Pretransplant dialysis status and outcome of renal transplantation in North American children: a NAPRTCS Study. North American Pediatric Renal Transplant Cooperative Study.
There are no large studies of the effect of pretransplant dialysis status on the outcome of renal transplantation (Tx) in children. This study evaluated the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry data for the outcome of Tx in pediatric patients who either (1) received their transplants preemptively or (2) were maintained on dialysis before receiving their transplants. We compared graft survival and patient survival rates, incidence of acute tubular necrosis (ATN), acute rejection episodes, and causes of graft failure in peritoneal dialysis (PD) patients with those maintained on hemodialysis (HD) and those undergoing preemptive Tx (PTx). Primary Tx was performed in 2495 children (59% male; 61% Caucasian; 1090 PD, 780 HD, 625 PTx) between 1/1/1992 and 12/31/1996. The overall graft survival rates of the PD and HD groups were similar, but were less than that of the PTx group (3-year: 82% PD and HD, 89% PTx, overall P = 0.0003). Improved graft survival in the PTx group was present only in recipients of grafts from living donors. There was no difference in the overall patient survival rate at 3 years, or in time to first acute-rejection episodes in the three groups. The incidence of ATN in the first 7 days post-Tx was higher in PD and HD patients than in PTx patients (11% PD and 12% HD vs. 2% PTx, P<0.001; HD vs. PD, P = NS). The major single cause of graft failure in each group was: PD, vascular thrombosis (200%); HD, chronic rejection (27%); PTx, acute and chronic rejection (21% each). NAPRTCS data show that graft survival is improved in patients receiving PTx, compared with those receiving PD and HD. Graft loss resulting from vascular thrombosis is more common in children who receive PD than in those receiving HD.


Quantitative image signature and machine learning-based prediction of outcomes in cerebral cavernous malformations.
There is increasing interest in novel prognostic tools and predictive biomarkers to help identify, with more certainty, cerebral cavernous malformations (CCM) susceptible of bleeding if left untreated. We developed explainable quantitative-based machine learning models from magnetic resonance imaging (MRI) in a large CCM cohort to demonstrate the value of artificial intelligence and radiomics in complementing natural history studies for hemorrhage and functional outcome prediction. One-hundred-eighty-one patients from a prospectively registered cohort of 366 adults with CCM were included. Fluid attenuated inversion recovery (FLAIR) T2-weighted brain images were preprocessed, and CCM and surrounding edema were segmented before radiomic feature computation. Minority class oversampling, dimensionality reduction and feature selection methods were applied. With prospective hemorrhage as primary outcome, machine learning models were built, cross-validated, and compared using clinico-radiologic, radiomic, and combined features. SHapley Additive exPlanations (SHAP) was used for interpretation to determine the radiomic features with most contribution to hemorrhage prediction. The highest performances in hemorrhage predictions on the test set were combining radiomic and clinico-radiological features with an area under the curve (AUC) of 83% using linear regression and selected features, and an F1 score of 61% and 85% sensitivity using K-nearest neighbors with principal component analysis (PCA). Multilayer perceptron had the best performance predicting modified Rankin Scale ≥ 2 with an AUC of 74% using PCA derived features. For interpretation of the selected radiomic signature XGBoost model, Shapley additive explanations highlighted 6 radiomic features contributing the most to hemorrhage prediction. Quantitative image-based modeling using machine learning has the potential to highlight novel imaging biomarkers that predict hemorrhagic and functional outcomes, ensuring more precise and personalized care for CCM patients.


Potential Targets and Mechanisms of Bitter Almond-Licorice for COVID-19 Treatment Based on Network Pharmacology and Molecular Docking.
The outbreak of Corona Virus Disease 2019 (COVID-19) has resulted in millions of infections and raised global attention. Bitter almonds and licorice are both Traditional Chinese Medicines (TCM), often used in combination to treat lung diseases. Several prescriptions in the guidelines for the diagnosis and treatment of coronavirus disease 2019 (trial version ninth) contained bitter almond-licorice, which was effective in the treatment of COVID-19. However, the active ingredients, drug targets and therapeutic mechanisms of bitter almonds-licorice for the treatment of COVID-19 remain to be elucidated. The active ingredients and targets were derived from the Traditional Chinese Medicine Systems Pharmacology (TCMSP). Meanwhile, targets associated with COVID-19 were obtained from the GeneCards database, PharmGkb database and DrugBank database. Then, the potential targets of bitter almond-licorice against COVID-19 were screened out. Protein-protein interaction (PPI) networks and core targets were analyzed through the String database and Cytoscape software. In addition, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed based on potential targets using R statistical software. Finally, molecular docking was used to validate the binding of the active ingredients to the core targets. The results of the TCMSP database showed that the bitter almond-licorice had 89 active components against COVID-19, involving 102 targets. PPI network and core target analysis indicated that IL-6, TNF, MAPK1, and IL1B were the key targets against COVID-19. In addition, GO and KEGG enrichment analysis showed that the bitter almond-licorice were involved in various biological processes through inflammation-related pathways such as TNF signaling pathway and IL-17 signaling pathway. Finally, molecular docking approaches confirmed the affinity between the active components of the bitter almond-licorice and the therapeutic targets. The bitter almond-licorice could be used to treat COVID-19 by inhibiting inflammatory responses and regulating cellular stress. This work is based on data mining and molecular docking, and the findings need to be interpreted with caution.</P>.


The effect of sex and severity of aggression on formal and informal social agents' involvement in partner violence.
Involvement by formal and informal social agents plays a major role in coping with the problem of partner violence. Based on data from the First National Israeli Survey of Family Violence, the present study attempted to answer whether the sex of the aggressor and the severity of his or her aggression affect formal and informal social involvement in partner violence. Data were obtained from a stratified probability sample of 2,544 women drawn from the general population in Israel. Findings show that the severity of aggression by both sexes affects informal social involvement similarly. But in regard to formal involvement, gender is of top importance, and only the severity of men's aggression influences formal social involvement. The findings indicate society's perceptions of partner violence and how it copes with the problem. These perceptions and their theoretical and practical implications are discussed. The discussion focuses on examining the factors that promote social construction of partner violence as identified in this study and the implications of this construction on dealing with the problem.


Blind image quality assessment using a general regression neural network.
We develop a no-reference image quality assessment (QA) algorithm that deploys a general regression neural network (GRNN). The new algorithm is trained on and successfully assesses image quality, relative to human subjectivity, across a range of distortion types. The features deployed for QA include the mean value of phase congruency image, the entropy of phase congruency image, the entropy of the distorted image, and the gradient of the distorted image. Image quality estimation is accomplished by approximating the functional relationship between these features and subjective mean opinion scores using a GRNN. Our experimental results show that the new method accords closely with human subjective judgment.


Novel bacteriological assay for detection of potential antiviral agents.
A prototype assay for the initial screening of potential antiviral agents that uses bacterial growth on selective media is described. The human immunodeficiency virus (HIV) protease recognition sequence was inserted into the tetracycline resistance (Tet) protein encoded by plasmid pBR322 of Escherichia coli. Expression of both the HIV protease and the modified Tet protein prevented growth in the presence of tetracycline. However, inhibition of the HIV protease restored tetracycline resistance. Thus, potential HIV protease inhibitors can be identified by their ability to confer tetracycline resistance to this bacterial strain. The assay is simple, rapid, and inexpensive, and this concept can be applied to the search for inhibitors of other viral proteases.


Combination therapies with oxaliplatin and oral capecitabine or intravenous 5-FU show similar toxicity profiles in gastrointestinal carcinoma patients if hand-food syndrome prophylaxis is performed continuously.
The use of anticancer drugs in palliative settings is often limited by their severe toxic effects. In gastrointestinal carcinomas the 5-fluorouracil-based palliative regimen FOLFOX-4 is often preferred to the equally effective, but more convenient oral capecitabine-based regimen XELOX. This preference is mainly based on the fact that the highly effective oral agent capecitabine induces hand-foot syndrome (HFS). In this study, we investigated whether the continuous administration of skin prophylaxis (10% urea, panthenol, bisabolol, vitamin A, C and E) is capable of protecting against capecitabine-induced HFS and allowing a more convenient oral therapeutic option. In this retrospective analysis, the toxicity profiles, according to NCI CTCAE 3.0 criteria, of 54 patients with gastrointestinal cancer who received either XELOX (34 patients) or FOLFOX-4 (20 patients) were compared using Fisher tests. The treatment protocols that were compared, herein, did not differ significantly in the majority of the analyzed items, with the exception of increased nausea (XELOX-70), fatigue (XELOX-130) and tumor pain (XELOX-70 and XELOX-130). No significant differences were observed among the various groups with regard to emesis, diarrhea, mucositis, exanthema, alopecia, loss of weight and the incidence of infections. In particular, no significant differences in toxicity levels occurred in terms of dose, and HFS was limited if skin prophylaxis was performed continuously. XELOX-based palliative regimens provide an equally effective and comparably toxic therapeutic alternative to FOLFOX-4 if HFS prophylaxis is performed continuously. Since the oral administration of capecitabine is a more convenient method of application, it provides patients with a quality of life-preserving therapeutic alternative.


Characterisation of integrons and antibiotic resistance genes in Danish multiresistant Salmonella enterica Typhimurium DT104.
The presence and genetic content of integrons was investigated in eight Salmonella enteritica Typhimurium DT104 isolates from different pig herds in Denmark. Two different integrons were identified using PCR and sequencing. Each of the integrons carried a single resistance cassette in addition to the sull and qacE delta 1 genes characteristic of integrons. The first integron encoded the ant (3")-1a gene that specified resistance to spectinomycin and streptomycin. The second contained the pse-1 beta-lactamase gene. All the multiresistant strains contained both integrons. The presence of these two integrons did not account for the total phenotypic resistance of all the isolates and does not exclude the presence of other mobile DNA elements.


