Centiles for the shock index among injured children in the prehospital setting.

OBJECTIVE: The shock index (SI), the ratio of heart rate to systolic blood pressure, is a clinical tool for assessing injury severity. Age-adjusted SI models may improve predictive value for injured children in the out-of-hospital setting. We sought to characterize the proportion of children in the prehospital setting with an abnormal SI using established criteria, describe the age-based distribution of SI among injured children, and determine prehospital interventions by SI. METHODS: We performed a multi-agency retrospective cross-sectional study of children (<18 years) in the prehospital setting with a scene encounter for suspected trauma and transported to the hospital between 2018 and 2022 using the National Emergency Medical Services (EMS) Information System datasets. Our exposure of interest was the first calculated SI. We identified the proportion of children with an abnormal SI when using the SI, pediatric age-adjusted (SIPA); and the pediatric SI (PSI) criteria. We developed and internally validated an age-based distributional model for the SI using generalized additive models for location, scale, and shape to describe the age-based distribution of the SI as a centile or Z-score. We evaluated EMS interventions (basic airway interventions, advanced airway interventions, cardiac interventions, vascular access, intravenous fluids, and vasopressor use) in relation to both the SIPA, PSI, and distributional SI values. RESULTS: We analyzed 1,007,863 pediatric EMS trauma encounters (55.0% male, median age 13 years [IQR, 8-16 years]). The most common dispatch complaint was for traffic/transport related injury (32.9%). When using the PSI and SIPA, 13.1% and 16.3% were classified as having an abnormal SI, respectively. There were broad differences in the percentage of encounters classified as having an abnormal SI across the age range, varying from 5.1 to 22.8% for SIPA and 3.7-20.1% for PSI. The SIPA values ranged from the 75th to 95th centiles, while the PSI corresponded to an SI greater than the 90th centile, except in older children. The centile distribution for SI declined during early childhood and stabilized during adolescence and demonstrated a difference of <0.1% at cutoff values. An abnormal PSI, SIPA and higher SI centiles (>90th centile and >95th centiles) were associated with interventions related to basic and advanced airway management, cardiac procedures, vascular access, and provision of intravenous fluids occurred with greater frequency at higher SI centiles. Some procedures, including airway management and vascular access, had a smaller peak at lower (<10th) centiles. DISCUSSION: We describe the empiric distribution of the pediatric SI across the age range, which may overcome limitations of extant criteria in identifying patients with shock in the prehospital setting. Both high and low SI values were associated with important, potentially lifesaving EMS interventions. Future work may allow for more precise identification of children with significant injury using cutpoint analysis paired to outcome-based criteria. These may additionally be combined with other physiologic and mechanistic criteria to assist in triage decisions.

Direct evidence of cellular transformation by prion-like p53 amyloid infection.

Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.

Secretory phospholipase (sPLA2-IIA) regulates breast cancer stem cells differentiation and metastatic potential.

Breast cancer is the second most cancer worldwide in females. The primary factor responsible for tumor recurrence is the presence of breast cancer stem cells (BCSCs), which escape the chemo-radiotherapy. In this study, we have investigated the role of Secretory phospholipase-A2 Group 2A (sPLA2-IIA) that is overexpressed in BCSCs of MCF7 and MDA-MB-231 breast cancer cell lines. Further, overexpression of sPLA2-IIA revealed an increased EGFR/JNK/c-JUN/c-FOS signaling in BCSCs, while sPLA2-IIA knockdown significantly reduced the percentage of BCSCs and decreased signaling in both the cell lines. Importantly, sPLA2-IIA knockdown showed differentiation of BCSCs. Strikingly, PET imaging showed a decreased metastatic potential of BCSCs. Our study revealed a novel role of sPLA2-IIA in regulating BCSCs, which play a crucial role in regulating the differentiation and metastatic potential of BCSCs.

Design, characterization and evaluation of a new 99mTc-labeled folate derivative with affinity towards folate receptor.

Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new 99mTc-labeled radiotracer for the aforementioned application following the well-established 99mTc-'4+1' chemistry. Formation of the desired [99mTc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the 99mTc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application.

OUTCOMES OF MISSED DIAGNOSIS OF PEDIATRIC APPENDICITIS, NEW-ONSET DIABETIC KETOACIDOSIS, AND SEPSIS IN FIVE PEDIATRIC HOSPITALS.

BACKGROUND: Missed diagnosis can predispose to worse condition-specific outcomes. OBJECTIVE: To determine 90-day complication rates and hospital utilization after a missed diagnosis of pediatric appendicitis, new-onset diabetic ketoacidosis (DKA), and sepsis. METHODS: We evaluated patients under 21 years of age visiting five pediatric emergency departments (EDs) with a study condition. Case patients had a preceding ED visit within 7 days of diagnosis and underwent case review to confirm a missed diagnosis. Control patients had no preceding ED visit. We compared complication rates and utilization between case and control patients after adjusting for age, sex, and insurance. RESULTS: We analyzed 29,398 children with appendicitis, 5366 with DKA, and 3622 with sepsis, of whom 429, 33, and 46, respectively, had a missed diagnosis. Patients with missed diagnosis of appendicitis or DKA had more hospital days and readmissions; there were no significant differences for those with sepsis. Those with missed appendicitis were more likely to have abdominal abscess drainage (adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 2.4-3.6) or perforated appendicitis (aOR 3.1, 95% CI 2.5-3.8). Those with missed DKA were more likely to have cerebral edema (aOR 4.6, 95% CI 1.5-11.3), mechanical ventilation (aOR 13.4, 95% CI 3.8-37.1), or death (aOR 28.4, 95% CI 1.4-207.5). Those with missed sepsis were less likely to have mechanical ventilation (aOR 0.5, 95% CI 0.2-0.9). Other illness complications were not significantly different by missed diagnosis. CONCLUSIONS: Children with delayed diagnosis of appendicitis or new-onset DKA had a higher risk of 90-day complications and hospital utilization than those with a timely diagnosis.

Critical Emergency Department Interventions and Clinical Deterioration in Children With Nonsevere Traumatic Intracranial Hemorrhage.

OBJECTIVE: Substantial practice variation exists in the management of children with nonsevere traumatic intracranial hemorrhage (tICH). A comprehensive understanding of rates and timing of clinically important tICH, including critical interventions and deterioration, along with associated clinical and neuroradiographic characteristics, will inform accurate risk stratification. METHODS: We conducted a single-center retrospective cohort study of children aged younger than 18 years evaluated in the emergency department (ED) from May 1, 2014 to February 28, 2020 with tICH and initial Glasgow Coma Scale (GCS) score of higher than 8. We determined rates of clinically important tICH after injury and within 96 hours of ED arrival, defined as immediate ED interventions (intubation, hyperosmotic agents, or neurosurgery within 4 hours of arrival) or clinically important deterioration (signs/symptoms with change in management). Associations between outcome and clinical and neuroradiographic characteristics were calculated using individual logistic regression models. RESULTS: Our sample included 135 children. Clinically important tICH was observed in 13.3% (n = 18); 9 (6.7%) underwent immediate ED interventions and 9 (6.7%) developed deterioration. Most (93.3%, n = 127) presented with an initial GCS ≥ 14, including all children who later deteriorated. Initial GCS (P = 0.001) and nonaccidental trauma (P = 0.024) mechanism were associated with the outcome. None of the 71 (52.6%) children with initial GCS ≥ 14, isolated, nonepidural hemorrhage after accidental injury developed clinically important tICH. CONCLUSIONS: Clinically important tICH occurred in 13% of children with nonsevere tICH, and 7% of children who did not undergo immediate ED interventions later deteriorated, all of whom had an initial GCS ≥ 14. However, a subgroup of children was identified as low risk based on clinical and neuroradiographic characteristics.

