The Relationship Between Hospital Capability and Mortality in Sepsis: Development of a Sepsis-Related Hospital Capability Index.

OBJECTIVES: Regionalized sepsis care could improve sepsis outcomes by facilitating the interhospital transfer of patients to higher-capability hospitals. There are no measures of sepsis capability to guide the identification of such hospitals, although hospital case volume of sepsis has been used as a proxy. We evaluated the performance of a novel hospital sepsis-related capability (SRC) index as compared with sepsis case volume. DESIGN: Principal component analysis (PCA) and retrospective cohort study. SETTING: A total of 182 New York (derivation) and 274 Florida and Massachusetts (validation) nonfederal hospitals, 2018. PATIENTS: A total of 89,069 and 139,977 adult patients (≥ 18 yr) with sepsis were directly admitted into the derivation and validation cohort hospitals, respectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We derived SRC scores by PCA of six hospital resource use characteristics (bed capacity, annual volumes of sepsis, major diagnostic procedures, renal replacement therapy, mechanical ventilation, and major therapeutic procedures) and classified hospitals into capability score tertiles: high, intermediate, and low. High-capability hospitals were mostly urban teaching hospitals. Compared with sepsis volume, the SRC score explained more variation in hospital-level sepsis mortality in the derivation (unadjusted coefficient of determination [ R2 ]: 0.25 vs 0.12, p < 0.001 for both) and validation (0.18 vs 0.05, p < 0.001 for both) cohorts; and demonstrated stronger correlation with outward transfer rates for sepsis in the derivation (Spearman coefficient [ r ]: 0.60 vs 0.50) and validation (0.51 vs 0.45) cohorts. Compared with low-capability hospitals, patients with sepsis directly admitted into high-capability hospitals had a greater number of acute organ dysfunctions, a higher proportion of surgical hospitalizations, and higher adjusted mortality (odds ratio [OR], 1.55; 95% CI, 1.25-1.92). In stratified analysis, worse mortality associated with higher hospital capability was only evident among patients with three or more organ dysfunctions (OR, 1.88 [1.50-2.34]). CONCLUSIONS: The SRC score has face validity for capability-based groupings of hospitals. Sepsis care may already be de facto regionalized at high-capability hospitals. Low-capability hospitals may have become more adept at treating less complicated sepsis.

Computerized electrocardiogram data transformation enables effective algorithmic differentiation of wide QRS complex tachycardias.

BACKGROUND: Accurate automated wide QRS complex tachycardia (WCT) differentiation into ventricular tachycardia (VT) and supraventricular wide complex tachycardia (SWCT) can be accomplished using calculations derived from computerized electrocardiogram (ECG) data of paired WCT and baseline ECGs. OBJECTIVE: Develop and trial novel WCT differentiation approaches for patients with and without a corresponding baseline ECG. METHODS: We developed and trialed WCT differentiation models comprised of novel and previously described parameters derived from WCT and baseline ECG data. In Part 1, a derivation cohort was used to evaluate five different classification models: logistic regression (LR), artificial neural network (ANN), Random Forests [RF], support vector machine (SVM), and ensemble learning (EL). In Part 2, a separate validation cohort was used to prospectively evaluate the performance of two LR models using parameters generated from the WCT ECG alone (Solo Model) and paired WCT and baseline ECGs (Paired Model). RESULTS: Of the 421 patients of the derivation cohort (Part 1), a favorable area under the receiver operating characteristic curve (AUC) by all modeling subtypes: LR (0.96), ANN (0.96), RF (0.96), SVM (0.96), and EL (0.97). Of the 235 patients of the validation cohort (Part 2), the Solo Model and Paired Model achieved a favorable AUC for 103 patients with (Solo Model 0.87; Paired Model 0.95) and 132 patients without (Solo Model 0.84; Paired Model 0.95) a corroborating electrophysiology procedure or intracardiac device recording. CONCLUSION: Accurate WCT differentiation may be accomplished using computerized data of (i) the WCT ECG alone and (ii) paired WCT and baseline ECGs.

A multi-modal diagnostic model improves detection of cardiac amyloidosis among patients with diagnostic confirmation by cardiac biopsy.

