristics among Rwandan youth identified in this study provides an opportunity for policy makers to tailor future tobacco control policies, and implement coordinated, high-impact interventions to prevent initiation of tobacco use among the youth. [ABSTRACT FROM AUTHOR]

Influenza virus causes a heterogeneous respiratory infectious disease ranging from self-limiting symptoms to non-resolving pathology in the lungs. Worldwide, seasonal influenza infections claim ~500,000 lives annually. Recent reports describe pathologic pulmonary sequelae that result in remodeling the architecture of lung parenchyma following respiratory infections. These dysfunctional recovery processes that disproportionately impact the elderly have been understudied. Macrophages are involved in tissue remodeling and are critical for survival of severe influenza infection. Here, we found intrinsic deficiency of the nuclear receptor PPAR-γ in myeloid cells delayed the resolution of pulmonary inflammation following influenza infection. Mice with myeloid cell-specific PPAR-γ deficiency subsequently presented with increased influenza-induced deposition of pulmonary collagen compared to control mice. This dysfunctional lung remodeling was progressive and sustained for at least 3 months following infection of mice with myeloid PPAR-γ deficiency. These progressive changes were accompanied by a pro-fibrotic gene signature from lung macrophages and preceded by deficiencies in activation of genes involved with damage repair. Importantly similar aberrant gene expression patterns were also found in a secondary analysis of a study where macrophages were isolated from patients with fibrotic interstitial lung disease. Quite unexpectedly, mice with PPAR-γ deficient macrophages were more resistant to bleomycin-induced weight loss whereas extracellular matrix deposition was unaffected compared to controls. Therefore PPAR-γ expression in macrophages may be a pathogen-specific limiter of organ recovery rather than a ubiquitous effector pathway in response to generic damage. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment is a common systemic manifestation of chronic obstructive pulmonary disease (COPD). However, its pathophysiological origins are not understood. Since, cognitive function relies on efficient communication between distributed cortical and subcortical regions, we investigated whether people with COPD have disruption in white matter connectivity. Methods: Structural networks were constructed for 30 COPD patients (aged 54–84 years, 57% male, FEV1 52.5% pred.) and 23 controls (aged 51–81 years, 48% Male). Networks comprised 90 grey matter regions (nodes) interconnected by white mater fibre tracts traced using deterministic tractography (edges). Edges were weighted by the number of streamlines adjusted for a) streamline length and b) end-node volume. White matter connectivity was quantified using global and nodal graph metrics which characterised the networks connection density, connection strength, segregation, integration, nodal influence and small-worldness. Between-group differences in white matter connectivity and within-group associations with cognitive function and disease severity were tested. Results: COPD patients’ brain networks had significantly lower global connection strength (p = 0.03) and connection density (p = 0.04). There was a trend towards COPD patients having a reduction in nodal connection density and connection strength across the majority of network nodes but this only reached significance for connection density in the right superior temporal gyrus (p = 0.02) and did not survive correction for end-node volume. There were no other significant global or nodal network differences or within-group associations with disease severity or cognitive function. Conclusion: COPD brain networks show evidence of damage compared to controls with a reduced number and strength of connections. This loss of connectivity was not sufficient to disrupt the overall efficiency of network organisation, suggesting that it has redundant capacity that makes it resilient to damage, which may explain why cognitive dysfunction is not severe. This might also explain why no direct relationships could be found with cognitive measures. Smoking and hypertension are known to have deleterious effects on the brain. These confounding effects could not be excluded. [ABSTRACT FROM AUTHOR]

There was a pandemic of influenza A (H1N1) in 2009; in Korea, there was also an H1N1 epidemic in 2016. We aim to investigate whether survival had improved in the setting of recent advances in intensive care unit (ICU) management. We conducted a retrospective analysis of acute respiratory failure patients with H1N1 influenza pneumonia in 2016 and 2009 respectively at two tertiary referral hospitals in Korea. A total of 28 patients were treated in 2016, and 34 in 2009. There was no significant difference in SOFA scores on ICU admission day. In-hospital mortality was significantly lower in patients of 2016 compared to those of 2009 (18% vs. 44% P = 0.028). By multivariable analyses, the treatment year 2016 was associated with a greater likelihood of survival. Compared to the patients treated in 2009, those treated in 2016 were one seventh as likely to die after adjusting for other clinical variables (hazard ratio for mortality, 0.15; 95% confidence interval. 0.03–0.63, P = 0.010). Improved survival in patients who underwent extracorporeal membrane oxygenation treatment (in-hospital mortality, 17% vs. 60%, P = 0.242) and decreased tidal volumes during mechanical ventilation (median 5.4 mL/kg vs. median 9.2 mL/kg, P = 0.018) were observed in 2016 compared to 2009. Treatment outcomes for patients with H1N1 acute respiratory failure improved from 2009 to 2016 in two tertiary referral centers in South Korea. [ABSTRACT FROM AUTHOR]

Background: COPD is a common HIV comorbidity, and HIV-infected individuals have a higher incidence and earlier onset of COPD compared to HIV-uninfected individuals. While the pathogenesis of HIV-associated COPD is largely unknown, chronic inflammation may contribute. Four pneumoproteins known to be markers of lung injury and inflammation have been associated with COPD in HIV-uninfected individuals: PARC/CCL-18, SP-D, CC-16, and sRAGE. Objective: To determine whether these pneumoproteins are also associated with pulmonary function and COPD Assessment Test (CAT) scores in HIV-infected individuals. Methods: Associations between plasma pneumoprotein levels and pulmonary function were determined in a cross-sectional study of otherwise healthy HIV-infected individuals enrolled between September 2016 and June 2017. Covariates included HIV-associated (antiretroviral therapy, CD4 count, and viral load) and COPD-associated (smoking and BMI) covariates. Results: Among 65 participants, 78.5% were male, 50.8% had undetectable viral load, and 76.9% were ever-smokers. Mean post-bronchodilator FEV1/FVC was 0.71, and mean DLco%predicted was 61%. Higher PARC/CCL-18 was associated with lower DLco%predicted and higher CAT score. Higher CC-16 was associated with lower DLco%predicted and lower FVC%predicted. Conclusions: This exploratory analysis is the first to characterize associations between these four pneumoproteins and pulmonary function in an HIV-infected cohort. Our findings suggest the pathogenesis of HIV-associated COPD may differ from that of non-HIV-associated COPD due to HIV-specific inflammatory changes affecting DLco. PARC/CCL-18 is associated with structural and functional pulmonary abnormalities and may be an important COPD biomarker candidate in HIV infection. Our study is a preliminary step toward finding clinically relevant COPD biomarkers in high-risk populations. [ABSTRACT FROM AUTHOR]

Introduction: In critically ill patients undergoing prolonged mechanical ventilation (MV), the difference in long-term outcomes between patients with or without tracheostomy remains unexplored. Methods: Ancillary study of a prospective international multicentre observational cohort in 21 centres in France and Belgium, including 2087 patients, with a one-year follow-up after admission. We included patients with a MV duration ≥10 days, with or without tracheostomy. We explored the one-year mortality with a classical Cox regression model (adjustment on age, SAPS II, baseline diagnosis and withdrawal of life-sustaining therapies) and a Cox regression model using tracheostomy as a time-dependant variable. Results: 29.5% patients underwent prolonged MV, out of which 25.6% received tracheostomy and 74.4% did not. At one-year, 45.2% patients had died in the tracheostomy group and 51.5% patients had died in the group without tracheostomy (p = 0.001). In the Cox-adjusted regression model, tracheostomy was not associated with improved one-year outcome (HR CI95 0.7 [0.5–1.001], p = 0.051), as well as in the model using tracheostomy as a time-dependent variable (OR CI 95 1 [0.7–1.4], p = 0.9). Conclusions: In our study, there was no statistically significant difference in the one-year mortality of patients undergoing prolonged MV when receiving tracheostomy or not. Trial registration: [ABSTRACT FROM AUTHOR]