Combinatorial cetuximab targeted polymeric nanocomplexes reduce PRC1 level and abrogate growth of metastatic hepatocellular carcinoma in vivo with efficient radionuclide uptake.

Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NP + Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18 ±â€¯1.0% ID/g, P < .0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, P < .0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.

Association of Clinical Guidelines and Decision Support with Computed Tomography Use in Pediatric Mild Traumatic Brain Injury.

OBJECTIVE: To examine whether the presence of clinical guidelines and clinical decision support (CDS) for mild traumatic brain injury (mTBI) are associated with lower use of head computed tomography (CT). STUDY DESIGN: We conducted a cross-sectional study of 45 pediatric emergency departments (EDs) in the Pediatric Hospital Information System from 2015 through 2019. We included children discharged with mTBI and surveyed ED clinical directors to ascertain the presence and implementation year of clinical guidelines and CDS. The association of clinical guidelines and CDS with CT use was assessed, adjusting for relevant confounders. As secondary outcomes, we evaluated ED length of stay and rates of 3-day ED revisits and admissions after revisits. RESULTS: There were 216 789 children discharged with mTBI, and CT was performed during 20.3% (44 114/216 789) of ED visits. Adjusted hospital-specific CT rates ranged from 11.8% to 34.7% (median 20.5%, IQR 17.3%, 24.3%). Of the 45 EDs, 17 (37.8%) had a clinical guideline, 9 (20.0%) had CDS, and 19 (42.2%) had neither. Compared with EDs with neither a clinical guideline nor CDS, visits to EDs with CDS (aOR 0.52 [0.47, 0.58]) or a clinical guideline (aOR 0.83 [0.78, 0.89]) had lower odds of including a CT for mTBI. ED length of stay and revisit rates did not differ based on the presence of a clinical guideline or CDS. CONCLUSIONS: Clinical guidelines for mTBI, and particularly CDS, were associated with lower rates of head CT use without adverse clinical outcomes.

Use of Neuroimaging for Children With Seizure in General and Pediatric Emergency Departments.

BACKGROUND: Seizure is a common reason for children to visit the emergency department (ED). Pediatric and general EDs may obtain computed tomography (CT) scans of the head for seizure at different rates. OBJECTIVE: To compare rates of head CT for pediatric seizure between general and pediatric EDs. METHODS: This was a retrospective cohort study using the National Hospital Ambulatory Medical Care Survey for patients <21 years of age presenting to an ED with a chief complaint or diagnosis of seizure between 2006 to 2017. Of these patients, we compared head CT use between general and pediatric EDs among patients with fever, trauma, and co-diagnosis of epilepsy using univariable risk differences and in a multivariable logistic regression model. RESULTS: More than 5 (5.4) million (78.8%) and 1.5 million (21.2%) pediatric patients with seizure presented to general and pediatric EDs, respectively. Of those, 22.4% (1.21 million) and 13.2% (192,357) underwent CT scans of the head, respectively, a risk difference of 9.2% (95% confidence interval [CI] 2.3-16.1). General EDs obtained CT scans of the head more often in patients with epilepsy (risk difference 17.9% [95% CI 4.0-31.9]), without fever (12.2% [95% CI 3.1-21.4]), and without trauma (10.6% [95% CI 4.4-16.8]). Presenting to a general ED, being afebrile, or having trauma were associated with head CT with adjusted odds ratios of 1.7 (95% CI 1.0-3.2), 4.9 (95% CI 2.6-9.2), and 2.0 (95% CI 1.2-3.4), respectively. Age, gender, and epilepsy were not associated with head CT among all patients with seizure. CONCLUSIONS: Children with seizure are more likely to undergo CT scans of the head at general EDs compared with pediatric EDs.

Epidemiology of Critical Interventions in Children With Traumatic Intracranial Hemorrhage.