BACKGROUND: Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed. OBJECTIVES: We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard. METHODS: Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression. RESULTS: The overall cohort was characterized by elevated BNP (median 727 ng/mL), increased left ventricular wall thickness (IWT; median 1.7 cm), and reduced voltage-to-mass ratio (median 0.06 mm/[g/m2]). One hundred and thirteen patients (46%) had either light chain (n = 53) or transthyretin (n = 60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e', and low limb lead voltage (<0.5 mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity). CONCLUSION: Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease.

Trends in Sodium Intake in Children and Adolescents in the US and the Impact of US Department of Agriculture Guidelines: NHANES 2003-2016.

OBJECTIVE: To examine trends in sodium intake and the impact of nutritional guidelines in the US pediatric population. STUDY DESIGN: Sodium intake data collected between 2003 and 2016 in the US National Health and Nutrition Examination Surveys (NHANES) were analyzed. Trends in intake for individuals aged 4-17 years and subgroups based on age, sex, and race and ethnicity were examined. Adherence to US Department of Agriculture guidelines was assessed. RESULTS: A total of 16 013 individuals (50.6% male) were included in the analysis. The median sodium intake was 2840 mg/day (95% CI, 2805-2875 mg/day), decreasing from 2912 mg/day (95% CI 2848-2961 mg/day) in 2003-2004 to 2787 mg/day (95% CI, 2677-2867 mg/day) in 2015-2016 (P = .005). Intake increased with age (2507 mg/day for individuals aged 4-8, 2934 mg/day for those aged 9-13 years, and 3124 mg/day for those aged 14-17 years; P < .001) and was greater in males than in females (3053 mg/day vs 2624 mg/day; P < .001). Caucasians, Hispanics, and African Americans consumed 2860, 2733, and 2880 mg/day, respectively (P < .001). Population adherence to US Department of Agriculture recommendations was 25.0% in 2003-2010 and 25.5% in 2011-2016 (P = .677). No age, sex, or racial/ethnicity subgroup had an adherence rate >30% after implementation of pediatric guidelines in 2010. CONCLUSIONS: Sodium intake remains elevated in all pediatric population segments, and guideline adherence is poor. A greater effort to reduce sodium consumption is needed to mitigate future cardiovascular disease risk.

Maximal dose-response of vitamin-K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis.

Low concentrations of serum vitamin K accompany high concentrations of undercarboxylated osteocalcin (ucOC) and osteoporotic fractures. Although vitamin K2 (MK-4) is approved as a therapeutic agent for the treatment of osteoporosis in some countries, the dose-response is unknown. The objective of this study was to assess the improvement in carboxylation of osteocalcin (OC) in response to escalating doses of MK-4 supplementation. A nine-week, open-labeled, prospective cohort study was conducted in 29 postmenopausal women who suffered hip or vertebral compression fractures. Participants took low-dose MK-4 (0.5 mg) for 3 weeks (until the second visit), then medium-dose MK-4 (5 mg) for 3 weeks (until the third visit), then high-dose MK-4 (45 mg) for 3 weeks. The mean ± SD age of the participants was 69 ± 9 years. MK-4 dose (p < 0.0001), but neither age nor other relevant medications (e.g. bisphosphonates) correlated with improvement in %ucOC. As compared to baseline concentrations (geometric mean ± SD) of 16.8 ± 2.4, 0.5 mg supplementation halved %ucOC to 8.7 ± 2.2 (p < 0.0001) and the 5-mg dose halved %ucOC again (to 3.9 ± 2.2; p = 0.0002 compared to 0.5-mg dose). However, compared to 5 mg/day, there was no additional benefit of 45 mg/day (%ucOC 4.6; p = NS vs. 5-mg dose). MK-4 supplementation resulted in borderline increases in γ-carboxylated osteocalcin (glaOC; p = 0.07). There were no major side effects of MK-4 supplementation. In postmenopausal women with osteoporotic fractures, supplementation with either 5 or 45 mg/day of MK-4 reduces ucOC to concentrations typical of healthy, pre-menopausal women.

Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft.