Background: The long-term outcomes of artificial nutrition in older people with dysphagia remain uncertain. Enteral nutrition via percutaneous endoscopic gastrostomy (PEG) is one of the major methods of artificial nutrition. Enteral feeding is indicated for patients with a functional gastrointestinal tract. However, total parenteral nutrition (TPN) is often inappropriately chosen for artificial nutrition in Japan, even in patients with a functional gastrointestinal tract, as PEG has recently been viewed as an unnecessary life-prolonging treatment in Japan. This study aimed to compare the long-term outcomes between PEG and TPN. Methods: This single-center retrospective cohort study investigated long-term outcomes in older patients with dysphagia who received PEG or TPN between January 2014 and January 2017. The primary outcome was survival time. Secondary outcomes were oral intake recovery, discharge to home, and the incidence of severe pneumonia and sepsis. We performed 1-to-1 propensity score matching using a 0.05 caliper. The Kaplan–Meier method, log-rank test, and Cox regression analysis were used to compare the survival time between groups. Results: We identified 253 patients who received PEG (n = 180) or TPN (n = 73). Older patients, those with lower nutritional states, and severe dementia were more likely to receive TPN. Propensity score matching created 55 pairs. Survival time was significantly longer in the PEG group (median, 317 vs 195 days; P = 0.017). The hazard ratio for PEG relative to TPN was 0.60 (95% confidence interval: 0.39–0.92; P = 0.019). There were no significant differences between the groups in oral intake recovery and discharge to home. The incidence of severe pneumonia was significantly higher in the PEG group (50.9% vs 25.5%, P = 0.010), whereas sepsis was significantly higher in the TPN group (10.9% vs 30.9%, P = 0.018). Conclusions: PEG was associated with a significantly longer survival time, a higher incidence of severe pneumonia, and a lower incidence of sepsis compared with TPN. [ABSTRACT FROM AUTHOR]

Background: Pulmonary embolism (PE) is correlated with increased mortality among patients with lung cancer (LC). The characteristics of patients with LC presenting with PE have not been fully established, and our meta-analysis aims to comprehensively investigate the clinical characteristics associated with PE in patients with LC to help physicians identify PE earlier in these patients. Methods: Multiple databases were searched, including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure and Wanfang. Odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were used as effect measures for dichotomous and continuous variables, respectively. Moreover, Egger’s test, Begg’s test and a sensitivity analysis were performed to assess the publication bias and reliability of the articles. Results: In total, 16 studies were included in our meta-analysis. The results indicated that history of chronic obstructive pulmonary disease (OR = 2.59, 95% CI: 1.09, 6.15; P = 0.03), adenocarcinoma (OR = 2.28, 95% CI: 1.88, 2.77; P < 0.01), advanced tumour stage (TNM III-IV vs. I-II, OR = 2.38, 95% CI: 1.99, 2.86; P < 0.01), history of central venous catheter (OR = 1.95, 95% CI: 1.36, 2.78; P < 0.01), history of chemotherapy (OR = 2.32, 95% CI: 1.80, 2.99, P < 0.01), high levels of D-dimer (WMD = 4.31, 95% CI: 2.53, 6.10; P < 0.01) and carcinoembryonic antigen (WMD = 10.30, 95% CI: 9.95, 10.64; P < 0.01) and a low level of partial pressure of oxygen (WMD = -25.97, 95% CI: -31.31, -20.62; P < 0.01) were clinical features of LC patients with PE compared to those without PE. Conclusions: These results reveal that LC patients with PE have specific clinical features, including but not limited to several cancer- and treatment-related factors, that may help their early identification. [ABSTRACT FROM AUTHOR]

Observational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia. Data were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature. Of 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. Crude 30-day mortality was 3.5% (9/257) and 10.9% (107/986) in the de-escalation and continuation groups, respectively. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.39 (95%CI: 0.19–0.79). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.56 (95%CI: 0.27–1.12) to 1.04 (95%CI: 0.49–2.23), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. This study suggests the effect of de-escalation on mortality needs further well-designed prospective research to determine effect size more accurately. [ABSTRACT FROM AUTHOR]

Genome-wide association study (GWAS) loci for several immunity-mediated diseases (early onset asthma, inflammatory bowel disease (IBD), primary biliary cholangitis, and rheumatoid arthritis) map to chromosomal region 17q12-q21. The predominant view is that association between 17q12-q21 alleles and increased risk of developing asthma or IBD is due to regulatory variants. ORM sphingolipid biosynthesis regulator (ORMDL3) residing in this region is the most promising gene candidate for explaining association with disease. However, the relationship between 17q12-q21 alleles and disease is complex suggesting contributions from other factors, such as trans-acting genetic and environmental modifiers or circadian rhythms. Circadian rhythms regulate expression levels of thousands of genes and their dysregulation is implicated in the etiology of several common chronic inflammatory diseases. However, their role in the regulation of the 17q12-q21 genes has not been investigated. Moreover, the core clock gene nuclear receptor subfamily 1, group D, member 1 (NR1D1) resides about 200 kb distal to the GWAS region. We hypothesized that circadian rhythms influenced gene expression levels in 17q12-q21 region and conversely, regulatory elements in this region influenced transcription of the core clock gene NR1D1 in cis. To test these hypotheses, we examined the diurnal expression profiles of zona pellucida binding protein 2 (ZPBP2/Zpbp2), gasdermin B (GSDMB), and ORMDL3/Ormdl3 in human and mouse tissues and analyzed the impact of genetic variation in the ZPBP2/Zpbp2 region on NR1D1/Nr1d1 expression. We found that Ormdl3 and Zpbp2 were controlled by the circadian clock in a tissue-specific fashion. We also report that deletion of the Zpbp2 region altered the expression profile of Nr1d1 in lungs and ileum in a time-dependent manner. In liver, the deletion was associated with enhanced expression of Ormdl3. We provide the first evidence that disease-associated genes Zpbp2 and Ormdl3 are regulated by circadian rhythms and the Zpbp2 region influences expression of the core clock gene Nr1d1. [ABSTRACT FROM AUTHOR]

The alteration of the microbial community in the upper respiratory tract (URT) can contribute to the colonization and invasion of respiratory pathogens. However, there are no studies regarding whether the characteristics of the URT microbiota can be affected by infections in lower respiratory tract (LRT). To elucidate the microbial profiles of the URT during pneumonia, the oral, nasal, and lung microbiota was evaluated at the early phase in a murine pneumonia model by direct intratracheal inoculation of Klebsiella pneumoniae. The meta 16S rRNA sequencing of bronchoalveolar lavage fluid after K. pneumoniae inoculation presented alterations in the beta diversity of the microbes, but not in the alpha diversity. At this point, a significant increase in microbial alpha diversity was observed in the oral cavity, but not in the nasal cavity. The significant increase was observed in the family Carnobacteriaceae and family Enterococcaceae. These results suggest that characterizing the microbial community of the respiratory tract may not just involve a simple downstream relationship from the URT to the LRT. The health status of the LRT may influence the oral microbiota. Thus, evaluation of the oral microbiota may contribute towards monitoring lung health; the oral microbiota may act as a diagnostic marker of pneumonia. [ABSTRACT FROM AUTHOR]

