Improving Accuracy of Administrative Data for Perforated Appendicitis Classification.

INTRODUCTION: Reliance on International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes may misclassify perforated appendicitis with resultant research, fiscal, and public health implications. We aimed to improve the accuracy of administrative data for perforated appendicitis classification relying on ICD-10-CM codes from 2015 to 2018. METHODS: We conducted a retrospective study of randomly sampled patients aged ≤18 years diagnosed with acute appendicitis from eight children's hospitals. Patients were identified using the Pediatric Health Information System, and true perforation status was determined by medical record review. We developed two algorithms by leveraging Pediatric Health Information System data elements and data mining (DM) approaches. The two developed algorithm performance was compared against algorithms that exclusively relied on ICD-10-CM codes using area under the curve and other measures. RESULTS: Of 1051 clinically validated encounters that were included, 383 (36.4%) patients were identified to have perforated appendicitis. The two algorithms developed using DM approaches primarily leveraged ICD-10-CM codes and length of stay. DM-developed algorithms had a significantly higher accuracy than algorithms relying exclusively on ICD-10-CM (P value < 0.01): sensitivity and specificity for DM-developed algorithms were 0.86-0.88 and 0.95-0.97, respectively, which were overall higher than algorithms that relied on only ICD-10-CM. CONCLUSIONS: This study provides an algorithm that can improve the accuracy of perforated appendicitis classification using commonly available elements in administrative data. We recommend that this algorithm is used in future appendicitis classification to ensure valid reporting, hospital-level benchmarking, and fiscal or public health assessments.

Antegrade Continence Enema Alone for the Management of Functional Constipation and Segmental Colonic Dysmotility (ACE-FC): A Pediatric Colorectal and Pelvic Learning Consortium Study.

PURPOSE: The purpose of the study was to determine if antegrade continence enema (ACE) alone is an effective treatment for patients with severe functional constipation and segmental colonic dysmotility. METHODS: A retrospective study of patients with functional constipation and segmental colonic dysmotility who underwent ACE as their initial means of management. Data was collected from six participating sites in the Pediatric Colorectal and Pelvic Learning Consortium. Patients who had a colonic resection at the same time as an ACE or previously were excluded from analysis. Only patients who were 21 years old or younger and had at least 1-year follow-up after ACE were included. All patients had segmental colonic dysmotility documented by colonic manometry. Patient characteristics including preoperative colonic and anorectal manometry were summarized, and associations with colonic resection following ACE were evaluated using Fisher's exact test and Wilcoxon rank-sum test. p-Values of less than 0.05 were considered significant. Statistical analyses and summaries were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, United States). RESULTS: A total of 104 patients from 6 institutions were included in the study with an even gender distribution (males n = 50, 48.1%) and a median age of 9.6 years (interquartile range 7.4, 12.8). At 1-year follow-up, 96 patients (92%) were successfully managed with ACE alone and 8 patients (7%) underwent subsequent colonic resection for persistent symptoms. Behavioral disorder, type of bowel management, and the need for botulinum toxin administered to the anal sphincters was not associated with the need for subsequent colonic resection. On anorectal manometry, lack of pelvic floor dyssynergia was significantly associated with the need for subsequent colonic resection; 3/8, 37.5% without pelvic dyssynergia versus 1/8, 12.5% (p = 0.023) with pelvic dyssynergia underwent subsequent colonic resection. CONCLUSION: In patients with severe functional constipation and documented segmental colonic dysmotility, ACE alone is an effective treatment modality at 1-year follow-up. Patients without pelvic floor dyssynergia on anorectal manometry are more likely to receive colonic resection after ACE. The vast majority of such patients can avoid a colonic resection.

Biophysical characterization of a riboflavin-conjugated dendrimer platform for targeted drug delivery.

The present study describes the biophysical characterization of generation-five poly(amidoamine) (PAMAM) dendrimers conjugated with riboflavin (RF) as a cancer-targeting platform. Two new series of dendrimers were designed, each presenting the riboflavin ligand attached at a different site (isoalloxazine at N-3 and d-ribose at N-10) and at varying ligand valency. Isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) were used to determine the binding activity for riboflavin binding protein (RfBP) in a cell-free solution. The ITC data shows dendrimer conjugates have K(D) values of ≥ 465 nM on a riboflavin basis, an affinity ~93-fold lower than that of free riboflavin. The N-3 series showed greater binding affinity in comparison with the N-10 series. Notably, the affinity is inversely correlated with ligand valency. These findings are also corroborated by DSC, where greater protein-conjugate stability is achieved with the N-3 series and at lower ligand valency.

Examining long-term intervention effects to promote teacher problem-solving and communication skills in the rural context.

