IMPORTANCE: Current evidence suggests that nonoperative management of uncomplicated appendicitis is safe, but overall effectiveness is determined by combining medical outcomes with the patient’s and ...family’s perspective, goals, and expectations. OBJECTIVE: To determine the effectiveness of patient choice in nonoperative vs surgical management of uncomplicated acute appendicitis in children. DESIGN, SETTING, AND PARTICIPANTS: Prospective patient choice cohort study in patients aged 7 to 17 years with acute uncomplicated appendicitis presenting at a single pediatric tertiary acute care hospital from October 1, 2012, through March 6, 2013. Participating patients and families gave informed consent and chose between nonoperative management and urgent appendectomy. INTERVENTIONS: Urgent appendectomy or nonoperative management entailing at least 24 hours of inpatient observation while receiving intravenous antibiotics and, on demonstrating improvement of symptoms, completion of 10 days of treatment with oral antibiotics. MAIN OUTCOMES AND MEASURES: The primary outcome was the 1-year success rate of nonoperative management. Successful nonoperative management was defined as not undergoing an appendectomy. Secondary outcomes included comparisons of the rates of complicated appendicitis, disability days, and health care costs between nonoperative management and surgery. RESULTS: A total of 102 patients were enrolled; 65 patients/families chose appendectomy (median age, 12 years; interquartile range IQR, 9-13 years; 45 male 69.2%) and 37 patients/families chose nonoperative management (median age, 11 years; IQR, 10-14 years; 24 male 64.9%). Baseline characteristics were similar between the groups. The success rate of nonoperative management was 89.2% (95% CI, 74.6%-97.0%) at 30 days (33 of 37 children) and 75.7% (95% CI, 58.9%-88.2%) at 1 year (28 of 37 children). The incidence of complicated appendicitis was 2.7% in the nonoperative group (1 of 37 children) and 12.3% in the surgery group (8 of 65 children) (P = .15). After 1 year, children managed nonoperatively compared with the surgery group had fewer disability days (median IQR, 8 5-18 vs 21 15-25 days, respectively; P < .001) and lower appendicitis-related health care costs (median IQR, $4219 $2514-$7795 vs $5029 $4596-$5482, respectively; P = .01). CONCLUSIONS AND RELEVANCE: When chosen by the family, nonoperative management is an effective treatment strategy for children with uncomplicated acute appendicitis, incurring less morbidity and lower costs than surgery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01718275
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Acute graft-versus-host disease (GVHD) is a rare complication after solid organ transplantation (SOT) that carries high mortality. Caused by immunocompetent donor leukocytes within ...the transplanted organ, which become activated against recipient tissues, GVHD typically develops 2 to 12 weeks after SOT and can affect the skin, gastrointestinal tract, liver, and bone marrow. Signs and symptoms are nonspecific and include a rash, nausea, appetite loss, diarrhea, and cytopenias. Pancytopenia from marrow-directed GVHD is the primary driver of mortality. The diagnosis of GVHD is often delayed but should be confirmed by biopsy of an affected organ. Evidence of donor chimerism in blood or marrow supports the diagnosis. When GVHD is diagnosed we initiate treatment with systemic corticosteroids. At that time, if GVHD only involves skin or oral mucosa we also decrease maintenance immunosuppression levels to allow the recipient to reject the donor immune cells. For GVHD involving the marrow we initiate an allogeneic hematopoietic cell donor search early. In this article, we describe 3 cases of GVHD after SOT, outline our approach to diagnosis and management, and then provide analysis of the 3 instructive cases.
Acute graft-versus-host disease following solid organ transplantation is rare, and the diagnosis is often delayed. Fatality rates are high. Cooper and Abkowitz use 3 illustrative case studies to highlight existing knowledge and provide diagnostic and therapeutic decision trees to assist clinicians faced with this challenging disease.
