100 multivisceral transplants at a single center.
The objective of this study was to summarize the evolution of multivisceral transplantation over a decade of experience and evaluate its current status. Multivisceral transplantation can be valuable for the treatment of patients with massive abdominal catastrophes. Its major limitations have been technical and rejection of the intestinal graft. This study consisted of an outcome analysis of 98 consecutive patients who received multivisceral transplantation at our institution. This represents the largest single center experience to date. The most common diseases in our population before transplant were intestinal gastroschisis and intestinal dysmotility syndromes in children, and mesenteric thrombosis and trauma in adults. Kaplan Meier estimated patient and graft survivals for all cases were 65% and 63% at 1 year, 49% and 47% at 3 years, and 49% and 47% at 5 years. Factors that adversely influenced patient survival included transplant before 1998 (P = 0.01), being hospitalized at the time of transplant (P = 0.05), and being a child who received Campath-1H induction (P = 0.03). Among 37 patients who had none of these 3 factors (15 adults and 22 children), estimated 1- and 3-year survivals were 89% and 71%, respectively. Patients transplanted since 2001 had significantly less moderate and severe rejections (31.6% vs 67.6%, P = 0.0005) with almost half of these patients never developing rejection. Multivisceral transplantation is now an effective treatment of patients with complex abdominal pathology. The incidences of serious acute rejection and patient survival have improved in the most recent experience. Our results show that the multivisceral graft seems to facilitate engraftment of transplanted organs and raises the possibility that there is a degree of immunologic protection afforded by this procedure.


Miraculous Meaning: Threatened Meaning Increases Belief in Miracles.
For many, religious belief is a source of meaning and a resource for coping with life stressors that have the potential to undercut meaning. In the present study, we sought to further probe the connection between religion and meaning by focusing on the potential for threatened meaning to inspire belief in miraculous testimonials. We threatened meaning with a meaninglessness manipulation and then had participants read testimonials in which people described miraculous experiences involving supernatural agents and rate the extent to which they believed these testimonials to be credible and true. Meaning threat, relative to a control condition, increased belief in miraculous stories.


Cesarean section is not protective against adverse neurological outcome in survivors of preterm delivery due to overt chorioamnionitis.
To determine whether the mode of delivery has a protective value on the immediate adverse neonatal neurological outcome of infants born from pregnancies complicated by preterm chorioamnionitis. A comparison of the immediate and long-term neurological outcome of preterm neonates (24-34 weeks' gestation) of pregnancies complicated by chorioamnionitis, was made between those born by Cesarean section and by vaginal delivery. Of the 73 newborns, 54 (74%) survived the neonatal period; two (2.7%) had incomplete records, leaving 71 for analysis. Thirty (42.2%) were delivered by Cesarean section and 41 (57.7%) vaginally. The obstetric and neonatal characteristics were comparable. Twenty-four (80%) survived in the Cesarean group and 30 (73.2%) in the vaginal delivery group (NS). There was no significant difference in the immediate adverse neonatal neurological outcome between Cesarean and vaginal deliveries. The mode of delivery did not significantly affect the immediate neurological status of preterm infants exposed to antenatal intrauterine infection.


Efficacy and safety of Mojeaga remedy in combination with conventional oral iron therapy for correcting anemia in obstetric population: A phase II randomized pilot clinical trial.
To our knowledge, there is no prior randomized trial on the efficacy of Mojeaga remedy (a special blend of Alchornea cordifolia, Pennisetum glaucum and Sorghum bicolor extracts) when co-administered with standard-of-care for correction of anemia in obstetrics practice. This study determined the efficacy, safety and tolerability of Mojeaga as adjunct to conventional oral iron therapy for correction of anemia in obstetric population. A pilot open-label randomized clinical trial. Participants with confirmed diagnosis of anemia in three tertiary hospitals in Nigeria were studied. Eligible participants were randomized 1:1 to either Mojeaga syrups 50 mls (200mg/50mls) administered three times daily in conjunction with conventional iron therapy (Mojeaga group) for 2 weeks or conventional iron therapy alone without Mojeaga (standard-of-care group) for 2 weeks. Repeat hematocrit level were done 2 weeks post-initial therapy. Primary outcome measures were changes in hematocrit level and median hematocrit level at two weeks post therapy. Maternal adverse events and neonatal outcomes (birth anomalies, low birthweight, preterm rupture of membranes and preterm labor) were considered the safety outcome measures. Analysis was by intention-to-treat. Ninety five participants were enrolled and randomly assigned to the Mojeaga group (n = 48) or standard-of-care group (n = 47). The baseline socio-demographic and clinical characteristics of the study participants were similar. At two weeks follow-up the median rise in hematocrit values from baseline (10.00±7.00% vs 6.00±4.00%;p<0.001) and median hematocrit values (31.00±2.00% vs 27.00±3.00%;p<0.001) were significantly higher in the Mojeaga group. There were no treatment-related serious adverse events, congenital anomalies or deaths in the Mojeaga group and incidence of other neonatal outcomes were similar (p>0.05). Mojeaga represents a new adjuvants for standard-of-care option for patients with anemia. Mojeaga remedy is safe for treating anemia during pregnancy and puerperium without increasing the incidence of congenital anomalies, or adverse neonatal outcomes. www.pactr.samrc.ac.za: PACTR201901852059636 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=5822).


A Single-Session Online Cognitive Bias Modification of Interpretations Modified for Adults With Anxiety and Depressive Symptoms.
Anxiety and depression are common, co-occurring, and costly mental health disorders. Cognitive bias modification aims to modify biases to reduce associated symptoms. Few studies have targeted multiple biases associated with both anxiety and depression, and those that have lacked a control condition. This study piloted a single-session online cognitive bias modification (known as CBM-IA) designed to target two biases associated with anxiety and depression-interpretation bias and attribution style-in adults with varying levels of anxiety and depressive symptoms. Participants (18-26 years) with at least mild levels of anxiety/stress and depressive symptoms on the DASS-21 were randomly allocated to an intervention (n = 23) or a control (n = 22) condition. The training consisted of a single-session online CBM-IA to encourage positive interpretations and a positive attribution style. Interpretation bias, attribution style, anxious and depressive mood states, and anxiety, stress and depressive symptoms improved at posttraining and at follow-up, irrespective of condition. Changes in interpretation bias from pre- to posttraining were significantly associated with changes in anxious mood state. CBM-IA, as implemented in this single-session pilot study, did not significantly reduce targeted biases and symptoms compared to a control condition. This adds to the mixed evidence on the efficacy of single-session CBM-I for altering biases and symptoms.


Human tissue kallikrein 7, a novel biomarker for advanced ovarian carcinoma using a novel in situ quantitative method of protein expression.
Kallikreins, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. Here, we sought to determine the prognostic value of kallikrein 7 (hk7) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. A tissue array composed of 150 advanced-stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of kallikrein 7 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Mean follow-up time of the cohort was 34.35 months. One hundred and twenty eight of 150 cases had sufficient tissue for AQUA. In univariate survival analysis, low tumor hk7 expression was associated with better outcome for overall survival (OS) and disease-free survival in 3 years (P values 0.032 and 0.037, respectively). In multivariate survival analysis, adjusting for well-characterized prognostic variables, low tumor hk7 expression level was the most significant predictor variable for OS (95% confidence interval 0.125-0.729, P = 0.007). High tumor hk7 protein expression is associated with inferior patient outcome in ovarian cancer. hk7 may represent a promising prognostic factor in ovarian cancer.


Ligusticum chuanxiong exerts neuroprotection by promoting adult neurogenesis and inhibiting inflammation in the hippocampus of ME cerebral ischemia rats.
Cerebral ischemia, also known as stroke, can stimulate the proliferation and migration of endogenous neural stem cells (NSCS) in subventricular zone of the lateral ventricle and subgranularzone of the dentate gyrus in the adult hippocampus as a defense response to damage. However, the proliferation of endogenous NSCS is insufficient for central nervous system repair. Neurogenesis and anti-neuroinflammation are two important aspects for neuroprotection. Rhizome Ligusticum chuanxiong (LC), the dried rhizomes of Ligusticum striatum DC., has been widely used to treat stroke for over hundreds of years in Traditional Chinese Medicine. of the study: Previous reports on pharmacological mechanism of LC mainly focus on the cerebral blood flow and thrombolysis. We aim to explore whether LC provides neuroprotective effect by increasing neurogenesis and inhibiting the IL-1β, TNF-α and expressions of glial fibrillary acidic protein. LC extract was delivered to microsphere-embolized (ME) cerebral ischemia Wister rats to examine its neuroprotection. Body weight, neurological scores, hematoxylin-eosin staining (HE), TUNEL assay were conducted for neurological damage. Neurogenesis was evaluated by assessing the expression of Doublecortin (DCX) and neurogenic differentiation1 (NeuroD1) through immunofluorescence staining. Western blot performed to measure the protein levels of growth associated protein-43(GAP-43), glial fibrillary acidic protein (GFAP). IL-1β and TNF-α was detected by Elisa. LC alleviated pathomorphological change and apoptosis of neurons in the hippocampus caused by ME surgery. Furthermore, LC significantly increased the DCX in the DG of adult rat hippocampus at 14 days after surgery. A significant upregulation of GAP-43 compared to the ME after LC was administered. Besides, LC decreased pro-inflammatory cytokine (IL-1β, TNF-α) and protein level of GFAP. The finding suggested that LC had the ability to protect neurons by promoting the endogenous proliferation of neuroblast and production of neural differentiation factor in rats after ischemia injury. Meanwhile, LC can anti-neuroinflammation, which is important for the treatment of neuron injury. Accordingly, LC perhaps a promising medicine for neuron damage therapy after cerebral ischemia.


Impact of terminal tip location of midline catheters on catheter-related complications and indwelling duration in elderly patients.
To investigate the relationship between the position of the midline catheter tip and the frequency and type of complications associated with its placement. A cohort study was performed on patients between May 2018 and December 2021 who underwent midline catheter placement at our institution. Patients were divided into two groups, superficial implementation and deep implementation, based on the midline catheter tip location relative to the clavicle. Clinical data and outcome parameters, including the numbers and types of midline catheter-related complications, day of occurrence and catheter indwell duration, were recorded. Catheter-related complications occurred in 14 individuals. Compared with the superficial implementation group, the incidence of complications in the deep catheterization group was significantly reduced, with a delayed first occurrence time, and a prolonged catheter indwelling time. The results suggested that locating the midline catheter tip in the distal segment of the axillary vein may reduce catheter-related complication incidence and prolong the indwelling duration.


