Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A.
Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3beta phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3beta have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.


Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice.
Although Hedgehog (Hh) signaling regulates cell differentiation during pancreas organogenesis, the consequences of pathway up-regulation in adult β-cells in vivo have not been investigated. Here, we elevate Hh signaling in β-cells by expressing an active version of the GLI2 transcription factor, a mediator of the Hh pathway, in β-cells that are also devoid of primary cilia, a critical regulator of Hh activity. We show that increased Hh signaling leads to impaired β-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice. This phenotype was accompanied by reduced expression of both genes critical for β-cell function and transcription factors associated with their mature phenotype. Increased Hh signaling further correlated with increased expression of the precursor cell markers Hes1 and Sox9, both direct Hh targets that are normally excluded from β-cells. Over time, the majority of β-cells down-regulated GLI2 levels, thereby regaining the full differentiation state and restoring normoglycemia in transgenic mice. However, sustained high Hh levels in some insulin-producing cells further eroded the β-cell identity and eventually led to the development of undifferentiated pancreatic tumors. Summarily, our results indicate that deregulation of the Hh pathway impairs β-cell function by interfering with the mature β-cell differentiation state.


Disease state prediction for 2019 novel coronavirus (COVID-19) pneumonia using CT manifestations and body temperature dynamic analysis: A SQUIRE-compliant study.
2019 Novel Coronavirus (COVID-19) is a new acute infectious disease of respiratory system, posed a great threat to human health because of its strong infectivity and rapid progress. This study aimed to assess the severity of COVID-19 Pneumonia by analyzing the change of CT manifestations and body temperature.This retrospective review included 22 patients with COVID-19 pneumonia. The imaging manifestations and clinical features were observed and evaluated.Most of the infected patients were men (13/22, 59%). Fever (>38°C) (17/22, 77%) and cough (6/22, 27%) were the main symptoms. Leukocytes count decreased in 23% of patients and lymphocyte decreased in 41%. Twenty-one patients with pneumonia had abnormal findings on chest CT. The special CT manifestations were observed at the first CT examination when the lesions progressed, including a single ground glass nodule with uneven density, multiple ground glass opacities distributed in subpleural, and the ground glass opacities confined in superior lobe. The special CT manifestations were observed at the first CT examination when the lesions resolved, including ground glass opacities with homogeneous density. The lesion involved in the bilateral lungs and the absorption of the lesions mainly occurred in bilateral inferior lobes. Three patients had normalized body temperature increased more than 1°C within 1 to 2 days after admission. Ten patients fluctuated more than 1°C within 1 to 7 days after admission and the second CT scans showed the disease was at the progressive stage.Dynamic analysis of CT manifestations and body temperature have the potential to predict the severity of COVID-19 pneumonia.


Mouse muscle epsilon- and gamma-containing acetylcholine receptors expressed in Xenopus laevis oocytes do not differ in their degradation half-lives.
Mouse acetylcholine receptors (AChRs) consisting of either the embryonic form (2 alpha, 1 beta, 1 delta and 1 gamma) or the adult form (2 alpha, 1 beta, 1 delta and 1 epsilon) were expressed in Xenopus laevis oocytes. As expected, the single channel conductance was approximately 52 pS and the exponential decay time constants were 2.2 and 8.2 ms for the gamma-AChR and respectively 65 pS and 0.6 and 2.8 ms for the epsilon-AChR. No difference was seen in the degradation rate between the gamma- and epsilon-containing AChRs, both having a half-life of about 5 days.


Support vector regression scoring of receptor-ligand complexes for rank-ordering and virtual screening of chemical libraries.
The community structure-activity resource (CSAR) data sets are used to develop and test a support vector machine-based scoring function in regression mode (SVR). Two scoring functions (SVR-KB and SVR-EP) are derived with the objective of reproducing the trend of the experimental binding affinities provided within the two CSAR data sets. The features used to train SVR-KB are knowledge-based pairwise potentials, while SVR-EP is based on physicochemical properties. SVR-KB and SVR-EP were compared to seven other widely used scoring functions, including Glide, X-score, GoldScore, ChemScore, Vina, Dock, and PMF. Results showed that SVR-KB trained with features obtained from three-dimensional complexes of the PDBbind data set outperformed all other scoring functions, including best performing X-score, by nearly 0.1 using three correlation coefficients, namely Pearson, Spearman, and Kendall. It was interesting that higher performance in rank ordering did not translate into greater enrichment in virtual screening assessed using the 40 targets of the Directory of Useful Decoys (DUD). To remedy this situation, a variant of SVR-KB (SVR-KBD) was developed by following a target-specific tailoring strategy that we had previously employed to derive SVM-SP. SVR-KBD showed a much higher enrichment, outperforming all other scoring functions tested, and was comparable in performance to our previously derived scoring function SVM-SP.


CyberKnife radiosurgery for vestibular schwannoma.
The CyberKnife is newly developed equipment for radiosurgery and fractionated radiosurgery. The authors report on their experience using the CyberKnife in 38 patients with vestibular schwannoma who were treated between 1998 to 2002. During this period, 38 patients with vestibular schwannoma were treated using CyberKnife fractionated radiosurgery. Before undergoing fractionated radiosurgery, 14 patients had Gardner Robertson classes I or II hearing (the serviceable hearing group), and 24 patients had classes III to V hearing (the non-serviceable hearing group). The treatment volumes of these two groups were 0.5 to 24.0 cm (3) (mean 4.7 cm (3)), and 0.5 to 41.6 cm (3) (mean 8.2 cm (3)). Target irradiation was administered in 1 - 3 fractions (mean 2.5 fractions). The total marginal radiation doses were 15.0 to 20.5 Gy (mean 17.0 Gy), and 11.9 to 20.1 Gy (mean 16.9 Gy), respectively. After a mean follow-up period of 31.9 months (range 12 to 59 months, median 27 months), 94 % of the tumors were controlled. Only one patient in the group with non-serviceable hearing underwent additional surgical resection for a presumed increase in tumor size. The hearing preservation rate was 93 %. Facial weakness did not develop in any of the patients in the serviceable hearing group. New trigeminal symptoms did not develop in any patients in either group. Although a longer and more extensive follow-up is needed, CyberKnife fractionated radiosurgery is considered to be safe and effective, even in patients with large tumors.


Detection and Characterization of Musculoskeletal Cancer Using Whole-Body Magnetic Resonance Imaging.
Whole-body magnetic resonance imaging (WB-MRI) is gradually being integrated into clinical pathways for the detection, characterization, and staging of malignant tumors including those arising in the musculoskeletal (MSK) system. Although further developments and research are needed, it is now recognized that WB-MRI enables reliable, sensitive, and specific detection and quantification of disease burden, with clinical applications for a variety of disease types and a particular application for skeletal involvement. Advances in imaging techniques now allow the reliable incorporation of WB-MRI into clinical pathways, and guidelines recommending its use are emerging. This review assesses the benefits, clinical applications, limitations, and future capabilities of WB-MRI in the context of other next-generation imaging modalities, as a qualitative and quantitative tool for the detection and characterization of skeletal and soft tissue MSK malignancies.


Pseudocoarctation of the aorta--a case report.
We report a case of a 43-year-old woman with pseudocoarctation of the aorta manifested by a superior mediastinal mass on the chest roentgenogram. Evaluation was made using computed tomography (CT), magnetic resonance imaging (MRI) and digital subtraction angiography (DSA). No other congenital anomalies or aneurysms below the kinked area of the aorta could be found. The characteristic "kink" of the aorta and the absence of true coarctation were evident in the sagittal plane by MRI. MRI is of great value for examining disorders of the aorta.


Effectiveness of a brief motivational intervention in the management of risky alcohol use in primary care: ALCO-AP20 study protocol.
Motivational interviewing (MI) could be a method for minimizing alcohol-related harm. The study aims to assess the effectiveness of a brief intervention, based on a MI, in patients with risky alcohol use attended in Primary Care (PC). A cluster-randomized, two-arm parallel, multicenter, open-label, controlled clinical trial. Fifty PC healthcare professionals from the province of Córdoba (Spain) will be randomized to one of the two study groups: (1) Experimental Group (EG): MI-based approach; (2) Control Group (CG): Usual care based on health advice. EG intervention: Professionals will receive a training program focused on MI, consisting of a training workshop and the use of pre- and post-workshop questionnaires to measure knowledge and skills acquired, as well as the degree of empathy, with a videotape of the health professionals with standardized patients, before and after the workshop, and subsequent training feedback. CG intervention: Workshop on the management of risky alcohol use based on health advice; participants will also complete the pre-and post-workshop questionnaires and be videotaped. Study population: Patients ≥ 14 years old with risky alcohol consumption (28 Standard Drink Units-SDU-/week in men and 17 SDU/week in women) or excessive alcohol use (≥ 6 SDU in men or ≥ 4 SDU in women, in less than 2 h). It would be necessary to include 110 subjects/group to find a difference of 20% between the percentage of patients in abstinence between EG (37%) and CG (20%), alpha error of 5%, and statistical power of 80%. Assuming a loss rate of 5% and the cluster design effect, the number of subjects to be recruited is estimated at 197/group. The follow-up period will be 12 months. The primary outcome variables will be the self-reported alcohol use level and the Alcohol Use Disorders Identification Test (AUDIT) questionnaire score. The study aims to demonstrate the effectiveness of the motivational approach in the comprehensive treatment of the patient with risky alcohol use, improving the empathy of the healthcare professionals and strengthening the healthcare professional-patient relationship to achieve the behavioral change of the patients with this problem in primary care consultations. ClinicalTrials.gov.


Web-based data collection in midwifery clinical education.
A Web-based computerized database for clinical data collection use by midwifery and nurse practitioner students was developed and revised over 2 years. The database provided insight into the number and diversity of clients seen as well as the student's level of autonomy. Students documented a selected set of data elements sensitive to nursing and midwifery care for all client encounters. Analysis of the clinical encounter data entered by nurse-midwifery students in the Antepartum Care course during two winter semesters included 1,417 client encounters. Results of the analyses are presented as well as educational and clinical issues involved in the development and maintenance of the database. Future work includes refining the current database, expanding the data set to include the ACNM nurse-midwifery clinical data sets for antepartum and intrapartum care, and pilot testing the Web-based version in Fall 2003 by using wireless, handheld technology.


