Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation.
Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. The mechanism of LV dysfunction in primary severe MR is entirely unknown. Here, we developed the first mouse model of severe MR. Valvular damage was achieved by severing the mitral valve leaflets and chords with iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocyte morphology, LV fibrosis, and cell death. Finally, dysregulated pathways were assessed by RNA-sequencing analysis and immunofluorescence. In the ensuing 15 weeks after the induction of MR, gradual LV dilatation and dysfunction occurred, resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass and increased cardiomyocyte length but not width, with electron microscopic evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mammalian target of rapamycin and calcineurin pathways. Inhibition of mammalian target of rapamycin signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 (crumbs homolog 2) along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Electron microscopy images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts. These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.


Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction.
The combination of glycoprotein IIb/IIIa inhibitors and heparin has not been compared with bivalirudin in studies specifically involving patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compared the two treatments in this patient population. Immediately before PCI, we randomly assigned, in a double-blind manner, 1721 patients with acute non-ST-segment elevation myocardial infarction to receive abciximab plus unfractionated heparin (861 patients) or bivalirudin (860 patients). The study tested the hypothesis that abciximab and heparin would be superior to bivalirudin with respect to the primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days. Secondary end points included the composite of death, any recurrent myocardial infarction, or urgent target-vessel revascularization (efficacy end point) and major bleeding (safety end point) within 30 days. The primary end point occurred in 10.9% of the patients in the abciximab group (94 patients) and in 11.0% in the bivalirudin group (95 patients) (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P=0.94). Death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the patients in the abciximab group (110 patients) and in 13.4% in the bivalirudin group (115 patients) (relative risk, 0.96; 95% CI, 0.74 to 1.25; P=0.76). Major bleeding occurred in 4.6% of the patients in the abciximab group (40 patients) as compared with 2.6% in the bivalirudin group (22 patients) (relative risk, 1.84; 95% CI, 1.10 to 3.07; P=0.02). Abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary end point and increased the risk of bleeding among patients with non-ST-segment elevation myocardial infarction who were undergoing PCI. (Funded by Nycomed Pharma and others; ISAR-REACT 4 ClinicalTrials.gov number, NCT00373451.).


ERK5 regulation in naïve T-cell activation and survival.
ERK5 has been implicated in regulating the MEF2-dependent genes Klf2 and nur77 downstream of the TCR and the maintenance of expression of CD62L on peripheral T cells. Based on this data, knockout of ERK5 would be predicted to compromise T-cell development and the maintenance of T cells in the periphery. Using an ERK5 conditional knockout, driven by CD4-CRE or Vav-CRE transgenes resulting in the loss of ERK5 in T cells, we have found that ERK5 is not required for T-cell development. In addition, normal numbers of T cells were found in the spleens and lymph nodes of these mice. We also find that TCR stimulation is not a strong signal for ERK5 activation in primary murine T cells. ERK5 was found to contribute to the induction of Klf2 but not nur77 mRNA following TCR activation. Despite the reduction in Klf2 mRNA, no effect was seen in ERK5 knockouts on either the mRNA levels for the Klf2 target genes CD62L, CCR7 and S1P, or the cell surface expression of CD62L. These results suggest that while ERK5 does contribute to Klf2 regulation in T cells, it is not essential for the expression of CD62L or T-cell survival.


In vivo testing of the protection provided by non-latex gloves against a 2-hydroxyethyl methacrylate-containing acetone-based dentin-bonding product.
In dentistry, allergic contact dermatitis to acrylates and allergic contact urticaria to latex are important occupational hazards. There is a need to identify non-latex gloves which are suitable for dental work but at the same time provide adequate protection against acrylate monomers. In a previous study, a new open-chamber system was used for testing the in vivo protection of 6 different gloves against an acrylate-containing ethanol-based dental adhesive. A nitrile glove gave the best protection among the gloves suitable for dental work. In the present study, the test model was used to investigate the in vivo protection of 7 non-latex gloves against a dental bonding product containing 2-hydroxyethyl methacrylate (2-HEMA) in an acetone/water vehicle. Eight 2-HEMA-allergic patients participated. Two neoprene gloves gave the best protection. The protection of the poorest glove was comparable to that of the positive control (no glove). The study produced in vivo data useful in the implementation of individual preventative measures against contact allergy to acrylates.


Adenoviral expression of murine serum amyloid A proteins to study amyloid fibrillogenesis.
Serum amyloid A (SAA) proteins are one of the most inducible acute-phase reactants and are precursors of secondary amyloidosis. In the mouse, SAA1 and SAA2 are induced in approximately equal quantities in response to amyloid induction models. These two isotypes differ in only 9 of 103 amino acid residues; however, only SAA2 is selectively deposited into amyloid fibrils. SAA expression in the CE/J mouse species is an exception in that gene duplication did not occur and the CE/J variant is a hybrid molecule sharing features of SAA1 and SAA2. However, even though it is more closely related to SAA2 it is not deposited as amyloid fibrils. We have developed an adenoviral vector system to overexpress SAA proteins in cell culture to determine the ability of these proteins to form amyloid fibrils, and to study the structural features in relation to amyloid formation. Both the SAA2 and CE/J SAA proteins were synthesized in large quantities and purified to homogeneity. Electron microscopic analysis of the SAA proteins revealed that the SAA2 protein was capable of forming amyloid fibrils, whereas the CE/J SAA was incapable. Radiolabelled SAAs were associated with normal or acute-phase high-density lipoproteins (HDLs); we examined them for their clearance from the circulation. In normal mice, SAA2 had a half-life of 70 min and CE/J SAA had a half-life of 120 min; however, in amyloid mice 50% of the SAA2 cleared in 55 min, compared with 135 min for the CE/J protein. When the SAA proteins were associated with acute-phase HDLs, SAA2 clearance was decreased to 60 min in normal mice compared with 30 min in amyloidogenic mice. Both normal and acute-phase HDLs were capable of depositing SAA2 into preformed amyloid fibrils, whereas the CE/J protein did not become associated with amyloid fibrils. This established approach opens the doors for large-scale SAA production and for the examination of specific amino acids involved in the fibrillogenic capability of the SAA2 molecule in vitro and in vivo.


A novel strategy for evaluating the effects of an electronic test ordering alert message: Optimizing cardiac marker use.
Laboratory ordering functions within computerized provider order entry (CPOE) systems typically support the display of electronic alert messages to improve test utilization or implement new ordering policies. However, alert strategies have been shown to vary considerably in their success and the characteristics contributing to an alert's success are poorly understood. Improved methodologies are needed to evaluate alerts and their mechanisms of action. Clinicians order inpatient and emergency department laboratory tests using our institutional CPOE system. We analyzed user interaction data captured by our CPOE system to evaluate how clinicians responded to an alert. We evaluated an alert designed to implement an institutional policy restricting the indications for ordering creatine kinase-MB (CKMB). Within 2 months of alert implementation, CKMB-associated searches declined by 79% with a corresponding decline in CKMB orders. Furthermore, while prior to alert implementation, clinicians searching for CKMB ultimately ordered this test 99% of the time, following implementation, only 60% of CKMB searches ultimately led to CKMB test orders. This difference presumably represents clinicians who reconsidered the need for CKMB in response to the alert, demonstrating the alert's just-in-time advisory capability. In addition, as clinicians repeatedly viewed the alert, there was a "dose-dependant" decrease in the fraction of searches without orders. This presumably reflects the alerting strategy's long-term educational component, as clinicians aware of the new policy will not search for CKMB when not indicated. Our analytic approach provides insight into the mechanism of a CPOE alert and demonstrates that alerts may act through a combination of just-in-time advice and longer term education. Use of this approach when implementing alerts may prove useful to improve the success of a given alerting strategy.


Interferon alpha plus 13-cis-retinoic acid modulation of BCL-2 plus paclitaxel for recurrent small-cell lung cancer (SCLC): an Eastern Cooperative Oncology Group study (E6501).
Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC. Patients with recurrent SCLC and measurable disease were treated with interferon alpha at 6 million units/m² subcutaneously and 13-CRA 1 mg/kg orally on days 1 and 2 and paclitaxel 75 mg/m² intravenously on day 2 of each week for 6 weeks of an 8-week treatment cycle. Treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Bcl-2 levels were assessed in peripheral blood mononuclear cells (PBMCs). Thirty-seven patients were enrolled; 34 were included in the intention-to-treat analysis as 3 patients were ineligible for the study. There were 3 partial responses (9 %), and 5 patients had stable disease (15 %) as best response. The median PFS was 2 months, and median OS was 6.2 months. Although mean Bcl-2 protein levels decreased with therapy in PBMCs, there was no association between Bcl-2 levels and response rate or survival. Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC.


Gout and Hospital Admission for Ambulatory Care-Sensitive Conditions: Risks and Trajectories.
To investigate the risks and trajectories of hospital admission for ambulatory care-sensitive conditions (ACSCs) in gout. Among individuals aged 35 years to 85 years residing in Skåne, Sweden, in 2005, those with no doctor-diagnosed gout during 1998 to 2005 (n = 576,659) were followed from January 1, 2006, until a hospital admission for an ACSC, death, relocation outside Skåne, or December 31, 2016. Treating a new gout diagnosis (International Classification of Diseases, 10th revision, code M10) as a time-varying exposure, we used Cox proportional and additive hazard models to estimate the effects of gout on hospital admissions for ACSCs. We investigated the trajectory of hospital admissions for ACSCs from 3 years before to 3 years after gout diagnosis using generalized estimating equations and group-based trajectory modeling in an age-and sex-matched cohort study. Gout was associated with a 41% increased rate of hospital admission for ACSCs (hazard ratio 1.41, 95% CI 1.35-1.47), corresponding to 121 (95% CI 104-138) more hospital admissions for ACSCs per 10,000 person-years compared with those without gout. Our trajectory analysis showed that higher rates of hospital admission for ACSCs among persons with gout were observed from 3 years before to 3 years after diagnosis, with the highest prevalence rate ratio (2.22, 95% CI 1.92-2.53) at the 3-month period after diagnosis. We identified 3 classes with distinct trajectories of hospital admissions for ACSCs among patients with gout: almost none (88.5%), low-rising (9.7%), and moderate-sharply rising (1.8%). The Charlson Comorbidity Index was the most important predictor of trajectory class membership. Increased risk of hospital admissions for ACSCs in gout highlights the need for better management of the disease through outpatient care, especially among foreign-born, older patients with comorbidities.