OBJECTIVE: To estimate rates of critical medical and neurosurgical interventions and resource utilization for children with traumatic intracranial hemorrhage (ICH). METHODS: This was a retrospective study of children younger than 18 years hospitalized in 1 of 35 hospitals in the Pediatric Health Information System from 2009 to 2019 for ICH. We defined critical intervention as a critical medical (hyperosmotic agents and intubation) or neurosurgical intervention. We determined rates of critical interventions, intensive care unit (ICU) admission, and repeat neuroimaging. We used hierarchical logistic regression to identify high-level factors associated with undergoing critical interventions, controlling for hospital-level effects. RESULTS: There were 12,714 children with ICH included in the study. Median (interquartile range) age was 4.3 (0.7-11.0) years. Twelve percent (n = 1470) of children underwent a critical clinical intervention. Critical medical interventions occurred in 10% (n = 1219), and neurosurgical interventions occurred in 3% (n = 419). Intensive care unit admission occurred in 44% (n = 5565), whereas repeat neuroimaging occurred in 40% (n = 5072). Among ICU patients, 79% (n = 4366) did not undergo a critical intervention. Of the 11,244 children with no critical interventions, 39% (n = 4366) underwent ICU admission, and 37% (n = 4099) repeat neuroimaging. After controlling for hospital, children with isolated subdural (P = 0.013) and isolated subarachnoid (P < 0.001) hemorrhage were less likely to receive critical interventions. CONCLUSIONS: Critical medical interventions occurred in 10% of children with ICH, and neurosurgical interventions occurred in 3%. Intensive care unit admission and repeat neuroimaging are common, even among those who did not undergo critical interventions. Selective utilization of ICU admission and repeat neuroimaging in children who are at low risk of requiring critical interventions could improve overall quality of care and decrease unnecessary resource utilization.

Synthesis, biological evaluation, and molecular docking analysis of phenstatin based indole linked chalcones as anticancer agents and tubulin polymerization inhibitors.

A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.

Should the Absence of Urinary Nitrite Influence Empiric Antibiotics for Urinary Tract Infection in Young Children?

OBJECTIVES: Screening for urinary tract infection (UTI) includes urinary nitrite testing by dipstick urinalysis. Gram-negative enteric organisms produce urinary nitrite and represent the most common uropathogens. Enterococcus, a less common uropathogen, does not produce nitrite and has a unique antibiotic resistance pattern. Whether to adjust empiric antibiotics in the absence of urinary nitrite has not been established. Our primary objective was to determine prevalence of enterococcal UTI among young children with a nitrite negative urinalysis. METHODS: A retrospective study of children aged less than 2 years evaluated in the emergency department for possible UTI and had a paired urinalysis and urine culture was performed. Urinary tract infection was defined by catheterized culture yielding greater than or equal to 50,000 colony-forming units per milliliter of a single uropathogen. Prevalence of uropathogens among nitrite negative samples was studied. RESULTS: A total of 7599 children were studied. Median (interquartile range) age was 5.6 (2.3-11.2) months, and 57% were female. Prevalence of UTI was 8.1%. Enterococcus was the uropathogen in 2.1% of UTIs, and all cases had negative dipstick nitrite. Among nitrite negative UTIs, 95.6% of uropathogens were gram-negative and only 3.2% (confidence interval, 1.8%-5.3%) were enterococcus. None of the 200 UTIs with positive nitrite yielded enterococcus (upper confidence interval, 1.4%). Among children with positive leukocyte esterase and negative nitrite, only 0.7% of cases had enterococcal UTI. CONCLUSIONS: Only 3% of nitrite negative UTIs were caused by enterococcus. Given the low prevalence of enterococcal UTI, the absence of dipstick nitrite should not affect routine empiric antibiotic choice for presumptive UTI in young children.

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer.

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.

Age-Stratified Risk of Critical Illness in Young Children Presenting to the Emergency Department with Suspected Influenza.