Purpose: Respiratory variations in pulse pressure (dPP) and photoplethysmographic waveform amplitude (dPOP) are used for evaluation of volume status in mechanically ventilated patients. Amplification of intrathoracic pressure changes may enable their use also during spontaneous breathing. We investigated the association between the degree of hypovolemia and dPP and dPOP at different levels of two commonly applied clinical interventions; positive expiratory pressure (PEP) and continuous positive airway pressure (CPAP). Methods: 20 healthy volunteers were exposed to progressive hypovolemia by lower body negative pressure (LBNP). PEP of 0 (baseline), 5 and 10 cmH2O was applied by an expiratory resistor and CPAP of 0 (baseline), 5 and 10 cmH2O by a facemask. dPP was obtained non-invasively with the volume clamp method and dPOP from a pulse oximeter. Central venous pressure was measured in 10 subjects. Associations between changes were examined using linear mixed-effects regression models. Results: dPP increased with progressive LBNP at all levels of PEP and CPAP. The LBNP-induced increase in dPP was amplified by PEP 10 cmH20. dPOP increased with progressive LBNP during PEP 5 and PEP 10, and during all levels of CPAP. There was no additional effect of the level of PEP or CPAP on dPOP. Progressive hypovolemia and increasing levels of PEP were reflected by increasing respiratory variations in CVP. Conclusion: dPP and dPOP reflected progressive hypovolemia in spontaneously breathing healthy volunteers during PEP and CPAP. An increase in PEP from baseline to 10 cmH2O augmented the increase in dPP, but not in dPOP. [ABSTRACT FROM AUTHOR]

Background: Knowledge of antibiotic prescription practices in low- and middle-income countries is limited due to a lack of adequate surveillance systems. Objective: To assess the prescription of antibiotics for the treatment of acute respiratory tract infections (ARIs) in primary care. Method: An explanatory sequential mixed-methods study was conducted in 4 private not-for-profit outreach clinics located in slum areas in Nairobi, Kenya. Claims data of patients who received healthcare between April 1 and December 27, 2016 were collected in real-time through a mobile telephone-based healthcare data and payment exchange platform (branded as M-TIBA). These data were used to calculate the percentage of ARIs for which antibiotics were prescribed. In-depth interviews were conducted among 12 clinicians and 17 patients to explain the quantitative results. Results: A total of 49,098 individuals were registered onto the platform, which allowed them to access healthcare at the study clinics through M-TIBA. For 36,210 clinic visits by 21,913 patients, 45,706 diagnoses and 85,484 medication prescriptions were recorded. ARIs were the most common diagnoses (17,739; 38.8%), and antibiotics were the most frequently prescribed medications (21,870; 25.6%). For 78.5% (95% CI: 77.9%, 79.1%) of ARI diagnoses, antibiotics were prescribed, most commonly amoxicillin (45%; 95% CI: 44.1%, 45.8%). These relatively high levels of prescription were explained by high patient load, clinician and patient perceptions that clinicians should prescribe, lack of access to laboratory tests, offloading near-expiry drugs, absence of policy and surveillance, and the use of treatment guidelines that are not up-to-date. Clinicians in contrast reported to strictly follow the Kenyan treatment guidelines. Conclusion: This study showed successful quantification of antibiotic prescription and the prescribing pattern using real-world data collected through M-TIBA in private not-for-profit clinics in Nairobi. [ABSTRACT FROM AUTHOR]

Background: Accurate prognostic evaluation is a key factor in the clinical management of patients affected by severe acute brain injury (ABI) and helps planning focused therapies, better caregiver’s support and allocation of resources. Aim of the study was to assess factors independently associated with both the short and long-term outcomes after rehabilitation in patients affected by ABI in the setting of a single Rehabilitation Unit specifically allocated to these patients. Methods and findings: In all patients (567) with age ≥ 18 years discharged from the Unit in the period 2006/2015 demographic, etiologic, comorbidity indicators, and descriptors of the disability burden (at hospital admission and discharge) were evaluated as potential prognostic factors of both short-term (4 classes of disability status at discharge) and long-term (mortality) outcomes. A comprehensive analytical method was adopted to combine several tasks. Select the factors with a significant independent association with the outcome, assess the relative weights and the “stability” (by bootstrap resampling) of them and estimate the role of the prognostic models in the clinical framework considering “cost” and “benefits”. The generalized ordered logistic model for ordinal dependent variables was used for the short-term outcome while the Cox proportional hazard model was used for the long-term outcome. The final short-term model identified 7 factors that independently account for 37% of the outcome variability as shown by pseudo R2 (pR2) = 0.37. The disability status descriptors show the strongest association since they account for more than 60% of the pR2, followed by age (14.8%), the presence of percutaneous endoscopic gastrostomy or nasogastric intubation (14.4%), a longer stay in the acute ward (5.9%) and concomitant coronary disease (1.3%). The final multivariable Cox model identified 4 factors that independently account for 52% of the outcome variability (R2 = 0.52). The disability extent and the disability recovered lead the long-term mortality since they account for the 53% of the global R2. The relevant effect of age (42%) is appreciable only after 2 years given the significant interaction with time. A longer stay in the acute ward explains the remaining fraction (5%). Considering ‘cost and benefits’, the decision curve analysis shows that the clinical benefit achieved by using both prognostic models is greater than the other possible action strategies, namely ‘treat all’ and ‘treat none. Several less obvious characteristics of the prognostic models are appreciated by integrating the results of multiple analytical methods. Conclusion: The comprehensive analytical tool aimed to integrate statistical significance, weight, “stability” and clinical “net” benefit, gives back a prognostic framework explaining a relevant portion of both outcomes’ variability in which the strong association of the disability status with both outcomes is comparable to and followed by a time modulated role of age. Our data do not support a differentiated association of traumatic vs non-traumatic etiology. The results encourage the use of integrated approach to analyze cohort data. [ABSTRACT FROM AUTHOR]

Objective: A clinical decision support system (CDSS) for empirical antibiotic treatment has the potential to increase appropriate antibiotic use. Before using such a system on a broad scale, it needs to be tailored to the users preferred way of working. We have developed a CDSS for empirical antibiotic treatment in hospitalized adult patients. Here we determined in a usability study if the developed CDSS needed changes. Methods: Four prespecified patient cases, based on real life clinical scenarios, were evaluated by 8 medical residents in the study. The “think-aloud” method was used, and sessions were recorded and analyzed afterwards. Usability was assessed by 3 evaluators using an augmented classification scheme, which combines the User Action Framework with severity rating of the usability problems and the assessment of the potential impact of these problems on the final task outcomes. Results: In total 51 usability problems were identified, which could be grouped into 29 different categories. Most (n = 17/29) of the usability problems were cosmetic problems or minor problems. Eighteen (out of 29) of the usability categories could have an ordering error as a result. Classification of the problems showed that some of the problems would get a low priority based on their severity rating, but got a high priority for their impact on the task outcome. This effectively provided information to prioritize system redesign efforts. Conclusion: Usability studies improve lay-out and functionality of a CDSS for empirical antibiotic treatment, even after development by a multidisciplinary system. [ABSTRACT FROM AUTHOR]

Background: The duration of antidepressant use affects the treatment of depression. Using the National Health Insurance database, which covers almost the entire national population, we verified the factors associated with the inadequate short-term use of initially prescribed antidepressants and their effects on the relapse and recurrence of depressive episodes. Methods: There were 752,190 patients included who had been newly prescribed antidepressants in 2012 with the diagnosis of depressive disorder. They were followed-up until December 31, 2015. They were classified as short-term and long-term antidepressant users depending on whether they used a specific initial antidepressant for at least four weeks. Sociodemographic, clinical, and medical utilization factors affecting the duration of antidepressant use were investigated. We also identified whether the duration of antidepressant use affected the risk of relapse and recurrence, which was defined by the restarting of antidepressants. Results: Initial antidepressants were taken for less than 28 days by 458,057 (60.84%) patients. Tricyclic antidepressants were used as the initial antidepressant more frequently than selective serotonin reuptake inhibitors (64.5% versus 19.3%). The type of initial antidepressant, polypharmacy, psychiatric and medical comorbidities, type of insurance coverage, and type of medical institution visited were associated with short-term use. Short-term use marginally increased the risk of relapse and recurrence of depressive episodes (Hazard ratio: 1.06, 95% confidence intervals 1.048–1.075). Conclusions: Short-term antidepressant use is widespread in Korea, and assessment in various aspects are necessary to set proper treatment plans. [ABSTRACT FROM AUTHOR]