Background This study reports national estimates of population characteristics and outcomes for patients with esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and evaluates the ...relationships between hospital volume and outcomes. Methods Patients admitted within 30 days of life who had International Classification of Diseases, 9th Edition, Clinical Modification diagnosis and procedure codes relevant to EA/TEF during 1999−2012 were identified with the Pediatric Health Information System database. Baseline demographics, comorbidities, and postoperative outcomes, including predictors of in-hospital mortality, were examined up to 2 years after EA/TEF repair. Results We identified 3,479 patients with EA/TEF treated at 43 children's hospitals; 37% were premature and 83.5% had ≥1 additional congenital anomaly, with cardiac anomalies (69.6%) being the most prevalent. Within 2 years of discharge, 54.7% were readmitted, 5.2% had a repeat TEF ligation, 11.4% had a repeat operation for their esophageal reconstruction, and 11.7% underwent fundoplication. In-hospital mortality was 5.4%. Independent predictors of mortality included lower birth weight, congenital heart disease, other congenital anomalies, and preoperative mechanical ventilation. There was no relationship between hospital volume and mortality or repeat TEF ligation. Conclusion This study describes population characteristics and outcomes, including predictors of in-hospital mortality, in EA/TEF patients treated at children's hospitals across the United States. Across these hospitals, rates of mortality or repeat TEF ligation were not dependent on hospital volume.
Fenretinide (4-HPR) is a synthetic retinoid that has cytotoxic activity against cancer cells. Despite substantial in vitro cytotoxicity, response rates in early clinical trials with 4-HPR have been ...less than anticipated, likely due to the low bioavailability of the initial oral capsule formulation. Several clinical studies have shown that the oral capsule formulation at maximum tolerated dose (MTD) achieved <10 µmol/L concentrations in patients. To improve bioavailability of 4-HPR, new oral powder (LYM-X-SORB®, LXS) and intravenous lipid emulsion (ILE) formulations are being tested in early-phase clinical trials. ILE 4-HPR administered as five-day continuous infusion achieved over 50 µmol/L at MTD with minimal systemic toxicities; multiple complete and partial responses were observed in peripheral T cell lymphomas. The LXS oral powder 4-HPR formulation increased plasma levels approximately two-fold at MTD in children without dose-limiting toxicities and demonstrated multiple complete responses in recurrent neuroblastoma. The clinical activity observed with new 4-HPR formulations is attributed to increased bioavailability. Phase I and II clinical trials of both LXS 4-HPR and ILE 4-HPR are in progress as a single agent or in combination with other drugs.
Impact statement
One of the critical components in drug development is understanding pharmacology (especially pharmacokinetics) of the drugs being developed. Often the pharmacokinetic properties, such as poor solubility leading to poor bioavailability, of the drug can limit further development of the drug. The development of numerous drugs has often halted at clinical testing stages, and several of them were due to the pharmacological properties of the agents, resulting in increased drug development cost. The current review provides an example of how improved clinical activity can be achieved by changing the formulations of a drug with poor bioavailability. Thus, it emphasizes the importance of understanding pharmacologic characteristics of the drug in drug development.
Because up to 12% of obstetric patients meet criteria for the diagnosis of thrombocytopenia in pregnancy, it is not infrequent that the anesthesiologist must decide whether to proceed with a ...neuraxial procedure in an affected patient. Given the potential morbidity associated with general anesthesia for cesarean delivery, thoughtful consideration of which patients with thrombocytopenia are likely to have an increased risk of spinal epidural hematoma with neuraxial procedures, and when these risks outweigh the relative benefits is important to consider and to inform shared decision making with patients. Because there are substantial risks associated with withholding a neuraxial analgesic/anesthetic procedure in obstetric patients, every effort should be made to perform a bleeding history assessment and determine the thrombocytopenia etiology before admission for delivery. Whereas multiple other professional societies (obstetric, interventional pain, and hematologic) have published guidelines addressing platelet thresholds for safe neuraxial procedures, the US anesthesia professional societies have been silent on this topic. Despite a paucity of high-quality data, there are now meta-analyses that provide better estimations of risks. An interdisciplinary taskforce was convened to unite the relevant professional societies, synthesize the data, and provide a practical decision algorithm to help inform risk-benefit discussions and shared decision making with patients. Through a systematic review and modified Delphi process, the taskforce concluded that the best available evidence indicates the risk of spinal epidural hematoma associated with a platelet count ≥70,000 × 106/L is likely to be very low in obstetric patients with thrombocytopenia secondary to gestational thrombocytopenia, immune thrombocytopenia (ITP), and hypertensive disorders of pregnancy in the absence of other risk factors. Ultimately, the decision of whether to proceed with a neuraxial procedure in an obstetric patient with thrombocytopenia occurs within a clinical context. Potentially relevant factors include, but are not limited to, patient comorbidities, obstetric risk factors, airway examination, available airway equipment, risk of general anesthesia, and patient preference.