A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors, but fails to mobilize 33% of normal allogeneic sibling donors in 1 apheresis. We hypothesized that changing the route of administration of plerixafor from SC to IV may overcome the low stem cell yields and allow collection in 1 day. A phase 1 trial followed by a phase 2 efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0.32 mg/kg. The primary outcome of reducing the failure to collect ≥2 × 106 CD34+/kg recipient weight in 1 apheresis collection to ≤10% was not reached. The failure rate was 34%. Studies evaluating the stem cell phenotype and gene expression revealed a novel plasmacytoid dendritic cell precursor preferentially mobilized by plerixafor with high interferon-α producing ability. The observed cytomegalovirus (CMV) viremia rate for patients at risk was low (15%), as were the rates of acute grade 2-4 graft-versus-host disease (GVHD) (21%). Day 100 treatment related mortality was low (3%). In conclusion, plerixafor results in rapid stem cell mobilization regardless of route of administration and resulted in novel cellular composition of the graft and favorable recipient outcomes. These trials were registered at clinicaltrials.gov as #NCT00241358 and #NCT00914849.

Detecting associations between intact connectomes and clinical covariates using recursive partitioning object-oriented data analysis.

Many neuroscientists are interested in how connectomes (graphical representations of functional connectivity between areas of the brain) change in relation to covariates. In statistics, changes like this are analyzed using regression, where the outcomes or dependent variables are regressed onto the covariates. However, when the outcome is a complex object, such as connectome graphs, classical regression models cannot be used. The regression approach developed here to work with complex graph outcomes combines recursive partitioning with the Gibbs distribution. We will only discuss the application to connectomes, but the method is generally applicable to any graphical outcome. The method, called Gibbs-RPart, partitions the covariate space into a set of nonoverlapping regions such that the connectomes within regions are more similar than they are to the connectomes in other regions. This paper extends the object-oriented data analysis paradigm for graph-valued data based on the Gibbs distribution, which we have applied previously to hypothesis testing to compare populations of connectomes from distinct groups (see the work of La Rosa et al).

Intraoperative Methadone in Same-Day Ambulatory Surgery: A Randomized, Double-Blinded, Dose-Finding Pilot Study.

BACKGROUND: Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery. METHODS: A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects. RESULTS: Median (interquartile range) methadone doses were 6 (5-6) and 9 (8-9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3-11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1-3.3; P < .001) but not 0.1 mg/kg methadone (5.0 mg, 3.3-8.1; P = .60). Dose-escalation ended at 0.15 mg/kg methadone. Total in-hospital nonmethadone opioid use after short-duration opioid, 0.1 mg/kg methadone, and 0.15 mg/kg methadone was 35.3 (25.0-44.0), 7.1 (3.7-10.0), and 3.3 (0.1-5.8) mg morphine equivalents, respectively (P < .001 for both versus control). In-hospital pain scores and side effects were not different between groups. In the 30 days after discharge, patients who received methadone 0.15 mg/kg had less pain at rest (P = .02) and used fewer opioid pills than controls (P < .0001), whereas patients who received 0.1 mg/kg had no difference in pain at rest (P = .69) and opioid use compared to controls (P = .08). CONCLUSIONS: In same-day discharge surgery, this pilot study identified a single intraoperative dose of methadone (0.15 mg/kg ideal body weight), which decreased intraoperative and postoperative opioid requirements and postoperative pain, compared with conventional intermittent short-duration opioids, with similar side effects.

Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study.

BACKGROUND: Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). METHODS: We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. FINDINGS: We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0·0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0·0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0·0011) and lower proportions of both Negativicutes (p=0·0013) and the combined Clostridia-Negativicutes class (p=0·0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. INTERPRETATION: A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. FUNDING: National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute.

Patterned progression of bacterial populations in the premature infant gut.

In the weeks after birth, the gut acquires a nascent microbiome, and starts its transition to bacterial population equilibrium. This early-in-life microbial population quite likely influences later-in-life host biology. However, we know little about the governance of community development: does the gut serve as a passive incubator where the first organisms randomly encountered gain entry and predominate, or is there an orderly progression of members joining the community of bacteria? We used fine interval enumeration of microbes in stools from multiple subjects to answer this question. We demonstrate via 16S rRNA gene pyrosequencing of 922 specimens from 58 subjects that the gut microbiota of premature infants residing in a tightly controlled microbial environment progresses through a choreographed succession of bacterial classes from Bacilli to Gammaproteobacteria to Clostridia, interrupted by abrupt population changes. As infants approach 33-36 wk postconceptional age (corresponding to the third to the twelfth weeks of life depending on gestational age at birth), the gut is well colonized by anaerobes. Antibiotics, vaginal vs. Caesarian birth, diet, and age of the infants when sampled influence the pace, but not the sequence, of progression. Our results suggest that in infants in a microbiologically constrained ecosphere of a neonatal intensive care unit, gut bacterial communities have an overall nonrandom assembly that is punctuated by microbial population abruptions. The possibility that the pace of this assembly depends more on host biology (chiefly gestational age at birth) than identifiable exogenous factors warrants further consideration.