Strategies to promote the professional transition of new graduate nurse practitioners: A systematic review.
New graduate nurse practitioner (NP) postgraduate support programs and interventions have proliferated, sparking controversy. The Institute of Medicine/National Academy of Medicine recommends residency programs for new graduate NPs; however, the NP community debates whether new graduate NPs need additional training and whether such training compromises patient access to care. This systematic review aimed to synthesize evidence regarding the effectiveness of interventions and strategies to promote the professional transition of new graduate NPs. Interventions identified in the current literature included fellowship programs and a webinar. Strategies included mentorship, experiential learning, interprofessional training, and professional socialization. The studies reviewed primarily evaluated NPs' perceptions of the interventions' effects on their professional transitions. The findings from this systematic review highlight challenges in evidencing postgraduate support programs. The small number of available studies underscores a critical problem for the NP community: additional evidence is needed to inform whether and how to support new graduate NPs as they transition to practice.


Physical activity and sociodemographic variables related to global health, quality of life, and psychological factors in breast cancer survivors.
Breast cancer is one of the most common cancers affecting women worldwide and depression and anxiety are disturbing side effects of cancer diagnosis and treatment. The aim of this study was to examine the associations of physical activity in global health, quality of life (QoL), and psychological factors (depressive symptoms, self-esteem, and anxiety) in breast cancer survivors after completing cancer treatment and through survivorship. Demographic variables (marital status, education, income), medical status (cancer stage), and level of physical activity (metabolic equivalent of task [MET]) were tested as predictors of depressive mood, anxiety, self-esteem, and QoL in younger and older breast cancer survivors. One hundred and seventy-one Greek breast cancer survivors, who had completed cancer treatment at least one and a half years ago, were included in this study. Demographic and medical information, self-reported and objective physical activity levels, global health, QoL, depressive symptoms, self-esteem, and anxiety were assessed in all participants. Active women had lower depressive symptoms, less anxiety, higher self-esteem, and better global health and QoL, compared to the inactive ones, even in the long term after completing treatment through survivorship. Exercise had significant positive correlations with self-esteem, global health, and QoL (physical, role, emotional, cognitive, and social aspects). Moreover, significant negative correlations with anxiety and depressive symptoms were found. Multiple regression analysis revealed that MET and covariates such as income, education, and stage of cancer were significant predictors of depressive symptoms, self-esteem, anxiety, global health, and QoL in younger survivors, while MET, income, education, stage of cancer, and marital status were significant predictors of dependent variables for the older ones. It can be concluded that exercise should be recommended to cancer survivors even after treatment completion and through survivorship to achieve higher self-esteem, better QoL, and decreased anxiety and depressive symptoms.


A numerical and experimental investigation of transitional pulsatile flow in a stenosed channel.
In the present paper, a closely coupled numerical and experimental investigation of pulsatile flow in a prototypical stenotic site is presented. Detailed laser Doppler velocimetry measurements upstream of the stenosis are used to guide the specification of velocity boundary conditions at the inflow plane in a series of direct numerical simulations (DNSs). Comparisons of the velocity statistics between the experiments and DNS in the post-stenotic area demonstrate the great importance of accurate inflow conditions, and the sensitivity of the post-stenotic flow to the disturbance environment upstream. In general, the results highlight a borderline turbulent flow that sequentially undergoes transition to turbulence and relaminarization. Before the peak mass flow rate, the strong confined jet that forms just downstream of the stenosis becomes unstable, forcing a role-up and subsequent breakdown of the shear layer. In addition, the large-scale structures originating from the shear layer are observed to perturb the near wall flow, creating packets of near wall hairpin vortices.


Reducing the risk of viral contamination during the coronavirus pandemic by using a protective curtain in the operating room.
Airborne transmission diseases can transfer long and short distances via sneezing, coughing, and breathing. These airborne repertory particles can convert to aerosol particles and travel with airflow. During the Coronavirus disease 2019 (COVID-19) pandemic, many surgeries have been delayed, increasing the demand for establishing a clean environment for both patient and surgical team in the operating room. This study aims to investigate the hypothesis of implementing a protective curtain to reduce the transmission of infectious contamination in the surgical microenvironment of an operating room. In this regard, the spread of an airborne transmission disease from the patient was evaluated, consequently, the exposure level of the surgical team. In the first part of this study, a mock surgical experiment was established in the operating room of an academic medical center in Norway. In the second part, the computational fluid dynamic technique was performed to investigate the spread of airborne infectious diseases. Furthermore, the field measurement was used to validate the numerical model and guarantee the accuracy of the applied numerical models. The results showed that the airborne infectious agents reached the breathing zone of the surgeons. However, using a protective curtain to separate the microenvironment between the head and lower body of the patient resulted in a 75% reduction in the spread of the virus to the breathing zone of the surgeons. The experimental results showed a surface temperature of 40 ˚C, which was about a 20 ˚C increase in temperature, at the wound area using a high intensity of the LED surgical lamps. Consequently, this temperature increase can raise the patient's thermal injury risk. The novel method of using a protective curtain can increase the safety of the surgical team during the surgery with a COVID-19 patient in the operating room.


Seasonal changes in plant-water relations influence patterns of leaf display in Miombo woodlands: evidence of water conservative strategies.
Water availability has frequently been linked to seasonal leaf display in seasonally dry ecosystems, but there have been few ecohydrological investigations of this link. Miombo woodland is a dominant seasonally dry tropical forest ecosystem type in southern Africa; however, there are few data on the relationship between seasonal dynamics in plant-water relations and patterns of leaf display for Miombo woodland. Here we investigate this relationship among nine key Miombo woodland tree species differing in drought tolerance ability and leaf phenology. Results of this study showed that seasonal patterns of leaf phenology varied significantly with seasonal changes in stem water relations among the nine species. Leaf shedding coincided with the attainment of seasonal minimum stem water potential. Leaf flush occurred following xylem rehydration at the peak of the dry season suggesting that endogenous plant factors play a pivotal role in seasonal leaf display in this forest type. Drought-tolerant deciduous species suffered significantly higher seasonal losses in xylem hydraulic conductivity than the drought-intolerant semi-evergreen tree species (P < 0.05). There was a significant and positive correlation between species drought tolerance index and species' seasonal loss in hydraulic conductivity (P < 0.05), confirming the ecological role of long-distance xylem transport in this seasonally dry tropical forest. Our results reveal that water stress in seasonally dry tropical forests selects for water conservative traits that protect the vulnerable xylem transport system. Therefore, seasonal rhythms in xylem transport dictate patterns of leaf display in seasonally dry tropical forests.


A retrospective evaluation of the causes of death of 448 insured French horses in 1995.
Epidemiological studies should allow comparisons to be made of the prevalence of disease in populations from different countries, but the population characteristics and health problems in French horses are not well established. We have conducted a retrospective evaluation of the causes of death and vital characteristics of insured horses in France for the year 1995, with a view to comparison with published data from other countries. Files on 448 deceased horses were provided by nine insurance companies. Most of the animals were used for breeding (60%), followed by leisure (20%), eventing and racing (10% each). Physical characteristics were associated significantly with occupational categories. The overall mortality rate was 2.47%, and was due, in decreasing order, to foaling (24%), colic (21%) or locomotor (21%), cardiovascular (9%), neurological (8%), respiratory (5%) or infectious (4%) disease. Infectious disease was more frequent in younger animals (p < 0.05) and locomotor disease in racehorses (p < 0.01). Horses aged over 15 years had a lower incidence of colic (p <0.05). The cause of death was not significantly linked to breed, insurance value or season. Despite some selection bias, the study provides useful information about mortality in the French equine population.


A case of melioidosis probably acquired by inhalation of dusts during a helicopter flight in a healthy traveler returning from Singapore.
We present a case of melioidosis in an Italian male returning from Singapore after a short travel. He probably acquired the disease by inhalation, which is not the typical mode of transmission, in the absence of evident risk factors. The diagnosis was confirmed by real-time polymerase chain reaction of the culture while serology was useful to assess professional exposure among laboratory workers. Treatment consisted of an initial intensive phase with meropenem and trimethoprim-sulfamethaxazole (TMP-SMX), followed by 6 months of eradication therapy with TMP-SMX.


Pancreaticoduodenal arterial aneurysms.
Experience with four aneurysms of the pancreaticoduodenal artery is reviewed and compared to the reported experience of 19 other cases. In view of the common presentation of such lesions as intra-abdominal hemorrhage preceded by non-specific abdominal pain and other digestive symptoms, it is suggested that angiography perfomed preoperatively or intraoperatively allows definitive diagnosis and leads to specific therapy.


Formative usability evaluation of a fixed-dose pen-injector platform device.
This article for the first time presents a formative usability study of a fixed-dose pen injector platform device used for the subcutaneous delivery of biopharmaceuticals, primarily for self-administration by the patient. The study was conducted with a user population of both naïve and experienced users across a range of ages. The goals of the study were to evaluate whether users could use the devices safely and effectively relying on the instructions for use (IFU) for guidance, as well as to benchmark the device against another similar injector established in the market. Further objectives were to capture any usability issues and obtain participants' subjective ratings on the properties and performance of both devices. A total of 20 participants in three groups studied the IFU and performed simulated injections into an injection pad. All participants were able to use the device successfully. The device was well appreciated by all users with, maximum usability feedback scores reported by 90% or more on handling forces and device feedback, and by 85% or more on fit and grip of the device. The presence of clear audible and visible feedbacks upon successful loading of a dose and completion of injection was seen to be a significant improvement over the benchmark injector. The observation that the platform device can be safely and efficiently used by all user groups provides confidence that the device and IFU in their current form will pass future summative testing in specific applications.


Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria?
Background Previous reviews of the diagnosis for rheumatoid arthritis (RA) have not compared anti-mutated citrullinated vimentin (MCV) with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) in respect of sensitivity, specificity and the area under the curve (AUC) against disease controls for differential diagnosis. This meta-analysis aims to evaluate the value of anti-MCV in the diagnosis for RA, the combined sensitivity of anti-MCV and anti-CCP, and certain clinical characteristics related to the performance of anti-MCV. Methods Medline, Embase, Cochrane Library and Web of Science were searched for articles published up to 25 August 2018. A total of 33 studies including 6044 RA patients and 5094 healthy or disease controls achieved inclusive criteria. QUADAS-2 was applied to evaluate the quality of the included studies. The bivariate random effects model was employed in primary data synthesis to evaluate the diagnostic performance. Results The sensitivity of anti-MCV, anti-CCP and RF in RA diagnosis against a disease control group was 0.71, 0.71, 0.77, with the specificity of 0.89, 0.95, 0.73, and the AUC of the SROC of 0.89, 0.95, 0.82, respectively. The predesign of the primary study and diagnostic criteria were statistically significant as sources of heterogeneity. Anti-MCV and anti-CCP tests demonstrated a sensitivity of 0.77 when performed in parallel, with a sensitivity of 0.60 when performed in series; whereas, the combination of anti-MCV and RF presented a sensitivity of 0.64 when used in series. Conclusions Anti-MCV demonstrates comparable diagnostic value to anti-CCP and RF, thus it can be an effective diagnostic marker for RA and may be written into the next authoritative criteria.


Combined cryo-maze procedure and mitral valve repair through a ministernotomy.
Atrial fibrillation is associated with increased morbidity and mortality in patients undergoing mitral valve surgery. There is a growing consensus that patients with preexisting atrial fibrillation should undergo surgical ablation at the time of mitral valve surgery. Novel surgical ablation techniques, including cryoablation, have been developed to facilitate concurrent minimally invasive procedures. This video tutorial describes a combined cryo-maze procedure and mitral valve repair through an upper ministernotomy in a patient with long-standing persistent atrial fibrillation and severe mitral regurgitation.


Replisome instability, fork collapse, and gross chromosomal rearrangements arise synergistically from Mec1 kinase and RecQ helicase mutations.
The yeast checkpoint kinases Mec1 and Rad53 are required for genomic stability in the presence of replicative stress. When replication forks stall, the stable maintenance of replisome components requires the ATR kinase Mec1/Ddc2 and the RecQ helicase Sgs1. It was unclear whether either Mec1 or Sgs1 action requires the checkpoint effector kinase, Rad53. By combining sgs1Delta with checkpoint-deficient alleles, we can now distinguish the role of Mec1 at stalled forks from that of Rad53. We show that the S-phase-specific mec1-100 allele, like the sgs1Delta mutation, partially destabilizes DNA polymerases at stalled forks, yet combining the mec1-100 and sgs1Delta mutations leads to complete disassociation of the replisome, loss of RPA, irreversible termination of nucleotide incorporation, and compromised recovery from hydroxyurea (HU) arrest. These events coincide with a dramatic increase in both spontaneous and HU-induced chromosomal rearrangements. Importantly, in sgs1Delta cells, RPA levels at stalled forks do not change, although Ddc2 recruitment is compromised, explaining the partial Sgs1 and Mec1 interdependence. Loss of Rad53 kinase, on the other hand, does not affect the levels of DNA polymerases at arrested forks, but leads to MCM protein dissociation. Finally, confirming its unique role during replicative stress, Mec1, and not Tel1, is shown to modify fork-associated histone H2A.


Parent-Reported Social-Communicative Skills of Children with 22q11.2 Copy Number Variants and Siblings.
22q11.2 deletion (22q11.2DS) and 22q11.2 duplication (22q11.2Dup) confer risk for neurodevelopmental difficulties, but the characterization of speech-language and social skills in 22q11.2Dup is still limited. Therefore, this study aims to delineate social-communicative skills in school-aged children with 22q11.2Dup (n = 19) compared to their non-carrier siblings (n = 11) and age-matched children with 22q11.2DS (n = 19). Parents completed two standardized questionnaires: the Children's Communication Checklist (CCC-2), screening speech, language, and social skills, and the Social Responsiveness Scales (SRS-2), assessing deficits in social behavior. Parents report that both children with 22q11.2Dup and 22q11.2DS show more social-communicative deficits than the general population; children with 22q11.2Dup seem to take an intermediate position between their siblings and children with 22q11.2DS. Compared to 22q11.2DS, they demonstrate less frequent and less severe problems, and more heterogeneous social-communicative profiles, with fewer restricted interests and repetitive behaviors. In siblings of 22q11Dup, milder social-communicative difficulties and equally heterogeneous profiles are reported, which might indicate that-in addition to the duplication-other factors such as the broader genetic context play a role in social-communicative outcomes.


[Clinical study of blood cardioplegia--for aerobic metabolism during aortic cross-clamping].
Blood cardioplegia is considered to be superior in oxygenating potential, buffering potential, oncotic, and other physiologic effects. In clinical cases, however, it is unproven whether aerobic metabolism can be obtained by using blood cardioplegia during aortic cross-clamping. Aerobic metabolism during aortic cross-clamping was therefore evaluated in patients with valvular heart disease who underwent relatively long periods of ischemic arrest. Myocardial metabolism of oxygen, lactate and pyruvate was studied in 14 patients under 126 +/- 41.2 min of cardiac arrest, and intramyocardial carbon dioxide tension (PmCO2) was also monitored continuously in 23 patients who received 121 +/- 29.8 min of aortic cross-clamping. After aortic cross-clamping, 4 degrees C St. Thomas solution was infused for immediate cooling, followed by blood cardioplegia for replenishment every 20-25 min. Blood cardioplegia and myocardial temperature were maintained within 15-20 degrees C by using an automatic cardiac hypothermia control system. Myocardial oxygen extraction during the pre-ischemic period was 26.8 +/- 13.3%. At 15 and 30 min after reperfusion, it was 30.0 +/- 10.8% and 33.8 +/- 8.2%, respectively. During ischemic arrest, myocardial oxygen extraction decreased, but the infusion of blood cardioplegia kept it above 14.0 +/- 9.3% at all times. As for lactate metabolism, although some cases showed lactate production even before the aortic cross-clamping, lactate extraction was attained in some cases during blood cardioplegia perfusion. Changes in excess lactate and redox potential of lactate and pyruvate (delta Eh) showed that aerobic metabolism could be obtained in 13/32 (41%) infusions of blood cardioplegia. PmCO2 at the aortic cross-clamp was 47.0 +/- 27.7 mmHg, and gradually rose during the ischemic arrest, but only as far as 68.4 +/- 64.8 mmHg at the time of cross-clamp release. PmCO2 decreased with each infusion of blood cardioplegia, and the decrease lasted up to 10 minutes. Though PmCO2 began to rise thereafter, the effect of blood cardioplegia continued as long as 20-25 min after the infusion. In conclusion, blood cardioplegia provides aerobic metabolism during aortic cross-clamping even in clinical setting, provided that cardiac hypothermia and delivery of cardioplegic solution are maintained appropriately.


Effect of thermal and mechanical loading on marginal adaptation and microtensile bond strength of a self-etching adhesive with caries-affected dentin.
This study evaluated the effect of thermal and mechanical loading on marginal adaptation and microtensile bond strength in total-etch versus self-etch adhesive systems in caries-affected dentin. FORTY CLASS II CAVITIES WERE PREPARED ON EXTRACTED PROXIMALLY CARIOUS HUMAN MANDIBULAR FIRST MOLARS AND WERE DIVIDED INTO TWO GROUPS: Group I - self-etch adhesive system restorations and Group II - total-etch adhesive system restorations. Group I and II were further divided into sub-groups A (Without thermal and mechanical loading) and B (With thermal and mechanical loading of 5000 cycles, 5 ± 2°C to 55 ± 2°C, dwell time 30 seconds, and 150,000 cycles at 60N). The gingival margin of the proximal box was evaluated at 200X magnification for marginal adaptation in a low vacuum scanning electron microscope. The restorations were sectioned, perpendicular to the bonded surface, into 0.8 mm thick slabs. All the specimens were subjected to microtensile bond strength testing. The marginal adaptation was analyzed using descriptive studies, and the bond strength data was analyzed using the one-way analysis of variance (ANOVA) test. The total-etch system performed better under thermomechanical loading.


Gonadotropin-releasing hormone (GnRH) immunoreactive system in the brain of the dwarf gourami (Colisa lalia) as revealed by light microscopic immunocytochemistry using a monoclonal antibody to common amino acid sequence of GnRH.
The present paper aims to give a morphological basis for the study of the terminal nerve system and its relation to the whole gonadotropin-releasing hormone (GnRH) immunoreactive (ir) neuronal system. We examined the GnRH-ir neuronal system of a tropical fish, the dwarf gourami, by using a recently developed monoclonal antibody against GnRH (LRH13) which recognizes the amino acid sequence common to all known variants of GnRH (Park and Wakabayashi, Endocrinol. Jpn. 33:257-272, '86). The ganglion cells of the terminal nerve (TN-ggl cells) in the transitional area between the olfactory bulb and the telencephalon reacted strongly with the LRH13. A distinct bundle of axons emanating from the TN-ggl cells ran caudally through the ventral telencephalon and the preoptic area. Some of these axons entered the optic nerve and innervated the retina. The remaining axons continued caudally to enter the hypothalamus and the midbrain. A second group of GnRH-ir cell bodies was found in the preoptic area. A distinct bundle of GnRH-ir fibers originating from these cell bodies innervated the pituitary. This pathway is equivalent to the preoptico-infundibular pathway of other vertebrates, and the GnRH in this pathway is presumed to function as hypophysiotrophic hormone to facilitate the release of gonadotropins from the pituitary. The distribution of GnRH-ir fibers in the brain was extensive. Most fibers apparently originated from the TN-ggl cells and covered various brain regions from the olfactory bulb to the spinal cord. They were especially abundant in the olfactory bulb, ventral telencephalon, preoptic area, optic tectum, and some hypothalamic areas. Thus, GnRH might function as a neuromodulator and/or neurotransmitter in these areas. The abundant GnRH-ir fibers in the ventral telencephalon and the preoptic area might affect some aspects of sexual behavior, since these areas have been suggested to be involved in the control of sexual behavior in teleosts.