PET/CT in the Diagnosis and Workup of Sarcoidosis: Focus on Atypical Manifestations.
Sarcoidosis is a multisystem disease characterized by the formation of noncaseating granulomas. Lung and intrathoracic lymph nodes are classic sites of involvement; however, sarcoidosis can affect any site in the body. The clinical course is extremely variable, and the imaging features are diverse and dependent on the affected site, degree of inflammation, and treatment the patient receives. Atypical manifestations and imaging findings can make diagnosis and/or management challenging. In addition, assessment of treatment response can be difficult in the setting of chronic disease. Fluorine 18 fluorodeoxyglucose (FDG) PET/CT is sensitive for assessment of the inflammatory activity of sarcoidosis in any organ. Although FDG PET/CT is not included in the standard workup for sarcoidosis, there has been growing evidence that supports the value of this examination in guiding diagnosis and management. FDG PET/CT may be especially useful for assessing reversible granuloma, treatment response, disease extent, occult disease, and cardiac or osseous sarcoidosis, and determining the most suitable biopsy site. Capability to image the entire body during a single examination is advantageous in cases of systemic disease such as sarcoidosis. The authors review the use of FDG PET/CT, providing up-to-date evidence and describing various cases of sarcoidosis in which FDG PET/CT has an important role in diagnosis and/or management. They also discuss the usefulness of FDG PET/CT in cases of selective manifestations of sarcoidosis. ©RSNA, 2018.


An epitope on the transferrin receptor preferentially exposed during tumor progression in human lymphoma is close to the ligand binding site.
We have previously reported an anti-transferrin receptor antibody, Trump, which was originally selected for its ability to discriminate low- and high-grade lymphomas. This feature was distinct from the other anti-transferrin receptor antibodies such as OKT9. In the present study, further immunochemical analysis was performed to define the nature of the antigenic site recognized by the Trump antibody. Trump was found to block the binding of transferrin both to solubilized and to surface transferrin receptors; conversely, transferrin could block the binding of Trump only to surface transferrin receptors. Therefore, the epitope recognized by Trump is near but not identical to the transferrin binding site. Stimulation of peripheral blood lymphocytes with phytohemagglutinin induced both the OKT9 epitope and the Trump epitope, but 12-phorbol 13 myristate acetate induced only the OKT9 epitope. Growth of some cell lines was inhibited by Trump but not by OKT9. No structural difference was found between transferrin receptor molecules reactive with Trump and those reactive with OKT9. In support of these results, Trump was able to immunoprecipitate transferrin receptor molecules solubilized from low-grade follicular lymphoma cells even though it did not bind to the receptors exposed on the surface of these cells. These findings imply that low-grade lymphoma cells differ from high-grade lymphoma cells not in the structures of their transferrin receptors but in their exposure of the molecule on the cell surface.


PA student assessment of body mass index in children using visual cues.
Pediatric weight or body mass index often is underestimated by providers when relying solely upon visual cues. This study sought to determine physician assistant (PA) students' and recent graduates' ability to accurately assess BMI for age in patients ages 3 to 5 years using visual cues. PA students and recent graduates visually assessed pictures of three children ages 3 to 5 years-one obese, one overweight, and one with healthy weight-for BMI categorization via online survey. Responses were scored for accuracy. Ninety-eight PA students and recent graduates completed the assessment. Accuracy for BMI categorization was low, especially in the obese and overweight children for visual assessment alone. Accuracy improved slightly when height and weight data were provided. PA student and recent graduate visual assessment for categorization of BMI is unreliable, similar to studies with other providers. PAs should be aware of discrepancy and not rely on visual assessment to determine weight-related interventions.


Central Nervous System Tumor With BCL6 Corepressor Internal Tandem Duplication: Treatment Course of a Long-term Survivor.
Central nervous system (CNS) tumor with BCL6 corepressor (BCOR) internal tandem duplication (ITD) is a newly described CNS tumor, characterized by in-frame ITDs of the BCOR gene. There is no standard practice regarding the management of this tumor. We report the clinical course of a 6-year-old boy who presented to the hospital with worsening headaches. Computed tomography scan showed a large right-sided parietal supratentorial mass and brain magnetic resonance imaging confirmed a 6×8×6.7 cm lobulated, solid but heterogeneous mass in the right parieto-occipital region. While initial pathology suggested a WHO grade 3 anaplastic meningioma, additional investigation with molecular analysis confirmed the diagnosis of high-grade neuroepithelial tumor with BCOR exon 15 ITD. This diagnosis was renamed CNS tumor with BCOR ITD in the 2021 WHO CNS tumor classification. The patient received 54 Gy of focal radiation and has no evidence of disease recurrence after 48 months from the end of treatment. As this is a newly discovered entity with only a few previous reports in the scientific literature, this report presents a unique treatment for this CNS tumor compared with those previously described.


Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study.
Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma. An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 microg/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days. Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 microg/m(2) and 50% received bryostatin at 65 microg/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses. Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials.


Fermented medicinal herbs improve hematological and physiological profile of Striped catfish (Pangasianodonhypophthalmus).
This study sought to determine the effect of fermented medicinal herbs (FMH), i.e. cutchery ( Kaempferia galanga), turmeric ( Curcuma longa) and curcuma ( Curcuma xanthorrhiza) in combination with molasses and probiotic drink (Yakult), administered orally on the hematological and physiological profile of striped catfish ( Pangasianodon hypophthalmus). A complete randomized design (CRD) experiment was used with four levels of treatments, namely P0 (control), P1 (FMH 100 mL/kg), P2 (FMH 200 mL/kg) and P3 (FMH 300 mL/kg) of feed. The fish were kept in a farm in cages at 75 fish/m 3 and fed with the experimental diets for 60 days. The results revealed that FMH (P2) dietary administration improved hematological and physiological profile of catfish, i.e total erythrocytes of 2.81 x 10 6 cells/mm 3, hematocrit values of 39.00%, hemoglobin levels of 10.73 g/dL, total leukocytes of 11.41 x 10 4 cells/mm 3, blood glucose 97.33 mg/dL, and total serum protein 4.10 mg/dL compared to controls with 1.89 x 10 6 cells/mm 3, 32.33 %, g/dL, 9.67 x 10 4 cells/mm 3, 67.33 mg/dL, and total serum protein of 3.10 mg/dL, respectively. Moreover, the diet improved special growth rate, feed conversion ratio, feed efficiency and the survival rate of catfish. The hematological and physiological profile of catfish improvement are considered to be due to the content of secondary metabolites of FMH, namely curcuminoids, vitamin C, essential oils, tannins, and flavonoids, which trigger immunostimulation. The presence of curcuminoids provide an antioxidant effect on cell membranes reducing erythrocyte cell membrane damage due to oxidation. Similarly, flavonoids are natural antioxidants, which are credited with the ability of reducing free radicals and anti-free radicals.


Aspergillus fischeri Mediated Biosynthesis of Gold Nanoparticles and their Beneficially Comparative Effect on Normal and Cancer Cell Lines.
Along with the intensified use of metal nanoparticles, growing concern of their adverse outcome on human health has also expanded, indicating that this work is an integral part of nanobioscience study. The aim of this study was to evaluate varied effect of biosynthesized gold nanoparticles (AuNPs) on normal and cancerous mammalian cells. AuNP synthesized and characterized by different characterization methods, here are produced by specifically isolated Aspergillus species, which is hardly explored in precious scientific findings. These bio-synthesized AuNP are then tested by MTT assay and further confirmed by different fluorescent staining methods. The AuNPs synthesized here are fairly monodispersed and uniform in shape as confirmed by the relatively tall and dominant UV spectroscopy peak at 540 nm and TEM images showing round shaped particles at a magnification of 20 and 50 nm size ranges. The crystalline powder formed peaks at 2θ angles specific for AuNPs verifying their presence and FT-IR validates presence of side groups which help in stabilization of particulates. We have clearly proved that the less toxic nature of these AuNPs on mouse fibroblasts cells and comparatively elevated inhibiting effect on cancer cells at as low as 1 µg/mL concentration of AuNP. Condensation of nucleus and damage of cells seen in fluorescent images also substantiates the results. This conclusion is encouraging to the nanoscientists to study elaborately their system pathways which might be responsible for varied toxicity levels of these AuNPs in mammalian cells and pursue different methods in biomedical applications.


gamma-Aminobutyric acid-induced potentiation of cortical hemiplegia.
A novel model of hemiplegia in young and aged rats is described. Osmotic minipumps were used to deliver a chronic (7 days), localized application of gamma-aminobutyric acid (GABA) (100 micrograms/microliter/h), to the somatomotor cortex of unrestrained rats. This resulted in an easily quantifiable, contralateral and reversible motor syndrome in both young and aged animals. In the young group, the motor deficit cleared over 5-day period, while in the aged animals it persisted for at least a 2-week period. Control animals treated with saline-filled minipumps did not develop a long-lasting motor deficit. The GABA-induced facilitation of hemiplegia due to small motor cortex lesions and the age effects on behavioral recovery of function are discussed. Cortical inhibitory mechanisms may play a role in debilitating syndromes such as stroke or post-epileptic paralysis.


