Carbachol induces a rapid and sustained hydrolysis of polyphosphoinositide in bovine tracheal smooth muscle measurements of the mass of polyphosphoinositides, 1,2-diacylglycerol, and phosphatidic acid.
The effects of carbachol on polyphosphoinositides and 1,2-diacylglycerol metabolism were investigated in bovine tracheal smooth muscle by measuring both lipid mass and the turnover of [3H]inositol-labeled phosphoinositides. Carbachol induces a rapid reduction in the mass of phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-monophosphate and a rapid increase in the mass of 1,2-diacylglycerol and phosphatidic acid. These changes in lipid mass are sustained for at least 60 min. The level of phosphatidylinositol shows a delayed and progressive decrease during a 60-min period of carbachol stimulation. The addition of atropine reverses these responses completely. Carbachol stimulates a rapid loss in [3H]inositol radioactivity from phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-monophosphate associated with production of [3H]inositol trisphosphate. The carbachol-induced change in the mass of phosphoinositides and phosphatidic acid is not affected by removal of extracellular Ca2+ and does not appear to be secondary to an increase in intracellular Ca2+. These results indicate that carbachol causes phospholipase C-mediated polyphosphoinositide breakdown, resulting in the production of inositol trisphosphate and a sustained increase in the actual content of 1,2-diacylglycerol. These results strongly suggest that carbachol-induced contraction is mediated by the hydrolysis of polyphosphoinositides with the resulting generation of two messengers: inositol 1,4,5-trisphosphate and 1,2-diacylglycerol.


Lambdoid Craniosynostosis in an Infant With Congenital Cystic Adenomatoid Malformation (CCAM).
Both congenital cystic adenomatoid malformation (CCAM) and lambdoid craniosynostosis are exceedingly rare, with estimated incidences of around 1 in 30,000 live births for each. Herein, we present a case of a patient with prenatally diagnosed CCAM requiring 4 doses of prenatal steroids and ultimately thoracotomy with right lower lobectomy. The operation was uncomplicated, and genome-wide analysis of SNPs revealed no pathologic abnormalities. Development was normal until head shape changes were noted at 5 months of age at which point evaluation by a craniofacial surgeon and 3D CT imaging revealed left-sided lambdoid craniosynostosis. The patient underwent uncomplicated posterior and middle vault expansion and remodeling of his lambdoid synostosis at 11 months of age. This paper explores the etiopathogenesis of CCAM and lambdoid craniosynostosis in an attempt to identify common pathways involved in the development of these exceedingly rare diseases which, to date, have not been described in the peer-reviewed literature.


Antiviral effect of cidofovir on parvovirus B19 replication.
Parvovirus B19 (B19V) is a human ssDNA virus responsible for a wide range of clinical manifestations, still lacking for a specific antiviral therapy. The identification of compounds active against B19V may add therapeutic options to the treatment of B19V infections, that now entirely relies on symptomatic treatments. In the search for compounds possibly inhibiting B19V replication, a particular focus was raised to cidofovir, an acyclic nucleoside phosphonate broadly active against dsDNA viruses. The present study was aimed at evaluating the effect of cidofovir against B19V in two model systems, the UT7/EpoS1 cell line and erythroid progenitor cells (EPC), generated from peripheral blood mononuclear cells. Experiments were carried out at different multiplicity of infections and cidofovir concentrations (0-500 μM) during a course of infection. The effects of cidofovir on B19V replication were assessed by qPCR assays while influence of cidofovir on host cells was measured by cell proliferation and viability assays. Our findings demonstrated that cidofovir has a relevant inhibiting activity on B19V replication within infected UT7/EpoS1, and that the effect on B19V DNA amounts is dose-dependent allowing for the determination of EC50 and EC90 values (7.45-41.27 μM, and 84.73-360.7 μM, respectively). In EPCs, that constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect was demonstrated to a lesser extent, however provoking a significant reduction on B19V DNA amounts at 500 μM (68.2-92.8%). To test infectivity of virus released from EPCs cultured in the presence of cidofovir, cell culture supernatants were used as inoculum for a further course of infection in UT7/EpoS1 cells, indicating a significant reduction in viral infectivity at 500 μM cidofovir. Since the drug did not interfere with the overall cellular DNA synthesis and metabolic activity, the observed effect of cidofovir could be likely related to a specific inhibition of B19V replication.


The distribution and human health risk assessment of eight neonicotinoid residues in agricultural soils from four provinces, south China.
The widespread use of neonicotinoid (neonic) insecticides in China's agricultural sector has led to high residual concentrations in the agroecosystem. Since soil is the primary source of direct pesticide exposure, soil contamination is a significant concern, particularly in regions with extensive agricultural production. This study aims to determine the spatial distribution of neonics in farmlands from four southern provinces that are home to China's crucial commercial grain bases. By combining eight neonics into imidacloprid-equivalent total neonics (IMIRPF) using the relative potency factor method, the ecological risks to humans were also assessed. The results showed that imidacloprid had the highest detection rate (96%-100%), followed by thiamethoxam and clothianidin, which ranged from 44% to 64%. Maximum and average IMIRPF values in soil samples from Zhejiang Province were 277.02 and 46.05 μg kg-1 (dry weight), respectively. Guangdong (maximum = 191.62 μg kg-1, mean = 39.70 μg kg-1) and Jiangxi (maximum = 199.13 μg kg-1, mean = 28.95 μg kg-1) had comparable IMIRPF while Jiangsu had the lowest level of total neonics, with a maximum of 86.07 μg kg-1 and a mean of 19.49 μg kg-1. A significant positive correlation between IMIRPF and total organic carbon in soils was also found. The average daily doses of neonics from soil-borne exposure through food intake, soil ingestion, inhalation, and dermal contact calculated for adults and children in each province were all lower than the reference dose (RfD, 57 μg kg-1 d-1) of imidacloprid. However, the potential health risk to human health cannot be disregarded, given their increasing use and pervasiveness in the environment. Our results help to raise concerns about the safety of the agroecological environment under neonic exposure in the major agricultural provinces of southern China.


Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy.
Chemical sympathectomy of adult mice with 6-hydroxydopamine (6-OHDA) either prior to or following epicutaneous sensitization with the trinitrophenyl (TNP) hapten decreased the delayed hypersensitivity (DH) response to ear challenge. To determine if uptake of 6-OHDA into sympathetic nerve terminals, and their subsequent destruction, was required for suppression of DH, the catecholamine uptake blocker, desipramine, was employed to block 6-OHDA-induced sympathetic denervation. Pretreatment with desipramine prevented the depression of DH. In vivo treatment with the beta blocker, propranolol, did not alter the 6-OHDA effect, eliminating the potential contribution of released catecholamines, acting on beta-adrenoceptors, to DH reduction. Sympathectomy before sensitization also diminished hapten-specific T cell reactivity of sensitized lymph node (LN) cells, as measured in vitro by IL-2 production and CTL generation. In vivo DNA synthesis in draining LN in response to immunization was modestly decreased following 6-OHDA. Thus, sympathetic denervation appears to impair T cell activity in vivo and in vitro. Overall, these results indicate the SNS plays a role in generation of cell-mediated immunity.


Sex and social status modify the effects of fluoxetine on socioemotional behaviors in Syrian hamsters and rhesus macaques.
Social subordination increases risk for psychiatric disorders, while dominance increases resilience to these disorders. Fluoxetine, a selective serotonin (5HT) reuptake inhibitor whose actions are mediated in part by the 5HT1A receptor (5HT1AR), has sex- and social status-specific effects on socioemotional behavior and aggressive behavior. However, the impact of social status on these sex-specific effects remains unclear. The current study evaluated the impact of acute fluoxetine treatment and social status on dominance-related behaviors in female and male hamsters, and the impact of chronic fluoxetine treatment on socioemotional behavior and 5HT1AR binding potential (5HT1ARBP) in female rhesus macaques. We hypothesized that sex differences in the effects of fluoxetine on aggression in hamsters would be diminished in dominant and enhanced in subordinate males and that aggression in female hamsters would be enhanced in dominants and diminished in subordinates. In female rhesus macaques, we hypothesized that chronic fluoxetine would alter socioemotional behaviors and site-specific 5HT1ARBP in a status-dependent manner. Male (n = 46) and female (n = 56) hamsters were paired with conspecifics for three days to establish social rank. Hamsters received a single dose of 20 mg/kg fluoxetine or vehicle two-hours prior to a test with a non-aggressive intruder. Female rhesus monkeys (n = 14) housed were administered fluoxetine (2.8 mg/kg/day) or vehicle injections chronically for 14-days, separated by a three-week washout period. On Day 15, positron emission tomography neuroimaging for 5HT1ARBP was conducted. Fluoxetine treatment decreased aggression in subordinate female monkeys and subordinate female hamsters but not in dominant females of either species. Fluoxetine decreased aggression in dominant but not in subordinate male hamsters. Fluoxetine also reduced and increased prefrontal 5HT1ARBP in dominant and subordinate females, respectively. Taken together, these results provide cross-species evidence that social status and sex impact how increased 5HT modulates agonistic behavior.


Trade openness and CO2 emanations: a heterogeneous analysis on the developing eight (D8) countries.
The focus of this exploration was to examine the linkage between trade openness and CO2 effusions in the developing eight (D8) countries. An unbalanced panel dataset spanning the period 1990 to 2016 was employed for the study's analysis. From the results, the studied panel was heterogeneous and cross-sectionally correlated. Also, all the series gained stationarity after first difference and were materially cointegrated in the long run. The elastic effects of the input variables on the output variable were explored through the DCCEMG estimator, with the support of the AMG and the CCEMG estimators. From the results, trade openness increased CO2 emanations in the D8. Also, economic growth, energy consumption, and financial development promoted CO2 secretions in the nations; however, foreign direct investments mitigated the excretion of CO2 in the countries. On the causal connections amid the series, there was a bidirectional causality between trade openness and CO2 emanations. Also, a one-way causal movement from energy consumption, foreign direct investments, and financial development to CO2 effluents was discovered. Based on the findings, it was recommended among others that effective trade policies that could enhance the transfer of cleaner technologies to the countries should be formulated.


