Plastic Surgery Residents' Understanding and Attitudes Toward Biostatistics: A National Survey.
An understanding of biostatistics is a critical skill for the practicing plastic surgeon. The purpose of the present study was to assess plastic surgery residents' attitudes and understanding of biostatistics. This was a cross-sectional study of plastic surgery residents. A survey assessing resident attitudes regarding biostatistics, confidence with biostatistical concepts, and objective knowledge of biostatistics was distributed electronically to trainees in plastic surgery programs in the United States. Bivariate and regression analyses were used to identify significant associations and adjust for confounders/effect modifiers. One hundred twenty-three residents responded to the survey (12.3% response rate). Respondents expressed positive attitudes regarding biostatistics in plastic surgery practice, but only moderate levels of confidence with various biostatistical concepts. Both attitudes and confidence were positively associated with the number of plastic surgery journals read monthly and formal coursework in biostatistics (P < 0.01). Resident attitudes were positively correlated with confidence (r = 0.33, P < 0.01). The mean percentage of correct responses on knowledge-assessments was 43.6% (20.8%). Integrated residents performed better than independent track residents (P = 0.04). Residents had difficulty with study design, the correct use of analysis of variance, regression analysis, and identifying a statistically significant result. Resident confidence was moderately correlated with performance (r = 0.31, P = 0.01). Plastic surgery residents place a high degree of importance on knowledge of biostatistics in the practice of plastic surgery but have only a fair understanding of core statistical concepts.


Recent data on cannabinoids and their pharmacological implications in neuropathic pain.
Natural cannabinoids have been used for centuries for their psychotropic properties, but their possible therapeutic implications in analgesia have been recently documented. The present review intended to make an analysis of the neuroanatomy and physiology of the cannabinoid system (receptors, functions, agents acting on these receptors) and of its implications in neuropathic pain. There were also described the complex phenomena implicated in the generation and maintenance of neuropathic pain, by high lightening the implications of endogenous cannabinoids in this complex of painful conditions. The pharmacological analgesia test proves of cannabinoid implication in neuropathic pain was sustained by many studies presented in this paper. Therapeutic approaches using natural and synthetic cannabinoid receptor agonists were reviewed. Therapeutic perspectives in neuropathic pain might involve the development of new agents that influence the cannabinoid system. Thus, peripheral acting cannabinoid 1 receptors agonists, selective cannabinoid 2 receptor agonists and also modulators of endocannabinoids metabolism might be a way to success in the treatment of this complex entity called neuropathic pain.


Multi-scale magnetic coupling of Fe@SiO2@C-Ni yolk@triple-shell microspheres for broadband microwave absorption.
Magnetic core@shell and yolk@shell microspheres have received extensive attention; however, the realization of microwave performance enhancement remains a critical challenge for their actual applications. Herein, inspired by multi-scale magnetic coupling interactions, a synchronous in situ reduction process was developed to successfully fabricate Fe@SiO2@C-Ni (FSCN) yolk@triple-shell microspheres based on the Fe3O4@SiO2 substrate. Owing to the unique multi-scale magnetic coupling interactions in their delicate structure, (i) in each microsphere, abundant Ni NPs with optimized size could affect the density distribution and orientation of the magnetic stray field radiating from the Fe core, and (ii) via the coupling interactions between adjacent composite microspheres, the saturation magnetization was significantly enhanced to support strong magnetic loss capability. Moreover, the special yolk@multi-shell structure offered an optimized impedance balance, facilitating the propoagation of the incoming microwaves into the absorber. Both multiple interfacial polarization and synergistic effects from magnetic units (Fe and Ni) and dielectric shell (SiO2 and carbon) contributed to electromagnetic wave attenuation. The FSCN composite material exhibited excellent absorption performance with an intense reflection loss (-45.5 dB) and bandwidth absorption (8.2 GHz and 9.8-18 GHz) at the film thickness of only 2 mm. Our new findings provide important design implications for functional spheres and high-performance lightweight microwave absorbers.


Knitting and weaving artificial muscles.
A need exists for artificial muscles that are silent, soft, and compliant, with performance characteristics similar to those of skeletal muscle, enabling natural interaction of assistive devices with humans. By combining one of humankind's oldest technologies, textile processing, with electroactive polymers, we demonstrate here the feasibility of wearable, soft artificial muscles made by weaving and knitting, with tunable force and strain. These textile actuators were produced from cellulose yarns assembled into fabrics and coated with conducting polymers using a metal-free deposition. To increase the output force, we assembled yarns in parallel by weaving. The force scaled linearly with the number of yarns in the woven fabric. To amplify the strain, we knitted a stretchable fabric, exhibiting a 53-fold increase in strain. In addition, the textile construction added mechanical stability to the actuators. Textile processing permits scalable and rational production of wearable artificial muscles, and enables novel ways to design assistive devices.


Serum VEGF as a predictive marker of glycemic control and diabetic nephropathy in Chinese older adults with type 2 diabetes mellitus.
Recent researches have demonstrated good correlation between vascular endothelial growth factor (VEGF) and diabetic nephropathy (DN); however, this relationship seems less clear-cut when VEGF was measured in blood samples. We tended to explore the possible association between serum VEGF and glycemic control and diabetic nephropathy severity in Chinese older adults with type 2 diabetes mellitus (T2DM). This study retrospectively enrolled 595 older T2DM adults at random. Participants were clinically grouped across the urine albumin-to-creatinine ratio (UACR) and the HbA1c tertiles by genders. Linear regressions were performed for the correlation of VEGF with HbA1c and UACR and binary logistic regressions for the odds of DN after adjusting for confounders. The receiver operating characteristic (ROC) curves were conducted for the predictive value of VEGF for DN. Both males and females with DN exhibited higher VEGF levels than non-DN (P < 0.001). Furthermore, a positive correlation of VEGF with UACR and HbA1c was presented regardless of adjusting confounding factors (P < 0.001). Serum VEGF level and fasting plasma glucose (FPG) were independent risk factors of DN in older adults of both genders (P < 0.05), while the risk prediction of DN by HbA1c only reflected in female patients (P < 0.05). The ROC curve of VEGF for DN had the area under curve (AUC) of 0.819 for males and 0.793 for females, indicating the clinical value of serum VEGF as a predictive biomarker. Serum VEGF was strongly associated with UACR and HbA1c in both genders, and could be regarded as a predictive biomarker for glycemic control and diabetic nephropathy in older adults with T2DM.


Rrm2b deletion causes mitochondrial metabolic defects in renal tubules.
Renal diseases impose considerable health and economic burdens on health systems worldwide, and there is a lack of efficient methods for the prevention and treatment due to their complexity and heterogeneity. Kidneys are organs with a high demand for energy produced by mitochondria, in which Rrm2b has critical functions as reported. The Rrm2b kidney-specific knockout mice we generated exhibited age-dependent exacerbated features, including mitochondrial dysfunction and increased oxidative stress; additionally, resulted in severe disruption of mitochondria-related metabolism. Rrm2b is vital not only to supply dNTPs for DNA replication and repair, but also to maintain structural integrity and metabolic homeostasis in mitochondria. Thence, Rrm2b deletion might induce chronic kidney defects in mice. This model can facilitate exploration of novel mechanisms and targeted therapies in the kidney diseases and has important translational and clinical implications.


Risk Factors for Renal Function Impairment Following Radiofrequency Ablation of Renal Tumors.
To evaluate the various factors that affect renal function following percutaneous radiofrequency ablation (RFA) therapy in patients with renal tumors. Between 2010 and 2018, 91 patients diagnosed with renal tumors using ultrasonography and CT-guided RFA were enrolled. We retrospectively investigated the serum creatinine (SCr) level and estimated glomerular filtration rates immediately prior to RFA and during post-treatment follow-up. The patients were divided into two groups based on the degree of change in SCr level (0.3 mg/dL). Group comparisons were performed using univariable and multivariable logistic regression analyses to determine the factors impacting renal function. Impaired renal function was associated with solitary kidney, chronic kidney disease (CKD) over stage 3, and pyeloureteral injury. Sex, age, other cancers, tumor size, location, growth pattern, and proximity to the collecting system were not significantly associated with impaired renal function. There was a difference in the overall change over time between the association with and without solitary kidney, CKD stage 3, and pyeloureteral injury. Among the medical conditions present prior to RFA, solitary kidney and CKD over stage 3 could be considered as risk factors for impaired renal function. Post-procedural pyeloureteral injury can also be considered a risk factor.


Effect of target removal on goldfish optic nerve regeneration: analysis of fast axonally transported proteins.
How is axonal transport in regenerating neurons affected by contact with their synaptic target? We investigated whether removing the target (homotopic) lobe of the goldfish optic tectum altered the incorporation of 3H-proline into fast axonally transported proteins in the regenerating optic nerve. Regeneration was induced either by an optic tract lesion (to reveal the changes in the original axon segment that remained connected to the cell body) or by an optic nerve lesion (to reveal the changes in the newly formed axon segment). Of 26 proteins analyzed by 2-dimensional gel electrophoresis and fluorography, all but one showed increased labeling as a result of tectal lobe ablation. By 2 d after the lesion, significantly increased labeling of some proteins was seen with a 6-hr labeling interval, but not with a 24-hr labeling interval. This is probably indicative of an increased velocity of transport, which may have been a nonspecific consequence of the surgery. Otherwise, tectal lobe removal had relatively little effect until 3 weeks, when there was a transitory increase in labeling of transported proteins in the new axon segments of the tectum-ablated animals. Beginning at 5 weeks, tectal lobe ablation caused considerably higher labeling of many of the proteins in the original axon segments. Because this was seen with both 6-hr and 24-hr labeling intervals, it is probably indicative of increased protein synthesis. The increased synthesis lasted until at least 12 weeks, though some proteins were beginning to show a diminished effect at this time. In the late stages of regeneration (8-12 weeks), there was also increased labeling of proteins in the new axon segments as a result of the absence of the target tectal lobe. This included a disproportionately large increase in the relative contribution of cytoskeletal proteins and of protein 4, which is the goldfish equivalent of the growth-associated protein GAP-43 (neuromodulin). We conclude that, after the regenerating axons begin to innervate the tectum, the expression of most of the proteins in fast axonal transport is down-regulated by interaction between the axons and their target. However, the changes in expression may be preceded by a modulation of the turnover and/or deposition of proteins in the newly formed axon segment.