Body image, anthropometric measures, and eating-disorder prevalence in auxiliary unit members.
Medical professionals have recognized eating disorders and related problems in competitive athletes. Auxiliary members (color guard, dance, majorettes) experience the same appearance-related pressures observed in sports commonly associated with eating disorders. To estimate eating-disorder prevalence based on associated eating-disorder characteristics and behaviors in female auxiliary members and to compare perceived and ideal body images and anthropometric measurements between at-risk and not-at-risk participants for eating-disorder characteristics and behaviors. Cross-sectional design. Three universities in the southeastern United States. Participants (n = 101, mean age = 19.2 +/- 1.2 years) represented 3 auxiliary units, including color guard (n = 35), dance line (n = 47), and majorettes (n = 19). Participants self-reported menstrual history, height, and weight. Anthropometric measurements included height, weight, body fat percentage, and waist and hip circumferences. We screened for eating-disorder risk behavior with the Eating Attitudes Test (EAT)-26 and for body dissatisfaction with the Figural Stimuli Survey. Based on the EAT-26, we estimated eating-disorder prevalence among members to measure 29.7% (95% confidence interval = 20.8%, 38.6%). The EAT-26 results revealed that 21% of participants used purgatives and 14% vomited to control weight or shape. The at-risk group had higher scores on the EAT-26 total (P <or= .01) and on the dieting (P <or= .01), oral control (P = .02), and bulimia (P = .01) subscales. Hip circumference (P = .01), self-reported weight (P = .03), measured weight (P = .04), difference between measured and preferred weights (P = .02), and calculated target weight (P = .02) were different between the at-risk and not-at-risk groups. Collegiate auxiliary unit members may have an unacceptable prevalence of eating disorders. Our results validate concerns that auxiliary members may exhibit an unacceptable eating-disorder risk, highlighting the need to examine and address unhealthy weight-management behaviors independent of eating-disorder status.


Early vs Single Match in the Transition to Residency: Analysis Using NRMP Data From 2014 to 2021.
An Early Result Acceptance Program (ERAP) has been proposed for obstetrics and gynecology (OB/GYN) to address challenges in the transition to residency. However, there are no available data-driven analyses on the effects of ERAP on the residency transition. We used National Resident Matching Program (NRMP) data to simulate the outcomes of ERAP and compare those to what occurred in the Match historically. We simulated ERAP outcomes in OB/GYN, using the de-identified applicant and program rank order lists from 2014 to 2021, and compared them to the actual NRMP Match outcomes. We report outcomes and sensitivity analyses and consider likely behavioral adaptations. Fourteen percent of applicants receive a less preferred match under ERAP, while only 8% of applicants receive a more preferred match. Less preferred matches disproportionately affect DOs and international medical graduates (IMGs) compared to US MD seniors. Forty-one percent of programs fill with more preferred sets of applicants, while 24% fill with less preferred sets of applicants. Twelve percent of applicants and 52% of programs are in mutually dissatisfied applicant-program pairs (a pair in which both prefer each other to the match each received). Seventy percent of applicants who receive less preferred matches are part of a mutually dissatisfied pair. In 75% of programs with more preferred outcomes, at least one assigned applicant is part of a mutually dissatisfied pair. In this simulation, ERAP fills most OB/GYN positions, but many applicants and programs receive less preferred matches, and disparities increase for DOs and IMGs. ERAP creates mutually dissatisfied applicant-program pairs and problems for mixed-specialty couples, which provides incentives for gamesmanship.


Current status of the metabolic engineering of microorganisms for biohydrogen production.
The improvement of H2 production capabilities of hydrogen (H2)-producing microorganisms is a challenging issue. Microorganisms have evolved for fast growth and substrate utilization rather than H2 production. To develop good H2-producing biocatalysts, many studies have focused on the redirection and/or reconstruction of cellular metabolisms. These studies included the elimination of enzymes and carbon pathways interfering or competing with H2 production, the incorporation of non-native metabolic pathways leading to H2 production, the utilization of various carbon substrates, the rectification of H2-producting enzymes (nitrogenase and hydrogenase) and photophosphorylation systems, and in silico pathway flux analysis, among others. Owing to these studies, significant improvements in the yield and rate of H2 production, and in the stability of H2 production activity, were reached. This review presents and discusses the recent developments in biohydrogen production, with a focus on metabolic pathway engineering.


Assessment of the administration of maropitant and loperamide to dogs with cancer for the prevention and reduction of adverse effects associated with the administration of paclitaxel.
To evaluate the efficacy of maropitant and loperamide for the prevention and reduction of adverse gastrointestinal effects associated with administration of paclitaxel to dogs with cancer. 168 dogs with cancer. The study comprised 2 phases. For phase 1, dogs in the intervention group were administered maropitant and loperamide followed by paclitaxel. Outcomes were compared with those for a control group that received only maropitant and paclitaxel. For phase 2, all dogs of phase 1 that did not receive maropitant and loperamide and that had adverse gastrointestinal effects were enrolled; they received maropitant and loperamide and another dose of paclitaxel. In phase 1, significantly fewer dogs in the intervention group had adverse effects. For dogs that had adverse effects, the intervention group had a lower severity of lack of appetite and lethargy. Also, adverse effects for dogs in the intervention group were of significantly shorter duration than for the control group. In phase 2, significant reductions in adverse effects were observed after administration of maropitant and loperamide. In those dogs that still had adverse effects after administration of maropitant and loperamide, there was a significant reduction in severity of signs of nausea and lethargy. A combination of maropitant and loperamide was found to be safe for use and effective for reducing or preventing signs of paclitaxel-induced gastrointestinal effects in dogs.


Uremia accelerates both atherosclerosis and arterial calcification in apolipoprotein E knockout mice.
Chronic renal failure (CRF) favors the development of atherosclerosis and excessive calcification of atheromatous lesions. CRF was induced in apolipoprotein E knockout (apoE(-/-)) mice to study (1) a possible acceleration of aortic atherosclerosis, (2) the degree and type of vascular calcification, and (3) factors involved in the calcification process. For creating CRF, 8-wk-old apolipoprotein E gene knockout (apoE(-/-)) mice underwent partial kidney ablation. Control animals underwent sham operation. Aortic atherosclerotic plaques and calcification were evaluated using quantitative morphologic image processing. At 6 wk after nephrectomy, CRF mice had significantly higher serum urea, cholesterol, and triglyceride concentrations than non-CRF controls. The serum levels of advanced oxidation protein products were elevated in the uremic group and were correlated with serum urea levels. Atherosclerotic lesions in thoracic aorta were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. The relative proportion of calcified area to total surface area of both atherosclerotic lesions and lesion-free vascular tissue was increased in aortic root of uremic apoE(-/-) mice when compared with controls. The calcium deposits were made of hydroxyapatite and calcite crystals. In addition, plaques from uremic animals showed a significant increase in collagen content, whereas the degree of macrophage infiltration was comparable in both groups. There was no difference in mean arterial BP. These findings demonstrate that CRF aggravates atherosclerosis in apoE(-/-) mice. Moreover, CRF enhances arterial calcification at both atheromatous intimal sites and atheroma-free medial sites. We anticipate that this experimental model will be useful to test treatment strategies aimed at decreasing the accelerated atherosclerosis and arterial calcification in uremia.


Properties of a tardigrade desiccation-tolerance protein aerogel.
Lyophilization is promising for tackling degradation during the drying and storage of protein-based drugs. Tardigrade cytosolically abundant heat soluble (CAHS) proteins are necessary and sufficient for desiccation-tolerance in vivo and protein protection in vitro. Hydrated CAHS proteins form coiled-coil-based fine-stranded, cold-setting hydrogels, but the dried protein remains largely uncharacterized. Here, we show that dried CAHS D gels (i.e., aerogels) retain the structural units of their hydrogels, but the details depend on prelyophilization CAHS concentrations. Low concentration samples (<10 g/L) form thin (<0.2 μm) tangled fibrils lacking regular structure on the micron scale. Upon increasing the concentration, the fibers thicken and form slabs comprising the walls of the aerogel pores. These changes in morphology are associated with a loss in disorder and an increase in large β sheets and a decrease in α helices and random coils. This disorder-to-order transition is also seen in hydrated gels as a function of concentration. These results suggest a mechanism for pore formation and indicate that using CAHS proteins as excipients will require attention to initial conditions because the starting concentration impacts the lyophilized product.


Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells.
Hydrogen peroxide and other reactive oxygen species are intimately involved in endothelial cell signaling. In many cell types, the AMP-activated protein kinase (AMPK) has been implicated in the control of metabolic responses, but the role of endothelial cell redox signaling in the modulation of AMPK remains to be completely defined. We used RNA interference and pharmacological methods to establish that H(2)O(2) is a critical activator of AMPK in cultured bovine aortic endothelial cells (BAECs). H(2)O(2) treatment of BAECs rapidly and significantly increases the phosphorylation of AMPK. The EC(50) for H(2)O(2)-promoted phosphorylation of AMPK is 65 + or - 15 microM, within the physiological range of cellular H(2)O(2) concentrations. The Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) inhibitor STO-609 abolishes H(2)O(2)-dependent AMPK activation, whereas eNOS inhibitors enhance AMPK activation. Similarly, siRNA-mediated knockdown of CaMKKbeta abrogates AMPK activation, whereas siRNA-mediated knockdown of eNOS leads to a striking increase in AMPK phosphorylation. Cellular imaging studies using the H(2)O(2) biosensor HyPer show that siRNA-mediated eNOS knockdown leads to a marked increase in intracellular H(2)O(2) generation, which is blocked by PEG-catalase. eNOS(-/-) mice show a marked increase in AMPK phosphorylation in liver and lung compared to wild-type mice. Lung endothelial cells from eNOS(-/-) mice also show a significant increase in AMPK phosphorylation. Taken together, these results establish that CaMKKbeta is critically involved in mediating the phosphorylation of AMPK promoted by H(2)O(2) in endothelial cells, and document that eNOS is an important negative regulator of AMPK phosphorylation and intracellular H(2)O(2) generation in endothelial cells.


Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia.
Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TRKA) selectivity- and metabolic stability-guided structure-activity relationship (SAR) exploration were carried out to discover a highly potent (IC50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability (t1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.