Treatment of traumatized refugee children with Eye Movement Desensitization and Reprocessing in a psychodynamic context.
This study examines the effects of a psychodynamic approach of Eye Movement Desensitization and Reprocessing (EMDR) in treatment of traumatized refugee children. Among a child psychiatric outpatient refugee team, 13 children with post-traumatic stress disorder (PTSD), were treated by EMDR incorporated in a traditional psychodynamic therapeutic approach. The Posttraumatic Stress Symptom Scale for Children (PTSS-C) and the Global Assessment of Functioning (GAF) were administered before and after the treatment, to measure the effects. After treatment, a significant improvement was noticed in the functioning level and all PTSS-C scales, mostly in re-experiencing and least in the avoidance symptoms. The improvement in the functioning level was significantly correlated with the reduction of the PTSD-non-related and the depression, but not with that of the PTSD-related symptoms. Used in a psychodynamic context, EMDR is suggested to be effective treatment for traumatized refugee children. Our findings support the hypothesis of child-specific criteria for PTSD.


Predictive factors for oropharyngeal dysphagia after prolonged orotracheal intubation.
Lesions in the oral cavity, pharynx and larynx due to endotracheal intubation can cause reduction in the local motility and sensitivity, impairing the swallowing process, resulting in oropharyngeal dysphagia. To verify the predictive factors for the development of oropharyngeal dysphagia and the risk of aspiration in patients with prolonged orotracheal intubation admitted to an intensive care unit. This is an observational, analytical, cross-sectional and retrospective data collection study of 181 electronic medical records of patients submitted to prolonged orotracheal intubation. Data on age; gender; underlying disease; associated comorbidities; time and reason for orotracheal intubation; Glasgow scale on the day of the Speech Therapist assessment; comprehension; vocal quality; presence and severity of dysphagia; risk of bronchoaspiration; and the suggested oral route were collected. The data were analyzed through logistic regression. The level of significance was set at 5%, with a 95% Confidence Interval. The prevalence of dysphagia in this study was 35.9% and the risk of aspiration was 24.9%. As the age increased, the altered vocal quality and the degree of voice impairment increased the risk of the presence of dysphagia by 5-; 45.4- and 6.7-fold, respectively, and of aspiration by 6-; 36.4- and 4.8-fold. The increase in the time of orotracheal intubation increased the risk of aspiration by 5.5-fold. Patients submitted to prolonged intubation who have risk factors associated with dysphagia and aspiration should be submitted to an early speech-language/audiology assessment and receive appropriate and timely treatment. The recognition of these predictive factors by the entire multidisciplinary team can minimize the possibility of clinical complications inherent to the risk of dysphagia and aspiration in extubated patients.


Perspective: Should Exclusive Breastfeeding Still Be Recommended for 6 Months?
The WHO recommends exclusive breastfeeding of infants for the first 6 mo of life (EBF-6). We reviewed the evidence behind concerns related to this recommendation. The risk of iron deficiency among EBF-6 infants can be significantly reduced if delayed cord clamping is performed in all newborns. At the moment there is no population-level evidence indicating that exclusive breastfeeding for 6 mo compared with <6 mo increases the risk of developing food allergies. Mild to moderate maternal undernutrition may reduce amounts of some nutrients in breast milk but does not directly diminish milk volume. Persistent reports of insufficient milk by women globally are likely to be the result of lack of access to timely lactation counseling and social support rather than primary biological reasons. All newborns should have their growth, hydration status, and development carefully monitored. In instances where formula supplementation is required, it should be done under the guidance of a qualified provider taking into account that early introduction of breast-milk supplements is a risk factor for early termination of exclusive breastfeeding and any breastfeeding. We found no evidence to support changes to the EBF-6 public health recommendation, although variability in inter-infant developmental readiness is recognized. We suggest that infant and young feeding guidelines make clear that complementary foods should be introduced at around 6 mo of age, taking infant developmental readiness into account.


A comparison of changes in rhythms of sacral skin blood flow in response to heating and indentation.
To differentiate blood flow control mechanisms associated with indentation from those associated with heating and to discern heat-induced and pressure-induced changes by comparing the effect of externally applied stress on skin blood flow (SBF) to the response to externally applied heat. Repeated-measures design. A university research laboratory. Ten healthy, young adults (5 men, 5 women; mean age +/- standard deviation, 30.0+/-3.1y). Intervention Incremental heat (35 degrees -45 degrees C, 1 degrees step/min) and pressure (0-60 mmHg, 5 mmHg step/3 min) on the sacrum using a computer-controlled indenter. Sessions for heat and pressure protocols were separated by 7+/-2 days. We used a Laserflo Blood Perfusion Monitor 2 and Softip pencil probe to measure capillary blood perfusion and wavelet analysis to decompose the blood flow signal. The power spectrum was divided into 5 ranges corresponding to metabolic, neurogenic, myogenic, respiratory, and cardiac control mechanisms. The average relative (ie, normalized) power in each frequency range was computed to determine of the relative contribution of each control mechanism. Power in the myogenic frequency range was higher after incremental pressure and lower after incremental heating, whereas power in the metabolic frequency range was lower after incremental pressure and higher after incremental heating ( P <.01). Mean blood flow decreased as pressure increased from 0 to 15 mmHg; mean blood flow increased as pressure increased from 15 to 60 mmHg. SBF, as recorded by the laser Doppler, suggests that there may be a myogenic control mechanism mediating blood flow after incremental tissue loads and that a metabolic control mechanism may mediate blood flow after heat application to the tissue. The study of local blood flow control mechanisms and their response to pathomechanical perturbations may be possible using wavelet analysis of blood flow oscillations. More research is needed to establish the clinical utility of these findings in the development of support surfaces intended to reduce the risk of developing pressure ulcers.


Outpatient Antibiotic Prescribing for Acute Respiratory Infections During Influenza Seasons.
Acute respiratory infections (ARIs) are the syndrome for which antibiotics are most commonly prescribed; viruses for which antibiotics are ineffective cause most ARIs. To characterize antibiotic prescribing among outpatients with ARI during influenza season and to identify targets for reducing inappropriate antibiotic prescribing for common ARI diagnoses, including among outpatients with laboratory-confirmed influenza. Cohort study enrolling outpatients aged 6 months or older with ARI evaluated at outpatient clinics associated with 5 US Influenza Vaccine Effectiveness Network sites during the 2013-2014 and 2014-2015 influenza seasons. All patients received influenza testing by real-time reverse transcriptase-polymerase chain reaction for research purposes only. Antibiotic prescriptions, medical history, and International Classification of Diseases, Ninth Revision diagnosis codes were collected from medical and pharmacy records, as were group A streptococcal (GAS) testing results in a patient subset. Visit for ARI, defined by a new cough of 7 days' duration or less. Antibiotic prescription within 7 days of enrollment. Appropriateness of antibiotic prescribing was based on diagnosis codes, clinical information, and influenza and GAS testing results. Of 14 987 patients with ARI (mean [SD] age, 32 [24] years; 8638 [58%] women; 11 892 [80%] white), 6136 (41%) were prescribed an antibiotic. Among these 6136 patients, 2522 (41%) had diagnoses for which antibiotics are not indicated; 2106 (84%) of these patients were diagnosed as having a viral upper respiratory tract infection or bronchitis (acute or not otherwise specified). Among the 3306 patients (22%) not diagnosed as having pneumonia and who had laboratory-confirmed influenza, 945 (29%) were prescribed an antibiotic, accounting for 17% of all antibiotic prescriptions among patients with nonpneumonia ARI. Among 1248 patients with pharyngitis, 1137 (91%) had GAS testing; 440 of the 1248 patients (35%) were prescribed antibiotics, among whom 168 (38%) had negative results on GAS testing. Of 1200 patients with sinusitis and no other indication for antibiotic treatment who received an antibiotic, 454 (38%) had symptoms for 3 days or less prior to the outpatient visit, suggesting acute viral sinusitis not requiring antibiotics. Antibiotic overuse remains widespread in the treatment of outpatient ARIs, including among patients with laboratory-confirmed influenza, although study sites may not be representative of other outpatient settings. Identified targets for improved outpatient antibiotic stewardship include eliminating antibiotic treatment of viral upper respiratory tract infections and bronchitis and improving adherence to prescribing guidelines for pharyngitis and sinusitis. Increased access to sensitive and timely virus diagnostic tests, particularly for influenza, may reduce unnecessary antibiotic use for these syndromes.


COMPUTED TOMOGRAPHIC FEATURES OF INCISOR PSEUDO-ODONTOMAS IN PRAIRIE DOGS (CYNOMYS LUDOVICIANUS).
Maxillary incisor pseudo-odontomas are common in pet prairie dogs and can cause progressive respiratory obstruction, while mandibular pseudo-odontomas are rarely clinically significant. The aim of this retrospective cross-sectional study was to describe CT features of maxillary and mandibular incisor pseudo-odontomas vs. normal incisors in a group of pet prairie dogs. All pet prairie dogs with head CT scans acquired during the period of 2013-2015 were included. A veterinary radiologist who was aware of final diagnosis reviewed CT scans and recorded qualitative features of affected and normal incisors. Mean density values for the pulp cavity and palatal and buccal dentin were also recorded. A total of 16 prairie dogs were sampled (12 normal maxillary incisors, 20 confirmed maxillary incisor pseudo-odontomas, 20 normal mandibular incisors, 12 presumed mandibular incisor pseudo-odontomas). Maxillary incisors with confirmed pseudo-odontomas had a significantly hyperattenuating pulp and dentin in the reserve crown and apical zone, when compared to normal maxillary incisors. Pseudo-odontomas appeared as enlargements of the apical zone with a globular/multilobular hyperattenuating mass formation haphazardly arranged, encroaching on midline and growing caudally and ventrally. Presumed mandibular incisor pseudo-odontomas had similar CT characteristics. In 60% of prairie dogs with maxillary incisor pseudo-odontomas, the hard palate was deformed and the mass bulged into the oral cavity causing loss of the palatine bone. The common nasal meatus was partially or totally obliterated in 81.8% of prairie dogs with maxillary pseudo-odontomas. Findings supported the use of CT for characterizing extent of involvement and surgical planning in prairie dogs with pseudo-odontomas.


