BIOTECHNOLOGY, NANOTECHNOLOGY, AND PHARMACOGENOMICS AND PHARMACEUTICAL COMPOUNDING, PART 2.
This article, which represents part 2 of a two part article, completes the discussion on the rapidly changing world of pharmaceuticals as biotechnology continues to grow and nanotechnology appears on the horizon.


Epidemiology of eye-related emergencies in children under 18 years of age at a General Hospital in Spain from 2019 to 2021.
To know which ophthalmological pathologies are the most prevalent attending the emergency department. To assess what changes have occurred because of the COVID pandemic. Review of emergency reports in children under 18 years of age attended in our Hospital from January 2019 to December 2021. Comparison of pre-pandemic, pandemic and "back-to-normal" data when comparing the periods 2019-2021 with each other. There is a 57% reduction in the eye-related emergency visits in 2020. This reduction affects the three more prevalent diagnostic groups: conjunctivitis and red eye (69% fall), trauma and foreign body (45% decrease) and palpebral pathology (35% less). In 2021 there is a partial recovery in the three groups, but not reaching the 2019 data. On the other side, eye and periocular pain show an increase in consultation in both 2020 (16,7% more) and 2021 (100% increase). There are differences in the distribution of eye-related conditions that consulted at the Emergency Department at our hospital during years 2019-2021. This suggests a more rational use of the Health System, less banal pathology attending and an impact of mobility restrictions, handwashing and face masks wearing on ophthalmological pathology.


Malabsorption of thyroxine, calcium, and vitamin D in a thyroparathyroidectomized woman: efficacy of therapy with medium-chain triglyceride oil.
A 28-year-old woman with surgically induced hypothyroidism and hypoparathyroidism required large doses of replacement medications due to malabsorption from short bowel syndrome. Malabsorption of thyroxine was documented using the technique of double isotope radioiodothyronine turnover studies. Therapy with medium-chain triglyceride oil improved her malabsorption and favorably influenced the absorption of her medications.


Anti-inflammatory studies on Polygonum glabrum.
Anti-inflammatory studies were conducted on a hot water decoction and on an ethanol extract of the stems of Polygonum glabrum. Effective anti-inflammatory activity was demonstrated against acute carrageenan-induced paw oedema, exudate and granuloma formation in the granuloma pouch test, acute and delayed reactions in formaldehyde arthritis, and acute primary and delayed secondary reactions in adjuvant-induced polyarthritis in albino rats. The acute toxicity in albino mice and 1-month studies on subacute toxicity in rats suggested a good margin of safety. The extract was more effective parenterally than by oral administration.


Side effects of transdermal scopolamine.
Motion sickness can be experienced as the result of air or sea travel. Scopolamine can be used before travel to prevent this illness. This report describes two patients who used transdermal scopolamine preparations and experienced hallucinations and then confusion as side effects. The discussion concerns the recognition and treatment of these adverse effects.


Intensification of GVHD prophylaxis interferes with the effects of pretransplant herpes virus serology on the occurrence of grades II-IV acute graft-versus-host disease.
The effects of pretransplant herpes virus serology on the occurrence of grades II-IV acute graft-versus-host disease (GVHD) were studied in 262 recipients and their HLA-identical family donors. In 131 recipients on standard GVHD prophylaxis (either methotrexate or cyclosporin A) significant effects were observed for donor HSV serology (seropositivity associated with increased risk for GVHD) and donor EBV serology (seronegativity associated with increased risk). However, these effects were nonsignificant in the other 131 recipients on intensified GVHD prophylaxis (i.e., methotrexate combined with cyclosporin A, in vivo anti-T-cell monoclonal antibodies, or various procedures to reduce the T-cell numbers in the transplants.


Periodontopathogenic microbiota, infectious mechanisms and preterm birth: analysis with structural equations (cohort-BRISA).
The association between periodontopathogenic microbiota and preterm birth (PTB) has been overly studied. However, the biological mechanisms involved are little known. The objective is to evaluate the effect of periodontopathogenic bacteria burden (PBB), periodontal disease and other infections during pregnancy on preterm birth (PTB), through Structural Equation Modeling. This was a case-control study nested in a prospective cohort called BRISA, including 330 pregnant women, 110 cases and 220 controls. This study included the following variables: cytokines interleukin-10 (IL-10) and transforming growth factor beta (TGF-β), periodontal disease, PBB, age, socioeconomic status (SES), systemic infections and PTB. The correlations between variables were analyzed using Standardized Coefficient (SC). Greater PBB interfered positively with the occurrence of periodontal disease (SC: 0.027; p: 0.011), but these were not associated with the cytokines studied, nor with PTB. The lower serum levels of IL-10 (SC - 0.330; p 0.022) and TGF-β (SC - 0.612; p < 0.001), and the presence of other systemic infections during pregnancy (SC 0.159; 0.049) explained the higher occurrence of PTB. It is possible that only the more severe periodontal disease and other systemic infections are capable of altering the cascade of cytokines regulating the inflammatory process and have an effect on the occurrence of PTB.


Diaporthe species occurring on Lithocarpus glabra in China, with descriptions of five new species.
The Diaporthe species include important plant pathogenic fungi with wide host ranges and geographic distributions. In this paper, species associated with Lithocarpus glabra were examined using a multi-locus phylogeny based on a combined rDNA-internal transcribed spacer (ITS), and partial translation elongation factor 1-alpha (TEF1), beta tubulin (TUB), and calmodulin (CAL) regions. The phylogenies inferred from combined multi-locus sequences grouped isolates from L. glabra into seven distinct lineages with high branch support, which corresponded to two previously described species and five novel species described in this paper. Our results indicate a high species diversity of Diaporthe associated with L. glabra, and host association is further proved not reliable for species delimitation. Three species previously described in Phomopsis were transferred to Diaporthe in the present paper. A synopsis of morphological characters of the 14 species currently known from Fagaceae is provided.


Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Société Française de Neurochirurgie.
Cavernous angiomas, which are vascular malformations mostly located in the central nervous system, may be inherited as an autosomal dominant disorder known as familial cerebral cavernoma (FCC). FCC has been studied in Hispanoamerican families, in which a strong founder effect was shown. We studied the families of 57 non-Hispanic patients with cavernous angiomas. All 28 neurosurgery centres in France collaborated in the study. Inclusion criteria were: families of index patients known to have at least one clinically affected relative, and families of index patients with multiple cavernous angiomas who initially presented as sporadic cases. Clinical and cerebral magnetic resonance imaging (MRI) investigations were done in all patients and in other at-risk individuals who consented to take part. On MRI, 16 of 22 sporadic index patients had relatives with cavernous angiomas. 51 multiple-case families, including 100 patients with symptoms and 164 symptom-free individuals had MRI lesions. Most FCC patients had multiple lesions and there was a strong correlation between number of lesions and age (p<0.01). The sensitivity of gradient-echo sequences was higher than that of standard MRI for detection of small cavernous angiomas. Pattern of inheritance was autosomal dominant, with incomplete clinical penetrance. The occurrence of de-novo mutations was strongly suggested in some families. Neuroimaging penetrance of FCC is much higher than clinical penetrance. 75% of sporadic cases with multiple lesions are in fact familial cases. The proportion of patients developing clinical symptoms is higher in the hereditary form than in the sporadic form of the disorder.


[FROM THEORY TO THE CLINIC - IS IT POSSIBLE TO DETECT DIFFERENT TYPES OF ANOMIA ACCORDING TO THE LEXICAL RETRIEVAL MODEL?]
The lexical retrieval model describes the process of naming - from the level of an abstract concept representation to the production of the word. Lexical retrieval includes several distinct levels. A deficit in any of these levels causes anomia, a naming deficit, and deficits in different levels cause different types of anomia. To examine whether the theoretical model can be applied in the clinic. Namely, whether it is possible to identify, for a specific patient, the exact impaired lexical retrieval level, and to show that different patients are impaired in different levels. The performance of 24 participants with aphasia, with lexical retrieval deficits, were analyzed. The analysis included performance on a naming test - including analysis of error types and of the effects that modulate naming errors. We also analyzed the performance in other language tasks that examine the different levels of lexical retrieval, including tasks that do not involve naming. Different types of anomia were found for the different participants. The various types of anomia are reflected in different sorts of naming errors, in different effects that modulate naming errors, and in different performance patterns in the other language tasks. The theoretical model of lexical retrieval can underpin descriptions of clinical phenomena. The findings support the view that the relations between theory and clinic are bidirectional - theories constitute an anchor for the description of clinical phenomena, and clinical findings can support, or refute, theory. The distinction between the different types of anomia is important for choosing the appropriate treatment for each patient.


European Training Assessment Programme 2.0.
The European Training Assessment Programme (ETAP) 2.0 offers a structured assessment of radiology training institutions applying for certification, without geographical constraints. It applies, in fact, to both European and non-European institutions, which fulfill the eligibility criteria and wish to obtain a European certification.ETAP 2.0 aims to provide centres that offer specialty training in radiology with an objective assessment by external assessors of their training programmes. ETAP 2.0 also aims to develop assessment systems and guidelines to be used by postgraduate education authorities at a national level.The online evaluation system facilitates the application process as well as the assessment and subsequent certification. The platform enables users - both representatives of applicant institutions and assessors - to easily and efficiently store, access, and manage documents and information at any time, thereby facilitating the certification process.


Fruit-CoV: An efficient vision-based framework for speedy detection and diagnosis of SARS-CoV-2 infections through recorded cough sounds.
COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This deadly virus has spread worldwide, leading to a global pandemic since March 2020. A recent variant of SARS-CoV-2 named Delta is intractably contagious and responsible for more than four million deaths globally. Therefore, developing an efficient self-testing service for SARS-CoV-2 at home is vital. In this study, a two-stage vision-based framework, namely Fruit-CoV, is introduced for detecting SARS-CoV-2 infections through recorded cough sounds. Specifically, audio signals are converted into Log-Mel spectrograms, and the EfficientNet-V2 network is used to extract their visual features in the first stage. In the second stage, 14 convolutional layers extracted from the large-scale Pretrained Audio Neural Networks for audio pattern recognition (PANNs) and the Wavegram-Log-Mel-CNN are employed to aggregate feature representations of the Log-Mel spectrograms and the waveform. Finally, the combined features are used to train a binary classifier. In this study, a dataset provided by the AICovidVN 115M Challenge is employed for evaluation. It includes 7,371 recorded cough sounds collected throughout Vietnam, India, and Switzerland. Experimental results indicate that the proposed model achieves an Area Under the Receiver Operating Characteristic Curve (AUC) score of 92.8% and ranks first on the final leaderboard of the AICovidVN 115M Challenge. Our code is publicly available.


