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We sought to determine the secondary overtriage rate of pediatric trauma patients admitted to pediatric trauma centers. We hypothesized that pediatric secondary overtriage (POT) would constitute a large percentage of admissions to PTC.The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2003 to 2017 for pediatric (age ≤ 18 y) trauma patients transferred to accredited pediatric trauma centers in Pennsylvania (n = 6). Patients were stratified based on discharge within (early) and beyond (late) 24 h following admission. POT was defined as patients transferred to a PTC with an early discharge. Multilevel mixed-effects logistic regression model controlling for demographic and injury severity covariates were utilized to determine the adjusted impact of injury patterns on early discharge.A total of 37,653 patients met inclusion criteria. For transfers, POT compromised 18,752 (49.8%) patients. Compared to POT, non-POT were more severely injured (ISS: 10 versus 6;P0.001) and spent less time in the ED (Min: 181 versus 207;P0.001). In adjusted analysis, concussion, closed skull vault fractures, supracondylar humerus fractures, and consults to neurosurgery were associated with increased odds of POT. Overall, femur fracture, child abuse evaluation, and consults to plastic surgery, orthopedics, and ophthalmology were all associated with a decreased risk of being POT.POT comprises 49.8% of PTC transfer admissions in Pennsylvania's trauma system. Improving community resources for management of pediatric concussion and mild TBI could result in decreased rates of POT to PTCs. Developing better inter-facility transfer guidelines and increased education of adult TC and nontrauma center hospitals is needed to decrease POT.Epidemiologic study, level III.

A high fruit and vegetable (FV) diet reduces asthma exacerbations in adults; this has not been examined in children to date.To investigate the effect of a 6-month, high FV diet on the time to first asthma exacerbation in children with asthma, in a parallel-group, randomized, controlled trial.Children (aged 3-11 years) with asthma, history of exacerbations and usual low FV intake (≤3 serves/day) were randomized to the intervention (high FV diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF-α, CRP, and IL-6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G-protein coupled receptor (GPR) 41/43 and HDAC (1-11) expression.67 children were randomized between September 2015 and July 2018. FV intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569; control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553; control vs. intervention) were similar between groups. In per-protocol analysis, airway reactance z-scores increased in the intervention versus control group (XA high FV diet did not affect asthma exacerbations over the 6-month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma.

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

Airway inflammation plays a key role in asthma pathogenesis but is heterogeneous in nature. There has been significant scientific discovery with regard to type 2-driven, eosinophil-dominated asthma, with effective therapies ranging from inhaled corticosteroids to novel biologics. However, studies suggest that approximately 1 in 5 adults with asthma have an increased proportion of neutrophils in their airways. These patients tend to be older, have potentially pathogenic airway bacteria and do not respond well to classical therapies. Currently, there are no specific therapeutic options for these patients, such as neutrophil-targeting biologics.Neutrophils comprise 70% of the total circulatory white cells and play a critical defence role during inflammatory and infective challenges. This makes them a problematic target for therapeutics. Furthermore, neutrophil functions change with age, with reduced microbial killing, increased reactive oxygen species release and reduced production of extracellular traps with advancing age. Therefore, different therapeutic strategies may be required for different age groups of patients.The pathogenesis of neutrophil-dominated airway inflammation in adults with asthma may reflect a counterproductive response to the defective neutrophil microbial killing seen with age, resulting in bystander damage to host airway cells and subsequent mucus hypersecretion and airway remodelling. However, in children with asthma, neutrophils are less associated with adverse features of disease, and it is possible that in children, neutrophils are less pathogenic.In this review, we explore the mechanisms of neutrophil recruitment, changes in cellular function across the life course and the implications this may have for asthma management now and in the future. We also describe the prevalence of neutrophilic asthma globally, with a focus on First Nations people of Australia, New Zealand and North America.

Constipation is a prevalent and distressing symptom affecting people with cancer. It may be a chronic condition, or it may be caused by the effects of the disease, its treatment, or the side effects of symptom management, including the use of opioids. These evidence-based guidelines can assist clinicians in the decision-making process, guiding patients to effective interventions to decrease the incidence and severity of constipation.

Background Cystic fibrosis (CF) is characterised by reduced airway clearance, microbial accumulation, inflammation, and lung function decline. Certain bacterial species may contribute disproportionately to worsening lung disease. However, the relative importance of these microorganisms compared to the absolute abundance of all bacteria is uncertain. We aimed to identify the characteristics of lower airway microbiology that best reflect CF airway inflammation and disease in children. Methods Analysis was performed on bronchoalveolar lavage (BAL) fluid from 78 participants of the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial, aged 4.5–5.5 years. Universal bacterial quantitative PCR (qPCR), species-specific qPCR, and 16S rRNA gene sequencing were performed on DNA extracts to determine total bacterial load, species-specific load and taxa relative abundance. Quantification of pre-specified pathogens was performed by culture-based methods. Bacteriological data were related to neutrophil counts, interleukin-8, lung function, and two computed-tomography based measures, CF-CT (as the primary measure) and PRAGMA. Results Of all bacteriological measures assessed, total bacterial load determined by qPCR correlated most strongly with structural disease (CF-CT total score, rs=0.30, P=0.0095). Specifically, total bacterial load correlated with bronchiectasis, airway wall thickening, mucus plugging and parenchymal disease sub-scores. In contrast, culture-based quantification, microbiota-derived measures, and pathogen-specific qPCR-based quantification were weakly associated with total CF-CT. Regression analyses supported correlation findings, with total bacterial load explaining the greatest variance in total CF-CT (R2=0.097, P=0.0061). Correlations with PRAGMA score were comparable to CF-CT total score. Conclusions Within the ACFBAL trial, culture-independent quantification of total bacteria provided the most clinically-informative bacteriological measure in 5-year-old CF patients.

Childhood onset chronic inflammatory demyelinating polyneuropathy (CIDP) often requires long-term immunomodulatory therapy. We report a comprehensive review of our treatment of pediatric CIDP with a focus on high-dose weekly corticosteroids ("pulse oral corticosteroids"), a treatment method that is not commonly reported. We retrospectively reviewed medical records of pediatric patients with CIDP treated at our center between 2000 and 2018 for whom we had at least 12 mo follow-up. Here, we describe the demographics, disease course, treatment regimens, and long-term outcomes of these patients. Twenty-five patients were identified for analysis. Pulse oral corticosteroid monotherapy was the predominant maintenance treatment in 56% of patients. Patients were followed for a median of 4 y. Side effects were seen in a minority of patients. The probability of a normal exam or being off treatment at last follow-up was similar regardless of predominant maintenance therapy. Pulse oral corticosteroid therapy is a safe and effective long-term treatment option in children with CIDP.

Genetic background is a key but sometimes overlooked factor that profoundly impacts disease susceptibility and presentation in both humans and disease models. Here we show that deficiency of KLOTHO protein, an important renal regulator of mineral homeostasis and a cofactor for FGF23, causes different phenotypes in 129S1/SvlmJ (129) and C57BL/6J (B6) mouse strains. The 129 strain is more severely affected, with decreased longevity, decreased body weight, and increased amounts of kidney calcification compared with B6 mice. Reciprocal F1 crosses of the strains also indicate a parentage effect on the Klotho phenotype with F1 KLOTHO-deficient progeny of B6 mothers and 129 fathers having more kidney calcification than progeny of 129 mothers and B6 fathers. Comparing and contrasting the genetic architecture leading to different phenotypes associated with specific inbred mouse strains may reveal previously unrecognized and important metabolic interactions affecting chronic kidney disease.