Topical Decolonization Does Not Eradicate the Skin Microbiota of Community-Dwelling or Hospitalized Adults.

Topical antimicrobials are often employed for decolonization and infection prevention and may alter the endogenous microbiota of the skin. The objective of this study was to compare the microbial communities and levels of richness and diversity in community-dwelling subjects and intensive care unit (ICU) patients before and after the use of topical decolonization protocols. We enrolled 15 adults at risk for Staphylococcus aureus infection. Community subjects (n = 8) underwent a 5-day decolonization protocol (twice daily intranasal mupirocin and daily dilute bleach-water baths), and ICU patients (n = 7) received daily chlorhexidine baths. Swab samples were collected from 5 anatomic sites immediately before and again after decolonization. A variety of culture media and incubation environments were used to recover bacteria and fungi; isolates were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry. Overall, 174 unique organisms were recovered. Unique communities of organisms were recovered from the community-dwelling and hospitalized cohorts. In the community-dwelling cohort, microbial richness and diversity did not differ significantly between collections across time points, although the number of body sites colonized with S. aureus decreased significantly over time (P = 0.004). Within the hospitalized cohort, richness and diversity decreased over time compared to those for the enrollment sampling (from enrollment to final sampling, P = 0.01 for both richness and diversity). Topical antimicrobials reduced the burden of S. aureus while preserving other components of the skin and nasal microbiota.

Gibbs distribution for statistical analysis of graphical data with a sample application to fcMRI brain images.

This paper develops object-oriented data analysis (OODA) statistical methods that are novel and complementary to existing methods of analysis of human brain scan connectomes, defined as graphs representing brain anatomical or functional connectivity. OODA is an emerging field where classical statistical approaches (e.g., hypothesis testing, regression, estimation, and confidence intervals) are applied to data objects such as graphs or functions. By analyzing data objects directly we avoid loss of information that occurs when data objects are transformed into numerical summary statistics. By providing statistical tools that analyze sets of connectomes without loss of information, new insights into neurology and medicine may be achieved. In this paper we derive the formula for statistical model fitting, regression, and mixture models; test their performance in simulation experiments; and apply them to connectomes from fMRI brain scans collected during a serial reaction time task study. Software for fitting graphical object-oriented data analysis is provided.

Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.

BACKGROUND: Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption. PROCEDURE: Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125 mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded. RESULTS: Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9 hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12 hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children. CONCLUSIONS: Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.

Age-related effects on circadian phase in the sleep of patients with depression and insomnia.

We examined whether an age-related phase advance was present in 60 patients with depression and insomnia (mean age 41.5 [12.5] years) using diaries and 5 weekdays of actigraphy. Actigraphy was analyzed with functional data analysis. The low point of activity (bathyphase) for each subject was fitted by cosine function with 24-hr cycle time. Linear regression analysis revealed that increasing age was associated with earlier bedtimes (p < 0.001), shorter sleep latencies (p < 0.05), and earlier bathyphase (p < 0.001). These findings are consistent with prior reports of age-dependent phase-advances in sleep behavior in self-reported good sleepers and reinforce the premise that individualized behavioral therapy of older persons with insomnia may require prescription of earlier bedtimes and earlier rise times than would be employed in younger persons with insomnia. Further, we demonstrate that aging of the sleep system, at least as reflected in actigraphy, occurs as early as the third decade.

Incidental Coronary Arterial Calcification for Cardiovascular Risk Assessment in Men With Prostate Cancer Undergoing PET/CT Imaging.