CRISPR/dCas9-mediated epigenetic modification reveals differential regulation of histone acetylation on Aspergillus niger secondary metabolite.
Epigenetic studies on secondary metabolites (SMs) mainly relied so far on non-selective epigenetic factors deletion or feeding epigenetic inhibitors in Aspergillus niger. Although technologies developed for epigenome editing at specific loci now enable the direct study of the functional relevance of precise gene regulation and epigenetic modification, relevant assays are limited in filamentous fungi. Herein, we show that CRISPR/dCas9-mediated histone epigenetic modification systems efficiently reprogramed the expression of target genes in A. niger. First, we constructed a p300-dCas9 system and demonstrated the activation of a EGFP fluorescent reporter. Second, by precisely locating histone acetylase p300 on ATG adjacent region of secondary metabolic gene breF, the transcription of breF was activated. Third, p300-dCas9 was guided to the native polyketide synthase (PKS) gene fuml, which increased production of the compound fumonisin B2 detected by HPLC and LC-MS. Then, endogenous histone acetylase GcnE-dCas9 and histone deacetylases HosA-dCas9 and RpdA-dCas9 repressed the transcription of breF. Finally, by targeting HosA-dCa9 fusion to pigment gene fwnA, we confirmed that histone deacetylase HosA activated the expression of fwnA, accelerated the synthesis of melanin. Targeted epigenome editing is a promising technology and this study is the first time to apply the epigenetic CRISPR/dCas9 system on regulating the expression of the secondary metabolic genes in A. niger.


The association of health and voluntary early retirement pension and the modifying effect of quality of supervision: Results from a Danish register-based follow-up study.
The aims of this article are to (1) determine whether and to what extent general perceived health and quality of supervision predict voluntary early retirement pension (VERP) and (2) assess whether quality of supervision modifies the association between general perceived health and VERP. Employees aged 49-64 years who participated in the Danish Work Environment Cohort Study in 2000 were selected. Their questionnaire data about health and work were linked to register data on social transfer payments, among others VERP, from 2001 to 2012 in the Danish Register for Evaluation of Marginalization ( N=1167). Cox proportional hazards analyses were performed to identify the prospective association of general perceived health and quality of supervision on VERP. Relative excess risks due to interaction (RERIs) were calculated to assess whether quality of supervision modified the association between health and VERP. Employees with poor health at baseline had an increased risk of VERP during follow-up (hazard ratio [HR]=1.23; 95% confidence interval [CI] 1.02-1.49). Quality of supervision at baseline was not associated to VERP during follow-up (HR=1.04; 95% CI 0.90-1.21). There was no statistically significant interaction of poor health and poor quality of supervision with regard to risk of VERP (RERI=-0.33; 95% CI -1.79 to 1.14). This study did not support the notion that quality of supervision buffers the association between poor health and VERP. Future research is needed to determine whether other aspects of supervision, for example supervisors' opportunities to effectuate workplace adjustments, may modify the association of poor health and VERP.


The Normal Inhibition of Associations is Impaired by Clonidine in Tourette Syndrome.
We examined the inhibition of stimulus-stimulus associations (formally 'conditioned inhibition') in Tourette syndrome (TS). The present study used video game style conditioned inhibition procedures suitable for children and adolescents. We tested 15 participants with a clinical diagnosis of TS in the absence of co-morbid attention deficit hyperactivity disorder and compared them with 19 typically developing age and sex matched controls (both groups aged 10-20 years). All children were tested for inhibition by summation test using two test stimuli in each of two conditioned inhibition tasks. TS participants showed overall normal inhibition of stimulus-stimulus associations, and there was no correlation between inhibitory learning scores and symptom severity ratings. However, there was a clear reduction in conditioned inhibition in 7 TS participants medicated with clonidine. There was no significant effect of medication on excitatory learning of the stimulus-stimulus associations. We suggest that clonidine's effect on inhibitory as opposed to excitatory learning could be related to reduced noradrenergic activity. In terms of clinical implications for TS, impaired conditioned inhibition could reduce the ability of susceptible individuals to learn to control tics in the presence of associative triggers.


Human papillomavirus (HPV) type 16 E7 protein bodies cause tumour regression in mice.
Human papillomaviruses (HPV) are the causative agents of cervical cancer in women, which results in over 250 000 deaths per year. Presently there are two prophylactic vaccines on the market, protecting against the two most common high-risk HPV types 16 and 18. These vaccines remain very expensive and are not generally affordable in developing countries where they are needed most. Additionally, there remains a need to treat women that are already infected with HPV, and who have high-grade lesions or cervical cancer. In this paper, we characterize the immunogenicity of a therapeutic vaccine that targets the E7 protein of the most prevalent high-risk HPV - type 16 - the gene which has previously been shown to be effective in DNA vaccine trials in mice. The synthetic shuffled HPV-16 E7 (16E7SH) has lost its transforming properties but retains all naturally-occurring CTL epitopes. This was genetically fused to Zera®, a self-assembly domain of the maize γ-zein able to induce the accumulation of recombinant proteins into protein bodies (PBs), within the endoplasmic reticulum in a number of expression systems. High-level expression of the HPV 16E7SH protein fused to Zera® in plants was achieved, and the protein bodies could be easily and cost-effectively purified. Immune responses comparable to the 16E7SH DNA vaccine were demonstrated in the murine model, with the protein vaccine successfully inducing a specific humoral as well as cell mediated immune response, and mediating tumour regression. The fusion of 16E7SH to the Zera® peptide was found to enhance the immune responses, presumably by means of a more efficient antigen presentation via the protein bodies. Interestingly, simply mixing the free PBs and 16E7SH also enhanced immune responses, indicating an adjuvant activity for the Zera® PBs.


Fine-Grained Visual-Text Prompt-Driven Self-Training for Open-Vocabulary Object Detection.
Inspired by the success of vision-language methods (VLMs) in zero-shot classification, recent works attempt to extend this line of work into object detection by leveraging the localization ability of pretrained VLMs and generating pseudolabels for unseen classes in a self-training manner. However, since the current VLMs are usually pretrained with aligning sentence embedding with global image embedding, the direct use of them lacks fine-grained alignment for object instances, which is the core of detection. In this article, we propose a simple but effective fine-grained visual-text prompt-driven self-training paradigm for open-vocabulary detection (VTP-OVD) that introduces a fine-grained visual-text prompt adapting stage to enhance the current self-training paradigm with a more powerful fine-grained alignment. During the adapting stage, we enable VLM to obtain fine-grained alignment using learnable text prompts to resolve an auxiliary dense pixelwise prediction task. Furthermore, we propose a visual prompt module to provide the prior task information (i.e., the categories need to be predicted) for the vision branch to better adapt the pretrained VLM to the downstream tasks. Experiments show that our method achieves the state-of-the-art performance for open-vocabulary object detection, e.g., 31.5% mAP on unseen classes of COCO.


A new concept for noninvasive tinnitus treatment utilizing multimodal pathways.
Current noninvasive treatments for tinnitus have shown mixed results. There have been encouraging developments in using invasive brain or vagal nerve stimulation to modulate neural populations driving the tinnitus percept. However, these invasive treatments can only be used in a small patient population with severe conditions. In this preliminary study, we present a new treatment option we call Multimodal Synchronization Therapy (MST), which attempts to achieve synchronized and localized brain activation without invasive neural stimulation. MST combines multiple sensory, motor, limbic, and cognitive inputs to elicit activation of multimodal neurons to potentially modulate specific neurons driving the tinnitus percept. We present preliminary data in a guinea pig model showing activation of somatosensory and auditory pathways to alter neural activity within the inferior colliculus, a multimodal integration region that has shown pathological changes in animals and patients with tinnitus. Electrical stimulation of different body locations induced excitatory responses in the inferior colliculus, eliciting responses in up to 41% of all recording sites for a given somatic site. Paired somatic and acoustic stimulation resulted in enhanced or suppressed acoustic-driven neural activity in the inferior colliculus that varied depending on stimulation and recording location. Similar modulation effects were observed in the auditory cortex, which may relate to changes in auditory perception. Further studies need to incorporate multiple multimodal pathways and must also confirm that MST can suppress the abnormal neural patterns that directly drive the tinnitus percept.


The addition of radiotherapy to chemotherapy does not improve outcome of early stage Hodgkin's lymphoma patients: a retrospective long-term follow-up analysis of a regional Italian experience.
We retrospectively reviewed 139 stage I-II HL patients who were diagnosed and followed up in an Italian northern region (Liguria) from 1995 to 2007, and who received either chemotherapy (CT) alone (mainly doxorubicin, bleomycin, vinblastine, and dacarbazine; ABVD) or a combined modality treatment (chemotherapy + radiotherapy, CT + RT). The two therapeutic groups were comparable for clinical and histologic features. Complete remission rate after CT + RT was higher than what was achieved with CT alone (96% vs. 84%, respectively, p = 0.03). Relapse rate (12%) was the same in both groups and disease-free survival curves were comparable (82% and 83%, p = 0.47). The overall survival of the two therapeutic groups is comparable. No second tumors have been reported among patients receiving chemotherapy alone, whereas a second neoplasia has been diagnosed in four patients (in two cases possibly radiotherapy related) in the CT + RT group (5%, p = 0.09) In conclusion, our retrospective study shows that CT + limited RT is an effective and well-tolerated option for early stage Hodgkin's lymphoma, even if the use of RT is associated with a certain risk of developing a second tumor. However, four to six courses of ABVD can lead to similar, optimal, long-term disease control without exposing patients to the risk of a second neoplasia.


