CT presentations of adult and pediatric SARS-CoV-2 patients: A review of early COVID-19 data.

OBJECTIVE: Initial COVID-19 reports described a variety of clinical presentations, but lower respiratory abnormalities are most common and chest CT findings differ between adult and pediatric patients. We aim to summarize early CT findings to inform healthcare providers on the frequency of COVID-19 manifestations specific to adult or pediatric patients, and to determine if the sensitivity of CT justifies its use in these populations. METHODS: PubMed was searched for the presence of the words "CT, imaging, COVID-19" in the title or abstract, and 17 large-scale PubMed and/or Scopus studies and case reports published between January 1, 2020 and April 15, 2020 were selected for data synthesis. RESULTS: Initial CT scans identified ground-glass opacities and bilateral abnormalities as more frequent in adults (74%, n = 698, and 89%, n = 378, respectively) than children (60%, n = 25, and 37%, n = 46). At 14+ days, CT scans evidenced varied degrees of improvement in adults but no resolution until at least 26 days after the onset of flu-like symptoms. In pediatric patients, a third (n = 9) showed additional small nodular GGOs limited to a single lobe 3-5 days after an initial CT scan. CONCLUSION: Early adult CT findings suggest the limited use of CT as a supplemental tool in diagnosing COVID-19 in symptomatic adult patients, with a particular focus on identifying right and left lower lobe abnormalities, GGOs, and interlobular septal thickening. Early pediatric CT findings suggest against the use of CT if RT-PCR is available given its significantly lower sensitivity in this population and radiation exposure.

[CT Presentations of Adult and Pediatric SARS-COV-2 Patients: A Review of Early COVID-19 Data]. / Comparación de los hallazgos en la tomografía computarizada de pacientes adultos y pediátricos con COVID-19.

Objective: Initial COVID-19 reports described a variety of clinical presentations, but lower respiratory abnormalities are most common and chest CT findings differ between adult and pediatric patients. We aim to summarize early CT findings to inform healthcare providers on the frequency of COVID-19 manifestations specific to adult or pediatric patients, and to determine if the sensitivity of CT justifies its use in these populations. Methods: PubMed was searched for the presence of the words "CT, imaging, COVID-19" in the title or abstract, and 17 large-scale PubMed and/or Scopus studies and case reports published between January 1, 2020 and April 15, 2020 were selected for data synthesis. Results: Initial CT scans identified ground-glass opacities and bilateral abnormalities as more frequent in adults (74%, n = 698, and 89%, n = 378, respectively) than children (60%, n = 25, and 37%, n = 46). At 14+ days, CT scans evidenced varied degrees of improvement in adults but no resolution until at least 26 days after the onset of flu-like symptoms. In pediatric patients, a third (n = 9) showed additional small nodular GGOs limited to a single lobe 3-5 days after an initial CT scan. Conclusión: Early adult CT findings suggest the limited use of CT as a supplemental tool in diagnosing COVID-19 in symptomatic adult patients, with a particular focus on identifying right and left lower lobe abnormalities, GGOs, and interlobular septal thickening. Early pediatric CT findings suggest against the use of CT if RT-PCR is available given its significantly lower sensitivity in this population and radiation exposure.

Clinical characteristics of optic neuritis in Taiwanese children.

PURPOSE: To document the etiology, clinical presentation, and visual prognosis of optic neuritis in Taiwanese children. METHODS: Retrospectively reviewed children younger than 18 years old with optic neuritis in Chang Gung Memorial Hospital and Chang Gung Children's Hospital from 1998 to 2009. RESULTS: There were 24 children (38 eyes) with optic neuritis in that period. Overall, 14 patients (58.3%) were female and 10 patients (41.7%) were male. In total, 14 patients (58.3%) had bilateral involvement, and 10 patients (41.7%) had unilateral involvement. Out of 38 eyes, 24 (63.2%) had disc swelling. Out of 24 patients, 21 (87.5%) underwent intravenous steroid therapy (10 to 30 mg/kg/day) for 3-5 days, and followed by an oral taper. Out of 24 patients, 20 (83.3%) achieved final visual acuity (VA) of 20/40 or better. However, a poor visual outcome (four patients) (VA<20/40) was correlated with pale disc at presentation (P=0.002, Pearson χ (2)-test) and age older than 10 years (P=0.012, Fisher's exact test). Five patients were diagnosed with acute disseminated encephalomyelitis (ADEM) (21%), and three patients were diagnosed with multiple sclerosis (MS) (12.5%). Patients with ADEM did not have a better visual outcome than patients with MS (P=0.643, Fisher's exact test). CONCLUSIONS: Visual recovery from optic neuritis was favorable in Taiwanese children. A poor visual outcome was correlated with pale disc at presentation and patients' age older than 10 years. ADEM is the most common associated systemic disease; MS is relatively rare.