The Influence of Patient-Provider Language Concordance in Cancer Care: Results of the Hispanic Outcomes by Language Approach (HOLA) Randomized Trial.
Delivering linguistically competent care is critical to serving patients who have limited English proficiency (LEP) and represents a key national strategy to help reduce health disparities. Current acceptable standards of communication with patients who have LEP include providers communicating through professional interpretive services or bilingual providers speaking the patients' preferred language directly. This randomized clinical trial tests the effect of patient-provider language concordance on patient satisfaction. Eighty-three adult Spanish-speaking patients with cancer were randomly assigned to receive care from either (1) 1 of 2 bilingual physicians speaking to the patient directly in Spanish or (2) the same physicians speaking English and using a professional interpreter service. Validated questionnaires were administered to assess patient-reported satisfaction with both provider communication and overall care. Transcripts of initial consultations were analyzed for content variations. Compared with patients receiving care through professional interpretive services, patients cared for in direct Spanish reported significantly improved general satisfaction, technical quality of care (mean composite score [MCS], 4.41 vs 4.06; P = .005), care team interpersonal manner (MCS, 4.37 vs 3.88; P = .004), communication (MCS, 4.50 vs 4.25; P = .018), and time spent with patient,(MCS, 4.30 vs 3.92; P = .028). Specific to physician communication, patients rated direct-Spanish care more highly in perceived opportunity to disclose concerns (MCS 4.91 vs 4.62; P = .001), physician empathy (MCS, 4.94 vs 4.59; P <.001), confidence in physician abilities (MCS, 4.84 vs 4.51; P = .001), and general satisfaction with their physician (MCS, 4.88 vs 4.59; P <.001). Analyzing the content of consultation encounters revealed differences between study arms, with the direct-Spanish arm having more physician speech related to patient history verification (mean number of utterances, 13 vs 9; P = .01) and partnering activities (mean utterances, 16 vs 5; P <.001). Additionally, patients in the direct-Spanish arm were more likely to initiate unprompted speech (mean utterances, 11 vs 3; P <.001) and asked their providers more questions (mean utterances, 11 vs 4; P = .007). This study shows improved patient-reported satisfaction among patients with cancer who had LEP and were cared for in direct Spanish compared with interpreter-based communication. Further research into interventions to mitigate the patient-provider language barrier is necessary to optimize care for this population.


Mononuclear cell adhesion and cell adhesion molecule liberation after X-irradiation of activated endothelial cells in vitro.
Increased expression of cell adhesion molecules on endothelial cells is an important early event in inflammation. Low-dose radiotherapy is very effective anti-inflammatory treatment. The hypothesis that it may act by modulation of cell adhesion molecule expression in activated endothelial cells and the subsequent adhesion of mononuclear cells onto the activated endothelial cells was tested. EA.hy.926 endothelial cells were irradiated with 0.3-10 Gy X-rays at different times before or after stimulation with TNFalpha. ICAM-1 or E-selectin expression was measured by ELISA and FACS. Isolated peripheral blood mononuclear cells were incubated with an activated and irradiated confluent monolayer of endothelial cells 4 h, 12 h or 24 h after stimulation, and adhesion was determined in dynamic and static adhesion assays. In the static adhesion assay, where integrin-mediated adhesion dominates, radiation doses of 0.3-0.6 Gy reduced the adhesion of mononuclear cells onto EA.hy.926-EC in vitro by 25-40% and 15-25% of the control level 4 h and 24 h after stimulation, respectively, but increased adhesion 12 h after stimulation. In the dynamic adhesion assay, where selectin-mediated adhesion dominates, radiation doses of 0.3-0.6 Gy reduced the adhesion events by 40-50% and 30-40% of the control level 4 h and 24 h after stimulation, respectively, and again increased adhesion 12h after stimulation. X-ray doses of < or =5 Gy did not induce ICAM-1 expression, or modulate TNFalpha-induced ICAM-1 expression. E-selectin expression was, however, increased in a dose-dependent way 6 h after irradiation. In contrast, X-irradiation 2-5 h before stimulation decreased the characteristic transient expression of E-selectin after TNFalpha stimulation. Modulation of E-selectin liberation on activated endothelial cells may be one mechanism to decrease leukocyte adhesion after low-dose irradiation in vitro, and could be involved in the therapeutic action of anti-inflammatory radiotherapy.


The MRD1 (P-glycoprotein) and MRP (P-190) transporters do not play a major role in the intrinsic multiple drug resistance of Jurkat T lymphocytes.
The response of T cells in relation to the cell cycle has not been extensively studied. We have attempted to address this question using Jurkat T cells treated with cytostatic drugs known to arrest cells at various transition points of their cycle. We tested various concentrations of drugs that act at G1/S (hydroxyurea, lovastatin, thymidine), early S [aphidicolin, cyclosporin A (CsA), rapamycin] or G2 + M (colchicine, nocodazole) in 24 h cultures. Cytofluorimetric analyses showed that cycling Jurkat cells were equally distributed between the G1 (44.9 +/- 6.5%) and S (42.3 +/- 8.0%) phases. Cell distribution in G2 + M was 12.7 +/- 2.8%. Hydroxyurea but not lovastatin increased the percentage of cells in S phase to ca 60-70% and both drugs decreased it to ca 30% in G1. Thymidine had no effects. Aphidicolin increased the distribution in S phase to ca 70% with a decrease in G1 to ca 30%. CsA and rapamycin increased the percentage of the cells in G1 to ca 70% and decreased it to ca 25% in S phase. Nocodazole increased cell distribution in G2 + M to ca 60% and induced a decrease in G1 to ca 10%. The effects of the drugs were not related to their toxicity and their limited efficiency raised the possibility that Jurkat cells possessed an intrinsic resistance to these xenobiotics. Time-course analysis showed (scanning electron microscopy) that the early morphological changes induced by colchicine were reversible. Drug efflux experiments (vinblastine) suggested that an ATP-dependent process could be involved. However, Northern blot analyses showed a weak signal for MDR1 (MDR, multiple drug resistance). In contrast, a probe for multidrug resistance-associated protein (P-190; MRP) showed a strong signal in Jurkat and peripheral lymphocytes. The presence of drugs (CsA, nocodazole, thymidine) (24 h) did not up-regulate its message and cell treatment with BSO only moderately affected the efficiency of the glutathione S-conjugate MRP transporter. Our data suggest that the intrinsic multidrug resistance of leukemic Jurkat T cells does not appear to involve the MDR1 and MRP members of the ABC family of reverse drug transporters and these observations raise the possibility of the involvement of multi-faceted mechanisms.


Nitrosated urea pesticide metabolites and other nitrosamides. Activity in clastogenicity and SCE assays, and aberration kinetics in Chinese hamster V79-E cells.
The nitrosoureas 1-methyl-1-nitroso-3-phenylurea, 1-ethyl-1-nitroso-3-phenylurea, 1-methyl-1-nitroso-3-(p-fluorophenyl)urea, 1-methyl-1-nitroso-3-(p-chlorophenyl)urea, and 1-methyl-1-nitroso-3-(p-bromophenyl)urea, as well as their non-nitrosated parent compounds, were checked for induction of chromosomal aberrations and sister-chromatid exchanges in V79-E cells without metabolic activation in vitro. For comparison, methylnitrosourea, ethylnitrosourea and nitrosocarbaryl were included in this study. Whereas the non-nitrosated agents were inactive, the nitroso derivatives were potent clastogens and inducers of SCEs. Clastogenicity parallels SCE induction, but the latter assay is about 10 times more sensitive (based on concentration of substance) than the clastogenicity assay. The dependence of aberration frequency on sampling time, which was studied for 5 nitroso compounds, revealed striking differences. As demonstrated by differential chromatid staining, the lag phase until maximal aberration rates may cover more than 2 cell cycles. Preventive oncological aspects of these nitrosamides and the mechanism of aberration kinetics are discussed.


Increase in types IV and VI collagen in cherry haemangiomas.
The capillaries in cherry haemangiomas show perivascular hyalinized sheaths. In order to clarify the nature of this sheath material, the extracellular matrix of cherry haemangiomas from 20 normal volunteers (age range 30-64 years) was investigated using immunohistochemical and electronmicroscopical methods. Antibodies against collagen types III, IV and VI and laminin were used. Hyaluronic acid was visualized using the hyaluronic acid binding region of the cartilage proteoglycan as ligand. Electronmicroscopically, the sheaths contained multilaminated basement membrane-like material, collagen fibres 20-25 nm thick with a periodicity of 67 nm and broad-banded aggregates with a periodicity of 100 nm (zebra bodies or fibrous long-spacing fibres). Immunohistochemically, type IV collagen was stained throughout the whole sheath material. Staining for laminin was more confined to the endothelial side of the sheath. Intense staining for type III collagen and hyaluronic acid was found in the connective tissue of the subpapillary layer and between the cherry haemangioma capillaries. Much weaker staining for type III collagen and no staining for hyaluronic acid were found invariably in an area 4-10 microns thick directly around the capillaries. Both sheath material and intercapillary connective tissue of the haemangiomas showed pronounced staining for collagen type VI. Immunogold staining revealed that type VI collagen was localized to microfibrils 5-6 nm thick and to the broad-banded aggregates with 100 nm periodicity. These findings further underline the assumption that the broad-banded aggregates consist of type VI collagen.


Site-Dependent Lineage Preference of Adipose Stem Cells.
Adult stem cells have unique properties in both proliferation and differentiation preference. In this study, we hypothesized that adipose stem cells have a depot-dependent lineage preference. Four rabbits were used to provide donor-matched adipose stem cells from either subcutaneous adipose tissue (ScAT) or infrapatellar fat pad (IPFP). Proliferation and multi-lineage differentiation were evaluated in adipose stem cells from donor-matched ScAT and IPFP. RNA sequencing (RNA-seq) and proteomics were conducted to uncover potential molecular discrepancy in adipose stem cells and their corresponding matrix microenvironments. We found that stem cells from ScAT exhibited significantly higher proliferation and adipogenic capacity compared to those from donor-matched IPFP while stem cells from IPFP displayed significantly higher chondrogenic potential compared to those from donor-matched ScAT. Our findings are strongly endorsed by supportive data from transcriptome and proteomics analyses, indicating a site-dependent lineage preference of adipose stem cells.