Background: Pleural fluid homocysteine (HCY) can be useful for diagnosis of malignant pleural effusion (MPE). There are no published studies comparing the diagnostic accuracy of HCY with other tumour markers in pleural fluid for diagnosis of MPE. The aim was to compare the accuracy of HCY with that of carcinoembryonic antigen (CEA), cancer antigen (CA) 15.3, CA19.9 and CA125 in pleural fluid and to develop a probabilistic model using these biomarkers to differentiate benign (BPE) from MPE. Methods: Patients with pleural effusion were randomly included. HCY, CEA, CA15.3, CEA19.9 and CA125 were quantified in pleural fluid. Patients were classified into two groups: MPE or BPE. By applying logistic regression analysis, a multivariate probabilistic model was developed using pleural fluid biomarkers. The diagnostic accuracy was determined by receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC). Results: Population of study comprised 133 patients (72 males and 61 females) aged between 1 and 96 years (median = 70 years), 81 BPE and 52 MPE. The logistic regression analysis included HCY (p<0.0001) and CEA (p = 0.0022) in the probabilistic model and excluded the other tumour markers. The probabilistic model was: HCY+CEA = Probability(%) = 100×(1+e-z)-1, where Z = 0.5471×[HCY]+0.3846×[CEA]–8.2671. The AUCs were 0.606, 0.703, 0.778, 0.800, 0.846 and 0.948 for CA125, CA19.9, CEA, CA15.3, HCY and HCY+CEA, respectively. Conclusions: Pleural fluid HCY has higher accuracy for diagnosis of MPE than CEA, CA15.3, CA19.9 and CA125. The combination of HCY and CEA concentrations in pleural fluid significantly improves the diagnostic accuracy of the test. [ABSTRACT FROM AUTHOR]

Background: Gastroenteritis (GE) and respiratory tract infection (RTI) outbreaks are a significant issue in nursing homes. This study aimed to describe GE and RTI outbreaks with infection and all-cause lethality rates according to the individual characteristics of nursing home residents. Methods: Clinical and virological surveillance were conducted (2007 to 2018). Virus stratifications for the analysis were: outbreaks with positive norovirus or influenza identifications (respectively NoV+ or Flu+), episodes with no NoV or influenza identification or testing (respectively NoV- or Flu-). Associations between individual variables (sex, age, length of stay (LOS), autonomy status) and infection and lethality rates were tested with univariate and Mantel-Haenszel (MH) methods. Results: 61 GE outbreaks and 76 RTI oubreaks (total 137 outbreaks) were recorded involving respectively 4309 and 5862 residents. In univariate analysis, higher infection rates and age were associated in NoV+, NoV-, and Flu+ contexts, and lower infection rates were associated with longer stays (NoV+ and NoV-). In MH stratified analysis (virus, sex (female/male)) adjusted for LOS (<4 or ≥4 years), the odds of being infected remained significant among older residents (≥86 years): NoV+/male (Odds ratio (ORMH): 1.64, 95% confidence interval (CI): 1.16–2.30) and Flu+/female and male (respectively ORMH: 1.50, CI: 1.27–1.79 and 1.73, CI: 1.28–2.33). In univariate analysis, lower autonomy status (NoV+, Flu+ and Flu-) and increased age (Flu+) were associated with higher lethality. In MH adjusted analysis, significant ORage adjusted for autonomy was: Flu+/ ≥86 years compared with <86 years, 1.97 (1.19–3.25) and ORautonomy adjusted for age for the more autonomous group (compared with the less autonomous group) was: Flu+, 0.41 (0.24–0.69); Flu-, 0.42 (0.20, 0.90). Conclusion: The residents of nursing homes are increasingly elderly and dependent. The specific infection and lethality risks according to these two factors indicate that surveillance and infection control measures are essential and of high priority. [ABSTRACT FROM AUTHOR]

Objective: Regular physical activity may be associated with improved lung function via reduced systemic inflammation, although studies exploring this mechanism are rare. We evaluated the role of C-reactive protein in blood, which is a common marker of systemic inflammation, on the association of physical activity with forced expiratory volume in one second and forced vital capacity. Methods: Cross-sectional data on spirometry, C-reactive protein levels and self-reported physical activity (yes/no; ≥2 times and ≥1hr per week of vigorous physical activity) were available in the European Community Respiratory Health Survey (N = 2347 adults, 49.3% male, 28–56 years-old). A subsample was also assessed 10 years later using the International Physical Activity Questionnaire, and tertiles of Metabolic Equivalent of Task—minutes per week spent in vigorous, moderate and walking activities were calculated (N = 671, 49.6% male, 40–67 years-old). Adjusted cross-sectional mixed linear regression models and the “mediate” package in “R” were used to assess the presence of mediation. Results: Despite positive significant associations between nearly all physical activity metrics with forced expiratory volume in one second and forced vital capacity, there was no evidence that C-reactive protein levels played a role. An influence of C-reactive protein levels was only apparent in the smaller subsample when comparing the medium to low tertiles of moderate activity (mean difference [95% CIs]: 21.1ml [5.2, 41.9] for forced expiratory volume in one second and 17.3ml [2.6, 38.0] for forced vital capacity). Conclusions: In a population of adults, we found no consistent evidence that the association of physical activity with forced expiratory volume in one second or forced vital capacity is influenced by the level of C-reactive protein in blood. [ABSTRACT FROM AUTHOR]

Pigs are anatomically, genetically and physiologically comparable to humans and represent a natural host for influenza A virus (IAV) infections. Thus, pigs may represent a relevant biomedical model for human IAV infections. We set out to investigate the systemic as well as the local immune response in pigs upon two subsequent intranasal infections with IAV H1N1pdm09. We detected decreasing numbers of peripheral blood lymphocytes after the first infection. The simultaneous increase in the frequencies of proliferating cells correlated with an increase in infiltrating leukocytes in the lung. Enhanced perforin expression in αβ and γδ T cells in the respiratory tract indicated a cytotoxic T cell response restricted to the route of virus entry such as the nose, the lung and the bronchoalveolar lavage. Simultaneously, increasing frequencies of CD8αα expressing αβ T cells were observed rapidly after the first infection, which may have inhibited uncontrolled inflammation in the respiratory tract. Taking together, the results of this study demonstrate that experimental IAV infection in pigs mimics major characteristics of human seasonal IAV infections. [ABSTRACT FROM AUTHOR]

Recent studies have begun to elucidate a role for E3 ubiquitin ligases as important mediators of the innate immune response. Our previous work defined a role for the ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) in mouse and human innate immunity. Here, we present novel data describing a role for NKLAM in regulating the immune response to Sendai virus (SeV), a murine model of paramyxoviral pneumonia. NKLAM expression was significantly upregulated by SeV infection. SeV-infected mice that are deficient in NKLAM demonstrated significantly less weight loss than wild type mice. In vivo, Sendai virus replication was attenuated in NKLAM-/- mice. Autophagic flux and the expression of autophagy markers LC3 and p62/SQSTM1 were also less in NKLAM-/- mice. Using flow cytometry, we observed less neutrophils and macrophages in the lungs of NKLAM-/- mice during SeV infection. Additionally, phosphorylation of STAT1 and NFκB p65 was lower in NKLAM-/- than wild type mice. The dysregulated phosphorylation profile of STAT1 and NFκB in NKLAM-/- mice correlated with decreased expression of numerous proinflammatory cytokines that are regulated by STAT1 and/or NFκB. The lack of NKLAM and the resulting attenuated immune response is favorable to NKLAM-/- mice receiving a low dose of SeV; however, at a high dose of virus, NKLAM-/- mice succumbed to the infection faster than wild type mice. In conclusion, our novel results indicate that NKLAM plays a role in regulating the production of pro-inflammatory cytokines during viral infection. [ABSTRACT FROM AUTHOR]