Conjoint behavioral consultation (CBC), a teacher-parent partnership intervention, has been shown to yield immediate improvements in problem-solving skills and communication quality with parents for kindergarten through third grade teachers in rural schools. The purpose of the present study was to determine whether CBC can yield maintained effects on teacher skills and communication over a 1-year follow-up period. We used an experimental design to examine maintenance effects of CBC (nCBC = 84, nControl = 68). Outcomes were assessed four times: baseline, 12-week posttest (immediate effects), and twice during a 1-year follow-up period (maintenance effects). Longitudinal growth modeling revealed that immediate improvements in perceived problem-solving competence and communication quality with parents for teachers in the CBC condition compared to teachers in the control condition were maintained 1-year postintervention. CBC appears to support teachers' professional practices over time. Implications for enhancing families' and schools' capacities to address student behavior concerns are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Association between COVID-19 related elective surgery cancellations and pediatric inguinal hernia complications: A nationwide multicenter cohort study.

BACKGROUND: Optimal inguinal hernia repair timing remains controversial. It remains unclear how COVID-19 related elective surgery cancellations impacted timing of inguinal hernia repair and whether any delays led to complications. This study aims to determine whether elective surgery cancellations are safe in pediatric inguinal hernia. METHODS: This multicenter retrospective cohort study at 14 children's hospitals included patients ≤18 years who underwent inguinal hernia repair between September 13, 2019, through September 13, 2020. Patients were categorized by whether their inguinal hernia repair occurred before or after their hospital's COVID-19 elective surgery cancellation date. Incarceration and emergency department encounters were compared between pre and postcancellation. RESULTS: Of 1,404 patients, 604 (43.0%) underwent inguinal hernia repair during the postcancellation period, 92 (6.6%) experienced incarceration, and 213 (15.2%) had an emergency department encounter. The postcancellation period was not associated with incarceration (odds ratio 1.54; 95% confidence interval 0.88-2.71; P = .13) or emergency department encounters (odds ratio 1.53; 95% confidence interval 0.94-2.48; P = .09) despite longer median times to inguinal hernia repair (precancellation 29 days [interquartile range 13-55 days] versus postcancellation 31 days [interquartile range 14-73 days], P = .01). Infants were more likely to have the emergency department be their index presentation in the postcancellation period (odds ratio 1.69; 95% confidence interval 1.24-2.31; P < .01). CONCLUSION: Overall, COVID-19 elective surgery cancellations do not appear to increase the likelihood of incarceration or emergency department encounters despite delays in inguinal hernia repair, suggesting that cancellations are safe in children with inguinal hernia. Assessment of elective surgery cancellation safety has important implications for health policy.

Risk profile of subcutaneous port placement in small children.

BACKGROUND/PURPOSE: Long-term central venous access is a safe and common procedure in children. However, complications with devices are a reality. Smaller children are thought to have a higher rate of complication after port placement, and some surgeons avoid placing ports with an arbitrary weight cutoff out of concern for surgical site morbidity. METHODS: We performed a multi-institutional retrospective review of 500 patients less than 5 years of age undergoing port placement at three large volume children's hospitals from 2014 to 2018. Patients were divided by weight greater than or less than 10 kg at the time of insertion. Statistical analysis was performed to evaluate for differences in outcomes between the two groups. RESULTS: The majority of ports were placed for chemotherapy access (71.8%). Other indications included long-term infusions (18.8%) and difficult chronic IV access (9.4%). Of the 500 charts reviewed, 110 (22%) experienced some documented complication (28.9% <10 kg, 20.6% >10 kg, p = 0.096). There were no differences between the two groups in terms of the type or timing of complications. Overall, 16.3% of ports required removal prior to the end of therapy owing to a complication. Complication rate per day with the port in place was not different between the two groups (<10 kg: 0.68 complications/1000 port-days vs >10 kg 0.44 complications/1000 port-days, p = 0.068). CONCLUSION: Weight less than 10 kg was not associated with a significantly higher incidence of any type of port complication in our cohort. This suggests that concern for complications should not exclude children less than 10 kg from port placement. TYPE OF STUDY: Multi-institutional retrospective review. LEVEL OF EVIDENCE: Level III.

Conjoint behavioral consultation in rural schools: Do student effects maintain after 1 year?

