Forward genetic screens in mice provide an unbiased means to identify genes and other functional genetic elements in the genome. Previously, a large scale ENU mutagenesis screen was conducted to ...query the functional content of a ~50 Mb region of the mouse genome on proximal Chr 5. The majority of phenotypic mutants recovered were embryonic lethals.
We report the high resolution genetic mapping, complementation analyses, and positional cloning of mutations in the target region. The collection of identified alleles include several with known or presumed functions for which no mutant models have been reported (Tbc1d14, Nol14, Tyms, Cad, Fbxl5, Haus3), and mutations in genes we or others previously reported (Tapt1, Rest, Ugdh, Paxip1, Hmx1, Otoe, Nsun7). We also confirmed the causative nature of a homeotic mutation with a targeted allele, mapped a lethal mutation to a large gene desert, and localized a spermiogenesis mutation to a region in which no annotated genes have coding mutations. The mutation in Tbc1d14 provides the first implication of a critical developmental role for RAB-GAP-mediated protein transport in early embryogenesis.
This collection of alleles contributes to the goal of assigning biological functions to all known genes, as well as identifying novel functional elements that would be missed by reverse genetic approaches.
Pediatric sepsis and bacterial infection cause significant morbidity and mortality worldwide, with immunocompromised patients being at particularly high risk of rapid deterioration and death. This ...study evaluated if PERSEVERE, PERSEVERE-II, or the PERSEVERE biomarkers, can reliably estimate the risk of clinical deterioration and 28-day mortality among immunocompromised pediatric patients. This is a single-center prospective cohort study conducted from July 2016 through September 2017 incorporating 400 episodes of suspected bacterial infection from the inpatient units at Cincinnati Children's Hospital Medical Center, a large, tertiary care children's hospital. The primary analysis assessed clinical deterioration within 72 hours of evaluation for infection. Secondarily, we assessed 28-day mortality. Clinical deterioration was seen in 15% of subjects. Twenty-eight day mortality was 5%, but significantly higher among critically ill patients. Neither PERSEVERE nor PERSEVERE-II performed well to predict clinical deterioration or 28-day mortality, thus we derived new stratification models using the PERSEVERE biomarkers with both high sensitivity and negative predictive value. In conclusion, we evaluated previously validated biomarker risk models in a novel population of largely non-critically ill immunocompromised pediatric patients, and attempted to stratify patients based on a new outcome metric, clinical deterioration. The new highly predictive models indicate common physiologic pathways to clinical deterioration or death from bacterial infection.
Quality improvement initiatives to decrease rates of nephrotoxic medication exposure have reduced rates of acute kidney injury (AKI) in noncritically ill children. The objective of our study was to ...analyze the implementation of a similar program in critically ill children and to measure important balancing measures including opioid and benzodiazepine exposure.
Prospective quality improvement study.
PICU at Children's Hospital Colorado between 2018 and 2020.
All children admitted to PICU.
Quality improvement initiative called Nephrotoxic Injury Negated by Just-In-Time Action (NINJA).
Eight thousand eight hundred thirty-three PICU patient admissions were included. Mean rates of nephrotoxic medication exposure/1,000 PICU patient days decreased from 46 to 26, whereas rates of nephrotoxic AKI/1,000 PICU patient days did not change. Nonsteroidal anti-inflammatory drug dispenses per 1,000 patient days were reduced from 521 to 456. Similarly, opioid and benzodiazepine exposures per 1,000 patient days were reduced from 812 to 524 and 441 to 227, respectively, during the study observation period.
The NINJA intervention was efficaciously implemented in our single-center PICU. Nephrotoxic exposure is a modifiable factor that did not inadvertently increase exposure to opioids and benzodiazepines.
Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is ...associated with poor outcomes in children with septic shock.
Retrospective analysis of a pediatric septic shock database.
Twenty-nine PICUs in the United States.
Eight hundred ninety children 10 years and younger with septic shock.
None.
We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1-3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0-6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3-3.5; p = 0.002). The secondary analysis yielded similar results.
Hyperchloremia is independently associated with poor outcomes among children with septic shock.
To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation ...regimen.
Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy.
The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point.
T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.
Fears about macro-level crime join those about local volume crime, inter-communal
conflicts and governance emerging to manage them, presenting challenges for
analysing commonalities and differences ...at various spatial levels. Governance
theories crystallize in debates about security. Realist governmentality theory
transcends discourse analysis of mentalities of government, and a focus on security,
arguing that security practices manifest the struggle by local state institutions
for sovereign control over populations and territories (biopolitics). Illustrated by
rural and urban examples of biopolitical struggles, this highlights interaction
between official and informal biopolitics, the latter involving communal groups
attempting to govern from below. This creates tensions between
universalistic/liberal, and particularistic, nationalist agendas, and also the
recognition of multi-cultural, communal identities and interests.
Background: Prior research has suggested that patients who travel out of their neighborhood for elective care from specialized medical centers may have better outcomes than local patients with the ...same illnesses who are treated at the same centers. We hypothesized that this phenomenon, often called “referral bias” or “distance bias,” may also be evident in curative-intent cancer trials at specialized cancer centers. Methods: We evaluated associations between overall survival and progression-free survival and the distance from the patient residence to the treating institution for 110 patients treated on one of four phase II curative-intent chemoradiotherapy protocols for locoregionally advanced squamous cell cancer of the head and neck conducted at the University of Chicago over 7 years. Results: Using Cox regression that adjusted for standard patient-level disease and demographic factors and neighborhood-level economic factors, we found a positive association between the distance patients traveled from their residence to the treatment center and survival. Patients who lived more than 15 miles from the treating institution had only one-third the hazard of death of those living closer (hazard ratio HR = 0.32, 95% confidence interval CI = 0.12 to 0.84). Moreover, with every 10 miles that a patient traveled for care, the hazard of death decreased by 3.2% (HR = 0.97, 95% CI = 0.94 to 0.99). Similar results were obtained for progression-free survival. Conclusion: Results of phase II curative-intent clinical trials in oncology that are conducted at specialized cancer centers may be confounded by patient travel distance, which captures prognostic significance beyond cancer stage, performance status, and wealth. More work is needed to determine what unmeasured factors travel distance is mediating.
Herein, we review the current guidelines for the management of children with an acute asthma exacerbation. We focus on management in the emergency department, inpatient, and ICU settings.
The most ...recent statistics show that the prevalence of asthma during childhood has decreased in certain demographic subgroups and plateaued in other subgroups. However, acute asthma accounts for significant healthcare expenditures. Although there are few, if any, newer therapeutic agents available for management of acute asthma exacerbations, several reports leveraging quality improvement science have shown significant reductions in costs of care as well as improvements in outcome.
Asthma is one of the most common chronic conditions in children and the most common reason that children are admitted to the hospital. Nevertheless, the evidence to support specific agents in the management of acute asthma exacerbations is surprisingly limited. The management of acute exacerbations focuses on reversal of bronchospasm, correction of hypoxia, and prevention of relapse and recurrence. Second-tier and third-tier agents are infrequently used outside of the ICU setting. Reducing the variation in treatment is likely to lead to lower costs and better outcomes.
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