Abortion, social inequity, and women's health: obstetrician-gynecologists as agents of change.
Unsafe abortion persists as a serious health problem for women. It is rooted in poverty, social inequity, and denial of women's basic human rights. As experience from Latin America and other regions demonstrates, obstetrician-gynecologists can be leaders in supporting reproductive rights and access to safe abortion, through their professional societies and also by way of their roles as providers, academicians, and advocates. Ob-gyns are often most effective when working in partnership with women's organizations, lawyers, and other stakeholders.


Lipid metabolism in colon cancer: Role of Liver X Receptor (LXR) and Stearoyl-CoA Desaturase 1 (SCD1).
Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. Although several genetic alterations have been associated with CRC onset and progression, nowadays the reprogramming of cellular metabolism has been recognized as a fundamental step of the carcinogenic process. Intestinal tumor cells frequently display an aberrant activation of lipid metabolism. Indeed, to satisfy the growing needs of a continuous proliferation, cancer cells can either increase the uptake of exogenous lipids or upregulate the endogenous lipogenesis and cholesterol synthesis. Therefore, strategies aimed at limiting lipid accumulation are now under development in order to counteract malignancies. Two major players of lipids metabolism have been so far identified for their contribution to CRC development: the nuclear receptor Liver X Receptor (LXRs) and the enzyme Stearoyl-CoA Desaturase 1 (SCD1). Whereas LXR is mainly recognized for its role as a cholesterol sensor, finally promoting the loss of cellular cholesterol and whole-body homeostasis, SCD1 acts as the major regulator of new fatty acids, finely tuning the monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA) ratio. Intriguingly, SCD1 is directly regulated by LXRs. Despite LXRs agonists have elicited great interest as a promising therapeutic target for cancer, LXR's ability to induce SCD1 and new fatty acids synthesis represent a major obstacle in the development of new effective treatments. Thus, further investigations are required to fully dissect the concomitant modulation of both players, to develop specific therapies aimed at blocking intestinal cancer cells proliferation, eventually counteracting CRC progression.


Automatic inference of hypoglycemia causes in type 1 diabetes: a feasibility study.
Hypoglycemia is the most common adverse consequence of treating diabetes, and is often due to suboptimal patient self-care. Behavioral interventions by health professionals and self-care education helps avoid recurrent hypoglycemic episodes by targeting problematic patient behaviors. This relies on time-consuming investigation of reasons behind the observed episodes, which involves manual interpretation of personal diabetes diaries and communication with patients. Therefore, there is a clear motivation to automate this process using a supervised machine learning paradigm. This manuscript presents a feasibility study of automatic identification of hypoglycemia causes. Reasons for 1885 hypoglycemia events were labeled by 54 participants with type 1 diabetes over a 21 months period. A broad range of possible predictors were extracted describing a hypoglycemic episode and the subject's general self-care from participants' routinely collected data on the Glucollector, their diabetes management platform. Thereafter, the possible hypoglycemia reasons were categorized for two major analysis sections - statistical analysis of relationships between the data features of self-care and hypoglycemia reasons, and classification analysis investigating the design of an automated system to determine the reason for hypoglycemia. Physical activity contributed to 45% of hypoglycemia reasons on the real world collected data. The statistical analysis provided a number of interpretable predictors of different hypoglycemia reasons based on self-care behaviors. The classification analysis showed the performance of a reasoning system in practical settings with different objectives under F1-score, recall and precision metrics. The data acquisition characterized the incidence distribution of the various hypoglycemia reasons. The analyses highlighted many interpretable predictors of the various hypoglycemia types. Also, the feasibility study presented a number of concerns valuable in the design of the decision support system for automatic hypoglycemia reason classification. Therefore, automating the identification of the causes of hypoglycemia may help objectively to target behavioral and therapeutic changes in patients' care.


Application of reverse transcriptase PCR-based T-RFLP to perform semi-quantitative analysis of metabolically active bacteria in dairy fermentations.
A method consisting of reverse transcriptase (RT)-PCR amplification of 16S rRNA from the total microbial community, coupled with T-RFLP, was optimized for semi-quantitative characterization of the metabolically active population in defined strain cultures of Lactococcus lactis ssp. lactis and Leuconostoc citreum, two mesophilic lactic acid bacteria (LAB) species routinely used in cheese manufacture. The set of PCR primers selected efficiently amplified the 16S rRNA from both bacterial species. The digestion of the PCR products with DdeI yielded different terminal restriction fragments (T-RFs) for each species. Nevertheless, additional T-RFs due to formation of chimeric molecules and pseudo-T-RFs derived from partly single-stranded 16S rRNA amplicons were observed in both species, although in minor amounts. Twenty PCR cycles were determined as the optimum to minimize the presence of artifactual fragments and to avoid underestimation of populations due to the saturation effect on DNA quantification caused by a PCR product excess. T-RFLP analysis showed a good repeatability when applied to mixed dairy cultures. Dynamics of two defined mixed starters consisting of a L. lactis ssp. lactis strain and a L. citreum strain were studied by this method and results compared to those obtained by a culture-dependent technique. The data indicated the suitability of T-RFLP to perform semi-quantitative analyses of microbial populations. Some slight differences could be explained by the presence of metabolically active cells that could not be detected by colony counting. RT-PCR-based T-RFLP can be an alternative to classical methods in order to study dynamics of metabolically active populations in relatively simple microbial ecosystems, such as defined dairy starter cultures.


Signal detection in FDA AERS database using Dirichlet process.
In the recent two decades, data mining methods for signal detection have been developed for drug safety surveillance, using large post-market safety data. Several of these methods assume that the number of reports for each drug-adverse event combination is a Poisson random variable with mean proportional to the unknown reporting rate of the drug-adverse event pair. Here, a Bayesian method based on the Poisson-Dirichlet process (DP) model is proposed for signal detection from large databases, such as the Food and Drug Administration's Adverse Event Reporting System (AERS) database. Instead of using a parametric distribution as a common prior for the reporting rates, as is the case with existing Bayesian or empirical Bayesian methods, a nonparametric prior, namely, the DP, is used. The precision parameter and the baseline distribution of the DP, which characterize the process, are modeled hierarchically. The performance of the Poisson-DP model is compared with some other models, through an intensive simulation study using a Bayesian model selection and frequentist performance characteristics such as type-I error, false discovery rate, sensitivity, and power. For illustration, the proposed model and its extension to address a large amount of zero counts are used to analyze statin drugs for signals using the 2006-2011 AERS data.


Development and optimization of microfluidic assisted manufacturing process to produce PLGA nanoparticles.
Nanomedicine consists in the application of nanotechnology in medicine to revolutionize the healthcare sector through transformative new diagnostic and therapeutic tools. In this field, nanostructures or nanocarriers (i.e., nanoparticles) are extensively used as a drug delivery system. Despite the well-defined profits offered by nanomedicines based on poly (lactic-co-glycolic acid) (PLGA), the major barriers hampering the launch of a nanoparticles-based product on the market are batch-to-batch variations and its lack of reproducibility from the benchtop to an industrial scale production. Currently, microfluidics technology has emerged as potential tool to achieve a continuous manufacturing with a precise control over fluids mixing and particles quality attributes. This work aims at defining a tailored strategy to produce PLGA NPs, exploiting a new microfluidic device. Moreover, Design of Experiments (DoE) and computational fluid dynamics approaches were exploited to understand the main process parameters and material attributes affecting the quality of the final product as well as the NPs manufacturing process. Finally, the ability to incorporate a drug into the PLGA nanoparticles was investigated by using Curcumin as model payload reaching encapsulation efficiency in the rank 28-44%. This paper is proposed as useful guide for the preparation of PLGA NPs by microfluidic technique.


Radial artery-second dorsal metacarpal vein arteriovenous fistula in the first interdigital space for hemodialysis: Utilization of the most peripheral site and autologous vein in the upper limb - A case report.
The creation of the first arteriovenous fistula (AVF) as far distally in the upper limb as possible is ideal. We developed a new operative technique for creating a radial artery-second dorsal metacarpal vein AVF in the first interdigital space. This technique involves the creation of the AVF using the most peripheral site and autologous vein in the upper limb. We herein describe the steps of this technique and its successful performance in a 71-year-old man with end-stage renal disease. This technique has several advantages including preserving many future vascular access options and providing a long segment of arterialized vein for cannulation. We consider this technique to be a worthwhile option and recommend the use in patients with the proper vessels for the creation of the AVF.


Identification of seven-gene marker to predict the survival of patients with lung adenocarcinoma using integrated multi-omics data analysis.
The mechanism of cancer occurrence and development could be understood with multi-omics data analysis. Discovering genetic markers is highly necessary for predicting clinical outcome of lung adenocarcinoma (LUAD). Clinical follow-up information, copy number variation (CNV) data, single nucleotide polymorphism (SNP), and RNA-Seq were acquired from The Cancer Genome Atlas (TCGA). To obtain robust biomarkers, prognostic-related genes, genes with SNP variation, and copy number differential genes in the training set were selected and further subjected to feature selection using random forests. Finally, a gene-based prediction model for LUAD was validated in validation datasets. The study filtered 2071 prognostic-related genes and 230 genomic variants, 1878 copy deletions, and 438 significant mutations. 218 candidate genes were screened through integrating genomic variation genes and prognosis-related genes. 7 characteristic genes (RHOV, CSMD3, FBN2, MAGEL2, SMIM4, BCKDHB, and GANC) were identified by random forest feature selection, and many genes were found to be tumor progression-related. A 7-gene signature constructed by Cox regression analysis was an independent prognostic factor for LUAD patients, and at the same time a risk factor in the test set, external validation set, and training set. Noticeably, the 5-year AUC of survival in the validation set and training set was all ˃ 0.67. Similar results were obtained from multi-omics validation datasets. The study builds a novel 7-gene signature as a prognostic marker for the survival prediction of patients with LUAD. The current findings provided a set of new prognostic and diagnostic biomarkers and therapeutic targets.