Origin of the anomalous absence of hydride formation by ZrPd2.
Intermetallic compounds based on hydrogen absorbing elements usually form stable hydrides. This is the case for PdZr2. Surprisingly, ZrPd2 does not absorb hydrogen although both compounds have the same crystal structure and satisfy the empirical geometrical criteria for hydride formation. Results of ab initio calculations reveal an unanticipated purely electronic origin. These results have implications in the search for new intermetallics for hydrogen storage.


Psychiatric health care provider attitudes towards implantable medication.
Medication nonadherence is a major problem in psychiatry. Introduction of implantable psychiatric medication could alleviate the need to take daily medication, significantly decreasing the rate of nonadherence. This survey assessed psychiatric health care professionals' opinions regarding implants. An email was sent to potential participants including an explanation of the study and a link to an online survey. Email addresses of faculty in the Department of Psychiatry were obtained from websites of United States medical schools. To assess which provider characteristics were most important in consideration of implants, logistic regression models were employed. For assessing which patient characteristics were associated with providers' opinions, logistic regression models using generalized estimating equations tested associations between patient factors and implant decision. Eighty-six percent of respondents supported implants for a subset of patients. Four provider characteristics influenced support for implants including type of work, caseload, percent of patients with schizophrenia and percent of patients with bipolar disorder. Seven patient characteristics significantly influenced provider opinions including illness severity, length of illness, medication compliance, diagnosis, type of medication, family support, and patient age. Although dozens of factors influence the future of implants, the surveyed population showed moderate to strong support for this novel treatment.


Treatment of tendinopathies with platelet-rich plasma.
Pain and dysfunction related to tendinopathy are often refractory to traditional treatments and offer a unique challenge to physicians, because no gold standard treatment exists. Injectable biologics may represent a new modality in conjunction with a multifaceted treatment approach. Platelet-rich plasma (PRP) injections are not associated with the systemic or tendon degradation risks of corticosteroids or the inherent risks of surgery. Studies are promising but have not been replicated with high-powered evidence at the clinical level. Further evidence to expand understanding of the role of PRP in the treatment of tendinopathy is needed.


Socioeconomic inequalities in curative healthcare-seeking for children under five before and after the free healthcare initiative in Sierra Leone: analysis of population-based survey data.
Socioeconomic inequalities between and within countries lead to disparities in the use of health services. These disparities could lead to child mortality in children under 5 years by depriving them of healthcare. Therefore, initiatives to remove healthcare fees such as the Free Healthcare Initiative (FHCI) adopted in Sierra Leone can contribute to reducing these inequities in healthcare-seeking for children. This study aimed to assess the socioeconomic inequalities in healthcare-seeking for children under 5 years of age before and after the implementation of the FHCI. Data were included on 1207, 2815, 1633, and 1476 children under 5 years of age with fever from the 2008, 2013, 2016, and 2019 nationwide surveys, respectively. Concentration curves were drawn for the period before (2008) and after (2013-2019) the implementation of the FHCI to assess socioeconomic inequalities in healthcare-seeking. Finally, Erreyger's corrected concentration indices were calculated to understand the magnitude of these inequalities. Before the implementation of the FHCI, there were inequalities in healthcare-seeking for children under five (Erreyger's corrected concentration index (CI) = 0.168, standard error (SE) = 0.049; p < 0.001) in favor of the wealthy households. These inequalities decreased after the implementation of the FHCI (CI = 0.061, SE = 0.033; p = 0.06 in 2013, CI = 0.039, SE = 0.04; p = 0.32 in 2016, and CI = - 0.0005, SE = 0.362; p = 0.98 in 2019). Furthermore, before the implementation of the FHCI, a significant pro-rich inequality in the districts of Kenema (CI = 0.117, SE = 0.168, p = 0.021), Kono (CI = 0.175, SE = 0.078, p = 0.028) and Western Area Urban (CI = 0.070, SE = 0.032, p = 0.031) has been observed. After the implementation of the FHCI in 2019, these disparities were reduced, 11 of the 14 districts had a CI around the value of equality, and only in 2 districts the pro-rich inequality were significant (Western Area Urban (CI = 0.035, SE = 0.016, p = 0.039) and Western Area Rural (CI = 0.066, SE = 0.030, p = 0.027)). The results of this study demonstrated that socio-economic inequalities in healthcare-seeking for children have been considerably reduced after the FHCI in Sierra Leone. To further reduce these inequalities, policy actions can focus on the increase of availability of health services in the districts where the healthcare-seeking remained pro-rich.


Risk factors and outcomes of conversion to open surgery in endoscopic thyroidectomy via bilateral areola approach: a retrospective Chinese population study.
Although endoscopic thyroidectomy via the bilateral areola approach (ETBAA) has shown cosmetic advantage over open surgery, the risk factors of conversion to open surgery and its impact on patients remain unknown. The objective of this study is to analyze the predictors for conversion to open procedure in patients who underwent ETBAA and its related outcomes. The clinical data of patients who underwent ETBAA from May 2010 to May 2019 were analyzed retrospectively. The patients were divided into two groups according to operation notes: the conversion group and the non-conversion group. Univariate and multivariate logistic regression analyses were performed to investigate the risk factors for conversion to open surgery. Altogether, 140 patients were included in this study. Sixteen (11.4%) patients underwent conversion during ETBAA. Four factors demonstrated significant difference between the two groups: sex (P = 0.001), body mass index (BMI) (P = 0.021), thyroid peroxidase antibody (TPOAb) level (P = 0), and antithyroglobulin antibody (ATG) level (P = 0). Further univariate and multivariate logistic regression analysis revealed that male sex (P = 0.006), TPOAb level>7.8 IU/ml (P = 0.005), and ATG level>79 IU/ml (P = 0.003) had a significant correlation with conversion to open surgery in ETBAA. Prolonged operative time, increased surgical cost, and less patient cosmetic satisfaction were demonstrated in the conversion group (P < 0.05). Male sex, high TPOAb level, and high ATG level were independent risk factors for conversion. Conversion to open surgery in ETBAA is associated with prolonged operative time, increased surgical cost and less patient cosmetic satisfaction.


Incidence of Intravenous Medication Errors in a Chinese Hospital.
The purpose of this study was to explore intravenous (IV) medication errors in a Chinese hospital. The specific objectives were to 1) explore and measure the frequency of IV medication errors by direct observation and identify clues to their causes in Chinese hospital inpatient wards and 2) identify the clinical importance of the errors and find the potential risks in the preparation and administration processes of IV medications. A prospective study was conducted by using the direct observational method to describe IV medication errors on two general surgery patient wards in a large teaching hospital in Beijing, China. A trained observer accompanied nurses during IV preparation rounds to detect medication errors. The difference in mean error rates between total parenteral nutrition (TPN) and non-TPN medications was tested by using the Mann-Whitney U test. A final total of 589 ordered IV doses plus 4 unordered IV doses as prepared and administered to the patients was observed from August 3, 2010, to August 13, 2010. The overall error rate detected on the study ward was 12.8%. The most frequent errors by category were wrong dose (5.4%), wrong time (3.7%), omission (2.7%), unordered dose (0.7%), and extra dose (0.3%). Excluding wrong time errors, the error rate was 9.1%. Non-TPN medications had significantly higher error rates than did TPN medications including wrong time errors (P = 0.0162). A typical inpatient in a Chinese hospital was subject to about one IV error every day. Pharmacists had a very limited role in ensuring the accuracy of IV medication preparation and administration processes.


Long-term psychologic implications of congenital heart disease: a 25-year follow-up.
Patients with various types of congenital heart disease were contacted 25 years after their original examination at the Mayo Clinic. In addition to providing their current health status, level of education achieved, and current occupation, they were asked to complete a detailed standardized questionnaire to assess their degree of psychologic stress. Of the original 463 patients, 168 completed and returned the psychologic questionnaires. These patients had evidence of psychologic stress in excess of that expected on the basis of normative data. Furthermore, the degree of stress was unrelated to the clinical severity of the original cardiac defect. In addition, the psychologic stress occurred despite "success" as defined by educational achievement and occupational level. One can speculate that as children these patients were exposed to environmental stresses that may well have been colored by parental attitudes and perceptions.


Neuritin improves the neurological functional recovery after experimental intracerebral hemorrhage in mice.
Stroke is one of the leading causes of death worldwide, with intracerebral hemorrhage (ICH) being the most lethal subtype. Neuritin (Nrn) is a neurotropic factor that has been reported to have neuroprotective effects in acute brain and spinal cord injury. However, whether Nrn has a protective role in ICH has not been investigated. In this study, ICH was induced in C57BL/6 J mice by injection of collagenase VII, while the overexpression of Nrn in the striatum was induced by an adeno-associated virus serotype 9 (AAV9) vector. We found that compared with GFP-ICH mice, Nrn-ICH mice showed improved performance in the corner, cylinder and forelimb tests after ICH, and showed less weight loss and more rapid weight recovery. Overexpression of Nrn reduced brain lesions, edema, neuronal death and white matter and synaptic integrity dysfunction caused by ICH. Western blot results showed that phosphorylated PERK and ATF4 were significantly inhibited, while phosphorylation of Akt/mammalian target of rapamycin was increased in the Nrn-ICH group, compared with the GFP-ICH group. Whole cell recording from motor neurons indicated that overexpression of Nrn reversed the decrease of spontaneous excitatory postsynaptic currents (sEPSCs) and action potential frequencies induced by ICH. These data show that Nrn improves neurological deficits in mice with ICH by reducing brain lesions and edema, inhibiting neuronal death, and possibly by increasing neuronal connections.


PtM/Mx By (M=Ni, Co, Fe) Heterostructured Nanobundles as Advanced Electrocatalyst for Hydrogen Evolution Reaction.
Optimizing the electronic and synergistic effect of hybrid electrocatalysts based on Pt and Pt-based nanocatalysts is of tremendous importance towards a superior hydrogen evolution performance under both acidic and alkaline conditions. However, developing an ideal Pt-based hydrogen evolution reaction (HER) electrocatalyst with moderated electronic structure as well as strong synergistic effect is still a challenge. Herein, we fabricated boron (B)-doped PtNi nanobundles by a two-step method using NaBH4 as the boron source to obtain PtNi/Ni4 B3 heterostructures with well-defined nanointerfaces between PtNi and Ni4 B3 , achieving an enhanced catalytic HER performance. Especially, the PtNi/Ni4 B3 nanobundles (PtNi/Ni4 B3 NBs) can deliver a current density of 10 mA cm-2 at the overpotential of 14.6 and 26.5 mV under alkaline and acidic media, respectively, as well as outstanding electrochemical stability over 40 h at the current density of 10 mA cm-2 . Remarkably, this approach is also universal for the syntheses of PtCo/Co3 B and PtFe/Fe49 B with outstanding electrocatalytic HER performance.