Importance: Despite its efficacy, low tidal volume ventilation (LTVV) remains severely underutilized for patients with acute respiratory distress syndrome (ARDS). Physician under-recognition of ARDS is a significant barrier to LTVV use. We propose a computational method that addresses some of the limitations of the current approaches to automated measurement of whether ARDS is recognized by physicians. Objective: To quantify patient and physician factors affecting physicians’ tidal volume selection and to build a computational model of physician recognition of ARDS that accounts for these factors. Design, setting, and participants: In this cross-sectional study, electronic health record data were collected for 361 ARDS patients and 388 non-ARDS hypoxemic (control) patients in nine adult intensive care units at four hospitals between June 24 and December 31, 2013. Methods: Standardized tidal volumes (mL/kg predicted body weight) were chosen as a proxy for physician decision-making behavior. Using data-science approaches, we quantified the effect of eight factors (six severity of illness, two physician behaviors) on selected standardized tidal volumes in ARDS and control patients. Significant factors were incorporated in computational behavioral models of physician recognition of ARDS. Results: Hypoxemia severity and ARDS documentation in physicians’ notes were associated with lower standardized tidal volumes in the ARDS cohort. Greater patient height was associated with lower standardized tidal volumes (which is already normalized for height) in both ARDS and control patients. The recognition model yielded a mean (99% confidence interval) physician recognition of ARDS of 22% (9%-42%) for mild, 34% (19%-49%) for moderate, and 67% (41%-100%) for severe ARDS. Conclusions and relevance: In this study, patient characteristics and physician behaviors were demonstrated to be associated with differences in ventilator management in both ARDS and control patients. Our model of physician ARDS recognition measurement accounts for these clinical variables, providing an electronic approach that moves beyond relying on chart documentation or resource intensive approaches. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is associated with substantial cardiovascular morbidity. Atrial fibrillation (AF) is a prevalent arrhythmia that increases the risk of both stroke and cardiovascular mortality. Information about the mortality risk among patients with advanced CKD and new-onset AF (NAF) in the presence and absence of dialysis is important. However, the association between advanced CKD and NAF in patients with and without dialysis is unclear. Objective: To investigate long-term outcomes of the association between advanced CKD and NAF in patients with and without dialysis. Methods: We conducted a nested case-control study based on the National Health Insurance Program in Taiwan. Each participant aged 20 years and older who had CKD with dialysis from 2000 to 2013 was assigned to the dialysis group, whereas sex-, age-, CKD duration-, and index date-matched participants without dialysis were randomly selected and assigned to the non-dialysis group. We used the Cox regression model to estimate the hazard ratio (HR) with the 95% confidence interval (CI) for mortality in CKD patients with combined dialysis and NAF. Patients with neither NAF nor dialysis served as the reference group. Results: We identified 3,673 dialysis cases and 7,346 Non-dialysis matched controls for enrolment in the study. The crude mortality rates were 3.3 (95% CI: 3.1–3.5), 10.98 (95% CI: 9.3–13.0), 9.2 (95% CI: 8.7–10.0), and 18.0 (95% CI: 15.4–21.2) in the [Non-dialysis, non-NAF], [Non-dialysis, NAF], [Dialysis, non-NAF], and [Dialysis, NAF] groups, respectively. After adjustment for age, gender, and co-morbidities, the aHRs were 2.0 (95% CI: 1.7–2.3), 2.7 (95% CI: 2.5–2.9), and 3.5 (95% CI: 2.9–4.1) in the [Non-Dialysis, NAF], [Dialysis, non-NAF], and [Dialysis, NAF] groups compared with the [Non-Dialysis, non-NAF] group, respectively. The Kaplan-Meier survival curves showed the highest mortality risk in the [Dialysis, NAF] group among the study groups. Patients with concurrent peritoneal dialysis and AF had the highest mortality risk: aHR = 4.3 (95% CI: 2.3–8.0). However, there was a relatively lower effect of NAF on mortality in patients on dialysis than in patients who were not. Conclusions: Patients with advanced CKD and NAF had a significantly increased risk of mortality. Dialysis is not risky for patients with concurrent CKD and NAF. Dialysis offers a sufficient survival benefit to be considered as a standard treatment, as indicated by the superior physical status of patients on dialysis. [ABSTRACT FROM AUTHOR]

Background & aims: Pulmonary arterial hypertension is a severe disease associated with frequent hospitalisations. This retrospective analysis of the French medical information PMSI-MSO database aimed to describe incident cases of patients with pulmonary arterial hypertension hospitalised in France in 2013 and to document associated hospitalisation costs from the national health insurance perspective. Methods: Cases of pulmonary arterial hypertension were identified using a diagnostic algorithm. All cases hospitalised in 2013 with no hospitalisation the previous two years were retained. All hospital stays during the year following the index hospitalisation were extracted, and classified as incident stays, monitoring stays or stays due to disease worsening. Costs were attributed from French national tariffs. Results: 384 patients in France were hospitalised with incident pulmonary arterial hypertension in 2013. Over the following twelve months, patients made 1,271 stays related to pulmonary arterial hypertension (415 incident stays, 604 monitoring stays and 252 worsening stays). Mean age was 59.6 years and 241 (62.8%) patients were women. Liver disease and connective tissue diseases were documented in 62 patients (16.1%) each. Thirty-one patients (8.1%) died during hospitalisation and four (1.0%) received a lung/heart-lung transplantation. The total annual cost of these hospitalisations was € 3,640,382. € 2,985,936 was attributable to standard tariffs (82.0%), € 463,325 to additional ICU stays (12.7%) and € 191,118 to expensive drugs (5.2%). The mean cost/stay was € 2,864, ranging from € 1,282 for monitoring stays to € 7,285 for worsening stays. Conclusions: Although pulmonary arterial hypertension is rare, it carries a high economic burden. [ABSTRACT FROM AUTHOR]

In 2014, the World Health Organization (WHO) proposed a new severe influenza surveillance case definition, which has not been evaluated in a high human immunodeficiency virus (HIV) prevalence setting. Our study aimed to assess the performance of this proposed case definition in identifying influenza among HIV-uninfected and HIV-infected children aged <5 years in South Africa. We prospectively enrolled children aged <5 years hospitalised with physician-diagnosed lower respiratory tract infection (LRTI) at two surveillance sites from January 2011 to December 2015. Epidemiologic and clinical data were collected. We tested nasopharyngeal aspirates for influenza using reverse transcription polymerase chain reaction. We used logistic regression to assess factors associated with influenza positivity among HIV-infected and HIV-uninfected children. We calculated sensitivity and specificity for different signs and symptoms and combinations of these for laboratory-confirmed influenza. We enrolled 2,582 children <5 years of age with LRTI of whom 87% (2,257) had influenza and HIV results, of these 14% (318) were HIV-infected. The influenza detection rate was 5% (104/1,939) in HIV-uninfected and 5% (16/318) in HIV-infected children. Children with measured fever (≥38°C) were two times more likely to test positive for influenza than those without measured fever among the HIV-uninfected (OR 2.2, 95% Confidence Interval (CI) 1.5–3.4; p<0.001). No significant association was observed between fever and influenza infection among HIV-infected children. Cough alone had sensitivity of 95% (95% CI 89–98%) in HIV-uninfected and of 100% (95% CI 79–100%) in HIV-infected children but low specificity: 7% (95% CI 6–8%) and 6% (95% CI 3–9%) in HIV-uninfected and HIV-infected children, respectively. The WHO post-2014 case definition for severe acute respiratory illness (SARI—an acute respiratory infection with history of fever or measured fever of ≥ 38°C and cough; with onset within the last ten days and requires hospitalization), had a sensitivity of 66% (95% CI 56–76%) and specificity of 46% (95% CI 44–48%) among HIV-uninfected and a sensitivity of 63% (95% CI 35–84%) and a specificity of 42% (95% CI 36–48%) among HIV-infected children. The sensitivity and specificity of the WHO post-2014 case definition for SARI were similar among HIV-uninfected and HIV-infected children. Our findings support the adoption of the 2014 WHO case definition for children aged <5 years irrespective of HIV infection status. [ABSTRACT FROM AUTHOR]