Flash autoclave settings may influence eradication but not presence of well-established biofilms on orthopaedic implant material.
Flash autoclaving is one of the most frequently utilized methods of sterilizing devices, implants or other materials. For a number of decades, it has been common practice for surgeons to remove implantable devices, flash autoclave and then reimplant them in a patient. Data have not yet indicated the potential for biofilms to survive or remain on the surface of orthopaedic-relevant materials following flash autoclave. In this study, monomicrobial and polymicrobial biofilms were grown on the surface of clinically relevant titanium materials and exposed to flash autoclave settings that included varying times and temperatures. Data indicated that when the sterilization and control temperatures of an autoclave were the same, biofilms were able to survive flash autoclaving that was performed for a short duration. Higher temperature and increased duration rendered biofilms non-viable, but none of the autoclave settings had the ability to remove or disperse the presence of biofilms from the titanium surfaces. These findings may be beneficial for facilities, clinics, or hospitals to consider if biofilms are suspected to be present on materials or devices, in particular implants that have had associated infection and are considered for re-implantation. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1543-1550, 2018.


Decisions with Confidence: Application to the Conformation Sampling of Molecules in the Solid State.
Accurate conformations of a molecule are critical for reliable prediction of its properties, so good predictive models require good conformations. Here, we present a method for conformer sampling based on distance geometry, implemented in our conformation generator OMEGA, which we apply to both macrocycles and druglike molecules. We validate it in the usual fashion, reproducing conformations from the solid state, and compare its performance in detail to other methods. We find that OMEGA performs well on three key criteria: accuracy, speed, and ensemble size. To support our conclusions quantitatively, particularly on accuracy, we developed a workflow for method comparison that uses parameter estimation, inference from confidence intervals, classical null hypothesis significance testing, Bayesian estimation, and effect size. The workflow is designed to be robust to the highly skewed performance data often found when validating tools in computational chemistry and to provide reliable, easy to interpret results. In this workflow, we emphasize the importance of confidently distinguishing between methods, with particular reference to a priori estimation of sample size and statistical power (false negative or Type II error rate), a topic almost completely ignored hitherto in computational chemistry.


Subtype selective NMDA receptor antagonists: evaluation of some novel alkynyl analogues.
A benzylpiperidine analogue with an acetylenic linker, 5-(3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.


Early selective-attention effects on the evoked potential: a critical review and reinterpretation.
Recent research on the effect of selective attention on the N1, component of the evoked potential is reviewed. These studies are based on the finding of Hillyard Hink, Schwent and Picton (1973) that this component is selectively enhanced in response to attended stimuli when a very rapid rate of stimulus delivery is used. On the basis of the subsequent set of experiments, the conditions and limits of the existence of the auditory 'N1 effect' are now quite clear. Moreover, this finding has been extended to somatosensory and visual modalities. In the present review a detailed examination of these studies has suggested a re-interpretation of the N1 effect. According to this reinterpretation, it is not a 'true' N1 component which is enhanced but the effect is produced by a summation of a negative shift with the evoked-potential wave form. Under some conditions such as those involving a very fast rate of stimulus delivery, this effect commences very early, making the N1 component appear larger. It is suggested that this shift reflects orienting to, and further processing of, an input found relevant in a preliminary sensory analysis. Topographical evidence for this kind of interpretation is provided by several studies. This negative shift is, hence, associated with voluntary attention. Some of the reviewed studies have described a rather similar negative shift as a correlate of involuntary attention to rare stimuli among the much more frequent, 'standard', stimuli.


An Exploratory Analysis of the Association Between Hospital Labor Costs and the Quality of Care.
The competent healing touch of a caregiver is a critical component to the care patients receive. The more skilled the provider, the higher the likelihood outcomes will be delivered in a safe and effective manner. Unfortunately, in recent years, hospitals in the United States have faced immense financial pressures that are threatening their economic sustainability and patients' access to care in the future. Through the recent COVID-19 pandemic, the cost of delivering healthcare has continued to escalate, while the demand for patient care has exceeded many hospitals' capacity. Most troubling is the impact that the pandemic has had on the healthcare workforce, which has resulted in many hospitals struggling to fill vacancies at ever-increasing cost - all while under immense pressure to deliver quality patient care. What remains uncertain is whether the increase in labor costs has been matched with a commensurate rise in the quality of care or if quality has deteriorated as the labor force mix has changed to include more contract and temporary staff. Thus, in the enclosed study, we sought to determine what association, if any, exists between hospitals' cost of labor and the quality of care delivered. Drawing from a representative national sample of nearly 3214 short-term acute care hospitals' common quality measures from the year 2021, we examined the labor cost-quality relationship via multivariate linear and logistic regression and found there is a persistent negative association across all quality outcome variables studied. These findings lead us to believe simply paying more for hospital labor does not, by itself, ensure a positive patient outcome. We contend cautious use of temporary staff, measured adoption of short-term financial incentives, and robust staff development all should be considered as features of future workforce planning.


Glycosylamines of 4,6-O-butylidene-alpha-D-glucopyranose: synthesis and characterization of glycosylamines, and the crystal structure of 4,6-O-butylidene-N-(o-chlorophenyl)-beta-D-glucopyranosylamine.
A total of nine glycosylamines of 4,6-O-butylidene-alpha-D-glucopyranose were synthesized using primary amines having various groups in their ortho- or para-positions. Among these, six are monoglycosylamines, including one primary glycosylamine, and three are bis-glycosylamines. All these compounds were characterized by 1H, 1H-1H COSY, 1H-13C COSY and 13C NMR spectroscopy and FTIR spectra. The FAB mass spectra provided the molecular weights of the products by exhibiting the corresponding molecular ion peaks. The crystal structure of 4,6-O-butylidene-N-(o-chlorophenyl)-beta-D-glucopyranosylamine revealed the C-1 glycosylation, the beta-anomeric nature, and the 4C1 chair conformation of the saccharide unit in the product. In the lattice two types of dimers exist. While one type of dimer is formed through O-H...O type of interactions, the other type is formed via C-H...O type of interactions. In the direction of these C-H...O type of interactions, the dimeric units are connected to form a chain.


Flow cytofluorometric evidence for the differential radioresponsiveness of aneuploid and diploid cervix tumours.
We are presently involved in a prospective study of the relationship between DNA content profiles, and their changes during treatment, determined by flow cytofluorometry, and patient prognosis and response to therapy for cancer of the uterine cervix. To date, 348 patients have been included in the study over a 54-month period. Data on these patients have shown that DNA aneuploid tumours are significantly more radioresponsive than diploid cervix tumours. Analysis of the data on 213 patients with a minimum follow-up time of 15 months has, however, failed to show an overall more favourable prognosis conferred by tumour DNA aneuploidy. Analysis of the relationship between clinical stage and disease state and tumour DNA ploidy, however, suggests that aneuploid tumours metastasize to distant sites at an earlier stage of the disease than diploid tumours and local recurrence rates for diploid tumours, in late stage disease, are double those for aneuploid tumours. Improved staining procedures, and instrument modification, has also shown that cervix tumour heterogeneity is of considerably greater frequency than at first appeared to be the case (approximately 75% of DNA aneuploid tumours show heterogeneity.


Neuroinflammatory transcriptional signatures in the entorhinal cortex based on lipopolysaccharide-induced depression model in mice.
The inflammation and immune hypothesis of major depressive disorder (MDD) explains the mechanism of neuroinflammatory response to promote depression-like behaviors and provides targets for immunotherapy. Previous studies revealed that the neuronal function of the entorhinal cortex (EC) was relative to the depression symptoms in MDD. However, it remains largely unknown what role of neuroinflammation plays in the EC. Hence, we used immunofluorescence to determine c-Fos expression in the EC of lipopolysaccharide (LPS)-treated mice. Mice model was constructed of 10-day LPS treatment, and depression-related behaviors were assessed. We used gene expression microarray to determine differentially expressed genes (DEGs) in the EC of LPS group comparing to control group, and molecular verification was performed by quantitative real-time PCR and Western blot. We found that c-Fos expression was significant reduced in the two layers (Lateral 3.25 mm and 3.00 mm) of the EC in LPS-treated mice compared to saline-treated mice. Mice in LPS group exhibited depression- and anxiety-like behaviors in chronic model. Gene expression analyses identified 339 DEGs in the EC between LPS and control group. The molecular verification showed activation of IL-1R1/NF-κB/CCL5 signaling and upregulation of markers of astrocyte (GFAP) and microglia (AIF1 and CD86) in the EC. Our results suggested that LPS-induced neuroinflammation inhibited neuronal activity in the EC of mice, and that activation of IL-1R1/NF-κB/CCL5 signaling could be involved in the neuroinflammation in the EC of LPS-treated depression model.


Diabetic lipemia with eruptive xanthomatosis in a lean young female with apolipoprotein E4/4.
Eruptive xanthomas in adults are usually indicative of chylomicronemia. Although diabetes mellitus is the most common secondary cause of chylomicronemia, which is designated as diabetic lipemia, the clinical characteristics of diabetes with regard to development of xanthomas are not well defined. In this paper, we describe a young female who displayed eruptive xanthomas as an initial manifestation of diabetic lipemia. The patient was a 20-year-old female with a body mass index of 18.9 kg/m2 and Marfanoid appearance. Her past history was unremarkable, except for patent ductus arteriosus and mild mental retardation. She was admitted to our division for eruptive xanthomas on the extremities and marked hyperglycemia (random glucose, 520 mg/dl) and hypertriglyceridemia (6880 mg/dl). She was diagnosed with Type 2 diabetes based on the positive family history of diabetes, residual secretory capacity of insulin, and absence of autoantibodies related to Type 1 diabetes. Based on the increase in the concentrations of both chylomicrons and very low density lipoproteins, type V hyperlipoproteinemia was diagnosed. After the initiation of insulin therapy, both hypertriglyceridemia and eruptive xanthomas subsided, without administering any hypolipidemic agents. Minimal model analysis of a frequently sampled intravenous glucose tolerance test revealed severe insulin resistance, despite the absence of obesity. Post-heparin lipoprotein lipase (LPL) activity was moderately decreased, and common mutations in the LPL gene were not demonstrated by genetic screening. The apolipoprotein E phenotype was E4/4, which is known to be associated with type V hyperlipoproteinemia. Hypoadiponectinemia of 1.7 microg/ml was also revealed, which may, in part, account for the insulin resistance and decreased LPL activity. In conclusion, the clustering of apolipoprotein E4/4 and hypoadiponectinemia, in addition to insulin resistance and poor glycemic control, might have resulted in hypertriglyceridemia with eruptive xanthomatosis in this subject.