Transplantation of cultivated oral mucosal epithelial cells for severe corneal burn.

PURPOSE: To access the feasibility of using cultivated oral mucosal epithelial cell transplantation (COMET) for the management of severe corneal burn. METHODS: COMET was performed to promote re-epithelialization in two eyes with acute alkaline burn and one eye with chronic alkaline burn, and to reconstruct the ocular surface in two eyes with chronic thermal burn. Autologous oral mucosal epithelial cells obtained from biopsy were cultivated on amniotic membrane. Immunoconfocal microscopy for keratins and progenitor cell markers was performed to characterize the cultivated epithelial sheet. Following transplantation, the clinical outcome and possible complications were documented. The patients were followed for an averaged 29.6+/-3.6 (range: 26-34) months. RESULTS: Cultivated oral mucosal epithelial sheet expressed keratin 3, 13, and progenitor cell markers p63, p75, and ABCG2. After COMET, all the corneas became less inflamed, and the corneal surface was completely re-epithelialized in 6.0+/-3.2 (range: 3-10) days in all but one patients. Microperforation occurred in one patient, and a small persistent epithelial defect developed in another. Both were solved uneventfully. In all patients, superficial corneal blood vessels invariably developed, and to further improve vision, conjunctivo-limbal autografting (N=3) and/or penetrating keratoplasty (N=3) were performed subsequently. The vision of all patients showed substantial improvement after additional surgeries. CONCLUSIONS: This study showed the potential of COMET to promote re-epithelialization and reduce inflammation in acute corneal burn, and to reconstruct the corneal surface in chronic burn. COMET may, therefore, be considered an alternative treatment for severe corneal burn.

A different approach to assess resident phacoemulsification learning curve: analysis of both completion and complication rates.

PURPOSE: To assess phacoemulsification learning curve by analysing residents' surgical completion and complication rates. METHODS: This prospective study included 226 cases of phacoemulsification performed by 11 senior residents under a single supervisor during a 27-month period. Both completion and complication rates were collected to assess their surgical results. 'Short-term completion rate (STCR)', the frequency of the surgeries completed exclusively by the residents during every five consecutive cases, was used in the evaluation of the learning curve parameter. RESULTS: These residents could complete phacoemulsification independently in 101 surgeries (44.7%). Intraoperative complications occurred in 62 cases (27.4%), of which 11 cases were complicated with vitreous loss (4.9%). By tracing different residents' individual STCRs, we found that the learning curve for phacoemulsification surgery to be of an exponential pattern, and the first STCR of 60% to be a good representation of the exponential point. Before the residents' first STCR of 60%, their average completion rate was only 16.7% and complication rate was as high as 39.2%. While after that point, the average completion rate accelerated to 76.4% and complication rate decreased to 14.2%. CONCLUSION: The learning curve of phacoemulsification is of an exponential pattern and the trainees' STCR can be a useful parameter to evaluate their surgical performance.

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells.

The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.

Purification of hematopoietic stem cells using the side population.

Hematopoietic stem cells (HSCs) primarily reside in bone marrow, are defined by their ability to maintain blood homeostasis, and replenish themselves through self-renewal. Although HSC purification schemes vary from laboratory to laboratory, the resulting cell populations are similar, if not the same. This chapter will discuss different enrichment methods for HSCs and provide a detailed protocol for staining HSC with Hoechst 33342 for the side population (SP).