Key Components in eHealth Interventions Combining Self-Tracking and Persuasive eCoaching to Promote a Healthier Lifestyle: A Scoping Review.
The combination of self-tracking and persuasive eCoaching in automated interventions is a new and promising approach for healthy lifestyle management. The aim of this study was to identify key components of self-tracking and persuasive eCoaching in automated healthy lifestyle interventions that contribute to their effectiveness on health outcomes, usability, and adherence. A secondary aim was to identify the way in which these key components should be designed to contribute to improved health outcomes, usability, and adherence. The scoping review methodology proposed by Arskey and O'Malley was applied. Scopus, EMBASE, PsycINFO, and PubMed were searched for publications dated from January 1, 2013 to January 31, 2016 that included (1) self-tracking, (2) persuasive eCoaching, and (3) healthy lifestyle intervention. The search resulted in 32 publications, 17 of which provided results regarding the effect on health outcomes, 27 of which provided results regarding usability, and 13 of which provided results regarding adherence. Among the 32 publications, 27 described an intervention. The most commonly applied persuasive eCoaching components in the described interventions were personalization (n=24), suggestion (n=19), goal-setting (n=17), simulation (n=17), and reminders (n=15). As for self-tracking components, most interventions utilized an accelerometer to measure steps (n=11). Furthermore, the medium through which the user could access the intervention was usually a mobile phone (n=10). The following key components and their specific design seem to influence both health outcomes and usability in a positive way: reduction by setting short-term goals to eventually reach long-term goals, personalization of goals, praise messages, reminders to input self-tracking data into the technology, use of validity-tested devices, integration of self-tracking and persuasive eCoaching, and provision of face-to-face instructions during implementation. In addition, health outcomes or usability were not negatively affected when more effort was requested from participants to input data into the technology. The data extracted from the included publications provided limited ability to identify key components for adherence. However, one key component was identified for both usability and adherence, namely the provision of personalized content. This scoping review provides a first overview of the key components in automated healthy lifestyle interventions combining self-tracking and persuasive eCoaching that can be utilized during the development of such interventions. Future studies should focus on the identification of key components for effects on adherence, as adherence is a prerequisite for an intervention to be effective.


Cell Illustrator 4.0: a computational platform for systems biology.
Cell Illustrator is a software platform for Systems Biology that uses the concept of Petri net for modeling and simulating biopathways. It is intended for biological scientists working at bench. The latest version of Cell Illustrator 4.0 uses Java Web Start technology and is enhanced with new capabilities, including: automatic graph grid layout algorithms using ontology information; tools using Cell System Markup Language (CSML) 3.0 and Cell System Ontology 3.0; parameter search module; high-performance simulation module; CSML database management system; conversion from CSML model to programming languages (FORTRAN, C, C++, Java, Python and Perl); import from SBML, CellML, and BioPAX; and, export to SVG and HTML. Cell Illustrator employs an extension of hybrid Petri net in an object-oriented style so that biopathway models can include objects such as DNA sequence, molecular density, 3D localization information, transcription with frame-shift, translation with codon table, as well as biochemical reactions.


Pseudoprogression and peritumoral edema due to intratumoral necrosis after Gamma knife radiosurgery for meningioma.
Peritumoral cerebral edema is reported to be a side effect that can occur after stereotactic radiosurgery. We aimed to determine whether intratumoral necrosis (ITN) is a risk factor for peritumoral edema (PTE) when gamma knife radiosurgery (GKRS) is performed in patients with meningioma. In addition, we propose the concept of pseudoprogression: a temporary volume expansion that can occur after GKRS in the natural course of meningioma with ITN. This retrospective study included 127 patients who underwent GKRS for convexity meningioma between January 2019 and December 2020. Risk factors for PTE and ITN were investigated using logistic regression analysis. Analysis of variance was used to determine whether changes in tumor volume were statistically significant. After GKRS, ITN was observed in 34 (26.8%) patients, and PTE was observed in 10 (7.9%) patients. When postoperative ITN occurred after GKRS, the incidence of postoperative PTE was 18.970-fold (p = 0.009) greater. When a 70% dose volume ≥ 1 cc was used, the possibility of ITN was 5.892-fold (p < 0.001) higher. On average, meningiomas with ITN increased in volume by 128.5% at 6 months after GKRS and then decreased to 94.6% at 12 months. When performing GKRS in meningioma, a 70% dose volume ≥ 1 cc is a risk factor for ITN. At 6 months after GKRS, meningiomas with ITN may experience a transient volume expansion and PTE, which are characteristics of pseudoprogression. These characteristics typically improve at 12 months following GKRS.


Marketing of drugs for rare diseases is speeding up in China: Looking at the example of drugs for mucopolysaccharidosis.
In May 2019, China National Medical Products Administration approved the marketing of an elosulfase alfa injection (brand name: Vimizim) from BioMarin Pharmaceutical for the treatment of patients with mucopolysaccharidosis (MPS) type IVA. This is the first drug to treat MPS in China, and it has ended the "dearth of medicines" to treat MPS in China, a situation that has persisted for many years. One can reasonably say that the drug has benefited from the continuous reform of the drug review and approval system in China and the increasing attention paid to rare diseases. At present, China has implemented a series of preferential policies for the review and approval of drugs for rare diseases, mainly including priority review and approval, accelerated review and approval, special review and approval (mainly simplified review and approval), data protection, and communication. Moreover, China now has a specific reference for the review and approval of drugs for rare diseases with the creation of China's First List of Rare Diseases and the publication of two batches of the List of Overseas New Drugs Urgently Needed in Clinical Settings. Drug review and approval has been significantly accelerated, as has marketing. The two batches of lists of new drugs, issued in November 2018 and May 2019, include 43 drugs for rare diseases (58.1% of all drugs in the lists), 37 of which were included in China's First List of Rare Diseases. The lists also include three other drugs for MPS. As of July 1, 2019, four drugs for rare diseases from the first batch of new drugs have been approved for marketing. In order to further improve the review and approval of drugs for rare diseases in China, a special department should be established for the evaluation of drugs for rare diseases, research on and management of drugs in the post-approval phase should be enhanced, international cooperation in research on use of drugs to treat rare diseases should be enhanced, and the incentive policy for marketing drugs for rare diseases should be improved.


Safety and immunogenicity of subcutaneous H. influenzae vaccines in 15-17 month-old children.
To evaluate the safety and immunogenicity of subcutaneously administered PRP and PRP-D, one hundred and one healthy 15 to 17 month-old children were randomly assigned to receive two subcutaneous doses, 2 months apart, of either vaccine. The incidence of local and systemic reactions did not differ significantly between the two groups. PRP antibody levels in the pre-immunization sera of 95% of subjects were below the level associated with immediate protection from Hib disease (less than 0.15 microgram/ml). After the first dose, 32% of PRP and 70% of PRP-D (p less than 0.001) recipients achieved antibody levels of greater than or equal to 0.15 microgram/ml, and 8% and 26% (p = 0.003) respectively achieved levels greater than or equal to 1 microgram/ml, a level believed to predict long-term protection. After the second dose, antibody levels greater than or equal to 0.15 microgram/ml were reached in 38% of PRP and 88% of PRP-D (p less than 0.001) recipients and levels of greater than or equal to 1 microgram/ml were reached in 22% and 78% respectively (p less than 0.001). The geometric mean levels of PRP antibody after immunization were significantly higher in the PRP-D group after both the first and second doses (p less than 0.001). These results suggest that subcutaneous administration of both vaccines is safe, but PRP-D results in significantly higher antibody levels compared to PRP. The levels were lower than what has been reported following intramuscular administration.


Association between Backward Walking and Cognition in Parkinson Disease: A Systematic Review.
Backward walking often occurs in everyday life. It is more complex than forward walking and is associated with decreased coordination. However, it is unclear if a reduced backward walking performance is associated with impaired cognition. This could be particularly relevant as gait and cognitive deficits commonly occur in Parkinson's disease. The objective of this systematic review was to synthesize the evidence on the association between backward walking and cognition in persons with Parkinson's disease. The electronic databases PubMed and Web of Science were systematically searched, and the quality of eligible studies was assessed. Two studies met the inclusion criteria, but study protocols, investigated population, and outcome measures differed substantially. One study showed lower backward walking speed in patients with Parkinson's disease with poorer attention test performances. The second study showed a weak correlation between executive cognitive functions and backward walking speed. Given the low number of studies, the heterogenous study design, and the inconsistent results, the present review highlights the need to further investigate the association between backward walking and cognition in patients with Parkinson's disease.


Morphological description of Taenia saginata asiatica (Cyclophyllidea: Taeniidae) from man in Asia.
In order to clarify the taxonomic status of the Taenia saginata-like tapeworm in East Asia, the morphological characteristics of the adult and cysticercus of classical T. saginata (American, Swiss and Poland strains) and the Taiwan Taenia were compared in the present study. The morphologic characteristics of these two parasites are very similar. The protoscolex of cysticercus of the Taiwan Taenia has a sunken rostellum while that of classical T. saginata has only an apical pit. In addition, the rostellum of the Taiwan Taenia cysticercus is usually surrounded by two rows of rudimentary hooklets. However, this structure is rarely found in classical T. saginata. Based on the results of molecular studies and morphological characteristics, the T. saginata-like tapeworm in East Asia represents a subspecies of T. saginata, named T. saginata asiatica.