Major historical advances in cystic fibrosis (CF) respiratory clinical care, including mechanical airway clearance and inhaled medications, have aimed to address the consequences of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. In contrast, CFTR modulator therapies instead target the underlying protein defect that leads to CF lung disease. The extent to which these therapies might reduce susceptibility to chronic lung infections remains to be seen. However, by improving airway clearance, reducing the requirement for antibiotics, and in some cases, through direct antimicrobial effects, CFTR modulators are likely to result in substantial changes in CF airway microbiology. These changes could contribute substantially to the clinical benefit associated with modulator therapies, as well as providing an important indicator of treatment efficacy and residual pathophysiology. Indeed, the widespread introduction of modulator therapies might require us to re-consider our models of CF airway microbiology.

Background Extended hospital length of stay (LOS) is widely associated with significant healthcare costs. Since LOS is a known surrogate for cost, we sought to evaluate outliers. We hypothesized that particular characteristics are likely predictive of trauma high resource consumers (THRC) and can be used to more effectively manage care of this population. Methods The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2003-2017 for all adult (age ≥15) trauma patients admitted to accredited trauma centers in Pennsylvania. THRC were defined as patients with hospital LOS two standard deviations above the population mean or ≥22 days (pResults A total of 465,601 patients met inclusion criteria [THRC: 16,818 (3.6%); non-THRC 448,783 (96.4%)]. Compared to non-THRC counterparts, THRC patients were significantly more severely injured (median ISS: 9 vs. 22, pConclusions Reintubation, major surgery, gunshot wound to abdomen, along with injury to the spine, upper or lower extremities are all strongly predictive of THRC. Understanding the profile of the THRC will allow clinicians and case management to proactively put processes in place to streamline care and potentially reduce costs and LOS.

BackgroundChronic airway inflammation is the main driver of pathogenesis in respiratory diseases such as severe asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF) and bronchiectasis. While the role of common pathogens in airway inflammation is widely recognised, the influence of other microbiota members is still poorly understood.MethodsWe hypothesised that the lung microbiota contains bacteria with immunomodulatory activity which modulate net levels of immune activation by key respiratory pathogens. Therefore, we assessed the immunomodulatory effect of several members of the lung microbiota frequently reported as present in CF lower respiratory tract samples.ResultsWe show that Rothia mucilaginosa, a common resident of the oral cavity that is also often detectable in the lower airways in chronic disease, has an inhibitory effect on pathogen- or lipopolysaccharide-induced pro-inflammatory responses, in vitro (three-dimensional cell culture model) and in vivo (mouse model). Furthermore, in a cohort of adults with bronchiectasis, the abundance of Rothia species was negatively correlated with pro-inflammatory markers (interleukin (IL)-8 and IL-1β) and matrix metalloproteinase (MMP)-1, MMP-8 and MMP-9 in sputum. Mechanistic studies revealed that R. mucilaginosa inhibits NF-κB pathway activation by reducing the phosphorylation of IκBα and consequently the expression of NF-κB target genes.ConclusionsThese findings indicate that the presence of R. mucilaginosa in the lower airways potentially mitigates inflammation, which could in turn influence the severity and progression of chronic respiratory disorders.

CASE A 79-year-old woman presented after a ground level fall with the inability to bear weight on her right hip. Radiographs and computed tomography (CT) imaging were negative for a femoral neck fracture. Her medical comorbidities precluded magnetic resonance imaging (MRI), so dual-energy CT with focused evaluation for bone edema was performed, identifying a femoral neck fracture that was stabilized surgically. CONCLUSION Dual-energy CT with processing for edema can successfully identify nondisplaced femoral neck fractures in MRI-contraindicated patients. This imaging modality could be useful for diagnosing femoral neck stress fractures and ipsilateral femoral neck fractures in patients sustaining high-energy femoral shaft fractures.

Inbred mice are the most popular animals used for in vivo liver research. These mice are genetically defined, readily available, less expensive to maintain than larger animals, and enjoy a broad array of commercial reagents for scientific characterization. C57BL/6 mice are the most commonly used strain. However, other strains discussed, including BALB/c, C3H, A/J, and FVB/N, may be better suited to a particular disease model or line of investigation. Understanding the phenotypes of different inbred mouse strains facilitates informed decision making during experimental design. Model systems influenced by strain-dependent phenotype include tissue regeneration, drug-induced liver injury (DILI; e.g., acetaminophen), fibrosis (e.g., carbon tetrachloride, CCl4), Fas-induced apoptosis, cholestasis, alcohol-induced liver disease and cirrhosis, nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH), and hepatocellular carcinoma (HCC). Thoughtful consideration of the strengths and weaknesses of each inbred strain in a given model system will lead to more robust data and a clearer understanding of translational relevance to human liver disease.

Summary Background Soluble fibre modulates airway inflammation in animal models. The aim of this study was to investigate the effects of soluble fibre supplementation, with and without a probiotic, on plasma short chain fatty acids (SCFA), airway inflammation, asthma control and gut microbiome in adults with asthma. Methods A randomised, double-blinded, placebo controlled 3-way cross-over trial in 17 subjects with stable asthma at the Hunter Medical Research Institute, Newcastle, Australia. Subjects received 3 × 7 day oral interventions in random order; soluble fibre (inulin 12 g/day), soluble fibre + probiotic (inulin 12 g/day + multi-strain probiotic >25 billion CFU) and placebo. Plasma SCFA, sputum cell counts and inflammatory gene expression, asthma control gut microbiota, adverse events including gastrointestinal symptoms were measured. Findings There was no difference in change in total plasma SCFA levels (μmol/L) in the placebo versus soluble fibre (Δmedian [95% CI] 16·3 [−16·9, 49·5], p = 0·335) or soluble fibre+probiotic (18·7 [−14·5, 51·9], p = 0·325) group. Following the soluble fibre intervention there was an improvement in the asthma control questionnaire (ACQ6) (∆median (IQR) -0·35 (−0·5, −0·13), p = 0·006), sputum %eosinophils decreased (−1.0 (−2·5, 0), p = 0·006) and sputum histone deacetylase 9 (HDAC9) gene expression decreased (−0.49 (−0.83, −0.27) 2-ΔCt, p = .008). Individual bacterial operational taxonomic units changed following both inulin and inulin+probiotic arms. Interpretation Soluble fibre supplementation for 7 days in adults with asthma did not change SCFA levels. Within group analysis showed improvements in airway inflammation, asthma control and gut microbiome composition following inulin supplementation and these changes warrant further investigation, in order to evaluate the potential of soluble fibre as a non-pharmacological addition to asthma management. Fund John Hunter Hospital Charitable Trust.