Interventions for relieving pain associated with panretinal photocoagulation: a prospective randomized trial.

PURPOSE: To evaluate the efficacy of pain relief by oral diazepam, acetaminophen, mefenamic acid, intramuscular ketorolac tromethamine, and peribulbar anaesthesia in panretinal photocoagulation (PRP). METHODS: A total of 220 patients with proliferative diabetic retinopathy requiring PRP treatment were enrolled in this study. Before laser treatment, the patients were allocated randomly to one of eight groups: group 1: diazepam (n=22), group 2: acetaminophen (n=21), group 3: mefenamic acid (n=21), group 4: diazepam and acetaminophen (n=22), group 5: diazepam and mefenamic acid (n=22), group 6: peribulbar anaesthesia with lidocaine (n=23), group 7: intramuscular injection of ketorolac tromethamine (n=22), group 8: placebo (n=67). Pain after the laser treatment was assessed by a verbal descriptive scale. Blood pressure and heart rate were measured before and after laser treatment. RESULTS: Patients receiving peribulbar anaesthesia had a significantly lower pain score than the control group (P<0.0001). Additionally, the peribulbar anaesthesia-treated group had the significantly least PRP-associated rise in either systolic (P=0.043) or diastolic blood pressure rates (P=0.030). There were no significant differences in pain score using other anesthetic agents when compared with the control group. There were no significant changes in heart rate after PRP treatment. CONCLUSION: Peribulbar anaesthesia is effective in reducing pain and blood pressure increase after PRP treatment. Oral diazepam, mefenamic acid, and acetaminophen (either alone or in combination with each other) are not effective in preventing PRP treatment-associated pain. Intramuscular injection of ketorolac tromethamine is also not effective in reducing PRP-associated pain.

Progress report on the guidance for industry for statistical aspects of the design, analysis, and interpretation of chronic rodent carcinogenicity studies of pharmaceuticals.

The U.S. Food and Drug Administration (FDA) is in the process of preparing a draft Guidance for Industry document on the statistical aspects of carcinogenicity studies of pharmaceuticals for public comment. The purpose of the document is to provide statistical guidance for the design of carcinogenicity experiments, methods of statistical analysis of study data, interpretation of study results, presentation of data and results in reports, and submission of electronic study data. This article covers the genesis of the guidance document and some statistical methods in study design, data analysis, and interpretation of results included in the draft FDA guidance document.

Weighted p-value adjustments for animal carcinogenicity trend test.

A typical animal carcinogenicity experiment routinely analyzes approximately 10-30 tumor sites. Comparisons of tumor responses between dosed and control groups and dose-related trend tests are often evaluated for each individual tumor site/type separately. p-Value adjustment approaches have been proposed for controlling the overall Type I error rate or familywise error rate (FWE). However, these adjustments often result in reducing the power to detect a dose effect. This paper proposes using weighted adjustments by assuming that each tumor can be classified as either class A or class B based on prior considerations. The tumors in class A, which are considered as more critical endpoints, are given less adjustment. Two weighted methods of adjustments are presented, the weighted p adjustment and weighted alpha adjustment. A Monte Carlo simulation shows that both weighted adjustments control the FWE well. Furthermore, the power increases if a treatment-dependent tumor is analyzed as in class A tumors and the power decreases if it is analyzed as in class B tumors. A data set from a National Toxicology Program (NTP) 2-year animal carcinogenicity experiment with 13 tumor types/sites observed in male mice was analyzed using the proposed methods. The modified poly-3 test was used to test for increased carcinogenicity since it has been adopted by the NTP as a standard test for a dose-related trend. The unweighted adjustment analysis concluded that there was no statistically significant dose-related trend. Using the Food and Drug Administration classification scheme for the weighted adjustment analyses, two rare tumors (with background rates of 1% or less) were analyzed as class A tumors and 11 common tumors (with background rates higher than 1%) as class B. Both weighted analyses showed a significant dose-related trend for one rare tumor.

Bioassays of shortened duration for drugs: statistical implications.