The influence of topical use of tranexamic acid in reducing blood loss on early operation for thoracolumbar burst fracture: a randomized double-blinded controlled study.
To investigate the safety and efficacy of topical use of tranexamic acid (TXA) on early operation for thoracolumbar burst fracture (TBF). Patients with acute TBF requiring early decompression were prospectively collected. The enrolled patients were randomly assigned to TXA and control group, in which wound surface was soaked with TXA or the same volume of normal saline for 5 min after wound incision, respectively. The total blood loss (TBL), intraoperative blood loss (IBL), postoperative blood loss (PBL), hemoglobin (HGB) levels on preoperatively (pre-op) and postoperatively, and amount of allogenic blood transfusion were recorded. Furthermore, the general information was also compared between groups. There were 39 and 37 patients enrolled in TXA and control group for final analysis. The demographics data showed no significant difference between groups (P > 0.05), but operation time and IBL were significantly decreased in TXA group (P < 0.05). Further analysis showed that HGB level was significantly higher in the TXA group at POD1, while the TBL and PBL were significantly less than those in the control group (P < 0.05), but similar to HBL (P > 0.05). The postoperative ambulation time, removal time of drainage tube, length of hospital stay, and blood transfusion rate were also significantly less in TXA group (P < 0.05). At the final follow-up, no neurological deteriorations and no TXA-related complications were observed in both groups. This RCT first demonstrated that topical TXA usage after wound incision could effectively reduce IBL without increasing risk of complications, beneficial to enhanced recovery after early operation for TBF.


Leucine to proline substitution by SNP at position 197 in Caspase-9 gene expression leads to neuroblastoma: a bioinformatics analysis.
To understand the role of CASP9 (Caspase-9) gene products in relation to neuroblastoma disease, we have analyzed the single nucleotide polymorphisms (SNPs) associated with this gene. This can help us understand the genetic variations that can alter the function of the gene products. A total of 941 SNPs are investigated for CASP9 gene. To determine whether a non-synonymous SNP (nsSNP) in this gene affects its protein product, we used certain computational tools which predicted one nsSNP, rs1052574, to have deleterious phenotypic effect. This polymorphic variant results in amino acid substitution from leucine to proline at 197 position, i.e., from acyclic amino acid to a 5-membered amino acid which resides in the buried area of the protein with a high level of conservation. This amino acid substitution shows a transition from helix to coil in the mutant protein. Hence, due to the complete alteration in the structural property of the amino acid side chain, the stability of the protein is reduced which may affect the function of CASP9 protein, leading to deregulation of apoptosis and neuroblastoma development.


The inhibiting effect of the Coptis chinensis polysaccharide on the type II diabetic mice.
In this paper, we investigated the effects of Coptis chinensis polysaccharide (CCP) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. CCP was prepared by extraction from Coptis chinensis and oral given to the mice. C57BL/6J mice in each of the 5 groups (eight mice per group) were given either the normal diet (ND) (D12450B, 10% kcal% fat; Research diet, New Brunswick, NJ, USA), HFD (D12451, 45% kcal% fat; Research diet, New Brunswick, NJ, USA), or HFD with CCP of differing hardness (500, 1000, and 2000ppm) for 20 weeks. Mice given an HFD with CCP showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that CCP improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that CCP recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, β-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with CCP. CCP increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. CCP stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that CCP has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake.


The structure of attrition during appraisal.
Most attrition research has focused on dropping out once the patient has arrived at the clinic. However, many potential patients, who are in need of service, do not contact clinics. Such patients are said to be in the appraisal stage of treatment. Discontinuation of appraisal, for whatever reason, can be termed "attrition." Such attrition has not received adequate attention. A conceptual model of the appraisal process is given, and a review is made of current research bearing on the conditions under which appraisals continued or discontinued by an individual. Recommendations for future research are made.


Natural killer cell mediated cytotoxicity of tumor cells initiated by neem leaf preparation is associated with CD40-CD40L-mediated endogenous production of interleukin-12.
Neem leaf preparation (NLP) was found to activate natural killer (NK) cells (CD56(+)CD3(-)) to enhance their cytotoxic ability to tumor cells and stimulate the release of interleukin-12 (IL-12) from macrophages from healthy individuals and head-and-neck squamous cell carcinoma patients. NLP upregulated cytotoxic (CD16(+) and CD56(dim)) NK cells, and the cytotoxicity of NK-sensitive K562 cells by NLP-stimulated peripheral blood mononuclear cells decreased significantly after IL-12 neutralization. This NK-mediated cytotoxicity was manifest by upregulation of IL-12-dependent intracellular expression of the perforin-granzyme B system. Moreover, NK cytotoxic function was abolished after use of concanamycin A, a perforin inhibitor, but not by brefeldin A, a Fas inhibitor, confirming the participation of the perforin-granzyme B system. In addition NLP upregulated the expression of CD40 in CD14(+) monocytes and CD40L in CD56(+) lymphocytes. Neutralization of CD40 and CD40L in NLP-stimulated peripheral blood mononuclear cells culture resulted in significant downregulation of IL-12 release and cytotoxicity of NK cells, demonstrating the role of a CD40-CD40L interaction in the observed functions. Signals involved in the NLP-induced release of IL-12, and thereby induction of NK cell cytotoxicity, are mediated by activating p38MAPK pathway, but not through the ERK1/2 signaling pathway. Overall the results suggest that NLP effects NK cellular cytotoxicity by CD40-CD40L-mediated endogenous production of IL-12, which critically controls perforin-dependent tumor cell cytotoxicity.


The Relationship between the Distribution of Home Medical Clinics and Home Care Service Offices in Japan.
The increasing number of older people in Japan has led to a need for cooperation between home medical and care services. The collaboration between medical and care provisions in home settings is thus a matter for concern. The present study examines the distribution of and relationship between the number of home medical clinics (HMCs) and home care service offices (HCOs) in Japan. We used national data, detailing the total population, percentage of older adults, and number of HMCs and HCOs. Overall, 23,428 HMCs and 35,612 HCOs were identified nationwide. While the southwestern region of Japan had a high number of HMCs relative to the northeastern region, there was not such a clear difference in the regional distribution of number of HCOs. A linear regression analyses, adjusted for the percentage of older people, revealed a significant positive correlation between the number of HMCs per 10,000 older people and HCOs per 10,000 older people (β = 0.58, p < 0.001). These findings may allow us to understand advances in cooperation between home medical and care services in Japan.


Mevastatin ameliorates sphingosine 1-phosphate-induced COX-2/PGE2-dependent cell migration via FoxO1 and CREB phosphorylation and translocation.
Sphingosine 1-phosphate (S1P), an important inflammatory mediator, has been shown to regulate COX-2 production and promote various cellular responses such as cell migration. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA), effectively inhibits inflammatory responses. However, the mechanisms underlying S1P-evoked COX-2-dependent cell migration, which is modulated by mevastatin in human tracheal smooth muscle cells (HTSMCs) remain unclear. The expression of COX-2 was determined by Western blotting, real time-PCR and promoter analyses. The signalling molecules were investigated by pretreatment with respective pharmacological inhibitors or transfection with siRNAs. The interaction between COX-2 promoter and transcription factors was determined by chromatin immunoprecipitation assay. Finally, the effect of mevastatin on HTSMC migration and leukocyte counts in BAL fluid and COX-2 expression induced by S1P was determined by a cell migration assay, cell counting and Western blot. S1P stimulated mTOR activation through the Nox2/ROS and PI3K/Akt pathways, which can further stimulate FoxO1 phosphorylation and translocation to the cytosol. We also found that S1P induced CREB activation and translocation via an mTOR-independent signalling pathway. Finally, we showed that pretreatment with mevastatin markedly reduced S1P-induced cell migration and COX-2/PGE2 production via a PPARγ-dependent signalling pathway. Mevastatin attenuates the S1P-induced increased expression of COX-2 and cell migration via the regulation of FoxO1 and CREB phosphorylation and translocation by PPARγ in HTSMCs. Mevastatin could be beneficial for prevention of airway inflammation in the future.


Progesterone activates GPR126 to promote breast cancer development via the Gi pathway.
GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.


Laparoscopic versus open surgery for left flexure colon cancer: A propensity score matched analysis from an international cohort.
Surgical treatment of splenic flexure cancer (SFC) still presents some debated issues, including the role of laparoscopic surgery. The literature is based on small single-centre series, while randomized controlled studies comparing open and laparoscopic treatment for colon cancer exclude SFC. This study aimed to determine the role of laparoscopic surgery in the treatment of SFC, comparing short- and long-term outcomes with open surgery. This was an international multicentre retrospective cohort study that analysed patients from 10 tertiary referral centres. From a cohort of 641 cases, 484 patients with Stage I-III SFC submitted to elective surgery with curative intent were selected. After 1:1 propensity score matching, 130 patients in the laparoscopic group (LapGroup) were compared with 130 patients in the open surgery group (OpenGroup). After propensity score matching, the two groups were comparable for demographic and clinical parameters. OpenGroup presented a higher incidence of overall (P = 0.02) and surgery-related complications (P = 0.05) but a similar rate of severe complications (P = 0.75). Length of stay was notably shorter in the LapGroup (P = 0.001). Overall (P = 0.793) as well as cancer-specific survival (P = 0.63) did not differ between the two groups. Elective laparoscopic surgery for Stage I-III SFC is feasible and associated with improved short-term postoperative outcomes compared to open surgery. Moreover, laparoscopic surgery appears to provide excellent long-term cancer outcomes.