A flow cytometric assay technology based on quantum dots-encoded beads.
A flow cytometric detecting technology based on quantum dots (QDs)-encoded beads has been described. Using this technology, several QDs-encoded beads with different code were identified effectively, and the target molecule (DNA sequence) in solution was also detected accurately by coupling to its complementary sequence probed on QDs-encoded beads through DNA hybridization assay. The resolution of this technology for encoded beads is resulted from two longer wavelength fluorescence identification signals (yellow and red fluorescent signals of QDs), and the third shorter wavelength fluorescence signal (green reporting signal of fluorescein isothiocyanate (FITC)) for the determination of reaction between probe and target. In experiment, because of QDs' unique optical character, only one excitation light source was needed to excite the QDs and probe dye FITC synchronously comparing with other flow cytometric assay technology. The results show that this technology has present excellent repeatability and good accuracy. It will become a promising multiple assay platform in various application fields after further improvement.


Influence of previous abortions and new paternity on the risk of hypertension in nulliparous parturients in Ibadan: a cohort study.
This study aims to determine the influence of previous abortions and new paternity on the risk of hypertension in a cohort of nulliparous women. A prospective cohort study was conducted with development of hypertension in pregnancy as outcome variable. Explanatory variables were previous abortions and paternity. Univariate analysis was by t-test, χ(2) test and Fisher's exact test where applicable. Logistic regression was utilized for multivariate analysis. Stata was utilized for all the analyses. The level of statistical significance was set as P < 0.05. Same paternity abortions reduced the risk of hypertension (OR 0.48, 95% CI 0.31-0.73). Previous abortions did not reduce the odds of hypertension in pregnancy (OR 1.25, 95% CI 0.83-1.88). Rural dwelling reduced the odds of developing hypertension in pregnancy (OR 0.54, 95% CI 0.42-0.70). The result of this study supports the immunological theory of the etiology of hypertension in pregnancy.


The inhibition of aldose reductase on mucus production induced by interleukin-13 in the human bronchial epithelial cells.
This study investigated whether aldose reductase (AR) inhibition affects interleukin (IL)-13-induced mucus production in the human bronchial epithelial cell line-16 (HBE16) cells. The HBE16 cells were cultured with AR inhibitors (zopolrestat) or were transfected with an AR small interfering (si)RNA. Subsequently, the cells were stimulated with 10 ng/ml IL-13 for 2h. The levels of mucin (MUC)5AC mRNA and protein were measured by using RT-PCR or ELISA. Intracellular reactive oxygen species (ROS) were measured fluorimetrically with the CM-H2DCFDA probe. Western blotting was performed to determine the levels of AR, phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and phosphorylated Janus kinase 2 (p-JAK2). The results show that treatment with zopolrestat or transfection with AR siRNA significantly suppressed IL-13-stimulated MUC5AC mRNA and protein in the HBE16 cells (P<0.05). AR inhibition could suppress IL-13-induced ROS generation, the phosphorylation of JAK2/STAT6 pathway and the activation of nuclear factor (NF)-kappa B, thereby decreasing mucus production in vitro (all P<0.05). Therefore, the inhibition of AR could be a therapeutic target for mucus hypersecretion in chronic inflammation lung disease.


Prevalence and distribution of Aggregatibacter actinomycetemcomitans and its cdtB gene in subgingival plaque of Chinese periodontitis patients.
Aggregatibacter actinomycetemcomitans (A.actinomycetemcomitans) is an important periodontal pathogen that can participate in periodontitis and other non-oral infections. The cytolethal distending toxin (Cdt) is among the virulence factors produced by this bacterium. This study was to elucidate the distribution of A.actinomycetemcomitans and the prevalence of its cdtB gene in Chinese subjects. A total of 255 subgingival samples were obtained from 30 subjects. Samples were collected from periodontal healthy sites as well as shallow, moderate and deep pockets. The absolute quantity of A.actinomycetemcomitans and cdtB gene were determined by real-time polymerase chain reaction. A.actinomycetemcomitans was detected in 92 of 105 (87.6%) samples of aggressive periodontitis (AgP) patients, in 73 of 79 (92.4%) samples of chronic periodontitis ( CP) patients and in 5 of 71 (7.0%) samples of periodontal healthy subjects. The cdtB gene was detected in 72 sites (78.3%) with AgP infected with A.actinomycetemcomitans, 54 sites (74.0%) with CP infected with A.actinomycetemcomitans and none in healthy sites infected with A.actinomycetemcomitans. In addition, quantity of A.actinomycetemcomitans and cdt gene in samples from deep pockets were significant larger than moderate, shallow and healthy sites (P < 0.05). In comparison to CP, AgP patients were infected with increased numbers of cdt genotype in deep pockets (P < 0.05). This study suggests that the cdtB gene are prevalent in A.actinomycetemcomitans, and the distribution of cdt genotype strain may be correlated with AgP and serious periodontal inflammation.


Middle-Upper Pleistocene climate changes shaped the divergence and demography of Cycas guizhouensis (Cycadaceae): Evidence from DNA sequences and microsatellite markers.
Climatic oscillations in the Pleistocene have had profound effects on the demography and genetic diversity of many extant species. Cycas guizhouensis Lan &R.F. Zou is an endemic and endangered species in Southwest China that is primarily distributed along the valleys of the Nanpan River. In this study, we used four chloroplast DNAs (cpDNA), three nuclear genes (nDNA) and 13 microsatellite (SSR) loci to investigate the genetic structure, divergence time and demographic history of 11 populations of C. guizhouensis. High genetic diversity and high levels of genetic differentiation among the populations were observed. Two evolutionary units were revealed based on network and Structure analysis. The divergence time estimations suggested that haplotypes of C. guizhouensis were diverged during the Middle-Upper Pleistocene. Additionally, the demographic histories deduced from different DNA sequences were discordant, but overall indicated that C. guizhouensis had experienced a recent population expansion during the post-glacial period. Microsatellite data revealed that there was a contraction in effective population size in the past. These genetic features allow conservation measures to be taken to ensure the protection of this endangered species from extinction.


Long-term results of suprapubic bladder neck closure for treatment of the devastated outlet.
To assess the long-term success of suprapubic bladder neck closure in patients with irreparably damaged bladder outlets. A cohort of 35 patients with intractable urinary incontinence secondary to severe posterior urethral/bladder neck damage underwent suprapubic bladder neck closure. Patients were assessed with regard to the success of procedure, as well as early and late complications. With a mean follow-up of 79 months (range 12 to 164), suprapubic bladder neck closure was successful in 29 (83%) of 35 patients. One revision of the bladder neck improved the success rate to 94% (33 of 35). Early and late complications, excluding bladder neck fistula, were reported in 3 (9%) and 5 (14%) of 35 patients, respectively. High success and acceptable complication rates can be achieved with suprapubic bladder neck closure for the treatment of severe urinary incontinence secondary to a devastated bladder outlet.


Audio-visual communication and its use in palliative care.
The technology of telemedicine has been used for over 20 years, involving different areas of medicine, providing medical care for the geographically isolated patients, and uniting geographically isolated clinicians. Today audio-visual technology may be useful in palliative care for the patients lacking access to medical services due to the medical condition rather than geographic isolation. We report results of a three-month trial of using audio-visual communications as a complementary tool in care for a complex palliative care patient. Benefits of this system to the patient included 1) a daily limited physical examination, 2) screening for a need for a clinical visit or admission, 3) lip reading by the deaf patient, 4) satisfaction by the patient and the caregivers with this form of communication as a complement to telephone communication. A brief overview of the historical prospective on telemedicine and a listing of applied telemedicine programs are provided.


Bodily Complexity: Integrated Multicellular Organizations for Contraction-Based Motility.
Compared to other forms of multicellularity, the animal case is unique. Animals-barring some exceptions-consist of collections of cells that are connected and integrated to such an extent that these collectives act as unitary, large free-moving entities capable of sensing macroscopic properties and events. This animal configuration is so well-known that it is often taken as a natural one that 'must' have evolved, given environmental conditions that make large free-moving units 'obviously' adaptive. Here we question the seemingly evolutionary inevitableness of animals and introduce a thesis of bodily complexity: The multicellular organization characteristic for typical animals requires the integration of a multitude of intrinsic bodily features between its sensorimotor, physiological, and developmental aspects, and the related contraction-based tissue- and cellular-level events and processes. The evolutionary road toward this bodily complexity involves, we argue, various intermediate organizational steps that accompany and support the wider transition from cilia-based to contraction/muscle-based motility, and which remain insufficiently acknowledged. Here, we stress the crucial and specific role played by muscle-based and myoepithelial tissue contraction-acting as a physical platform for organizing both the multicellular transmission of mechanical forces and multicellular signaling-as key foundation of animal motility, sensing and maintenance, and development. We illustrate and discuss these bodily features in the context of the four basal animal phyla-Porifera, Ctenophores, Placozoans, and Cnidarians-that split off before the bilaterians, a supergroup that incorporates all complex animals.


NanoString nCounter Technology: High-Throughput RNA Validation.
NanoString nCounter is a multiplex nucleic acid hybridization technology that enables reliable and reproducible assessment of the expression of up to 800 genes or 228 gene fusions in 12 samples in a single assay. The technique works well with a variety of starting materials from fresh or formalin-fixed tissues, cell lysates or biological fluid samples. As low as 1 ng RNA input per sample is needed. In addition to gene expression, copy number variation, single nucleotide variation and chimeric RNAs can be analyzed. In this chapter, we discuss the design, setup, and performance of a NanoString-based RNA assay for gene expression or fusion transcript assessment.