Comparing Cryo-EM Reconstructions and Validating Atomic Model Fit Using Difference Maps.
Cryogenic electron microscopy (cryo-EM) is a powerful technique for determining structures of multiple conformational or compositional states of macromolecular assemblies involved in cellular processes. Recent technological developments have led to a leap in the resolution of many cryo-EM data sets, making atomic model building more common for data interpretation. We present a method for calculating differences between two cryo-EM maps or a map and a fitted atomic model. The proposed approach works by scaling the maps using amplitude matching in resolution shells. To account for variability in local resolution of cryo-EM data, we include a procedure for local amplitude scaling that enables appropriate scaling of local map contrast. The approach is implemented as a user-friendly tool in the CCP-EM software package. To obtain clean and interpretable differences, we propose a protocol involving steps to process the input maps and output differences. We demonstrate the utility of the method for identifying conformational and compositional differences including ligands. We also highlight the use of difference maps for evaluating atomic model fit in cryo-EM maps.


Non-Tuberculous Mycobacteria and Aspergillus Lung Co-Infection: Systematic Review.
Non-tuberculous mycobacteria (NTM) and Aspergillus pulmonary co-infection occurs in patients with underlying lung disease and is rarely reported. We conducted a systematic search of NTM and Aspergillus pulmonary co-infection in PubMed, EMBASE, and Cochrane Library to identify cases published from 1977 to May 2022. We included 507 articles comprising 1538 cases (only 817 patients with partial relevant clinical data). Of these, 54.3% of patients were men, with a mean age of 57.7 years. Chronic obstructive pulmonary disease (21.1%), previous diagnosis of tuberculosis (18%), and asthma (11.1%) were the most common chronic lung diseases, and corticosteroids were used in 36.8% of patients. The most frequent symptoms were cough (68.2%), dyspnea (59.1%), and hemoptysis (34.1%). The most common radiological findings were bronchiectasis (52.3%) and cavitation (40.8%). NTM and Aspergillus were treated simultaneously in 47.3% of cases, whereas NTM-targeted therapy only was performed in 23.4% and Aspergillus only in 1.6%. The remaining 27.7% did not receive any treatment and were considered to be colonized. The global mortality rate was 43% (159/370). There was an increased prevalence of NTM and pulmonary aspergillosis among patients with underlying chronic lung diseases, which led to severe pulmonary affection with a poor global prognosis.


Molecular characterization of kisspeptin receptors and gene expression analysis during oogenesis in the Russian sturgeon (Acipenser gueldenstaedtii).
Sturgeons belong to a subclass of fishes that derived from ray-finned fish ancestors preceding the emergence of teleosts. The Russian sturgeon (Acipenser gueldenstaedtii) is a late-maturing fish with the females reaching puberty under aquaculture conditions at 6-10 years of age. Since kisspeptin has been shown to be a key hormone involved in regulation of major reproductive processes of many vertebrate species, this study was conducted to better understand the kisspeptin receptor (KissR) in sturgeon. In this study we have cloned Russian sturgeon KissR1 from brain mRNA and observed the ontogeny of rsKissR1 mRNA expression in ovarian follicles. Multiple sequence alignment of KissR1, KissR4, and their orthologs revealed that the Russian sturgeon (rs) KissR1 sequence shares 64%-77% identity with elephant shark, coelacanth, and gar and 44-58% identity with tetrapod and teleost KissR1 sequences, while KissR4 seemed to share <65% identity to eel KissR2 and ~57% identity to Perciformes and Cypriniformes. Further rsKissR4 showed <97% identity to reed fish KissR4, <63% with Squamata (Reptiles) and gar KissR4. A phylogenetic analysis revealed that rsKissR1 is more closely related to coelacanth and gar KissR1 than teleost, while rsKissR4 was part of the KissR4 clade and shared higher similarity with Actinopterygiian sequences. We have further predicted homology models for both rsKiss receptors and performed in-silico analyses of their binding to a kiss-10 peptide. Both sturgeon and zebrafish Kiss1 and Kiss2 activated rsKissR1 via both PKC/Ca2+ and PKA/cAMP signal-transduction pathways, while rsKissR2 was found to be less effective and was not activated by stKiss peptides. Ovarian rsKissR transcript levels for 10 fishes were determined by real-time PCR and significantly increased concomitantly with oogenesis, where the highest level of expression was evident in black follicles. These data suggest that extra-neuronal expression of the kisspeptin receptor may be involved in sturgeon reproduction in a manner dependent on reproductive development.


Au decorated BiVO4 inverse opal for efficient visible light driven water oxidation.
Photocatalytic water splitting provides an effective way to prepare hydrogen and oxygen. However, the weak light utilization and sluggish kinetics in the oxygen evolution reaction (OER) process substantially retard the photocatalytic efficiency. In this context, modification of the semiconductors to overcome these limits has been the effective strategy for obtaining highly-efficient photocatalytic water oxidation. Here, plasmonic Au has been loaded onto BiVO4 inverse opal (IO) for photocatalytic water oxidation. It is discovered that the IO structure provides higher specific surface area and favors light absorption on BiVO4. In the meantime, the plasmonic Au can simultaneously enhance the light-utilization capability and photogenerated charge carrier utilization ability of the BiVO4 IO. As a result, a high photocurrent density and long photogenerated charge carrier lifetime can be achieved on the optimized Au-BiVO4 IO, thereby obtaining a superior photocatalytic activity with an oxygen production rate of 9.56 μmol g-1 h-1.


Leptin requirement for conception, implantation, and gestation in the mouse.
The ob/ob mouse has a complete absence of circulating leptin, resulting in obesity and infertility. Using the minimum daily dose of leptin required to maintain normal body weight and sexual maturation (5 mg/kg, ip), leptin-treated ob/ob females were mated with either wild-type (+/+) or leptin-treated ob/ob males. The leptin treatment continued throughout pregnancy until weaning or was withdrawn at 0.5, 3.5, 6.5, or 14.5 d post coitum (dpc). Normal pregnancy and parturition with pups of normal weight resulted when ob/ob females were mated with +/+ males and leptin treatment was continued throughout pregnancy (6 of 8 pregnancies), to 14.5 dpc (6 of 8 pregnancies), or to 6.5 dpc (9 of 12 pregnancies). Pregnancy did not result when treatment was stopped at 3.5 dpc (1 of 7 pregnancies) or 0.5 dpc (0 of 6 pregnancies). Similar results were obtained when leptin-treated ob/ob females were mated with leptin-treated ob/ob males. The newborn pups failed to survive after birth in groups treated with leptin up to 14.5 and 6.5 dpc despite reinstating leptin at birth. This appeared to be due to a lack of development of the mammary glands. In conclusion, we have shown that leptin is essential for normal preimplantation and/or implantation processes. It is also essential for normal development of the mammary glands, but is not required for pregnancy and parturition once implantation is established.


Management of laryngopharyngeal reflux: an unmet medical need.
Laryngopharyngeal reflux (LPR) is defined by the association of laryngeal symptoms with laryngeal inflammation at laryngoscopy. However, these symptoms are difficult to characterize and the laryngoscopic signs lack specificity. Moreover, to date, the diagnosis of LPR can rely neither on esophageal investigations (endoscopy, pH/impedance monitoring) nor on response to high dose proton pump inhibitors because of a high placebo effect. Therefore, there is a need for the development of new tools which may help to better identify the subgroup of patients with laryngeal symptoms related to supra-esophageal reflux.


A realist evaluation to identify targets to improve the organization of compression therapy for deep venous thrombosis- and chronic venous disease patients.
Although compression therapy is well established for patients with deep venous thrombosis (DVT) and chronic venous disease (CVD), considerable variation exists in its organization in clinical practice which may impact patient outcomes. The current study aims to deepen our understanding of the main drivers of the complex care organization for compression therapy and to identify targets for improvement. This realist evaluation includes a mixed-method design consisting of semi-structured interviews with patients and health care professionals involved in compression therapy (n = 30), stakeholder meetings (n = 2) and surveys (n = 114). Data were collected to create the content of context-mechanism-outcome-configurations (CMOcs) important in compression therapy. Based on these CMOcs, targets for improvement to optimize the organization of compression care were identified. We identified overarching context factors and mechanisms targeting four optimal outcomes for the organization of compression therapy: selecting initial compression therapy types that support patient's self-reliance (1), evidence based selection of elastic compression stocking type and class (2), patient-based selection of assistive devices (3), individualizing treatment duration for DVT patients (4a) and providing follow-up for CVD patients (4b). We found that increasing health care professionals' knowledge of compression therapy, the availability of unambiguous protocols and guidelines, increasing patient involvement (and if applicable their informal care giver) in the decision making process, the accessible availability of resources, and increasing interdisciplinary consultation enhanced desirable outcomes. These targets triggered mechanisms such as increased health care professionals' willingness, confidence and motivation to provide patient-based care and increased patients' self-confidence and self-efficacy. This study provides a detailed insight into what needs to be in place to optimize compression care and identified five main targets for improvement.


Acute kidney injury after procedures of orthotopic liver transplantation.
The incidence of acute kidney injury (AKI) after orthotopic liver transplantation (OLT) ranges from 40 to 70%, with 8-17% of these patients requiring renal replacement therapy. The aetiology of this syndrome is multi-factorial, and its most common cause is ischaemia in the early postoperative period, and toxicity of immunosuppressive drugs and infectious complications at long term. AKI significantly increases the risk of death and development of chronic renal failure in the late post-OLT period. We discussed in short in our work the risk factors of AKI, diagnostics and clinical management in this group of patients.


Quality Over Quantity: Standardization of Pediatric HeartWare Ventricular Assist Device Dressing Changes.
Pediatric patients are unique both in their diagnosis and clinical presentation before implantation of a ventricular assist device (VAD) and in their driveline site characteristics post-implant. There is limited evidence in scholarly literature that describes complications of pediatric VAD driveline sites or approaches by which to manage them. The Cardiac Center at The Children's Hospital of Philadelphia (CHOP) follows a standard of care for HeartWare VAD (HVAD) dressing changes in the inpatient setting with the goal of transitioning patients to weekly dressing changes by the time they are discharged to home. As a patient with an HVAD nears discharge, members of an interprofessional team collaborate with insurance providers and home care agencies to procure the appropriate supplies needed at home. Individualized plans of care are necessary for patients who are unable to transition to weekly dressings; however, customized products (such as silicone foam border dressings and antimicrobial agents) may be challenging to supply as single items from home care agencies. Between March 2014 and June 2017, 15 patients underwent HVAD implantation, and eight (53%) were discharged home. Ten patients (67%) were able to transition to weekly dressing changes. Individualized plans of care for driveline site management were required for six (40%) patients with persistent drainage. Three patients (20%) experienced a driveline site infection. This article describes how a quality improvement (QI) initiative using rapid-cycle improvement methodology was executed to standardize HVAD dressing changes in our pediatric population.