Whether early placement of an inferior vena cava filter reduces the risk of pulmonary embolism or death in severely injured patients who have a contraindication to prophylactic anticoagulation is not known.In this multicenter, randomized, controlled trial, we assigned 240 severely injured patients (Injury Severity Score15 [scores range from 0 to 75, with higher scores indicating more severe injury]) who had a contraindication to anticoagulant agents to have a vena cava filter placed within the first 72 hours after admission for the injury or to have no filter placed. The primary end point was a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment; a secondary end point was symptomatic pulmonary embolism between day 8 and day 90 in the subgroup of patients who survived at least 7 days and did not receive prophylactic anticoagulation within 7 days after injury. All patients underwent ultrasonography of the legs at 2 weeks; patients also underwent mandatory computed tomographic pulmonary angiography when prespecified criteria were met.The median age of the patients was 39 years, and the median Injury Severity Score was 27. Early placement of a vena cava filter did not result in a significantly lower incidence of symptomatic pulmonary embolism or death than no placement of a filter (13.9% in the vena cava filter group and 14.4% in the control group; hazard ratio, 0.99; 95% confidence interval [CI], 0.51 to 1.94; P = 0.98). Among the 46 patients in the vena cava filter group and the 34 patients in the control group who did not receive prophylactic anticoagulation within 7 days after injury, pulmonary embolism developed in none of those in the vena cava filter group and in 5 (14.7%) in the control group, including 1 patient who died (relative risk of pulmonary embolism, 0; 95% CI, 0.00 to 0.55). An entrapped thrombus was found in the filter in 6 patients.Early prophylactic placement of a vena cava filter after major trauma did not result in a lower incidence of symptomatic pulmonary embolism or death at 90 days than no placement of a filter. (Funded by the Medical Research Foundation of Royal Perth Hospital and others; Australian New Zealand Clinical Trials Registry number, ACTRN12614000963628.).

Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Necrotizing enterocolitis (NEC) is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota1–3. The incidence of NEC is substantially lower in infants fed with maternal milk, although the mechanisms that underlie this benefit are not clear4–6. Here we show that maternal immunoglobulin A (IgA) is an important factor for protection against NEC. Analysis of IgA binding to fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that before the onset of disease, NEC was associated with increasing domination by Enterobacteriaceae in the IgA-unbound fraction of the microbiota. Furthermore, we confirmed that IgA is critical for preventing NEC in a mouse model, in which pups that are reared by IgA-deficient mothers are susceptible to disease despite exposure to maternal milk. Our findings show that maternal IgA shapes the host–microbiota relationship of preterm neonates and that IgA in maternal milk is a critical and necessary factor for the prevention of NEC. Immunoglobulin A antibodies in maternal milk are required for prevention of necrotizing enterocolitis in preterm neonates.

Introduction: Vena cava filters have been used as a primary means to prevent symptomatic pulmonary embolism (PE) in trauma patients who cannot be anticoagulated after severe injury, but the economic implications for this practice remain unclear. Methods: Using a healthcare system perspective to analyze the a priori primary outcome of the da Vinci trial, we report the cost-effectiveness of using vena cava filters as a primary means to prevent PE in patients who have contraindications to prophylactic anticoagulation after major trauma. Results: Of the 240 patients enrolled, complete, prospectively collected, hospital cost data during the entire hospital stay − including costs for the filter, medical/nursing/allied health staff, medical supplies, pathology tests, and radiological imaging − were available in 223 patients (93%). Patients allocated to the filter group ( n = 114) were associated with a reduced risk of PE (0.9%) compared to those in the control group ( n = 109, 5.5%; p = 0.048); and the filter’s benefit was more pronounced among those who could not be anticoagulated within 7 days (filter: 0% vs control: 16%, Bonferroni-corrected p = 0.02). Overall, the cost needed to prevent one PE was high (AUD $379,760), but among those who could not be anticoagulated within 7 days, the costs to prevent one PE (AUD $36,156; ~ USD $26,032) and gain one quality-adjusted life-year (AUD $30,903; ~ USD $22,250) were substantially lower. Conclusion: The cost of using a vena cava filter to prevent PE for those who have contraindications to prophylactic anticoagulation within 3 days of injury is prohibitive, unless such contraindications remain for longer than 7 days. (Australian New Zealand Clinical Trials Registry no.: ACTRN12614000963628)

INTRODUCTION Benzodiazepines (BZDs) modulate peripheral γ-amino-butyric acid type A on macrophages causing immunomodulation. They inhibit proinflammatory cytokines increasing infections. Prior studies have also shown that infections can increase thrombotic complications. We sought to examine this relationship in trauma patients. We hypothesized that the presence of BZDs on admission urine drug screen (UDS) would increase rates of both complications. METHODS All patients submitted to the Pennsylvania Trauma Outcome Study database from 2003 to 2018 were queried. Those with a positive UDS for BZDs were analyzed. Infectious complications were defined as pneumonia, urinary tract infection, sepsis, wound, and soft tissue infection, and thrombotic complications were defined as presence of pulmonary embolism or deep vein thrombosis. Logistic regressions controlling for demographic and injury covariates assessed the adjusted impact of BZDs on infectious and thrombotic complications. RESULTS A total of 3,393 patients (2.08%) had infectious complications, and 3,048 (1.87%) had thrombotic complications. Furthermore, 33,260 patients (20.4%) had a positive UDS for BZDs on admission. Univariate analysis showed that those positive for BZDs had higher rates of infectious (3.33% vs. 1.76%, p < 0.001) and thrombotic (2.84% vs. 1.62%, p < 0.001) complications. Multivariate analysis revealed that BZDs significantly increased the odds of infectious and thrombotic complications. Patients who tested positive for BZDs and subsequently developed infection had increased odds (adjusted odds ratio, 1.65; p < 0.001) of developing thrombotic complications. CONCLUSION Trauma patients with a positive UDS for BZDs had higher odds of both infectious and thrombotic complications. Moreover, odds of thrombotic complications were higher in those with infections. LEVEL OF EVIDENCE Epidemiological, level III.

BACKGROUND: In response to the opioid epidemic, many states have enacted policies limiting opioid prescriptions. There is a paucity of evidence of the impact of opioid prescribing interventions in primary care populations, including whether unintended consequences arise from limiting the availability of prescribed opioids. OBJECTIVE: Our aim was to compare changes in opioid overdose and related adverse effects rate among primary care patients following the implementation of state-level prescribing policies. DESIGN: A cohort of primary care patients within an interrupted time series model. PARTICIPANTS: Electronic medical record data for 62,776 adult (18+ years) primary care patients from a major medical center in Vermont from January 1, 2016, to June 30, 2018. INTERVENTIONS: State-level opioid prescription policy changes limiting dose and duration. MAIN MEASURES: Changes in (1) opioid overdose rate and (2) opioid-related adverse effects rate per 100,000 person-months following the July 1, 2017, prescription policy change. KEY RESULTS: Among primary care patients, there was no change in opioid overdose rate following implementation of the prescribing policy (incidence rate ratio; IRR: 0.64, 95% confidence interval; CI: 0.22–1.88). There was a 78% decrease in the opioid-related adverse effects rate following the prescribing policy (IRR: 0.22, 95%CI: 0.09–0.51). This association was moderated by opioid prescription history, with decreases observed among opioid-naïve patients (IRR: 0.18, 95%CI: 0.06–0.59) and among patients receiving chronic opioid prescriptions (IRR: 0.17, 95%CI: 0.03–0.99), but not among those with intermittent opioid prescriptions (IRR: 0.51, 95%CI: 0.09–2.82). CONCLUSIONS: Limiting prescription opioids did not change the opioid overdose rate among primary care patients, but it reduced the rate of opioid-related adverse effects in the year following the state-level policy change, particularly among patients with chronic opioid prescription history and opioid-naïve patients. Limiting the quantity and duration of opioid prescriptions may have beneficial effects among primary care patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06831-4.