Asymmetric distribution of dense bands in muscle cells of mammalian arterioles.
Arterioles from viscera of mice, rats, guinea pigs, rabbits, sheep, and pigs were examined by electron microscopy. In all the organs and species investigated the muscle cells of the tunica media are arranged in tight helices and make several full turns. The myofilaments also are arranged approximately circumferentially, although there is often a little divergence between bundles of myofilaments in different areas of the same cell. The dense bands are conspicuous and anchor the myofilaments to the cell membrane; they are markedly larger and more numerous on the regions of the cell membrane facing the adventitia than on those facing the intima. This asymmetrical distribution is interpreted as essential to an efficient mechanism for constriction of the lumen.


Delayed emergence of behavioral and electrophysiological effects following juvenile ketamine exposure in mice.
Frequent ketamine abuse in adulthood correlates with increased risk of psychosis, as well as cognitive deficits, including disruption of higher-order executive function and memory formation. Although the primary abusers of ketamine are adolescents and young adults, few studies have evaluated its effects on juvenile cognition. Therefore, the current study analyzes the effect of adolescent ketamine exposure on cognitive development. Juvenile mice (4 weeks of age) were exposed to chronic ketamine (20 mg kg(-1), i.p. daily) for 14 days. Mice were tested immediately after exposure in the juvenile period (7 weeks of age) and again as adults (12 weeks of age). Measures included electroencephalography (EEG) in response to auditory stimulation, the social choice test, and a 6-arm radial water maze task. Outcome measures include low-frequency EEG responses, event-related potential (ERP) amplitudes, indices of social behavior and indices of spatial working memory. Juvenile exposure to ketamine was associated with electrophysiological abnormalities in adulthood, particularly in induced theta power and the P80 ERP. The social choice test revealed that ketamine-exposed mice failed to exhibit the same age-related decrease in social interaction time as controls. Ketamine-exposed mice outperformed control mice as juveniles on the radial water maze task, but did not show the same age-related improvement as adult controls. These data support the hypothesis that juvenile exposure to ketamine produces long-lasting changes in brain function that are characterized by a failure to progress along normal developmental trajectories.


The addition of tramadol to lidocaine does not reduce tourniquet and postoperative pain during iv regional anesthesia.
We conducted a prospective, randomized, double-blind study to determine whether the combination of tramadol with lidocaine 0.5% had an analgesic effect on tourniquet pain during iv regional anesthesia and also on postoperative pain. Thirty patients scheduled for carpal tunnel decompression were included in the study. Each patient received 3 mg.kg(-1) of plain lidocaine 0.5% with 100 mg of tramadol (Group T) or 2 mL of isotonic saline (Group C). The mixture was injected into the isolated and exsanguinated arm. Pain was assessed using a linear visual analog scale and a verbal rate scale during the surgical procedure and the postoperative period (240 min) and subsequently at interview at 24 hr. Analgesic consumption was recorded. There was no difference in the pain scales and analgesic request at any of the time periods studied. We conclude, therefore, that for carpal tunnel operation under iv regional anesthesia, the combination of tramadol and lidocaine is not more effective than lidocaine alone.


Objectification decreases prosociality: the mediating role of relative deprivation.
Objectification denies individuals' personhood and renders them as tools for facilitating others' goal achievement. With two studies (N = 446), the present investigation aimed to contribute to the literature by testing whether and how objectification impacts prosociality, including prosocial intention and prosocial behavior. Study 1, with a correlational design, aimed to test whether participants with greater experience of objectification would report lower levels of prosociality, and to test whether participants' relative deprivation could account for the proposed association between objectification and prosociality. To further test these associations and provide causal evidence, in Study 2, we manipulated objectification by asking participants to imagine future objectification experiences. These studies converged in support of the negative relationship between objectification and prosocial intention, as well as the mediating role of relative deprivation. Regarding prosocial behavior, our findings support a mediating mechanism between objectification and prosocial behavior, although the evidence for the effect of objectification on prosocial behavior is not sufficient. These findings enrich our understanding of the consequences of objectification, while highlighting interpersonal processes' contribution to prosocial intention and behavior. The limitations and potential future directions were discussed.


Priapism associated with trazodone therapy.
Priapism associated with medication use is well known as one of the most difficult forms of priapism to treat. We report 2 cases of priapism and prolonged erection associated with trazodone therapy. The literature is reviewed and potential treatment options are discussed.


Apolipoprotein B: the Rosetta Stone of lipidology.
This review summarizes the evidence that apolipoprotein B (apoB) integrates the conventional lipid markers - total cholesterol, triglycerides, LDL-cholesterol, and non-HDL-cholesterol - into a single index that accurately and simply quantitates the atherogenic risk due to the apoB lipoprotein particles. Marked hypertriglyceridemia remains the essential signal for hyperchylomicronemia and potential pancreatitis. However, with the exception of Lp(a) and the abnormal cholesterol-enriched remnant particles that are the hallmark of type III hyperlipoproteinemia, recent evidence from discordance analyses and Mendelian randomization indicate that apoB integrates the risk due to the atherogenic lipoprotein particles because all LDL particles are, within the limits of our ability to measure any differences, equally atherogenic and all, except the largest VLDL particles are, within the limits of our ability to measure any differences, equally atherogenic. Measuring apoB as well as the conventional lipids is essential for accurate diagnosis. For almost all follow-up, however, apoB is all that need be measured. ApoB is the Rosetta Stone of lipidology because dyslipoproteinemia cannot be understood unless apoB is measured.


Unintended consequences of healthcare reform in South Korea: evidence from a regression discontinuity in time design.
To address concerns over the financial stability of South Korea's National Health Insurance (NHI) programme, the government transitioned from an outpatient copayment system to a coinsurance system in 2007. This policy aimed to reduce healthcare overutilization by increasing patients' financial responsibility for outpatient services. Using comprehensive data on NHI beneficiaries, this study employs a regression discontinuity in time (RDiT) design to assess the policy's impact on outpatient healthcare utilization and expenditures. We focus on changes in overall outpatient visits, average healthcare cost per visit and total outpatient healthcare expenditures. Our findings indicate that the transition from outpatient copayment to coinsurance led to a substantial increase in outpatient healthcare utilization (up to 90%) while decreasing medical expenditures per visit by 23%. The policy shift incentivized beneficiaries to seek more medical treatments during the grace period and enroll in supplemental private health insurance, which provided access to additional medical services at lower marginal costs. The policy change and the emergence of supplemental private insurance contributed to moral hazard and adverse selection issues, culminating in South Korea becoming the country with the highest per capita utilization of outpatient health services worldwide since 2012. This study underscores the importance of carefully considering the unintended consequences of policy interventions in the healthcare sector.


Kinetics of phenanthrene desorption from activated carbons to water.
We determined the kinetics of phenanthrene desorption from three activated carbons to water using Tenax beads as an infinite sink for organic compounds in water. Desorption kinetic data very well fitted a biphasic kinetic model based on the presence of two different adsorption sites, viz. low-energy sites and high-energy sites. Rate constants for desorption to water from these two types of sites in the three activated carbons did not reveal a relation with activated carbon grain size. These rate constants were comparable to those for desorption of various organic compounds from hard carbon in various sediments.


Minocycline treatment suppresses juvenile development and growth by attenuating insulin/TOR signaling in Drosophila animal model.
Minocycline is a broad spectrum, semi-synthetic tetracycline analog that is used to treat bacterial infection. Recently, this drug has been receiving increasing attention for its non-antibiotic properties, including anti-inflammatory, tumor suppressive, and neuroprotective effects. Drosophila is a useful model organism for studying human metabolism and disease. In this study, we investigated the effects of minocycline on juvenile development and growth in Drosophila. Feeding minocycline to Drosophila larvae suppresses larval body growth and delays the timing of pupation in a dose-dependent manner. We found that the drug treatment decreased the activated form of Akt and S6K in peripheral tissues, which suggested that the insulin/target of rapamycin (TOR) signaling had been attenuated. Specifically enhancing TOR activity in the prothoracic gland (PG), the ecdysone-generating organ, attenuated the drug-induced developmental delay, which is consistent with the critical role of PG's TOR signaling in determining pupation time. Our results reveal previously unrecognized effects of minocycline and offer a new potential therapeutic opportunity for various pathological conditions associated with insulin/TOR signaling.


Inadvertent ocular perforation and intravitreal injection of an anesthetic agent during retrobulbar injection.
We report the clinical management of a patient who sustained scleral perforation and intraocular injection of local anesthetic agent during retrobulbar block. We discuss the management options for this rare complication of local anesthesia in cataract surgery.


Nigral grafts in neonatal rats protect from aphagia induced by subsequent adult 6-OHDA lesions: the importance of striatal location.
Previous studies have shown that dopamine-rich nigral grafts, implanted bilaterally into the intact neonatal brain, will provide some protection from the eating disorders induced by subsequent nigrostriatal 6-OHDA lesions. This has been repeated in the present study using unilaterally transplanted nigral grafts. Following adult lesions, the control animals displayed the full syndrome of aphagia, adipsia and akinesia. By contrast, 37% of the rats in the transplanted group recommenced eating following the adult lesion. Recovery was related to the size and position of the graft: protection was associated in particular with transplants located in the posterior-ventral neostriatum. The results are discussed in terms of specific patterns of graft-host interaction that may underlie protection of the regulation of eating from the loss of forebrain dopamine systems.