Neutrophil cytosolic factor 2 (NCF2) gene polymorphism is associated with juvenile-onset systemic lupus erythematosus, but probably not with other autoimmune rheumatic diseases in children.
Genetic variations of neutrophil cytosolic factor 2 (NCF2), a subunit of NADPH oxidase, are usually associated with chronic granulomatous disease, and their relationship with autoimmune disorders through the defective NADPH oxidase function during phagocytosis is suggested. Our study aimed to explore whether there is an association between the non-synonymous single nucleotide polymorphism in the NCF2 gene (rs17849502, NC_000001.11:g.183563445G>T) and the development of juvenile autoimmune rheumatic diseases. In order to test this hypothesis, we conducted a pilot case-control study. In total, 709 children and adolescents, all Belarusians, were involved in the study including patients with juvenile-onset systemic lupus erythematosus (JSLE), juvenile idiopathic arthritis (JIA), Kawasaki disease (KD), and subjects without autoimmune and inflammatory diseases as the clinical control, as well as health newborns as the population control. Real-time polymerase chain reaction was used for genotyping. The minor T allele of NCF2 occurred most frequently in patients with JSLE (OR = 2.60, 95% CI = 1.18-5.73, p = 0.023 as compared to the clinical control). In groups with JIA and KD, its frequency did not differ from the control. The TT genotype was only observed in 5.7% of patients with JSLE (p = 0.007), but not in other groups. Therefore, our study suggested that NCF2 rs17849502 polymorphism is a potential genetic risk factor for JSLE, while it is probably not for such autoimmune rheumatic diseases as JIA or KD.


Intravenous carbohydrate over-feeding: a method for rapid nutritional repletion.
Forty-four measurements of resting energy expenditure (REE) and respiratory quotient (RQ), and sequential measurements of body composition and nitrogen excretion were made in a cachectic male patient with inactive Crohn's disease, who was repleted with intravenous nutrition alone, over a period of 62 days. The initial energy intake (EI) of 10 MJ/day was increased to 21 MJ/day by three stepwise increments ( approximately 4MJ) in the glucose content of the feed. REE increased from 4.2 to 6.8 kJ/min, and body weight from 53 to 76kg. REE rose by a progressively greater amount with each increment in energy intake (DeltaREE DeltaEl = 0.12 to 0.26 ). The RQ increased progressively to a value up to 1.19 and persisted above 1.0 even 9h after the feed was stopped. The results suggest that the increase in REE a) was due to a combination of increasing lean body mass and increasing diet-induced thermogenesis, b) dissipated only a small proportion of the total energy infused, and c) was associated with net lipid synthesis from carbohydrate whilst on and off the feed. The results are discussed in relation to the energy equivalent of ATP and the circulating concentrations of insulin and the flux of substrates across forearm tissue.


Anatomic basis of the middle temporal artery periosteal rotational flap in otologic surgery.
To describe the elements critical to successful middle temporal artery periosteal rotational flap harvest and utilization based on the anatomic features of the middle temporal artery. Description of anatomy based on cadaver dissection. Seventy temporal fossa dissections were performed on 35 adult human cadavers. Sixty-nine of 70 dissections had an identifiable middle temporal artery muscular branch pedicle in the periosteum deep to the temporalis muscle. Pedicle length was at least 7 cm in 32 of 38 (84%) male cadavers and in 20 of 31 (65%) female cadavers (P = 0.054), whereas the average length required to reach the digastric ridge from the pedicle base to the digastric ridge in a mastoidectomy cavity was 5.2 cm. The pedicle sharply transitions from a posterior to a posterior-superior course 0.93 cm superior (range: 0.5-1.9 cm) and 0.04 cm posterior (range: 1.4 cm posterior-0.7 cm anterior) to the spine of Henle. Branching occurred in 26 of 69 pedicles (38%), and 20 of 31 (65%) branches were oriented posteriorly. If temporalis muscle fibers are not incorporated into the flap, the thickness is roughly three times that of a standard temporalis fascia graft. The muscular branch of the middle temporal artery is reliably identified in the periosteum deep to the posterior aspect of the temporalis muscle, and this vessel is sufficiently robust to provide axial blood supply to a rotational periosteal flap that has sufficient thickness and length to allow a variety of applications in otologic surgery. NA. Laryngoscope, 126:1426-1432, 2016.


The 5-lipoxygenase-activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma.
GSK2190915, a potent 5-lipoxygenase-activating protein inhibitor, prevents the synthesis of leukotrienes and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). To assess the effect of GSK2190915 on the allergen-induced asthmatic responses. Nineteen eligible male subjects with mild asthma were enrolled in and completed this four-centre, double-blind, two-way crossover study (ClinicalTrials.gov NCT00748306). Subjects took GSK2190915 100 mg and placebo orally once daily for 5 days in randomized order. On Day 1 and 4 they had a methacholine challenge, on Day 3 they had an inhaled allergen challenge, and on Days 4 and 6 they had sputum induction. GSK2190915 attenuated the early (0-2 h) and late (4-10 h) asthmatic responses to inhaled allergen compared with placebo. There was a statistically significant attenuation of the early asthmatic response (EAR) by GSK2190915; treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) EAR was 0.408 L (0.205, 0.611). There was a statistically significant attenuation of the late asthmatic response (LAR) by GSK2190915; the treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) LAR was 0.229 L (0.041, 0.417). There was a statistically significant attenuation of allergen-induced sputum eosinophil count on Day 4 following GSK2190915: mean treatment difference (95% CI) between GSK2190915 and placebo was -9.95% (-18.15%, -1.77%). Compared with placebo, GSK2190915 100 mg reduced median sputum LTB(4) by > 90% on Days 4 and 6. There was no effect on methacholine PC(20) post allergen. GSK2190915 was generally well tolerated. GSK2190915 shows potential as a treatment for patients with asthma.


Subnormal postconceptional levels of prolactin do not interfere with the early events of human pregnancy.
To elucidate the role of bromocriptine treatment and serum prolactin levels in peri-implantational events, 30 healthy women asking for "morning after" type contraception were given bromocriptine. Treatment was started 30.6 +/- 18.4 (mean +/- SD) hours after unprotected intercourse and continued until the next menstruation. Blood samples were taken before and 1 and 2 weeks after initiation of treatment, and the samples were assayed for concentrations of prolactin, progesterone, human chorionic gonadotropin (hCG), and pregnancy-specific beta1-glycoprotein (PSBG) by radioimmunoassay. Prolactin concentrations fell significantly (P less than 0.001) from the pretreatment level of 11.4 +/- 7.9 ng/ml (mean +/- SD) to 2.8 +/- 2.3 ng/ml at 1 week and to 1.9 +/- 0.6 ng/ml after 2 weeks of treatment. Five women had demonstrable hCG in serum 8 to 15 days after unprotected intercourse, and one of them also had PSBG 14 days postcoitum. Pregnancy advanced normally until legal termination in three women, whereas menstruation-like bleeding ensued in two. Our results suggest that neither bromocriptine treatment nor a subnormal maternal serum prolactin level interferes with the early development of human pregnancy.


Medication Non-adherence: a Major Cause of Resistant Hypertension.
As the global burden of hypertension continues to rise, it remains suboptimally controlled despite increased awareness. Poor medication adherence is a well-recognized although underestimated contributing factor of uncontrolled hypertension. This review focuses on medication non-adherence as an important cause of apparent treatment-resistant hypertension and its impact on patient's well-being. In addition to biochemical screening, electronic technology-including electronic medication packaging devices such as medication event monitoring system, device integrated care delivery systems like digital medicine, and blood pressure telemonitoring-provides reliable objective data that enables healthcare providers to make decisions that enhance adherence and improve blood pressure control. Consistent medication adherence is a key factor to sustained blood pressure control. Evaluation and correct assessment for adherence should be an integral part of management of patients with apparent treatment-resistant hypertension. Clinicians need to recognize key clues linked to suboptimal adherence or non-adherence that can result in poor outcomes.


Ochratoxin A-induced cytotoxicity, genotoxicity and reactive oxygen species in kidney cells: An integrative approach of complementary endpoints.
Ochratoxin A (OTA) is a well-known nephrotoxic and potential carcinogenic agent but no consensus about the molecular mechanisms underlying its deleterious effects has been reached yet. The aim of this study is to integrate several endpoints concerning OTA-induced toxicological effects in Vero kidney cells in order to obtain additional mechanistic data, especially regarding the influence of reactive oxygen species (ROS). One innovative aspect of this work is the use of the superoxide dismutase mimic (SODm) MnTnHex-2-PyP as a mechanistic tool to clarify the involvement of oxidative stress in OTA toxicity. The results showed concentration and time-dependent cytotoxic effects of OTA (crystal violet, neutral red and LDH leakage assays). While the SODm mildly increased cell viability, trolox and ascorbic acid had no effect with regards to this endpoint. OTA induced micronuclei formation. Using the FPG modified comet assay, OTA modestly increased the % of DNA in tail, revealing the presence of oxidative DNA lesions. This mycotoxin increased apoptosis, which was attenuated by SODm. In addition, the SODm decreased the ROS accumulation observed in DHE assay. Taken together, our data suggest that ROS partially contribute to the cytotoxicity and genotoxicity of OTA, although other mechanisms may be relevant in OTA-induced deleterious effects.


Spontaneous eye motility following a unilateral vestibular lesion.
The strong imbalance of the output of vestibular nuclei, resulting from a hemilabyrinthectomy, causes among other postural and ocular symptoms, a failure to hold a steady ocular position in the dark. In this study the time course of the spontaneous eye motility following a right hemilabyrinthectomy was analyzed. In all animals, at the first recordings, drifts of 0.8-1.0 degrees/s were present. These drifts were directed to the lesion side, then they shifted their trajectory more than once. At the final recordings, most animals exhibited very slow drifts (0.05-0.1 degrees/s) directed to the intact side suggesting an overcompensation of the initial extreme rightward deviation.