OBJECTIVE: To investigate the risk of critical illness by age group among young children without a chronic condition presenting to the emergency department (ED) with suspected influenza. STUDY DESIGN: Retrospective study of patients aged <2 years presenting to the ED with suspected influenza (defined by diagnostic codes for influenza or influenza-like illness) from 2009 to 2017 in 49 hospitals in the Pediatric Health Information System. Patients with chronic conditions were excluded. The main clinical outcomes were intensive care unit (ICU) admission, ventilatory support, vasopressor administration, and mortality, which were compared independently by age group (<3 months, 3 to <6 months, 6 to <12 months, and 12 to <24 months). To compare outcomes by age, we estimated the prevalence of each outcome by age group after fitting logistic regression models to control for demographic differences between groups. RESULTS: A total of 55 986 children were studied. Overall admission and ICU admission rates were 20% and 2%, respectively. After adjustment for demographic variables, infants aged <3 months had higher rates of ICU admission (2.7%; 95% CI, 2.0%-3.3%; P < .001 compared with other age groups) and ventilatory support (2.5%; 95% CI, 1.9%-3.2%; P < .001 compared with other age groups); however, there were no differences in vasopressor administration. The overall case fatality rate was low (0.007%) and thus could not be compared across age groups. CONCLUSIONS: Infants aged <3 months with suspected influenza are at greatest risk for critical illness. Although critical illness is uncommon, these findings should be incorporated into acute management decisions, including the need for specified outpatient follow-up or hospitalization, and public health efforts should focus on prevention and disease-modifying interventions in this high-risk population.

Microscopic Bacteriuria Detected by Automated Urinalysis for the Diagnosis of Urinary Tract Infection.

OBJECTIVE: To evaluate the test performance of microscopic bacteriuria by automated urinalysis for presumptive urinary tract infection (UTI) in young children. STUDY DESIGN: This is a retrospective cross-sectional study of children aged <2 years evaluated for UTI in a single large emergency department with paired automated microscopic urinalysis and culture. Test characteristics were calculated for automated microscopic bacteriuria and pyuria, and a practical diagnostic threshold of bacteriuria was determined. Standard test performance measures and receiver operator characteristic curves were generated. The diagnostic performance of bacteriuria was compared with microscopic pyuria. RESULTS: Two thousand five hundred fifty-four children with a median age of 6.1 months were studied, 19% of whom had a positive urine culture. Automated microscopic bacteriuria ≥1+ resulted in a positive likelihood ratio (LR+) of 4.5 (95% CI, 3.9-5.2) and negative LR (LR-) of 0.52 (95% CI, 0.47-0.57). Pyuria alone (≥5 WBC/high-power field) had a LR+ of 4.5 (95% CI, 4.1-5.0) and a LR- of 0.14 (95% CI, 0.11-0.18), whereas the addition of automated microscopic bacteriuria ≥1+ improved the LR+ to 16.3 (95% CI, 12.6-21.1) but raised the LR- to 0.51 (95% CI, 0.47-0.56). Test performance of automated microscopic bacteriuria measured by area under the curve analysis was lower (0.73; 95% CI, 0.70-0.76) than for pyuria (0.92; 95% CI, 0.90-0.93). Isolated automated microscopic bacteriuria without pyuria occurred in only 204 patients (8.0%), among whom only 20 (9.8%) had a positive urine culture. CONCLUSIONS: Microscopic bacteriuria measured by automated urinalysis augments the diagnostic value of pyuria for identifying presumptive UTI in young children aged <2 years. Bacteriuria is diagnostically inferior to microscopic pyuria, and in children with bacteriuria without pyuria, presumptive UTI is unlikely.

The Importance of Urine Concentration on the Diagnostic Performance of the Urinalysis for Pediatric Urinary Tract Infection.