[Regulation of ion transport in mitochondria by respiratory chain enzymes and ATPase].
The effects of the respiratory chain inhibitors as well as those of the inhibitors and substrates of ATP-synthetase in Ca2+ and K+ transport induced in the mitochondria upon the medium acidification in the presence of phosphate or arsenate, were investigated. Evidence has been obtained suggesting that under the experimental conditions used the transmembrane fluxes of K+ and Ca2+ are paralleled with H+ leakage through the proton channel of ATPase. It was found also that the system inducing cation fluxes at low pH values included peroxidation and hydrolysis of phospholipids. A scheme of regulation of ion transport in the mitochondria involving oxidative phosphorylation and oxidation and hydrolysis of lipids is proposed.


Respiratory tissue-associated commensal bacteria offer therapeutic potential against pneumococcal colonization.
Under eubiotic conditions commensal microbes are known to provide a competitive barrier against invading bacterial pathogens in the intestinal tract, on the skin or on the vaginal mucosa. Here, we evaluate the role of lung microbiota in Pneumococcus colonization of the lungs. In eubiosis, the lungs of mice were dominantly colonized by Lactobacillus murinus. Differential analysis of 16S rRNA gene sequencing or L. murinus-specific qPCR of DNA from total organ homogenates vs.broncho alveolar lavages implicated tight association of these bacteria with the host tissue. Pure L. murinus conditioned culture medium inhibited growth and reduced the extension of pneumococcal chains. Growth inhibition in vitro was likely dependent on L. murinus-produced lactic acid, since pH neutralization of the conditioned medium aborted the antibacterial effect. Finally, we demonstrate that L. murinus provides a barrier against pneumococcal colonization in a respiratory dysbiosis model after an influenza A virus infection, when added therapeutically.


Isolation of a new soluble antigen from the yeast phase of Histoplasma capsulatum.
A method is described by which a soluble antigen was prepared from the yeast phase of Histoplasma capsulatum. This soluble preparation had a specificity greater than that of whole-cell yeast-phase antigens. In complement fixation tests with sera from human cases of histoplasmosis, blastomycosis, and coccidioidomycosis, the soluble antigen reacted in 12.1% of 141 tests with heterologous sera, whereas conventional whole-cell yeast antigens reacted in 47.3% of 91 tests with heterologous sera. The reactivities of the two types of antigens with homologous sera were essentially the same.


Transcatheter intraarterial perfusion: MR monitoring of chemoembolization for hepatocellular carcinoma--feasibility of initial clinical translation.
To prospectively test the hypothesis that intraprocedural transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging can be used to successfully measure reductions in perfusion to the targeted hepatocellular carcinoma (HCC) and the adjacent surrounding liver tissue during MR-interventional radiology (IR)-monitored transcatheter arterial chemoembolization (TACE). This HIPAA-compliant prospective study was approved by the institutional review board. An MR-IR unit was used to perform TACE in 10 patients with HCC (seven male, three female; eight younger than 69 years, two older than 69 years). Intraprocedural reductions in tumor perfusion before and after TACE were monitored with TRIP MR imaging. Time-signal intensity curves were derived, and semiquantitative spatially resolved area under the time-signal intensity curve maps of tumor perfusion before and after TACE were produced. Mean perfusion values before and after TACE for liver tumors and adjacent liver tissue were compared by using a mixed-model analysis, with alpha = .05. Perfusion reductions were measured successfully with TRIP MR imaging in 18 separate tumors during 13 treatment sessions. Perfusion maps showed significant perfusion reductions for tumors (P < .013) but not for adjacent nontumorous liver tissue (P = .21). For tumors, the mean perfusion value was 193 arbitrary units (AU) +/- 223 (standard deviation) before TACE and 45.3 AU +/- 91.9 after TACE, with a mean reduction in baseline perfusion of 74.6% +/- 24.8. For adjacent liver tissue, the mean perfusion value was 124 AU +/- 93.5 before TACE and 93.2 AU +/- 72.3 after TACE, with a mean reduction in baseline perfusion of 24.2% +/- 14.5. TRIP MR imaging can be used to detect intraprocedural changes in perfusion to HCC and surrounding liver parenchyma during MR-IR-monitored TACE.


The protective effects of the Lactarius deliciosus and Agrocybe cylindracea mushrooms on histopathology of carbon tetrachloride induced oxidative stress in rats.
We investigated the protective effects of L. deliciosus and A. cylindracea supplementation against carbon tetrachloride (CCI4) induced oxidative stress by measuring levels of adenosine deaminase (ADA) and myeloperoxidase (MPO), and by observing histopathological changes in liver and kidney tissues of rats. We divided 36 rats into six groups: control, CCl4, L. deliciosus, A. cylindracea, CCl4 + L. deliciosus, and CCl4 + A. cylindracea. We found that administration of CCI4, A. cylindracea, and CCl4 + A. cylindracea increased MPO and ADA levels. We observed severe hepato-renal degenerative and necrotic lesions in the CCI4, A. cylindracea and CCl4 + A. cylindracea groups. Severe lesions of the liver and kidney were not observed with A. cylindracea administration. CCI4 induced hepato-renal lesions were ameliorated by L. deliciosus extract supplementation. L. deliciosus could be an important dietary antioxidant for preventing histologic lesions in liver and kidney due to CCI4 induced oxidative stress in rats.


[Corneal melting after cross-linking and deep lamellar keratoplasty in a keratoconus patient].
We present the case of a 45-year-old patient with severe atopic disease and keratoconus who suffered from corneal melting following cross-linking and deep anterior lamellar keratoplasty (DALK) due to subclinical infection with Herpes simplex virus (HSV). Penetrating keratoplasty and intensive antiviral and immunosuppressive medical treatment were necessary to control the infection. The case demonstrates the difficulties in the treatment of keratoconus in patients with severe atopic disease.


Comparison of field-scale herbicide runoff and volatilization losses: an eight-year field investigation.
An 8-yr study was conducted to better understand factors influencing year-to-year variability in field-scale herbicide volatilization and surface runoff losses. The 21-ha research site is located at the USDA-ARS Beltsville Agricultural Research Center in Beltsville, MD. Site location, herbicide formulations, and agricultural management practices remained unchanged throughout the duration of the study. Metolachlor [2-chloro--(2-ethyl-6-methylphenyl)--(2-methoxy-1-methylethyl) acetamide] and atrazine [6-chloro--ethyl--(1-methylethyl)-1,3,5-triazine-2,4-diamine] were coapplied as a surface broadcast spray. Herbicide runoff was monitored from a month before application through harvest. A flux gradient technique was used to compute volatilization fluxes for the first 5 d after application using herbicide concentration profiles and turbulent fluxes of heat and water vapor as determined from eddy covariance measurements. Results demonstrated that volatilization losses for these two herbicides were significantly greater than runoff losses ( < 0.007), even though both have relatively low vapor pressures. The largest annual runoff loss for metolachlor never exceeded 2.5%, whereas atrazine runoff never exceeded 3% of that applied. On the other hand, herbicide cumulative volatilization losses after 5 d ranged from about 5 to 63% of that applied for metolachlor and about 2 to 12% of that applied for atrazine. Additionally, daytime herbicide volatilization losses were significantly greater than nighttime vapor losses ( < 0.05). This research confirmed that vapor losses for some commonly used herbicides frequently exceeds runoff losses and herbicide vapor losses on the same site and with the same management practices can vary significantly year to year depending on local environmental conditions.


Osteopontin induces multiple changes in gene expression that reflect the six "hallmarks of cancer" in a model of breast cancer progression.
Tumor progression is a multistep process, which enables cells to evolve from benign to malignant tumors. This progression has been suggested to depend on six essential characteristics identified as the "hallmarks of cancer," which include: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Osteopontin (OPN) is an integrin-binding protein that has been shown to be associated with the progression of several cancer types, and to play an important functional role in various aspects of malignancy, particularly tissue invasion and metastasis. Here we studied genes regulated by OPN in a model of human breast cancer using oligonucleotide microarray technology by comparing the gene-expression profiles of 21NT mammary carcinoma cells transfected to overexpress OPN versus mock-transfected control cells. From over 12,000 human genes, we identified 99 known human genes differentially regulated by OPN whose expression changed by at least 1.5-fold and showed statistically significant differences in mean expression levels between groups. Functional classification of these genes into the hallmarks of cancer categories showed that OPN can affect the expression of genes involved in all six categories in this model. Furthermore, we were able to validate the expression of 18/19 selected candidate genes by quantitative real-time PCR, further supporting our microarray findings. This study provides the first evidence that OPN can lead to numerous gene expression changes that influence multiple aspects of tumor progression and malignant growth.


Sexual Offending: Adverse Childhood Experiences, Shame, and Self-Compassion Explain the Variance in Self-Harm and Harm Towards Others?
Research investigating potential pathways from Adverse Childhood Experiences (ACEs) to later self-harming and offending behaviours has inconsistent findings. Past research, however, has not fully explored the interplay between ACEs and modifiable psychological factors, such as shame and self-compassion. The present study explored the relationship between ACE, shame, and self-compassion to identify their role in explaining the variance in later harm in a sample of individuals who have committed sexual offences. Two hundred and fifty adults incarcerated for sexual offences participated. Multiple Regression and Mediation Analyses were applied to establish if ACE, shame and self-compassion explained the variance in harm and explore potential psychological pathways between ACE and harm, with shame and self-compassion as potential modifiable mediators. ACE, shame and self-compassion explained 55% of self-harm and 52% of psychological and physical harm variance. A more complex relationship was indicated for sexual harm, with only 19% of the variance explained by the model. The study increases our understanding of the relationship between variables and potential modifiable pathways between ACEs and later harming behaviours in a sample of individuals with sexual convictions. These modifiable psychological factors could be targeted to increase resilience, post-traumatic growth and reduce the risk of harm in later life.