[Problems in randomized controlled trial on acupuncture and moxibustion for migraine in the development of international standard of Guideline for Clinical Practice of Acupuncture and Moxibustion: Migraine].
Regarding the development of international standard of Guideline for Clinical Practice of Acupuncture and Moxibustion: Migraine, the existing problems of the design and methodology of randomized controlled trial (RCT) on acupuncture and moxibustion for migraine were summarized in views of participant, intervention, control, outcome and study design. Four directions need to be further explored, (1) research of adolescent migraine, special subtype of migraine and migraine in a special population; (2) research of the immediate analgesic effect of acupuncture and moxibuation at the attack stage of migraine and the therapeutic effect of migraine at each stage; (3) research on safety and health economics; (4) clinical trial registration of acupuncture and moxibustion. In study, the target population should be further determined and specialized, the diagnosis criteria of western medicine and traditional Chinese medicine be generalized and concentrated, the staging and type division of disease be accurate, the intervention procedure be integrated, the control design be rationalized, the outcomes be validated, and the description of randomization and blinding be clarified.


Accessing Colony Boundary Strengthening of Fully Lamellar TiAl Alloys via Micromechanical Modeling.
In this article, we present a strategy to decouple the relative influences of colony, domain and lamella boundary strengthening in fully lamellar titanium aluminide alloys, using a physics-based crystal plasticity modeling strategy. While lamella and domain boundary strengthening can be isolated in experiments using polysynthetically twinned crystals or mircomechanical testing, colony boundary strengthening can only be investigated in specimens in which all three strengthening mechanisms act simultaneously. Thus, isolating the colony boundary strengthening Hall-Petch coefficient K C experimentally requires a sufficient number of specimens with different colony sizes λ C but constant lamella thickness λ L and domain size λ D , difficult to produce even with sophisticated alloying techniques. The here presented crystal plasticity model enables identification of the colony boundary strengthening coefficient K C as a function of lamella thickness λ L . The constitutive description is based on the model of a polysynthetically twinned crystal which is adopted to a representative volume element of a fully lamellar microstructure. In order to capture the micro yield and subsequent micro hardening in weakly oriented colonies prior to macroscopic yield, the hardening relations of the adopted model are revised and calibrated against experiments with polysynthetically twinned crystals for plastic strains up to 15%.


Perceptions of physical restraints use in the elderly among registered nurses and nurse assistants in a single acute care hospital.
Physical restraint use among hospitalized older adults remains an important issue. Despite evidence indicating that restraints can be harmful and strict regulatory rules restricting the use of restraints, healthcare practitioners continue to utilize physical restraints, often in the name of safety. The purpose of this study was to examine the perceptions regarding physical restraint use among registered nurses (RNs) and nursing assistants (NAs). The Perceptions of Restraint Use Questionnaire (PRUQ) was used to evaluate nursing staff perceptions. The overall mean score for the PRUQ was 2.8 out of a possible 5, indicating a neutral perception. Both RNs and NAs identified treatment interference as the most important reason for restraining a patient and substituting of restraints for staff as the least important reason. This study revealed an overall less favorable perception of restraints than previous studies. NAs favored physical restraint for fall prevention more than RNs. It was also noted that protection from physical abuse and patient combativeness was the most salient reason cited by the emergency department staff.


[Nutritional characterization of produced fish for human consumption in Bucaramanga, Colombia].
This research involves the nutritional characterization of the most commonly cultivated fish in the region. The species under study were: Rainbow trout (Salmo gairdnerii), tilapia roja (Oreocliromis sp), cachama blanca (Piaractus brachypomus), bocachico (Prochilodus reticulatus magdalenae) and catfish (Pseudoplatystoma faciatum). A sea fish, coho Salmon (Oncorhynchus kisutch), was used as reference because it is the imported species most used in the region, and it also contains n-3 fatty acids. For each fish sample moisture, ash, protein content, total fat, minerals (iron, calcium and phosphorous) and a fatty acid profile were determined. Results show a total protein content in between 16.4 and 22.6 g/100 g fillet for fresh water fish. Total fat amounts for trout are the highest (8.1 g/100 g fillet), while catfish has the lowest fat content (0.4 g/100 g fillet). Trout was found to be the most important source of n-3 fatty acids (EPA+DHA) and phosphorous, with values ranging from 0.25% to 0.52%, and 250 to 346 mg/100 g fillet, respectively. Catfish and trout exhibited the highest iron content, with values ranging from 3 to 6mg/100 g fillet. Salmon, on the other hand, showed a high n-3 fatty acid content of 1.16% to 2.25%, when compared to fresh water fish. Calcium content is low in all species under scrutiny. Fresh water fish, other than trout, show no significant amount of n-3 fatty acids. However, all of them are a good source of protein. The obtained results allowed to determine the profile of oily acids of produced fish for human consumption in the region, demonstrating that the trout is the species with major quantity of oily acids n-3 specially DHA and of the minerals the phosphorus. Other species (kinds) catfish, bocachico, tilapia and cachama, are not a source of oily acids n-3, but they are an important source of protein.


Bisphenol A interferes with thyroid specific gene expression.
Bisphenol A (BPA) is an endocrine-disrupting chemical that leads to low-dose human exposure due to its ability to leach from chemically derived products, as polycarbonate plastics and epoxy resin. In addition to its known xeno-endocrine action, BPA exerts a wide range of metabolic effects. Despite the documented BPA exposure outcomes on synthesis of thyroid hormones, there are not any data available on its actions on the thyroid follicular cells, site of synthesis of the thyroid hormones. Recently, it has been shown that several environmental pollutants, as BPA, can exert a thyroid disrupting activity. In this study, we employed in vitro and in vivo (zebrafish) models to examine the effects of BPA in regulating the expression of genes involved in the thyroid hormone synthesis and of their transcriptional regulators at BPA doses as low as 10(-9)M, a dose that is environmentally pertinent and far below the one detected in infants plasma. In both systems we could detect an altered expression of the genes involved in thyroid hormones synthesis and of thyroid specific transcriptional factors in BPA dose and time dependent manner. Our results suggest that BPA exerts a direct effect on thyroid follicular cell. We show that these cells can "sense" very low amount of BPA. Thus they, potentially, represent an ideal in vitro system to develop assays to detect BPA and other pollutants with thyroid disrupting activity at level far below the ones considered to be environmental relevant. Moreover, this report may provide new insight into the mode of BPA-induced deregulation of physiological processes as well as on the extensively debated molecular pathways underlying its biological activities.


Activation of c-Jun N-terminal kinase is required for mevastatin-induced apoptosis of salivary adenoid cystic carcinoma cells.
Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, originally developed for lowering cholesterol. Statins also have pleiotropic effects, independent of cholesterol-lowering effects, including induction of apoptosis in various cell lines. However, the mechanism underlying statin-induced apoptosis is still not fully understood. This study aims to explore the proapoptotic effects and underlying mechanisms of statins on human salivary adenoid cystic carcinoma (SACC). Exposure of SACC cells to mevastatin resulted in cell growth inhibition and apoptosis in a dose-dependent manner, accompanied by the release of cytochrome c and cleavage of caspase-3. A remarkable decrease in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and increase in phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase were observed. Furthermore, the JNK-specific inhibitor SP600125, but not the p38-specific inhibitor SB203580, abolished mevastatin-induced cell growth inhibition and apoptosis in SACC cells. This was supported by results in which the JNK inhibitor efficiently blocked mevastatin-induced JNK phosphorylation, but not p38 phosphorylation, and further decreased mevastatin-induced phosphorylation of ERK1/2. Taken together, the results suggest that the JNK pathway was required for mevastatin-induced cell growth inhibition and apoptosis in SACC cells. Statins could be potential anticancer agents for SACC chemotherapy.


Effect of prenatal treatment with busulfan on the hypothalamo-pituitary axis, genital tract and testicular histology of prepubertal male rats.
Female Wistar rats were treated with busulfan or with solvent on Day 20 of pregnancy. Thirty male offspring of each group were killed at 38 days of age. In busulfan-treated rats, compared to controls, hypothalamic LH-RH content was decreased by 52%, whereas pituitary LH and FSH concentrations were increased by 60 and 43% respectively. Plasma LH and FSH were increased by 112 and 275% respectively. Prolactin concentrations were not changed, but plasma testosterone concentration was decreased by 48%. The total number of Leydig cells per testis was decreased by 52%, and LH binding sites per testis were decreased by 70%. The total number of Sertoli cells was decreased by 44%, while FSH binding sites per testis were decreased by 62%. Spermatogenesis was practically absent after prenatal exposure to busulfan. These data demonstrate that on Day 20 of pregnancy all the dividing cells in the fetal testes were depleted by an antimitotic treatment. The stimulation of the hypothalamo-pituitary axis could have been partly induced by the decrease in testosterone production, and by the aplasia of germ cells involving modifications of the remaining Sertoli and Leydig cells.


Experience, prevalence, need for treatment and cost of care for caries: A multicenter study in a developing country.
To assess the experience, prevalence, need for treatment and economic impact of caries among students 6-12 years old in four cities in Mexico. Cross-sectional clinical study. Elementary public schools. 500 schoolchildren aged 6 to 12 years. Oral clinical examinations using WHO criteria for caries in the primary (dmft) and permanent (DMFT) dentitions. Indicators of caries in the primary and permanent dentitions: experience, prevalence, severity and the Significant Caries Index. In addition, we calculated the treatment needs, dental care rate and cost of care. dmft in the primary dentition was 2.59±2.83, and DMFT was 0.82±1.44 in the permanent dentition. Caries prevalence reached 67.7% in the primary and 34.1% in permanent dentition. The treatment needs index was 85.9% and 91.3% in the primary and permanent dentitions, respectively; the dental care index was 13.9% and 8.5%, respectively. The cost of care for caries in the primary dentition was estimated at $22.087 millions of international dollars (PPP US$) when amalgam was the restorative material used, and PPP US$19.107 millions for glass ionomer. For the permanent dentition, the cost was PPP US$7.431 millions when amalgam was used and PPP US$7.985 millions when resin/composite was used as restorative material. The prevalence and experience of caries in the primary dentition were 50% greater than those of other studies carried out in Mexico. In the permanent dentition they were less. There is considerable need for the treatment of caries and minimal experience with restorative care. The cost of care for caries may be assumed to be high for a health system such as Mexico's.