PCA062, a P-cadherin Targeting Antibody-Drug Conjugate, Displays Potent Antitumor Activity Against P-cadherin-expressing Malignancies.
The cell surface glycoprotein P-cadherin is highly expressed in a number of malignancies, including those arising in the epithelium of the bladder, breast, esophagus, lung, and upper aerodigestive system. PCA062 is a P-cadherin specific antibody-drug conjugate that utilizes the clinically validated SMCC-DM1 linker payload to mediate potent cytotoxicity in cell lines expressing high levels of P-cadherin in vitro, while displaying no specific activity in P-cadherin-negative cell lines. High cell surface P-cadherin is necessary, but not sufficient, to mediate PCA062 cytotoxicity. In vivo, PCA062 demonstrated high serum stability and a potent ability to induce mitotic arrest. In addition, PCA062 was efficacious in clinically relevant models of P-cadherin-expressing cancers, including breast, esophageal, and head and neck. Preclinical non-human primate toxicology studies demonstrated a favorable safety profile that supports clinical development. Genome-wide CRISPR screens reveal that expression of the multidrug-resistant gene ABCC1 and the lysosomal transporter SLC46A3 differentially impact tumor cell sensitivity to PCA062. The preclinical data presented here suggest that PCA062 may have clinical value for treating patients with multiple cancer types including basal-like breast cancer.


Cytotoxic and anti-inflammatory constituents from Momordica cochinchinensis seeds.
Five new lignans mubiesins A - E (1-5), together with twenty-seven known compounds (6-32), were isolated from the cytotoxicity and anti-inflammation portions of Momordica cochinchinensis seeds which were widely used for various tumors and inflammations. Their structures were elucidated by extensive spectroscopic analyses (HR-MS, UV, CD, IR, 1D-NMR, and 2D-NMR). Their cytotoxic and anti-inflammatory activities were evaluated in vitro. Various lignans and saponins showed the significant activities, they could obviously inhibit the growth of tumor cells and the release of NO and TNF-α in RAW 264.7 cells induced by LPS.


New Target of Oxidative Stress Regulation in Cochleae: Alternative Splicing of the p62/Sqstm1 Gene.
We investigated oxidative stress and antioxidant response in the p62/Sqstm1-Keap1-Nrf2 pathway in C57BL/6 mice cochleae during age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL), and the function of full-length and variant p62 in the regulation of Nrf2 activation. Groups of young (2 months), old (13-14 months), control, and acoustic trauma (AT) mice were examined cochlear damage and oxidative stress as follows: auditory brainstem response and hair cell counts; malondialdehyde (MDA) levels measured by assay kit and 7,8-dihydro-8-oxoguanine (8-oxoG) detected by immunohistochemistry. Full-length and variant p62 were examined for expression in cochleae, hippocampus (HIP), and auditory cortex (AC) using immunoblotting. Keap1-Nrf2 pathway activation was based on immunoblotting of nuclear Nrf2 and quantitative real-time PCR of Nrf2 target genes HO-1/NQO-1. The oxidative function of full-length and variant p62 was examined in HEI-OC-1 cells by flow cytometry. The results showed hearing loss, and cochlear hair cell loss was associated with MDA accumulation and 8-oxoG expression during ARHL and NIHL. Nrf2 showed no obvious changes in nuclear protein. Expression levels mRNA for HO-1 and NQO1 were lower in old mice and mildly greater in AT Mice. The expression of p62 splicing variant lacking the Keap1-interacting region was greater than full-length p62 in cochleae. However, the expression of p62 splicing variant was lesser than full-length p62 in HIP and AC. For HEI-OC-1 cells, overexpression of full-length p62 decreased ROS levels induced by H2O2. Oxidative stress is closely related to ARHL and NIHL. Changing the ratio of full-length to variant p62 protein expression may be a new target to reduce the level of oxidative stress in cochleae.


Anesthetic methods in rats determine outcome after experimental focal cerebral ischemia: mechanical ventilation is required to obtain controlled experimental conditions.
Anesthetic agents, pH, blood gases and blood pressure have all been found to influence the pathophysiology of experimental stroke. In experimental research, rats are predominantly used to investigate the effects of focal cerebral ischemia. Chloral hydrate, applied intraperitoneally (i.p.), and halothane, applied via face-mask in spontaneously breathing animals or via endotracheal tube in mechanically ventilated animals are popular methods of anesthesia. We investigated the potential of these anesthetic methods to maintain physiologic conditions during focal cerebral ischemia and their influence on postischemic mortality and histological outcome. Thirty male Sprague-Dawley rats were subjected to 90 min of middle cerebral artery occlusion by insertion of an intraluminal thread and assigned to one of three groups (n=10 each): (A) chloral hydrate i.p./spontaneously breathing; (B) halothane in 70:30 (%) N2O/O2 via face-mask/spontaneously breathing; and (C) halothane in 70:30 (%) N2O/O2 via endotracheal tube/mechanically ventilated. Physiologic parameters were measured before, during, and after ischemia. Infarct volume was histologically assessed after 7 days. All anesthetic techniques except mechanical ventilation via an endotracheal tube resulted in considerably fluctuating blood gases levels, hypercapnia, acidosis and low blood pressure. All spontaneously breathing animals (groups A and B) exhibited a higher postischemic mortality and significantly larger infarct volumes than group C with intubated and ventilated animals. Intra- and postischemic physiologic parameters such as blood pressure, pH, and blood gases critically determine outcome after focal cerebral ischemia. Although anesthesia by halothane via face-mask allowed better control of depth of anesthesia than chloral hydrate, we have found this method to be unsatisfactory due to insufficient control of ventilation and waste of anesthetic gases. Experiments with rats requiring normal physiologic parameters should be performed under conditions of controlled mechanical ventilation and sufficient analgesia.


Evaluation of a recombinant Klebsiella oxytoca strain for ethanol production from cellulose by simultaneous saccharification and fermentation: comparison with native cellobiose-utilising yeast strains and performance in co-culture with thermotolerant yeast and Zymomonas mobilis.
In the simultaneous saccharification and fermentation to ethanol of 100 g l(-1) microcrystalline cellulose, the cellobiose-fermenting recombinant Klebsiella oxytoca P2 outperformed a range of cellobiose-fermenting yeasts used in earlier work, despite producing less ethanol than reported earlier for this organism under similar conditions. The time taken by K. oxytoca P2 to produce up to about 33 g l(-1) ethanol was much less than for any other organism investigated, including ethanol-tolerant strains of Saccharomyces pastorianus, Kluyveromyces marxianus and Zymomonas mobilis. Ultimately, it produced slightly less ethanol (maximum 36 g l(-1)) than these organisms, reflecting its lower ethanol tolerance. Significant advantages were obtained by co-culturing K. oxytoca P2 with S. pastorianus, K. marxianus or Z. mobilis, either isothermally, or in conjunction with temperature-profiling to raise the cellulase activity. Co-cultures produced significantly more ethanol, more rapidly, than either of the constituent strains in pure culture at the same inoculum density. K. oxytoca P2 dominated the early stages of the co-cultures, with ethanol production in the later stages due principally to the more ethanol tolerant strain. The usefulness of K. oxytoca P2 in cellulose simultaneous saccharification and fermentation should be improved by mutation of the strain to increase its ethanol tolerance.


Integrating Health and Social Care Services.
A recent UK Government draft Heath White Paper follows the NHS England long term plan when it states that NHS England requires "a new framework that builds on changes already being made as well as building in the flexibility to support the system to tackle challenges of the future". At present the structure of Health and Social Care Services UK reporting to Government seems unhelpfully complex and opaque. The purpose of this paper is to contribute to the building of a new framework using a generic approach to identify and use 'systemic processes' to facilitate the integration of Health and Social Care services in NHS England and elsewhere. We highlight some of the critical issues that are currently hindering integration and set out a new way of understanding the structure of NHS England through an 'inside-out' analysis of systemic processes. We describe and give three examples of existing systemic processes as 'Consulting a patient', 'Enhancing a Single point of access' - to mental health services and 'Delivering health and social care services England'. Rethinking the interactions between existing organisations could arguably bring considerable benefits including cost savings, better co-ordination, less 'admin' stress on staff where the work is done and provide more organisational adaptability in an uncertain future. Ultimately our suggestions are aimed at helping people to deliver better patient care - the impelling purpose of all health and social care services.


High-content, targeted RNA-seq screening in organoids for drug discovery in colorectal cancer.
Organoids allow the recapitulation of intestinal homeostasis and cancerogenesis in vitro; however, RNA sequencing (RNA-seq)-based methods for drug screens are missing. We develop targeted organoid sequencing (TORNADO-seq), a high-throughput, high-content drug discovery platform that uses targeted RNA-seq to monitor the expression of large gene signatures for the detailed evaluation of cellular phenotypes in organoids. TORNADO-seq is a fast, highly reproducible time- and cost-effective ($5 per sample) method that can probe cell mixtures and their differentiation state in the intestinal system. We apply this method to isolate drugs that enrich for differentiated cell phenotypes and show that these drugs are highly efficacious against cancer compared to wild-type organoids. Furthermore, TORNADO-seq facilitates in-depth insight into the mode of action of these drugs. Our technology can easily be adapted to many other systems and will allow for more systematic, large-scale, and quantitative approaches to study the biology of complex cellular systems.


