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BackgroundPrevious epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data.MethodsData were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models.ResultsAmong 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes.ConclusionsUrinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Author(s): Mitchell M. Levy [sup.1], Andrew Rhodes [sup.2], Gary S. Phillips [sup.3], Sean R. Townsend [sup.4], Christa A. Schorr [sup.5], Richard Beale [sup.6], Tiffany Osborn [sup.7], Stanley Lemeshow [sup.8], Jean-Daniel [...], Purpose To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. Design Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005 through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. Setting Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. Patients Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. Methods A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. Results Overall lower mortality was observed in high (29.0 %) versus low (38.6 %) resuscitation bundle compliance sites (p < 0.001) and between high (33.4 %) and low (32.3 %) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7 % per site for every 3 months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4 % (95 % CI 1-7 %; p = 0.012) for every 10 % increase in site compliance with the resuscitation bundle. Conclusions This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25 % relative risk reduction in mortality rate. Every 10 % increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

Background: Respiratory variation in carotid artery peak systolic velocity (ΔVpeak) assessed by point-of-care ultrasound (POCUS) has been proposed as a noninvasive means to predict fluid responsiveness. We aimed to evaluate the ability of carotid ΔVpeak as assessed by novice physician sonologists to predict fluid responsiveness. Methods: This study was conducted in 2 intensive care units. Spontaneously breathing, nonintubated patients with signs of volume depletion were included. Patients with atrial fibrillation/flutter, cardiogenic, obstructive or neurogenic shock, or those for whom further intravenous (IV) fluid administration would be harmful were excluded. Three novice physician sonologists were trained in POCUS assessment of carotid ΔVpeak. They assessed the carotid ΔVpeak in study participants prior to the administration of a 500 mL IV fluid bolus. Fluid responsiveness was defined as a ≥10% increase in cardiac index as measured using bioreactance. Results: Eighty-six participants were enrolled, 50 (58.1%) were fluid responders. Carotid ΔVpeak performed poorly at predicting fluid responsiveness. Test characteristics for the optimum carotid ΔVpeak of 8.0% were: area under the receiver operating curve = 0.61 (95% CI: 0.48-0.73), sensitivity = 72.0% (95% CI: 58.3-82.56), specificity = 50.0% (95% CI: 34.5-65.5). Conclusions: Novice physician sonologists using POCUS are unable to predict fluid responsiveness using carotid ΔVpeak. Until further research identifies key limiting factors, clinicians should use caution directing IV fluid resuscitation using carotid ΔVpeak. [ABSTRACT FROM AUTHOR]

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population‐based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person‐years of follow‐up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77–0.99) and 0.85: (0.73–0.99), respectively. Being later‐born was associated with similarly reduced hazards of CL and ALL compared to being first‐born; HRs = 0.78: 95% CI: 0.58–1.05 and 0.73: 0.52–1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later‐born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06–0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures. What's new? Can birth order affect childhood leukemia risk? Children with older siblings encounter more infectious pathogens than first‐born children, and fewer childhood infections might contribute to increased risk of childhood leukemia. Here, the authors studied birth order as a proxy for childhood infections. They conducted a prospective study and found that later‐born children had reduced risk of childhood leukemia compared with first‐borns. The effect was strongest in children with fathers age 30 or older, and in children with birth weight less than 3 kg. [ABSTRACT FROM AUTHOR]

Rationale: In 2013, the New York State Department of Health (NYSDOH) began a mandatory state-wide initiative to improve early recognition and treatment of severe sepsis and septic shock.Objectives: This study examines protocol initiation, 3-hour and 6-hour sepsis bundle completion, and risk-adjusted hospital mortality among adult patients with severe sepsis and septic shock.Methods: Cohort analysis included all patients from all 185 hospitals in New York State reported to the NYSDOH from April 1, 2014, to June 30, 2016. A total of 113,380 cases were submitted to NYSDOH, of which 91,357 hospitalizations from 183 hospitals met study inclusion criteria. NYSDOH required all hospitals to submit and follow evidence-informed protocols (including elements of 3-h and 6-h sepsis bundles: lactate measurement, early blood cultures and antibiotic administration, fluids, and vasopressors) for early identification and treatment of severe sepsis or septic shock.Measurements and Main Results: Compliance with elements of the sepsis bundles and risk-adjusted mortality were studied. Of 91,357 patients, 74,293 (81.3%) had the sepsis protocol initiated. Among these individuals, 3-hour bundle compliance increased from 53.4% to 64.7% during the study period (P < 0.001), whereas among those eligible for the 6-hour bundle (n = 35,307) compliance increased from 23.9% to 30.8% (P < 0.001). Risk-adjusted mortality decreased from 28.8% to 24.4% (P < 0.001) in patients among whom a sepsis protocol was initiated. Greater hospital compliance with 3-hour and 6-hour bundles was associated with shorter length of stay and lower risk and reliability-adjusted mortality.Conclusions: New York's statewide initiative increased compliance with sepsis-performance measures. Risk-adjusted sepsis mortality decreased during the initiative and was associated with increased hospital-level compliance. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case-control studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre-diagnostic exposure assessments and biological samples.Methods: Eligibility criteria, follow-up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses.Results: Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388 120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother-child pairs within 5 years. Harmonised data currently includes over 20 "core" variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades.Conclusions: The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case-control studies offer the potential for breakthroughs in paediatric cancer aetiologic research. [ABSTRACT FROM AUTHOR]