Host-microbiome interactions exert a profound influence on human physiology and health outcomes. In particular, certain characteristics of commensal microbiota during a critical period in early life are essential for the establishment of immune tone and metabolic control. An increasing body of evidence suggests that early life exposures that disrupt these interactions can substantially influence life-long risks for respiratory disease. Here, we explore how such early life exposures, including antibiotic exposure, maternal diet, preterm birth, mode of delivery, breastfeeding, and environmental variables shape the infant microbiome, and the mechanisms by such changes can in turn impact respiratory health.

Summary Background & aims Dyslipidemia is a major cardiovascular disease risk factor. Research has proposed mechanisms whereby yogurt may improve circulating lipid concentrations. However, at the population level, the association of yogurt, as distinct from other dairy foods, with these important risk factors is poorly understood. This study aimed to determine whether the circulating lipid profile associated with yogurt is different to the circulating lipid profile that is associated with non-yogurt dairy products, specifically milk and cheese. Methods The current study included the 192,564 US Veterans enrolled in the Million Veteran Program who reported frequency of yogurt consumption (assessed via food frequency questionnaire) and had lipid concentrations assessed. Trends were evaluated with linear regression. Mean age was 65 (SD = 11) years [20, 100 years]. Results A one serve/day higher yogurt consumption was positively associated (coefficient ± SE) with the concentration of high-density lipoprotein cholesterol (HDLC) in individuals who were not (0.26 ± 0.12 mg/dL, P value = 0.025), and who were (0.25 ± 0.09, P value = 0.004), using antilipemic agents. Furthermore, higher yogurt consumption was inversely associated with the concentration of triglycerides, but only in individuals who were not using antilipemic agents (−1.46 ± 0.58, P value = 0.012). Conclusion These apparent beneficial associations of yogurt with HDLC and triglycerides were independent of consumption of non-yogurt dairy foods and were not observed for consumption of either milk or cheese. In this prospective cohort study of U.S. Veterans, we found a beneficial relationship between higher frequency of yogurt consumption with circulating HDLC and triglyceride concentrations that was distinct from non-yogurt dairy foods.

Fanconi anemia (FA) is a hereditary disorder caused by mutations in any 1 of 22 FA genes. The disease is characterized by hypersensitivity to interstrand crosslink (ICL) inducers such as mitomycin C (MMC). In addition to promoting ICL repair, FA proteins such as RAD51, BRCA2, or FANCD2 protect stalled replication forks from nucleolytic degradation during replication stress, which may have a profound impact on FA pathophysiology. Recent studies showed that expression of the putative DNA/RNA helicase SLFN11 in cancer cells correlates with cell death on chemotherapeutic treatment. However, the underlying mechanisms of SLFN11-mediated DNA damage sensitivity remain unclear. Because SLFN11 expression is high in hematopoietic stem cells, we hypothesized that SLFN11 depletion might ameliorate the phenotypes of FA cells. Here we report that SLFN11 knockdown in the FA patient-derived FANCD2-deficient PD20 cell line improved cell survival on treatment with ICL inducers. FANCD2−/−SLFN11−/− HAP1 cells also displayed phenotypic rescue, including reduced levels of MMC-induced chromosome breakage compared with FANCD2−/− cells. Importantly, we found that SLFN11 promotes extensive fork degradation in FANCD2−/− cells. The degradation process is mediated by the nucleases MRE11 or DNA2 and depends on the SLFN11 ATPase activity. This observation was accompanied by an increased RAD51 binding at stalled forks, consistent with the role of RAD51 antagonizing nuclease recruitment and subsequent fork degradation. Suppression of SLFN11 protects nascent DNA tracts even in wild-type cells. We conclude that SLFN11 destabilizes stalled replication forks, and this function may contribute to the attrition of hematopoietic stem cells in FA.

Background Given their mostly rural/suburban locations, level II trauma centers (TCs) may offer greater exposure to and experience in managing geriatric trauma patients. We hypothesized that geriatric patients would have improved outcomes at level II TCs compared to level I TCs. Methods The Pennsylvania Trauma Outcome Study (PTOS) database was retrospectively queried from 2003 to 2017 for geriatric (age ≥65 years) trauma patients admitted to level I and II TCs in Pennsylvania. Patient demographics, injury severity, and clinical outcomes were compared to assess differences in care between level I and II TCs. A multivariate logistic regression model assessed the adjusted impact of care at level I vs II TCs on mortality, complications, and functional status at discharge (FSD). The National Trauma Data Bank (NTDB) was retrospectively queried for geriatric (age ≥65 years) trauma admissions to state-accredited level I or level II TCs in 2013. Results 112 648 patients met inclusion criteria. The proportion of geriatric trauma patients across level I and level II TCs were determined to be 29.1% and 36.2% ( P Discussion Level I and level II TCs had similar rates of mortality, complications, and functional outcomes despite a higher proportion (but lower absolute number) of geriatric patients being admitted to level II TCs. Future consideration for location of centers of excellence in geriatric trauma should include both level I and II TCs.

As critical care medicine has evolved, advanced monitoring and technology means procedures previously confined to the operating room can be safely performed in the ICU under a team-guided delivery system. The safe and efficient completion of these procedures requires an interdisciplinary approach involving nursing, respiratory therapy, and providers along with other supportive specialties. Even emergency procedures reliant on “low-frequency, high-stakes” decision-making can be improved by crew resource management and the fundamentals of teamwork and collaborative care.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common after major trauma. The major pathogenic mechanisms of DVT and PE include a hypercoagulable state,1 venous stasis2,3 and vascular injury—collectively also called Virchow’s triad...

Background The gut microbiota influences many aspects of host physiology, including immune regulation, and is predictive of outcomes in cancer patients. However, whether conventional myelosuppressive chemotherapy affects the gut microbiota in humans with non-haematological malignancy, independent of antibiotic exposure, is unknown. Methods Faecal samples from 19 participants with non-haematological malignancy, who were receiving conventional chemotherapy regimens but not antibiotics, were examined prior to chemotherapy, 7–12 days after chemotherapy, and at the end of the first cycle of treatment. Gut microbiota diversity and composition was determined by 16S rRNA gene amplicon sequencing. Results Compared to pre-chemotherapy samples, samples collected 7–12 days following chemotherapy exhibited increased richness (mean 120 observed species ± SD 38 vs 134 ± 40; p = 0.007) and diversity (Shannon diversity: mean 6.4 ± 0.43 vs 6.6 ± 0.41; p = 0.02). Composition was significantly altered, with a significant decrease in the relative abundance of gram-positive bacteria in the phylum Firmicutes (pre-chemotherapy median relative abundance [IQR] 0.78 [0.11] vs 0.75 [0.11]; p = 0.003), and an increase in the relative abundance of gram-negative bacteria (Bacteroidetes: median [IQR] 0.16 [0.13] vs 0.21 [0.13]; p = 0.01 and Proteobacteria: 0.015 [0.018] vs 0.03 [0.03]; p = 0.02). Differences in microbiota characteristics from baseline were no longer significant at the end of the chemotherapy cycle. Conclusions Conventional chemotherapy results in significant changes in gut microbiota characteristics during the period of predicted myelosuppression post-chemotherapy. Further study is indicated to link microbiome changes during chemotherapy to clinical outcomes.

Background Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group. Methods Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. Measurements: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS). Results Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621–809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1–619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1–49] (r = − 0.42, p = 0.03), and PINP (r = − 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1–49] (r = − 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = − 0.39, p = 0.04), and OC [1–49] (r = − 0.35, p = 0.06). Conclusion Serum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover. Trial registration Irish Medicines Board Clinical Trial Number – CT900/459/1 and EudraCT Number – 2007-005018-37. Registration date: 07-09-2007.