Understanding the experiences of lung cancer patients during the COVID-19 pandemic: a qualitative interview study.
The study explores experiences of lung cancer patients during COVID-19 and considers how changes to care delivery and personal lives affected patient needs. Semi-structured telephone interviews were conducted to explore experiences of lung cancer patients during COVID-19. Interviews were audio-recorded, transcribed verbatim and analysed thematically. Interview participants were purposively selected based on age, gender, treatment status, timing of diagnosis (pre/post first COVID-19 lockdown) from a sample of lung cancer patients (any histological subtype/any cancer stage/any point in treatment) who had completed a questionnaire exploring how participants' lives were impacted by the pandemic and their thoughts on clinical care and remote communication. Thirty lung cancer patients who participated in the questionnaire study were approached and participated in an interview. Three themes were identified: (1) Adapting to new modes of communication (focusing on experiences of remote communication); (2) Experience of care delivery during the pandemic (describing how all aspects of care delivery had been affected); (3) Impact of the COVID-19 pandemic on quality of life (QOL) (focus on the psychological impact and feeling of reduced support). Themes 1 and 2 are heavily interlinked and both had bearing on patients' QOL experience. Lung cancer patients were impacted psychologically by changes to care delivery and changes in their personal life. The findings highlight some benefits to remote consultations but the stage of the treatment pathway and illness trajectory should be considered when determining if this is appropriate. Participants felt support from peers, family and friends was limited during the pandemic.


Overexpression of thrombospondin-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma.
The roles of thrombospondin-1 (THBS-1) in tumor growth and metastasis are complicated and its function as a cancer inhibitor or promoter remains controversial. This clinical study investigated the functional roles of THBS-1 in gastric carcinoma by examining the expression patterns of THBS-1 protein and mRNA levels during gastric cancer development. Eighty-two gastric carcinomas were included in this study. THBS-1, α-smooth muscle actin, and CD34 proteins were localized by immunohistochemical staining, and the levels of THBS-1 mRNA were quantified by real-time polymerase chain reaction. THBS-1 mRNA expression in gastric carcinoma tissues was significantly higher than in adjacent non-cancerous stomach tissues (P = 0.03). Tumor THBS-1 mRNA expression level was significantly related to lymph node metastasis (P = 0.031), tumor size (P = 0.021) and patient age (P = 0.005). THBS-1 protein was mainly located in stromal myofibroblasts, and was undetectable in tumor cells. Myofibroblasts may be mainly derived from stromal fibroblasts in gastric cancer. The abundance of myofibroblasts was positively correlated with tumor growth and nodal metastasis in gastric carcinoma (P = 0.03, P = 0.0008, respectively). This clinical study revealed that overexpression of THBS-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. THBS-1 may activate latent transforming growth factor-β1 to stimulate fibroblasts to differentiate into myofibroblasts, though further studies are needed to validate this hypothesis. These results suggest that THBS-1 and myofibroblasts may serve as novel targets for strategies aimed at protection against and treatment of gastric carcinoma.


Revisit of typical counterclockwise atrial flutter wave in the ECG: electroanatomic studies on the determinants of the morphology.
Cavotricuspid isthmus-dependent counterclockwise atrial flutter (typical AFL) is characterized by negative saw-tooth morphology flutter wave (F-wave) in the inferior leads, which is classified as type 1 with purely negative F-wave without positive terminal deflection (PTD), type 2 with small PTD, and type 3 with broad PTD. The determinants of these morphological differences remain to be elucidated. Of 72 patients (58 males, 65 ± 13 years) with typical AFL, 19 were classified as type 1 and 53 as types 2 and 3. We created an electroanatomic map of the right atrium (RA) during AFL and determined which RA site activation corresponded to which F-wave component by analyzing the activation map. It was revealed that F-wave component from the nadir to terminal deflection point coincided with the cranio-caudal activation of the RA free wall (RAFW) in all types. The bipolar voltage map showed that type 1 had the greater extent of low voltage (<0.5 mV) area (LVA) in RAFW (39 ± 24%) than types 2 and 3 (4 ± 3%) (P < 0.0001), explaining the absence of PTD in type 1. In types 2 and 3, F-wave amplitude determining the PTD magnitude was highly correlated with the longitudinal distance between two points on RAFW corresponding to the nadir and peak of F-wave (r = 0.73, P < 0.0001). Terminal positivity and amplitude of F-wave in typical AFL are primarily related to the RAFW activity: negatively by the extent of LVA and positively by the longitudinal vector of activation.


Microcalorimetric measurements of the microbial activities of single- and mixed-species with trivalent iron in soil.
A microcalorimetric technique was applied to a series of experiments to follow the toxic effect caused by the trivalent iron on the single and mixed microbes in sterilized soil that was inoculated with the single Bacillus subtilis (B. subtilis) (prokaryotic bacterium), single Candida humicola (C. humicola) (eukaryotic fungus) and the mixed-species. The microbial activity was stimulated by the addition of 5.0mg glucose and 5.0mg ammonium sulfate under a 35% controlled humidity in the studied soil samples of 1.2g. The power-time curves from every experiment were analyzed, and from these analyses characteristic parameters, such as growth rate constant (k) and total thermal effect (Q) which can reflect the biochemical reactions were determined. The mixed-species have moderate tolerance to the iron overload, comparing with single species, and exhibit synergistic interaction in exponential growth phase (0-400.0 microg mL(-1)). Meanwhile, there is no much difference in the thermal effect (Q) per gram soil sample for the single and mixed culture. This also validates that the nutrient substances in natural environment determine the organisms' metabolic activities. Ultraviolet-visible spectrophotometry and dissolved oxygen sensor also were successfully applied to reflect the activities of B. subtilis and C. humicola in the pure culture. The investigation could provide insight into the microbial ecology of bacteria and fungi in ecological niches.


Surgical implantation and functional assessment of an invasive telemetric system to measure autonomic responses in domestic pigs.
The first aim of this study was to establish a surgical procedure to implant a new telemetric device for the continuous recording of electrocardiogram (ECG) and blood pressure (BP) in freely moving pigs. A second aim was the functional assessment of cardiovascular parameters, including heart rate variability (HRV) and blood pressure variability (BPV), so that these data could be used as the basis for the objective evaluation of autonomic activity and balance in different behavioural contexts. Eleven domestic pigs (German Landrace) underwent surgery for the placement of a telemetric device. At day 15 after surgery, 512 consecutive inter-beat intervals and pressure waves were analysed using different detection methods (automatic and manually corrected) while the animals were resting or feeding, respectively. HRV and BPV were calculated. Incomplete datasets were found in four pigs due to missing ECG or BP signals. Technical and surgical issues concerning catheterisation and detachment of the negative ECG lead were continuously improved. In the remaining pigs, excellent signal quality (manually corrected data of 1%) was obtained during resting and acceptable signal quality (<10%) was obtained during feeding. Automatic triggering was sufficiently reliable to eliminate errors in BP recordings during active behaviour, but this was not the case for ECG recordings. Sympathetic arousal with accompanying vagal withdrawal during feeding was documented. The established surgical implantation and functional assessment of the telemetric system with the reliable registration of cardiovascular parameters in freely moving pigs could serve as a basis for future studies of autonomic regulation in context of stress and animal welfare.


Millimeter-thick xenoislet-laden fibers as retrievable transplants mitigate foreign body reactions for long-term glycemic control in diabetic mice.
Transplantation technologies of pancreatic islets as well as stem cell-derived pancreatic beta cells encapsulated in hydrogel for the induction of immunoprotection could advance to treat type 1 diabetes mellitus, if the hydrogel transplants acquire retrievability through mitigating foreign body reactions after transplantation. Here, we demonstrate that the diameter of the fiber-shaped hydrogel transplants determines both in vivo cellular deposition onto themselves and their retrievability. Specifically, we found that the in vivo cellular deposition is significantly mitigated when the diameter is 1.0 mm and larger, and that 1.0 mm-thick xenoislet-laden fiber-shaped hydrogel transplants can be retrieved after being placed in the intraperitoneal cavities of immunocompetent diabetic mice for more than 100 days, during which period the hydrogel transplants can normalize the blood glucose concentrations of the mice. These findings could provide an innovative concept of a transplant that would promote the clinical application of stem cell-derived functional cells through improving their in vivo efficacy and safety.


Emerging role of liver X receptors in cardiac pathophysiology and heart failure.
Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.


Motor Impairment Three Months Post Stroke Implies A Corresponding Cognitive Deficit.
While both motor and cognitive impairment are common after stroke, the focus of (early) treatment has always been on motor deficit. The objective of the current study was to explore the link between motor and cognitive performance in stroke patients and to examine whether motor performance is associated with cognitive functioning at three months post stroke. In both stroke patients (n = 142) and controls (n = 135), with the groups matched on age, gender and premorbid IQ, motor functioning was evaluated using both objective (Purdue Pegboard Test) and subjective measures (specific items from the Frenchay Activities Index and Barthel Index). Cognition, specifically information processing speed, working memory and cognitive flexibility, was assessed using objective tasks. The data were analyzed using Pearson product-moment correlation coefficients and logistic regression. Significant correlations between motor and cognitive functioning were found in stroke patients. The objective motor task was stronger than subjective measures in statistically explaining and predicting cognitive deficit, irrespective of stroke severity. We conclude that motor impairment at three months post-stroke should serve as a 'red flag' for professionals: cognitive impairment is likely and should also be evaluated.


Comparison of Ultrasonography and Short-Segment Nerve Conduction Study in Ulnar Neuropathy at the Elbow.
To assess the correlation between ultrasonographic and electrodiagnostic findings to determine the localization of the ulnar trapping at the elbow. Cross-sectional and noninterventional trial. Physical medicine and rehabilitation department of a teaching hospital. Patients (N=14) diagnosed with ulnar nerve entrapment using short-segment nerve conduction study. The elbow area was divided into 4 segments with 2-cm intervals. All patients underwent ultrasonographic and electrodiagnostic examinations. The nerve conduction velocity (NCV) of each segment was measured. The cross-sectional area (CSA) of the ulnar nerve was measured at 5 levels. The proximal CSA/distal CSA ratio (PDR) was calculated by proportioning the CSA values for each segment. The highest PDR was accepted as a trapping segment, whereas the segment with the lowest NCV was accepted electrophysiologically (provided it was <50m/s). A total of 80 PDR and NCV measurements were taken from 20 elbows. A statistically significant negative correlation (r=-.554; P<.001) was found between general PDR and NCV values. When we assumed that the NCV value <50m/s as the criterion standard for diagnosis, the cutoff value for the PDR was found to be 1.08, with a sensitivity of 70% and a specificity of 92.5%. The minimum NCV value and the maximum PDR value were mostly seen in the third segment compatible with the cubital tunnel. Ultrasonography seems to be advantageous because it is more comfortable for the patient and requires shorter time than does electroneuromyography. To our knowledge, this is the first study to detect ulnar nerve entrapment by using not only CSA but also PDR as a ratio method with ultrasound.