Cooperation between geriatricians and general practitioners for improved pharmacotherapy in home-dwelling elderly people receiving polypharmacy - the COOP Study: study protocol for a cluster randomised controlled trial.
Polypharmacy and inappropriate drug use is associated with negative health outcomes among older people. Various interventions for improving drug treatment have been evaluated, but the majority of studies are limited by the use of surrogate outcomes or suboptimal design. Thus, the potential for clinically significant improvements from different interventions is still unclear. The main objective of this study is therefore to evaluate the effect upon patient-relevant endpoints of a cooperation between geriatricians and general practitioners on complex drug regimens in home-dwelling elderly people. This is a cluster randomised, single-blind, controlled trial where general practitioners are invited to participate with patients from their lists. The patients must be 70 years or older, use at least seven different medications and have their medications administered by the home nursing service. We plan to recruit 200 patients, with randomisation at physician level. The intervention consists of three main parts: (1) clinical geriatric assessment of the patient, combined with a thorough review of their medications; (2) a meeting between the geriatrician and general practitioner, where the two physicians combine their competence and knowledge and discuss the drug list systematically; (3) clinical follow-up, depending on the medication changes that have been done. The study period is 24 weeks, and the patients are assessed at baseline, 16 and 24 weeks. The primary outcome measure is health-related quality of life according to the 15D instrument. Secondary outcome measures include physical and cognitive functioning, medication appropriateness, falls, carer burden, use of health services (hospital or nursing home admissions, use of home nursing services) and mortality. Our choice of patient-relevant outcome measures will hopefully provide new knowledge on the potential for clinical improvements after performing comprehensive medication reviews in home-dwelling elderly people receiving polypharmacy. ClinicalTrials.gov, NCT02379455 . Registered on 27 February 2015.


Repair of oligodeoxyribonucleotides by O(6)-alkylguanine-DNA alkyltransferase.
Activity of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) is an important source of tumor cell resistance to alkylating agents. AGT inhibitors may prove useful in enhancing chemotherapy. AGT is inactivated by reacting stoichiometrically with O(6)-benzylguanine (b(6)G), which is currently in clinical trials for this purpose. Short oligodeoxyribonucleotides containing a central b(6)G are more potent inactivators of AGT than b(6)G. We examined whether human AGT could react with oligodeoxyribonucleotides containing multiple b(6)G residues. The single-stranded 7-mer 5'-d[T(b(6)G)(5)G]-3' was an excellent AGT substrate with all five b(6)G adducts repaired although one adduct was repaired much more slowly. The highly b(6)G-resistant Y158H and P140K AGT mutants were also inactivated by 5'-d[T(b(6)G)(5)G]-3'. Studies with 7-mers containing a single b(6)G adduct showed that 5'-d[TGGGG(b(6)G)G]-3' was more poorly repaired by wild-type AGT than 5'-d[T(b(6)G)GGGGG]-3' and 5'-d[TGG(b(6)G)GGG]-3' and was even less repairable by mutants Y158H and P140K. This positional effect was unaffected by interchanging the terminal 5'- or 3'-nucleotides and was also observed with single-stranded 16-mer oligodeoxyribonucleotides containing O(6)-methylguanine, where a minimum of four nucleotides 3' to the lesion was required for the most efficient repair. Annealing with the reverse complementary strands to produce double-stranded substrates increased the ability of AGT to repair adducts at all positions except at positions 2 and 15. Our results suggest that AGT recognizes the polarity of single-stranded DNA, with the best substrates having an adduct adjacent to the 5'-terminal residue. These findings will aid in designing novel AGT inhibitors that incorporate O(6)-alkylguanine adducts in oligodeoxyribonucleotide contexts.


Navigating COVID-19 and related challenges to completing clinical trials: Lessons from the PATRIOT and STEP-UP randomized prevention trials.
High follow-up is critical in randomized clinical trials. We developed novel approaches to modify in-person visits and complete follow-up during COVID-19. Since these strategies are broadly applicable to circumstances wherein follow-up is difficult, they may help in contingency planning. The objective of this article is to develop and evaluate new approaches to replace detailed, in-person study visits for two trials focused on preventing diabetic foot complications. A quasi-experimental pre-post design compared approaches for follow-up during COVID-19 to approaches pre-COVID-19. Study subjects were outpatients at two Veterans Affairs Medical Centers. Following a research "hold," research resumed in February 2021 for Self-monitoring, Thermometry and Educating Patients for Ulcer Prevention (STEP UP) (n = 241), which focused on preventing recurrent foot ulcers, and in April 2021 for Preventing Amputation by Tailored Risk-based Intervention to Optimize Therapy (PATRIOT) (n = 406), which focused on preventing pre-ulcerative and ulcerative lesions. To complete data collection, we shortened visits, focused on primary and secondary outcomes, and conducted virtual visits when appropriate. For STEP UP, we created a 20-min assessment process that could be administered by phone. Since PATRIOT required plantar photographs to assess foot lesions, we conducted short face-to-face visits. We explored differences and assessed proportion completing visit, visit completion/100 person-months and compared COVID-19 to pre- COVID-19 using unadjusted risk ratios, incidence rate ratios, all with associated 95% confidence intervals (CIs). Finally, we report time-to-visit curves. In both studies, participants whose follow-up concluded pre- COVID-19 seemed older than those whose follow-up concluded during COVID-19 (PATRIOT: 68.0 (67.2, 68.9) versus 65.2 years (61.9, 68.5); STEP UP: 67.5 (66.2, 68.9) versus 65.3 (63.3, 67.3)). For STEP UP, we completed 91 visits pre- COVID-19 (37.8% (31.6%, 44.2%)) and 63 visits during COVID-19 (78.8% (68.2%, 87.1%)). This was over 1309 person-months pre-COVID-19, and over 208.8 person-months during COVID-19; the visit completion rate/100 person-months were: pre-COVID-19 7.0 (5.6, 8.5), COVID-19 30.2 (23.2, 38.6); risk ratio: 2.1 (1.7, 2.5); and incidence rate ratio 4.3 (3.1, 5.9). Similarly, for PATRIOT, we completed 316 visits pre-COVID-19 (77.8% (73.5%, 81.8%)) and 27 assessments during COVID-19 (84.4% (67.2%, 94.7%)). This was over 1192.7 person-months pre-COVID-19 and 39.3 person-months during COVID-19. The visit completion rate/100 person-months in PATRIOT were: pre-COVID-19 2.7 (2.4, 3.0), COVID-19 6.9 (4.5, 10); risk ratio 1.1 (0.9, 1.3); incidence rate ratio 2.6 (1.8, 3.8). For both studies, the follow-up curves began separating at < 2 months. We achieved higher completion rates during COVID-19 compared to pre-COVID-19 by modifying visits and focusing on primary and secondary outcomes. These strategies prevent excessive missing data, support more valid conclusions, and improve efficiency. They may provide important alternative strategies to achieving higher follow-up in randomized clinical trials.


Three-dimensional-construct bioreactor conditioning in human tendon tissue engineering.
Human tendon tissue engineering attempts to address the shortage of autologous tendon material arising from mutilating injuries and diseases of the hand and forearm. It is important to maximize the tissue-engineered construct's (TEC's) biomechanical properties to ensure that the construct is in its strongest possible state before reimplantation. In this study, we sought to determine the bioreactor treatment parameters that affect these properties. Using small- and large-chamber three-dimensional-construct bioreactors (SCB and LCB, respectively), we applied cyclic axial load to TECs comprising reseeded human flexor and extensor tendons of the hand. First, small-sample pilot studies using the LCB were performed on matched-paired full-length flexor tendons to establish proof of concept. Next, large-sample studies using the SCB were performed on matched-paired extensor tendon segments to determine how reseeding, load duty cycle, load magnitude, conditioning duration, and testing delay affected ultimate tensile stress (UTS) and elastic modulus (EM). We found that compared with reseeded matched-paired controls under dynamic-loading at 1.25 N per TEC for 5 days, (1) acellular TECs had lower UTS (p=0.04) and EM (p<0.01), (2) unloaded TECs had lower UTS (p=0.01) and EM (p=0.02), (3) static-loaded TECs had lower UTS (p=0.01) and EM (p<0.01), (4) TECs conditioned for 3 days had lower UTS (p=0.03) and EM (p=0.04), and (5) TECs conditioned for 8 days had higher UTS (p=0.04) and EM (p=0.01). However, TECs conditioned at higher loads (2.5 N per TEC) and lower loads (0.625 N per TEC) possessed similar UTS (p=0.83 and p=0.89, respectively) and EM (p=0.48 and p=0.89, respectively) as controls stimulated with 1.25 N per TEC. After cycle completion, there is attrition of UTS (p=0.03) and EM (p=0.04) over a 2-day period. Our study showed that the material properties of human allograft TECs can be enhanced by reseeding and dynamic-conditioning. While conditioning duration has a significant effect on material properties, the load magnitude does not. The issue of attrition in biomechanical properties with time following cycle completion must be addressed before bioreactor preconditioning can be successfully introduced as a step in the processing of these constructs for clinical application.