Importance: The death of a pediatric patient with sepsis motivated New York to mandate statewide sepsis treatment in 2013. The mandate included a 1-hour bundle of blood cultures, broad-spectrum antibiotics, and a 20-mL/kg intravenous fluid bolus. Whether completing the bundle elements within 1 hour improves outcomes is unclear.Objective: To determine the risk-adjusted association between completing the 1-hour pediatric sepsis bundle and individual bundle elements with in-hospital mortality.Design, Settings, and Participants: Statewide cohort study conducted from April 1, 2014, to December 31, 2016, in emergency departments, inpatient units, and intensive care units across New York State. A total of 1179 patients aged 18 years and younger with sepsis and septic shock reported to the New York State Department of Health who had a sepsis protocol initiated were included.Exposures: Completion of a 1-hour sepsis bundle within 1 hour compared with not completing the 1-hour sepsis bundle within 1 hour.Main Outcomes and Measures: Risk-adjusted in-hospital mortality.Results: Of 1179 patients with sepsis reported at 54 hospitals (mean [SD] age, 7.2 [6.2] years; male, 54.2%; previously healthy, 44.5%; diagnosed as having shock, 68.8%), 139 (11.8%) died. The entire sepsis bundle was completed in 1 hour in 294 patients (24.9%). Antibiotics were administered to 798 patients (67.7%), blood cultures were obtained in 740 patients (62.8%), and the fluid bolus was completed in 548 patients (46.5%) within 1 hour. Completion of the entire bundle within 1 hour was associated with lower risk-adjusted odds of in-hospital mortality (odds ratio [OR], 0.59 [95% CI, 0.38 to 0.93], P = .02; predicted risk difference [RD], 4.0% [95% CI, 0.9% to 7.0%]). However, completion of each individual bundle element within 1 hour was not significantly associated with lower risk-adjusted mortality (blood culture: OR, 0.73 [95% CI, 0.51 to 1.06], P = .10; RD, 2.6% [95% CI, -0.5% to 5.7%]; antibiotics: OR, 0.78 [95% CI, 0.55 to 1.12], P = .18; RD, 2.1% [95% CI, -1.1% to 5.2%], and fluid bolus: OR, 0.88 [95% CI, 0.56 to 1.37], P = .56; RD, 1.1% [95% CI, -2.6% to 4.8%]).Conclusions and Relevance: In New York State following a mandate for sepsis care, completion of a sepsis bundle within 1 hour compared with not completing the 1-hour sepsis bundle within 1 hour was associated with lower risk-adjusted in-hospital mortality among patients with pediatric sepsis and septic shock. [ABSTRACT FROM AUTHOR]

Objectives: In accordance with Rory's Regulations, hospitals across New York State developed and implemented protocols for sepsis recognition and treatment to reduce variations in evidence informed care and preventable mortality. The New York Department of Health sought to develop a risk assessment model for accurate and standardized hospital mortality comparisons of adult septic patients across institutions using case-mix adjustment.Design: Retrospective evaluation of prospectively collected data.Patients: Data from 43,204 severe sepsis and septic shock patients from 179 hospitals across New York State were evaluated.Settings: Prospective data were submitted to a database from January 1, 2015, to December 31, 2015.Interventions: None.Measurement and Main Results: Maximum likelihood logistic regression was used to estimate model coefficients used in the New York State risk model. The mortality probability was estimated using a logistic regression model. Variables to be included in the model were determined as part of the model-building process. Interactions between variables were included if they made clinical sense and if their p values were less than 0.05. Model development used a random sample of 90% of available patients and was validated using the remaining 10%. Hosmer-Lemeshow goodness of fit p values were considerably greater than 0.05, suggesting good calibration. Areas under the receiver operator curve in the developmental and validation subsets were 0.770 (95% CI, 0.765-0.775) and 0.773 (95% CI, 0.758-0.787), respectively, indicating good discrimination. Development and validation datasets had similar distributions of estimated mortality probabilities. Mortality increased with rising age, comorbidities, and lactate.Conclusions: The New York Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination. This sepsis-specific model provides an accurate, comprehensive method for standardized mortality comparison of adult patients with severe sepsis and septic shock. [ABSTRACT FROM AUTHOR]