Effect of different finishing times on surface roughness and maintenance of polish in nanoparticle and microhybrid composite resins.
The objective of the study was to evaluate the effect of immediate polishing, after 24 h and after 1 week, on the surface roughness of two micro-hybrid resins (Esthet-X; Opallis) and one nanoparticle resin (Filtek Z350), as well as verifying maintenance of the polish after 1 year, simulated by means of thermal cycling. Forty-three specimens of each material were made and divided into a control group and three experimental groups. The control group specimens received no surface treatment. Group 1 received finishing with an extra-fine diamond drill and posterior polishing with the systems Enhance and PoGo, immediately after polymerization. Group 2 received the same procedures; however, these were carried out after 24 h of storage. Group 3 received the surface treatment after 7 days of storage. After that, the surface roughness was evaluated by a profilometer. After the initial reading, the specimens were submitted to thermal cycling for 10,000 cycles. After thermal cycling, a new roughness reading was taken. The results showed a higher roughness value for the resin Esthet-X, and the resins Opallis and Z350 presented the same roughness values. As regards the time when polishing was performed, specimens polished immediately after polymerization presented higher roughness values in comparison with the other two periods. After thermal cycling, the statistical analysis showed that the Opallis resin polish had been maintained, whereas for the other two resins, there was a significant reduction in surface smoothness. The surface roughness was influenced by the material and also by the period of polishing; the surface roughness of all tested materials were at a clinically acceptable level.


A glass of water immediately increases gastric pH in healthy subjects.
Onset of action of antisecretory agents is of pivotal importance for patients with gastroesophageal reflux disease (GERD) treated "on-demand." To study the acute effect of acid-inhibiting drugs and water administration on gastric pH. A cross-over study was performed in 12 H. pylori (-), healthy subjects (6 men; mean age: 26 years). A single oral dose of the following agents was received with a wash-out period between each study: a glass of water (200 ml), antacid, ranitidine, omeprazole, esomeprazole, and rabeprazole. Gastric pH was recorded for 6 h after drug intake. Water increased gastric pH >4 in 10/12 subjects after 1 min. The time (median) needed to pH >4 was for: antacid 2 min, ranitidine 50 min, omeprazole 171 min, esomeprazole 151 min, and rabeprazole 175 min. Gastric pH >4 lasted for 3 min after water and for 12 min after antacids; it remained >4 until the end of recording in: 4/12 subjects with ranitidine, 11/12 with rabeprazole, and all with omeprazole and esomeprazole. Water and antacid immediately increased gastric pH, while PPIs showed a delayed but prolonged effect compared to ranitidine.


Pesticide removal from container nursery runoff in constructed wetland cells.
The increased use of pesticides by container nurseries demands that practices for removal of these potential contaminants from runoff water be examined. Constructed wetlands may be designed to clean runoff water from agricultural production sites, including container nurseries. This study evaluated 14 constructed wetlands cells (1.2 by 4.9 m or 2.4 by 4.9 m, and 30 or 45 cm deep) that collected pesticide runoff from a 465-m2 gravel bed containerized nursery in Baxter, TN. One-half of the cells were vegetated with bulrush, Scirpus validus. The cells were loaded at three rates or flows of 0.240, 0.120, and 0.060 m3 d(-1). Herbicides-simazine (Princep) [2-chloro-4,6-bis(ethylamino)-s-triazine] and metolachlor (Pennant) [2-chloro-N-(2-ethyl-6-methylphenyl)-N-2-methoxy-1-methylethyl-acetamide] -were applied to the gravel portion of the container nursery at rates of 4.78 and 239 kg ha(-1), respectively, 9 July 1998, and at rates of 2.39 and 1.19 kg ha(-1), respectively, 17 May 1999. Pesticides entering the wetland and wetland cell water samples were analyzed daily to determine pesticide removal. At the slower flow rate, which corresponds to lower mass loading and greater hydraulic retention times (HRTs), a greater percentage of pesticides was removed. During the 2-yr period, cells with plants removed 82.4% metolachlor and 77.1% simazine compared with cells without plants, which removed 63.2% metolachlor and 64.3% simazine. At the lowest flow rate and mass loading, wetland cells removed 90.2% metolachlor and 83% simazine. Gravel subsurface flow constructed wetlands removed most of the pesticides in runoff water with the greatest removal occurring at lower flow rates in vegetated cells.


Facilitating skilled right hand motor function in older subjects by anodal polarization over the left primary motor cortex.
Healthy ageing is accompanied by limitations in performance of activities of daily living and personal independence. Recent reports demonstrated improvements in motor function induced by noninvasive anodal direct current stimulation (tDCS) of the primary motor cortex (M1) in young healthy adults. Here we tested the hypothesis that a single session of anodal tDCS over left M1 could facilitate performance of right upper extremity tasks required for activities of daily living (Jebsen-Taylor hand function test, JTT) in older subjects relative to Sham in a double-blind cross-over study design. We found (a) significant improvement in JTT function with tDCS relative to Sham that outlasted the stimulation period by at least 30 min, (b) that the older the subjects the more prominent this improvement appeared and (c) that consistent with previous results in younger subjects, these effects were not accompanied by any overt undesired side effect. We conclude that anodal tDCS applied over M1 can facilitate performance of skilled hand functions required for activities of daily living in older subjects.


Research methods priorities in geriatric palliative medicine.
Continuing the momentum of geriatric palliative medicine research achieved during the past decade requires a focus on research methods priorities that span the continuum of research from small pilot studies testing new interventions to large multisite studies evaluating implementation of proven interventions and models of care. Each phase of this continuum presents unique challenges for investigators who are designing, conducting, and reporting results of these scientific endeavors. The goal of this article is to describe the top priorities in research methods for the field of geriatric palliative medicine that will enable the field to rapidly respond to the changing landscape of health care policy and quality improvement initiatives.


Vascularity of myocardium and gastrocnemius muscle in rats selectively bred for endurance running capacity.
We tested the hypothesis that changes in the arteriolar branching architecture contributed to increased running capacity of rats subjected to two-way artificial selection for intrinsic aerobic endurance treadmill running capacity resulting in strains of low-capacity and high-capacity endurance rats. Hearts and gastrocnemius muscles were harvested from each strain, and the microvasculature's branching geometry measured from micro-CT images. The vascular branching geometry of the hearts and skeletal muscle from the high capacity was indistinguishable from low-capacity rats. Our hypothesis was not supported. Neither remodeling nor an increase in arteriolar microvasculature branching appears to play a role in the enhanced performance of the high capacity rats. We are led to speculate that endothelial tolerance for shear stress and/or increased coupling of myocardial muscle fiber metabolic-to-contractile function is increased in the high-capacity runner strain to the effect of allowing either higher flow rate per unit volume of muscle or more efficient use of oxygen and nutrients in the high-capacity endurance rats.


Evaluating an Alleged Mimic of the Monarch Butterfly: Neophasia (Lepidoptera: Pieridae) Butterflies are Palatable to Avian Predators.
Some taxa have adopted the strategy of mimicry to protect themselves from predation. Butterflies are some of the best representatives used to study mimicry, with the monarch butterfly, Danaus plexippus (Lepidoptera: Nymphalidae) a well-known model. We are the first to empirically investigate a proposed mimic of the monarch butterfly: Neophasia terlooii, the Mexican pine white butterfly (Lepidoptera: Pieridae). We used captive birds to assess the palatability of N. terlooii and its sister species, N. menapia, to determine the mimicry category that would best fit this system. The birds readily consumed both species of Neophasia and a palatable control species but refused to eat unpalatable butterflies such as D. plexippus and Heliconius charithonia (Lepidoptera: Nymphalidae). Given some evidence for mild unpalatability of Neophasia, we discuss the results considering modifications to classic mimicry theory, i.e., a palatability-based continuum between Batesian and Müllerian mimicry, with a quasi-Batesian intermediate. Understanding the ecology of Neophasia in light of contemporary and historical sympatry with D. plexippus could shed light on the biogeography of, evolution of, and predation pressure on the monarch butterfly, whose migration event has become a conservation priority.


Observing Power-Law Dynamics of Position-Velocity Correlation in Anomalous Diffusion.
In this Letter, we present a measurement of the phase-space density distribution (PSDD) of ultracold ^{87}Rb atoms performing 1D anomalous diffusion. The PSDD is imaged using a direct tomographic method based on Raman velocity selection. It reveals that the position-velocity correlation function C_{xv}(t) builds up on a time scale related to the initial conditions of the ensemble and then decays asymptotically as a power law. We show that the decay follows a simple scaling theory involving the power-law asymptotic dynamics of position and velocity. The generality of this scaling theory is confirmed using Monte Carlo simulations of two distinct models of anomalous diffusion.


Acute Respiratory Distress Syndrome in Burn Patients: A Comparison of the Berlin and American-European Definitions.
The purpose of this study was to compare the Berlin definition to the American-European Consensus Conference (AECC) definition in determining the prevalence of acute respiratory distress syndrome (ARDS) and associated mortality in the critically ill burn population. Consecutive patients admitted to our institution with burn injury that required mechanical ventilation for more than 24 hours were included for analysis. Included patients (N = 891) were classified by both definitions. The median age, % TBSA burn, and injury severity score (interquartile ranges) were 35 (24-51), 25 (11-45), and 18 (9-26), respectively. Inhalation injury was present in 35.5%. The prevalence of ARDS was 34% using the Berlin definition and 30.5% using the AECC definition (combined acute lung injury and ARDS), with associated mortality rates of 40.9 and 42.9%, respectively. Under the Berlin definition, mortality rose with increased ARDS severity (14.6% no ARDS; 16.7% mild; 44% moderate; and 59.7% severe, P < 0.001). By contrast, under the AECC definition increased mortality was seen only for ARDS category (14.7% no ARDS; 15.1% acute lung injury; and 46.0% ARDS, P < 0.001). The mortality of the 22 subjects meeting the AECC, but not the Berlin definition was not different from patients without ARDS (P = .91). The Berlin definition better stratifies ARDS in terms of severity and correctly excludes those with minimal disease previously captured by the AECC.


[Diagnostic imaging of the rotator cuff].
The importance of imaging modalities in the evaluation of the rotator cuff has increased thanks to the development of non-invasive methods. An optimum application of the technique, appreciation of the anatomical details and imaging pitfalls, and proper interpretation of clinical findings should be incorporated in order to increase diagnostic accuracy. Ultrasonography (US) and magnetic resonance imaging (MRI) are commonly used for rotator cuff pathologies. The former has a high diagnostic accuracy in full-thickness tears, but requires operator dependency and long-term training. Both US and MRI require sophisticated equipment and present difficulties in distinguishing between partial and small full-thickness tears. In full-thickness tears, MRI may be more appropriate if imaging findings are likely to alter the course of surgical treatment. However, it is not necessary in patients in whom US may clearly show tendinosis. Magnetic resonance imaging or MR arthrography may be required in order to evaluate partial tears or suspicious small full-thickness tears in patients unresponsive to conservative therapy. A close collaboration is essential between the radiologist and the shoulder surgeon in the interpretation of clinical findings. The diagnostic accuracy will increase if the examinations are performed by a musculoskeletal radiologist.