BackgroundChronic infection and concomitant airway inflammation is the leading cause of morbidity and mortality for people living with cystic fibrosis (CF). Although chronic infection in CF is undeniably polymicrobial, involving a lung microbiota, infection surveillance and control approaches remain underpinned by classical aerobic culture-based microbiology. How to use microbiomics to direct clinical management of CF airway infections remains a crucial challenge. A pivotal step towards leveraging microbiome approaches in CF clinical care is to understand the ecology of the CF lung microbiome and identify ecological patterns of CF microbiota across a wide spectrum of lung disease. Assessing sputum samples from 299 patients attending 13 CF centres in Europe and the USA, we determined whether the emerging relationship of decreasing microbiota diversity with worsening lung function could be considered a generalised pattern of CF lung microbiota and explored its potential as an informative indicator of lung disease state in CF.ResultsWe tested and found decreasing microbiota diversity with a reduction in lung function to be a significant ecological pattern. Moreover, the loss of diversity was accompanied by an increase in microbiota dominance. Subsequently, we stratified patients into lung disease categories of increasing disease severity to further investigate relationships between microbiota characteristics and lung function, and the factors contributing to microbiota variance. Core taxa group composition became highly conserved within the severe disease category, while the rarer satellite taxa underpinned the high variability observed in the microbiota diversity. Further, the lung microbiota of individual patient were increasingly dominated by recognised CF pathogens as lung function decreased. Conversely, other bacteria, especially obligate anaerobes, increasingly dominated in those with better lung function. Ordination analyses revealed lung function and antibiotics to be main explanators of compositional variance in the microbiota and the core and satellite taxa. Biogeography was found to influence acquisition of the rarer satellite taxa.ConclusionsOur findings demonstrate that microbiota diversity and dominance, as well as the identity of the dominant bacterial species, in combination with measures of lung function, can be used as informative indicators of disease state in CF.

In 1999, Ramsey and colleagues published the results of a clinical trial of aerosolised tobramycin in cystic fibrosis (CF) to target chronic Pseudomonas aeruginosa infection.1 In keeping with their earlier demonstration of efficacy,2 they reported treatment to be associated with a reduction in P. aeruginosa sputum density and substantial clinical benefit (improved lung function and reduced risk of hospitalisation). Consistent findings were reported in subsequent studies,3 4 leading tobramycin inhaled powder/solution (TIP/S) maintenance therapy to go on to become the most common antibiotic used to treat people with cystic fibrosis (PWCF). While none of these studies related clinical outcome to microbiological impact directly, it is widely assumed that depletion of P. aeruginosa underpins TIP/S benefit. This presumptive mechanism of TIP/S, and its limitation to those with chronic P. aeruginosa infection, has been challenged by two recent studies. In this issue, Heirali and colleagues report an investigation of the microbial predictors of response to TIP/S in adults with CF.5 16S rRNA gene amplicon sequencing was applied to banked sputum samples from 41 patients with chronic P. aeruginosa infection who had received TIP/S for at least 1 year and from whom sputum samples were available before and after the initiation of therapy. Somewhat unexpectedly, their study determined response to therapy (defined by the absence of a net decrease in forced expiratory volume in one second (FEV1)) to be associated with higher relative abundance of staphylococci …

Our goal was to elucidate microRNAs (miRNAs) that may repress the excess bone morphogenetic protein (BMP) signaling observed during pathological calcification in theKlothomouse model of kidney disease. We hypothesized that restoring healthy levels of miRNAs that post-transcriptionally repress osteogenic calcific factors may decrease aortic calcification. Our relative abundance profiles of miRNAs in healthy aorta differ greatly from those in calcified mouse aorta. Many of these miRNAs are predicted to regulate proteins involved in BMP signaling and may control osteogenesis. Two differentially regulated miRNAs, miR-145 and miR-378, were selected based on three criteria: reduced levels in calcified aorta, the ability to target more than one protein in the BMP signaling pathway, and conservation of targeted sequences between humans and mice. Forced expression using a lentiviral vector demonstrated that restoring normal levels repressed the synthesis of BMP2 and other pro-osteogenic proteins and inhibited pathological aortic calcification inKlothomice with renal insufficiency. This study identified miRNAs that may impact BMP signaling in both sexes and demonstrated the efficacy of selected miRNAs in reducing aortic calcificationin vivo. Calcification of the aorta and the aortic valve resulting from abnormal osteogenesis is common in those with kidney disease, diabetes, and high cholesterol. Such vascular osteogenesis is a clinically significant feature. The calcification modulating miRNAs described here are candidates for biomarkers and “miRNA replacement therapies” in the context of chronic kidney disease and other pro-calcific conditions.

BackgroundMassive transfusion protocols (MTP) are a routine component of any major trauma center’s armamentarium in the management of exsanguinating hemorrhages. Little is known about the potential complications of those that survive a MTP. We sought to determine the incidence of venous thromboembolism (VTE) following MTP. We hypothesized that MTP would be associated with a higher risk of VTE when compared with a risk-adjusted control population without MTP.MethodsThe Pennsylvania Trauma Outcome Study database was retrospectively queried from 2015 to 2018 for trauma patients who developed VTE and survived until discharge at accredited trauma centers in Pennsylvania. Patient demographics, injury severity, and clinical outcomes were compared to assess differences in VTE development between MTP and non-MTP patients. A multivariate logistic regression model assessed the adjusted impact of MTP on VTE development.Results176 010 patients survived until discharge, meeting inclusion criteria. Of those, 1667 developed a VTE (pulmonary embolism [PE]: 662 [0.4%]; deep vein thrombosis [DVT]: 1142 [0.6%]; PE and DVT: 137 [0.1%]). 1268 patients (0.7%) received MTP and, of this subset of patients, 171 (13.5%) developed a VTE during admission. In adjusted analysis, patients who had a MTP and survived until discharge had a higher odds of developing a VTE (adjusted odds ratio: 2.62; 95% CI: 2.13-3.24; P < .001).DiscussionMTP is a harbinger for higher risk of VTE in those patients who survive. This may, in part, be related to the overcorrection of coagulation deficits encountered in the hemorrhagic event. A high index of suspicion for the development of VTE as well as aggressive VTE prophylaxis is warranted in those patients who survive MTP.

Summary Studies investigating whether there is a causative link between the gut microbiota and lifespan have largely been restricted to invertebrates or to mice with a reduced lifespan because of a genetic deficiency. We investigate the effect of early-life antibiotic exposure on otherwise healthy, normal chow-fed, wild-type mice, monitoring these mice for more than 700 days in comparison with untreated control mice. We demonstrate the emergence of two different low-diversity community types, post-antibiotic microbiota (PAM) I and PAM II, following antibiotic exposure. PAM II but not PAM I mice have impaired immunity, increased insulin resistance, and evidence of increased inflammaging in later life as well as a reduced lifespan. Our data suggest that differences in the composition of the gut microbiota following antibiotic exposure differentially affect host health and longevity in later life.

Summary Background Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Methods In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year. Findings Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies. Funding Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC).

Lymphatic filariasis affects ∼120 million people and can result in elephantiasis and hydrocele. Here, we report the nearly complete genome sequence of the best-studied causative agent of lymphatic filariasis, Brugia malayi. The assembly contains four autosomes, an X chromosome, and only eight gaps but lacks a contiguous sequence for the known Y chromosome.