Optimization of the selectivity of a cyanopropyl stationary phase for the gas chromatographic analysis of trans fatty acids.
The quantification of monounsaturated and polyunsaturated trans fatty acids in partially hydrogenated fats by gas-liquid chromatography on a CP-Select CB-FAME capillary column was optimized using equivalent chain length values of fatty acids methyl esters that could coelute in the temperature range from 155 to 200 degrees C. The most appropriate temperature for the simultaneous determination of these trans isomers is around 197 degrees C. It is proposed a system to discriminate trans from cis octadecenoic fatty acid methyl esters based on the angular coefficient values of the equivalent chain length curves. The limits of detection and quantification were 0.28 and 0.93 mg g(-1). Quantification was performed in the range from 0.93 to 280 mg g(-1). Quantification accuracy was estimated by spike recovery of elaidic and trans-13-octadecenoic acids in hydrogenated fat samples. The obtained levels were from 97.60 to 103.28% for elaidic acid and from 98.12 to 99.27% for trans-13-octadecenoic acid. These results indicate that the accuracy of the methodology proposed for the quantification of monounsaturated and polyunsaturated trans fatty acids in hydrogenated fats is adequate.


Long-term treatment outcome in acromegaly.
A number of groups have developed guidelines to indicate whether an individual with acromegaly has been cured by treatment. However, studies to date do not provide a robust definition of biochemical remission of the disorder based on correlation with long-term outcome. Available data suggest that those with a random serum growth hormone (GH) level of <2.5 microg/l, or a glucose-suppressed GH level of <1 microg/l following treatment have mortality figures indistinguishable from the general population. However, the confidence limits for these mortality estimates are quite wide. It remains possible that growth hormone levels lower than 1 microg/l for random samples, or even lower when using ultrasensitive GH assays, may indicate superior outcome, but this remains to be confirmed. There are limited data relating serum insulin-like growth factor-I (IGF-I) levels to outcome, although normalisation of serum IGF-I clearly improves outcome compared with continued elevation of measurements after treatment. Current evidence suggests that a post-treatment random serum GH <2.5 microg/l and a normal serum IGF-I value defines biochemical cure. Available data suggest that achieving similar growth hormone levels after treatment also reduces the prevalence of chronic complications of the disorder, which is subsequently reflected in improved mortality.


A randomised trial of [18F]PSMA-1007-PET/CT versus NaF-PET/CT for staging primary prostate cancer: A trial protocol.
Prostate-specific membrane antigen (PSMA)-positron emission tomography/contrast-enhanced computed tomography (PET/CT) is a sensitive imaging modality for prostate cancer (PCa). Due to lack of knowledge of the patient benefit, PSMA-PET/CT is not yet recommended in the European guidelines for staging and treatment planning of patients with newly diagnosed PCa. We will investigate the potential difference in progression-free survival (PFS) and quality of life (QoL) of using PSMA-PET/CT versus sodium fluoride (NaF)-PET/CT for staging and treatment planning in patients with newly diagnosed PCa. This is a prospective randomised controlled multicentre trial carried out at three centres in the Region of Southern Denmark. The primary endpoint is PFS. Secondary endpoints are residual disease, stage migration, impact on treatment strategies, stage distribution, QoL and diagnostic accuracy measures. Patients eligible for the study have newly diagnosed unfavourable intermediate- or high-risk PCa. A total of 448 patients will be randomised 1:1 into two groups: (A) a control group staged with Na[18F]F-PET/CT and (B) an intervention group staged with [18F]PSMA-1007-PET/CT. A subgroup in the intervention group will have a supplementary blinded Na[18F]F-PET/CT performed for the purpose of performing accuracy analyses. QoL will be assessed at baseline and with regular intervals (3-12 months) during the study period. Treatment decisions are achieved at multidisciplinary team conferences based on the results of the respective scans and according to current Danish guidelines. The Regional Committees on Health Research Ethics for Southern Denmark (S-20190161) and the Danish Medicines Agency (EudraCT Number 2021-000123-12) approved the study, and it has been registered on clinicaltrials.gov (Record 2020110469).


Strontium isotope (87Sr/86Sr) data from archaeological sites in Utah, USA.
The information presented here includes the results of strontium isotope analysis on 75 baseline samples from nine Fremont sites in Utah. The baseline samples are of lagomorphs and rodents with limited foraging ranges. The baseline ranges for each site were calculated with two standard deviations. Also included are the raw strontium isotopic data for 30 large game samples from Wolf Village, a Fremont site in Utah. Additional data include a map showing the location of the sites in this study, box plots portraying the local ranges of nine Fremont sites in Utah, and an individual value plot comparing the Wolf Village large game samples to the strontium baseline for the site. These data compliment the discussions and interpretations found in "Identifying Strontium Baselines and Large Game Animal Trade at Fremont Sites through Strontium Isotope (87Sr/86Sr) Analysis" [1].


Fibrinolytic activity in the walls of cerebral saccular aneurysms.
The fibrinolytic activity of 28 cerebral saccular aneurysms from 24 patients and of controls consisting of 10 cerebral arteries has been studied by Todd's autography technique. An increased activity was seen in the minute adventitial vessels and in the endothelium in ruptured cerebral saccular aneurysms, but the aneurysms showed somewhat less activity than the surrounding arteries. Seven patients with subarachnoid haemorrhage had the same increase in fibrinolytic activity in the aneurysmal wall despite antifibrinolytic therapy ante mortem. This finding has been discussed.


Some properties of beta-D-galactosidase from the adult filarial nematode Setaria digitata.
beta-D-galactosidase (beta-D-galactoside galactohydrolase, E.C. 188.8.131.52) activity was localised in the digestive tract of Setaria digitata. The enzyme extract shows maximum activity in the pH range between 3.5 and 5.0 and at 45 degrees C. The enzyme shows the Km value of 3.636 mM for the substrate 6-bromo-2-naphthyl beta-D-galactoside and Vmax of 28.57 nmol 6-bromo-2-naphthol liberated mg-1 protein min-1. Activation/inhibition of the enzyme by various ions, medicinal plants and drugs has been studied. Polyacrylamide gel electrophoresis revealed that the enzyme exists as single form. The medicinal plants and the drug filarin effectively inhibit the enzyme. The significance of these results are discussed in relation to chemotherapy.


Magnetic and mesoporous molecularly imprinted polymer synthesized by rational computation design: Sample preparation and analysis of ractopamine.
Through density functional theory calculations was studied theoretically the formation process of a magnetic and mesoporous molecularly imprinted polymer for ractopamine (RAC), evaluating the molecular electrostatic potential map, functional monomers, functional monomer / template stoichiometry and crosslink agents. The results revealed that the best conditions for the synthesis were established with acrylic acid as functional monomer in a 1: 4 stoichiometry using acetonitrile as the solvent and ethylene glycol dimethacrylate as crosslink agent. It was observed that nine hydrogen bonds established between the RAC and acrylic acid play a key role on the pre-polymerization complex. In addition, three analytical methods using HPLC, UHPLC and CE instruments were optimized for rapid analysis. The adsorbent was experimentally synthesized considering the best conditions found at the molecular level and characterized by FTIR, DRX, TGA, SEM, TEM, surface analysis, and wettability. After that, the synthesized material was used in magnetic solid phase extraction combined with capillary electrophoresis in a preliminary RAC recovery study from milk samples. Finally, greenness metric with a score of 0.55 have been obtained for the sample preparation procedure using the online AGREEprep metric.


Adsorption and desorption characteristics of endosulfan in two typical agricultural soils in Southwest China.
Endosulfan is an organochlorine pesticide widely used in Southwest China. In this paper, the adsorption and desorption characteristics of endosulfan in two typical agricultural soils (latosol and lateritic red soil) in this area were studied. The results showed that Langmuir isothermal equation could well describe the adsorption thermodynamic characteristics of endosulfan in latosol and lateritic red soil, and the maximum adsorption capacities of α-endosulfan were 0.186 and 0.209 mg/g, while those of β-endosulfan were 0.140 and 0.148 mg/g, respectively. Endosulfan adsorption in the two soils was an exothermic physicochemical process, but dominated by physical process. The adsorption kinetic characteristics of endosulfan in the two soils could be well described by second-order kinetic equation, and the initial rate constants were 0.228 and 0.325 mg/(g min) for α-endosulfan, while those were 0.119 and 0.125 mg/(g min) for β-endosulfan, respectively. The adsorbed endosulfan in the two soils was difficult to be desorbed into the liquid phase, and showed weak desorption hysteresis. These results implied that endosulfan could be firmly adsorbed by the two soils, and their adsorption and desorption abilities may be related to the contents of soil clay and organic matter.


Chromosome-wide gene silencing initiates Y degeneration in Drosophila.
Y degeneration is characterized by pseudogenization of its gene content, an accumulation of repetitive DNA and transcriptional inactivation associated with changes in chromatin structure. The sequence of events leading to genetically inert Y chromosomes, however, is unknown. Does the accumulation of nonsense and missense mutations at protein-coding Y genes trigger their transcriptional downregulation, or does transcriptional silencing of genes precede and expedite the decay of Y-linked genes at the amino acid level? Here, we study patterns of gene expression of the recently formed neo-Y chromosome of Drosophila albomicans, which displays few signs of degeneration of protein-coding genes. We show that chromosome-wide downregulation initiates the processes of Y evolution. This implies that the massive degeneration of protein-coding genes observed at many evolving Y-chromosomes may have limited deleterious effects, and instead, decay of regulatory functions is the initial trigger reducing fitness of the Y.