BACKGROUND: Cardiovascular (CV) disease is common among men with prostate cancer and the leading cause of death in this population. There is a need for CV risk assessment tools that can be easily implemented in the prostate cancer treatment setting. METHODS: Consecutive patients who underwent positron emission tomography/computed tomography (PET/CT) for recurrent prostate cancer at a single institution from 2012 to 2017 were identified retrospectively. Clinical data and coronary calcification on nongated CT imaging were obtained. The primary outcome was major adverse CV event (MACE; myocardial infarction, coronary or peripheral revascularization, stroke, heart failure hospitalization, or all-cause mortality) occurring within 5 years of PET/CT. RESULTS: Among 354 patients included in the study, there were 98 MACE events that occurred in 74 patients (21%). All-cause mortality was the most common MACE event (35%), followed by coronary revascularization/myocardial infarction (26%) and stroke (19%). Coronary calcification was predictive of MACE (HR = 1.9, 95% CI: 1.1-3.4, P = .03) using adjusted Kaplan-Meier analysis. As a comparator, the Framingham risk score was calculated for 198 patients (56%) with complete clinical and laboratory data available. In this subgroup, high baseline Framingham risk (corresponding to 10-year risk of CV disease > 20%) was not predictive of MACE. CONCLUSIONS: MACE was common (21%) in men with recurrent prostate cancer undergoing PET/CT over 5 years of follow-up. Incidental coronary calcification on PET/CT was associated with increased risk of MACE and may have utility as a CV risk predictor that is feasible to implement among all prostate cancer providers.

Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection.

BACKGROUND: Clostridium difficile is a leading hospital-acquired infection. Many patients remain symptomatic for several days on appropriate antibiotic therapy. To assess the contribution of ongoing infection vs persistent inflammation, we examined the correlation between fecal cytokine levels, fecal C. difficile burden, and disease outcomes in C. difficile infection (CDI). METHODS: We conducted a prospective cohort study in Barnes Jewish Hospital between June 2011 and May 2012 of hospitalized adults with CDI. We determined fecal interleukin 8 (IL-8) and lactoferrin protein concentrations by enzyme immunoassay. We used real-time polymerase chain reaction (PCR) to measure relative fecal IL-8 and CXCL-5 RNA transcript abundances, and quantitative PCR to enumerate C. difficile burden. RESULTS: Of 120 study subjects, 101 (84%) were started on metronidazole, and 33 of those (33%) were subsequently given vancomycin. Sixty-two (52%) patients had diarrhea persistent for 5 or more days after starting CDI therapy. Initial fecal CXCL-5 messenger RNA (mRNA), IL-8 mRNA, and IL-8 protein correlated with persistent diarrhea and use of vancomycin. Time to diarrhea resolution was longer in patients with elevated fecal cytokines at diagnosis. Fecal cytokines were more sensitive than clinical severity scores in identifying patients at risk of treatment failure. Clostridium difficile burden did not correlate with any measure of illness or outcome at any point, and decreased equally with metronidazole and vancomycin. CONCLUSIONS: Persistent diarrhea in CDI correlates with intestinal inflammation and not fecal pathogen burden. These findings suggest that modulation of host response, rather than adjustments to antimicrobial regimens, might be a more effective approach to patients with unremitting disease.

Hemodynamic Predictors of Stabilization When Using Temporary Mechanical Support for Cardiogenic Shock from Acute on Chronic Heart Failure.

Cardiogenic shock from acute on chronic heart failure is a lethal condition that frequently requires temporary mechanical circulatory support devices (tMCS) as a bridge to stabilization, durable support, or heart transplantation. However, there are limited data on methods to optimize use of tMCS in this population. We identified patients who received tMCS devices for cardiogenic shock from acute on chronic heart failure at a single center from August 2016 to July 2020. All the patients had invasive hemodynamic data before and immediately after tMCS placement. We classified patients according to whether they showed stabilization or decompensation with tMCS. We then evaluated hemodynamics pre-tMCS, post-tMCS, and the change in hemodynamics with tMCS (∆-tMCS) and assessed their relationship with clinical outcomes. Among 111 patients who received tMCS, 71 stabilized, and 40 decompensated. Post-tMCS hemodynamics were more likely than were pre-tMCS or ∆-tMCS to predict stabilization. Post-tMCS cardiac index >2.1 (area under the curve: 92.2) and cardiac power index >0.3 (area under the curve: 89.6) were the best predictors of stabilization. Patients who decompensated had increased in-hospital all-cause mortality (hazard ratio 3.06 [1.29 to 7.24], p = 0.011), cardiovascular mortality, and increased hospital and intensive care unit length of stay and were less likely to receive left ventricular assist device or heart transplant (hazard ratio 0.56 [0.36 to 0.88], p = 0.01). In conclusion, among patients with cardiogenic shock from acute on chronic heart failure who received tMCS, post-tMCS cardiac index and cardiac power index were highly predictive of stabilization. Those who decompensated had increased mortality, hospital length of stay, and intensive care unit length of stay and were less likely to receive heart replacement therapy.