Dermal cellular responses of helminth-free and Ostertagia ostertagi-infected calves to intradermal injections of soluble extracts from O. ostertagi L3 larvae.
Twelve calves were raised helminth-free until 9 weeks of age when six were orally inoculated with 100,000 Ostertagia ostertagi infective stage larvae (L3). Three uninfected and three experimentally infected calves received intradermal injections of sterile saline and soluble larval extract (SLE) from O. ostertagi L3 with a protein concentration ranging from 1 to 200 micrograms ml-1. Biopsies were performed 48 h post-injection. A kinetic study was performed on the remaining six calves, three infected and three uninfected, using a 100 micrograms ml-1 concentration of SLE and taking biopsies 1, 4, 8, 12, 24, and 72 h post-injection at both the saline and SLE-injected sites. All calves had an immediate wheal and increase in skin thickness at the SLE-injected sites. The numbers of eosinophils infiltrating SLE-injected sites as compared to saline-injected sites were significant in both uninfected and infected calves, but the infected calves had significant numbers to a wider range of SLE concentrations and had significantly higher numbers than uninfected calves in the kinetic study. Infected calves also had significant numbers of basophils in the dose response study at concentrations of 5 and 100 micrograms ml-1 SLE. Neutrophil infiltration was similar in both groups and was significant at SLE-injected sites early in the kinetic study. Detectable mast cells were decreased in SLE-injected sites of infected animals and perivascular accumulation of mononuclear and some polymorphonuclear cells was observed in the deep dermis of infected animals.


Preparation of trinitrophenylated red cells for antibody independent lysis by complement.
Based on the earlier observation that DNP-HSA interacts directly with C1q, a subcomponent of the first component of complement (Loos and König, 1977), evidence is presented that TNP bound to erythrocytes (E-TNP) can interact with the whole complement sequence leading to the lysis of the TNP-carrying erythrocytes; in this test system the erythrocytes are used as an indicator of the TNP-complement reaction. To exclude any antibody-mediated lysis either the heterologus sera were exhaustively absorbed with the erythrocytes used in the test system or serum and erythrocytes of one individual person were taken. The strongly temperature-dependent interaction of TNP-sulfonic acid with the erythrocytes resulted in the formation of E-TNP as well as of a TNP-protein complex released into the supernatant. The TNP-protein complex strongly inhibited purified C1 similar to DNP-HSA. The antibody independent lysis of E-TNP by complement was dependent upon the TNP concentration per cell, the temperature and time as well as the complement concentration. The reaction of E-TNP with complement showed similar characteristics to those for the reaction of antibody sensitized erythrocytes (EA) with complement. E-TNP is a helpful tool to study antibody-independent activation of the complement system.


In vivo regulation of glucose transporter genes at glucose concentrations between 0 and 500 mg/L in a wild type of Saccharomyces cerevisiae.
When the yeast Saccharomyces cerevisiae consumes glucose, the expression of the genes for the glucose transport is controlled via signal transduction pathways and sensor molecules. Most publications describe the behavior of deletion strains while little is published about the in vivo regulation of glucose transporters in a wild type of S. cerevisiae. Here a global gene expression analysis via microarray experiments from cultivations with glucose concentrations of 50, 70, 100 and 500 mg/L is presented. This permits the observation of the fine-tuning of gene expression in dependency on the glucose concentration. We detected indications that the transport system for high glucose concentrations is activated at glucose concentrations between 50 and 100 mg/L. The regulation of genes coding enzymes for the signal pathways and of those encoding the transporters themselves supports this assumption. The expression of sensor-, signal- and transporter genes will be discussed in detail. In addition, new information about the behavior of the so far little described carriers HXT8, HXT12, HXT13, HXT17 and GAL2 will be given. According to our findings, HXT13 is active during starvation. HXT12, HXT17 and GAL2 are used at low glucose concentrations. The carrier HXT8 supports the glucose transport both during starvation and at low glucose concentrations.


Posterior capsule edema in adhesive capsulitis: comparison with established non-contrast MRI findings and multivariable analysis.
To evaluate posterior glenohumeral capsule edema compared to other MRI findings in adhesive capsulitis (AC). This study was approved by the local Institutional Review Board and it is HIPAA compliant. A retrospective search identified subjects who received fluoroscopically guided intra-articular corticosteroid injections for AC and had an MRI within 6 months prior to injection. The study group was compared with an age-, sex-, and side-matched control group who underwent the same procedures but did not have AC. MRIs were evaluated for edema of posterior capsule, anterior capsule, axillary pouch, coracohumeral ligament (CHL) and rotator interval (RI), thickness of axillary pouch and CHL, thickness of anterior capsule, RI and subcoracoid fat replacement, and teres minor atrophy and edema. Multivariable analysis was performed. A total of 57 subjects with AC and 57 matched controls were studied: mean age 52 ± 7 (range 31-71) years, 37 female and 20 male, 22 right and 35 left. Posterior capsule edema was more common in the AC group vs. control group (66.7 vs 17.5%, p < 0.001). Multivariable analysis showed posterior capsule edema, CHL edema, and axillary pouch (glenoid) thickness (optimum cutoff = 4 mm) were significant independent predictors of AC. Simplified analysis using these three variables had an area under the curve of 0.860 (95%CI: 0.792-0.928). With all three variables present, the sensitivity and specificity for AC were 32% and 98%, respectively. Posterior joint capsule edema may be helpful to confirm AC. Posterior capsule edema, CHL edema, and axillary pouch (glenoid) thickness produce a strong model for distinguishing AC from controls. Edema involving the posterior shoulder joint capsule is an imaging marker of capsulitis and is useful in differentiating patients with adhesive capsulitis from those without in conjunction with other proven MRI findings. • Posterior capsule edema has a sensitivity of 66.7% and a specificity of 82.5% for the detection of adhesive capsulitis. • Posterior capsule edema, coracohumeral ligament (CHL) edema, and axillary pouch (glenoid) thickness were significant independent predictors of adhesive capsulitis, and combining these variables together produces a very strong model for distinguishing cases from controls (AUC = 0.860). • Optimal cutoff values for CHL, axillary pouch (humeral), axillary pouch (glenoid), and axillary pouch (total) thickness were 2.5, 2.6, 4, and 6.3 mm, respectively.


[Precancerous conditions of the digestive system: true risk or a paper tiger? The esophagus].
The incidence of the squamous cell carcinoma of the esophagus shows geographical variations. As a rule it is found in heavy smokers and alcoholics. Multicentricity (mouth, hypopharynx, esophagus) is very frequent and accompanied by large dysplasias of different stages. The adenocarcinoma develops on the metaplastic cylindric epithelium of the Barrett esophagus. Positive dysplasias are highly suspicious of the development of a carcinoma and demand the reconfirmation of the finding by a second pathologist. In this case the resection of the esophagus has to be done. The abdominal-cervical method should be preferred.


Prediction of stillbirth low resource setting in Northern Uganda.
Women of Afro-Caribbean and Asian origin are more at risk of stillbirths. However, there are limited tools built for risk-prediction models for stillbirth within sub-Saharan Africa. Therefore, we examined the predictors for stillbirth in low resource setting in Northern Uganda. Prospective cohort study at St. Mary's hospital Lacor in Northern Uganda. Using Yamane's 1967 formula for calculating sample size for cohort studies using finite population size, the required sample size was 379 mothers. We doubled the number (to > 758) to cater for loss to follow up, miscarriages, and clients opting out of the study during the follow-up period. Recruited 1,285 pregnant mothers at 16-24 weeks, excluded those with lethal congenital anomalies diagnosed on ultrasound. Their history, physical findings, blood tests and uterine artery Doppler indices were taken, and the mothers were encouraged to continue with routine prenatal care until the time for delivery. While in the delivery ward, they were followed up in labour until delivery by the research team. The primary outcome was stillbirth 24 + weeks with no signs of life. Built models in RStudio. Since the data was imbalanced with low stillbirth rate, used ROSE package to over-sample stillbirths and under-sample live-births to balance the data. We cross-validated the models with the ROSE-derived data using K (10)-fold cross-validation and obtained the area under curve (AUC) with accuracy, sensitivity and specificity. The incidence of stillbirth was 2.5%. Predictors of stillbirth were history of abortion (aOR = 3.07, 95% CI 1.11-8.05, p = 0.0243), bilateral end-diastolic notch (aOR = 3.51, 95% CI 1.13-9.92, p = 0.0209), personal history of preeclampsia (aOR = 5.18, 95% CI 0.60-30.66, p = 0.0916), and haemoglobin 9.5 - 12.1 g/dL (aOR = 0.33, 95% CI 0.11-0.93, p = 0.0375). The models' AUC was 75.0% with 68.1% accuracy, 69.1% sensitivity and 67.1% specificity. Risk factors for stillbirth include history of abortion and bilateral end-diastolic notch, while haemoglobin of 9.5-12.1 g/dL is protective.


Correlation between Tissue Cellularity and Metabolism Represented by Diffusion-Weighted Imaging (DWI) and 18F-FDG PET/MRI in Head and Neck Cancer (HNC).
This study aimed to assess the association of 18F-Fluorodeoxyglucose positron-emission-tomography (18F-FDG/PET) and DWI imaging parameters from a primary tumor and their correlations with clinicopathological factors. We retrospectively analyzed primary tumors in 71 patients with proven HNC. Primary tumor radiological parameters: DWI and FDG, as well as pathological characteristics were analyzed. Spearman correlation coefficient was used to assess the correlation between DWI and FDG parameters, ANOVA or Kruskal-Wallis, independent sample t-test, Mann-Whitney test, and multiple regression were performed on the clinicopathological features that may affect the 18F- FDG and apparent-diffusion coefficient (ADC) of the tumor. No significant correlations were observed between DWI and any of the 18F-FDG parameters (p > 0.05). SUVmax correlated with N-stages (p = 0.023), TLG and MTV correlated with T-stages (p = 0.006 and p = 0.001), and ADC correlated with tumor grades (p = 0.05). SUVmax was able to differentiate between N+ and N- groups (p = 0.004). Our results revealed a non-significant correlation between the FDG-PET and ADC-MR parameters. FDG-PET-based glucose metabolic and DWI-MR-derived cellularity data may represent different biological aspects of HNC.