Frigoriflavimonas asaccharolytica gen. nov., sp. nov., a novel psychrophilic esterase and protease producing bacterium isolated from Antarctica.
The rod-shaped and Gram-stain-negative bacterial strain 16FT, isolated from an air sample collected at King George Island, maritime Antarctica, was investigated to determine its taxonomic status. Strain 16FT is strictly aerobic, catalase positive, oxidase positive and non-motile. Strain 16FT hydrolyses casein, lecithin, Tween 20, 60 and 80, but not aesculin, gelatin and starch. Growth of strain 16FT is observed at 0-20 °C (optimum 10 °C), pH 5.0-8.0 (optimum pH 6.0), and in the presence of 0-2.0% NaCl (optimum 0.5%). The predominant menaquinone is MK-6, and the major fatty acids comprise anteiso-C15:0 and iso-C15:0. The major polar lipids are phosphatidylethanolamine, ornithine lipid OL2, unidentified phospholipid PL1 and the unidentified lipids L3 and L6 lacking functional groups. The DNA G + C content based on the draft genome sequence is 32.3 mol%. Sequence analysis of the 16S rRNA gene indicates the highest similarity to Kaistella palustris 3A10T (95.4%), Kaistella chaponensis Sa 1147-06 T (95.2%), Kaistella antarctica AT1013T (95.1%), Kaistella carnis NCTC 13525 T (95.1%) and below 95.0% to other species with validly published names. Phylogenetic analysis based on 16S rRNA gene and whole-genome sequences places strain 16FT in a distinct branch, indicating a separate lineage within the family Weeksellaceae. Based on the data from our polyphasic approach, 16FT represents a novel species of a new genus, for which the name Frigoriflavimonas asaccharolytica gen. nov, sp. nov. is proposed. The type strain is 16FT (= CCM 8975 T = CGMCC No.1.16844 T).


Risk factor for breast cancer development under exposure to bovine leukemia virus in Colombian women: A case-control study.
Viruses have been implicated in cancer development in both humans and animals. The role of viruses in cancer is typically to initiate cellular transformation through cellular DNA damage, although specific mechanisms remain unknown. Silent and long-term viral infections need to be present, in order to initiate cancer disease. In efforts to establish a causative role of viruses, first is needed to demonstrate the strength and consistency of associations in different populations. The aim of this study was to determine the association of bovine leukemia virus (BLV), a causative agent of leukemia in cattle, with breast cancer and its biomarkers used as prognosis of the severity of the disease (Ki67, HER2, hormonal receptors) in Colombian women. An unmatched, observational case-control study was conducted among women undergoing breast surgery between 2016-2018. Malignant samples (n = 75) were considered as cases and benign samples (n = 83) as controls. Nested-liquid PCR, in-situ PCR and immunohistochemistry were used for viral detection in blood and breast tissues. For the risk assessment, only BLV positive samples from breast tissues were included in the analysis. BLV was higher in cases group (61.3%) compared with controls (48.2%), with a statistically significant association between the virus and breast cancer in the unconditional logistic regression (adjusted-OR = 2.450,95%CI:1.088-5.517, p = 0.031). In this study, BLV was found in both blood and breast tissues of participants and an association between breast cancer and the virus was confirmed in Colombia, as an intermediate risk factor.


The Warsaw breakage syndrome-related protein DDX11 is required for ribosomal RNA synthesis and embryonic development.
DDX11 was recently identified as a cause of Warsaw breakage syndrome (WABS). However, the functional mechanism of DDX11 and the contribution of clinically described mutations to the pathogenesis of WABS are elusive. Here, we show that DDX11 is a novel nucleolar protein that preferentially binds to hypomethylated active ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF) and the RNA polymerase I (Pol I). DDX11 knockdown changed the epigenetic state of rDNA loci from euchromatic structures to more heterochromatic structures, reduced the activity of UBF, decreased the recruitment of UBF and RPA194 (a subunit of Pol I) to rDNA promoter, suppressed rRNA transcription and thereby inhibited growth and proliferation of HeLa cells. Importantly, two indentified WABS-derived mutants, R263Q and K897del, and a Fe-S deletion construct demonstrated significantly reduced binding abilities to rDNA promoters and lowered DNA-dependent ATPase activities compared with wild-type DDX11. Knockdown of the zebrafish ortholog of human DDX11 by morpholinos resulted in growth retardation and vertebral and craniofacial malformations in zebrafish, concomitant with the changes in histone epigenetic modifications at rDNA loci, the reduction of Pol I recruitment to the rDNA promoter and a significant decrease in nascent pre-RNA levels. These growth disruptions in zebrafish in response to DDX11 reduction showed similarities to the clinically described developmental abnormalities found in WABS patients for the first time in any vertebrate. Thus, our results indicate that DDX11 functions as a positive regulator of rRNA transcription and provides a novel insight into the pathogenesis of WABS.


Transfer of retinoic acid from its complex with cellular retinoic acid-binding protein to the nucleus.
Cellular retinoic acid-binding protein (CRABP), a potential mediator of retinoic acid action, enables retinoic acid to bind in a specific manner to nuclei and chromatin isolated from testes of control and vitamin A-deficient rats. The binding of retinoic acid was followed after complexing [3H]retinoic acid with CRABP purified from rat testes. The binding was specific, saturable, and temperature dependent. If CRABP charged with nonlabeled retinoic acid was included in the incubation, binding of radioactivity was diminished, whereas inclusion of free retinoic acid, or the complex of retinol with cellular retinol binding protein (CRBP) or serum retinol binding protein had no effect. Approximately 4.0 X 10(4) specific binding sites for retinoic acid were detected per nucleus from deficient animals. The number of binding sites observed was influenced by vitamin A status. Refeeding vitamin A-deficient rats (4 h) with retinoic acid lowered the amount of detectable binding sites in the nucleus. CRABP itself did not remain bound to these sites, indicating a transfer of retinoic acid from its complex with CRABP to the nuclear sites. Further, CRBP, the putative mediator of retinol action, was found to enable retinol to be bound to testicular nuclei, in an interaction similar to the binding of retinol to liver nuclei described previously.


Is daily mortality associated specifically with fine particles?
Recent epidemiologic studies have consistently reported increased daily mortality associated with exposures to particulate air pollution. Currently, particulate mass is measured as particles smaller than 10 microns (PM10). Fine (PM2.5) and coarse (PM10-PM2.5) mass and sulfate particle concentrations were measured in six eastern U.S. cities for eight years, and aerosol acidity concentrations were measured for approximately one year. Daily mortality for these metropolitan areas was combined with particulate air pollution and weather measurements. City-specific associations with each measure of particle pollution were estimated by Poisson regression, adjusting for time trends and weather by nonparametric methods. Combined effect estimates were calculated as the inverse variance weighted mean of the city-specific estimates. PM10, PM2.5, and SO4= were each significantly associated with increased daily mortality, while no associations were found with coarse mass nor with aerosol acidity (H+) concentrations. The strongest association was found with PM2.5. A 10 micrograms/m3 increase in two-day mean PM2.5 was associated with a 1.5% (95% CI 1.1% to 1.9%) increase in total daily mortality. Somewhat larger increases were found for deaths caused by chronic obstructive pulmonary disease (+3.3%) and by ischemic heart disease (+2.1%). These data suggest that increased daily mortality is specifically associated with particle mass constituents found in the aerodynamic diameter size range under 2.5 microns, that is, with combustion-related particles.


Mutations in the first exon are associated with altered transcription of c-myc in Burkitt lymphoma.
The c-myc proto-oncogene is involved in chromosomal translocations that are specifically and consistently found in Burkitt lymphoma. Although these translocations are thought to lead to a deregulation of c-myc expression, the structural and functional basis of this phenomenon has not been identified. Mutations in a specific region spanning approximately 70 base pairs and located at the 3' border of the first exon of translocated c-myc alleles were consistently detected in Burkitt lymphoma cells carrying classic (8:14) as well as variant (8:22 and 2:8) translocations. These structural alterations were accompanied by an altered pattern of c-myc transcription, namely, the removal of a block to transcriptional elongation that has been mapped to the same region. Thus, specific c-myc mutations leading to the alleviation of this block to transcriptional elongation may represent a general mechanism causing c-myc activation in Burkitt lymphoma.


Inhibition of d-tubocurarine-induced histamine release by halothane.
To determine whether anesthetics modify mediator release, the authors measured the amount of histamine released by d-tubocurarine (dTC) in human foreskin preparations in the presence of high (2.0%) and low (0.5%) halothane concentrations and nitrous oxide (10%). Freshly excised human foreskins were divided into four matched pieces. Two matched pieces were aerated with oxygen, and the other two with an oxygen-anesthetic gas mixture. One chamber of each served as a control, while the other was stimulated with 3 X 10(-5) M d-tubocurarine for 30 min. Supernatant histamine concentrations were measured by automated fluorometry. Percent histamine release was determined by dividing the experimentally released histamine concentration by the total histamine released after the tissue was sonicated and boiled. Neither halothane nor N2O alone altered spontaneous histamine release. Histamine release by d-tubocurarine was significantly reduced by 2% halothane compared to d-tubocurarine alone (2.8% +/- 0.9 vs. 13.9% +/- 3.7, mean + SEM) (P less than 0.05) in the in vitro preparation. Histamine release was reduced in the preparations pretreated with 0.5% halothane group, but this was not statistically significant (P greater than 0.05) when compared to d-tubocurarine alone. N2O (10%) did not reduce d-tubocurarine-induced histamine release. The authors conclude that halothane, in clinically used concentrations, significantly impairs histamine release from human neonatal foreskin preparations.


Portacaval shunt for familial heterozygous hypercholesterolemia.
Two patients with heterozygous familial type 2 hypercholesterolemia are reported upon following treatment with end-to-side portacaval shunting. In both, the portacaval shunt decreased the cholesterol level by about 40 per cent. No adverse effects of the operation could be seen in either patient at 30 months, and no return of cardiovascular disease is evident in either patient. In one patient with large xanthelasmas, the lesions became a much duller yellow color and regressed from an elevated to flat appearance. However, the margins of the lesions did not change significantly. In young patients with heterozygous type 2 hypercholesterolemia in whom cardiovascular complications pose a major threat to life, a portacaval shunt is an effective means of reducing the cholesterol level. The benefits to the patient outweight the risks of operation. In one patient, an anxiety reaction developed which her psychiatrist related to a stressful situation. There were no clinical signs of encephalopathy, no response to protein restriction and a minimal elevation of the serum ammonia level, 86 versus 70 micrograms per cent as the upper limit of normal.