Anaplastic Transformation of Differentiated Papillary Thyroid Carcinoma Presenting as Cauda Equina Syndrome.
BACKGROUND Papillary thyroid carcinoma is usually an indolent disease, with an almost 80% 5-year survival rate for metastatic disease. Conversely, anaplastic thyroid cancer is much more aggressive, with median overall survival rates of 4 months. CASE REPORT A 67-year-old woman presented with metastatic papillary thyroid cancer with bone metastasis, including an unstable L4 pathological fracture. Initially, she underwent lumbar stabilization surgery, followed by high-dose palliative radiotherapy to the lumbar spine. Subsequently, a total thyroidectomy was performed, followed by an ablative dose of radioiodine and supraphysiological doses of levothyroxine to achieve TSH suppression to less than 0.1 mU/L. The treatment dose of radioiodine was administered 4 times at 6-month intervals. The treatment was well tolerated, with a dramatic thyroglobulin response, and the disease remained radioiodine-sensitive. Prior to a fifth planned dose of radioiodine, our patient presented with cauda equina syndrome and underwent urgent decompressive surgery. Further oncological treatment was planned; however, she deteriorated rapidly following surgery, and repeat imaging showed progressive disease at the surgical site. Histopathology from the lumbar decompression revealed anaplastic thyroid cancer. Our patient died 5 weeks after surgery. CONCLUSIONS This is the first published case of transformation from papillary to anaplastic thyroid cancer presenting as cauda equina compression. Transformation from papillary to anaplastic thyroid cancer has been previously described in the literature; however, it is rarely present distant from the neck, and has an aggressive course. Malignant transformation should be considered in cases of differentiated thyroid cancer that do not fit the previous disease trajectory.


In vitro inhibitory effects of components from Salvia miltiorrhiza on catalytic activity of three human Arachidonic acid ω-hydroxylases.
CYP4 enzymes are involved in the metabolism of xenobiotics and endogenous molecules. 20-Hydroxyeicosatetraenoic acid (20-HETE), the arachidonic acid (AA) ω-hydroxylation metabolite catalyzed by CYP4A/4F enzymes, is implicated in various biological functions. The goal of this investigation is to examine the inhibitory effects of components from Salvia miltiorrhiza(Danshen) on AA ω-hydroxylation using recombinant CYP4A11, CYP4F2, CYP4F3B, and microsomal systems. Tanshinone IIA had noncompetitive inhibition on CYP4F3B (Ki = 4.98 μM). Cryptotanshinone (Ki = 6.87 μM) and tanshinone I (Ki = 0.42 μM) had mixed-type inhibition on CYP4A11. Dihydrotanshinone I had mixed-type inhibition on CYP4A11 (Ki = 0.09 μM), and noncompetitive inhibition on CYP4F2 (Ki = 4.25 μM) and CYP4F3B (Ki = 3.08 μM). Salvianolic acid A had competitive inhibition on CYP4A11 (Ki = 19.37 μM), and noncompetitive inhibition on CYP4F2 (Ki = 15.28 μM) and CYP4F3B (Ki = 6.45 μM). Salvianolic acid C had noncompetitive inhibition on CYP4F2 (Ki = 5.70 μM) and CYP4F3B (Ki = 18.64 μM). In human kidney, human liver or rat heart microsomes, 20-HETE formation was significantly inhibited (P < 0.05) by dihydrotanshinone I (5 and 20 μM) and salvianolic acid A (20 and 50 μM). Given that low plasma concentrations of Danshen components after oral administration, Danshen preparations may not play pharmacological roles by inhibiting AA ω-hydroxylases; however, as Danshen components may reach high concentration in human intestine, drugs that have an important pre-systemic metabolism by these CYP4A/4F enzymes should avoid being co-administered with Danshen preparations.


A multi-class classification framework for disease screening and disease diagnosis of COVID-19 from chest X-ray images.
To accurately diagnose multiple lung diseases from chest X-rays, the critical aspect is to identify lung diseases with high sensitivity and specificity. This study proposed a novel multi-class classification framework that minimises either false positives or false negatives that is useful in computer aided diagnosis or computer aided detection respectively. To minimise false positives or false negatives, we generated respective stacked ensemble from pre-trained models and fully connected layers using selection metric and systematic method. The diversity of base classifiers was based on diverse set of false positives or false negatives generated. The proposed multi-class framework was evaluated on two chest X-ray datasets, and the performance was compared with the existing models and base classifiers. Moreover, we used LIME (Local Interpretable Model-agnostic Explanations) to locate the regions focused by the multi-class classification framework.


Immunogenicity of allogeneic mesenchymal stem cells transplanted via different routes in diabetic rats.
Due to their hypoimmunogenicity and unique immunosuppressive properties, mesenchymal stem cells (MSCs) are considered one of the most promising adult stem cell types for cell therapy. Although many studies have shown that MSCs exert therapeutic effects on several acute and subacute conditions, their long-term effects are not confirmed in chronic diseases. Immunogenicity is a major limitation for cell replacement therapy, and it is not well understood in vivo. We evaluated the immunogenicity of allogeneic MSCs in vivo by transplanting MSCs into normal and diabetic rats via the tail vein or pancreas and found that MSCs exhibited low immunogenicity in normal recipients and even exerted some immunosuppressive effects in diabetic rats during the initial phase. However, during the later stage in the pancreas group, MSCs expressed insulin and MHC II, eliciting a strong immune response in the pancreas. Simultaneously, the peripheral blood mononuclear cells in the recipients in the pancreas group were activated, and alloantibodies developed in vivo. Conversely, in the tail vein group, MSCs remained immunoprivileged and displayed immunosuppressive effects in vivo. These data indicate that different transplanting routes and microenvironments can lead to divergent immunogenicity of MSCs.


Forest soil CO2 efflux models improved by incorporating topographic controls on carbon content and sorption capacity of soils.
Improved models are needed to predict the fate of carbon in forest soils under changing environmental conditions. Within a temperate sugar maple forest, soil CO2 efflux averaged 3.58 µmol m-2 s-1 but ranged from 0.02 to 25.35 µmol m-2 s-1. Soil CO2 efflux models based on temperature and moisture explained approximately the same amount of variance on gentle and steep hillslopes (r2 = 0.506, p < 0.05 and r2 = 0.470, p < 0.05 respectively). When soil carbon content and sorption capacity were added to the models, the amount of explanation increased slightly on a gentle hillslope (r2 = 0.567, p < 0.05) and substantially on a steep hillslope (r2 = 0.803, p < 0.05). Within the organic-rich surface of the mineral soil, carbon content was positively related and sorption capacity was negatively related to soil CO2 efflux rates. There were general patterns of smaller carbon pools and lower sorption capacity in the upland positions than in the lowland and wetland positions, likely a result of hydrological transport of particulate and dissolved substances downslope, leading to higher soil CO2 efflux in the upland positions. However, the magnitude of the soil CO2 efflux was mitigated by the higher sorption capacity of the organic-rich surface layer of the mineral soils, which was negatively correlated to soil CO2 efflux. More accurate estimates of forest soil CO2 efflux must take into account topographic influences on the carbon pool, the environmental factors that affect rates of carbon transformation, as well as the physicochemical factors that determine the fraction of the carbon pool that can be transformed.


Circulating growth factors data associated with insulin secretagogue use in women with incident breast cancer.
Oral drugs stimulating insulin production may impact growth factor levels. The data presented shows the relationship between pre-existing insulin secretagogues use, growth factor profiles at the time of breast cancer diagnosis and subsequent cancer outcomes in women diagnosed with breast cancer and type 2 diabetes mellitus. A Pearson correlation analysis evaluating the relationship between growth factors stratified by diabetes pharmacotherapy and controls is also provided.


Pegylated IFNs for chronic hepatitis C: an update.
For over a decade, IFN-alpha(2) has been the standard treatment for chronic hepatitis C. However, the drug's rapid clearance and short half-life have led to low rates of sustained virological response. Pegylation is a well-established method of modifying the pharmacological properties of IFNs, causing significant improvements in pharmacokinetics, which in turn lead to improved efficacy. Two pegylated forms of IFN-alpha(2) have been developed: PEG-IFN-alpha(2b) and PEG-IFN-alpha(2a), and their efficacy has been established in randomised, controlled trials. However, the two differ significantly in structure, in vitro activity and pharmacological properties, and this may translate into -differences in clinical efficacy. Comparative trials have been initiated that will provide insight into relative importance of pharmacokinetics, bioactivity and dosing regimen.


Anti-streptococcal antibody and T-cell interactions with vascular endothelial cells initiate the development of rheumatic carditis.
The role of group A streptococcal and Streptococcus dysgalactiae subspecies equisimilis M-protein specific Abs and T-cells in endothelial cell activation was investigated using cultured rat aortic endothelial cells, and in a rat model of autoimmune valvulitis. Heat inactivated serum and mononuclear cells from streptococcal M-protein immunized rats independently induced upregulation of the endothelial cell adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in cultured cells. We also observed T-cell migration across endothelial cell monolayers incubated with serum from M-protein-immunized rats. Furthermore, we observed VCAM-1 and ICAM-1 expression in the myocardium of rats injected with M-protein compared to control animals. These observations support the contention that initial interactions between streptococcal M-protein specific Abs and/or T-cells with the heart endothelium lead to endothelial cell activation followed by transmigration of M-protein specific T-cells into heart tissue leading to an inflammatory process that leads to carditis in rheumatic fever and rheumatic heart disease.


Voriconazole hepatotoxicity in severe liver dysfunction.
There are no studies regarding to these effects in patients with severe liver dysfunction. The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B. This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group. Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p < 0.001). The control group developed alterations in the LFTs in only 10.3% of patients. Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead.


Roles of the elements of the triphasic control signal.
In fast (time-optimal) movements about many joint systems, the triphasic EMG pattern has been observed. Although the first agonist burst obviously initiates the movement, the roles of the second and third bursts, appearing in the antagonist and agonist respectively, have been less clear. In this study, the timing of experimentally measured EMG signals led to construction of a three-pulse control signal that produced an accurate simulation of experimentally measured time-optimal head rotations using a sixth-order nonlinear model in conjunction with an optimization algorithm. By ablating pulses from the model control signal and observing the resulting dynamics, the roles of the three pulses can be assessed. As a result, the pulses can be designated PA, the action pulse (for the first agonist burst), PB, the braking pulse (for the antagonist burst), and PC, the clamping pulse (for the second agonist burst). Comparison of dynamic parameters from the simulated movements revealed strategies used to generate control signals for movements of various speeds.