Objective: Airways of children with cystic fibrosis (CF) harbor complex polymicrobial communities which correlates with pulmonary disease progression and use of antibiotics. Throat swabs are widely used in young CF children as a surrogate to detect potentially pathogenic microorganisms in lower airways. However, the relationship between upper and lower airway microbial communities remains poorly understood. This study aims to determine (1) to what extent oropharyngeal microbiome resembles the lung microbiome in CF children and (2) if lung microbiome composition correlates with airway inflammation. Method: Throat swabs and bronchoalveolar lavage (BAL) were obtained concurrently from 21 CF children and 26 disease controls. Oropharyngeal and lung microbiota were analyzed using 16S rRNA deep sequencing and correlated with neutrophil counts in BAL and antibiotic exposure. Results: Oropharyngeal microbial communities clustered separately from lung communities and had higher microbial diversity (p < 0.001). CF microbiome differed significantly from non-CF controls, with a higher abundance of Proteobacteria in both upper and lower CF airways. Neutrophil count in the BAL correlated negatively with the diversity but not richness of the lung microbiome. In CF children, microbial genes involved in bacterial motility proteins, two-component system, flagella assembly, and secretion system were enriched in both oropharyngeal and lung microbiome, whereas genes associated with synthesis and metabolism of nucleic acids and protein dominated the non-CF controls. Conclusions: This study identified a unique microbial profile with altered microbial diversity and metabolic functions in CF airways which is significantly affected by airway inflammation. These results highlight the limitations of using throat swabs as a surrogate to study lower airway microbiome and metagenome in CF children. [ABSTRACT FROM AUTHOR]

Background: Malaria and schistosomiasis represent two of the most prevalent and disabling parasitic infections in developing countries. Few studies have evaluated the effect of maternal schistosomiasis and malaria in the peri-conceptional period on infant’s risk of infection. Methods: In Benin, women were followed from the preconception period until delivery. Subsequently, their children were followed from birth to 3 months of age. Pre-pregnancy malaria, malaria in pregnancy (MiP)—determined monthly using a thick blood smear—and urinary schistosomiasis—determined once before pregnancy and once at delivery using urine filtration—were the main maternal exposures. Infant’s febrile infection (fever with respiratory, gastrointestinal and/or cutaneous clinical signs anytime during follow-up) was the main outcome. In a secondary analysis, we checked the relation of malaria and schistosomiasis with infant’s hemoglobin (Hb) concentration. Both effects were separately assessed using logistic/mixed linear regression models. Results: The prevalence of MiP was 35.7% with 10.8% occurring during the 1st trimester, and the prevalence of schistosomiasis was 21.8%. From birth to 3 months, 25.3% of infants had at least one episode of febrile infection. In multivariate analysis, MiP, particularly malaria in the 1st trimester, was significantly associated with a higher risk of infant’s febrile infection (aOR = 4.99 [1.1; 22.6], p = 0.03). In secondary results, pre-pregnancy malaria and schistosomiasis were significantly associated with a lower infant’s Hb concentration during the first 3 months. Conclusion: We evidenced the deleterious effect of maternal parasitic infections on infant’s health. Our results argue in favor of the implementation of preventive strategies as early as in the peri-conception. [ABSTRACT FROM AUTHOR]

Introduction and objective: Children admitted to the pediatric intensive care unit after cardiovascular surgery usually require treatment with antibiotics due to suspicion of infection. The aim of this study was to assess the effectiveness of procalcitonin in decreasing the duration of antibiotic treatment in children after cardiovascular surgery. Methods: Prospective, interventional study carried out in a pediatric intensive care unit. Included patients under 18 years old admitted after cardiopulmonary bypass. Two groups were compared, depending on the implementation of the PCT-guided protocol to stop or de-escalate the antibiotic treatment (Group 1, 2011–2013 and group 2, 2014–2018). This new protocol was based on the decrease of the PCT value by 20% or 50% with respect to the maximum value of PCT. Primary endpoints were mortality, stewardship indication, duration of antibiotic treatment, and antibiotic-free days. Results: 886 patients were recruited. There were 226 suspicions of infection (25.5%), and they were confirmed in 38 cases (16.8%). The global rate of infections was 4.3%. 102 patients received broad-spectrum antibiotic (4.7±1.7 days in group 1, 3.9±1 days in group 2 with p = 0.160). The rate of de-escalation was higher in group 2 (30/62, 48.4%) than in group 1 (24/92, 26.1%) with p = 0.004. A reduction of 1.1 days of antibiotic treatment (group 1, 7.7±2.2 and group 2, 6.7±2.2, with p = 0.005) and 2 more antibiotic free-days free in PICU in group 2 were observed (p = 0.001), without adverse outcomes. Conclusions: Procalcitonin-guided protocol for stewardship after cardiac surgery seems to be safe and useful to decrease the antibiotic exposure. This protocol could help to reduce the duration of broad-spectrum antibiotics and the duration of antibiotics in total, without developing complications or adverse effects. [ABSTRACT FROM AUTHOR]

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are debilitating events and spur disease progression. Infectious causes are frequent; however, it is unknown to what extent exacerbations are caused by larger shifts in the airways’ microbiota. The aim of the current study was to analyse the changes in microbial composition between stable state and during exacerbations, and the corresponding immune response. Methods: The study sample included 36 COPD patients examined at stable state and exacerbation from the Bergen COPD Cohort and Exacerbations studies, and one patient who delivered sputum on 13 different occasions during the three-year study period. A physician examined the patients at all time points, and sputum induction was performed by stringent protocol. Only induced sputum samples were used in the current study, not spontaneously expectorated sputum. Sputum inflammatory markers (IL-6, IL-8, IL-18, IP-10, MIG, TNF-α) and antimicrobial peptides (AMPs, i.e. LL-37/hCAP-18, SLPI) were measured in supernatants, whereas target gene sequencing (16S rRNA) was performed on corresponding cell pellets. The microbiome bioinformatics platform QIIME2TM and the statistics environment R were applied for bioinformatics analyses. Results: Levels of IP-10, MIG, TNF-α and AMPs were significantly different between the two disease states. Of 36 sample pairs, 24 had significant differences in the 12 most abundant genera between disease states. The diversity was significantly different in several individuals, but not when data was analysed on a group level. The one patient case study showed longitudinal dynamics in microbiota unrelated to disease state. Conclusion: Changes in the sputum microbiota with changing COPD disease states are common, and are accompanied by changes in inflammatory markers. However, the changes are highly individual and heterogeneous events. [ABSTRACT FROM AUTHOR]

Purpose: In a retrospective cohort study, we report the current epidemiology of patients with multiple myeloma (MM) and analyze the real-world clinical outcomes of bortezomib-based therapy. Materials and methods: This retrospective study was mainly designed to evaluate the characteristics, treatment outcomes, and prognostic factors of patients with MM who received bortezomib-based therapy. We identified 5,726 patients in Taiwan with MM newly diagnosed between 2007 and 2015. Confidential data from the National Health Insurance Research Database (NHIRD) was used under strict guidelines, as it was made available in an electronic format for research purposes. In addition, we analyzed 96 patients who have been diagnosed with MM and were treated at the Tri-Service General Hospital (TSGH) between January 1, 2002, and December 31, 2018. Results: Patients receiving first-line treatment with bortezomib had longer overall survival (OS) compared to those who received non-first-line treatment (p<0.001). In addition, the statistically lowest risk of mortality was when patients received first-line bortezomib followed by an autologous hematopoietic stem cell transplant (adjusted hazard ratio = 0.39, p<0.001). In the TSGH study, the patients were enrolled between January 1, 2002, and December 31, 2018, with an initial diagnosis of MM; there were 96 individuals treated with bortezomib. There was no statistically significant difference in the OS or progression-free survival (PFS) according to the gender, myeloma type, International Staging System stage, or treatment regimen. There was a significant difference in the PFS in patients receiving first-line bortezomib treatment with transplantation compared to those without transplantation (p = 0.021). Conclusions: Bortezomib as a first-line treatment extended the OS in four-year mortality tracking and lowered the mortality risk according to the NHIRD analysis. In the TSGH analysis, the results indicated that the initial conditions of patients with MM have a lower influence on the OS and PFS after bortezomib-based therapy was administered. [ABSTRACT FROM AUTHOR]