Effects of silver nitrate and silver nanoparticles on a planktonic community: general trends after short-term exposure.
Among metal pollutants silver ions are one of the most toxic forms, and have thus been assigned to the highest toxicity class. Its toxicity to a wide range of microorganisms combined with its low toxicity to humans lead to the development of a wealth of silver-based products in many bactericidal applications accounting to more than 1000 nano-technology-based consumer products. Accordingly, silver is a widely distributed metal in the environment originating from its different forms of application as metal, salt and nanoparticle. A realistic assessment of silver nanoparticle toxicity in natural waters is, however, problematic and needs to be linked to experimental approaches. Here we apply metatranscriptome sequencing allowing for elucidating reactions of whole communities present in a water sample to stressors. We compared the toxicity of ionic silver and ligand-free silver nanoparticles by short term exposure on a natural community of aquatic microorganisms. We analyzed the effects of the treatments on metabolic pathways and species composition on the eukaryote metatranscriptome level in order to describe immediate molecular responses of organisms using a community approach. We found significant differences between the samples treated with 5 µg/L AgNO3 compared to the controls, but no significant differences in the samples treated with AgNP compared to the control samples. Statistical analysis yielded 126 genes (KO-IDs) with significant differential expression with a false discovery rate (FDR) <0.05 between the control (KO) and AgNO3 (NO3) groups. A KEGG pathway enrichment analysis showed significant results with a FDR below 0.05 for pathways related to photosynthesis. Our study therefore supports the view that ionic silver rather than silver nanoparticles are responsible for silver toxicity. Nevertheless, our results highlight the strength of metatranscriptome approaches for assessing metal toxicity on aquatic communities.


Use of analgesics and antibiotics in endodontics: current concepts.
In this review, the principal drugs used for prevention and treatment of pain--analgesics, and swelling--antibiotics, are examined. The rationale for prevention of pain and swelling is given. Then the specific drugs are considered. The analgesics evaluated include: the non-steroidal anti-inflammatory agents (e.g., aspirin, acetaminophen, ibuprofen, diflunisal); and the narcotics (e.g., codeine, oxycodone, hydrocodone, meperidine). The antibiotics evaluated include: the penicillins (e.g., penicillin V, ampicillin, methicillin); the cephalosporins (e.g., cephalexin, cefadroxil); the erythromycins (e.g., erythromycin stearate, erythromycin base); clindamycin; metronidazole; and some rarely used drugs (e.g., ciprofloxacin).


Notes from the field: use of genotyping to disprove a presumed outbreak of Mycobacterium tuberculosis - Los Angeles County, 2013-2014.
In early 2013, the Los Angeles County Department of Public Health learned of two patients diagnosed with tuberculosis (TB) who had received care at the same outpatient health care facility (facility A). Facility A is a center for infusions of chemotherapeutic and biologic agents and serves a large number of immunocompromised persons who were potentially exposed to infectious TB. If infected, immunocompromised persons are at elevated risk for progression to TB disease. The two patients (patient A and patient B) both had pulmonary TB, with acid-fast bacilli found on sputum-smear microscopy, and had visited facility A multiple times during their infectious periods. Despite initial concerns that these two cases could be the result of person-to-person transmission at facility A, genotyping of the Mycobacterium tuberculosis isolates from these two patients showed that they were infected with unrelated strains.


p-Cymene and Rosmarinic Acid Ameliorate TNBS-Induced Intestinal Inflammation Upkeeping ZO-1 and MUC-2: Role of Antioxidant System and Immunomodulation.
p-Cymene (p-C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p-C and RA (25-200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4+, CD8+, or CD3+CD4+CD25+) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p-C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p-C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.


Recruitment in a heterogeneous population of motor neurons that innervates the depressor muscle of the crayfish walking leg muscle.
According to the size principle the fine control of muscle tension depends on the orderly recruitment of motor neurons from a heterogeneous pool. We took advantage of the small number of excitatory motor neurons (about 12) that innervate the depressor muscle of the crayfish walking leg to determine if the size principle applies to this muscle. We found that in accordance with the size principle, when stimulated by proprioceptive input, neurons with small extracellular spikes were recruited before neurons with medium or large spikes. Because only a small fraction of the motor neurons responded strongly enough to sensory input to be recruited in this way, we extended our analysis to all neurons by characterizing properties that have classically been associated with recruitment order such as speed of axonal conduction and extracellular spike amplitude. Through a combination of physiological and anatomical criteria we were able to identify seven classes of excitatory depressor motor neurons. The majority of these classes responded to proprioceptive input with a resistance reflex, while a few responded with an assistance reflex, and yet others did not respond. Our results are in general agreement with the size principle. However, we found qualitative differences between neuronal classes in terms of synaptic input and neuronal structure that would in theory be unnecessary, according to a strict interpretation of the size principle. We speculate that the qualitative heterogeneity observed may be due to the fact that the depressor is a complex muscle, consisting of two muscle bundles that share a single insertion but have multiple origins.


Daily oral iron supplementation during pregnancy.
Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women, and it may also improve other maternal and birth outcomes. To assess the effects of daily oral iron supplements for pregnant women, either alone or in conjunction with folic acid, or with other vitamins and minerals as a public health intervention. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 July 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) (2 July 2012) and contacted relevant organisations for the identification of ongoing and unpublished studies. Randomised or quasi-randomised trials evaluating the effects of oral preventive supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy. We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. We included 60 trials. Forty-three trials, involving more than 27,402 women, contributed data and compared the effects of daily oral supplements containing iron versus no iron or placebo.Overall, women taking iron supplements were less likely to have low birthweight newborns (below 2500 g) compared with controls (8.4% versus 10.2%, average risk ratio (RR) 0.81; 95% confidence interval (CI) 0.68 to 0.97, 11 trials, 8480 women) and mean birthweight was 30.81 g greater for those infants whose mothers received iron during pregnancy (average mean difference (MD) 30.81; 95% CI 5.94 to 55.68, 14 trials, 9385 women). Preventive iron supplementation reduced the risk of maternal anaemia at term by 70% (RR 0.30; 95% CI 0.19 to 0.46, 14 trials, 2199 women) and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women). Although the difference between groups did not reach statistical significance, women who received iron supplements were more likely than controls to report side effects (25.3% versus 9.91%) (RR 2.36; 95% CI 0.96 to 5.82, 11 trials, 4418 women), particularly at doses 60 mg of elemental iron or higher. Women receiving iron were on average more likely to have higher haemoglobin (Hb) concentrations at term and in the postpartum period, but were at increased risk of Hb concentrations greater than 130g/L during pregnancy and at term. Twenty-three studies were conducted in countries that in 2011 had some malaria risk in parts of the country. In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. Only two of these reported malaria outcomes. There is no evidence that iron supplementation increases placental malaria. For some outcomes heterogeneity was higher than 50%. Prenatal supplementation with daily iron are effective to reduce the risk of low birthweight, and to prevent maternal anaemia and iron deficiency in pregnancy. Associated maternal side effects and particularly high Hb concentrations during pregnancy at currently used doses suggest the need to update recommendations on doses and regimens for routine iron supplementation.


Overrepresentation of 8q in carcinosarcomas and endometrial adenocarcinomas.
We report on genomic imbalances in 19 uterine and extrauterine carcinosarcomas and comparisons with findings in 7 endometrial adenocarcinomas using comparative genomic hybridization (CGH). In the carcinosarcomas, the number of imbalances ranged from 2 to 27. Overrepresentations predominated over losses (mean, 5.8 vs 4.3) and included gains or amplifications at 8q as the single most frequent change in 15 of 19 carcinosarcomas, followed by overrepresentations at 3q (9/19), 1q (7/19), 6p (7/19), and 12p (7/19). Losses were most common at 22q (9/19), 16q (8/19), 15q (7/19), 18q (7/19), Xp (6/19), and 9q (6/19). Among 3 carcinosarcomas in which carcinomatous and sarcomatous elements could be analyzed separately, gains of 8q were identified in both components of one tumor and in the sarcomatous component of another tumor. Additional CGH analyses of 7 endometrial adenocarcinomas revealed simpler copy number changes, including recurrent gains at 8q (4/7) and 1q (4/7), suggesting a central role of 8q gains in the pathogenesis of carcinosarcomas and endometrial adenocarcinomas.


CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms.
Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100% intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitial CD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders.


Comparative analysis of transposable elements in the melanogaster subgroup sequenced genomes.
Transposable elements (TEs) are indwelling components of genomes, and their dynamics have been a driving force in genome evolution. Although we now have more information concerning their amounts and characteristics in various organisms, we still have little data from overall comparisons of their sequences in very closely-related species. While the Drosophila melanogaster genome has been extensively studied, we have only limited knowledge regarding the precise TE sequences in the genomes of the related species Drosophila simulans, Drosophila sechellia and Drosophila yakuba. In this study we analyzed the number and structure of TE copies in the sequenced genomes of these four species. Our findings show that, unexpectedly, the number of TE insertions in D. simulans is greater than that in D. melanogaster, but that most of the copies in D. simulans are degraded and in small fragments, as in D. sechellia and D. yakuba. This suggests that all three species were invaded by numerous TEs a long time ago, but have since regulated their activity, as the present TE copies are degraded, with very few full-length elements. In contrast, in D. melanogaster, a recent activation of TEs has resulted in a large number of almost-identical TE copies. We have detected variants of some TEs in D. simulans and D. sechellia, that are almost identical to the reference TE sequences in D. melanogaster, suggesting that D. melanogaster has recently been invaded by active TE variants from the other species. Our results indicate that the three species D. simulans, D. sechellia, and D. yakuba seem to be at a different stage of their TE life cycle when compared to D. melanogaster. Moreover, we show that D. melanogaster has been invaded by active TE variants for several TE families likely to come from D. simulans or the ancestor of D. simulans and D. sechellia. The numerous horizontal transfer events implied to explain these results could indicate introgression events between these species.