Background Although the healthy human skin microbiome has been the subject of recent studies, it is not known whether alterations among commensal microbes contribute to surgical site infections (SSIs). Our objective in this study was to characterize temporal and spatial variation in the skin microbiota of patients undergoing colorectal surgery and determine if dysbiosis contributes to SSIs. Methods Sixty one adults scheduled to undergo elective colon or rectal resection were identified by convenience sampling. By analyzing bacterial 16S rRNA gene sequences isolated from clinical samples, we used a culture-independent strategy to monitor perioperative changes in microbial diversity of fecal samples and the skin. Results A total of 990 samples from 61 patients were analyzed. Alpha diversity on the skin decreased after surgery but later recovered at the postoperative clinic visit. In most patients, we observed a transient postoperative loss of skin commensals (Corynebacterium and Propionibacterium) at the surgical site, which were replaced by potential pathogens and intestinal anaerobes (eg, Enterobacteriaceae). These changes were not observed on skin that was uninvolved in the surgical incision (chest wall). One patient developed a wound infection. Incisional skin swabs from this patient demonstrated a sharp postoperative increase in the abundance of Enterococcus, which was also cultured from wound drainage. Conclusions We observed reproducible perioperative changes in the skin microbiome following surgery. The low incidence of SSIs in this cohort precluded analysis of associations between dysbiosis and infection. We postulate that real-time monitoring of the skin microbiome could provide actionable findings about the pathogenesis of SSIs.

Background: Inflammatory bowel disease (IBD) has a remitting and relapsing disease course; however, relatively little is understood regarding how inflammatory damage in acute colitis influences the microbiota, epithelial barrier, and immune function in subsequent colitis. Methods: Mice were administered trinitrobenzene sulphonic acid (TNBS) via enema, and inflammation was assessed 2 days (d2) or 28 days (d28) later. Colitis was reactivated in some mice by re-treating at 28 days with TNBS and assessing 2 days later (d30). Epithelial responsiveness to secretagogues, microbiota composition, colonic infiltration, and immune activation was compared between all groups Results: At day 28, the distal colon had healed, mucosa was restored, and innate immune response had subsided, but colonic transepithelial transport (P = 0.048), regulatory T-cell (TREG) infiltration (P = 0.014), adherent microbiota composition (P = 0.0081), and responsiveness of stimulated innate immune bone marrow cells (P < 0.0001 for IL-1β) differed relative to health. Two days after subsequent instillation of TNBS (d30 mice), the effects on inflammatory damage (P < 0.0001), paracellular permeability (P < 0.0001), and innate immune infiltration (P < 0.0001 for Ly6C+ Ly6G- macrophages) were reduced relative to d2 colitis. However, TREG infiltration was increased (P < 0.0001), and the responsiveness of stimulated T cells in the mesenteric lymph nodes shifted from pro-inflammatory at d2 to immune-suppressive at d30 (P < 0.0001 for IL-10). These effects were observed despite similar colonic microbiota composition and degradation of the mucosal layer between d2 and d30. Conclusions: Collectively, these results indicate that acute colitis chronically alters epithelial barrier function and both innate and adaptive immune responses. These effects reduce the consequences of a subsequent colitis event, warranting longitudinal studies in human IBD subjects. Refereed/Peer-reviewed

Signaling between intestinal microbiota and the brain influences neurologic outcome in multiple forms of brain injury. The impact of gut microbiota following traumatic brain injury (TBI) has not been well established. Our objective was to compare TBI outcomes in specific pathogen-free mice with or without depletion of intestinal bacteria. Adult male C57BL6/J SPF mice (n=6/group) were randomized to standard drinking water or ampicillin (1g/L), metronidazole (1g/L), neomycin (1g/L), and vancomycin (0.5g/L) (AMNV) containing drinking water 14 days prior to controlled cortical impact (CCI) model of TBI. 16S rRNA gene sequencing of fecal pellets was performed and alpha and beta diversity determined. Hippocampal neuronal density and microglial activation was assessed 72 hours post-injury by immunohistochemistry. In addition, mice (n=8–12/group) were randomized to AMNV or no treatment initiated immediately after CCI and memory acquisition (fear conditioning) and lesion volume assessed. Mice receiving AMNV had significantly reduced alpha diversity (p

Background Oxaliplatin is used extensively for the treatment of gastrointestinal cancer and other malignancies, with increased frequency of use in recent years. Hypersensitivity reactions (HSRs) can pose a major problem in clinical practice because they can limit the use of oxaliplatin in the care of malignancies in which it has proven efficacy. Nurses play an integral role in the administration of oxaliplatin; therefore, they need to be well educated in the prevention, detection, and management of HSRs. Objectives This article reviews the symptoms of HSRs associated with oxaliplatin, the specific management of HSRs associated with oxaliplatin, the role of desensitization, and the potential use of skin testing to better identify patients at risk for HSR. Methods This article reviews the literature related to the diagnosis, prevention, and management of HSRs associated with oxaliplatin and outlines nurses' role. Findings Oxaliplatin HSRs can occur at any cycle, but patients are at highest risk after they have received six prior infusions of oxaliplatin.

BACKGROUND While issues regarding triage of severely injured trauma patients are well publicized, little information exists concerning the difference between triage rates for patients transported by advanced life support (ALS) and basic life support (BLS). We sought to analyze statewide trends in undertriage (UT) and overtriage (OT) to address this question, hypothesizing that there would be a difference between the UT and OT rates for ALS compared with BLS over a 13-year period. METHODS All patients submitted to Pennsylvania Trauma Outcomes Study database from 2003 to 2015 were analyzed. Undertriage was defined as not calling a trauma alert for patients with an Injury Severity Score (ISS) of 16 or greater. Overtriage was defined as calling a trauma alert for patients with an ISS of 9 or less. A logistic regression was used to assess mortality between triage groups in ALS and BLS. A multinomial logistic regression assessed the adjusted impact of ALS versus BLS transport on UT and OT versus normal triage while controlling for age, sex, Glasgow Coma Scale, systolic blood pressure (SBP), pulse, Shock Index and injury year. RESULTS A total of 462,830 patients met inclusion criteria, of which 115,825 had an ISS of 16 or greater and 257,855 had an ISS of 9 or less. Both ALS and BLS had significantly increased mortality when patients were undertriaged compared with the reference group. Multivariate analysis in the form of a multinomial logistic regression revealed that patients transported by ALS had a decreased adjusted rate of undertriage (relative risk ratio, 0.92; 95% confidence interval, 0.87-0.97; p = 0.003) and an increased adjusted rate of OT (relative risk ratio, 1.59; 95% confidence interval, 1.54-1.64; p < 0.001) compared with patients transported by BLS. CONCLUSION Compared with their BLS counterparts, while UT is significantly lower, OT is substantially higher in ALS-further increasing the high levels of resource (over)utilization in trauma patients. Undertriage in both ALS and BLS are associated with increased mortality rates. Additional education, especially in the BLS provider, on identifying the major trauma victim may be warranted based on the results of this study. LEVEL OF EVIDENCE Epidemiological, Level III.

Hematologic B-cell malignancies, which have varying behavior patterns, disease processes, and treatment responses, include non-Hodgkin lymphoma, leukemias, and myeloma. Although monoclonal antibodies and other agents have led to dramatic advances in the treatment of B-cell malignancies, the development of small molecules have enhanced the ability to treat and manage these malignancies and their adverse events (AEs). Oncology nurses need to be educated on the unique side effects for each class of these agents so that they can administer interventions to prevent and manage AEs in patients.