Comparison of different DNA preparation protocols for PCR diagnosis of Human African Trypanosomosis in Côte d'Ivoire.
During a medical survey the sleeping sickness focus in Bonon, Ivory Coast, PCR with Trypanosoma brucei specific primers (TBR 1-2 from Parasitology 99 (1989) 57) was tested on DNA derived from blood samples. DNA purification using a chelating resin was performed either on whole blood or on the buffy coat prepared in two different ways. The preparation based on whole blood performed better than those using the buffy-coat. Using this first method, the sensitivity was 100% on parasitologically confirmed patients, and the specificity was 92%. However, problems of reproducibility of the technique were pointed out, particularly on samples from serologically positive but apparently aparasitemic individuals. It is suggested that the PCR could help in the diagnosis of Human African Trypanosomosis, but the use of other primers should be investigated.


Role of depression in the development of cardiometabolic multimorbidity: Findings from the UK Biobank study.
Depression has been acknowledged as a risk factor for cardiometabolic diseases, but its role in the development of cardiometabolic multimorbidity (CM) remains unclear. We aimed to prospectively investigate how depression affected the development of CM based on the UK Biobank study. We included 459,747 participants with none or one prior cardiometabolic disease. Depression was assessed by the clinical diagnosis and Patient Health Questionnaire (PHQ-2). CM was defined as the coexistence of two or more conditions of type 2 diabetes, stroke, and coronary heart disease (CHD). Multistate models were used to examine the role of depression in the transitions from baseline to single cardiometabolic diseases and subsequently to CM. During a median follow-up of 12.07 years, we documented 3413 incident CM cases among initially disease-free participants and 7461 cases among participants with one prior cardiometabolic disease, respectively. The hazard of developing CM associated with depression was higher among disease-free individuals than that among individuals with one cardiometabolic disease (HR, 95 % CI: 1.68, 1.54-1.83 vs 1.28, 1.20-1.35). Moreover, depression was significantly associated with all transitions from baseline to diabetes (HR, 95 % CI: 1.43, 1.37-1.50), stroke (1.28, 1.20-1.38), and CHD (1.35, 1.31-1.40). After the onset of these cardiometabolic diseases, the HR values (95 % CIs) of progression to CM were 1.26 (1.09-1.46) for diabetes, 1.43 (1.16-1.76) for stroke, and 1.23 (1.08-1.40) for CHD. Depression was an independent risk factor for CM, and adversely influenced the whole progression from disease-free status to CM.


Human immunodeficiency virus infection: a review of the mode of infection, pathogenesis, disease course, and the general and clinical manifestations.
Acquired immunodeficiency syndrome (AIDS) was first recognized in 1981 and in 1983 the virus responsible for this syndrome, the human immunodeficiency virus, was first isolated. There has been an increasing understanding of the many aspects related to infection with this virus and this review discusses the historical as well as the more recent findings related to infection with this virus. In particular, the pathogenesis, mode and course of infection are discussed followed by an overview of the general and oral manifestations of infection with this virus.


Changes in peak expiratory flow rates using two head-tilt/chin-lift maneuver angles in young healthy conscious volunteers.
The head-tilt/chin-lift (HT/CL) maneuver is simple and routinely used to open a closed upper airway. It has yet to be determined whether increasing the HT/CL angle further would be beneficial. We enrolled 60 (30 males) 20-year-old conscious participants. Pre-HT/CL, post-HT/CL #1, and post-HT/CL #2 positions were defined as positions in which the angle between the ear-eye line and the horizontal line was 80°, 65°, and 50°, respectively. Peak exploratory flow rates (PEFRs) pre-HT/CL, post-HT/CL #1, and post-HT/CL #2 positions were recorded continuously at 1-minute intervals (one set). Five sets of measurements were performed (total, 15 measurements for each participant). We analysed 900 measurements (180 sets). The mean PEFRs pre-HT/CL, post-HT/CL #1, and post-HT/CL #2 positions were 348.4 ± 96.9, 366.4 ± 104.9, and 378.8 ± 111.2 L/min (percentage change compared to pre-HT/CL, 5.2% and 8.7%), respectively. Significant differences were observed among pre-HT/CL, post-HT/CL #1, and post-HT/CL #2 positions in all participants, as well as in subgroup classified according to sex, and medians of height, body weight, and body mass index. Our findings suggest that a greater HT/CL angle would be beneficial, as the PEFR increased gradually. The decreasing manner in the PEFR increase with the HT/CL angle implies the existence of an angle threshold beyond which there were no further benefits in airflow, indicating a minimum in airway resistance. A HT/CL maneuver may be appropriate until locking the atlanto-occipital and cervical spine joints in extension occurs and the chest (sternal notch) begins to rise.


A metabolomic approach to quality determination and authentication of raw plant material in the fragrance field. Iris rhizomes: a case study.
This study aimed to discriminate 22 samples of commercial Iris rhizomes (orris root) by species and origin (Iris germanica (Morocco), I. albicans (Morocco), I. pallida (Morocco), I. pallida (China), I. pallida (Italy)) by applying a strategy derived from those adopted in metabolomics. The specimens' fingerprints from conventional analysis methods (LC-UV and/or LC-MS) were unable to provide clear discrimination. A strategy combining UHPLC/TOF-HRMS, in positive and negative modes, with multivariate statistical methods was therefore applied. Exact mass/retention time (EMRT) pairs obtained by UHPLC-TOF/HRMS were successfully submitted to statistical processing by principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), and then orthogonal partial least square-discriminant analysis (OPLS-DA), to extract the discriminating EMRT pairs through their trend views. 146 EMRT pairs were selected on the basis of their trend views, because they significantly varied, and 104 of them were included to discriminate between species and origins. 32 of them were tentatively identified as discriminating markers (flavonoids, isoflavonoids, triterpenoids, benzophenone derivatives and related glycosides …) from the reference database created on the basis of Iris genus components reported in the literature: eight of them specific for I. albicans, four for I. germanica, five for I. pallida (Italy), five for I. pallida (China), and ten for I. pallida (Morocco). The reliability of this strategy was confirmed by identifying species and origin of two unknown samples submitted to the same analytical procedure.


Early clinical exposure in medical education: the experience from Debre Tabor University.
The idea of early clinical exposure in Ethiopian medical schools is a young concept. Old and newly established universities across the nation are shifting towards incorporation of early clinical exposure (ECE) in their curricula. Debre Tabor University introduced ECE in undergraduate medical education from inception. This study generated evidence on students' experience and academic leaders' reflection on early clinical exposure implementation. This study was carried out to investigate medical students' perception towards early clinical exposure and its implementation process by instructors in undergraduate medical education at Debre Tabor University. A cross-sectional survey design that combines quantitative and qualitative methods was conducted in 2021. We asked fifth year medical students (42) to complete a self-administered questionnaire on 5-point Likert scale. The data were supplemented by semi-structured interview with 6 purposively selected academic leaders on the factors that facilitate or impede early clinical exposure implementation. The quantitative data were entered and analyzed using SPSS 20 to compute frequency, median and interquartile range. The qualitative data were analyzed thematically. The study findings suggest that early clinical exposure (ECE) has a positive impact on the development of students' professional knowledge, problem-solving skills, motivation, active learning, and community orientation. Specifically, 64.3% of the surveyed students believed that ECE was effective in constructing their professional knowledge, while 52.4% felt that it improved their problem-solving skills and facilitated constructive/active learning. Additionally, 57.1% of students reported that ECE improved their motivation and 50% noted that it facilitated community orientation. The study also identified several barriers to the implementation of ECE, with the heavy workload being the most commonly mentioned (78.6%). Other challenges included a loose linkage between academic and healthcare institutions (59.5%) and a lack of orientation on the implementation process (35.7%). Academic leaders reflected that ECE was beneficial in familiarizing students with the clinical environment, but staff commitment was crucial for its successful implementation. The study also found that heavy workload, lack of assessment dedicated to ECE on the curriculum, and poorly oriented staff about the program impeded its implementation. The findings of this study suggest that early clinical exposure was beneficial learning method. Teachers' commitment to their roles with adequate preparation, and the contribution of curriculum in providing the learning objective and cases for each session were factors that facilitate effective implementation of ECE. Heavy workload and poor orientation about the program could impede ECE implementation.


Promoted wet air oxidation of polynuclear aromatic hydrocarbons.
The treatment of an aqueous solution of four polycyclic aromatic hydrocarbons, namely acenaphthene, phenanthrene, anthracene and fluoranthene, under moderate conditions of temperature and pressure has been conducted in the presence and absence of free radical promoters (hydrogen peroxide or potassium monopersulfate). With no addition of promoters, the process achieves PAH conversion values in the range 80-100% at 190 degrees C and 50 bars of air pressure (80 min of reaction). Similar results are obtained in the presence of hydrogen peroxide, however, in this case, the time required is just 60 min with a sharp decrease in PAH concentration in the first 10-20 min. Additionally, temperature can be lowered to values in the range 100-150 degrees C. If potassium monopersulfate is used instead of hydrogen peroxide, an analogous behaviour is experienced, in the latter case, temperatures above 120 degrees C lead to an inhibition of anthracene oxidation, likely due to ineffective decomposition of the monopersulfate molecule.


[The clinical application of allergen-specific and total IgE determination in pediatric allergology (author's transl)].
Allergen specific IgE determination (Radio-Allergen-Sorbens-Test) were carried out on 150 patients 2 to 14 years old. The agreement with classical skin tests (Prick and intracutaneous tests) was for pollen allergies 87%, for allergies against house-dust and house-dust mites 80% and for allergies against animal denders 69%. There was however no agreement for allergies against molds (only 11%). The total IgE was measured in 51 children by radial immunodiffusion, pathologically high levels were found in 45% of patients. Allergen-specific IgE determinations (RAST) seem to be especially useful for young allergic children.


Light (phototherapy)--induced riboflavin deficiency in the neonate.
Phototherapy with blue light decomposes riboflavin, which has a maximum absorption at 450 nm. A study was designed to determine whether riboflavin deficiency developed in neonates who received phototherapy for moderate hyperbilirubinemia. Twenty-one infants with normal erythrocyte glucose-6-phosphate dehydrogenase activity were investigated. Five infants with moderate hyperbilirubinemia who did not require phototherapy served as the controls. Riboflavin deficiency was determined from the degree of saturation of erythrocyte glutathione reductase, a method shown to reflect riboflavin nutritional status in the neonate. Sixteen of 21 infants who were exposed to phototherapy developed riboflavin deficiency; all who had phototherapy for 49 hours or more developed the deficiency. That the concentration of serum bilirubin or the duration of hyperbilirubinemia was not a factor is supported by the fact that none of the controls became deficient. This observation may have important metabolic and clinical consequences for the neonate.