[Personal resources and negative and positive effects of traumatic events in a group of medical rescuers].
The purpose of the research was to investigate the role of personal resources, such as optimism and sense of selfefficacy in both negative (posttraumatic stress disorder (PTSD) symptoms) and positive (posttraumatic growth - PTG) effects of experienced trauma in a group of emergency service representatives. Data of 100 medical rescue workers, mostly men (59%) who have experienced traumatic events in their worksite were analyzed. The age of the participants ranged from 24 to 60 years (mean = 37.43; standard deviation = 8.73). Polish versions of the Impact of Event Scale - Revised and the Posttraumatic Growth Inventory were used to assess the negative and positive effects of experienced events. Optimism was assessed by the Life Orientation Test and sense of self-efficacy by the Generalized Self-Efficacy Scale. The obtained results revealed that optimism is negatively associated with symptoms of PTSD in men, and sense of self-efficacy - positively with the severity of growth after trauma in women. The analyzed personal resources play a diverse role in the emergence of negative and positive effects of experienced traumatic events, depending on the gender of the respondents. Med Pr 2016;67(5):635-644.


NT-proBNP point-of-care measurement as a screening tool for heart failure and CVD risk in type 2 diabetes with hypertension.
We used N-terminal pro-B-type natriuretic peptide (NT-proBNP) point-of-care testing (POCT) for heart failure risk stratification of individuals with type 2 diabetes for >10 years and hypertension. Overall 259 participants aged 50 years or older with type 2 diabetes (duration of >10 years), hypertension, and no overt cardiovascular disease (CVD) were recruited at two study centers. Patients' data were acquired and NT-proBNP levels were measured using the CARDIAC proBNP+ test (Roche) and the cobas h232 instrument (Roche). Participants were clustered into two groups according to their NT-proBNP concentration value: with NT-proBNP <125 pg/ml and with NT-proBNP ≥125 pg/ml. Mean age of the participants was 66.1 ± 9.2 years, 55.2 % were female, 60.6 % (n = 157) had a NT-proBNP <125 pg/ml and 39.4 % (n = 102 ≥ 125 pg/ml). Differences were observed among those with low and high NT-proBNP in mean age (63.4 ± 8.8 years vs. 70.1 ± 8.2 years, p < 0.001), diabetes duration (15.4 ± 5.9 years vs. 17.9 ± 7.3 years, p = 0.003), and estimated glomerular filtration rate (eGFR) (86 ± 16 ml/min/1.73 m2 vs. 76 ± 20 ml/min/1.73 m2, p < 0.001). NT-proBNP POCT is practical and can be pragmatically targeted for screening people with type 2 diabetes and hypertension for heart failure risk stratification in routine clinical practice.


Synthesis and insertion of cytochrome P-450 into endoplasmic reticulum membranes.
Treatment of rats with phenobarbital leads to a substantial increase in levels of translatable liver cytochrome P-450 mRNA. This mRNA is primarily associated with ribosomes bound to endoplasmic reticulum membranes which in an in vitro system synthesized approximately 10 times more cytochrome P-450 than did free polysomes from the same animals. Cytochrome P-450 synthesized by rough microsomes in vitro appears to be directly inserted into the membranes because it was not released by a treatment with low detergent concentrations that released albumin and other microsomal content proteins. The amino-terminal amino acid sequence of cytochrome P-450 synthesized in an mRNA-dependent system resembles in hydrophobicity the signal segment of presecretory proteins and therefore may serve to insert the polypeptide into the membrane during synthesis. In contrast to the situation with secretory proteins and several other membrane proteins, however, the putative insertion signal of cytochrome P-450 is not removed by a membrane-associated peptidase and remains in the mature polypeptide.


Preparation of an ultra fast binding cement from calcium silicate-based mixed oxide nanoparticles.
Building construction takes time, in part because the binding process of cement is based on the slow re-crystallization and precipitation of calcium silicate species. Since the material's reactivity is surface area limited, a reduction in particle size of Portland cements has been used to prepare faster binding formulations. The present work investigates a new and direct, one-step preparation of calcium silicate-based nanoparticles of a typical Portland cement composition by flame spray synthesis. Isothermal calorimetry revealed that the hardening of this new nano-cement corroborated a more than tenfold increase of initial reactivity with different reaction kinetics if compared to conventionally prepared cements. At present, the unfavourably high porosity of nano-cements, however, underlines the need for additional improvements of chemical composition and formulation to make these highly reactive materials applicable to modern construction work, where load-bearing strength is of importance.


Communication with substrate-borne signals in small plant-dwelling insects.
Vibratory signals of plant-dwelling insects, such as land bugs of the families Cydnidae and Pentatomidae, are produced mainly by stridulation and/or vibration of some body part. Signals emitted by the vibratory mechanisms have low-frequency characteristics with a relatively narrow frequency peak dominant around 100 Hz and differently expressed frequency modulation and higher harmonics. Such spectral characteristics are well tuned to the transmission properties of plants, and the low attenuation enables long-range communication on the same plant under standing wave conditions. Frequencies of stridulatory signals extend up to 10 kHz. In some groups, vibratory and stridulatory mechanisms may be used simultaneously to produce broadband signals. The subgenual organ, joint chordotonal organs, campaniform sensilla and mechanoreceptors, such as the Johnston's organ in antennae, are used to detect these vibratory signals. Species-specific songs facilitate mate location and recognition, and less species-specific signals provide information about enemies or rival mates.


Anti-CD47 treatment enhances anti-tumor T-cell immunity and improves immunosuppressive environment in head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is considered as an immunosuppressive disease, with impaired tumor-infiltrating T lymphocytes and increased suppressive immune cells. The efficacy of CD47 antibodies in immune checkpoint therapy is not clearly understood in HNSCC. In this study, human tissue microarrays and immunocompetent transgenic mouse models were used to explore the expression of CD47 and the use of CD47 antibodies in HNSCC. We identified overexpression of CD47 in HNSCC as compared with the control normal human tissue and also in HNSCC mouse models. The expression of CD47 also correlated with clinicopathological parameters as well as outcome. Furthermore, inhibition of CD47 delayed tumor growth and improved tumor microenvironment by stimulating effector T cells and decreasing suppressive immune cells and regulating the function of CD11b+ Ly6G+ MDSC. Our data suggest that CD47 blockade may be a potential immunotherapeutic target in human HNSCC.


Ethical Issues in Cerebral Organoid Research.
About ten years ago, reports of lab-grown "mini brains" or "brains in a dish" appeared in the media, falling somewhere between the curious and the alarming. The trigger of these reports was a new method to grow three-dimensional neural tissue from human stem cells that recapitulates, to some degree, the early development of brain tissue. Despite their relatively small size and other limitations, such model systems capture in part the structure and functions of regions of the human brain and can also be combined to form so-called assembloids.


Arterial, venous and other vascular risk factors in multiple sclerosis.
This article reviews vascular risk factors with specific emphasis on lipid abnormalities reported to be associated with multiple sclerosis (MS). The current paradigm of MS, supported only partially by MS lesion histopathology and its animal model (experimental allergic encephalomyelitis) considers MS to be a predominantly autoimmune disease. Until recently, most of the known risk factors for MS were interpreted in the context of the autoimmune theory, which still fails to explain why genetically close populations exposed to similar pathogens and/or environmental risk factors have different incidences of MS. Therapies which partially modulate the inflammatory arm of MS pathogenesis, fail to achieve similar benefits in later disease stages, when less inflammatory lesions and more neurodegeneration are present. Several studies have reported an increased cardiovascular morbidity in MS patients and that vascular comorbidity at any time during the disease course also increased the risk of progressive disability. A condition named chronic cerebrospinal venous insufficiency provided a different perspective, on the possible association of MS with the abnormalities of the venous system. Our recent findings revealed increased prevalence of chronic cerebrospinal venous insufficiency associated with MS disease progression as well as with other neurologic disorders. On the other hand, recently emerging evidence indicates that there is an association between lipoproteins and cholesterol metabolism and MS disease progression. Expanded disability status scale worsening was associated with higher baseline low-density lipoprotein and total cholesterol, and higher serum high-density lipoprotein levels were associated with lower contrast-enhancing T1-weigthed lesion volume. It is thought that apolipoprotein A-1 and paraoxonase anti-oxidant enzyme are associated with high-density lipoprotein and contribute to its anti-oxidant and anti-inflammatory properties. A significant inter-dependence was also recently demonstrated between vitamin D, one of the best known environmental risk factors for MS and MS disease progression and the serum lipid profile. Future work in this direction is required in order to better elucidate the role of lipid metabolism and vascular pathology in pathogenesis of MS.