We crafted human immunodeficiency virus (HIV)-like particles of diameter about 140 nm, which expressed two major HIV-1 proteins, namely, env and gag gene products, and used this reagent to simulate the rate of decay of HIV from the blood stream of BALB/c male mice. We found that most (~90%) of the particles were eliminated (cleared) from the blood by the liver sinusoidal endothelial cells (LSECs), the remainder from Kupffer cells; suggesting that LSECs are the major liver scavengers for HIV clearance from blood. Decay was rapid with kinetics suggesting second order with respect to particles, which infers dimerization of a putative receptor on LSEC. The number of HIV-like particles required for saturating the clearance mechanism was approximated. The capacity for elimination of blood-borne HIV-like particles by the sinusoid was 112 million particles per minute. Assuming that the sinusoid endothelial cells were about the size of glassadherent macrophages, then elimination capacity was more than 540 particles per hour per endothelial cell. [ABSTRACT FROM AUTHOR]

Objective: The Surviving Sepsis Campaign guidelines recommend obtaining a serum lactate measurement within 6 hours of presentation for all patients with suspected severe sepsis or septic shock. A lactate greater than 4 mmol/L qualifies for administration of early quantitative resuscitation therapy. We evaluated lactate elevation (with special attention to values > 4 mmol/L) and presence or absence of hypotension as a marker of clinical outcome. Design and Setting: The Surviving Sepsis Campaign developed a database to assess the overall effect of the sepsis bundles as a performance improvement tool for clinical practice and patient outcome. This analysis focuses on one element of the Surviving Sepsis Campaign's resuscitation bundle, measuring serum lactate in adult severe sepsis or septic shock patients and its interaction with hypotension. This analysis was conducted on data submitted from January 2005 through March 2010. Subjects: Data from 28,150 subjects at 218 sites were analyzed. Interventions: None. Measurements and Main Results: Unadjusted analysis of the 28,150 observations from the Surviving Sepsis Campaign database demonstrated a significant mortality increase with the presence of hypotension in conjunction with serum lactate elevation greater than 2 mmol/L. On multivariable analysis, only lactate values greater than 4 mmol/L, in conjunction with hypotension, significantly increased mortality when compared with the referent group of lactate values less than 2 mmol/L and not hypotensive. Mortality was 44.5% in patients with combined lactate greater than 4 mmol/L and hypotension when compared with 29% mortality in patients not meeting either criteria. Conclusions: Serum lactate was commonly measured within 6 hours of presentation in the management of severe sepsis or septic shock in this subset analysis of the Surviving Sepsis Campaign database in accordance with the Surviving Sepsis Campaign guidelines. Our results demonstrate that elevated lactate levels are highly associated with in-hospital mortality. However, only patients who presented with lactate values greater than 4 mmol/L, with and without hypotension, are significantly associated with in-hospital mortality and is associated with a significantly higher risk than intermediate levels (2–3 and 3–4 mmol/L). This supports the use of the cutoff of greater than 4 mmol/L as a qualifier for future clinical trials in severe sepsis or septic shock in patient populations who use quantitative resuscitation and the Surviving Sepsis Campaign bundles as standard of care. [ABSTRACT FROM AUTHOR]

Objective: This study examined polypharmacy patterns and rates over time among Medicaid-enrolled youths by comparing three enrollment groups (youths in foster care, with a disability, or from a family with low income).Methods: Serial cross-sectional trend analyses of Medicaid claims data were conducted for youths age 17 and younger who were continuously enrolled in Ohio Medicaid for a one-year period and prescribed one or more psychotropic medications during fiscal years 2002 (N=26,252) through 2008 (N=50,311). Outcome measures were any polypharmacy (three or more psychotropic medications from any drug class) and multiclass polypharmacy (three or more psychotropic medications from different drug classes).Results: Both types of polypharmacy increased across all three eligibility groups. Any polypharmacy increased from 8.8% to 11.5% for low-income youths (adjusted odds ratio [AOR]=1.12, 99% confidence interval [CI]=1.10-1.13), from 18.0% to 24.9% for youths with a disability (AOR=1.11, CI=1.09-1.13), and from 19.8% to 27.3% for youths in foster care (AOR=1.09, CI=1.07-1.11). Combinations associated with positive increases were two or more antipsychotics, two or more stimulants, and antipsychotics with stimulants.Conclusions: Polypharmacy increased across all enrollment groups, with the highest absolute rates for youths in foster care. Both the overall prevalence and increases in prescriptions for drug combinations with limited evidence of safety and efficacy, such as the prescription of two or more antipsychotics, underscore the need for targeted quality improvement efforts. System oversight and monitoring of psychotropic medication use appears to be warranted, especially for higher-risk groups, such as youths in foster care and those from low-income households who were prescribed multiple antipsychotics. [ABSTRACT FROM AUTHOR]