Background For decades, urgent operation has been considered the only appropriate management of acute appendicitis in children. The purpose of this study was to investigate the feasibility of ...nonoperative management of uncomplicated acute appendicitis in children. Study Design A prospective nonrandomized clinical trial of children with uncomplicated acute appendicitis comparing nonoperative management with urgent appendectomy was performed. The primary result was 30-day success rate of nonoperative management. Secondary outcomes included comparisons of disability days, missed school days, hospital length of stay, and measures of quality of life and health care satisfaction. Results Seventy-seven patients were enrolled during October 2012 to October 2013; 30 chose nonoperative management and 47 chose surgery. There were no significant differences in demographic or clinical characteristics. The immediate and 30-day success rates of nonoperative management were 93% (28 of 30) and 90% (27 of 30). There was no evidence of progression of appendicitis to rupture at the time of surgery in the 3 patients for whom nonoperative management failed. Compared with the surgery group, the nonoperative group had fewer disability days (3 vs 17 days; p < 0.0001), returned to school more quickly (3 vs 5 days; p = 0.008), and exhibited higher quality of life scores in both the child (93 vs 88; p = 0.01) and the parent (96 vs 90; p = 0.03), but incurred a longer length of stay (38 vs 20 hours; p < 0.0001). Conclusions Nonoperative management of uncomplicated acute appendicitis in children is feasible, with a high 30-day success rate and short-term benefits that include quicker recovery and improved quality of life scores. Additional follow-up will allow for determination of longer-term success rate, safety, and cost effectiveness.
This technical note presents experimental results using numerical features of fs-LIBS data to classify the assay value of a gaseous UF6 material. The data-driven feature vectors are computed by ...Higher Order Generalized Singular Value Decomposition (HOGSVD) and Dynamic Time Warp (DTW). The method achieves 96.97% accuracy in spectral classification testing with fs-LIBS samples obtained from a UF6 material with five known assay values ranging from 0.287% to 61.740%, with 100% accuracy for the four largest assay values ranging from 4.615% to 61.740%.
Acute graft‐versus‐host disease (GVHD) is a rare complication after orthotopic liver transplantation (OLT) that carries high mortality. We hypothesized that machine‐learning algorithms to predict ...rare events would identify patients at high risk for developing GVHD. To develop a predictive model, we retrospectively evaluated the clinical features of 1938 donor‐recipient pairs at the time they underwent OLT at our center; 19 (1.0%) of these recipients developed GVHD. This population was divided into training (70%) and test (30%) sets. A total of 7 machine‐learning classification algorithms were built based on the training data set to identify patients at high risk for GVHD. The C5.0, heterogeneous ensemble, and generalized gradient boosting machine (GGBM) algorithms predicted that 21% to 28% of the recipients in the test data set were at high risk for developing GVHD, with an area under the receiver operating characteristic curve (AUROC) of 0.83 to 0.86. The 7 algorithms were then evaluated in a validation data set of 75 more recent donor‐recipient pairs who underwent OLT at our center; 2 of these recipients developed GVHD. The logistic regression, heterogeneous ensemble, and GGBM algorithms predicted that 9% to 11% of the validation recipients were at high risk for developing GVHD, with an AUROC of 0.93 to 0.96 that included the 2 recipients who developed GVHD. In conclusion, we present a practical model that can identify patients at high risk for GVHD who may warrant additional monitoring with peripheral blood chimerism testing.
The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows ...associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9; Poverall ≤ 1.15 × 10−14), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.
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