Inhibitory plasticity in layer 1 - dynamic gatekeeper of neocortical associations.
Neocortical layer 1 is a major site of convergence for a variety of brain wide afferents carrying experience-dependent top-down information, which are integrated and processed in the apical tuft dendrites of pyramidal cells. Two types of local inhibitory interneurons, Martinotti cells and layer 1 interneurons, dominantly shape dendritic integration, and work from recent years has significantly advanced our understanding of the role of these interneurons in circuit plasticity and learning. Both cell types instruct plasticity in local pyramidal cells, and are themselves subject to robust plastic changes. Despite these similarities, the emerging hypothesis is that they fulfill different, and potentially opposite roles, as they receive different inputs, employ distinct inhibitory dynamics and are implicated in different behavioral contexts.


Intersectional Disparities in Youth Tobacco Use by Sexual and/or Gender Minority Status and Race and/or Ethnicity.
The current study applied an intersectional lens to examine societal factors, individual psychological outcomes, and youth combustible tobacco and vape use at the intersection of sexual and/or gender minority (SGM) status and race and/or ethnicity. Data were drawn from 133 969 youth respondents surveyed in the 2019-2020 California Student Tobacco Survey, a representative school-based survey of 8th and 10th-grade public school students throughout California. The impact of multiple marginalized group membership using four mutually exclusive intersectional positions (non-SGM white, SGM white, racial minority only, and both SGM and racial minority), in addition to specific differences across ten SGM by race and/or ethnicity groups (e.g. non-SGM black or African American, SGM black or African American, etc.) were assessed. Compared to heterosexual and cisgender white youth, SGM and racial minority adolescents were shown to experience poorer school tobacco education quality and cessation support, lower school and family connectedness, and higher anxiety and depression symptoms. SGM and racial minority youth had a higher prevalence of ever-combustible tobacco use but were less likely to be current vape users compared to non-SGM white respondents. In examining specific group differences, results revealed that SGM teens had the highest risk of ever combustible tobacco use. This disparity was amplified for those belonging to multiple marginalized groups, with black or AA SGM teens evidenced to be at the highest risk of current combustible tobacco. Information from this study has useful implications for SGM measurement in surveillance systems and highlights the usefulness of adopting an intersectional approach to inform equity-driven public health policy and intervention. This representative study of California youth supports that identifying as a sexual and/or gender minority (SGM) is an important risk factor for combustible tobacco use. Particularly, observed SGM disparities were magnified for the youth belonging to marginalized groups, as black or African American SGM teens were shown to be at the highest risk of current combustible tobacco use. Findings support that Intersectionality Theory represents a useful framework for examining tobacco-related disparities and underscores the importance of assessing how the intersection of multiple social categories impacts youth tobacco use.


[Benign breast diseases: hormonal studies in 125 cases (author's transl)].
The results of exploration of the corpus luteum in 125 patients with benign breast disease are analysed. In 109 patients, plasma oestradiol and progesterone were measured at various times during the hyperthermic phase of the menstrual cycle. The results obtained were compared with those obtained in normal women explored during the same phase of the cycle. The average daily values for plasma progesterone obtained in this group of 109 patients was significantly lower than that found in the normal women, whilst there was no change in oestradiol levels. In addition, 16 patients were studied daily throughout the period of hyperthermia. In 8 cases, there the hyperoestrogenism, with or without progesterone insifficiency of the corpus luteum. In all, secretory imbalance of the corpus luteum with a tendency to relative or absolute hyperoestrogenism was a constant finding in women with benign breast disease.


What are threshold concepts and how can they inform medical education?
The notion of "threshold concepts" is being widely applied and researched in many disciplines but is rarely discussed within medical education. This article is written by three medical educators who regularly draw on threshold concept theory in their work. They explore here the nature of threshold concepts and describe how the theory can offer medical educators new perspectives in terms of how they design curricula, approach teaching and support learners.


3-D volume scanning. A new technique for lumbar MR imaging.
A 3-D volume magnetic resonance (MR) acquisition utilizing a T1-weighted gradient-echo sequence provides an excellent image of the intradural nerve roots. In a 6 1/2 minute acquisition, 64 overlapping 2 mm slices can be obtained. High-quality reformats into other planes can be performed creating an "MR radiculogram" in considerably less time than necessary at present for a lumbar MRI study. In 30 patients with sciatica, the volume scan was compared to our standard lumbar MR protocol, consisting of sagittal and transverse spin-echo T1-weighted sequences and a long-TR sequence. The image sets were rated on a 5-point scale for disk herniation and nerve root compression at L 3-4, L 4-5, and L 5-S 1 on both sides; thus 180 locations were assessed. The volume scan invariably produced a better nerve root image than the standard examination, but the smaller signal to noise ratio affected especially the image of the vertebral body. Significant disagreement in ratings between the two techniques was seen at 7 locations for disk herniation, and at 6 locations for root compression. Review of the two studies upheld the verdict of the volume scan in 6 cases of herniation and 3 cases of root compression. Clear-cut verdicts (definitely normal or abnormal) were possible in over 90% with both techniques. Lumbar 3-D volume scanning thus appears to be at least equivalent to MR scanning protocols as currently used. Additionally, the nerve root is much better depicted with the volume scan, and examination time is considerably reduced.


Developmental regulation of neuronal K+ channels by target-derived TGF beta in vivo and in vitro.
The functional expression of Ca2+-activated K+ channels (KCa) in developing chick ciliary ganglion (CG) neurons requires interactions with target tissues and preganglionic innervation. Here, we show that the stimulatory effects of target tissues are mediated by an isoform of TGFbeta. Exposure of cultured CG neurons to TGFbeta1, but not TGFbeta2 or TGFbeta3, caused robust stimulation of KCa. The KCa stimulatory effects of target tissue extracts were blocked by a neutralizing pan-TGFbeta antiserum but not by specific TGFbeta2 or TGFbeta3 antisera. Intraocular injection of TGFbeta1 caused robust stimulation of KCa, whereas intraocular injection of pan-TGFbeta antiserum inhibited expression of KCa in CG neurons developing in vivo. The effects of TGFbeta1 were potentiated by beta-neuregulin-1, a differentiation factor expressed in preganglionic neurons.


Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.
In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating.


Strategic treatment of anovular dairy cows with GnRH.
The primary objective was to evaluate fertility of anovular dairy cows given GnRH 4 d after first postpartum timed AI (TAI). Secondary objectives were to determine ovulatory response to treatment, effect of treatment on serum progesterone (P(4)) concentrations, and the proportion with a short luteal phase. Lactating Holstein cows (n=1047) were submitted for first postpartum TAI using a Presynch+Ovsynch protocol. Anovular cows were identified from an initial 1047 lactating Holstein cows using transrectal ultrasonography, based on the absence of a CL at the first GnRH injection of a Presynch+Ovsynch protocol, and anovular cows were randomly assigned to receive either no further treatment (Control, n=85), or 100 microg of GnRH 4 d after TAI (GnRH treated; n=71). For GnRH treated cows, 51% responded by ovulating a follicle in response to GnRH treatment 4 d after TAI; however, pregnancies per AI (P/AI) did not differ between GnRH treated cows that ovulated (36%) compared to GnRH treated cows that did not ovulate (21%). There was a quadratic effect of P(4) at the PGF(2 alpha) injection of Ovsynch on P/AI, and cows with P(4)>or=1 ng/mL at the PGF(2 alpha) injection of Ovsynch had greater P/AI (41%) than cows with P(4)<1 ng/mL (12%); however, no treatment difference was detected. Overall, P/AI did not differ between control (30.1%) and GnRH treated (29.6%) treatments for synchronized cows. Although treatment of anovular cows with GnRH 4 d after TAI failed to improve fertility, variation among cows in serum P(4) at the PGF(2 alpha) injection of Ovsynch dramatically affected fertility of anovular dairy cows.


A novel two-stage evaluation system based on a Group-G1 approach to identify appropriate emergency treatment technology schemes in sudden water source pollution accidents.
Sudden water source pollution resulting from hazardous materials has gradually become a major threat to the safety of the urban water supply. Over the past years, various treatment techniques have been proposed for the removal of the pollutants to minimize the threat of such pollutions. Given the diversity of techniques available, the current challenge is how to scientifically select the most desirable alternative for different threat degrees. Therefore, a novel two-stage evaluation system was developed based on a circulation-correction improved Group-G1 method to determine the optimal emergency treatment technology scheme, considering the areas of contaminant elimination in both drinking water sources and water treatment plants. In stage 1, the threat degree caused by the pollution was predicted using a threat evaluation index system and was subdivided into four levels. Then, a technique evaluation index system containing four sets of criteria weights was constructed in stage 2 to obtain the optimum treatment schemes corresponding to the different threat levels. The applicability of the established evaluation system was tested by a practical cadmium-contaminated accident that occurred in 2012. The results show this system capable of facilitating scientific analysis in the evaluation and selection of emergency treatment technologies for drinking water source security.


Limitations of the Driver/Passenger Model in Cancer Prevention.
Mutations detected in cancers are often divided into "drivers" and "passengers." We suggest that this classification is potentially misleading for purposes of early detection and prevention. Specifically, some mutations are frequent in tumors and thus appear to be drivers, but are poor predictors of cancer; other mutations are individually rare and thus appear to be passengers, but may collectively explain a large proportion of risk. The assumptions bundled into the terms "driver" and "passenger" can lead to misunderstandings of neoplastic progression, with unintended consequences including overdiagnosis, overtreatment, and failure to identify the true sources of risk. We argue that samples from healthy, benign, or neoplastic tissues are critical for evaluating the risk of future cancer posed by mutations in a given gene. Cancer Prev Res; 9(5); 335-8. ©2016 AACR.