Data-driven cranial suture growth model enables predicting phenotypes of craniosynostosis.
We present the first data-driven pediatric model that explains cranial sutural growth in the pediatric population. We segmented the cranial bones in the neurocranium from the cross-sectional CT images of 2068 normative subjects (age 0-10 years), and we used a 2D manifold-based cranial representation to establish local anatomical correspondences between subjects guided by the location of the cranial sutures. We designed a diffeomorphic spatiotemporal model of cranial bone development as a function of local sutural growth rates, and we inferred its parameters statistically from our cross-sectional dataset. We used the constructed model to predict growth for 51 independent normative patients who had longitudinal images. Moreover, we used our model to simulate the phenotypes of single suture craniosynostosis, which we compared to the observations from 212 patients. We also evaluated the accuracy predicting personalized cranial growth for 10 patients with craniosynostosis who had pre-surgical longitudinal images. Unlike existing statistical and simulation methods, our model was inferred from real image observations, explains cranial bone expansion and displacement as a consequence of sutural growth and it can simulate craniosynostosis. This pediatric cranial suture growth model constitutes a necessary tool to study abnormal development in the presence of cranial suture pathology.


Clostridium difficile toxin A induces the release of neutrophil chemotactic factors from rat peritoneal macrophages: role of interleukin-1beta, tumor necrosis factor alpha, and leukotrienes.
Clostridium difficile produces a potent enterotoxin and cytotoxin, toxins A and B, respectively, which appear to be responsible for pseudomenbranous colitis and antibiotic-associated diarrhea. In the present study we explored the neutrophil migration evoked by toxin A in the peritoneal cavities and subcutaneous air pouches of rats and examined the role of macrophages and their inflammatory mediators in this process. Toxin A causes a significant dose-dependent neutrophil influx into the peritoneal cavity, with a maximal response at 0.1 microg/ml and at 4 h. The depletion of macrophages by peritoneal washing prevents the toxin A-induced neutrophil migration into the peritoneal cavity. In contrast, an increase in macrophages induced by peritoneal injection of thioglycolate amplifies this toxin effect on neutrophil migration. Furthermore, the injection of supernatants from toxin A-stimulated macrophages into the rat peritoneal cavity causes significant neutrophil migration. Pretreatment of rats with BWA4C, nordihydroguaiaretic acid, mepacrine, or dexamethasone inhibits the neutrophil migration evoked by toxin A in the peritoneal cavities. However, pretreatment with the cyclooxygenase inhibitor indomethacin or the platelet-activating factor antagonist BN52021 fails to alter toxin A-induced neutrophil migration. Toxin A was also injected into air pouches of normal rats or rats pretreated with anti-interleukin-1beta (anti-IL-1beta) or anti-tumor necrosis factor alpha (anti-TNF-alpha) antibodies. Anti-TNF-alpha or anti-IL-1beta antibodies significantly reduce the neutrophil migration induced by toxin A. These data suggest that neutrophil migration evoked by toxin A is in part dependent on macrophage-derived cytokines, such as TNF-alpha and IL-1beta, and leukotrienes. These mediators may help to explain the intense inflammatory colitis caused by C. dificile toxin A in an experimental animal model of this disease.


Absolute Differential Cross-Sections for Elastic Electron Scattering from Sevoflurane Molecule in the Energy Range from 50-300 eV.
We report the results of the measurements and calculations of the absolute differential elastic electron scattering cross-sections (DCSs) from sevoflurane molecule (C4H3F7O). The experimental absolute DCSs for elastic electron scattering were obtained for the incident electron energies from 50 eV to 300 eV, and for scattering angles from 25° to 125° using a crossed electron/target beams setup and the relative flow technique for calibration to the absolute scale. For the calculations, we have used the IAM-SCAR+I method (independent atom model (IAM) applying the screened additivity rule (SCAR) with interference terms included (I)). The molecular cross-sections were obtained from the atomic data by using the SCAR procedure, incorporating interference term corrections, by summing all the relevant atomic amplitudes, including the phase coefficients. In this approach, we obtain the molecular differential scattering cross-section (DCS), which, integrated over the scattered electron angular range, gives the integral scattering cross-section (ICS). Calculated cross-sections agree very well with experimental results, in the whole energy and angular range.


Repair integrity and functional outcome after arthroscopic rotator cuff repair: double-row versus suture-bridge technique.
Only a few studies have examined repair integrity and functional outcome after arthroscopic suture-bridge rotator cuff repair procedure. In addition, no reported study has compared outcomes between the suture-bridge and double-row techniques. This study compared the functional outcome and repair integrity of arthroscopic double-row and conventional suture-bridge repair in full-thickness rotator cuff tears. Cohort study; Level of evidence, 2. Fifty-two consecutive full-thickness rotator cuff tears with 1 to 4 cm of anterior to posterior dimension that underwent arthroscopic rotator cuff repair were included. A double-row technique was used in the first 26 consecutive shoulders, and a conventional suture-bridge technique was used in the next 26 consecutive shoulders. Fifty shoulders (92.5%) underwent magnetic resonance imaging or ultrasonography postoperatively. Clinical outcomes were evaluated a minimum 2 years (mean, 37.2 months; range, 24-54) postoperatively using the University of California at Los Angeles (UCLA), American Shoulder and Elbow Surgeons (ASES), and Constant scores. The postoperative cuff integrity was evaluated a mean of 33.0 (range, 10-54) months postoperatively. At the final follow-up, the average UCLA, ASES, and Constant scores improved significantly, to 32.3, 90.5, and 80.7, respectively, in the double-row group and to 30.6, 88.5, and 74.0, respectively, in the suture-bridge group. The UCLA, ASES, and Constant scores improved in both groups postoperatively (all P < .001); however, there was no significant difference between the 2 groups at final follow-up (P = .185, .585, and .053, respectively). The retear rate was 24% in the shoulders that underwent double-row repair and 20% in the shoulders that underwent suture-bridge repair; this difference was not statistically significant (P = .733). The arthroscopic conventional suture-bridge technique resulted in comparable patient satisfaction, functional outcome, and rates of retear compared with the arthroscopic double-row technique in full-thickness rotator cuff tears.


Immunocompromise syndrome in homosexual men. Prevalence of possible risk factors and screening for the prodrome using an accurate white cell count.
The immunocompromise syndrome in homosexual men in the USA is thought to be associated with cytomegalovirus (CMV) infection and nitrite intake. Such men often have a lymphopenia. In a clinic in London 76% of 46 unselected homosexual men and 50% of 76 heterosexual controls had serum CMV IgG antibody at a titre of 1/16 or more (p less than 0.01). No case of excretion of CMV in the urine was found. Thirty per cent of the homosexual men admitted to using nitrites. These figures suggest that this population of homosexual men uses nitrites less often than their counterparts in the USA and is less likely to have evidence of active or past CMV infection. In addition, these male homosexual patients seem to be less promiscuous than those reported from the USA. Mean accurate total and differential white blood cell counts, using the Haemalog D automatic white cell counter, were no different in homosexual men (and various at risk subgroups of them) than heterosexuals, suggesting that the prodrome to the immunocompromise syndrome was not present in the London clinic population.


Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. The Multicenter Study Group.
A total of 334 HIV-infected patients with oral candidiasis were randomly assigned to receive 14 days of treatment with either 100 mg of oral fluconazole once daily or 10 mg clotrimazole five times daily. Both treatments were clinically effective: 98% of evaluable fluconazole-treated patients and 94% of evaluable clotrimazole-treated patients were cured or showed improvement (p = NS). Fluconazole was more effective than clotrimazole in eradicating Candida from the oral flora by the end of therapy (65% versus 48%) (p = 0.005). In addition, patients in the fluconazole-treated group were more likely to remain asymptomatic through the second week of follow-up (82.3% versus 50.0%) (p < 0.001). This difference was no longer evident by the post-therapy visit during week 4. Seven patients treated with clotrimazole and two patients treated with fluconazole discontinued therapy because of side effects. Two patients in the fluconazole group were withdrawn from therapy because of elevated serum glutamic-oxaloacetic transaminase levels, one considered possibly related to drug therapy. Fluconazole was as effective as clotrimazole in the treatment of oral candidiasis and temporarily provided a more prolonged disease-free state. Future studies are needed to define the optimal regimen for both the treatment and prevention of recurrent oral candidiasis in HIV-infected patients, addressing special attention to the issue of compliance, cost, and emergence of resistance.


Blood pressure, edema and proteinuria in pregnancy. 4. Blood pressure relationships.
The significance of these and related data will be discussed in greater detail during the subsequent course of this workshop. For now, we can sum up our findings with the following general statements concerning this analysis: 1. Blood pressure elevation occuring alone during the course of pregnancy, in the absence of edema and/or proteinuria, affects perinatal survival adversely. 2. This relationship is most marked among nulliparas in the age range 20-34 years and is less pronounced, but still evident, in young nulliparas and in multiparas of comparable age. 3. The effect is greater among black patients than among white patients in the median-aged nulliparas and multiparas, but this difference is not mirrored in the young nulliparas studied. 4. Blood pressure elevations during weeks 20-28 of pregnancy result in much higher subsequent perinatal losses in white nulliparas (both median and young age groups) than comparable elevations earlier or later in pregnancy. 5. Among black nulliparas of median age, maximal blood pressure effect on outcome is encountered at the sixteenth week (the earliest available data), with continuing significant increases until the twenty-eighth week, and there is another increment at term. In younger black patients, the results from 20 through 28 weeks parallel those seen in white patients, but with an additional peak at term. 6. among multiparas, maximal effect occurs at 24-28 weeks in both black and white groups. 7. The critical blood pressure levels are significantly lower in early pregnancy than in late pregnancy. 8. Critical levels of blood pressure with advancing pregnancy appear to parallel the trend in mean blood pressures determined to exist for this series. 9. Utilizing blood pressure distribution data to set limits statistically, we find very meaningful increments in perinatal mortality rates for nulliparas presenting blood pressure elevations beyond the 95 percentile point. This holds also for diastolic or systolic levels when these are examined independently because neither alone yielded more convincing data than blood pressure combinations condidered together.