STUDY OBJECTIVE: The presence of leukocyte esterase by urine dipstick and microscopic pyuria are both indicators of possible urinary tract infection. The effect of urine concentration on the diagnostic performance of the urinalysis for pediatric urinary tract infection has not been studied. Our objective is to determine whether the urinalysis performance for detecting urinary tract infection varies by urine concentration as measured by specific gravity. METHODS: This was a retrospective cross-sectional study of the urine laboratory results of children younger than 13 years who presented to the emergency department during 68 months and had a paired urinalysis and urine culture obtained. Urinary tract infection was defined as pure growth of a uropathogen at standard culture thresholds. Test characteristics were calculated across 4 specific gravity groups (1.000 to 1.010, 1.011 to 1.020, 1.021 to 1.030, and >1.030). RESULTS: In total, 14,971 cases were studied. Median age was 1.5 years (interquartile range 0.4 to 5.5 years) and 60% were female patients. Prevalence of urinary tract infection was 7.7%. For the presence of leukocyte esterase and a range of pyuria cut points, the positive likelihood ratios decreased with increasing specific gravity. From most dilute to most concentrated urine, the positive likelihood ratio decreased from 12.1 (95% confidence interval [CI] 10.7 to 13.7) to 4.2 (95% CI 3.0 to 5.8) and 9.5 (95% CI 8.6 to 10.6) to 5.5 (95% CI 3.3 to 9.1) at a threshold of greater than or equal to 5 WBCs per high-power field and presence of leukocyte esterase, respectively. The negative likelihood ratios increased with increasing specific gravity for leukocyte esterase and microscopic pyuria. CONCLUSION: For the detection of pediatric urinary tract infection, the diagnostic performance of both dipstick leukocyte esterase and microscopic pyuria varies by urine concentration, and therefore the specific gravity should be considered when the urinalysis is interpreted.

Preliminary evaluation of indigenous 90 Y-labelled microspheres for therapy of hepatocellular carcinoma.

BACKGROUND & OBJECTIVES: Yttrium-90 ( 90 Y)-based radioembolization has been employed to treat hepatocellular carcinoma (HCC) as commercial radioactive glass and polymeric resin microspheres. However, in India and other Asian countries, these preparations must be imported and are expensive, validating the need for development of indigenous alternatives. This work was aimed to develop an economically and logistically favourable indigenous alternative to imported radioembolizing agents for HCC therapy. METHODS: The preparation of 90 Y-labelled Biorex 70 microspheres was optimized and in vitro stability was assessed. Hepatic tumour model was generated in Sprague-Dawley rats by orthotopic implantation of N1S1 rat HCC cell line. In vivo localization and retention of the 90 Y-labelled Biorex 70 microspheres was assessed for seven days, and impact on N1S1 tumour growth was studied by histological examination and biochemical assays. RESULTS: Under optimal conditions, >95% 90 Y-labelling yield of Biorex70 resin microspheres was obtained, and these showed excellent in vitro stability of labelling (>95%) at seven days. In animal studies, 90 Y-labelled Biorex 70 microspheres were retained (87.72±1.56% retained in liver at 7 days). Rats administered with 90 Y-labelled Biorex 70 microspheres exhibited lower tumour to liver weight ratio, reduced serum alpha-foetoprotein level and greater damage to tumour tissue as compared to controls. INTERPRETATION & CONCLUSIONS: 90 Y-labelled Biorex 70 microspheres showed stable retention in the liver and therapeutic effect on tumour tissue, indicating the potential for further study towards clinical use.

Thymoquinone prevents RANKL-induced osteoclastogenesis activation and osteolysis in an in vivo model of inflammation by suppressing NF-KB and MAPK Signalling.