The protein phosphatase inhibitor okadaic acid suppresses type I collagen gene expression in cultured fibroblasts at the transcriptional level.
Type I collagen is the most abundant component of the extracellular matrix of human connective tissues. We have examined the effect of okadaic acid (OA), an inhibitor of phosphoserine- and-phosphothreonine-specific protein phosphatases 1 and 2A, on type I collagen gene expression by fibroblasts in culture. Treatment of human skin fibroblasts with OA potently reduced type I and type III collagen mRNA levels, maximally by over 90%. The inhibitory effect of OA on type I and III collagen mRNA abundance was not prevented by cycloheximide, and was not affected by simultaneous treatment with dexamethasone or retinoic acid. OA also abrogated the enhancing effect of transforming growth factor-beta (TGF-beta) on type I and III collagen mRNA levels. Treatment of transiently transfected NIH-3T3 fibroblasts with OA suppressed the activity of a 3.5 kb human pro alpha 2(I) collagen promoter/chloramphenicol acetyltransferase construct maximally, by 70%. In addition, OA treatment of NIH-3T3 cells abrogated enhancement of pro alpha 2(I) collagen promoter activity by TGF-beta. These results indicate that protein phosphatases 1 and 2A have an important role as positive regulators of type I and III collagen gene expression. The results also suggest that selective inhibition of activity of protein phosphatases 1 and 2A may offer a novel approach for preventing excessive collagen accumulation in fibrotic disorders.


Use of a coded postcard to maintain anonymity in a highly sensitive mail survey: cost, response rates, and bias.
In a survey about euthanasia, 1,600 critical care nurses were randomly assigned to receive either three complete, anonymous mailings of the questionnaire or, with each mailing, a coded postcard to be returned separately from the questionnaire to reduce subsequent mailings to previous responders. The response rate in these two groups was 76.5% [95% confidence interval (CI) = 73.6-79.4%] and 69% (95% CI = 65.7-72.4%), respectively. The two strategies yielded similar responses, and costs were much lower for the postcard group. Using coded postcards to be returned separately from completed instruments appears to lower the response rate to anonymous mail surveys, but it also lowers cost and may not introduce additional bias.


Biofunctionalization of zinc oxide nanowires for DNA sensory applications.
We report on the biofunctionalization of zinc oxide nanowires for the attachment of DNA target molecules on the nanowire surface. With the organosilane glycidyloxypropyltrimethoxysilane acting as a bifunctional linker, amino-modified capture molecule oligonucleotides have been immobilized on the nanowire surface. The dye-marked DNA molecules were detected via fluorescence microscopy, and our results reveal a successful attachment of DNA capture molecules onto the nanowire surface. The electrical field effect induced by the negatively charged attached DNA molecules should be able to control the electrical properties of the nanowires and gives way to a ZnO nanowire-based biosensing device.


Eosinophils mediate the pathogenesis of halothane-induced liver injury in mice.
Drug-induced liver injury (DILI) is a major health issue, as it remains difficult to predict which new drugs will cause injury and who will be susceptible to this disease. This is due in part to the lack of animal models and knowledge of susceptibility factors that predispose individuals to DILI. In this regard, liver eosinophilia has often been associated with DILI, although its role remains unclear. We decided to investigate this problem in a murine model of halothane-induced liver injury (HILI). When female Balb/cJ mice were administered halothane, eosinophils were detected by flow cytometry in the liver within 12 hours and increased thereafter proportionally to liver damage. Chemokines, eotaxin-1 (CCL11) and eotaxin-2 (CCL24), which are known to attract eosinophils, increased in response to halothane treatment. The severity of HILI was decreased significantly when the study was repeated in wildtype mice made deficient in eosinophils with a depleting antibody and in eosinophil lineage-ablated ΔdblGata(-/-) mice. Moreover, depletion of neutrophils by pretreating animals with Gr-1 antibody prior to halothane administration failed to reduce the severity of HILI at antibody concentrations that did not affect hepatic eosinophils. Immunohistochemical staining for the granule protein, major basic protein, revealed that eosinophils accumulated exclusively around areas of hepatocellular necrosis. Our findings indicate that eosinophils have a pathologic role in HILI in mice and suggest that they may contribute similarly in many clinical cases of DILI.


Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count.
The effects of zinc therapy on plasma testosterone (T), dihydrotestosterone (DHT), and sperm count were studied in 37 patients with idiopathic infertility of more than five years duration. In the first group (T less than 4.8 ng/ml; 22 patients), T and DHT rose significantly after oral administration of zinc, as did the sperm count. Nine wives became pregnant, six within 3 months and three within 2 months of a second trial. In the second group (T greater than or equal to 4.8 ng/ml; 15 patients), T and sperm count were unaffected by zinc, while DHT increased significantly. There was no conception observed. The rationale of this treatment and the significance of the results are discussed.


How to Provide Gadolinium-Free PET/MR Cancer Staging of Children and Young Adults in Less than 1 h: the Stanford Approach.
To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h. In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [18F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests. Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [18F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %). Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.


Chiral Gold Nanorods with Five-Fold Rotational Symmetry and Orientation-Dependent Chiroptical Properties of Their Monomers and Dimers.
Chiral plasmonic nanoparticles have attracted much attention because of their strong chiroptical responses and broad scientific applications. However, the types of chiral plasmonic nanoparticles have remained limited. Herein we report on a new type of chiral nanoparticle, chiral Au nanorod (NR) with five-fold rotational symmetry, which is synthesized using chiral molecules. Three different types of Au seeds (Au elongated nanodecahedrons, nanodecahedrons, and nanobipyramids) are used to study the growth behaviors. Different synthesis parameters, including the chiral molecules, surfactant, reductant, seeds, and Au precursor, are systematically varied to optimize the chiroptical responses of the chiral Au NRs. The chiral scattering measurements on the individual chiral Au NRs and their dimers are performed. Intriguingly, the chiroptical signals of the individual chiral Au NRs and their end-to-end dimers are similar, while those of the side-by-side dimers are largely reduced. Theoretical calculations and numerical simulations reveal that the different chiroptical responses of the chiral NR dimers are originated from the coupling effect between the plasmon resonance modes. Our study enriches chiral plasmonic nanoparticles and provides valuable insight for the design of plasmonic nanostructures with desired chiroptical properties.


Warming effects on permafrost ecosystem carbon fluxes associated with plant nutrients.
Large uncertainties exist in carbon (C)-climate feedback in permafrost regions, partly due to an insufficient understanding of warming effects on nutrient availabilities and their subsequent impacts on vegetation C sequestration. Although a warming climate may promote a substantial release of soil C to the atmosphere, a warming-induced increase in soil nutrient availability may enhance plant productivity, thus offsetting C loss from microbial respiration. Here, we present evidence that the positive temperature effect on carbon dioxide (CO2 ) fluxes may be weakened by reduced plant nitrogen (N) and phosphorous (P) concentrations in a Tibetan permafrost ecosystem. Although experimental warming initially enhanced ecosystem CO2 uptake, the increased rate disappeared after the period of peak plant growth during the early growing season, even though soil moisture was not a limiting factor in this swamp meadow ecosystem. We observed that warming did not significantly affect soil extractable N or P during the period of peak growth, but decreased both N and P concentrations in the leaves of dominant plant species, likely caused by accelerated plant senescence in the warmed plots. The attenuated warming effect on CO2 assimilation during the late growing season was associated with lowered leaf N and P concentrations. These findings suggest that warming-mediated nutrient changes may not always benefit ecosystem C uptake in permafrost regions, making our ability to predict the C balance in these warming-sensitive ecosystems more challenging than previously thought.


Investigational cytokine-targeted therapies for ulcerative colitis.
Up to one-third of patients with ulcerative colitis (UC) do not respond to standard medications, including mesalamine, steroids and thiopurines. The recognition that UC-related pathological process is the result of an altered balance between inflammatory and counter-regulatory signals, mostly mediated by cytokines, has led to the development of novel compounds, which are now ready to move into clinical practice. This article summarizes the recent data on the development and use of compounds either inhibiting inflammatory cytokines or enhancing the activity of counter-regulatory cytokines in patients with UC and murine models of UC. A PubMed search was performed using the following keywords: 'ulcerative colitis', 'therapy', 'treatment' and 'cytokine'. In addition, ongoing clinical trials were checked and compounds were searched on the website of pharmaceutical companies. Several investigational cytokine-based therapies have provided promising results in attenuating clinical activity in patients with UC and mice with experimental colitis. However, clinical and immunological heterogeneity of UC patients, therapy-related side effects and redundant biological functions of cytokines represent potential pitfalls and should be considered in optimizing therapeutic strategies.