Low quality of routine microscopy for malaria at different levels of the health system in Dar es Salaam.
Laboratory capacity to confirm malaria cases in Tanzania is low and presumptive treatment of malaria is being practiced widely. In malaria endemic areas WHO now recommends systematic laboratory testing when suspecting malaria. Currently, the use of Rapid Diagnostic Tests (RDTs) is recommended for the diagnosis of malaria in lower level peripheral facilities, but not in health centres and hospitals. In this study, the following parameters were evaluated: (1) the quality of routine microscopy, and (2) the effects of RDT implementation on the positivity rate of malaria test results at three levels of the health system in Dar es Salaam, Tanzania. During a baseline cross-sectional survey, routine blood slides were randomly picked from 12 urban public health facilities in Dar es Salaam, Tanzania. Sensitivity and specificity of routine slides were assessed against expert microscopy. In March 2007, following training of health workers, RDTs were introduced in nine public health facilities (three hospitals, three health centres and three dispensaries) in a near-to-programmatic way, while three control health facilities continued using microscopy. The monthly malaria positivity rates (PR) recorded in health statistics registers were collected before (routine microscopy) and after (routine RDTs) the intervention in all facilities. At baseline, 53% of blood slides were reported as positive by the routine laboratories, whereas only 2% were positive by expert microscopy. Sensitivity of routine microscopy was 71.4% and specificity was 47.3%. Positive and negative predictive values were 2.8% and 98.7%, respectively. Median parasitaemia was only three parasites per 200 white blood cells (WBC) by routine microscopy compared to 1226 parasites per 200 WBC by expert microscopy. Before RDT implementation, the mean test positivity rates using routine microscopy were 43% in hospitals, 62% in health centres and 58% in dispensaries. After RDT implementation, mean positivity rates using routine RDTs were 6%, 7% and 8%, respectively. The sensitivity and specificity of RDTs using expert microscopy as reference were 97.0% and 96.8%. The positivity rate of routine microscopy remained the same in the three control facilities: 71% before versus 72% after. Two cross-sectional health facility surveys confirmed that the parasite rate in febrile patients was low in Dar es Salaam during both the rainy season (13.6%) and the dry season (3.3%). The quality of routine microscopy was poor in all health facilities, regardless of their level. Over-diagnosis was massive, with many false positive results reported as very low parasitaemia (1 to 5 parasites per 200 WBC). RDTs should replace microscopy as first-line diagnostic tool for malaria in all settings, especially in hospitals where the potential for saving lives is greatest.


Regulation of the retinal determination gene dachshund in the embryonic head and developing eye of Drosophila.
The retinal determination gene dachshund is distantly related to the family of Ski/Sno proto-oncogenes and influences the development of a wide range of tissues including the embryonic head, optic lobes, brain, central nervous system as well as the post-embryonic leg, wing, genital and eye-antennal discs. We were interested in the regulatory mechanisms that control the dynamic expression pattern of dachshund and in this report we set out to ascertain how the transcription of dachshund is modulated in the embryonic head and developing eye-antennal imaginal disc. We demonstrate that the TGFbeta signaling cascade, the transcription factor zerknullt and several other patterning genes prevent dachshund from being expressed inappropriately within the embryonic head. Additionally, we show that several members of the eye specification cascade influence the transcription of dachshund during normal and ectopic eye development. Our results suggest that dachshund is regulated by a complex combinatorial code of transcription factors and signaling pathways. Unraveling this code may lead to an understanding of how dachshund regulates the development of many diverse tissue types including the eye.


Benign focal seizures of adolescence: a prospective study.
To characterize the clinical and EEG findings and evolution of the syndrome of benign focal seizures of adolescence (BFSA), as described by Loiseau et al. A prospective study was performed in adolescents with normal clinical and neurologic examinations and normal neuroradiologic studies who had focal seizures that occurred isolated or in a cluster, with or without secondary generalization in the first 24 to 48 h after onset. None of the patients was treated with antiepileptic drugs (AEDs). Between January 1996 and January 2002, 15 patients with BFSA were enrolled in the study. Median age at onset of BFSA was 14 years. Thirteen patients had focal sensory or motor seizures. In two patients, the ictal manifestation was motion arrest associated with oral automatisms. Eight of them evolved to generalized tonic-clonic seizures. Thirteen patients had seizures only when awake, and the other two, both when awake and during sleep. Repeated interictal EEGs were normal, but in four of the patients who had seizures in a cluster, we were able to record an EEG within 8 h after seizure onset. Two of these four patients had focal seizures, and their waking EEG showed focal centroparietal theta activities. The other two patients had secondarily generalized seizures, and their waking EEG showed bilateral theta activities instead. Prognosis was excellent. BFSA is a well-defined seizure syndrome, recognizable by clinical and EEG features, as described by Loiseau et al. In teenagers with these electroclinical features with a normal neurologic examination and normal neuroradiologic findings, AEDs should be avoided.


Self-assembly of recombinant prion protein of 106 residues.
The central event in the pathogenesis of prion diseases is a profound conformational change of the prion protein (PrP) from an alpha-helical (PrP(C)) to a beta-sheet-rich isoform (PrP(Sc)). The elucidation of the mechanism of conformational transition has been complicated by the challenge of collecting high-resolution biophysical data on the relatively insoluble aggregation-prone PrP(Sc) isoform. In an attempt to facilitate the structural analysis of PrP(Sc), a redacted chimeric mouse-hamster PrP of 106 amino acids (MHM2 PrP106) with two deletions (Delta23-88 and Delta141-176) was expressed and purified from Escherichia coli. PrP106 retains the ability to support PrP(Sc) formation in transgenic mice, implying that it contains all regions of PrP that are necessary for the conformational transition into the pathogenic isoform [Supattapone, S., et al. (1999) Cell 96, 869-878]. Unstructured at low concentrations, recombinant unglycosylated PrP106 (rPrP106) undergoes a concentration-dependent conformational transition to a beta-sheet-rich form. Following the conformational transition, rPrP106 possesses properties similar to those of PrP(Sc)106, such as high beta-sheet content, defined tertiary structure, resistance to limited digestion by proteinase K, and high thermodynamic stability. In GdnHCl-induced denaturation studies, a single cooperative conformational transition between the unstructured monomer and the assembled beta-oligomer was observed. After proteinase K digestion, the oligomers retain an intact core with unusually high beta-sheet content (>80%). Using mass spectrometry, we discovered that the region of residues 134-215 of rPrP106 is protected from proteinase K digestion and possesses a solvent-independent propensity to adopt a beta-sheet-rich conformation. In contrast to the PrP(Sc)106 purified from the brains of neurologically impaired animals, multimeric beta-rPrP106 remains soluble, providing opportunities for detailed structural studies.


Linked Patient and Provider Impressions of Outpatient Teleneurology Encounters.
Teleneurology is common in clinical practice partly due to the SARS CoV-2 pandemic. Impressions about teleneurology from patients and providers alike are generally favorable; some of the reported benefits include ease of access to specialized health care, savings of time and money, and similar quality of care as an in-person visit. However, comparisons between patient and provider impressions about the same teleneurology encounter have not been described. In this study, we describe patient impressions about a teleneurology encounter and evaluate concordance with provider impressions about the same encounter. Patients and providers at the University of Pennsylvania Hospital Neurology Department were surveyed about their impressions of teleneurology between April 27, 2020, and June 16, 2020. A convenience sample of patients, whose providers completed a questionnaire, were contacted by telephone to solicit their impressions about the same encounter. Unique questionnaires for patients and providers focused on similar themes, such as adequacy of technology, assessment of history obtained, and overall quality of the visit. Summaries of patient responses are reported with the raw percent agreement between patients and providers for similar questions. One hundred thirty-seven patients completed the survey; 64 (47%) were male and 73 (53%) were female. Sixty-six (47%) patients had a primary diagnosis of PD, 42 (30%) a non-PD/parkinsonism movement disorder, and 29 (21%) a nonmovement disorder neurologic disease. One hundred one (76%) were established patient visits and 36 (26%) were new patient visits. Provider responses from 8 different physicians were included. Most of the patients responded that the ease of joining their visit, their comfort engaging with their physicians during their visit, understanding their plan of care after their visit, and the quality of care from their teleneurology visit were satisfactory. Patients and providers agreed about their impressions of the quality of the history obtained (87% agreement), patient-provider relationship (88% agreement), and overall quality of their experience (70% agreement). Patients had favorable impressions about their clinical experience with teleneurology and expressed an interest in incorporating telemedicine visits into their ongoing care. Patients and providers were highly concordant for the history obtained, patient-provider relationship, and overall quality.


Impact of malocclusion severity on oral health-related quality of life in an Iranian young adult population.
This study aimed to assess the relationship between malocclusion severity and oral health-related quality of life (QoL) of 18 to 25-year-old Iranians who sought orthodontic treatment. A total of 126 patients between 18 and 25 years attending some private orthodontic clinics answered the oral health impact profile-14 (OHIP-14) and a demographic questionnaire. Two calibrated orthodontists recorded the Index of Orthodontic Treatment Need-Dental Health Component (IOTN-DHC) determining the severity of malocclusion (Kappa = 0.8). The IOTN-Aesthetic Component (IOTN-AC) was reported by patients for assessing the perception of their esthetic severity of malocclusion. Logistic regression analysis was used. Level of significance was set at α = 0.05. The mean score of OHIP-14 was 20.87 ± 8.6. The frequency of patients with no/slight, borderline, and definite need for orthodontic treatment was determined as 13.4%, 23.8%, and 62.7%, respectively, by IOTN-DHC. There were significant correlations between borderline or definite need treatment and OHIP-14 overall score (P < 0.05). Patients with borderline and definite need for orthodontic treatment had 5 and 21 times lower QoL, respectively, than those with a slight need for orthodontic treatment. Based on IOTN-AC, 50.8% of the patients mentioned slight or no need based on IOTN-AC. No significant association was noted between IOTN-AC and OHIP-14 overall scores. The results showed negative impact of malocclusion severity on the QoL. This study highlighted the importance of individual assessment of orthodontic patients.


Experience sharing on the implementation of telehealth system in Hong Kong.
With the growth of the ageing population in Hong Kong, healthcare professionals believe that there will be a great demand of healthcare service at the community level. In 2000, the first prototype of telehealth system was developed, tested and validated by the School of Nursing, The Hong Kong Polytechnic University. With the advancement of information technology and inexpensive video- conference facility, an inter-clinic patient-centered healthcare information system has been evolved and used by a number of satellite clinics since 2003. In order to foster the importance of personal healthcare education at the community level, different versions of the telehealth system were designed and developed for school children and teenagers. Now the research team is focusing on the development of the pocket PC's version. Experience on the deployment of such technology-intensive system in healthcare was discussed in this paper.