Background Those older than 65 years represent the fastest growing demographic in the United States. As such, their care has been emphasized by trauma entities such as the American College of Surgeons Committee on Trauma. Unfortunately, much of that focus has been of their care once they reach the hospital with little attention on the access of geriatric trauma patients to trauma centers (TCs). We sought to determine the rate of geriatric undertriage (UT) to TCs within a mature trauma system and hypothesized that there would be variation and clustering of the geriatric undertriage rate (UTR) within a mature trauma system because of the admission of geriatric trauma patient to nontrauma centers (NTCs). Methods From 2003 to 2015, all geriatric (age >65 years) admissions with an Injury Severity Score of greater than 9 from the Pennsylvania Trauma Systems Foundation (PTSF) registry and those meeting trauma criteria (International Classification of Diseases, Ninth Revision: 800-959) from the Pennsylvania Health Care Cost Containment Council (PHC4) database were included. Undertriage rate was defined as patients not admitted to TCs (n = 27) divided by the total number of patients as from the PHC4 database. The PHC4 contains all inpatient admissions within Pennsylvania (PA), while PTSF reports admissions to PA TCs. The zip code of residence was used to aggregate calculations of UTR as well as other aggregate patient and census demographics, and UTR was categorized into lower, middle box, and upper quartiles. ArcGIS Desktop: Version 10.7, ESRI, Redlands, CA and GeoDa: Version 1.14.0, Open source license were used for geospatial mapping of UT with a spatial empirical Bayesian smoothed UTR, and Stata: Version 16.1, Stata Corp., College Station TX was used for statistical analyses. Results Pennsylvania Trauma Systems Foundation had 58,336 cases, while PHC4 had 111,626 that met the inclusion criteria, resulting in a median (Q1-Q3) smoothed UTR of 50.5% (38.2-60.1%) across PA zip code tabulation areas. Geospatial mapping reveals significant clusters of UT regions with high UTR in some of the rural regions with limited access to a TC. The lowest quartile UTR regions tended to have higher population density relative to the middle or upper quartile UTR regions. At the patient level, the lowest UTR regions had more racial and ethnic diversity, a higher injury severity, and higher rates of treatment at a TC. Undertriage rate regions that were closer to NTCs had a higher odds of being in the upper UTR quartile; 4.48 (2.52-7.99) for NTC with less than 200 beds and 8.53 (4.70-15.47) for NTC with 200 beds or greater compared with zip code tabulation areas with a TC as the closest hospital. Conclusion There are significant clusters of geriatric UT within a mature trauma system. Increased emphasis needs to focus prehospital on identifying the severely injured geriatric patient including specific geriatric triage protocols. Level of evidence Epidemiological, Level III.

Chronic disruption of the intestinal microbiota in adult cystic fibrosis (CF) patients is associated with local and systemic inflammation, and has been linked to the risk of serious comorbidities. Supplementation with high amylose maize starch (HAMS) might provide clinical benefit by promoting commensal bacteria and the biosynthesis of immunomodulatory metabolites. However, whether the disrupted CF gut microbiota has the capacity to utilise these substrates is not known. We combined metagenomic sequencing, in vitro fermentation, amplicon sequencing, and metabolomics to define the characteristics of the faecal microbiota in adult CF patients and assess HAMS fermentation capacity. Compared to healthy controls, the faecal metagenome of adult CF patients had reduced bacterial diversity and prevalence of commensal fermentative clades. In vitro fermentation models seeded with CF faecal slurries exhibited reduced acetate levels compared to healthy control reactions, but comparable levels of butyrate and propionate. While the commensal genus Faecalibacterium was strongly associated with short chain fatty acid (SCFA) production by healthy microbiota, it was displaced in this role by Clostridium sensu stricto 1 in the microbiota of CF patients. A subset of CF reactions exhibited enterococcal overgrowth, resulting in lactate accumulation and reduced SCFA biosynthesis. The addition of healthy microbiota to CF faecal slurries failed to displace predominant CF taxa, or substantially influence metabolite biosynthesis. Despite significant microbiota disruption, the adult CF gut microbiota retains the capacity to exploit HAMS. Our findings highlight the potential for taxa associated with the altered CF gut microbiotato mediate prebiotic effects in microbial systems subject to ongoing perturbation, irrespective of the depletion of common commensal clades.

OBJECTIVE: The purpose of this study was to examine associations of the mother-father relationship and social support with depressive symptoms during pregnancy among Black mothers and fathers. METHODS: Fifty Black mother-father dyads from the Midwest completed a packet of questionnaires that included conflict with partner, social support, depressive symptoms and socio-demographic characteristics. RESULTS: Twenty-four percent of mothers and 16% of fathers had Center for Epidemiological Studies-Depression (CES-D) scores ≥ 23, which have been correlated with major depression diagnosis. There were no differences in depressive symptoms between mothers and fathers. Fathers reporting high depressive symptoms were not more likely to be partnered with mothers reporting high depressive symptoms. Controlling for age, higher levels of conflict with partner and lower levels of social support predicted higher levels of depressive symptoms for both mothers and fathers. CLINICAL IMPLICATIONS: Black expectant mothers and fathers may be at risk for clinical depression. Fathers experienced comparable levels of depressive symptoms with mothers, indicating the need to consider fathers' psychological adjustment during pregnancy. Higher levels of conflict with partner and lower levels of social support predicted higher levels of depressive symptoms for both parents. Maternal-child nurses should assess for mothers' as well as fathers' experiences of depressive symptoms and the mother-father relationship when providing prenatal care.

The forensic pathologist is an integral part of the trauma surgery team. Trauma surgeons depend on autopsy descriptions for accurate measurement of the severity of trauma and determination of the chance of mortality. The outcome of liver injury improved greatly during the 20th century, primarily due to improved diagnostic and management techniques. In many trauma cases, survival depends on injuries to areas other than the liver. Measurement of the severity of liver trauma often uses the TRISS (Trauma and Injury Severity Score) method, which depends on the nature, location, and size of injuries. Injuries produced by blunt trauma depend on the direction of the force and its interaction with the anatomic structures that surround the liver. Sharp force and gunshot injuries depend on the portions of the liver involved and the amount of kinetic energy transmitted to the tissue. The liver is susceptible to injury from resuscitation, although these injuries are usually not severe. Acad Forensic Pathol. 2018 8(2): 184-191

BACKGROUND Proper triage of critically injured trauma patients to accredited trauma centers (TCs) is essential for survival and patient outcomes. We sought to determine the percentage of patients meeting trauma criteria who received care at non-TCs (NTCs) within the statewide trauma system that exists in the state of Pennsylvania. We hypothesized that a substantial proportion of the trauma population would be undertriaged to NTCs with undertriage rates (UTR) decreasing with increasing severity of injury. METHODS All adult (age ≥15) hospital admissions meeting trauma criteria (ICD-9, 800-959; Injury Severity Score [ISS], > 9 or > 15) from 2003 to 2015 were extracted from the Pennsylvania Health Care Cost Containment Council (PHC4) database, and compared with the corresponding trauma population within the Pennsylvania Trauma Systems Foundation (PTSF) registry. PHC4 contains all hospital admissions within PA while PTSF collects data on all trauma cases managed at designated TCs (Level I-IV). The percentage of patients meeting trauma criteria who are undertriaged to NTCs was determined and Network Analyst Location-Allocation function in ArcGIS Desktop was used to generate geospatial representations of undertriage based on ISSs throughout the state. RESULTS For ISS > 9, 173,022 cases were identified from 2003 to 2015 in PTSF, while 255,263 cases meeting trauma criteria were found in the PHC4 database over the same timeframe suggesting UTR of 32.2%. For ISS > 15, UTR was determined to be 33.6%. Visual geospatial analysis suggests regions with limited access to TCs comprise the highest proportion of undertriaged trauma patients. CONCLUSION Despite the existence of a statewide trauma framework for over 30 years, approximately, a third of severely injured trauma patients are managed at hospitals outside of the trauma system in PA. Intelligent trauma system design should include an objective process like geospatial mapping rather than the current system which is driven by competitive models of financial and health care system imperatives. LEVEL OF EVIDENCE Epidemiological study, level III; Therapeutic, level IV.