Declining survival rates in rodent carcinogenesis bioassays have raised a concern that continuing the practice of terminating such studies at 24 months could result in too few live animals at termination for adequate pathological evaluation. One option for ensuring sufficient numbers of animals at the terminal sacrifice is to shorten the duration of the bioassay, but this approach is accompanied by a reduction in statistical power for detecting carcinogenic potential. The present study was conducted to evaluate the loss of power associated with early termination. Data from drug studies in rats were used to formulate biologically based dose-response models of carcinogenesis using the 2-stage clonal expansion model as a context. These dose-response models, which were chosen to represent 6 variations of the initiation-promotion-completion cancer model, were employed to generate a large number of representative bioassay data sets using Monte Carlo simulation techniques. For a variety of tumor dose-response trends, tumor lethality, and competing risk-survival rates, the power of age-adjusted statistical tests to assess the significance of carcinogenic potential was evaluated at 18 and 21 months, and compared to the power at the normal 24-month stopping time. The results showed that stopping at 18 months would reduce power to an unacceptable level for all 6 submodels of the 2-stage clonal expansion model, with the pure-promoter and pure-completer models being most adversely affected. For the 21-month stopping time, the results showed that, unless pure promotion can be ruled out a priori as a potential carcinogenic mode of action, the loss of power is too great to warrant early stopping.

An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. I. Evidence for a confounding nonresponder phenotype.

We have completed 2 26-wk studies to evaluate the hemizygous transgenic Tg.AC mouse, which has been proposed as an alternative short term model for testing carcinogenicity. We attempted to evaluate the response to the known rodent carcinogens cyclophosphamide, phenolphthalein, and tamoxifen and to the noncarcinogen chlorpheniramine following topical application. In the first study, a weak response (2/17 animals) was observed to the positive control 12-O-tetradecanoylphorbol 13-acetate (TPA in ethanol, 1.25 micrograms), and no response was observed to cyclophosphamide, phenolphthalein, or chlorpheniramine, despite evidence for skin penetration. The second study compared 1.25 micrograms and 6.25 micrograms of TPA in ethanol and acetone solutions. Tamoxifen was also evaluated in both solvents and orally. No significant response was observed to tamoxifen by skin paint or oral routes. Over 60% of the high dose TPA-treated animals showed no (0 or 1) papilloma response, and 30% of the animals each developed more than 32 papillomas. The heterogenous response to high dose TPA may be related to variability in the responsiveness of hemizygous animals. In light of these findings, further Tg.AC studies should employ homozygous animals, and the underlying cause for heterogeneity in the tumorigenic response of Tg.AC mice should be identified and eliminated.

Overall false positive rates in tests for linear trend in tumor incidence in animal carcinogenicity studies of new drugs.

Based on results of simulation and empirical studies conducted within the Divisions of Biometrics, Center for Drug Evaluation and Research, Food and Drug Administration, and in collaboration with the National Toxicology Program, the Center has recently changed the significance levels for testing positive linear trend in incidence rate for common and rare tumors, respectively, from 0.01 and 0.05 to 0.005 and 0.025. The overall false positive rate resulting from the use of this new rule in the tests for linear trend in a two-species-two-sex study is about 10%, the rate that is judged as the most appropriate in a regulatory setting by the Center. This paper describes two of the studies.

A dynamic local bump system for producing synchrotron radiation with an alternating elliptical polarization.

To facilitate high-sensitivity soft X-ray magnetic circular dichroism experiments, a dynamic local bump system has been developed at the SRRC storage ring. This system was devised to vary dynamically the vertical slope of the electron beam in a bending magnet, producing, in the electron orbit plane, soft X-rays with an alternating elliptical polarization. The local bump was created by using two pairs of vertical correctors located on each side of the bending magnet. The bump strength coefficient was obtained both from calculated estimation and from measured beam-response matrices. Control electronics for proper bump strength settings were designed to incorporate the existing orbit-corrector function. A corresponding graphic user interface was implemented so that the bump amplitude could be easily adjusted. The performance of this system is presented. Disturbance on the stored electron beam orbit was observed while flipping the corrector polarity during EPBM (elliptical polarization from bending magnets) operation. A local feedback loop, developed to eliminate such disturbance on other beamlines, is also described.