Value-based pricing of a COVID-19 vaccine.
The purpose of this study is to determine the value-based price of a COVID-19 vaccine from a societal perspective in Germany. A decision model was constructed using, e.g., information on age-specific fatality rates, intensive care unit (ICU) costs and outcomes, and the full vaccination rate. Three strategies were analysed: vaccination (with 95 % and 50 % efficacy against death), a mitigation strategy, and no intervention. The base-case time horizon was 5 years. The value of a vaccine includes savings from avoiding COVID-19 mitigation measures and productivity loss, as well as health benefits from preventing COVID-19 related mortality. The value of an additional life year was borrowed from new, innovative oncological drugs, as cancer reflects a condition with a similar morbidity and mortality burden in the general population in the short term as COVID-19. A vaccine with a 95 % efficacy dominates the mitigation strategy strictly. The value-based price (€6,431) is thus determined by the comparison between vaccination and no intervention. The price is particularly sensitive to the full vaccination rate and the duration of vaccine protection. In contrast, the value of a vaccine with 50 % efficacy is more ambiguous. This study yields a value-based price for a COVID-19 vaccine with 95 % efficacy, which is considerably greater than the purchasing price.


Radiolytic one-electron reduction characteristics of tyrosine derivative caged by 2-oxopropyl group.
We employed X-irradiation to activate a caged amino acid with a 2-oxoalkyl group. We designed and synthesized tyrosine derivative caged by a 2-oxoalkyl group (Tyr(Oxo)) to evaluate its radiolytic one-electron reduction characteristics in aqueous solution. Upon hypoxic X-irradiation, Tyr(Oxo) released a 2-oxopropyl group to form the corresponding uncaged tyrosine. In addition, radiolysis of dipeptides containing Tyr(Oxo) revealed that the efficiency of radiolytic removal of 2-oxopropyl group increased significantly by the presence of neighboring aromatic amino acids.


LncRNAs in cancer: Regulatory and therapeutic implications.
Long noncoding RNAs (lncRNAs) comprise a class of RNAs that do not code for proteins but are critical in regulating diverse cellular processes and maintaining cell function. In doing so, they have, in recent years, added a potentially new and significant layer of biological regulation. These are more than 200 nucleotides in length and are implicated in a range of diseases and therefore have emerged as potential tools for possible therapeutic intervention. For a disease as complex as cancer, emerging technologies suggest the presence of mutations on genomic loci that do not encode proteins, but give rise to lncRNAs. Aberrant signatures of lncRNAs are now a consistent feature of almost all types of cancers and their associated complications. Analysis and characterisation of functional pathways that lncRNAs are involved with suggest that lncRNAs interact with the chromatin, the protein or with the RNA to demonstrate their cellular effects to modulate proliferation, migration, differentiation, apoptosis and cell death. This review summarizes the current knowledge of lncRNAs, their implications in diverse types of cancer and their possible therapeutic utility.


Clearance of apoptotic beta-cells is reduced in neonatal autoimmune diabetes-prone rats.
The kinetics of beta-cell death in neonatal diabetes-prone (BBdp) and diabetes-resistant (BBdr) BioBreeding rats was investigated using both direct (histochemical) and indirect (mathematical modelling) techniques. In both BBdp and BBdr rats, the incidence of TUNEL positive beta-cells increased until 10 days of age before declining. The number of apoptotic beta-cells was significantly higher in BBdp as compared to BBdr neonates from birth until 20 days of age (P<0.05). Using a mathematical model applied to the time course of beta-cell mass and replication rate, a wave of net beta-cell loss was detected between 10 and 20 days of age in both strains. In contrast to the observed difference in the incidence of TUNEL positive beta-cells, with the model-based approach we found no difference in the rate of beta-cell apoptosis between BBdp and BBdr rats prior to weaning. As the number of apoptotic cells present in a tissue depends on the rate at which cells die and the rate at which the apoptotic cell debris is cleared, we compared in vitro phagocytosis of apoptotic thymocytes by peritoneal macrophages from 2-week-old BBdp and BBdr rats. Macrophages from BBdp neonates engulfed significantly less apoptotic cells as compared to BBdr neonates (P<0.0005). Taken together, these findings suggest that there is impaired clearance of apoptotic beta-cells in diabetes-prone BB rats during the neonatal period.


Comparison of nociceptive behavior in prostaglandin E, F, D, prostacyclin and thromboxane receptor knockout mice.
Antagonist at specific prostaglandin receptors might provide analgesia with a more favourable toxicity profile compared with cyclooxygenase inhibitors. We analyzed nociceptive responses in prostaglandin D, E, F, prostacyclin and thromboxane receptor knockout mice and mice deficient of cyclooxygenase 1 or 2 to evaluate the contribution of individual prostaglandin receptors for heat, mechanical and formalin-evoked pain. None of the knockouts was uniformly protected from all of these pain stimuli but COX-1 and EP4 receptor knockouts presented with reduced heat pain and EP3 receptor and COX-2 knockout mice had reduced licking responses in the 2nd phase of the formalin assay. This was accompanied with reduced c-Fos immunoreactivity in the spinal cord dorsal horn in EP3 knockouts. Oppositely, heat pain sensitivity was increased in FP, EP1 and EP1+3 double mutant mice possibly due to a loss of FP or EP1 receptor mediated central control of thermal pain sensitivity. Deficiency of either EP2 or DP1 was associated with increased formalin-evoked flinching responses and c-Fos IR in dorsal horn neurons suggesting facilitated spinal cord pain reflex circuity. Thromboxane and prostacyclin receptor knockout mice showed normal pain behavior in all tests. The results suggest a differential, pain-stimulus and site-specific contribution of specific PG-receptors for the processing of the nociceptive stimuli, a differential modulation of nociceptive responses by COX-1 and COX-2 derived prostaglandins and compensatory and/or developmental adaptations in mice lacking specific PG receptors.


Evidence for multiple endothelin receptors in the guinea-pig pulmonary artery and trachea.
1. The responses of the three peptides, endothelin 1 (ET-1), endothelin 2 (ET-2) and endothelin 3 (ET-3) were analysed on isolated circular segments of pulmonary arteries and trachea from the guinea-pig. 2. In the pulmonary artery, the vasomotor responses to the endothelins, expressed as the maximum contraction (Emax%), had the order ET-1 greater than ET-2 greater than ET-3 while the order of potency (pD2) was ET-1 = ET-2 greater than ET-3. ET-1 and ET-2 caused cross-desensitization, but did not affect the responses to ET-3. ET-3 did not cause cross-desensitization to ET-1 or ET-2 although it induced homologous desensitization. Finally, the effects of ET-1 and ET-2 were additive to those of ET-3. The additive effect of ET-3 to those of ET-1 or ET-2 was more difficult to demonstrate, given the profound contraction produced by ET-1 and to a lesser extent by ET-2. 3. In the trachea, the rank order of potency, additivity and desensitization were different from the pulmonary artery. Basically, all three peptides were equipotent but less potent than ET-1 in the artery. There was no evidence for additivity and only a slight tendency to tachyphylaxis was seen. 4. The guinea-pig pulmonary artery appears to be endowed with one receptor type which is sensitive to ET-1/ET-2 and with another receptor type which responds preferentially to ET-3. In the trachea, neither of these receptors appears to be present since all three peptides apparently act on a homogeneous population of receptors with characteristics different from those of the two arterial receptors. This suggests a third non-isopeptide selective type of endothelin receptor.


Hemoperitoneum identified by focused assessment with sonography for trauma following cardiopulmonary resuscitation.
It is generally recognized that lives are saved by administering high-quality cardiopulmonary resuscitation (CPR) to patients in cardiac arrest. A focused assessment with sonography for trauma (FAST) examination is an effective and non-invasive method for detecting rare complications of CPR, such as hemorrhage from abdominal visceral injury. We report the case of a 56-year-old female suffering from intra-abdominal hemorrhage caused by a liver laceration following CPR. The hemoperitoneum was diagnosed by a FAST examination. Although severe complications of CPR are rare, they can be easily detected with the use of a FAST examination. A FAST examination should be considered as a post-resuscitation approach to assess for life-threatening complications in all patients following cardiopulmonary resuscitation.


Associations of prepubertal urinary phthalate metabolite concentrations with pubertal onset among a longitudinal cohort of boys.
Although phthalate exposures have been associated with adverse effects on male reproductive health, few studies have explored longitudinal associations with male pubertal development. We examined the association of prepubertal urinary concentrations of phthalate metabolites with age at pubertal onset in a prospective cohort of Russian boys. At enrollment at ages 8-9 years, medical history, dietary, and demographic information was collected. At entry and annually, physical examinations and pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV, in ml)] were conducted and spot urines were collected. Prepubertal urine samples (defined as either TV = 1, 2 and G = 1, 2 or TV = 3 and G = 1) were pooled for each boy and phthalate metabolite concentrations were quantified using isotope dilution LC-MS/MS at Moscow State University. We measured 15 metabolites including those from anti-androgenic parent phthalates (AAPs) such as di (2-ethylhexyl) (DEHP) and di-isononyl (DiNP) phthalates as well as monobenzyl (MBzP), mono-n-butyl (MnBP), and mono-isobutyl (MiBP) metabolites. We calculated the molar sums of DEHP (∑DEHP), DiNP (∑DiNP), and AAP (∑AAP) metabolites. Separate interval-censored models were used to assess associations of quartiles of prepubertal phthalate metabolites with each pubertal onset indicator, G2+, P2+ and TV > 3 mL, adjusted for covariates and urine specific gravity. 304 boys had 752 prepubertal urine samples (median 2, range: 1-6) for pooling. In adjusted models, higher urinary AAPs were consistently associated with later pubertal onset (P2) with mean shifts ranging from 8.4 to 14.2 months for the highest versus lowest quartiles. Significantly later onset for G2 and TV > 3 mL was observed for higher versus lower quartiles of MiBP, MBzP, ∑DEHP and ∑DiNP. On average, boys with higher concentrations of prepubertal urinary AAPs had later pubertal onset by six months to over a year. The impact of AAPs on timing of male puberty may be attributable to disruption of androgen-dependent biological pathways.