A 'Global Reference' Comparator for Biosimilar Development.
Major drug regulators have indicated in guidance their flexibility to accept some development data for biosimilars generated with reference product versions licensed outside their own jurisdictions, but most authorities require new bridging studies between these versions and the versions of them licensed locally. The costs of these studies are not trivial in absolute terms and, due to the multiplier effect of required repetition by each biosimilar sponsor, their collective costs are substantial. Yet versions of biologics licensed in different jurisdictions usually share the same development data, and any manufacturing changes between versions have been justified by a rigorous comparability process. The fact that a biosimilar is usually expected to be licensed in multiple jurisdictions, in each case as similar to the local reference product, confirms that minor analytical differences between versions of reference biologics are typically inconsequential for clinical outcomes and licensing. A greatly simplified basis for selecting a reference comparator, that does not require conducting new bridging studies, is proposed and justified based on the shared data of the reference product versions as well as the proof offered where biosimilars have already been approved. The relevance of this proposal to the interchangeability designation available in the US is discussed.


An examination of women experiencing obstetric complications requiring emergency care: perceptions and sociocultural consequences of caesarean sections in Bangladesh.
Little is known about the physical and socioeconomic postpartum consequences of women who experience obstetric complications and require emergency obstetric care (EmOC), particularly in resource-poor countries such as Bangladesh where historically there has been a strong cultural preference for births at home. Recent increases in the use of skilled birth attendants show socioeconomic disparities in access to emergency obstetric services, highlighting the need to examine birthing preparation and perceptions of EmOC, including caesarean sections. Twenty women who delivered at a hospital and were identified by physicians as having severe obstetric complications during delivery or immediately thereafter were selected to participate in this qualitative study. Purposive sampling was used for selecting the women. The study was carried out in Matlab, Bangladesh, during March 2008-August 2009. Data-collection methods included in-depth interviews with women and, whenever possible, their family members. The results showed that the women were poorly informed before delivery about pregnancy-related complications and medical indications for emergency care. Barriers to care-seeking at emergency obstetric facilities and acceptance of lifesaving care were related to apprehensions about the physical consequences and social stigma, resulting from hospital procedures and financial concerns. The respondents held many misconceptions about caesarean sections and distrust regarding the reason for recommending the procedure by the healthcare providers. Women who had caesarean sections incurred high costs that led to economic burdens on family members, and the blame was attributed to the woman. The postpartum health consequences reported by the women were generally left untreated. The data underscore the importance of educating women and their families about pregnancy-related complications and preparing families for the possibility of caesarean section. At the same time, the health systems need to be strengthened to ensure that all women in clinical need of lifesaving obstetric surgery access quality EmOC services rapidly and, once in a facility, can obtain a caesarean section promptly, if needed. While greater access to surgical interventions may be lifesaving, policy-makers need to institute mechanisms to discourage the over-medicalization of childbirth in a context where the use of caesarean section is rapidly rising.


Unilateral axial length elongation with chronic traumatic cataracts in young Kenyans.
To assess whether unilateral axial elongation in chronic traumatic cataract is associated with the time interval from trauma to surgery. PCEA Kikuyu Hospital Eye Unit, Nairobi, Kenya. This retrospective cohort study analyzed patients with traumatic cataract operated on between 1998 and 2007. Study patients (n = 13) had a delay from trauma to surgery of more than 1 year and an interocular axial length (AL) difference greater than 1.0 mm. Randomly selected age-matched control patients (n = 14) had less than 1 year delay between trauma and surgery. The correlation between interocular AL difference and surgical delay was calculated in each group. The median interval from trauma to surgical treatment in study patients was 8 years (range 1 to 27 years). Study patients had a significantly higher median interocular AL difference (3.09 mm; interquartile range [IQR] 2.45 to 4.13 mm) than control patients (0.24 mm; IQR 0.15 to 0.30 mm) (P = .000). The length of delay from trauma to surgical treatment did not correlate strongly with the interocular AL difference in study or control patients (R(2) = 0.0143 and R(2) = 0.1697, respectively). Unilateral AL elongation may occur in young adults with chronic traumatic cataract. Delay of more than 1 year from trauma to surgery was associated with axial elongation, although the degree of elongation did not correlate with duration of delay. Surgeons are advised to implant lower-power intraocular lenses in such patients based on biometry readings to avoid postoperative refractive surprises.


The effects of myokines on osteoclasts and osteoblasts.
Recently, muscle has received much attention as an endocrine organ regulating other biological targets, including the pancreas, liver, and adipose tissue. Although there is a possibility that muscle-secreting factors biochemically affect bone metabolism in a paracrine manner, the net effects of myokines on the biology of osteoclasts and osteoblasts, particularly on bone mass in vivo, have not yet been thoroughly investigated. Therefore, we performed in vitro as well as animal experiments using conditioned media (CM) collected from C2C12 myoblast and myotube cultures to better understand the interactions between muscle and bone. Compared with non-CM (i.e., control) and myoblast CM, myotube CM markedly inhibited in vitro bone resorption through the suppression of osteoclast differentiation and resorptive activity of individual osteoclasts. Consistently, the expressions of osteoclast differentiation markers, such as tartrate-resistant acid phosphatase (Trap) and calcitonin receptor (Ctr), decreased with myotube CM. Myotube CM significantly stimulated preosteoblast viability and migration and reduced apoptosis, thereby resulting in an increase in calvaria bone formation. Importantly, systemic treatment with myotube CM for 4 weeks increased bone per tissue volume by 30.7% and 19.6% compared with control and myoblast CM, respectively. These results support the hypothesis that muscle plays beneficial roles in bone health via secretion of anabolic factors, in addition to mechanical stimuli, and importantly indicate that muscle-derived factors can be potential therapeutic targets against metabolic bone diseases.


Dexamethasone and losartan combination treatment protected cigarette smoke-induced COPD in rats.
Chronic Obstructive Pulmonary Disease (COPD) is a dangerous prevalent smoking-related disease characterized by abnormal inflammation and oxidative stress and expected to be the third cause of death in the world next decade. Corticosteroids have low effects in decreasing numbers of inflammatory mediators specifically in long-term use. Our study designed to investigate the possible protective effects of combined dexamethasone (Dex) (2mg/kg) and losartan (Los) (30mg/kg angiotensin receptor blocker, it possesses antioxidant and anti-inflammatory properties in lung injury in mice) against cigarette -smoke (CS) induced COPD in rats compared with dexamethasone and losartan. Male Sprague Dawley rats (N = 40) divided into five groups (n = 8): control group, CS group, Dex group, Los group, and Dex +Los group. COPD induced in rats by CS exposure twice daily for 10 weeks. After the specified treatment period, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for measurement of SOD, NO, MDA, ICAM-, MMP-9, CRP, NF-κB and histopathology scoring. Our results indicated that Los+Dex significantly prevent CS-induced COPD emphysema, congested alveoli, and elevation of lung injury parameters in BALF. They also showed a significant decrease in MDA, ICAM-1, MMP-9, CRP, and NF-κB and a significant increase in SOD and NO. In conclusion, adding Los to Dex potentiating their activity in inhibition the progression of COPD based on its activity on oxidative stress, inflammation, and NF-κB protein expression.


Design and characterization of a high-power laser-induced acoustic desorption probe coupled with a fourier transform ion cyclotron resonance mass spectrometer.
We report here the construction and characterization of a high-power laser-induced acoustic desorption (LIAD) probe designed for Fourier transform ion cyclotron resonance mass spectrometers to facilitate analysis of nonvolatile, thermally labile compounds. This "next generation" LIAD probe offers significant improvements in sensitivity and desorption efficiency for analytes with larger molecular weights via the use of higher laser irradiances. Unlike the previous probes which utilized a power-limiting optical fiber to transmit the laser pulses through the probe, this probe employs a set of mirrors and a focusing lens. At the end of the probe, the energy from the laser pulses propagates through a thin metal foil as an acoustic wave, resulting in desorption of neutral molecules from the opposite side of the foil. Following desorption, the molecules can be ionized by electron impact or chemical ionization. Almost an order of magnitude greater power density (up to 5.0x10(9) W/cm2) is achievable on the backside of the foil with the high-power LIAD probe compared to the earlier LIAD probes (maximum power density approximately 9.0x10(8) W/cm2). The use of higher laser irradiances is demonstrated not to cause fragmentation of the analyte. The use of higher laser irradiances increases sensitivity since it results in the evaporation of a greater number of molecules per laser pulse. Measurement of the average velocities of LIAD-evaporated molecules demonstrates that higher laser irradiances do not correlate with higher velocities of the gaseous analyte molecules.


Tetanus toxoid immunization coverage among women in zone 3 of Dhaka city: the challenge of reaching all women of reproductive age in urban Bangladesh.
Neonatal tetanus is still an important public health problem in both urban and rural Bangladesh, with an estimated 41,000 cases occurring annually. This article analyses the coverage of tetanus toxoid (TT) immunizations among women of reproductive age in Zone 3 of Dhaka City in 1995. Although 85% of women with a child under 1 year of age had received two TT immunizations, only 11% of women of reproductive age had obtained the complete series of five TT immunizations and only 52% of women of reproductive age had received one or more TT immunizations. Access to TT immunization, as defined by having had at least one such immunization, was lower among women aged over 30 years and also among those aged under 20 years, especially those who were not yet married or who had not yet become pregnant. Characteristics associated with TT immunization status included the following: educational level of the woman, distance from the nearest immunization centre, and level of contact with family planning field workers. Additional characteristics that influenced women's TT immunization status included age, marital and working status, recency of migration from rural to urban area, and number of children. The relationships were complex and varied depending on the number of TT immunizations received (one or two) and on the type of analysis being carried out (bivariate or multivariate). The findings point to the need for a broad-based campaign to promote access to TT immunization as well as to promote the completion of all five TT doses in Bangladesh. Reducing missed opportunities for promotion of immunization as well as targeting home visitation of women in need of additional immunizations constitute further approaches to improving coverage. Although TT coverage rates were only marginally lower among women in slum households, such women were more likely than those in non-slum households to be pregnant and hence more likely to bear a baby at risk of neonatal tetanus. Furthermore, the environment of slum households, where deliveries normally take place, is more conducive to the development of neonatal tetanus among unprotected neonates; a strategy of focusing on slum households is therefore also needed.