Functions and Mechanisms of Fibroblast Growth Factor (FGF) Signalling in Drosophila melanogaster.
Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF) signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl) and Breathless (Btl) is particularly well studied. These FGF receptors affect gene expression, cell shape and cell-cell interactions during mesoderm layer formation, caudal visceral muscle (CVM) formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level.


Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells.
Cellular differentiation is governed by changes in gene expression, but at the same time, a cell's identity needs to be maintained through multiple cell divisions during maturation. In myeloid cell lines, retinoids induce gene expression and a well-characterized two-step lineage-specific differentiation. To identify mechanisms that contribute to cellular transcriptional memory, we analyzed the epigenetic changes taking place on regulatory regions of tissue transglutaminase, a gene whose expression is tightly linked to retinoid-induced differentiation. Here we report that the induction of an intermediary or "primed" state of myeloid differentiation is associated with increased H4 arginine 3 and decreased H3 lysine 4 methylation. These modifications occur before transcription and appear to prime the chromatin for subsequent hormone-regulated transcription. Moreover, inhibition of methyltransferase activity, pre-acetylation, or activation of the enzyme PAD4 attenuated retinoid-regulated gene expression, while overexpression of PRMT1, a methyltransferase, enhanced retinoid responsiveness. Taken together, our results suggest that H4 arginine 3 methylation is a bona fide positive epigenetic marker and regulator of transcriptional responsiveness as well as a signal integration mechanism during cell differentiation and, as such, may provide epigenetic memory.


Neurointerventional research between 2003 and 2012: slow growth, high interdisciplinary collaboration, and a low level of funding.
Neurointerventional therapy of cerebrovascular disease is a greatly expanding field across many specialty disciplines. The goal of this study was to analyze the characteristics and trends of scientific publications that focused on neurointervention during the past decade. A bibliometric evaluation of neurointerventional research published between 2003 and 2012 was conducted by using the PubMed data base. Analyzed parameters included the year of publication, type of document, language of the article, topic, declared funding, country of origin, type of collaboration between disciplines, the first author's specialty, and subject category and the Impact Factor of the publishing journal. Between 2003 and 2012, a total of 2123 articles were published, of which 1107 (52.1%) were original articles, 1948 (91.8%) were written in English, 192 (9.0%) received funding, 661 (31.1%) were published by the United States, and 1060 (49.9%) resulted from interdisciplinary collaboration. Neurosurgery departments produced the most articles (n = 910, 42.9%), followed by radiology (n = 747, 35.2%) and neurology (n = 270, 12.7%). The time-trend analysis in the number of publications demonstrated slow growth from 2003 to 2012, with an average annual growth rate of +6.0%. The fields of neurosurgery, radiology, and neurology have contributed substantially to neurointervention research. Slow growth, high interdisciplinary collaboration, and a low level of funding are peculiar characteristics of research in this field.


Controls on body size during the Late Permian mass extinction event.
This study examines the morphological responses of Late Permian brachiopods to environmental changes. Quantitative analysis of body size data from Permian-Triassic brachiopods has demonstrated significant, directional changes in body size before, during and after the Late Permian mass extinction event. Brachiopod size significantly reduced before and during the extinction interval, increased for a short time in more extinction-resistant taxa in the latter stages of extinction and then dramatically reduced again across the Permian/Triassic boundary. Relative abundances of trace elements and acritarchs demonstrate that the body size reductions which happened before, during and after extinction were driven by primary productivity collapse, whereas declining oxygen levels had less effect. An episode of size increase in two of the more extinction-resistant brachiopod species is unrelated to environmental change and possibly was the result of reduced interspecific competition for resources following the extinction of competitors. Based on the results of this study, predictions can be made for the possible responses of modern benthos to present-day environmental changes.


Evaluation of microincision vitrectomy surgery using wide-viewing system for complications with ocular sarcoidosis.
We evaluate the outcomes of microincision vitrectomy surgery (MIVS) using wide-viewing system for complications with ocular sarcoidosis resistance to medical treatment.Consecutive clinical records of 24 eyes (19 patients) with complications of ocular sarcoidosis underwent MIVS between April 2010 and December 2013 were retrospectively reviewed. MIVS and phacoemulsification were performed in 18 eyes and MIVS only in 6 eyes. Best-corrected visual acuity (BCVA), inflammation scores in the anterior segment and in the posterior segment, and central retinal thickness (CRT) of eyes with cystoid macular edema (CME) before surgery and after 1 week, 1, 3, 6, and 12 months were evaluated.LogMAR (log of the minimum angle of resolution) converted from BCVA was improved in 83.3% after 12 months and 66.7% showed improvement of more than 2 lines. The mean LogMAR was significantly improved from 1.14 ± 1.18 to 0.36 ± 0.79 in all eyes and 0.83 ± 0.86 to 0.23 ± 0.41 in eyes with MIVS and phacoemulsification, although no improvement was observed in eyes with MIVS only. Significant decrease of the mean anterior inflammation score was observed after 1 month in eyes with MIVS only and after 12 months in eyes with MIVS and phacoemulsification, and the mean posterior inflammation scores decreased after 1 week in all eyes. In eyes with preoperative CME, mean CRT was significantly decreased from 1 week after surgery. There was no case in which ocular inflammation was exacerbated by surgical stress. Improvement of visual acuity and resolution of ocular inflammation could be achieved by MIVS using wide-viewing system for complications of ocular sarcoidosis.


Investigation of the effect of different chelation solutions on penetration of resin-based and bioceramic sealers with a novel method.
This study aimed to investigate the effects of different chelation solutions on the penetration of resin-based and bioceramic root canal sealers into dentinal tubules using a device that assembles conventional microplate detection with automated digital microscopy. Eighty-four single-rooted teeth were prepared with 30.07 nickel-titanium instruments and divided into four groups of 21 according to the final irrigation solutions used: saline (control), ethylenediaminetetraacetic acid (EDTA), maleic acid (MA), and etidronic acid (HEBP). The samples were obturated with AH Plus, MTA Fillapex, or EndoSequence BC Sealer using the single-cone technique. The roots were then sectioned horizontally at 2, 6, and 10 mm and examined using a Cytation 5 reader and Gen5 software. Data were compared using two-way analysis of variance followed by univariate analyses and Tukey's multiple comparison test (p < .05). The mean penetration depth in the apical thirds was higher in the MA group than in the other groups (p = .013). The mean depth in the middle and coronal thirds was almost equal in the EDTA and HEBP groups. The mean depth was significantly higher in the coronal thirds of the root canals than in any other section in all final irrigation solution groups (p < .001). EndoSequence BC Sealer displayed higher penetration depth than AH Plus and MTA Fillapex, although the differences between the examined sealers were not statistically significant. The chelation solutions increased root canal sealer penetration into the dentinal tubule.


Advanced glycation end-products diminish tendon collagen fiber sliding.
Connective tissue aging and diabetes related comorbidity are associated with compromised tissue function, increased susceptibility to injury, and reduced healing capacity. This has been partly attributed to collagen cross-linking by advanced glycation end-products (AGEs) that accumulate with both age and disease. While such cross-links are believed to alter the physical properties of collagen structures and tissue behavior, existing data relating AGEs to tendon mechanics is contradictory. In this study, we utilized a rat tail tendon model to quantify the micro-mechanical repercussion of AGEs at the collagen fiber-level. Individual tendon fascicles were incubated with methylglyoxal (MGO), a naturally occurring metabolite known to form AGEs. After incubation in MGO solution or buffer only, tendons were stretched on the stage of a multiphoton confocal microscope and individual collagen fiber stretch and relative fiber sliding were quantified. Treatment by MGO yielded increased fluorescence and elevated denaturation temperatures as found in normally aged tissue, confirming formation of AGEs and related cross-links. No apparent ultrastructural changes were noted in transmission electron micrographs of cross-linked fibrils. MGO treatment strongly reduced tissue stress relaxation (p<0.01), with concomitantly increased tissue yield stress (p<0.01) and ultimate failure stress (p=0.036). MGO did not affect tangential modulus in the linear part of the stress-strain curve (p=0.46). Microscopic analysis of collagen fiber kinematics yielded striking results, with MGO treatment drastically reducing fiber-sliding (p<0.01) with a compensatory increase in fiber-stretch (p<0.01). We thus conclude that the main mechanical effect of AGEs is a loss of tissue viscoelasticity driven by matrix-level loss of fiber-fiber sliding. This has potentially important implications to tissue damage accumulation, mechanically regulated cell signaling, and matrix remodeling. It further highlights the importance of assessing viscoelasticity - not only elastic response - when considering age-related changes in the tendon matrix and connective tissue in general.