Effects of baicalein, an antioxidant, on the bioavailability of doxorubicin in rats: possible role of P-glycoprotein inhibition by baicalein.
The purpose of this thesis is to investigate the effects of baicalein, an antioxidant, on the bioavailability and pharmacokinetics of Doxorubicin (DOX) in rats. Thus, DOX was administered intravenously (i.v.; 10 mg x kg(-1)) or orally (p.o.; 50 mg x kg(-1)) with or without oral baicalein (0.3, 1.5 and 6 mg x kg(-1)). In the presence of 1.5 and 6 mg x kg(-1) of baicalein, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and the peak concentration (Cmax) of DOX were significantly greater and higher, respectively, than those of the control. Consequently, the absolute bioavailability (AB) of DOX in the presence of baicalein was 3.5-4.4%, which was significantly enhanced compared with that of the control group (2.2%). The relative bioavailability (RB) of DOX was 1.20 to 1.96 times higher than that of the control group. Compared to the intravenous control, the presence of oral baicalein increased the i.v. AUC of DOX and other pharmacokinetic parameters were not significantly affected. The enhanced bioavailability of oral DOX by oral baicalein may be due to the inhibition of both P-glycoprotein (P-gp) and the cytochrome P450 (CYP) 3A subfamily by baicalein in the intestine and/or liver. This result suggests that the development of oral DOX is feasible by combination with baicalein that would be more convenient than the i.v. dosage forms. Furthermore, since the present study raises the awareness about potential drug interactions by concomitant use of DOX with baicalein, the dosage regimen of DOX should be taken into consideration, if this result is confirmed in clinical studies.


A Prospective Evaluation of Point-of-Care Measurements of Maternal Glucose for the Diagnosis of Gestational Diabetes Mellitus.
Point-of-care (POC) measurement of glucose is currently recommended only for the monitoring of gestational diabetes mellitus (GDM). This prospective observational study evaluated the use of POC measurements of maternal glucose to diagnose GDM in women being screened selectively with a 1-step 75 g oral glucose tolerance test (OGTT). The strictest preanalytic and analytic international laboratory standards were applied to measure maternal plasma glucose at fasting and at 1 and 2 h post glucose load. The recent International Association of Diabetes and Pregnancy Study Groups diagnostic criteria were used. At the same time, maternal capillary glucose was measured. Because of differences in plasma and capillary glucose measurements, regression analysis of POC capillary glucose results vs laboratory plasma glucose results was conducted. The regression equations for plasma glucose were derived in a derivation cohort (n = 102). These equations were applied in the validation cohort (n = 100). Predicted and actual plasma glucose values were compared. Of the 202 women screened, 36.6% were nulliparous, 56.4% were obese, and 81.2% were Irish-born. Two thirds had a single risk factor for GDM, and a third had multiple risk factors. Based on the plasma measurements, 53.5% had GDM. As a predictor of GDM, the diagnostic accuracy of POC measurement was 83.0% (95% confidence interval, 74.2-89.8). In high-resource settings where measures to inhibit glycolysis are implemented, the use of POC measurements for the diagnosis of GDM is not justified based on this study. In low- and medium-resource settings, where measures to inhibit glycolysis are not achievable, regression analysis using POC measurements may be acceptable compared with plasma samples subject to glycolysis.


Aggregated recommendation through random forests.
Aggregated recommendation refers to the process of suggesting one kind of items to a group of users. Compared to user-oriented or item-oriented approaches, it is more general and, therefore, more appropriate for cold-start recommendation. In this paper, we propose a random forest approach to create aggregated recommender systems. The approach is used to predict the rating of a group of users to a kind of items. In the preprocessing stage, we merge user, item, and rating information to construct an aggregated decision table, where rating information serves as the decision attribute. We also model the data conversion process corresponding to the new user, new item, and both new problems. In the training stage, a forest is built for the aggregated training set, where each leaf is assigned a distribution of discrete rating. In the testing stage, we present four predicting approaches to compute evaluation values based on the distribution of each tree. Experiments results on the well-known MovieLens dataset show that the aggregated approach maintains an acceptable level of accuracy.


What Approaches to Thwart Bacterial Efflux Pumps-Mediated Resistance?
An effective response that combines prevention and treatment is still the most anticipated solution to the increasing incidence of antimicrobial resistance (AMR). As the phenomenon continues to evolve, AMR is driving an escalation of hard-to-treat infections and mortality rates. Over the years, bacteria have devised a variety of survival tactics to outwit the antibiotic's effects, yet given their great adaptability, unexpected mechanisms are still to be discovered. Over-expression of efflux pumps (EPs) constitutes the leading strategy of bacterial resistance, and it is also a primary driver in the establishment of multidrug resistance (MDR). Extensive efforts are being made to develop antibiotic resistance breakers (ARBs) with the ultimate goal of re-sensitizing bacteria to medications to which they have become unresponsive. EP inhibitors (EPIs) appear to be the principal group of ARBs used to impair the efflux system machinery. Due to the high toxicity of synthetic EPIs, there is a growing interest in natural, safe, and innocuous ones, whereby plant extracts emerge to be excellent candidates. Besides EPIs, further alternatives are being explored including the development of nanoparticle carriers, biologics, and phage therapy, among others. What roles do EPs play in the occurrence of MDR? What weapons do we have to thwart EP-mediated resistance? What are the obstacles to their development? These are some of the core questions addressed in the present review.


Oleuropein Curtails Pulmonary Inflammation and Tissue Destruction in Models of Experimental Asthma and Emphysema.
Airway inflammation has been implicated in evoking progressive pulmonary disorders including chronic obstructive pulmonary disease (COPD) and asthma as a result of exposure to inhaled irritants, characterized by airway fibrosis, mucus hypersecretion, and loss of alveolar integrity. The current study examined whether oleuropein, a phenylethanoid found in olive leaves, inhibited pulmonary inflammation in experimental models of interleukin (IL)-4-exposed bronchial BEAS-2B epithelial cells and ovalbumin (OVA)- or cigarette smoke (CS)-exposed BALB/c mice. Nontoxic oleuropein at 1-20 μM diminished eotaxin-1-mediated induction of α-smooth muscle actin and mucin 5AC in epithelial cells stimulated by IL-4 at the transcriptional levels. Oral supplementation of 10-20 mg/kg oleuropein reduced the airway influx of eosinophils and lymphocytes as well as IL-4 secretion in lung promoted by OVA inhalation or CS. In addition, oleuropein suppressed infiltration of macrophages and neutrophils through blocking OVA inhalation- and CS-promoted induction of ICAM-1, F4/80, CD68, and CD11b in airways. OVA-exposed pulmonary fibrosis was detected, while alveolar emphysema was evident in CS-exposed mouse lungs. In alveolar epithelial A549 cells exposed to CS extracts, oleuropein attenuated apoptotic cell loss. Collectively, oleuropein inhibited pulmonary inflammation leading to asthmatic fibrosis and alveolar emphysema driven by influx of inflammatory cells in airways exposed OVA or CS. Therefore, oleuropein may be a promising anti-inflammatory agent for treating asthma and COPD.


Nutritional Intervention for a Critically Ill Trauma Patient: A Case Report.
Critically ill trauma patients generally show good nutritional status upon initial hospitalization. However, they have a high risk of malnutrition due to hyper-metabolism during the acute phase. Hence, suitable nutritional support is essential for the optimal recovery of these patients; therefore, outcomes such as preservation of fat-free mass, maintenance of immune functions, reduction in infectious complications, and prevention of malnutrition can be expected. In this report, we present the experience of a patient subjected to 40 days of nutritional interventions during postoperative intensive care unit (ICU) care. Although the patient was no malnutrition at ICU admission, enteral nutrition (EN) was delayed for > 2 weeks because of several postoperative complications. Subsequently, while receiving parenteral nutrition (PN), the patient displayed persistent hypertriglyceridemia. As a result, his prescription of PN were converted to lipid-free PN. On postoperative day (POD) #19, the patient underwent jejunostomy and started standard EN. A week later, the patient was switched to a high-protein, immune-modulating formula for postoperative wound recovery. Thereafter, PN was stopped, while EN was increased. In addition, because of defecation issues, a fiber-containing formula was administered with previous formula alternately. Despite continuous nutritional intervention, the patient experienced a significant weight loss and muscle mass depletion and was diagnosed with severe malnutrition upon discharge from the ICU. To conclude, this case report highlights the importance of nutrition interventions in critically ill trauma patients with an increased risk of malnutrition, indicating the need to promptly secure an appropriate route of feeding access for active nutritional support of patients in the ICU.


Coordination Complexes of Titanium(IV) and Indium(III) Phthalocyanines with Carbonyl-Containing Dyes: The Formation of Singly Bonded Anionic Squarylium Dimers.
Reduction methods for the preparation of coordination complexes of titanium(IV) and indium(III) phthalocyanines (Pc) with organic dyes such as indigo, thioindigo, and squarylium dye III (SQ) have been developed, which allow one to obtain crystalline {cryptand(K+ )}{(cis-indigo-O,O)2- TiIV (Pc2- )}(Cl- )⋅C6 H4 Cl2 (1), {cryptand(K+ )}{(cis-thioindigo-O,O)2- InIII (Pc2- )}- ⋅C6 H4 Cl2 (2), and {cryptand(K+ )}{[(SQ)2 -O,O]2- InIII (Pc2- )}- ⋅3.5 C6 H4 Cl2 (3) complexes. The formation of these complexes is accompanied by the reduction of the starting dyes to the anionic state. Transition of trans-indigo or trans-thioindigo to the cis conformation in 1 and 2 provides coordination of both carbonyl oxygen atoms of the dye to TiIV Pc or InIII Pc. SQ is reduced to the radical anion state and forms unusual diamagnetic singly bonded (SQ- )2 dimers in 3. These dimers have two closely positioned carbonyl oxygen atoms coordinated to InIII Pc. Dianionic Pc2- macrocycles have been found in 1-3. The complexes contain two chromophore molecules at one metal center. However, their optical spectra are defined mainly by absorption bands of the metal phthalocyanines.


[Molecular biological study on hormones in Acipenseriformes].
Sturgeons belong to the Acipenseriformes, which provide an ideal model for evolutionary studies due to their unique characters. At present, many species of Acipenseriformes are very rare and near extinct. It is urgent to protect these species. However, data on molecular mechanisms of their growth and reproduction regulation are still limited. Hormones are important factors involved in these processes. In this paper, we summarized recent research progresses in the hormones in sturgeon, which will provide valuable information for further studies on molecular mechanisms of growth, sexual development, and reproduction regulation in Acipenseriformes.