Osteoclasts are multinuclear giant cells responsible for bone resorption in inflammatory bone diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Because of deleterious side effects with currently available drugs the search continues for novel effective and safe therapies. Thymoquinone (TQ), the major bioactive component of Nigella sativa has been investigated for its anti-inflammatory, antioxidant and anticancer activities. However, its effects in osteoclastogenesis have not been reported. In the present study we show for the first time that TQ inhibits nuclear factor-KB ligand (RANKL) induced osteoclastogenesis in RAW 264.7 and primary bone marrow derived macrophages (BMMs) cells. RANKL induced osteoclastogenesis is associated with increased expression of multiple transcription factors via activation of NF-KB, MAPKs signalling and reactive oxygen species (ROS). Mechanistically TQ blocked the RANKL induced NF-KB activation by attenuating the phosphorylation of IkB kinase (IKKα/ß). Interestingly, in RAW 264.7 cells TQ inhibited the RANKL induced phosphorylation of MAPKs and mRNA expression of osteoclastic specific genes such as TRAP, DC-STAMP, NFATc1 and c-Fos. In addition, TQ also decreased the RANKL stimulated ROS generation in macropahges (RAW 264.7) and H2O2 induced ROS generation in osteoblasts (MC-3T3-E1). Consistent with in vitro results, TQ inhibited lipopolysaccharide (LPS) induced bone resorption by suppressing the osteoclastogenesis. Indeed, micro-CT analysis showed that bone mineral density (BMD) and bone architecture parameters were positively modulated by TQ. Taken together our data demonstrate that TQ has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-KB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

Bioevaluation of (125) I Ocu-Prosta seeds for application in prostate cancer brachytherapy.

BACKGROUND & OBJECTIVES: In recent years, brachytherapy involving permanent radioactive seed implantation has emerged as an effective modality for the management of cancer of prostate. 125 I-Ocu-Prosta seeds were indigenously developed and studies were carried out to assess the safety of the indigenously developed 125 I-Ocu-Prosta seeds for treatment of prostate cancer. METHODS: Animal experiments were performed to assess the likelihood of in vivo release of 125 I from radioactive seeds and migration of seeds implanted in the prostate gland of the rabbit. In vivo release of 125 I activity was monitored by serial blood sampling from the auricular vein and subsequent measurement of 125 I activity. Serial computed tomography (CT) scans were done at regular intervals till 6 months post implant to assess the physical migration of the seeds. RESULTS: The laser welded seeds maintained their hermeticity and prevented the in vivo release of 125 I activity into the blood as no radioactivity was detected during follow up blood measurements. Our study showed that the miniature 125 I seeds were clearly resolved in CT images. Seeds remained within the prostate gland during the entire study period. Moreover, the seed displacement was minimal even within the prostate gland. INTERPRETATION & CONCLUSIONS: Our findings have demonstrated that indigenously developed 125 I-Ocu-Prosta seeds may be suitable for application in treatment of prostate cancer.

Development of 68Ga-labeled fatty acids for their potential use in cardiac metabolic imaging.

While [(11)C]palmitate continues to be a promising tracer for cardiovascular Positron Emission Tomography (PET) imaging, unfavourable logistics due to the short half-life of (11)C (20 min) and cumbersome labeling methodologies are the major impediments that limit its widespread use. In order to circumvent such limitations, an attempt has been made to explore the potential of (68)Ga-labeled fatty acid analogs for metabolic imaging owing to the availability of (68)Ga through a (68)Ge/(68)Ga generator on an on-demand basis. In this study, two fatty acid conjugates were synthesized by conjugation of p-SCN-benzyl NOTA with the ω-amino group of 11-amino undecanoic acid and 12-amino dodecanoic acid, respectively, under alkaline conditions. Both derivatives were radiolabeled in high yields with (68)Ga obtained from an in-house (68)Ge/(68)Ga generator. Biodistribution studies in Swiss mice showed reasonable myocardial uptake at 2 min for both derivatives (7.4 ± 2.8% ID/g for 11-carbon fatty acid-NOTA conjugate and 6.4 ± 2.1% ID/g for 12-carbon fatty acid-NOTA conjugate), which cleared rapidly over 30 min. However, significant activity was found in blood for both tracers, with heart/blood ratios observed to be below 0.5 at all time points, diminishing the potential of the synthesized complexes for cardiac imaging.