Alopecia Areata: a Comprehensive Review of Pathogenesis and Management.
Alopecia areata is a common hair loss condition that is characterized by acute onset of non-scarring hair loss in usually sharply defined areas ranging from small patches to extensive or less frequently diffuse involvement. Depending on its acuity and extent, hair loss is an important cause of anxiety and disability. The current understanding is that the condition represents an organ-specific autoimmune disease of the hair follicle with a genetic background. Genome-wide association studies provide evidence for the involvement of both innate and acquired immunity in the pathogenesis, and mechanistic studies in mouse models of alopecia areata have specifically implicated an IFN-γ-driven immune response, including IFNγ, IFNγ-induced chemokines and cytotoxic CD8 T cells as the main drivers of disease pathogenesis. A meta-analysis of published trials on treatment of alopecia areata states that only few treatments have been well evaluated in randomized trials. Nevertheless, depending on patient age, affected surface area and disease duration, an empiric treatment algorithm can be designed with corticosteroids and topical immunotherapy remaining the mainstay of therapy. The obviously limited success of evidence-based therapies points to a more important complexity of hair loss. At the same time, the complexity of pathogenesis offers opportunities for the development of novel targeted therapies. New treatment opportunities based on the results of genome-wide association studies that implicate T cell and natural killer cell activation pathways are paving the way to new approaches in future clinical trials. Currently, there are ongoing studies with the CTLA4-Ig fusion protein abatacept, anti-IL15Rβ monoclonal antibodies and the Janus kinase inhibitors tofacitinib, ruxolitinib and baricitinib. Ultimately, the options available for adapting to the disease rather than treating it in an effort to cure may also be taken into consideration in selected cases of long-standing or recurrent small spot disease.


Valproate-induced reversible sensorineural hearing loss: a case report with serial audiometry and pharmacokinetic modelling during a valproate rechallenge.
Hearing loss has been reported with valproic acid (VPA) use. However, this is the first case of VPA-induced hearing loss that was tested and confirmed with a VPA rechallenge, supported by serial audiometry and pharmacokinetic modelling. A 39-year-old truck driver with temporal lobe epilepsy was treated with VPA at 400 mg, twice daily, and developed hearing loss after each dose, but recovered within three hours. Hearing loss fully resolved after VPA discontinuation. Audiometry performed five hours after VPA rechallenge showed significant improvement in hearing thresholds. Pharmacokinetic modelling during the VPA rechallenge showed that hearing loss occurred at a level below the therapeutic range. Brainstem auditory evoked potential at three months after VPA discontinuation showed bilateral conduction defect between the cochlear and superior olivary nucleus, supporting a pre-existing auditory deficit. VPA may cause temporary hearing threshold shift. Pre-existing auditory defect may be a risk factor for VPA-induced hearing loss. Caution should be taken while prescribing VPA to patients with pre-existing auditory deficit.


Interorgan regulation of Drosophila intestinal stem cell proliferation by a hybrid organ boundary zone.
The molecular identities and regulation of cells at interorgan boundaries are often unclear, despite the increasingly appreciated role of organ boundaries in disease. Using Drosophila as a model, we here show that a specific population of adult midgut organ-boundary intestinal stem cells (OB-ISCs) is regulated by the neighboring hindgut, a developmentally distinct organ. This distinct OB-ISC control occurs through proximity to a specialized transition zone between the endodermal midgut and ectodermal hindgut that shares molecular signatures of both organs, which we term the hybrid zone (HZ). During homeostasis, proximity to the HZ restrains OB-ISC proliferation. However, injury to the adult HZ/hindgut drives upregulation of unpaired-3 cytokine, which signals through a Signal transducer and activator of transcription (STAT) protein to promote cell division only in OB-ISCs. If HZ disruption is severe, hyperplastic OB-ISCs expand across the interorgan boundary. Our data suggest that interorgan signaling plays an important role in controlling OB-ISCs in homeostasis and injury repair, which is likely to be crucial in prevention of disease.


Chiasmal apoplexy. Report of four cases.
Four patients with chiasmal syndromes were found to have intrachiasmal hematomas. Computerized tomography scans showed high-density suprasellar masses in all cases. Cryptic vascular anomalies were presumed to be responsible for spontaneous bleeding into the chiasm in three of the cases. In the remaining case, hemorrhage was due to an occult optic glioma. Surgical evacuation of clotted blood resulted in improved visual function in three of the four cases.


Reflex pupillary dilatation in response to skin incision and alfentanil in children anaesthetized with sevoflurane: a more sensitive measure of noxious stimulation than the commonly used variables.
Estimation of analgesia in anaesthetized children is often imprecise, and consequently, anaesthesiologists commonly evaluate children's response to surgical stimulation by movement or haemodynamic changes. In adults reflex pupillary dilatation has been demonstrated to be a very sensitive measure of noxious stimulation, correlated with opioid concentrations. The autonomic nervous control changes with age, raising the hypothesis that mechanisms involved in pupillary autonomic functions regarding both sympathetic and parasympathetic components may also differ between adults and children. In this pilot study, we tested the hypothesis that the pupillary reflex dilatation might allow assessment of noxious stimulation and analgesic effect of alfentanil in children under sevoflurane anaesthesia, as an alternative to haemodynamic and bispectral measures. After sevoflurane induction, 24 children were maintained in steady-state conditions at 1.5 MAC of sevoflurane in O(2)-N(2)O (50-50). An intense noxious stimulation was provided by standardized skin incision on the lower limb. A bolus of alfentanil (10 microg kg(-1)) was administered either 1 min (n=16) or 2 min (n=8) after skin incision. Haemodynamic values, bispectral index (BIS) and pupillary diameter (PD) were recorded just before stimulation and at 30-60 s intervals during 4 subsequent minutes. In all children PD increased significantly after noxious stimulation [+200 (40)%, at 60 s]. In contrast, mean heart rate and blood pressure increased only 11 (7)% and 10 (8)% respectively, 60 s after stimulation. BIS did not change significantly. In all children, alfentanil injection induced a rapid decrease of PD and restored pre-incision values in 2 min. PD is a more sensitive measure of noxious stimulation than the commonly used variables of heart rate, arterial blood pressure and BIS in children anaesthetized with sevoflurane.


Posttraumatic stress disorder symptoms and functional impairment among OEF and OIF National Guard and Reserve veterans.
The aims of the present investigation were (a) to examine associations between posttraumatic stress disorder (PTSD; diagnosis and symptoms) and different aspects of functioning, severity, and subjective distress among Operation Iraqi Freedom and Operation Enduring Freedom National Guard and Reserve veterans, and (b) to examine the unique contribution of PTSD symptom clusters to different aspects of functioning and distress. Participants were 124 veterans who had returned from war-zone deployment. A PTSD diagnosis and PTSD symptoms were significantly associated with nearly all of the psychosocial functioning and distress measures, controlling for Axis I disorders and other covariates. Of the PTSD symptom clusters, numbing/avoidance symptoms were the strongest predictors of interpersonal and social functioning, and hyperarousal symptoms were the strongest predictors of overall severity and distress.


Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases.
In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that accompanies their uptake by healthy cells. In this Account, we describe our quest for the ideal targeted therapeutic agent. This effort began with a search for ligands that would bind selectively to pathologic cells, displaying no affinity for healthy cells. After identification of an optimal targeting ligand, effort was focused on construction of linkers that would carry the attached drug to pathologic cells with receptors for the selected ligand. In the case of cancer, we exploited the well-characterized up-regulation of folate receptors on malignant cells to target folate-linked pharmaceuticals to cancer tissues in vivo. Drugs that have been linked to folic acid for tumor-selective drug delivery to date include (i) protein toxins, (ii) chemotherapeutic agents, (iii) gene therapy vectors, (iv) oligonucleotides (including small interfering RNA (siRNA)), (v) radioimaging agents, (vi) magnetic resonance imaging (MRI) contrast agents, (vii) liposomes with entrapped drugs, (viii) radiotherapeutic agents, (ix) immunotherapeutic agents, and (x) enzyme constructs for prodrug therapy. Current clinical trials of four folate-linked drugs demonstrate that folate receptor-targeting holds great promise for increasing the potency while reducing toxicity of many cancer therapies. In the course of developing folate-conjugated drugs for cancer, we discovered that folate receptors are also overexpressed on activated (but not resting or quiescent) macrophages. Recognizing that activated macrophages either cause or contribute to such diseases as rheumatoid arthritis, Crohn's disease, atherosclerosis, lupus, inflammatory osteoarthritis, diabetes, ischemia reperfusion injury, glomerulonephritis, sarcoidosis, psoriasis, Sjogren's disease, and vasculitis, we initiated studies aimed at developing folate-conjugated imaging and therapeutic agents for the diagnosis and treatment of such diseases. In very brief time, significant progress has been made towards identification of clinical candidates for targeted treatment of several inflammatory and autoimmune diseases. This Account summarizes the discovery and development of a variety of folate-targeted drugs for the diagnosis and therapy of cancers and inflammatory/autoimmune diseases.


Mental health outcomes among health-care workers dealing with COVID-19/severe acute respiratory syndrome coronavirus 2 pandemic: A systematic review and meta-analysis.
The psychological impact of COVID-19 on health-care workers (HCWs) has received attention from researchers to understand the extent of the effects of the ongoing pandemic on this population. The aim of this systematic review and meta-analysis was to synthesize the currently available literature on the topic to determine the prevalence of mental health problems in HCWs. We conducted a systematic review and meta-analysis, searching PubMed, PsycINFO, Scopus, and Cochrane Library databases for articles published from December 2019 to August 15, 2020. We identified studies reporting the prevalence of any mental health condition in HCWs involved directly or indirectly in providing services during the COVID-19 pandemic. The prevalence proportion for individual outcome was extracted as an estimate of interest. We performed random-effects meta-analyses evaluated using Q statistic, I 2 statistic, subgroup analyses, and sensitivity analyses and assessed study quality. This review was done in adherence to the Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. The study protocol was registered prospectively at PROSPERO (CRD42020182005). We identified 1958 studies, of which 33 studies including 39703 participants (with a median = 393; range = 88-14825) were finally included for analysis. The estimated overall prevalence were as follows: depression 32.4% (95% confidence interval [CI]: 25.9-39.3, I 2 = 99%), anxiety 32.5% (95% CI: 26.4-39.0, I 2 = 99%), insomnia or sleep disturbance 36.6% (95% CI: 36.6-48.3, I 2 = 99%), and stress 37.7% (95% CI: 24.0-52.3, I 2 = 100%). HCWs who are dealing with the COVID-19 pandemic have a significant prevalence of depression, anxiety, insomnia and poor sleep quality, and stress. The health-care workforce needs to practice self-care now more than ever, while health-care managers and policymakers need to factor in the mental health consequences of COVID-19 on their workforce.