32P-postlabelling of 7-methyl-dGMP ring-opened 7-methyl-dGMP and platinated dGpdG.
The 32P-postlabelling technique introduced by Randerath and coworkers was used to investigate the efficiency of the phosphorylation reaction by T4 polynucleotide kinase using three synthesized adducts: 7-methyl-dGMP, ring-opened 7-methyl-dGMP and platinated dGpdG. The methylated substrates were detected at sub-fmol sensitivities. 7-Methyl-dGMP was quantitatively phosphorylated at these low concentrations. The efficiency of phosphorylation of the ring-opened product was less (about one order of magnitude) and that of Pt(dGpdG) about three orders of magnitude less. These results show that T4 polynucleotide kinase phosphorylation is an efficient reaction with 7-methyl-dGMP and with ring-opened 7-methyl-dGMP, even though in the latter case longer incubation times may have to be used to boost the reaction towards completion. By contrast, the low level of phosphorylation with Pt(dGpdG) does not appear encouraging for quantitative determination requiring a high sensitivity.


Geochemistry, soils and cardiovascular diseases.
The hypothesis is presented that deficiencies or excesses in the content or availability of trace elements in rocks and soils, or in water flowing through them, may be a possible cause of certain chronic diseases, including cardiovascular ones. The geographic distribution of cardiovascular diseases is often associated with geochemical differences. This trend is particularly evident in the United States and in Europe, with higher rates for cardiovascular mortality in areas underlain by soils that are poor in most essential trace elements. Confirmation of this trend is found in connection with the degree of mineralization of local water supplies. Areas that are served by soft waters usually show higher rates of cardiovascular mortality and other forms of cardiovascular pathology, compared with the areas that are served by hard waters. Such a negative association between water hardness and cardiovascular pathology is evident in many countries, both industrialized and developing ones.


Observations on the natural history of Paget's disease.
Whole-body skeletal scintigraphy was performed in 4700 adult patients from south-east Scotland. In 3831 with proven or suspected malignant disease the prevalence of osteitis deformans in males is 0.006 in those aged 15-54 years, 0.026 in the age group 55-84 years and 0.24 over the age of 84 years. The corresponding figures in females are 0.002, 0.021 and 0.15. Previous estimates of prevalence should be increased by at least 25% to take account of peripheral and monostotic disease, which is more common than hitherto recognised. The increase in prevalence with age may not be linear. Possible associations with environmental and genetic factors which would account for such a distribution are considered. It is suggested that the conventional distinction between 'active' and 'burned out' Paget's disease may be incorrect.


Total costs of treating venous thromboembolism: implication of different cost perspectives in a Danish setting.
Aim: Optimal use of scarce resources is a focus in the healthcare sector, as resources devoted to health care are limited. Costs and health economic analyses can help guide decision-making concerning treatments. One important factor is the choice of cost perspective that can range from a focus on narrow drug budget costs to broader economic perspectives. In the case of treatment with oral anticoagulants in patients with venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, the aim of this cost analysis was to illustrate the differences in costs when applying different cost perspectives.Methods: In a cost analysis, pairwise comparisons of average costs of 6 months standard treatment with either a low molecular weight heparin parenteral anticoagulant (LMWH) and a Vitamin K Antagonist (VKA) versus one of the non-vitamin K oral anticoagulants [NOACs; dabigatran etexilate, rivaroxaban, apixaban, and edoxaban) used in daily clinical practice in Denmark for VTE patients were carried out. Each analysis included the results from five different cost analyses with increasingly broader cost perspectives going from the narrowest "drug cost only" perspective to the broadest "societal" perspective.Results: Focusing on "drug costs only", LMWH/VKA was associated with the lowest costs compared to all NOACs. However, including the economic impact of preventing recurrent VTE and limit bleedings, apixaban and rivaroxaban resulted in slightly lower health care costs than LMWH/VKA. When applying the "societal perspective", the total costs saved with apixaban and rivaroxaban compared to LMWH/VKA further increased, with apixaban having the lowest total costs.Conclusions: The present study's case of oral anticoagulants in VTE treatment illustrated the importance of the cost perspective in the choice of therapy. If decision-making were based on drug costs only, instead of applying a health care sector or societal cost perspective, suboptimal decisions may be likely.


Management of mobile thrombus of the thoracic aorta.
Mobile thrombus of the nonaneurysmal, nonatherosclerotic aorta is a rare condition but presents with catastrophic embolic events. We describe two cases that demonstrate differences in presentation and treatment strategies. We review the literature to discuss initial management as well as surgical options. However, due to the limited number of cases, no definitive guidelines for management exist.


Developing a functional assessment tool for the auditory performance of Arabic-speaking Egyptian hearing impaired children.
Auditory performance outcome of children with hearing impairment has been widely studied, and the related factors of the performance have been explored among different age groups for English speaking hearing impaired children. The objective of this study was to construct Arabic questionnaires for the evaluation of the auditory abilities of hearing impaired Egyptian Arabic-speaking children. Three Arabic questionnaires targeting the auditory abilities were constructed by selecting items from different English-based questionnaires and translating them into Arabic and adapted to Egyptian culture. The questionnaires were administered to 210 Arabic-speaking Egyptian children in the age range 1-12 years who were divided into three age groups. They included 90 hearing impaired children fitted with hearing aids and 30 hearing impaired children with a cochlear implant and 90 children with normal hearing (as a control group). Participants' responses were statistically analyzed to assess the validity and reliability of the questionnaires and to compare hearing impaired children with normal hearing children. There were non-significant differences between cochlear implanted children and children with hearing aids regarding auditory abilities performances. Language age and aided pure tone audiometry were considered the best predictors of auditory abilities of hearing impaired Egyptian children. The constructed Arabic questionnaires proved to be reliable and valid functional assessment tools that provide information about auditory behaviors of hearing impaired Egyptian children in everyday life and would complement other objective test results in evaluating and monitoring the performance of these children.


Physical fitness, insulin secretion, and glucose tolerance in healthy males and mild type-2 diabetes.
The nature of the relation between physical fitness and glucose homeostasis was evaluated in two studies: (A) a cross-sectional study on 108 middle-aged non-diabetic men; (B) a five-month training program involving nine males with non-insulin-dependent (type 2) diabetes. It was found that the level of physical fitness was positively related to glucose tolerance, and that this relation was largely independent of body weight and basal insulin secretion. Furthermore, the training program for the diabetics resulted in improved glucose tolerance without change in either body weight or glucose-induced insulin secretion. It is concluded that glucose balance is significantly influenced by the physical fitness level, which is likely to be an important element in the pathogenesis of type 2 diabetes as well as in the treatment of that disease.


Impact of intestinal colonization by Gram-negative bacteria on the incidence of bloodstream infections and lethality in critically ill neonates.
Early detection of antimicrobial-resistant microorganisms is crucial to prevent subsequent invasive infections and contain their spread in the Neonatal Intensive Care Unit (NICU). This study aims to investigate the association between intestinal colonization (IC) by Gram-negative bacteria and the risk of bloodstream infection (BSI) in critically ill neonates. Data from the electronic medical records of 678 newborns admitted to a NICU Brazilian between 2018 and 2022 were retrospectively analyzed. Participants were monitored by the National Health Security Network. Among neonates, 6.9 % had IC (56.9 % attributed to Acinetobacter baumannii); of these, 19.1 % developed BSI (66.7 % by Staphylococcus spp.). Within the A. baumannii colonization, 34.5 % occurred during an outbreak in September 2021. Colonized individuals had a longer mean length of stay (49.3 ± 26.4 days) and higher mortality rate (12.8 %) compared to non-colonized individuals (22.2 ± 16.9 days; 6.7 %, respectively). Previous use of antimicrobials and invasive devices significantly increased the risk of colonization. Colonization by drug-resistant microorganisms, along with the occurrence of BSI, was associated with increased mortality and reduced survival time. IC contributed to the incidence of BSI, leading to more extended hospital stays and higher mortality rates. Its early detection proved to be essential to identify an outbreak and control the spread of resistant microorganisms within the NICU.


Geographic Variation in Human Papillomavirus Vaccination Initiation and Completion Among Young Adults in the U.S.
This study explores how human papillomavirus vaccination initiation and completion among men and women aged 18-34 years varies by geographic region. Data from the 2015-2017 Behavioral Risk Factor Surveillance System were analyzed. Geographic regions for the selected states were defined as South, Northeast, and Midwest/West. Human papillomavirus vaccination initiation was defined as receipt of ≥1 dose, and completion was defined as receipt of ≥3 doses. Weighted, multivariable logistic regression models estimated the association between geographic region and vaccine uptake, adjusting for sociodemographic, health, and healthcare factors. Analyses were performed in November 2019. A total of 18,078 adults were included in the study, 80% of whom resided in the South. The overall vaccination initiation rate was 23.4%, and the completion rate was 11.0%. Initiation was higher among those who resided in the Northeast (38.6%), followed by Midwest/West (23.8%), and lowest for those in the South (21.8%) (p<0.0001). Completion rates followed the same trend as initiation. In the adjusted models, compared with the adults residing in the Northeast, those living in the South were less likely to initiate (AOR=0.47, 95% CI=0.40, 0.55) and complete (AOR=0.56, 95% CI=0.46, 0.68) human papillomavirus vaccination. Human papillomavirus vaccine uptake was low for all regions, but vaccine uptake was significantly lower in the South region. This demonstrates the need to identify barriers specifically associated with the Southern population, which may include differing levels of education and insurance. Such work is especially pertinent because many Southern states face increased risk of human papillomavirus-associated cancers such as cervix and oral cavity and pharynx cancers.