Background: Infection is a major complication in liver cirrhosis and causes major morbidity and mortality. However, the incidence and mortality related to these conditions in patients infected with hepatitis C virus (HCV) are unclear, as is whether antiviral therapy could change their infection risk.Methods and Findings: In this community-based cohort study, a total of 115,336 adults (mean age 52.2 years; 35.6% men) without cirrhosis participating in the New Taipei City Health Screening in 2005-2008 were classified as having noncirrhotic HCV (NC-HCV) (n = 2,839), noncirrhotic hepatitis B virus (NC-HBV) (n = 8,316), or no HBV or HCV infection (NBNC) (n = 104,181). Participants were followed to their first hospitalization for infection or death after data linkage with the Taiwan National Health Insurance Research Database (NHIRD) and Death Registry. A Cox proportional hazard regression model, adjusted for age, sex, body mass index (BMI), smoking, alcohol consumption, education level, diabetes, renal function, systemic steroids, and history of hospitalization, was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and individual sites of infection and infection-related mortality. The reference group was NBNC participants with normal to mildly elevated alanine aminotransferase (ALT) (<1.5 times upper normal limit [UNL]) levels. To further address the impact of antiviral treatment on infection risk, we conducted analyses of data from the nationwide NHIRD and compared the risks for hospitalization because of infections and infection-related deaths between patients with HCV who received antiviral therapy (n = 20,264) and those who remained untreated (n = 104,360). During a median 8.2-year follow-up, the incidence of hospitalization for infection was substantially higher in NC-HCV patients. Compared to the reference group, NC-HCV was associated with a significantly higher risk for hospitalization because of overall infections (adjusted HR: 1.22; 95% CI: 1.12-1.33), but we observed no increased risk for patients in the NC-HBV (adjusted HR: 0.94; 95% CI: 0.88-1.01) or NBNC group with moderate to markedly elevated ALT levels (adjusted HR: 1.03; 95% CI: 0.93-1.14). For specific sites of infection, the NC-HCV group had increased risks for septicemia and lower respiratory tract, reproductive, and urinary tract infections. We noted no increased risk for infection-related death among patients with NC-HCV. Patients with HCV who received antiviral therapy had significantly reduced infection-related hospitalization and death risks (adjusted HR: 0.79; 95% CI: 0.73-0.84 for infection-related hospitalization and adjusted HR: 0.08; 95% CI: 0.04-0.16 for infection-related deaths). Study limitations include the exclusion of patients with cirrhosis from the cohort, the possibility of unmeasured confounding, and the lack of information on direct-acting antiviral agents (DAAs).Conclusions: In this study, patients with NC-HCV were at increased risk for hospitalization for infection, while no increased risk was observed for NC-HBV-infected patients. [ABSTRACT FROM AUTHOR]

Purpose: Asthma is an important cause of morbidity and mortality worldwide and information on the prevalence of asthma in Nigeria is inconsistent. Nationally representative data, important for health planning is unavailable. We aimed to determine the current prevalence of asthma and allergic rhinitis in Nigeria. Materials and methods: A cross-sectional population survey conducted between June 2017 and March 2018 across five cities representing five geo-political zones in Nigeria. Validated screening questionnaires were used to identify persons with asthma and allergic rhinitis respectively. Asthma was defined as physician diagnosed asthma, clinical asthma and by presence of wheeze in the last 12 months respectively. Socio-demographic information, tobacco smoking, sources of household cooking fuel were also obtained. Results: A total of 20063 participants from 6024 households were screened. The prevalence (95% confidence interval) of physician diagnosed asthma, clinical asthma and wheeze was 2.5% (2.3–2.7%), 6.4% (6.0–6.64%) and 9.0% (8.6–9.4%) respectively. The prevalence of allergic rhinitis was 22.8% (22.2–23.4%). The prevalence of asthma and rhinitis increased with age (prevalence of clinical asthma: 3.1% (2.8–3.4%), 9.8% (9.1–10.5) and 10.7% (9.4%-12.0) among 6–17 years, 18–45 years and >45 years respectively). Prevalence also varied across different cities with the highest prevalence of clinical asthma occurring in Lagos (8.0%) and the lowest in Ilorin (1.1%). The frequency of allergic rhinitis among persons with clinical asthma was 74.7%. Presence of allergic rhinitis, family history of asthma, current smoking and being overweight were independent determinants of current asthma among adults. Conclusion: The prevalence of asthma and allergic rhinitis in Nigeria is high with variabilities across regions and age groups. The number of persons with clinical asthma in Nigeria (approximately 13 million) is likely to rank among the highest in Africa. This warrants prioritization by stakeholders and policy makers to actively implement risk reduction measures and increase investment in capacity building for the diagnosis and treatment of asthma and allergic rhinitis. [ABSTRACT FROM AUTHOR]

Background: This paper is aimed to (i) develop an innovative classification of COPD, multi-dimensional phenotype, based on a multidimensional assessment; (ii) describe the identified multi-dimensional phenotypes. Methods: An exploratory factor analysis to identify the main classificatory variables and, then, a cluster analysis based on these variables were run to classify the COPD-diagnosed 514 patients enrolled in the STORICO (trial registration number: NCT03105999) study into multi-dimensional phenotypes. Results: The circadian rhythm of symptoms and health-related quality of life, but neither comorbidity nor respiratory function, qualified as primary classificatory variables. Five multidimensional phenotypes were identified: the MILD COPD characterized by no night-time symptoms and the best health status in terms of quality of life, quality of sleep, level of depression and anxiety, the MILD EMPHYSEMATOUS with prevalent dyspnea in the early-morning and day-time, the SEVERE BRONCHITIC with nocturnal and diurnal cough and phlegm, the SEVERE EMPHYSEMATOUS with nocturnal and diurnal dyspnea and the SEVERE MIXED COPD distinguished by higher frequency of symptoms during 24h and worst quality of life, of sleep and highest levels of depression and anxiety. Conclusions: Our results showed that properly collected respiratory symptoms play a primary classificatory role of COPD patients. The longitudinal observation will disclose the discriminative and prognostic potential of the proposed multidimensional phenotype. Trial registration: Trial registration number: , date of registration: 10th April 2017. [ABSTRACT FROM AUTHOR]

Introduction: Genome-Wide Association Studies suggest glutathione S transferase C terminal domain (GSTCD) may play a role in development of Chronic Obstructive Pulmonary Disease. We aimed to define the potential role of GSTCD in airway inflammation and contraction using precision cut lung slice (PCLS) from wild-type (GSTCD+/+) and GSTCD knockout mice (GSTCD-/-). Methods: PCLS from age and gender matched GSTCD+/+ and GSTCD-/- mice were prepared using a microtome. Contraction was studied after applying either a single dose of Methacholine (Mch) (1 μM) or different doses of Mch (0.001 to 100 μM). Each slice was then treated with lipopolysaccharide (LPS) or vehicle (PBS) for 24 hours. PCLS contraction in the same airway was repeated before and after stimulation. Levels of TNFα production was also measured. Results: There were no differences in contraction of PCLS from GSTCD+/+ and GSTCD-/- mice in response to Mch (EC50 of GSTCD+/+ vs GSTCD-/- animals: 100.0±20.7 vs 107.7±24.5 nM, p = 0.855, n = 6 animals/group). However, after LPS treatment, there was a 31.6% reduction in contraction in the GSTCD-/- group (p = 0.023, n = 6 animals). There was no significant difference between PBS and LPS treatment groups in GSTCD+/+ animals. We observed a significant increase in TNFα production induced by LPS in GSTCD-/- lung slices compared to the GSTCD+/+ LPS treated slices. Conclusion: GSTCD knockout mice showed an increased responsiveness to LPS (as determined by TNFα production) that was accompanied by a reduced contraction of small airways in PCLS. These data highlight an unrecognised potential function of GSTCD in mediating inflammatory signals that affect airway responses. [ABSTRACT FROM AUTHOR]