Operational critical care. Intensive care and trauma.
Trauma management involves good prehospital, emergency, surgical, anaesthetic and intensive care decision-making. Optimal outcome depends on keeping abreast of the latest thinking in an ever-changing and increasingly technology-rich environment. The intensive care unit needs to represented as early as possible in the damage-control resuscitation phase. Improved trauma system care has resulted in an increasing number of multiply injured military patients surviving their initial trauma. These patients require intensive care and are at risk from sepsis and multiple organ failure. Attention to detail is important, preservation of organ function, infection control and nutrition to maintain muscle strength allowing normal metabolic function to return. Multiply injured patients often require lengthy periods of mechanical ventilation and a variety of therapeutic interventions may have to be considered during management of the disease process. As we are now seeing more survivors in the military trauma system the focus now needs to be morbidity reduction in order for these survivors to be best prepared for their rehabilitation phase of care.


Prehospital lactate improves accuracy of prehospital criteria for designating trauma activation level.
Trauma activation level is determined by prehospital criteria. The American College of Surgeons (ACS) recommends trauma activation criteria; however, their accuracy may be limited. Prehospital lactate has shown promise in predicting trauma center resource requirements. Our objective was to investigate the added value of incorporating prehospital lactate in an algorithm to designate trauma activation level. Air medical trauma patients undergoing prehospital lactate measurement were included. Algorithms using ACS activation criteria (ACS) and ACS activation criteria plus prehospital lactate (ACS+LAC) to designate trauma activation level were compared. Test characteristics and net reclassification improvement (NRI), which evaluates reclassification of patients among risk categories with additional predictive variables, were calculated. Algorithms were compared to predict trauma center need defined as more than 1 unit of blood in the emergency department; spinal cord injury; advanced airway; thoracotomy or pericardiocentesis; ICP monitoring; emergent operative or interventional radiology procedure; or death. There were 6,347 patients included. Twenty-eight percent had trauma center need. The ACS+LAC algorithm upgraded 256 patients and downgraded 548 patients compared to the ACS algorithm. The ACS+LAC algorithm versus ACS algorithm had an NRI of 0.058 (95% confidence interval [CI], 0.044-0.071; p < 0.01), with an event NRI of -0.5% and nonevent NRI of 6.2%. When weighted to favor changes in undertriage, the ACS+LAC still had a favorable overall reclassification (weighted NRI, 0.041; 95% CI, 0.028-0.054; p = 0.01). The ACS+LAC algorithm increased positive predictive value, negative predictive value, and accuracy. Over-triage was reduced 7.2%, while undertriage only increased 0.7%. The area under the curve was significantly higher for the ACS+LAC algorithm (0.79 vs. 0.76; p < 0.01). The ACS+LAC algorithm reclassified patients to more appropriate levels of trauma activation compared to the ACS algorithm. This overall benefit is achieved by significant reduction in overtriage relative to very small increase in undertriage. In the context of trauma team activation, this trade-off may be acceptable, especially in the current health care environment. Therapeutic/care management study, level III; prognostic/epidemiologic study, level III.


[Mediated short-term influence of alternating magnetic field on the epileptic brain].
The changes of bioelectric activity of the brain hemispheres were studied under the influence of an alternating magnetic field (AMF), directed on the hand of 20 epileptic patients and 18 healthy normals. Under AMF influence there was intensification of epileptic activity--elevation of the focal bioelectric characteristics and of the processes of generalization. It permitted to apply AMF for diagnosis of epileptic focus. Under AMF influence more stable changes in posterio-parietal areas of the right hemisphere occur. The authors came to the conclusion that AMF effects were mainly realized with participation of right hemisphere.


Impact of ferromanganese alloy plants on household dust manganese levels: implications for childhood exposure.
Adolescents living in communities with ferromanganese alloy plant activity have been shown to exhibit deficits in olfactory and fine motor function. Household dust may serve as an important manganese (Mn) exposure pathway to children, though dust Mn concentrations have not previously been measured to assess household contamination from ferromanganese alloy plant emissions. Here we determined the association between dust concentrations and surface loadings of Mn and other metals (Al, Cd, Cr, Cu, Fe, Pb, and Zn) in indoor and outdoor household dust from three Italian communities that differ by history of ferromanganese alloy plant activity: Bagnolo Mella, with an active ferromanganese alloy plant (n=178 households); Valcamonica, with historically active plants (n=166); and Garda Lake, with no history of ferromanganese plant activity (n=99). We also evaluated Mn levels in other environmental (soil, airborne particulates) and candidate biomarker (blood, hair, saliva, fingernails) samples from children within the households. Household dust Mn concentrations and surface loadings were significantly different between the three sites, with levels highest in Bagnolo Mella (outdoor median Mn concentration=4620, range 487-183,000µg/g), intermediate in Valcamonica (median=876, range 407-8240µg/g), and lowest in Garda Lake (median=407, range 258-7240µg/g). Outdoor dust Mn concentrations in Bagnolo Mella, but not the other communities, were significantly inversely related with distance from the plant (R(2)=0.6630, P<0.0001). Moreover, outdoor dust Mn concentrations and loadings were highly predictive of but significantly higher than indoor dust Mn concentrations and loadings by ~2 to ~7-fold (Mn concentrations) and ~7 to ~20-fold (Mn loadings). Finally, both indoor and outdoor dust Mn concentrations and outdoor dust Mn loading values were highly significantly correlated with both soil and air Mn concentrations, and with children's hair and fingernail Mn concentrations, but weakly or not associated with saliva or blood Mn levels. Given the evidence associating elevated Mn exposure with neurological impairments in children, these data support that dust Mn levels should be reduced in contaminated environments to protect the health of resident children.


Anaesthetic considerations in exomphalos repair: a report of 2 cases.
The anaesthetic management of two neonates with exomphalos associated syndromes for surgical repair are described. The technical advancements in the surgical and anaesthetic management of these neonates which have resulted in reduction in morbidity and mortality are discussed. The high incidence of associated anomalies and the problems they pose to the anaesthetist in addition to the usual challenges of neonatal anaesthesia are highlighted.


Serum angiotensin-converting enzyme is elevated in association with underground coal mining.
Serum angiotensin-converting enzyme activity (SACE) and lysozyme activity were measured in a group of 40 underground coal miners and two control groups, 20 subjects with sarcoidosis and 15 normal non-dust-exposed volunteers. The miners were grouped first according to whether they had recent exposure (still actively mining or retired three years or less prior to measurement) or temporally more distant exposure (retired more than three years prior to measurement). Secondly, they were grouped as to whether or not they had coal workers' pneumoconiosis (CWP). The subjects with sarcoidosis were grouped according to disease activity. As expected, the subjects with active sarcoidosis had elevated SACE activity compared with normal subjects. The coal miners as a group did not have elevation of their SACE activity. However, the coal miners with recent exposure had elevated SACE activity (57.1 +/- 3.9 U/ml) compared with normal controls (43.8 +/- 1.5 U/ml, p = 0.007). The SACE activity in miners without recent exposure was not elevated (39.8 +/- 1.3 U/ml) compared with the normal controls. No increase in SACE activity was found when the miners were grouped according to the presence or absence of CWP. In contrast, the miners' serum lysozyme activity was not elevated. Since alveolar macrophages are a potential source of SACE, elevation of SACE activity in underground coal miners may reflect alveolar macrophage activation caused by increased pulmonary mixed coal mine dust burden. Furthermore, since both SACE and serum lysozyme are elevated in association with silicosis, these findings may confirm that the macrophage responses to inhaled silica and coal dust differ.


VEGF and angiopoietins promote inflammatory cell recruitment and mature blood vessel formation in murine sponge/Matrigel model.
A key feature in the induction of pathological angiogenesis is that inflammation precedes and accompanies the formation of neovessels as evidenced by increased vascular permeability and the recruitment of inflammatory cells. Previously, we and other groups have shown that selected growth factors, namely vascular endothelial growth factor (VEGF) and angiopoietins (Ang1 and Ang2) do not only promote angiogenesis, but can also induce inflammatory response. Herein, given a pro-inflammatory environment, we addressed the individual capacity of VEGF and angiopoietins to promote the formation of mature neovessels and to identify the different types of inflammatory cells accompanying the angiogenic process over time. Sterilized polyvinyl alcohol (PVA) sponges soaked in growth factor-depleted Matrigel mixed with PBS, VEGF, Ang1, or Ang2 (200 ng/200 µl) were subcutaneously inserted into anesthetized mice. Sponges were removed at day 4, 7, 14, or 21 post-procedure for histological, immunohistological (IHC), and flow cytometry analyses. As compared to PBS-treated sponges, the three growth factors promoted the recruitment of inflammatory cells, mainly neutrophils and macrophages, and to a lesser extent, T- and B-cells. In addition, they were more potent and more rapid in the recruitment of endothelial cells (ECs) and in the formation and maturation (ensheating of smooth muscle cells around ECs) of neovessels. Thus, the autocrine/paracrine interaction among the different inflammatory cells in combination with VEGF, Ang1, or Ang2 provides a suitable microenvironment for the formation and maturation of blood vessels.