A study on the in vitro percutaneous absorption of silver nanoparticles in combination with aluminum chloride, methyl paraben or di-n-butyl phthalate.
Some reports indicate that the silver released from dermally applied products containing silver nanoparticles (AgNP) (e.g. wound dressings or cosmetics) can penetrate the skin, particularly if damaged. AgNP were also shown to have cytotoxic and genotoxic activity. In the present study percutaneous absorption of AgNP of two different nominal sizes (Ag15nm or Ag45nm by STEM) and surface modification, i.e. citrate or PEG stabilized nanoparticles, in combination with cosmetic ingredients, i.e. aluminum chloride (AlCl3), methyl paraben (MPB), or di-n-butyl phthalate (DBPH) was assessed using in vitro model based on dermatomed pig skin. The inductively coupled plasma mass spectrometry (ICP-MS) measurements after 24h in receptor fluid indicated low, but detectable silver absorption and no statistically significant differences in the penetration between the 4 types of AgNP studied at 47, 470 or 750μg/ml. Similarly, no significant differences were observed for silver penetration when the AgNP were used in combinations with AlCl3 (500μM), MPB (1250μM) or DBPH (35μM). The measured highest amount of Ag that penetrated was 0.45ng/cm2 (0.365-0.974ng/cm2) for PEG stabilized Ag15nm+MPB.


Lung ultrasound score severity cut-off points in COVID-19 pneumonia. A systematic review and validating cohort.
Our purpose was to establish different cut-off points based on the lung ultrasound score (LUS) to classify COVID-19 pneumonia severity. Initially, we conducted a systematic review among previously proposed LUS cut-off points. Then, these results were validated by a single-centre prospective cohort study of adult patients with confirmed SARS-CoV-2 infection. Studied variables were poor outcome (ventilation support, intensive care unit admission or 28-days mortality) and 28-days mortality. From 510 articles, 11 articles were included. Among the cut-off points proposed in the articles included, only the LUS > 15 cut-off point could be validated for its original endpoint, demonstrating also the strongest relation with poor outcome (odds ratio [OR] = 3.636, confidence interval [CI] 1.411-9.374). Regarding our cohort, 127 patients were admitted. In these patients, LUS was statistically associated with poor outcome (OR = 1.303, CI 1.137-1.493), and with 28-days mortality (OR = 1.024, CI 1.006-1.042). LUS > 15 showed the best diagnostic performance when choosing a single cut-off point in our cohort (area under the curve 0.650). LUS ≤ 7 showed high sensitivity to rule out poor outcome (0.89, CI 0.695-0.955), while LUS > 20 revealed high specificity to predict poor outcome (0.86, CI 0.776-0.917). LUS is a good predictor of poor outcome and 28-days mortality in COVID-19. LUS ≤ 7 cut-off point is associated with mild pneumonia, LUS 8-20 with moderate pneumonia and ≥20 with severe pneumonia. If a single cut-off point were used, LUS > 15 would be the point which better discriminates mild from severe disease.


Identification of the domain of Saccharomyces cerevisiae adenylate cyclase associated with the regulatory function of RAS products.
Various truncated CYR1 genes of Saccharomyces cerevisiae were fused to efficient promoters and expressed in Escherichia coli and S. cerevisiae cells with or without the RAS genes. The catalytic domain of adenylate cyclase encoded by the 3'-terminal 1.3 kb region of the open reading frame of the CYR1 gene produced cyclic AMP, irrespective of the presence of RAS genes. The product of the 3'-terminal 2.1 kb region of CYR1 showed guanine nucleotide-dependent adenylate cyclase activity and produced a large amount of cAMP in the presence of the RAS gene. Thus, the domain encoded by the 0.8 kb region adjacent to the catalytic domain is associated with the regulatory function of the RAS products. The cyr1 RAS1 RAS2 cells carrying the 3'-terminal 1.3 kb region of CYR1 were unable to respond to environmental signals such as sulfur starvation and temperature shift, but the cyr1 cells carrying the 2.1 kb region and at least one RAS gene were able to respond to these signals. The environmental signals may be transferred to the adenylate cyclase system through the RAS products.


Planning and Implementing an Organizational Health Assessment in a Community Mental Health Setting.
The workforce is the essential driver behind mental health service provision and the most valuable asset to any community mental health organization. To build and retain a stable and healthy workforce, systematic recruitment and retention strategies are needed. An organizational health assessment is a valuable tool in developing targeted organizational interventions to create a positive work environment and retain an engaged workforce. Starting in 2017, a large community mental health organization in Southern California implemented such an assessment to drive actionable steps to improve employee experience and decrease turnover. This case study describes the development and implementation of a low-cost organizational health assessment through five phases: development of the assessment, data collection, analysis, metrics and data visualization, and dissemination of findings and development of interventions. Key lessons learned include the importance of utilizing the findings and achieving staff and leadership buy-in.


Effects of fed-batch and continuous fermentations on human lysozyme production by Kluyveromyces lactis K7 in biofilm reactors.
Lysozyme is a lytic enzyme, which has antimicrobial activity. It has been used for food and pharmaceutical applications. This study was undertaken to evaluate fed-batch and continuous fermentations for the human lysozyme production in biofilm reactor. Results showed that addition of lactose the mid-log phase to make the concentration back to the initial level generates higher lysozyme production (177 U/ml) compared with lactose addition in late-log phase (174 U/ml) (p < 0.05). Moreover, fed-batch fermentation with glucose as initial carbon source and continuous addition of lactose with 0.6 ml/min for 10 h demonstrated significantly higher lysozyme production (187 U/ml) compared to the batch fermentation (173 U/ml) (p < 0.05). In continuous fermentation, biofilm reactor provided significantly higher productivity (7.5 U/ml/h) compared to the maximum productivity in suspended cell bioreactor (4 U/ml/h), because the biofilm reactor provided higher cell density at higher dilution rate compared to suspended cell reactor (p < 0.05).


Reversibility of the transformed and neoplastic phenotype. III. Long-term treatment with electrophoretically pure mouse interferon leads to the progressive reversion of the phenotype of X-ray transformed C3H/10T1/2 cells.
Electrophoretically pure mouse interferon induced the progressive reversion of the transformed phenotype of a clone of X-ray transformed C3H/10T1/2 cells. Cells of this clone did not harbor C-type particles and reverse transcriptase activity was not detected. Interferon-treated transformed cells were aligned without cellular overlapping and attained low cell densities. Morphologic changes were associated with the appearance of a thick layer of submembranous microfilaments. The tumorigenicity of interferon-treated cells was markedly reduced. Back reversion to the transformed phenotype occurred progressively when these cells were passaged in the absence of interferon. These results suggest that interferon may induce the reversion of the transformed phenotype by a mechanism other than by its antiviral activity.


Feelings of depression, pain and walking difficulties have the largest impact on the quality of life of people with multiple sclerosis, irrespective of clinical phenotype.
The symptoms that have the largest impact on health-related quality of life (HRQoL) in people with multiple sclerosis (MS) may vary by MS phenotype (relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)). Knowing these symptoms assists in symptom management. To examine the associations between 13 common MS symptoms and HRQoL in the total sample and stratified by MS phenotype. The study included 1985 participants. HRQoL was measured with two multi-attribute utility instruments: assessment of quality of life with eight dimensions (AQoL-8D) and European quality of life with five dimensions and five levels for each dimension (EQ-5D-5L). Multivariable linear regression was used to identify the symptoms that had the largest impact on the HRQoLs. Feelings of depression, pain, fatigue, and feelings of anxiety were most strongly associated with AQoL-8D and EQ-5D-5L. Walking difficulties additionally contributed to reduced EQ-5D-5L. The strongest single predictors in the multivariable analyses were feelings of depression or pain for AQoL-8D and walking difficulties for EQ-5D-5L, irrespective of MS phenotype. The strongest single predictors for the AQoL-8D and EQ-5D-5L were feelings of depression, pain and walking difficulties, irrespective of MS phenotype. Reducing these symptoms may have the largest impact on improving HRQoL in all MS phenotypes of people with MS.


Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study.
The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. We applied adjusted logistic regression models to data from patients aged 18-65 years presenting to South London and Maudsley NHS Foundation Trust with first-episode psychosis and population controls recruited from the same area of south London (UK) to estimate the effect of the frequency of use, and type of cannabis used on the risk of psychotic disorders. We then calculated the proportion of new cases of psychosis attributable to different types of cannabis use in south London. Between May 1, 2005, and May 31, 2011, we obtained data from 410 patients with first-episode psychosis and 370 population controls. The risk of individuals having a psychotic disorder showed a roughly three-times increase in users of skunk-like cannabis compared with those who never used cannabis (adjusted odds ratio [OR] 2·92, 95% CI 1·52-3·45, p=0·001). Use of skunk-like cannabis every day conferred the highest risk of psychotic disorders compared with no use of cannabis (adjusted OR 5·4, 95% CI 2·81-11·31, p=0·002). The population attributable fraction of first-episode psychosis for skunk use for our geographical area was 24% (95% CI 17-31), possibly because of the high prevalence of use of high-potency cannabis (218 [53%] of 410 patients) in our study. The ready availability of high potency cannabis in south London might have resulted in a greater proportion of first onset psychosis cases being attributed to cannabis use than in previous studies. UK National Institute of Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health, SLaM and the Institute of Psychiatry at King's College London, Psychiatry Research Trust, Maudsley Charity Research Fund, and th European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909 [Project EU-GEI]).


Construction and analysis of randomized protein-encoding libraries using error-prone PCR.
In contrast to site-directed mutagenesis and rational design, directed evolution harnesses Darwinian principles to identify proteins with new or improved properties. The critical first steps in a directed evolution experiment are as follows: (a) to introduce random diversity into the gene of interest and (b) to capture that diversity by cloning the resulting population of molecules into a suitable expression vector, en bloc. Error-prone PCR (epPCR) is a common method for introducing random mutations into a gene. In this chapter, we describe detailed protocols for epPCR and for the construction of large, maximally diverse libraries of cloned variants. We also describe the utility of an online program, PEDEL-AA, for analyzing the compositions of epPCR libraries. The methods described here were used to construct several libraries in our laboratory. A side-by-side comparison of the results is used to show that, ultimately, epPCR is a highly stochastic process.