Background The care of patients at individual trauma centers (TCs) has been carefully optimized, but not the placement of TCs within the trauma systems. We sought to objectively determine the optimal placement of trauma centers in Pennsylvania using geospatial mapping. Methods We used the Pennsylvania Trauma Systems Foundation (PTSF) and Pennsylvania Health Care Cost Containment Council (PHC4) registries for adult (age ≥15) trauma between 2003 and 2015 (n = 377,540 and n = 255,263). TCs and zip codes outside of PA were included to account for edge effects with trauma cases aggregated to the Zip Code Tabulation Area centroid of residence. Model assumptions included no previous TCs (clean slate); travel time intervals of 45, 60, 90, and 120 minutes; TC capacity based on trauma cases per bed size; and candidate hospitals ≥200 beds. We used Network Analyst Location-Allocation function in ArcGIS Desktop to generate models optimally placing 1 to 27 TCs (27 current PA TCs) and assessed model outcomes. Results At a travel time of 60 minutes and 27 sites, optimally placed models for PTSF and PHC4 covered 95.6% and 96.8% of trauma cases in comparison with the existing network reaching 92.3% or 90.6% of trauma cases based on PTSF or PHC4 inclusion. When controlled for existing coverage, the optimal numbers of TCs for PTSF and PHC4 were determined to be 22 and 16, respectively. Conclusions The clean slate model clearly demonstrates that the optimal trauma system for the state of Pennsylvania differs significantly from the existing system. Geospatial mapping should be considered as a tool for informed decision-making when organizing a statewide trauma system. Level of evidence Epidemiological study/Care management, level III.

Background The role of fecal microbiota transplant (FMT) in the treatment of pediatric inflammatory bowel disease (IBD) is unknown. The aims of this study were to assess safety, clinical response, and gut microbiome alterations in children with Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Methods In this open-label, single-center prospective trial, patients with IBD refractory to medical therapy underwent a single FMT by upper and lower endoscopy. Adverse events, clinical response, gut microbiome, and biomarkers were assessed at baseline, 1 week, 1 month, and 6 months following FMT. Results Twenty-one subjects were analyzed, with a median age of 12 years, of whom 57% and 28% demonstrated clinical response at 1 and 6 months post-FMT, respectively. Two CD patients were in remission at 6 months. Adverse events attributable to FMT were mild to moderate and self-limited. Patients prior to FMT showed decreased species diversity and significant microbiome compositional differences characterized by increased Enterobacteriaceae, Enterococcus, Haemophilus, and Fusobacterium compared with donors and demonstrated increased species diversity at 30 days post-FMT. At 6 months, these changes shifted toward baseline. Clinical responders had a higher relative abundance of Fusobacterium and a lower diversity at baseline, as well as a greater shift toward donor-like microbiome after FMT compared with nonresponders. Conclusions A single FMT is relatively safe and can result in a short-term response in young patients with active IBD. Responders possessed increased Fusobacterium prior to FMT and demonstrated more significant microbiome changes compared with nonresponders after FMT. Microbiome characteristics may help in predicting response.

Background G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Methods Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4month double-blind, placebo-controlled, crossover study of ivacaftor with 28days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. Results No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P = 0.95, square root ECV=−4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time ( P U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P =0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered ( P =0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor ( P =0.004, two-tailed paired Student's t- test). Conclusions The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

There is growing consensus that symptomatic uncomplicated diverticular disease is a chronic inflammatory condition, and that alterations in the fecal microbiota may contribute to its pathogenesis.The aim of this study was to relate the fecal microbiota composition in symptomatic uncomplicated diverticular disease to measures of inflammation, symptoms, and history of previous acute diverticulitis.Fecal microbiota composition in 28 individuals with symptomatic uncomplicated diverticular disease was characterized by 16S RNA gene amplicon sequencing. Microbiota composition was related to clinical history, symptom and inflammation measures, and demographic variables.Previous acute diverticulitis was associated with higher relative abundance of Pseudobutyrivibrio, Bifidobacterium, Christensenellaceae family, and Mollicutes RF9 order (P=0.004, 0.006, 0.010, and 0.019, respectively), but not microbiota alpha or beta diversity. A higher bloating severity score was significantly correlated with a higher relative abundance of Ruminococcus (P=0.032), and significantly inversely correlated with the relative abundance of the Roseburia (P=0.002). Fecal calprotectin levels were positively correlated with alpha diversity (Shannon index, P=0.005) and the relative abundance of Lactobacillus (P=0.004). Pain score was positively correlated with the relative abundance of Cyanobacterium (adjusted P=0.032).Patient symptoms in symptomatic diverticular disease are significantly correlated with features of the fecal microbiota. Our findings suggest the potential utility of therapies that target intestinal microbiology, such as dietary prebiotic supplements.

Previous research suggests adolescent trauma patients can be managed equally effectively at pediatric and adult trauma centers. We sought to determine whether this association would be upheld for adolescent severe polytrauma patients. We hypothesized that no difference in adjusted outcomes would be observed between pediatric trauma centers (PTCs) and adult trauma centers (ATCs) for this population.All severely injured adolescent (aged 12-17 years) polytrauma patients were extracted from the Pennsylvania Trauma Outcomes Study database from 2003 to 2015. Polytrauma was defined as an Abbreviated Injury Scale (AIS) score ≥3 for two or more AIS-defined body regions. Dead on arrival, transfer, and penetrating trauma patients were excluded from analysis. ATC were defined as adult-only centers, whereas standalone pediatric hospitals and adult centers with pediatric affiliation were considered PTC. Multilevel mixed-effects logistic regression models assessed the adjusted impact of center type on mortality and total complications while controlling for age, shock index, Injury Severity Score, Glasgow Coma Scale motor score, trauma center level, case volume, and injury year. A generalized linear mixed model characterized functional status at discharge (FSD) while controlling for the same variables.A total of 1,606 patients met inclusion criteria (PTC: 868 [54.1%]; ATC: 738 [45.9%]), 139 (8.66%) of which died in-hospital. No significant difference in mortality (adjusted odds ratio [AOR]: 1.10, 95% CI 0.54-2.24; p = 0.794; area under the receiver operating characteristic: 0.89) was observed between designations in adjusted analysis; however, FSD (AOR: 0.38, 95% CI 0.15-0.97; p = 0.043) was found to be lower and total complication trends higher (AOR: 1.78, 95% CI 0.98-3.32; p = 0.058) at PTC for adolescent polytrauma patients.Contrary to existing literature on adolescent trauma patients, our results suggest patients aged 12-17 presenting with polytrauma may experience improved overall outcomes when managed at adult compared to pediatric trauma centers.Epidemiologic study, level III.