Bloodstream infections (BSI) are associated with high mortality. Therefore, reliable methods of detection are of paramount importance. Efficient strategies to improve diagnostic yield of bacteraemia within the emergency department (ED) are needed. We conducted a retrospective analysis of all ED encounters in a high-volume, city-centre university hospital within Germany during a five-year study period from October 2013 to September 2018. A time-series analysis was conducted for all ED encounters in which blood cultures (BCs) were collected. BC detection rates and diagnostic yield of community-onset bacteraemia were compared during the study period (which included 45 months prior to the start of a new diagnostic Antibiotic Stewardship (ABS) bundle and 15 months following its implementation). BCs were obtained from 5,191 out of 66,879 ED admissions (7.8%). Bacteraemia was detected in 1,013 encounters (19.5% of encounters where BCs were obtained). The overall yield of true bacteraemia (defined as yielding clinically relevant pathogens) was 14.4%. The new ABS-related diagnostic protocol resulted in an increased number of hospitalised patients with BCs collected in the ED (18% compared to 12.3%) and a significant increase in patients with two or more BC sets taken (59% compared to 25.4%), which resulted in an improved detection rate of true bacteraemia (2.5% versus 1.8% of hospital admissions) without any decrease in diagnostic yield. This simultaneous increase in BC rates without degradation of yield was a valuable finding that indicated success of this strategy. Thus, implementation of the new diagnostic ABS bundle within the ED, which included the presence of a skilled infectious disease (ID) team focused on obtaining BCs, appeared to be a valuable tool for the accurate and timely detection of community-onset bacteraemia. [ABSTRACT FROM AUTHOR]

Objectives: To examine the morbidities associated with workplace injury and to explore how clinical variables modify the risk of injury recurrence. Methods: A case-control study was designed using Florida’s statewide inpatient, outpatient, and emergency visits data obtained from the Healthcare Cost and Utilization Project. We included adults who were admitted for a workplace injury (WPI) or injury at other places (IOP), and a matched population of random controls without WPI/IOP. The associations between WPI and clinical morbidities were assessed by univariate and multivariable regression, ranking predictors by information gain, area under the receiver operating characteristic (AUROC), and odds ratios. We analyzed WPI recurrence using survival methods (Kaplan-Meier, Cox regression, survival decision trees) and developed prediction models via regularized logistic regression, random forest, and AdTree. Performance was assessed by 10-fold cross-validation comparing AUROC, sensitivity, specificity, and Harrell’s c-index. Results: A total of 80,712 WPI, 161,424 IOP, and 161,424 control patients were included; 485 distinct clinical diagnostic and 160 procedure codes were analyzed after filtering. Acute bronchitis and bronchiolitis, sprains and strains of shoulder and upper arm, ankle and foot, or other and unspecified parts of back, accidents caused by cutting and piercing instruments or objects, and overexertion and strenuous movements were identified as important consequences of WPI. The prediction models of injury recurrence identified several key factors, such as insurance type and prior injury events, although none of the models exhibited high predictive performance (best AUROC = 0.60, best c-index = 0.62). Conclusions: WPI is associated to diverse serious physical comorbidity burden. There are demographic, social and clinical comorbidity components associated to the risk of WPI recurrence, although their predictive value is moderate, which warrants future investigation in other information source domains, e.g. deepening into the environmental and societal sphere. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is the result of chronic injury where fibroblasts become activated and secrete large amounts of extracellular matrix (ECM), leading to impaired fibroblasts degradation followed by stiffness and loss of lung function. Fructose-1,6-bisphosphate (FBP), an intermediate of glycolytic pathway, decreases PF development, but the underlying mechanism is unknown. To address this issue, PF was induced in vivo using a mouse model, and pulmonary fibroblasts were isolated from healthy and fibrotic animals. In PF model mice, lung function was improved by FBP as revealed by reduced collagen deposition and downregulation of ECM gene expression such as collagens and fibronectin. Fibrotic lung fibroblasts (FLF) treated with FBP for 3 days in vitro showed decreased proliferation, contraction, and migration, which are characteristic of myofibroblast to fibroblast phenotype reversal. ECM-related genes and proteins such as collagens, fibronectin and α-smooth muscle actin, were also downregulated in FBP-treated FLF. Moreover, matrix metalloproteinase (MMP) 1, responsible for ECM degradation, was produced only in fibroblasts obtained from healthy lungs (HLF) and FBP did not alter its expression. On the other hand, tissue inhibitor of metalloproteinase (TIMP)-1, a MMP1 inhibitor, and MMP2, related to fibroblast tissue-invasion, were predominantly produced by FLF and FBP was able to downregulate its expression. These results demonstrate that FBP may prevent bleomycin-induced PF development through reduced expression of collagen and other ECM components mediated by a reduced TIMP-1 and MMP2 expression. [ABSTRACT FROM AUTHOR]

Background: Frailty is a major health issue which impacts the life of older people, posing a significant challenge to the health system. One of the key emerging areas is the development of frailty interventions to halt or reverse the progression of the condition. In many countries, economic evidence is required to inform public funding decisions for such interventions, and cost-effectiveness models are needed to estimate long-term costs and effects. Such models should capture current clinical understanding of frailty, its progression and its health consequences. The objective of this paper is to present a conceptual model of frailty that can be used to inform the development of a cost-effectiveness model to evaluate frailty interventions. Methods: After critical analysis of the clinical and economic literature, a Delphi study consisting of experts from the disciplines of clinical medicine and epidemiology was undertaken to inform the key components of the conceptual model. We also identified relevant databases that can be used to populate and validate the model. Results: A list of significant health states/events for which frailty is a strong independent risk factor was identified (e.g., hip fracture, hospital admission, delirium, death). We also identified a list of important patient attributes that may influence disease progression (e.g., age, gender, previous hospital admissions, depression). A number of large-scale relevant databases were also identified to populate and validate the cost-effectiveness model. Face validity of model structure was confirmed by experts. Discussion and conclusions: The proposed conceptual model is being used as a basis for developing a new cost-effectiveness model to estimate lifetime costs and outcomes associated with a range of frailty interventions. Using an appropriate model structure, which more accurately reflects the natural history of frailty, will improve model transparency and accuracy. This will ultimately lead to better informed public funding decisions around interventions to manage frailty. [ABSTRACT FROM AUTHOR]

Background: Respiratory diseases, including pneumonia, are the second largest cause of under-five mortality in Mongolia and the most common cause of childhood hospitalization. However information regarding the contribution of Streptococcus pneumoniae to pneumonia causation in Mongolia is limited. We aimed to describe the epidemiology of hospitalized children aged 2–59 months with pneumonia, enrolled into a surveillance program in the period prior to pneumococcal conjugate vaccine (PCV) introduction, in Mongolia. Methods: An expanded pneumonia surveillance program enrolled children, who met the surveillance case definition, at participating hospitals, between April 2015 and May 2016. Cumulative incidence rates were calculated by district for all pneumonia endpoints using district specific denominators from the Mongolian Health Department census for 2016. Socio-economic and disease-associated factors were compared between districts using chi-squared tests. Results: A total of 4318 eligible children with pneumonia were enrolled over the 14 month period. Overall the incidence for all-cause pneumonia in children aged 12–59 months was 31.8 per 1000 population; children aged 2–11 months had an almost four-fold higher incidence than children aged 12–59 months. Differences were found between districts with regards to housing type, fuel used for cooking, hospital admission practices and the proportions of severe and primary endpoint pneumonia. Discussion: This study shows a high burden of pneumonia in children aged 2–59 months in Mongolia prior to PCV introduction. Rates differed somewhat by district and age group and were influenced by a number of socio-economic factors. It will be important to consider these differences and risk factors when assessing the impact of PCV introduction. [ABSTRACT FROM AUTHOR]