Challenging behavior problems are common in early childhood and, if left untreated, may escalate into more severe and intractable problems in adolescence and early adulthood. This trajectory is of particular importance in rural schools, where disruptive behaviors are more prominent than in urban and suburban schools. Conjoint behavioral consultation (CBC) is a family-school partnership intervention with documented efficacy in producing immediate decreases in child problem behaviors and increases in child adaptive behaviors and social skills. The purpose of the present study was to determine whether the immediate effects of CBC maintain over a 1-year follow-up period. Participants at study enrollment were students (N = 267) and their parents, as well as both the students' original (N = 152) and subsequent (N = 135) teachers in 45 Midwest rural schools. At the time of initial study enrollment, students were assigned randomly to an active CBC intervention or "business as usual" control condition. Results demonstrated that immediate effects of parent-rated adaptive and social skills and teacher-rated school problems were maintained at the 1-year follow-up. Additionally, for parent-rated adaptive skills and teacher-rated school problems, improvements during the maintenance phase were statistically equivalent to gains in the control group. However, increases in parent-rated social skills for the control group during the follow-up phase significantly outpaced increases among the CBC group. Implications for use of CBC in rural communities, as well as future research directions, are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The danger zone: Injuries and conditions associated with immediately fatal motorcycle crashes in the state of Michigan.

BACKGROUND: Immediately fatal motorcycle crashes have not been well characterized. This study catalogues injuries sustained in fatal motorcycle crashes and assesses the impact of crash conditions on injury patterns. METHODS: Autopsy records from the office of the medical examiner of Kent County, MI and publicly available traffic reports were queried for information pertaining to motorcyclists declared dead on-scene between January 1, 2007, and December 31, 2016. RESULTS: A total of 71 autopsies of on-scene motorcycle crash fatalities were identified. The two most prevalent injuries were traumatic brain injury (TBI) (85%) and rib fractures (79%). The majority of fatalities occurred in daylight hours (54.3%) and in a 55 mph speed limit zone (63.8%). CONCLUSIONS: This study provides a catalogue of the injuries sustained in immediately fatal motorcycle crashes and the associated conditions. Advocacy efforts that highlight the risks associated with motorcycle riding and that promote safe riding practices are warranted.

The efficacy of conjoint behavioral consultation in the home setting: Outcomes and mechanisms in rural communities.

This study reports the results of a randomized controlled trial examining the effect of Conjoint Behavioral Consultation (CBC), a family-school partnership intervention, on children's behaviors, parents' skills, and parent-teacher relationships in rural community and town settings. Participants were 267 children, 267 parents, and 152 teachers in 45 Midwestern schools. Using an Intent to Treat approach and data analyzed within a multilevel modeling framework, CBC yielded promising results for some but not all outcomes. Specifically, children participating in CBC experienced decreases in daily reports of aggressiveness, noncompliance, and temper tantrums; and increases in parent-reported adaptive skills and social skills at a significantly greater pace than those in a control group. Other outcomes (e.g., parent reports of internalizing and externalizing behaviors) suggested a nonsignificant effect at post-test. CBC parents reported using more effective parenting strategies, gaining more competence in their problem-solving practices, and feeling more efficacious for helping their child succeed in school than parents in the control group. Parents participating in CBC also reported significant improvements in the parent-teacher relationship, and the parent-teacher relationship mediated the effect of CBC on children's adaptive skills. Implications for practice in rural communities, study limitations, and directions for future research are discussed.

A randomized trial examining the effects of Conjoint Behavioral Consultation in rural schools: Student outcomes and the mediating role of the teacher-parent relationship.

The results of a large-scale randomized controlled trial of Conjoint Behavioral Consultation (CBC) on student outcomes and teacher-parent relationships in rural schools are presented. CBC is an indirect service delivery model that addresses concerns shared by teachers and parents about students. In the present study, the intervention was aimed at promoting positive school-related social-behavioral skills and strengthening teacher-parent relationships in rural schools. Participants were 267 students in grades K-3, their parents, and 152 teachers in 45 Midwest rural schools. Results revealed that, on average, improvement among students whose parents and teachers experienced CBC significantly outpaced that of control students in their teacher-reported school problems and observational measures of their inappropriate (off-task and motor activity) and appropriate (on-task and social interactions) classroom behavior. In addition, teacher responses indicated significantly different rates of improvement in their relationship with parents in favor of the CBC group. Finally, the teacher-parent relationship was found to partially mediate effects of CBC on several student outcomes. Unique contributions of this study, implications of findings for rural students, study limitations and suggestions for future research are discussed.

An isothermal titration and differential scanning calorimetry study of the G-quadruplex DNA-insulin interaction.

The binding of insulin to the G-quadruplexes formed by the consensus sequence of the insulin-linked polymorphic region (ILPR) was investigated with differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC). The thermal denaturation temperature of insulin was increased by almost 4 °C upon binding to ILPR G-quadruplex DNA as determined by DSC. The thermodynamic parameters (K(D), ΔH, ΔG, and ΔS) of the insulin-G-quadruplex complex were further investigated by temperature-dependent ITC measurement over the range of 10-37 °C. The binding of insulin to the ILPR consensus sequence displays micromolar affinity in phosphate buffer at pH 7.4, which is mainly driven by entropic factors below 25 °C but by enthalpic terms above 30 °C. The interaction was also examined in several different buffers, and results showed that the observed ΔH is dependent on the ionization enthalpy of the buffer used. This indicates proton release upon the binding of G-quadruplex DNA to insulin. Additionally, the large negative change in heat capacity for this interaction may be associated with the dominant hydrophobicity of the amino acid sequence of insulin's ß subunit, which is known to bind to the ILPR G-quadruplex DNA.