Role of the kidney in metabolic change of interleukin-2.

The metabolic change of human recombinant interleukin-2 (IL-2) was investigated by the use of 125I-labeled IL-2 (125I-IL-2). After intravenous injection into mice, the distribution of 125I-IL-2 in various organs revealed that the major portion of injected 125I-IL-2 was rapidly accumulated in the kidney. Simultaneous injection of an excess amount of cold IL-2 greatly reduced the distribution of 125I-IL-2 to the kidney, suggesting that the accumulation of 125I-IL-2 by the kidney was a specific reactivity between 125I-IL-2 and the kidney. The gel filtration profile of 125I-IL-2 in the serum specimens remained the same as that of the originally injected sample, and differed completely from that in the urine specimens, suggesting that 125I-IL-2 was metabolized in the kidney. To confirm this notion, 125I-IL-2 was incubated in vitro with kidney homogenate, which degraded 125I-IL-2 in acidic pH. After subcellular fractionation, the cytosol fraction of the kidney was shown to hydrolyze 125I-IL-2 with an optimal pH of 4. The reactivity of the kidney cytosol fraction with 125I-IL-2 was inhibitable by pepstatin, an acid protease inhibitor, but not by TLCK or TPCK. Additional experiments using a heat-treated kidney cytosol fraction plus cathepsin D, and pepstatin inhibition on the degradation of 125I-IL-2 by cathepsin D, a major acid protease in the kidney, resulted in the identification of this enzyme to be responsible for the degradation of 125I-IL-2. Overall, these results demonstrated that the kidney is the organ to metabolize IL-2 and that cathepsin D, a renal acid protease, is involved in the degradation of IL-2.

The use of the logistic model in space motion sickness prediction.

The one-equation and the two-equation logistic models were used to predict tested subjects' susceptibility to motion sickness in KC-135 parabolic flights using data from other ground-based motion sickness tests. A data set containing data from 6 provocative tests, 2 vestibular function tests, and 1 motion sickness experience questionnaire from 162 subjects was used in this study. The prediction results from the logistic models were compared with those from the previously-used Bayes linear discriminant analysis procedures. The results based on this data set show that the logistic models correctly predicted substantially more cases (an average of 13%) in the data subset used for model building. In the data subset used for model cross-validation, the logistic models correctly predicted 4% and 5% more cases in the prediction of vomit or nonvomit, and of degree of susceptibility, respectively. Overall, the logistic models ranged from 53 to 65% predictions of the three endpoint parameters, whereas the Bayes linear discriminant procedure ranged from 48 to 65% correct for the cross validation sample.

Hepatic portal vein infusion of glucose and sodium solutions on the control of saline drinking in the rat.

1. Rats were prepared under anaesthesia with non-occlusive catheters in hepatic portal vein (HP) and inferior vena cava (VC) and maintained under standard conditions. 2. Each rat received a series (3 day intervals) of 30 min infusions of different solutions or sham into HP or VC. Oral intake of 0.15 M-NaCl and water were measured for 30 min. Significant change in drinking behaviour was assumed when the response to HP infusion differed from both sham and VC infusion. 3. Saline drinking was inhibited by HP infusion of 1 M- or 2M-NaCl, an effect blocked by right vagotomy or by addition of 16 mM-KCl to the infusate. 4. Saline drinking was increased and water drinking decreased by HP infusion of 2 M-glucose but not sucrose or fructose. 5. Saline drinking was decreased by HP infusion of deoxy-D-glucose to inhibit glucose utilization or ouabain to inhibit (Na4-K+) ATPase. 6. Results are consistent with the presence of afferent nerve terminals in hepatic portal vessels which are sensitive to change in NaCl or glucose concentration and which, in response thereto, alter drinking behaviour. The effects of NaCl and glucose on the discharge rate of the nerve terminals may be interpreted in terms of changing activity or electrogenicity of a Na pump but changes in membrane conductance or Na influx cannot be ruled out.