Soluble urokinase plasminogen activator receptor--a valuable biomarker in systemic lupus erythematosus?
Systemic lupus erythematosus (SLE) is a potentially severe autoimmune condition with an unpredictable disease course, often with fluctuations in disease activity over time. Long term inflammation and drug-related side-effects may subsequently lead to permanent organ damage, a consequence which is intimately connected to decreased quality of life and mortality. New lupus biomarkers that convey information regarding inflammation and/or organ damage are thus warranted. Today, there is no clinical biomarker that indicates the risk of damage accrual. Herein we highlight the urokinase plasminogen activator receptor (uPAR) and especially its soluble form (suPAR) that besides having biological functions in e.g. proteolysis, cell migration and tissue homeostasis, recently has emerged as a promising biomarker of inflammation and prognosis of several disorders. A strong association between suPAR and organ damage in SLE was recently demonstrated, and preliminary data (presented in this review) suggests the possibility of a predictive value of suPAR blood levels. The involvement of suPAR in the pathogenesis of SLE remains obscure, but its effects in leukocyte recruitment, phagocytic uptake of dying cells (efferocytosis) and complement regulation suggests that the central parts of the SLE pathogenesis could be regulated by suPAR, and vice versa.


Waning Humoral Response 3 to 6 Months after Vaccination with the SARS-COV-2 BNT162b2 mRNA Vaccine in Dialysis Patients.
The short-term reported antibody response to SARS-COV-2 vaccination in dialysis patients is high, with a seroconversion response rate up to 97%. Data on the long-term durability of this response are scarce. Our objective was to characterize the long-term anti-spike antibody level in dialysis patients. In an observational study, we measured SARS-COV-2 anti-spike antibody levels in dialysis patients who completed 2 doses of the BNT162b2 mRNA SAR S-COV-2 vaccine at 1, 3 and 6 months after the second vaccine dose. We compared the response to dialysis patients who were infected with COVD-19 and to a control group of healthcare-employees. One hundred and forty-two dialysis patients who had been vaccinated (ages 64 ± 11.9 years, 61% male), 33 dialysis patients who had COVID-19 infection (ages 54 ± 14.3 years, 55% male) and 104 individuals in the control group (ages 50 ± 12.2 years, 44% male) were included. The response rate in the vaccinated dialysis patients was 94%, 78% and 73% at 1, 3 and 6 months after the second vaccine dose. In the COVID-19 infected dialysis group and in the control group, the response rate remained at 100% over 6 months. The percentage of change in antibody levels between one and 6 months was -66% in the vaccinated dialysis group, -28% in the control group (p < 0.001) and +48% in dialysis patients who had been infected with COVID-19 (p < 0.001). A non-responder status at 6 months was associated with a lower albumin level. No serious adverse events following vaccination were reported. In conclusion: the initially high response rate to the BNT162b2 vaccine in dialysis patients decreases rapidly. Our results indicate that an early booster (3rd) dose, at three months after the second dose, may be advised for this population to preserve the humoral immunity.


BMP7 Signaling in TGFBR2-Deficient Stromal Cells Provokes Epithelial Carcinogenesis.
Deregulated transforming growth factor-β (TGFβ) signaling is a common feature of many epithelial cancers. Deletion of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling cross-talk with the forestomach epithelium. Here, concurrent loss in TGFBR2 and SMAD4 completely abrogates the development of forestomach cancer. Bone morphogenic protein-7 (BMP7) was highly upregulated in forestomach cancer tissue, activating Smad1/5/8 signaling, cell proliferation, and HGF production in TGFBR2-deficient FSP1+ fibroblasts. This stimulation by BMP7 was lost in the combined TGFBR2 and SMAD4 double knockout fibroblasts, which included a profound decrease in HGF expression. Thus, Smad4-mediated signaling is required to initiate epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts.Implications: These findings reveal a complex cross-talk between epithelial cells and the stroma, wherein Smad4 is required to elicit squamous cell carcinomas in the forestomach of mice with TGFBR2-deficient stromal cells. Mol Cancer Res; 16(10); 1568-78. ©2018 AACR.


Interference of coronavirus infection by expression of immunoglobulin G (IgG) or IgA virus-neutralizing antibodies.
Immunoglobulin gene fragments encoding the variable modules of the heavy and light chains of a transmissible gastroenteritis coronavirus (TGEV)-neutralizing monoclonal antibody (MAb) have been cloned and sequenced. The selected MAb recognizes a highly conserved viral epitope and does not lead to the selection of neutralization escape mutants. The sequences of MAb 6A.C3 kappa and gamma 1 modules were identified as subgroup V and subgroup IIIC, respectively. The chimeric immunoglobulin genes encoding the variable modules from the murine MAb and constant modules of human gamma 1 and kappa chains were constructed by reverse transcriptase PCR. Chimeric immunoglobulins were stably or transiently expressed in murine myelomas or COS cells, respectively. The secreted recombinant antibodies had radioimmunoassay titers (i.e., the highest dilution giving a threefold increase over the background) higher than 10(3) and reduced the infectious virus more than 10(4)-fold. Recombinant dimeric immunoglobulin A (IgA) showed a 50-fold enhanced neutralization of TGEV relative to a recombinant monomeric IgG1 which contained the identical antigen binding site. Stably transformed epithelial cell lines which expressed either recombinant IgG or IgA TGEV-neutralizing antibodies reduced virus production by > 10(5)-fold after infection with homologous virus, although a residual level of virus production (< 10(2) PFU/ml) remained in less than 0.1% of the cells. This low-level persistent infection was shown not to be due to the selection of neutralization escape mutants. The implications of these findings for somatic gene therapy with recombinant antibodies are discussed.


Increased t-PA yields using ultrafiltration of an inhibitory product from CHO fed-batch culture.
Fed-batch operation for the production of t-PA using Chinese Hamster Ovary (CHO) cells was optimized using serial and parallel experimentation. The feed, an isotonic concentrate, was improved to obtain 2- to 2.5-fold increases in integrated viable cell days versus batch. With a low glucose inoculum train, the viability index was further increased up to 4.5-fold. Hydrolysates were substituted for the amino acid portion of the concentrate with no significant change in fed-batch results. The concentrate addition rate was based on a constant 4 pmol/cell.day glucose uptake rate that maintained a relatively constant glucose concentration (approximately 3 mM). Increased viable cell indices did not lead to concomitant increases in t-PA concentrations compared to batch. The fed-batch concentrate and feeding strategy were shown to be effective in hybridoma culture, where a 4-fold increase in viable cell index yielded a 4-fold increase in antibody concentration. The half-life of t-PA decreased from 43 to 15 days with decreasing cell viability (from 92% to 71%), but this was not sufficient to explain the apparent t-PA threshold. Instead, the CHO results were explained by a reduction in t-PA production at higher extracellular t-PA concentrations that limited the fed-batch maximum at 35 mg/L for the cell line investigated. Analysis of both the total and t-PA mRNA levels revealed no response to increasing extracellular t-PA concentrations upon exogenous additions. Instead, intracellular t-PA levels were increased, revealing a possible secretory pathway limitation. A new reactor configuration was developed using an acoustic filter to retain the cells in the reactor while an ultrafiltration module stripped t-PA from the clarified medium before the permeate was returned to the reactor. By adding this harvesting step, the t-PA fed-batch production was increased over 2-fold, up to a yield of 80 mg/L.


Relative temporal leading or following position of the contralateral limb generates different aftereffects in muscle phasing following adaptation training post-stroke.
Locomotor coordination depends on precise and appropriate adjustments of intra- and interlimb muscle activity phasing. Muscle coordination deficits, in the form of inappropriately phased muscle activity patterns, are well recognized in both the paretic and non-paretic limbs of stroke survivors. Our recent work demonstrated that muscle phasing can be systematically influenced by changing the relative angular positions of limbs in both neurologically intact individuals and people post-stroke. However, it is still unknown whether the observed transient changes in adjusted muscle phasing can be adapted following a short-bout of training on the split-crank ergometer. To explore the extent to which the non-paretic and paretic limbs of people with stroke can adapt to new muscle activity phasing changes, we examined the adaptation of muscle phasing following a short-bout of pedaling training at two specific relative spatial angular positions of limbs that had caused the greatest phasing changes in our previous studies. Twelve individuals with post-cerebral stroke and twelve age- and gender-matched control subjects participated in this study. We demonstrated that both intact and cerebrally impaired nervous systems are capable of adapting new muscle phasing patterns and producing aftereffects that persisted for at least 10 min. However, we observed a completely different trend of aftereffects in post-stroke subjects compared with controls. Specifically, in controls, the aftereffects were observed only in the leg that was in the following position during the adaptation training whereas in post-stroke subjects, aftereffects were observed only in the leg that acted as the leading leg during adaptation, regardless of the limb being paretic or non-paretic. These findings suggest that adapting a new muscle activity pattern during a bilateral locomotor task depends mainly on the relative temporal position of contralateral limb.


Dispatcher-assisted bystander cardiopulmonary resuscitation in a metropolitan city: a before-after population-based study.
The goal of this study was to determine the effects of dispatcher-assisted bystander cardiopulmonary resuscitation (DA-CPR) on outcomes of out-of-hospital cardiac arrest (OHCA). All EMS in a metropolitan city with a population of 10 million are dispatched by a single, centralized, and physician-supervised center. Data on patients with adult OHCA with cardiac etiology were collected from the dispatch center registry and from EMS run sheets and hospital medical record review from 2009 to 2011. A standardized DA-CPR protocol (aligned with the 2010 AHA guidelines) we implemented as an intervention in January 2011. The end points were survival to discharge, good neurological outcome, and bystander CPR rate. Multivariate logistic analysis was used to compare between intervention group (2011) and historical control group (2009-2010). Of 8.144 eligible patients, bystander CPR was performed for the patients in 5.7% (148/2600) of cases in 2009, 6.7% (190/2857) in 2010, and 12.4% (334/2686) in 2011 (p<0.001). The survival to discharge rates was 7.1% (2009), 7.1% (2010), and 9.4% (2011) (p=0.001). Good neurological outcomes occurred in 2.1% (2009), 2.0% (2010), and 3.6% (2011) of cases (p<0.001). The adjusted ORs (95% CIs) for survival to discharge compared with 2009 were 1.33 (1.07-1.66) in 2011 and 1.12 (0.89-1.41) in 2010. The adjusted ORs (95% CIs) for good neurological outcomes were 1.67 (1.13-2.45) in 2011 and 1.13 (0.74-1.72) in 2010. An EMS intervention using the DA-CPR protocol was associated with a significant increase in bystander CPR and an improved survival and neurologic outcome after OHCA.