Abdominal and pelvic radiographs of medical devices and materials-Part 1: gastrointestinal and vascular devices and materials.
When compared with chest radiographs, medical devices of the abdomen and pelvis are less frequently seen. However, with recent advances in technology the interpreting radiologists are seeing more medical objects on these radiographs. The identification of these devices and materials are crucial for not only enabling the radiologist to understand the underlying background pathology but also for evaluating any related complications. An online survey of literature showed our review article to be the most detailed. In this first part of our two-part series, we discuss about the various gastrointestinal and vascular devices and materials seen on abdominal and pelvic radiographs.


Targeting DNA Damage and Repair Machinery via Delivering WEE1 Inhibitor and Platinum (IV) Prodrugs to Stimulate STING Pathway for Maximizing Chemo-Immunotherapy in Bladder Cancer.
Both cisplatin-based chemotherapy and immune checkpoint blockers (ICBs)-based immunotherapy are the first-line treatments for patients with advanced bladder cancer. Cancer cells can develop resistance to cisplatin through extensive DNA repair, while a low response rate to ICBs is mostly due to the presence of an immunosuppressive microenvironment and low PD-L1 expression. Herein, a glutathione (GSH)-responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) is designed. NP2 can be triggered by GSH in cancer cells, and the released MK1775 can inhibit the activity of WEE1 protein, which ultimately increases DNA damage by cisplatin. Genome-wide RNA sequencing first reveals that NP2 can inhibit DNA repair machinery by interfering with the cell cycle and significantly activate the stimulator of interferon genes pathway. Tumor growth is significantly inhibited by NP2 in vivo. As innate and adaptive immune responses are stimulated, the immunosuppressive microenvironment is modified, and the "immune cold tumor" is transformed into an "immune hot tumor". In addition, NP2 can upregulate PD-L1 expression in tumor cells, thereby increasing the response rate of PD-L1 monoclonal antibody (αPD-L1) and eliciting long-term immune responses in both primary and metastatic tumors.


Evidence for nerve growth factor-mediated paracrine effects in human epidermis.
Nerve growth factor (NGF) is critical to the development and maintenance of the peripheral nervous system, but its possible roles in other organ systems are less well characterized. We have recently shown that human epidermal melanocytes, pigment cells derived from the neural crest, express the NGF receptor (p75 NGF-R) in vitro (Peacocke, M., M. Yaar, C. P. Mansur, M. V. Chao, and B. A. Gilchrest. 1988. Proc. Natl. Acad. Sci. USA. 85:5282-5286). Using cultured human skin-derived cells we now demonstrate that the melanocyte p75 NGF-R is functional, in that NGF stimulation modulates melanocyte gene expression; that exposure to an NGF gradient is chemotactic for melanocytes and enhances their dendricity; and that keratinocytes, the dominant epidermal cell type, express NGF messenger RNA and hence are a possible local source of NGF for epidermal melanocytes in the skin. These combined data suggest a paracrine role for NGF in human epidermis.


High co-occurrence of anorectal chlamydia with urogenital chlamydia in women visiting an STI clinic revealed by routine universal testing in an observational study; a recommendation towards a better anorectal chlamydia control in women.
Symptom- and sexual history-based testing i.e., testing on indication, for anorectal sexually transmitted infections (STIs) in women is common. Yet, it is unknown whether this strategy is effective. Moreover, little is known about alternative transmission routes i.e. by fingers/toys. This study assesses anorectal STI prevalence and infections missed by current testing practice, thereby informing the optimal control strategy for anorectal STIs in women. Women (n = 663) attending our STI-clinic between May 2012-July 2013 were offered routine testing for anorectal and urogenital Chlamydia trachomatis and Neisseria gonorrhoeae. Data were collected on demographics, sexual behaviour and symptoms. Women were assigned to one of the categories: indication (reported anal sex/symptoms), fingers/toys (only reported use of fingers/toys), or without indication. Of women, 92% (n = 654) participated. There were 203 reports (31.0%) of anal sex and/or symptoms (indication), 48 reports (7.3%) of only using fingers/toys (fingers/toys), and 403 reports (61.6%) of no anal symptoms, no anal sex and no anal use of fingers/toys (without indication). The overall prevalence was 11.2% (73/654) for urogenital chlamydia and 8.4% (55/654) for anorectal chlamydia. Gonorrhoea infections were not observed. Prevalence of anorectal chlamydia was 7.9% (16/203) for women with indication and 8.6% (39/451) for all other women (P = 0.74). Two-thirds (39/55) of anorectal infections were diagnosed in women without indication. Isolated anorectal chlamydia was rare (n = 3): of all women with an anorectal infection, 94.5% (52/55) also had co-occurrence of urogenital chlamydia. Of all women with urogenital chlamydia, 71.2% (52/73) also had anorectal chlamydia. Current selective testing on indication of symptoms and sexual history is not an appropriate control strategy for anorectal chlamydia in women visiting an STI clinic. Routine universal anorectal testing is feasible and may be a possible control strategy in women. Yet costs may be a problem. When more restricted control measures are preferred, possible alternatives include (1) anorectal testing only in women with urogenital chlamydia (problem: treatment delay or loss to follow up), and (2) direct treatment for urogenital chlamydia that is effective for anorectal chlamydia as well.


PHAROS-PHysical Assistant RObot System.
The great demographic change leading to an ageing society demands technological solutions to satisfy the increasing varied elderly needs. This paper presents PHAROS, an interactive robot system that recommends and monitors physical exercises designed for the elderly. The aim of PHAROS is to be a friendly elderly companion that periodically suggests personalised physical activities, promoting healthy living and active ageing. Here, it is presented the PHAROS architecture, components and experimental results. The architecture has three main strands: a Pepper robot, that interacts with the users and records their exercises performance; the Human Exercise Recognition, that uses the Pepper recorded information to classify the exercise performed using Deep Leaning methods; and the Recommender, a smart-decision maker that schedules periodically personalised physical exercises in the users' agenda. The experimental results show a high accuracy in terms of detecting and classifying the physical exercises (97.35%) done by 7 persons. Furthermore, we have implemented a novel procedure of rating exercises on the recommendation algorithm. It closely follows the users' health status (poor performance may reveal health problems) and adapts the suggestions to it. The history may be used to access the physical condition of the user, revealing underlying problems that may be impossible to see otherwise.


The Role of Phosphatidylethanolamine N-Methyltransferase (PEMT) and Its Waist-Hip-Ratio-Associated Locus rs4646404 in Obesity-Related Metabolic Traits and Liver Disease.
In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist-hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. PEMT expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, PEMT expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro Pemt knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in PEMT mRNA expression across the three studied tissues. Specifically, vis PEMT mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc PEMT expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT PEMT expression and also with diabetes-related traits. Our in vitro experiments supported the influence of PEMT on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that PEMT plays a role in regulating FD and has implications in metabolic diseases.


Eating Disorders in Children and Adolescents: A Practical Review and Update for Pediatric Gynecologists.
Eating disorders (EDs) are common among female adolescents and young adults and can have serious and diverse health consequences. Pediatric gynecology providers have the opportunity to play a vital role in the recognition of EDs in this population. Early medical detection and referral for appropriate evidence-based treatment can lead to better health outcomes for youth. In this article we aim to increase the awareness of the pediatric gynecologist of typical and subtle presentations of EDs, provide guidance for screening, discuss common and serious medical complications, and review treatment considerations for gynecologic issues in patients with EDs.


Expanded role of the Cu-sensing transcription factor Mac1p in Candida albicans.
As part of the innate immune response, the host withholds metal micronutrients such as Cu from invading pathogens, and microbes respond through metal starvation stress responses. With the opportunistic fungal pathogen Candida albicans, the Cu-sensing transcription factor Mac1p governs the cellular response to Cu starvation by controlling Cu import. Mac1p additionally controls reactive oxygen species (ROS) homeostasis by repressing a Cu-containing superoxide dismutase (SOD1) and inducing Mn-containing SOD3 as a non-Cu alternative. We show here that C. albicans Mac1p is essential for virulence in a mouse model for disseminated candidiasis and that the cellular functions of Mac1p extend beyond Cu uptake and ROS homeostasis. Specifically, mac1∆/∆ mutants are profoundly deficient in mitochondrial respiration and Fe accumulation, both Cu-dependent processes. Surprisingly, these deficiencies are not simply the product of impaired Cu uptake; rather mac1∆/∆ mutants appear defective in Cu allocation. The respiratory defect of mac1∆/∆ mutants was greatly improved by a sod1∆/∆ mutation, demonstrating a role for SOD1 repression by Mac1p in preserving respiration. Mac1p downregulates the major Cu consumer SOD1 to spare Cu for respiration that is essential for virulence of this fungal pathogen. The implications for such Cu homeostasis control in other pathogenic fungi are discussed.


Maternal dietary antigen avoidance during pregnancy and/or lactation for preventing or treating atopic disease in the child.
Some breastfed infants with atopic eczema benefit from elimination of cow milk, egg, or other antigens from their mother's diet. Maternal dietary antigens are also known to cross the placenta. To assess the effects of prescribing an antigen avoidance diet during pregnancy and/or lactation on maternal and infant nutrition and on the prevention or treatment of atopic disease in the child. We searched the Cochrane Pregnancy and Childbirth Group trials register (October 2002) and contacted researchers in the field. All randomized or quasi-randomized comparisons of maternal dietary antigen avoidance prescribed to pregnant or lactating women. We excluded trials of multimodal interventions that included manipulation of the infant's diet other than breast milk or of nondietary aspects of the infant's environment. We extracted data from published reports, supplemented by additional information received from the trialists we contacted. The evidence from 4 trials involving approximately 451 participants does not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on the incidence of atopic eczema during the first 12 to 18 months of life. Data on allergic rhinitis/conjunctivitis and urticaria are limited to a single trial each and are insufficient to draw meaningful inferences. Longer-term atopic outcomes have not been reported. The restricted diet during pregnancy was associated with a slightly but statistically significantly lower mean gestational weight gain, a nonsignificantly higher risk of preterm birth, and a nonsignificant reduction in mean birthweight.The evidence from 3 trials involving approximately 210 participants suggests a protective effect of maternal antigen avoidance during lactation on the incidence and severity of atopic eczema during the first 12 to 18 months, but methodologic shortcomings argue for caution in interpretation.One crossover trial involving 17 lactating mothers of infants with established atopic eczema found that maternal dietary antigen avoidance was associated with a nonsignificant reduction in eczema severity. Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal and/or fetal nutrition. Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed. Dietary antigen avoidance by lactating mothers of infants with atopic eczema may reduce the severity of the eczema, but larger trials are needed.