Atomic force microscopy probing of receptor-nanoparticle interactions for riboflavin receptor targeted gold-dendrimer nanocomposites.

Riboflavin receptors are overexpressed in malignant cells from certain human breast and prostate cancers, and they constitute a group of potential surface markers important for cancer targeted delivery of therapeutic agents and imaging molecules. Here we report on the fabrication and atomic force microscopy (AFM) characterization of a core-shell nanocomposite consisting of a gold nanoparticle (AuNP) coated with riboflavin receptor-targeting poly(amido amine) dendrimer. We designed this nanocomposite for potential applications such as a cancer targeted imaging material based on its surface plasmon resonance properties conferred by AuNP. We employed AFM as a technique for probing the binding interaction between the nanocomposite and riboflavin binding protein (RfBP) in solution. AFM enabled precise measurement of the AuNP height distribution before (13.5 nm) and after chemisorption of riboflavin-conjugated dendrimer (AuNP-dendrimer; 20.5 nm). Binding of RfBP to the AuNP-dendrimer caused a height increase to 26.7 nm, which decreased to 22.8 nm when coincubated with riboflavin as a competitive ligand, supporting interaction of AuNP-dendrimer and its target protein. In summary, physical determination of size distribution by AFM imaging can serve as a quantitative approach to monitor and characterize the nanoscale interaction between a dendrimer-covered AuNP and target protein molecules in vitro.

Molecular imaging reveals a role for AKT in resistance to cisplatin for ovarian endometrioid adenocarcinoma.

PURPOSE: Ovarian cancer is the fifth leading cause of cancer-related deaths among American women. Platinum-based chemotherapy, such as cisplatin, represents the standard-of-care for ovarian cancer. However, toxicity and acquired resistance to cisplatin have proven challenging in the treatment of patients with ovarian cancer. EXPERIMENTAL DESIGN: Using a genetically engineered mouse model of ovarian endometrioid adenocarcinoma (OEA) in combination with molecular-imaging technologies, we studied the activation of the AKT serine/threonine kinase in response to long-term cisplatin therapy. RESULTS: Treatment of cells in culture and tumor-bearing animals with cisplatin resulted in activation of AKT, a key mediator of cell survival. On the basis of these results, we investigated the therapeutic use of AKT inhibition in combination with cisplatin, which resulted in enhanced and prolonged induction of apoptosis and in significantly improved tumor control as compared with either agent alone. CONCLUSION: These results provide an impetus for clinical trials using combination therapy. To facilitate these trials, we also show the use of diffusion-weighted MRI as an imaging biomarker for evaluation of therapeutic efficacy in OEA.

Interactions between artemisinins and other antimalarial drugs in relation to the cofactor model--a unifying proposal for drug action.

Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox-active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid-methylene blue (MB), N-benzyl-1,4-dihydronicotinamide (BNAH)-MB, BNAH-lumiflavine, BNAH-riboflavin (RF), and NADPH-FAD-E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4-aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4-aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4-aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme-Fe(III) results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme-Fe(III) complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme-Fe(III) . The quinoline or arylmethanol reenters the DV, and so transfers more heme-Fe(III) out of the DV. In this way, the 4-aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme-Fe(III) and thence free Fe(III) concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe(III) to Fe(II) largely mediated by reduced flavin cofactors and likely also by NAD(P)H-Fre. Generation of ROS through oxidation of Fe(II) by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π complex formation between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for example. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca(2+) transporter. Thus, the effect exerted by artemisinins is more likely a downstream event involving ROS that will also be modulated by mutations in PfATP6. Such mutations attenuate, but cannot abrogate, antimalarial activities of artemisinins. Overall, parasite resistance to artemisinins arises through enhancement of antioxidant defense mechanisms.

Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study.

The present study screened riboflavin mimicking small molecules to determine their binding activity for the riboflavin binding protein. We performed thermodynamic and kinetic binding studies of these molecules using a combination of two analytical approaches; isothermal titration calorimetry and surface plasmon resonance spectroscopy. Screening of a biased set of non-riboflavin based small molecules by microcalorimetry led to the discovery of two known drug molecules, quinacrine and chloroquine, as favorable ligands for the riboflavin receptor with K(D) value of 264, and 2100 nM, respectively. We further demonstrated that quinacrine is a competitive ligand for the receptor as measured by surface plasmon resonance. Thus this study describes the identification of a novel class of dual acting riboflavin antagonists that target riboflavin receptor for cellular uptake and display multifunctional activities upon cellular entry.