Revisiting the psychometric properties of the Scoliosis Research Society-22 (SRS-22) French version.
Adolescent idiopathic scoliosis (AIS) is among the most common spinal deformities affecting adolescents. The Scoliosis Research Society-22 questionnaire is commonly used to assess health-related quality of life in AIS patients, including pain. The objective of this study is to verify the psychometric properties of the Scoliosis Research Society-22 French version (SRS-22fv) questionnaire. A prospective methodological design was used to verify the psychometric properties of the French version of the SRS-22fv. Participants were initially recruited from the orthopaedic scoliosis department at Sainte-Justine Hospital (Montreal, Canada) and completed the SRS-22fv and the SF-12 questionnaire. The SRS-22fv's structure was evaluated through principal component analysis (PCA). Linear regression was used to assess convergent validity between the SRS-22fv and the SF-12. Data was available from 352 participants with AIS. Most participants were female (87%, n = 307), and the average age was 14.3 (SD = 1.8) years. The mean thoracic and lumbar Cobb angles were 27.9° (SD = 3.3) and 23.6° (SD = 9.4), respectively. Overall, 71.4% (n = 252) of the participants presented with spinal pain. About one-third (29%) reported thoracic pain, and almost half (44%) experienced lumbar pain. The PCA identified four redundant items, which resulted in a modified 18-item questionnaire. In comparison to the original questionnaire, the modified version showed higher levels of internal consistency for four of the five factors, explained a greater proportion of the total variance (63.3%), and generated higher inter-item total correlations. We propose a shorter version of the SRS-22fv, thus the Canadian SRS-18fv, which showed an improved internal consistency and scale structure compared to the original SRS-22fv. We believe that this modified version would be better suited to assess the quality of life of adolescents with idiopathic scoliosis.


User Manuals for a Primary Care Electronic Medical Record System: A Mixed Methods Study of User- and Vendor-Generated Documents.
Tutorials and user manuals are important forms of impersonal support for using software applications including electronic medical records (EMRs). Differences between user- and vendor documentation may indicate support needs, which are not sufficiently addressed by the official documentation, and reveal new elements that may inform the design of tutorials and user manuals. What are the differences between user-generated tutorials and manuals for an EMR and the official user manual from the software vendor? Effective design of tutorials and user manuals requires careful packaging of information, balance between declarative and procedural texts, an action and task-oriented approach, support for error recognition and recovery, and effective use of visual elements. No previous research compared these elements between formal and informal documents. We conducted an mixed methods study. Seven tutorials and two manuals for an EMR were collected from three family health teams and compared with the official user manual from the software vendor. Documents were qualitatively analyzed using a framework analysis approach in relation to the principles of technical documentation described above. Subsets of the data were quantitatively analyzed using cross-tabulation to compare the types of error information and visual cues in screen captures between user- and vendor-generated manuals. The user-developed tutorials and manuals differed from the vendor-developed manual in that they contained mostly procedural and not declarative information; were customized to the specific workflow, user roles, and patient characteristics; contained more error information related to work processes than to software usage; and used explicit visual cues on screen captures to help users identify window elements. These findings imply that to support EMR implementation, tutorials and manuals need to be customized and adapted to specific organizational contexts and workflows. The main limitation of the study is its generalizability. Future research should address this limitation and may explore alternative approaches to software documentation, such as modular manuals or participatory design.


The organization of cholinergic projections in the visual thalamus of the mouse.
Cholinergic projections from the brainstem serve as important modulators of activity in visual thalamic nuclei such as the dorsal lateral geniculate nucleus (dLGN). While these projections have been studied in several mammals, a comprehensive examination of their organization in the mouse is lacking. We used the retrograde transport of viruses or cholera toxin subunit B (CTB) injected in the dLGN, immunocytochemical labeling with antibodies against choline acetyltransferase (ChAT), brain nitric oxide synthase (BNOS), and vesicular acetylcholine transporter (VAChT), ChAT-Cre mice crossed with a reporter line (Ai9), as well as brainstem virus injections in ChAT-Cre mice to examine the pattern of thalamic innervation from cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus (LDTg), and the parabigeminal nucleus (PBG). Retrograde tracing demonstrated that the dLGN receives input from the PPTg, LDTg, and PBG. Viral tracing in ChAT-Cre mice and retrograde tracing combined with immunocytochemistry revealed that many of these inputs originate from cholinergic neurons in the PBG and PPTg. Most notable was an extensive cholinergic projection from the PBG which innervated most of the contralateral dLGN, with an especially dense concentration in the dorsolateral shell, as well as a small region in the dorsomedial pole of the ipsilateral dLGN. The PPTg was found to provide a sparse somewhat diffuse innervation of the ipsilateral dLGN. Neurons in the PPTg co-expressed ChAT, BNOS, and VAChT, whereas PBG neurons expressed ChAT, but not BNOS or VAChT. These results highlight the presence of distinct cholinergic populations that innervate the mouse dLGN.


Catheter Ablation of Ventricular Tachycardia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is predominantly an inherited cardiomyopathy with typical histopathological characteristics of fibro-fatty infiltration mainly involving the right ventricular (RV) inflow tract, RV outflow tract, and RV apex in the majority of patients. The above pathologic evolution frequently brings patients with ARVD/C to medical attention owing to the manifestation of syncope, sudden cardiac death (SCD), ventricular arrhythmogenesis, or heart failure. To prevent future or recurrent SCD, an implantable cardiac defibrillator (ICD) is highly desirable in patients with ARVD/C who had experienced unexplained syncope, hemodynamically intolerable ventricular tachycardia (VT), ventricular fibrillation, and/or aborted SCD. Notably, the management of frequent ventricular tachyarrhythmias in ARVD/C is challenging, and the use of antiarrhythmic drugs could be unsatisfactory or limited by the unfavorable side effects. Therefore, radiofrequency catheter ablation (RFCA) has been implemented to treat the drug-refractory VT in ARVD/C for decades. However, the initial understanding of the link between fibro-fatty pathogenesis and ventricular arrhythmogenesis in ARVD/C is scarce, the efficacy and prognosis of endocardial RFCA alone were limited and disappointing. The electrophysiologists had broken through this frontier after better illustration of epicardial substrates and broadly application of epicardial approaches in ARVD/C. In recent works of literature, the application of epicardial ablation also successfully results in higher procedural success and decreases VT recurrences in patients with ARVD/C who are refractory to the endocardial approach during long-term follow-up. In this article, we review the important evolution on the delineation of arrhythmogenic substrates, ablation strategies, and ablation outcome of VT in patients with ARVD/C.


Controlling infections in hospitalized pretransplant candidates.
Infections in hospitalized patients awaiting solid organ transplantation can pose complicated diagnostic and therapeutic challenges. Goals of management include stabilizing the patient, treating or controlling infections, and decreasing the risk of reactivation of infection after transplant. Groups such as The Organ Procurement and Transplantation Network, American Society of Transplantation Infectious Diseases Community of Practice and the European Society of Clinical Microbiology and Infectious Diseases have updated their guidelines on screening and treatment of infection in transplant candidates. There are also recent developments in therapeutic options for tuberculosis, COVID-19, Clostridioides difficile colitis, bloodstream infections, and other common infections. Ideally, antimicrobial therapy should be complete prior to transplantation. In situations in which completion of therapy prior to transplant is not feasible, therapy may need to be prolonged or modified. In most situations, infections can be managed similarly to the general population, although some infections, particularly fungal and mycobacterial, require a different management approach. We review disease- and organ-specific management.


Conjunctive Continuous Performance Task (CCPT)--a pure measure of sustained attention.
Among the large variety of attentional tasks that have been used to study sustained attention, the Continuous Performance Task (CPT) is perhaps the most widely used. Despite substantial differences in task characteristics and demands, all CPT paradigms have been referred to as measures of sustained attention. In the present study we introduce a new variant of CPT, which minimizes perceptual and memory components while maximizing the sustained attention components of the task. In addition, we tested the contention that the ability to sustain attention should not be overly dependent on the specific stimuli and task-modality. To this end, we used a new visual Conjunctive CPT (CCPT) developed by Tsal, Shalev, & Mevorach (2005) and its auditory analogue. Using a Multi-Trait-Multi-Method (MTMM) analysis investigating reliability coefficients, convergent validity coefficients and divergent (discriminant) validity coefficients, we established that the new CCPT is a valid measure of sustained attention. In particular, high correlations were obtained between mean RT and SD-RT within each sensory modality. High correlations were also found between performance across sensory modalities (mean convergent validity: .71). Finally, low correlations (mean correlation of .18) were found between performance in the CCPT tasks and performance in two additional visuospatial attention tasks, which do not rely on sustained attention. These findings suggest that independent of sensory modality, the two CCPT tasks used here tap the same stable construct, namely, sustained attention. We conclude that when a measure of sustained attention is required, researchers should be aware of the caveats of standard CPT's and should be careful in selecting a proper task. Moreover, clinicians should appreciate that some CPT measures may reflect a combination of different cognitive operations rather than pure sustained attention.