Facilitators and barriers to latent tuberculosis infection treatment among primary healthcare workers in Malaysia: a qualitative study.
Healthcare workers (HCWs) have an increased risk of active and latent tuberculosis infection (LTBI) compared to the general population. Despite existing guidelines on the prevention and management of LTBI, little is known about why HCWs who tested positive for LTBI refuse treatment. This qualitative study sought to explore the facilitators and barriers to LBTI treatment uptake among primary HCWs in Malaysia. This qualitative study used a phenomenological research design and was conducted from July 2019 to January 2021. A semi-structured topic guide was developed based on literature and the Common-Sense Model of Self-Regulation. We conducted one focus group discussion and 15 in-depth interviews with primary care HCWs. Interviewees were 7 physicians and 11 allied HCWs who tested positive for LTBI by Tuberculin Skin Test or Interferon Gamma Release Assay. Audio recordings were transcribed verbatim and thematic analysis was used to analyse the data. We found four factors that serve as barriers to HCWs' LTBI treatment uptake. Uncertainties about the need for LTBI treatment, alongside several other factors including the attitude of the treating physician towards treatment, time constraints during clinical consultations, and concerns about the treatment itself. On the other hand, facilitators for LTBI treatment uptake can be grouped into two themes: diagnostic modalities and improving knowledge of LTBI treatment. Improving HCWs' knowledge and informative clinical consultation on LTBI and its treatment benefit, aided with a definitive diagnostic test can facilitate treatment uptake. Additionally, there is a need to improve infection control measures at the workplace to protect HCWs. Utilizing behavioural insights can help modify risk perception among HCWs and promote treatment uptake.


Polypharmacy and risk of mortality among patients with heart failure following hospitalization: a nested case-control study.
Heart failure (HF) is associated with morbidity, rehospitalization and polypharmacy. The incidence rate of mortality in HF patients with polypharmacy is poorly studied. We examine the association of polypharmacy with mortality risk in incident hospitalized HF patients with a primary diagnosis after discharge from the hospital using Quebec administrative databases, Canada from 1999 to 2015. Polypharmacy, cardiovascular (CV) polypharmacy and non-CV polypharmacy were respectively defined as exposure to ≥ 10 drugs, ≥ 5 CV drugs and ≥ 5 non-CV drugs within three months prior to the case or the control selection date. We conducted a nested case-control study to estimate rate ratios (RR) of all-cause mortality using a multivariate conditional logistic regression during one-year of follow-up. We identified 12,242 HF patients with a mean age of 81.6 years. Neither CV polypharmacy (RR 0.97, 95%CI 0.82-1.15) nor non-CV polypharmacy (RR 0.93, 95%CI 0.77-1.12) were associated with lower mortality risk. However, all polypharmacy (RR 1.31, 95%CI 1.07-1.61) showed an association with mortality risk. Myocardial infarction, valvular disease, peripheral artery disease, diabetes, major bleeding, chronic kidney disease, high comorbidity score, high Frailty score, hydralazine and spironolactone users were associated with increasing mortality risk, ranging from 15 to 61%, while use of angiotensin II inhibitors, beta-blockers, statins, anticoagulant, and antiplatelets were associated with lower risk, ranging from 23 to 32%.


Antibodies to hepatitis C virus (anti-HCV): prevalence in the same geographical area in dialysis patients, staff members, and blood donors.
We studied the anti-HCV prevalence in the same period in all the dialysis patients, staff members and blood donors of the same geographical area. In our opinion, the low prevalence (10.26%) in dialysis patients is strictly correlated to the low prevalence (0.46%) in blood donors.


Psychomotor skills and cognitive load training on a virtual reality laparoscopic simulator for tubal surgery is effective.
Validation of a virtual reality (VR) simulator for the training and assessment of laparoscopic tubal surgery and mapping of cognitive load. Prospective cohort study conducted at the Imperial College Virtual Reality Surgical Skills laboratory amongst 25 trainees and nine senior gynaecologists. Participants performed two sessions of salpingectomy and salpingotomy procedures on a VR simulator to assess construct validity. Nine novices performed ten such sessions to enable assessment of the learning curve. The relationship between cognitive load and the dexterity parameters was assessed. Simulator fidelity was reported by experienced and intermediate level gynaecologists. Statistical analyses utilised non-parametric tests, Kruskall-Wallis and Mann-Whitney U tests. Learning curves were assessed using the Friedman test and Wilcoxon Signed Ranks test. Relationship between dexterity metrics and cognitive load was performed using Spearman's rank order correlation. Salpingectomy demonstrated construct validity for time taken by experienced, intermediate and novice gynaecologists (median 170 vs. 191 vs. 313s (P=0.003) respectively) and movements (median 200 vs. 267 vs. 376s, P=0.045). Salpingotomy demonstrated construct validity for time taken (median 183 vs. 191 vs. 306s, P=<0.001) and movements (median 210 vs. 233 vs. 328s, P=0.005). Learning curve analysis for salpingectomy displayed a plateau for time taken after the eighth session, and the fourth session for movements. Salpingotomy displayed a plateau after the eighth session for both time taken and movements. Cognitive load correlated significantly with dexterity parameters. The fidelity scores were not significantly different between the two procedures (P=0.619). The LAP Mentor VR laparoscopic simulator is a valid and effective tool for training novice surgeons in ectopic pregnancy surgery. Reduction in cognitive load significantly correlates with the learning curves.


Overcoming challenges to support us resumption of high specific activity cobalt-60.
Domestic production of high specific activity 60Co was halted after a target rupture in 2012 at the Advanced Test Reactor (ATR). The Isotope Program (IP) within the US Department of Energy (DOE) Office of Science tasked a multilaboratory team of researchers and managers from Oak Ridge and Idaho National Laboratories with the redesign the radioisotope capsule. The objective of this effort was to create a more robust and reliable design, compared to the pre-2012 target. The team successfully completed this task to produce the DOE-IP cobalt (Co) production capsule design. Furthermore, 66 capsules were successfully fabricated by Oak Ridge National Laboratory (ORNL) and delivered to Idaho National Laboratory (INL) for irradiation in the ATR between January 2014 and October 2016. This paper describes the efforts of the team to prepare and disposition the two initial DOE-IP Co production capsules that were processed in March 2020. These efforts include performing accurate production predictions, experimentally validating predictions with assay measurements, shipping with the Orano-furnished Battelle Energy Alliance Research Reactor shipping package, and disassembling capsules at the isotope vendor site.


Dermabond tissue adhesive versus Steri-Strips in unilateral cleft lip repair: an audit of infection and hypertrophic scar rates.
The purpose of this study was to compare the infection and hypertrophic scar rates in unilateral cleft lip repairs, having had Steri-Strips or Dermabond tissue glue applied across the repair as the final stage. Retrospective study over 13 years of 307 unilateral cleft lip repairs by a single surgeon. The application of either Steri-Strips from 1992 to 1998 (121 patients) or Dermabond tissue adhesive from 1998 to 2006 (186 patients) was used in the final stage of the repair. Regional Centre for Cleft Lip and Palate Care, South West of England. 307 consecutive unilateral cleft lip patients seen from 1992 to 2006. There were five (4%) infections in the Steri-Strip group. All infections were with Staphylococcus aureus. No infections occurred in the Dermabond group (p< .001). There were 15 (12%) hypertrophic scars in the Steri-Strip group and 33 (18%) hypertrophic scars in the Dermabond group (p= .142). Revision surgery was required in a total of seven (6%) patients in the Steri-Strip group. No revisions were required in the Dermabond group (p. 1). We found a lower infection and revision rate and a similar hypertrophic scar rate when Dermabond was used instead of Steri-Strips in the final stage of unilateral cleft lip repair and suggest this study further supports the use of octyl-2-cyanoacrylate tissue adhesive in unilateral cleft lip repair.


Parenting correlates of child behavior problems in a multiethnic community sample of preschool children in northern Norway.
A multiethnic community sample of 191 families with four-year-old children in northern Norway was used to explore whether parenting factors were associated with child behavior problems, and whether these associations differed for boys and girls or for the two main ethnic groups in this region: the indigenous Sami and the majority Norwegians. The Child Behavior Checklist (CBCL) and a semi-structured interview on child-rearing were used as instruments. As would be expected from a developmental perspective, elevated scores of child behavior problems were associated with lower levels of parental cuddling and with higher levels of physical punishment. Family demographics such as low maternal age and single parenthood were also associated with more behavioral problems. Girls seemed to be more strongly influenced by child-rearing factors than boys. Subgroup analyses suggested that for harsh treatment, patterns of correlations differed between Sami and Norwegian groups, especially for boys. A positive correlation between physical punishment and externalizing problems emerged for Norwegian boys, but not for Sami boys. Teasing/ridiculing was positively correlated with internalizing problems for Norwegian boys, but inversely correlated for Sami boys. These findings emphasize the importance of taking the child's cultural context and gender into account when assessing parenting influences on behavioral problems in children.


Health-related quality of life in patients with Kashin-Beck disease is lower than in those with osteoarthritis: a cross-sectional study.
Kashin-Beck disease (KBD) is an endemic deformable bone and joint disease, which affects the quality of life (QOL) of patients. We conducted a cross-sectional study of the QOL of KBD patients by a new KBD quality of life (KBDQOL) questionnaire. A total of 252 KBD patients and 248 OA patients came from Northwest China, and 260 healthy people living in the same area as KBD and osteoarthritis (OA) patients served as the controls. KBDQOL questionnaire was used to evaluate the QOL of all objects. The average scores for physical functions, activity limitations, support of society, mental health and general health were significantly lower in KBD patients than that in OA patients and healthy people except for economics. Monofactor analysis showed that age, height, weight status, education level and grade of KBD had a significant effect on KBDQOL score. Multivariate analysis showed that grade of KBD was the influencing factor of physical function score; gender, age, height, grade of KBD and duration of symptoms were the influencing factors of activity restriction score; age and grade of KBD were factors affecting the general health score. The QOL of KBD patients was significantly lower than that of OA patients and healthy people. The KBDQOL questionnaire may be a promising tool for assessing the QOL of KBD patients.


Nutrition strategies to improve physical capabilities in Duchenne muscular dystrophy.
There is no current cure for Duchenne muscular dystrophy (DMD), and palliative and prophylactic interventions to improve the quality of life of patients remain limited, with the exception of corticosteroids. This article describes 2 potential nutritional interventions for the treatment of DMD, green tea extract (GTE) and the branched-chain amino acid leucine, and their positive effects on physical activity. Both GTE and leucine are suitable for human consumption, are easily tolerated with no side effects, and, with appropriate preclinical data, could be brought forward to clinical trials rapidly.