Patient and Hospital Characteristics Associated With the Interhospital Transfer of Adult Patients With Sepsis.

IMPORTANCE: The interhospital transfer (IHT) of patients with sepsis to higher-capability hospitals may improve outcomes. Little is known about patient and hospital factors associated with sepsis IHT. OBJECTIVES: We evaluated patterns of hospitalization and IHT and determined patient and hospital factors associated with the IHT of adult patients with sepsis. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: A total of 349,938 adult patients with sepsis at 329 nonfederal hospitals in California, 2018-2019. MAIN OUTCOMES AND MEASURES: We evaluated patterns of admission and outward IHT between low sepsis-, intermediate sepsis-, and high sepsis-capability hospitals. We estimated odds of IHT using generalized estimating equations logistic regression with bootstrap stepwise variable selection. RESULTS: Among the cohort, 223,202 (66.4%) were initially hospitalized at high-capability hospitals and 10,870 (3.1%) underwent IHT. Nearly all transfers (98.2%) from low-capability hospitals were received at higher-capability hospitals. Younger age (< 65 yr) (adjusted odds ratio [aOR] 1.54; 95% CI, 1.40-1.69) and increasing organ dysfunction (aOR 1.22; 95% CI, 1.19-1.25) were associated with higher IHT odds, as were admission to low-capability (aOR 2.79; 95% CI, 2.33-3.35) or public hospitals (aOR 1.35; 95% CI, 1.09-1.66). Female sex (aOR 0.88; 95% CI, 0.84-0.91), Medicaid insurance (aOR 0.59; 95% CI, 0.53-0.66), home to admitting hospital distance less than or equal to 10 miles (aOR 0.92; 95% CI, 0.87-0.97) and do-not-resuscitate orders (aOR 0.48; 95% CI, 0.45-0.52) were associated with lower IHT odds, as was admission to a teaching hospital (aOR 0.83; 95% CI, 0.72-0.96). CONCLUSIONS AND RELEVANCE: Most patients with sepsis are initially hospitalized at high-capability hospitals. The IHT rate for sepsis is low and more likely to originate from low-capability and public hospitals than from high-capability and for-profit hospitals. Transferred patients with sepsis are more likely to be younger, male, sicker, with private medical insurance, and less likely to have care limitation orders. Future studies should evaluate the comparative benefits of IHT from low-capability hospitals.

Sex-related differences in premature cardiovascular disease in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with an increased prevalence of premature atherosclerotic cardiovascular disease (ASCVD), however, little is known about sex-specific differences in premature ASCVD and its risk factors. OBJECTIVE: The present study seeks to assess the burden and risk factors for premature ASCVD among men and women with FH. METHODS: In this study we retrospectively examined sex-specific differences in ASCVD prevalence, risk factor burdens, and lipid treatment outcomes in 782 individuals with clinically or genetically confirmed FH treated in 5 U.S. lipid and genetics clinics. A generalized linear model using Binomial distribution with random study site effect and sex-stratified analysis was used to determine the strongest predictors of premature ASCVD, and lipid treatment outcomes. Covariates included age, sex, diabetes mellitus (DM), hypertension, and current smoking. RESULTS: Among the cohort, 98/280 men (35%) and 89/502 women (18%) had premature ASCVD (defined as <55 years in men and <65 years in women). Women with premature ASCVD had higher mean treated total cholesterol (216 vs. 179 mg/dl, p=<0.001) and LDL-C (135 vs. 109 mg/dl, p= 0.005). CONCLUSION: These data confirm that high percentages of women and men with FH develop premature ASCVD, and suggest that FH may narrow the observed sex difference in premature ASCVD onset. These data support more aggressive prevention and treatment strategies in FH, including in women, to reduce non-lipid risk factors and residual hypercholesterolemia.