Clinicians' abilities to estimate cardiac index in ventilated children and infants.
To evaluate the ability of clinicians involved in the provision of paediatric intensive care to estimate cardiac index in ventilated children, based on physical examination and clinical and bedside laboratory data. Clinicians were exposed to all available haemodynamic and laboratory data for each patient, allowed to make a physical examination, and asked to first categorize cardiac index as high, high to normal, low to normal, or low, and then to quantify this further with a numerical estimate. Cardiac index was measured simultaneously by femoral artery thermodilution (coefficient of variation 5.37%). One hundred and twelve estimates were made by 27 clinicians on 36 patients (median age 34.5 months). Measured cardiac index ranged from 1.39 to 6.84 1/min/m2. Overall, there was poor correlation categorically (kappa statistic 0.09, weighted kappa 0.169) and numerically (r = 0.24, 95% confidence interval 0.06 to 0.41), although some variation was seen among the various levels of seniority. Assuming that objective measurement, and hence manipulation, of haemodynamic variables may improve outcome, these findings support the need for a safe, accurate, and repeatable technique for measurement of cardiac index in children who are critically ill.


Evaluating the effect of city lock-down on controlling COVID-19 propagation through deep learning and network science models.
The special epistemic characteristics of the COVID-19, such as the long incubation period and the infection through asymptomatic cases, put severe challenge to the containment of its outbreak. By the end of March 2020, China has successfully controlled the within- spreading of COVID-19 at a high cost of locking down most of its major cities, including the epicenter, Wuhan. Since the low accuracy of outbreak data before the mid of Feb. 2020 forms a major technical concern on those studies based on statistic inference from the early outbreak. We apply the supervised learning techniques to identify and train NP-Net-SIR model which turns out robust under poor data quality condition. By the trained model parameters, we analyze the connection between population flow and the cross-regional infection connection strength, based on which a set of counterfactual analysis is carried out to study the necessity of lock-down and substitutability between lock-down and the other containment measures. Our findings support the existence of non-lock-down-typed measures that can reach the same containment consequence as the lock-down, and provide useful guideline for the design of a more flexible containment strategy.


Risk factors for severe delayed postpolypectomy bleeding.
Postpolypectomy bleeding is a rare but serious adverse event. The aim of this study was to identify factors associated with the risk of severe delayed postpolypectomy bleeding. This was a case-control study, comparing cases who developed hematochezia and required medical evaluation 6 hours to 14 days after colonoscopic polypectomy, and control patients who underwent polypectomy without delayed bleeding, and who were selected in approximately a 3 : 1 ratio. The following risk factors were specified a priori: resuming anticoagulation (within 1 week following polypectomy), aspirin use, hypertension, and polyp diameter. Of the 4592 patients who underwent colonoscopy with polypectomy, 41 patients (0.9 %) developed delayed postpolypectomy bleeding (cases), and 132 patients were selected as controls. The mean age was 64.3 years for cases and 65.4 years for controls. Cases presented on average 6 days after polypectomy (range 1 - 14 days), and 48 % required blood transfusion (average 4.2 units, range 0 - 17). Two patients required surgery. Anticoagulation was resumed following polypectomy in 34 % of cases compared with 9 % of controls (OR 5.2; 95 % CI 2.2 - 12.5; P < 0.001). For every 1 mm increase in polyp diameter, the risk of hemorrhage increased by 9 % (OR 1.09; 95 % CI 1.0 - 1.2; P = 0.008). Hypertension (OR 1.1) and aspirin use (OR 1.1) did not increase the risk of postpolypectomy bleeding. In exploratory analysis, diabetes (OR 2.5) and coronary artery disease (OR 3.0) were associated with postpolypectomy hemorrhage, but the association was no longer statistically significant once adjusted for the use of anticoagulation. Resuming anticoagulation following polypectomy and polyp diameter were strongly associated with increased risk of severe delayed postpolypectomy bleeding.


The Future of the Indispensable Insurer: The Biden Administration and Medicaid.
Medicaid presents both legislative and regulatory challenges and opportunities. As it moves a legislative agenda forward, the Biden administration also will confront a series of immediate regulatory matters, some of which have been made urgent because of pending judicial action. Chief among these pressing matters are ending Medicaid work requirements and block grant experiments, rescinding the public charge rule, ensuring optimal use of Medicaid's enrollment and renewal simplification tools, rescinding the Title X family planning rule (which has enormous implications for Medicaid beneficiaries), and, when the time comes, preparing states to wind down the "Families First" Medicaid maintenance of effort protection while avoiding erroneous beneficiary disenrollment. The administration could consider encouraging remaining nonexpansion states to pursue §1115 Medicaid expansion experiments; additionally, the administration could pursue Medicaid pandemic recovery demonstrations to support health system recovery during the long period that lies ahead. Thus, while certain advances must await legislation, the administration can move Medicaid forward through executive action.


Injury recurrence is lower at the highest professional football level than at national and amateur levels: does sports medicine and sports physiotherapy deliver?
Previous injury is a well-documented risk factor for football injury. The time trends and patterns of recurrent injuries at different playing levels are not clear. To compare recurrent injury proportions, incidences and patterns between different football playing levels, and to study time trends in recurrent injury incidence. Time-loss injuries were collected from injury surveillance of 43 top-level European professional teams (240 team-seasons), 19 Swedish premier division teams (82 team-seasons) and 10 Swedish amateur teams (10 team-seasons). Recurrent injury was defined as an injury of the same type and at the same site as an index injury within the preceding year, with injury <2 months defined as an early recurrence, and >2 months as a delayed recurrence. Seasonal trend for recurrent injury incidence, expressed as the average annual percentage of change, was analysed using linear regression. 13 050 injuries were included, 2449 (18.8%) being recurrent injuries, with 1944 early (14.9%) and 505 delayed recurrences (3.9%). Recurrence proportions were highest in the second half of the competitive season for all cohorts. Recurrence proportions differed between playing levels, with 35.1% in the amateur cohort, 25.0% in the Swedish elite cohort and 16.6% in the European cohort (χ(2) overall effect, p<0.001). A decreasing trend was observed in recurrent injury incidence in the European cohort, a -2.9% average annual change over the 14-year study period (95% CI -5.4% to -0.4%, p=0.026). Similarly, a decreasing tendency was also seen in the Swedish premier division. Recurrence proportions showed an inverse relationship with playing level, and recurrent injury incidence has decreased over the past decade.


Heart transplantation in elderly patients.
During 1985 to 1986, 57 orthotopic heart transplantations have been performed at the University of Minnesota, Minneapolis. All patients received triple-drug immunosuppressive therapy of cyclosporine, azathioprine, and prednisone. Twenty-three patients were aged 55 years or older (mean age 58.0 +/- 2.6 years); 34 patients were under the age of 55 years (mean age 39.1 +/- 13.2 years). The initial in-hospital stay averaged 13 +/- 4 days in the older group and 16 +/- 13 days in the younger group. Perioperative mortality was similar in the two groups. The incidence of cerebrovascular accident was similarly low in the two groups, whereas incidence of steroid-induced diabetes (17% versus 9%) and significant osteoporosis (13% versus 3%) was significantly higher in older patients. The probability of survival and the actuarial freedom from rejection were identical in the two groups with 1-year survival of 96% and 94% of patients free of rejection at 12 months. Although the incidence of infection was not significantly higher in older patients (0.82 episode per patient) than in younger patients (0.78 episode per patient), life-threatening infections (Cryptococcus meningitidis, disseminated herpes simplex) were observed only in older patients. These data suggest that (1) heart transplantation is a valid therapeutic option even in elderly patients with end-stage heart failure, (2) it can be performed in selected patients at no increased operative risk with excellent long-term survival, (3) however, older patients are at higher risk for serious infections and for developing steroid-related complications.


Transgene expression in the genome of Middle East respiratory syndrome coronavirus based on a novel reverse genetics system utilizing Red-mediated recombination cloning.
Middle East respiratory syndrome coronavirus (MERS-CoV) is a high-priority pathogen in pandemic preparedness research. Reverse genetics systems are a valuable tool to study viral replication and pathogenesis, design attenuated vaccines and create defined viral assay systems for applications such as antiviral screening. Here we present a novel reverse genetics system for MERS-CoV that involves maintenance of the full-length viral genome as a cDNA copy inserted in a bacterial artificial chromosome amenable to manipulation by homologue recombination, based on the bacteriophage λ Red recombination system. Based on a full-length infectious MERS-CoV cDNA clone, optimal genomic insertion sites and expression strategies for GFP were identified and used to generate a reporter MERS-CoV expressing GFP in addition to the complete set of viral proteins. GFP was genetically fused to the N-terminal part of protein 4a, from which it is released during translation via porcine teschovirus 2A peptide activity. The resulting reporter virus achieved titres nearly identical to the wild-type virus 48 h after infection of Vero cells at m.o.i. 0.001 (1×105 p.f.u. ml-1 and 3×105 p.f.u. ml-1, respectively), and allowed determination of the 50 % inhibitory concentration for the known MERS-CoV inhibitor cyclosporine A based on fluorescence readout. The resulting value was 2.41 µM, which corresponds to values based on wild-type virus. The reverse genetics system described herein can be efficiently mutated by Red-mediated recombination. The GFP-expressing reporter virus contains the full set of MERS-CoV proteins and achieves wild-type titres in cell culture.


Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA.
In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons. To determine whether genetic variation influences clinical MS patterns. Retrospective multicenter cohort study. Six hundred seventy-three African American and 717 white patients with MS. Patients with MS were genotyped for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset. Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti-aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1*15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) and risk of cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001). These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.


Occupational asthma due to manganese exposure: a case report.
Manganese belongs to a group of agents called "transitional metals" that are known to induce occupational asthma. However, well-documented cases of manganese-induced asthma have been lacking thus far. We have discussed a case of a 42-year-old non-smoking welder with work-related dyspnea. A number of clinical procedures were performed including clinical examination, routine laboratory tests, total serum IgE, skin prick tests to common aeroallergens and manganese nitrate, resting spirometry test, histamine challenge, and a single-blind, placebo-controlled specific inhalation challenge with 0.1% manganese chloride solution. Clinical findings and laboratory test results remained normal but a significant bronchial hyperreactivity was found. During the specific inhalation challenge, dyspnea and a significant decrease in forced expiratory volume (FEV1) were observed. An increased proportion of eosinophils and basophils in induced sputum could also be noted at 4 and 24 h after the challenge. The argument for recognizing the condition as occupational asthma was a positive clinical response to the specific challenge test as well as the morphological changes found in induced sputum. To our knowledge, this is the first well-documented case of manganese-induced occupational asthma.


Chitosan based delivery systems for mucosal immunization against bovine herpesvirus 1 (BHV-1).
Bovine herpesvirus 1 (BHV-1), is a major pathogen of cattle which causes serious infections, including infectious bovine rhinotracheitis (IBR)/infectious pustular vulvovaginitis (IPV). At present, BHV-1 is still a serious threat to animal health and productivity in Turkey, hence to develop a more efficient and economical vaccine system against BHV-1 is certainly an important necessity. A mucosal vaccination strategy would provide both mucosal and systemic immune responses to protect disease progression and transmission. However, vaccination through mucosal membranes requires adjuvants/delivery systems in order to enhance the immunogenicity of the antigens. Chitosan, which is a biodegradable, biocompatible and bioadhesive natural polysaccharide, has been shown to be promising both as a delivery system and an adjuvant for mucosal vaccination. In this study, microparticles with appropriate size (<10μm), positive surface charge and high loading efficiency (∼95%) were prepared for mucosal delivery of BHV-1, using various types of chitosan with different molecular weight and solubility. Particles were shown to be taken up by the cells, mostly around the nucleus, whereas with aggregates which were bigger in size were adsorbed at the surface. Furthermore, gel formulations with a suitable viscosity which would provide easy application and remain on the mucosa for extended period of time were also developed with a high zeta potential indicating a stable system. Both the BHV-1 loaded microparticle and gel formulations were shown to maintain cell viability and antigen integrity. Chitosan-based formulations are suggested as promising adjuvant/delivery systems for mucosal immunization against BHV-1.


Unit costs of inpatient days in district hospitals in South Africa.
This study aims to estimate the unit costs of inpatient days in five district hospitals in South Africa. The study is based on a costing exercise carried out in five district hospitals in South Africa. The hospitals were purposely selected to reflect those providing most of the services included in the district hospital package, the availability of good quality data, and the rural/urban variations in the country. The study calculated costs from the perspective of the healthcare facility. The ingredients approach was used, combining a top-down and step-down allocation of overhead costs of the six final cost centres. The measures of inpatient care used were: admissions, inpatient days and average length of stay. The unit costs of inpatient days were between US dollars (USD) 65.31 and USD 212.09 for maternity patients, USD 37.23 and USD 93.55 for surgical patients, USD 37.23 and USD 70.86 for medical patients, and USD 38.37 and USD 139.60 paediatric patients. The unit costs per inpatient days were between USD 38.04 and USD 103.68 in the five hospitals. Personnel costs were the major cost component and ranged from 73 percent to 82 percent of the unit costs. There was considerable variation in the unit costs of inpatient days in the hospitals studied. The average unit cost for maternity patients was more than double the average unit cost for medical patients. The very low bed occupancy rates in these hospitals are indicative of inefficiency in their operations. Measures need to be instituted to improve the efficiency of these hospitals in the provision of quality and effective healthcare services.


Energy restriction or improvements in diet quality: identifying the best pathway for a longer and healthier life.
Obesity is a major risk factor for chronic non-communicable diseases (NCDs) and it has increased to epidemic proportions. Unhealthy diet represents a modifiable risk factor for both obesity and NCDs, however, there is no universal dietary intervention to improve obesity-related NCDs and particularly to reduce the risk for major adverse cardiovascular events. Energy restriction (ER) and diet quality changes, with and without ER, have been widely investigated in preclinical and clinical studies, however, the potential underlying mechanisms driving the benefits of those dietary interventions remain largely unclear. ER affects multiple metabolic, physiological, genetic, and cellular adaptation pathways associated with prolonged lifespan, particularly in preclinical models, while these benefits remain to be established in humans. Moreover, the sustainability of ER and its implementation across the different diseases remains challenging. On the other hand, diet quality with improvements, with or without ER, has been associated with more favorable long-term metabolic and cardiovascular outcomes. This narrative review will describe the role of ER and/or diet quality improvements on the risk for NCDs. It will also discuss the potential mechanisms of action underlying the potential beneficial effects of those dietary approaches.


Assessment of trabecular bone mineral density using quantitative computed tomography in normal cats.
The aim of this study was to assess age-related changes and anatomic variation in trabecular bone mineral density (tBMD) using quantitative computed tomography (QCT) in normal cats. Seventeen normal cats were included in this study and divided into the following 3 age groups:<6 months (n=4), 2-5 years (n=10) and >6 years (n=3). A computed tomographic scan of each vertebra from the 12th thoracic to the 7th lumbar spine and the pelvis was performed with a bone-density phantom (50, 100 and 150 mg/cm(3), calcium hydroxyapatite, CIRS phantom(®)). On the central transverse section, the elliptical region of interest (ROI) was drawn to measure the mean Hounsfield unit (HU) value. Those values were converted to equivalent tBMD (mg/cm(3)) by use of the bone-density phantom and linear regression analysis (r(2) >0.95). The mean tBMD value of the thoracic vertebrae (369.4 ± 31.8 mg/cm(3)) was significantly higher than that of the lumbar vertebrae (285 ± 58.1 mg/cm(3)). The maximum tBMD occurred at the T12, T13 and L1 levels in all age groups. There was a statistically significant difference in the mean tBMD value among the 3 age groups at the T12 (P<0.001), T13 (P<0.001) and L4 levels (P=0.013), respectively. The present study suggests that age-related changes and anatomic variation in tBMD values should be considered when assessing tBMD using QCT in cats with bone disorders.


Syndrome of short P-R, narrow QRS and repetitive supraventricular tachyarrhythmias: the possible occurrence of the R-on-T phenomenon and the limits of this syndrome.
The R-on-T phenomenon was observed in two patients with narrow QRS complexes and repetitive supraventricular tachyarrhythmias. Case 1 had a typical Lown-Ganong-Levine syndrome in which the shortening of the P-R interval was due to a reduction of the A-H interval. In Case 2 the P-R interval (140 msec) was not short but the A-H interval was at the lower limits of normal (50 msec) and the P-A interval at the upper limits of normal (40 msec). Both patients showed the R-on-T phenomenon during periods of 1:1 A-V conduction occurring during atrial stimulation at a rate of 200/min (Case 1) and atrial flutter with a rate of 300/min (Case 2). Although total A-V conduction time was prolonged, the magnitude of this prolongation appeared to have been less than that occurring in normal subjects. This was attributed to the presence of an accessory pathway bypassing the area where the most significant delay occurred at the A-V node. The findings in Case 2 suggest, but do not prove, that a similar bypass might be operative in patients with atrial flutter with periods of 1:1 conduction, regardless as to whether the R-on-T phenomenon is, or is not, present.


Probe Oscillation Shear Elastography (PROSE): A High Frame-Rate Method for Two-Dimensional Ultrasound Shear Wave Elastography.
Ultrasound shear wave elastography (SWE) utilizes the propagation of induced shear waves to characterize the shear modulus of soft tissue. Many methods rely on an acoustic radiation force (ARF) "push beam" to generate shear waves. However, specialized hardware is required to generate the push beams, and the thermal stress that is placed upon the ultrasound system, transducer, and tissue by the push beams currently limits the frame-rate to about 1 Hz. These constraints have limited the implementation of ARF to high-end clinical systems. This paper presents Probe Oscillation Shear Elastography (PROSE) as an alternative method to measure tissue elasticity. PROSE generates shear waves using a harmonic mechanical vibration of an ultrasound transducer, while simultaneously detecting motion with the same transducer under pulse-echo mode. Motion of the transducer during detection produces a "strain-like" compression artifact that is coupled with the observed shear waves. A novel symmetric sampling scheme is proposed such that pulse-echo detection events are acquired when the ultrasound transducer returns to the same physical position, allowing the shear waves to be decoupled from the compression artifact. Full field-of-view (FOV) two-dimensional (2D) shear wave speed images were obtained by applying a local frequency estimation (LFE) technique, capable of generating a 2D map from a single frame of shear wave motion. The shear wave imaging frame rate of PROSE is comparable to the vibration frequency, which can be an order of magnitude higher than ARF based techniques. PROSE was able to produce smooth and accurate shear wave images from three homogeneous phantoms with different moduli, with an effective frame rate of 300 Hz. An inclusion phantom study showed that increased vibration frequencies improved the accuracy of inclusion imaging, and allowed targets as small as 6.5 mm to be resolved with good contrast (contrast-to-noise ratio ≥ 19 dB) between the target and background.