Dendroaspis natriuretic peptide regulates the cardiac L-type Ca2+ channel activity by the phosphorylation of α1c proteins.
Dendroaspis natriuretic peptide (DNP), a new member of the natriuretic peptide family, is structurally similar to atrial, brain, and C-type natriuretic peptides. However, the effects of DNP on the cardiac function are poorly defined. In the present study, we examined the effect of DNP on the cardiac L-type Ca(2+) channels in rabbit ventricular myocytes. DNP inhibited the L-type Ca(2+) current (I(Ca,L)) in a concentration dependent manner with a IC(50) of 25.5 nM, which was blocked by an inhibitor of protein kinase G (PKG), KT5823 (1 μM). DNP did not affect the voltage dependence of activation and inactivation of I(Ca,L). The α(1c) subunit of cardiac L-type Ca(2+) channel proteins was phosphorylated by the treatment of DNP (1 μM), which was completely blocked by KT5823 (1 μM). Finally, DNP also caused the shortening of action potential duration in rabbit ventricular tissue by 22.3 ± 4.2% of the control (n = 6), which was completely blocked by KT5823 (1 μM). These results clearly indicate that DNP inhibits the L-type Ca(2+) channel activity by phosphorylating the Ca(2+) channel protein via PKG activation.


Creating a database for health IT events via a hybrid deep learning model.
The use of poorly designed and improperly implemented health information technology (HIT) may compound risks because it can disrupt established work patterns and encourage workarounds. Analyzing and learning from HIT events could reduce the risks and improve safety but are limited by accessible HIT event reports. In this study, we propose a hybrid deep learning model to identify HIT event reports from the FDA resource and thus establish the first publicly accessible database for HIT event reports. 6994 samples (3521 HIT and 3473 non-HIT events) extracted from the FDA MAUDE database were employed to assess nine individual and 120 hybrid models on the task of HIT identification. The optimal model was evaluated on an independent dataset prior to its application for establishing the HIT event database. The hybrid model consisting of logistic regression, CNN, and Hierarchical RNN (ACC = 0.903, AUC = 0.954, F1 score = 0.876) is superior to all the other models. The causes of errors include lack of root cause (72.3%), short descriptions (19.7%), and model undertrained (8.0%). The accuracy of the hybrid model on an independent dataset is reported as 0.862. We applied the optimal model to the entire MAUDE database (1991-2018) and generated an HIT event database with 48,997 reports. The first HIT event database contains 48,997 reports with an annual growth rate of 10% (~5000 reports). The strategy of HIT event identification and establishment of the database could help healthcare professionals describe, understand, integrate the events and propose solutions in the context of a fuller spectrum of HIT events.


Invest in physical activity to protect and promote health: the 2020 WHO guidelines on physical activity and sedentary behaviour.
In this editorial we discuss the new 2020 World Health Organization guidelines on physical activity and sedentary behaviour and a series of related papers that are published simultaneously in IJBNPA. The new guidelines reaffirm that physical activity is a 'best buy' for public health and should be used to support governments to increase investment in policy and research to promote and ensure physical activity opportunities are available for everyone. New recommendations on sedentary behaviour and inclusion of specific guidelines for people living with disability and/or chronic disease and pregnant and postpartum women are major developments since 2010. We discuss research priorities, as well as policy implementation and the contribution to the sustainable development agenda. The new guidelines can catalyse the paradigm shifts needed to enable equitable opportunities to be physically active for everyone, everywhere, every day.


5-Acetyl-3-(5-phenyl-1H-pyrazol-3-yl)-1,3,4-thia-diazol-2(3H)-one monohydrate.
In the title hydrate, C13H10N4O2S·H2O, the dihedral angles between the central pyrazole ring and its pendant phenyl and thia-diazole rings are 9.93 (8) and 4.56 (7)°, respectively. In the crystal, the components are linked by N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds, generating [100] chains incorporating R 4 (4)(10) loops. A weak C-H⋯O inter-action helps to consolidate the packing.


Estimation of impurity profiles of drugs and related materials Part 18. Impurities and degradation products of mazipredone.
Reversed-phase HPLC methods using C-18 and C-8 columns as well as various isocratic and gradient systems with aqueous ammonium acetate, methanol and acetonitrile are described for the separation of the impurities of mazipredone (11beta,17-dihydroxy-21-(4-methyl-1-piperazinyl)-pregna-1,4-diene- 3,20-dione hydrochloride). These methods were used also for the estimation of the hydrolytic and oxidative degradation pathways of mazipredone in 0.1 M hydrochloric acid and sodium hydroxide at 80 degrees C. With the aid of HPLC-(APCI)-MS and HPLC-diode-array UV techniques 15 impurities and degradation products have been identified.


Cardiac autonomic functioning and post-traumatic stress: A preliminary study in youth at-risk for PTSD.
The identification of robust, psychophysiological markers of trauma-related distress is critical for developing comprehensive, trauma-informed, mental health assessments for youth. Thus, the present study examined the clinical utility of cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR), two composite indices of the sympathetic and parasympathetic nervous system. We hypothesized that CAB/CAR would more reliably index post-traumatic stress (PTS) responses compared to measuring the parasympathetic (i.e., respiratory sinus arrhythmia; RSA) and sympathetic (i.e., pre-ejection period; PEP) nervous systems in isolation. Our sample was comprised of 88 diverse, low-income youth (40.9% African-American and 36.4% White; 60.5% girls; Mage = 12.05 years; SDage = 1.57) who are at increased risk for adversity-exposure. RSA and PEP were measured during a 5-minute baseline period and 5-minute parent-child conflict discussion task. Adolescent-caregiver dyads completed a clinician-administered measure of the youth's lifetime trauma-exposure and current PTS. CAB represented the difference between RSA and PEP, while CAR was the summation of RSA and PEP. Analyses revealed that sympathetically-oriented CAB reactivity uniquely (a) indexed PTS, especially in the context of elevated trauma, and (b) distinguished between those with and without PTSD. Findings highlight the translational promise of using physiological markers that account for the balance between the parasympathetic and sympathetic nervous system.


Selective and reliable determination of obacunone in rat plasma using solid-phase extraction by liquid chromatography tandem mass spectrometry: Application to a pharmacokinetic study.
This study aimed to develop a highly selective, sensitive and fast liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the determination of obacunone in rat plasma. Sample preparation was accomplished by a simple solid-phase extraction procedure. Chromatographic separation was carried out on an ACQUITY BEH C18 column using acetonitrile/methanol (1:1, v/v) and 0.1% formic acid in water as mobile phase at a flow rate of 0.4 mL/min. Quantification was performed with multiple reactions monitoring in positive ion mode with the precursor-to-product ion transitions at m/z 455.2 > 161.1 for obacunone and m/z 515.2 > 161.1 for nomilin (internal standard). The assay was demonstrated to be linear over the concentration range of 0.1-1,000 ng/mL with correlation coefficient >0.999 (r > 0.999). The intra- and inter-day accuracy ranged from -8.33 to 10.40%, while the precision was <10.41%. The mean extraction recovery was >75.32%, and the assay was free of matrix effect. The validated LC-MS/MS method was successfully applied to the pharmacokinetic study of obacunone in rats after oral and intravenous administrations. The oral bioavailability of obacunone was 13.59%.


The prognostic value of adding systemic inflammation response index to Epstein-Barr virus DNA in childhood nasopharyngeal carcinoma: A real-world study.
To assess the prognostic value of the systemic inflammation response index (SIRI) combined with plasma load of Epstein-Barr virus (EBV) DNA in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC). A total of 205 consecutive patients with CALANPC were enrolled. We used recursive partitioning analysis (RPA) to classify patients into various risk groups, with a primary endpoint of overall survival (OS). Elevated SIRI (≥1.53) and EBV DNA (≥4000 copy/ml) were significantly associated with inferior OS in CALANPC. RPA categorized patients into low- and high-risk groups based on prognostic factors. Survival curves showed excellent discrimination in OS (95.3% vs 77.6%; p < 0.001) between the low- and high-risk groups. A significant improvement was confirmed using the prognostic methods for conventional TNM staging systems (p < 0.05). The combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination in CALANPC.


Raman spectroscopy towards clinical application: drug monitoring and pathogen identification.
Raman spectroscopy is a label-free method that measures quickly and contactlessly, providing detailed information from the sample, and has proved to be an ideal tool for medical and life science research. In this review, recent advances of the technique towards drug monitoring and pathogen identification by the Jena Research Groups are reviewed. Surface-enhanced Raman spectroscopy (SERS) and ultraviolet resonance Raman spectroscopy in hollow-core optical fibres enable the detection of drugs at low concentrations as shown for the metabolites of the immunosuppressive drug 6-mercaptopurine as well as antimalarial agents. Furthermore, Raman spectroscopy can be used to characterise pathogenic bacteria in infectious diseases directly from body fluids, making time-consuming cultivation processes dispensable. Using the example of urinary tract infection, it is shown how bacteria can be identified from patients' urine samples within <1 h. The methods cover both single-cell analysis and dielectrophoretic capturing of bacteria in suspension. The latter method could also be used for fast (<3.5 h) identification of antibiotic resistance as shown exemplarily for vancomycin-resistant enterococci.


Quinopeptide formation associated with the disruptive effect of epigallocatechin-gallate on lysozyme fibrils.
Numerous studies demonstrate that natural polyphenols can inhibit amyloid formation and disrupt preformed amyloid fibrils. In the present study, the fibril-disruptive effects of epigallocatechin-3-gallate (EGCG) were examined using lysozyme as a model protein. The results indicated that EGCG dose dependently inhibited lysozyme fibrillation and modified the peptide chains with quinonoid moieties under acidic conditions, as measured by ThT fluorescence, transmission electron microscopy, and an NBT-staining assay. Moreover, EGCG transformed the preformed lysozyme fibrils to amorphous aggregates through quinopeptide formation. The thiol blocker, N-ethylmaleimide, inhibited the disruptive effect of EGCG on preformed fibrils, suggesting that thiol groups are the binding sites for EGCG. We propose that the formation of quinone intermediates via oxidation and subsequent binding to lysozyme chains are the main processes driving the inhibition of amyloid formation and disruption of preformed fibrils by EGCG. The information presented in this study may provide fresh insight into the link between the antioxidant capacity and anti-amyloid activity of polyphenols.