Distinct functions for dopamine and serotonin in locomotor behaviour: evidence using the 5-HT1 agonist RU 24969 in globus pallidus-lesioned rats.
The locomotor effect of RU 24969, a potent 5-HT1 agonist, was tested in two experimental conditions. Firstly, 5-HT neurons were degenerated by i.c.v. infusion of 5,7-dihydroxytryptamine (5,7-DHT). Secondly, outputs of the nigrostriatal and mesolimbic dopaminergic (DAergic) systems were bilaterally disrupted by electrolytic lesion of the globus pallidus (GP). After both types of lesion, RU 24969 (1.25-5 mg/kg, i.p.) induced an intense and long-lasting hyperlocomotion which was more pronounced than in intact rats. The hyperlocomotion induced in 5,7-DHT lesioned rats as well as that in intact rats was abolished by the DA blocker haloperidol (0.5 mg/kg, i.p.). On the contrary the hyperlocomotion induced in GP-lesioned rats was either unmodified or increased both by haloperidol even at a very high dose (2 mg/kg, i.p.) and by methysergide (5 mg/kg, i.p.). It is concluded that (i) there is no DAergic link in the locomotor response to RU 24969, (ii) 5-HT1 receptors are involved in the motor execution of locomotion, (iii) DA initiates and controls the 5-HT-mediated locomotion in normal rats.


Effects of HIV Infection on Arterial Endothelial Function: Results From a Large Pooled Cohort Analysis.
To determine the effects of HIV serostatus and disease severity on endothelial function in a large pooled cohort study of people living with HIV infection and HIV- controls. Approach and Results: We used participant-level data from 9 studies: 7 included people living with HIV (2 treatment-naïve) and 4 had HIV- controls. Brachial artery flow-mediated dilation (FMD) was measured using a standardized ultrasound imaging protocol with central reading. After data harmonization, multiple linear regression was used to examine the effects of HIV- serostatus, HIV disease severity measures, and cardiovascular disease risk factors on FMD. Of 2533 participants, 986 were people living with HIV (mean 44.4 [SD 11.8] years old) and 1547 were HIV- controls (42.9 [12.2] years old). The strongest and most consistent associates of FMD were brachial artery diameter, age, sex, and body mass index. The effect of HIV+ serostatus on FMD was strongly influenced by kidney function. In the highest tertile of creatinine (1.0 mg/dL), the effect of HIV+ serostatus was strong (β=-1.59% [95% CI, -2.58% to -0.60%], P=0.002), even after covariate adjustment (β=-1.36% [95% CI, -2.46% to -0.47%], P=0.003). In the lowest tertile (0.8 mg/dL), the effect of HIV+ serostatus was strong (β=-1.90% [95% CI, -2.58% to -1.21%], P<0.001), but disappeared after covariate adjustment. HIV RNA viremia, CD4+ T-cell count, and use of antiretroviral therapy were not meaningfully associated with FMD. The significant effect of HIV+ serostatus on FMD suggests that people living with HIV are at increased cardiovascular disease risk, especially if they have kidney disease.


Paraneoplastic limbic encephalitis presenting as acute viral encephalitis.
To describe a case of limbic encephalitis which initially presented as viral limbic encephalitis and during the clinical evaluation a renal carcinoma was diagnosed. Patient with history of peripheral paresis of right facial nerve, 1 month after symptoms appearance and treatment, developed fever, vomiting, grand mal seizure, decreased level of consciousness, confusion, hallucinations and agitation. The patient initially presented a clinical picture of viral LE. which confirmed by CSF. MRI brain showed areas with pathological intensity signal in the region of limbic system unilateral. During the clinical evaluation a renal carcinoma was discovered and a nephrectomy has been performed. Although PLE typically presents as a chronic or subacute disease, it may be fulminant and clinically indistinguishable from an acute HSVE. This association pose the problem of a possible relation between this two syndromes and the correct diagnosis is very important, because there are effective treatments.


Factors influencing the yield of satellite DNA in extractions from Drosophila virilis and Drosophila melanogaster adults and embryos.
The application of different DNA extraction methods to identical batches of Drosophila virilis and Drosophila melanogaster flies or embryos has revealed that the ionic strength of a homogenization medium is of critical importance if chloroform extractions are performed. The low yield of satellite DNA after homogenization in low salt buffers is less severe if EDTA is included in the buffer. Phenol extraction procedures result in no such differential behavior of satellite and main band DNA, but under certain circumstances a particular satellite fraction of Drosophila virilis DNA may be lost.


Longitudinal Analysis of Humoral and Cellular Immune Response Following SARS-CoV-2 Vaccination Supports Utilizing Point-Of-Care Tests to Enhance COVID-19 Booster Uptake.
Individuals with weaker neutralizing responses show reduced protection with SARS-CoV-2 variants. Booster vaccines are recommended for vaccinated individuals, but the uptake is low. We present the feasibility of utilizing point-of-care tests (POCT) to support evidence-based decision-making around COVID-19 booster vaccinations. Using infectious virus neutralization, ACE2 blocking, spike binding, and TCR sequencing assays, we investigated the dynamics of changes in the breadth and depth of blood and salivary antibodies as well as T-cell clonal response following mRNA vaccination in a cohort of healthcare providers. We evaluated the accuracy of two POCTs utilizing either blood or saliva to identify those in whom humoral immunity was inadequate. >4 months after two doses of mRNA vaccine, SARS-CoV-2 binding and neutralizing Abs (nAbs) and T-cell clones declined 40-80%, and 2/3rd lacked Omicron nAbs. After the third mRNA booster, binding and neutralizing Abs increased overall in the systemic compartment; notably, individuals with previously weak nAbs gained sharply. The third dose failed to stimulate secretory IgA, but salivary IgG closely tracked systemic IgG levels. Vaccine boosting increased Ab breadth against a divergent bat sarbecovirus, SHC014, although the TCR-beta sequence breadth was unchanged. Post 3rd booster dose, Ab avidity increased for the Wuhan and Delta strains, while avidity against Omicron and SHC014 increased to levels seen for Wuhan after the second dose. Negative results on POCTs strongly correlated with a lack of functional humoral immunity. The third booster dose helps vaccinees gain depth and breadth of systemic Abs against evolving SARS-CoV-2 and related viruses. Our findings show that POCTs are useful and easy-to-access tools to inform inadequate humoral immunity accurately. POCTs designed to match the circulating variants can help individuals with booster vaccine decisions and could serve as a population-level screening platform to preserve herd immunity. SARS-CoV-2 point-of-care antibody tests are valuable and easy-to-access tools to inform inadequate humoral immunity and to support informed decision-making regarding the current and future booster vaccination.


Breastfeeding in the context of the COVID-19 pandemic: A discussion paper.
Breastfeeding offers one of the most fundamental global health benefits for babies. Breastmilk is lifesaving, providing not only nutrition but immunologic benefits and as such is strongly supported by the World Health Organization and leading healthcare associations worldwide. When the COVID-19 pandemic started in 2020, the impact of the restrictions to prevent the spread of the disease created challenges and questions about provision of safe, quality care, including breastfeeding practices, in a new 'normal' environment. Mothers were temporarily separated from their babies where infection was present or suspected, parents were prevented from being present on neonatal units and vital breastfeeding support was prevented. This discussion paper provides an overview of essential areas of knowledge related to practice for neonatal nurses and midwives who care for breastfeeding mothers and babies, in the context of the COVID-19 pandemic and the latest global guidance. Three areas will be discussed; the protective benefits of breastfeeding, keeping breastfeeding mothers and babies together and supporting mothers to breastfeed their babies. Finally, care recommendations are presented to serve as a summary of key points for application to practice for neonatal nurses and midwives.


The seven domains of action for a sustainable ocean.
The ocean strongly contributes to our well-being but is severely impacted by human activities. Here, I propose seven domains of action to structure our collective efforts toward a scientifically sound, just, and holistic governance of a sustainable ocean.


Virtual Reality Exposure Treatment in Phobias: a Systematic Review.
We compare the relative efficacy of virtual reality therapy exposure (VRET) versus in vivo therapy exposure among individuals suffering from phobias. A systematic search was completed up to 03 April 2020, using the following databases: ACM Digital Library, ResearchGate, IEEE, Science Direct, MIT PressJournals, Center for Direct Scientific Communication (CCSD) and Mary Ann Liebert Publishers. Five authors searched the databases using the following terms: Virtual Reality, Phobia, Mental health, Computing, Therapy, HMD, CAVE, Virtual ambient, in virtuo, Avoidance, Exposure, VRET, in vivo, Anxiety, Agoraphobia, Social Phobia, Stimuli, Cognitive-behaviour. All studies that evaluate the effect of in virtuo exposure towards phobia rehabilitation were selected. By reviewing the article, each author then applied the inclusion and exclusion criteria, and 30 articles were selected. Data extracted included the number of samples, amount of sessions, study variables that may affect the final outcome, therapy technology. The data provided was synthesized using a meta-analysis based on the results. The results demonstrated a positive outcome of Virtual Reality Exposure Treatment in the treatment of most phobias. In contrast, some of these treatments did not work for a few specific phobias in which the standard procedures were more effective. The findings suggest that for some specific phobias treatment, Virtual Reality Exposure Treatment does not reach the in vivo exposure level of immersion and presence. Further research is needed to perform studies with higher-dimension samples, since many papers report a low sample size and that is probably why many of them have inconclusive results.


Melting Process of the Peritectic Mixture of Lidocaine and Ibuprofen Interpreted by Site Percolation Theory Model.
Eutectic mixtures are often used in the design and delivery of drugs. In this study, we examined the peritectic mixture of lidocaine (LDC) and ibuprofen (IBP) using differential scanning calorimetry, Raman spectroscopy, and microscopy. The obtained phase diagram showed that as the mixture was heated, first LDC melted at 293 K, then IBP dissolved in the liquefied LDC at 310 K, and finally all remaining crystals melted. In the 1H NMR spectra, the signals of the carboxyl group in IBP and amide or amine group in LDC shifted to the low magnetic field in the IBP/LDC mixtures, because of the intermolecular interaction between these moieties. Using FTIR spectroscopy, the kinetic "reaction" order of the melting process in the mixtures with excess LDC, equimolar, and excess IBP was determined to be +1/2, -1/2, and 0, respectively. The 2 contacts between the liquidus line and the higher melting line at 310 K at IBP molar fractions of 1/3 and of 2/3 were explained on the basis of the site percolation theory.


Prevalence of chronic obstructive pulmonary disease in patients with rheumatoid arthritis: A cross-sectional study.
Rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) are both chronic inflammatory diseases; the prevalence of COPD in RA patients is known to be high. However, the prevalence of both RA and COPD differs according to sex; the relationship between RA and COPD may also vary according to sex. Therefore, we investigated the prevalence of COPD and its association in patients with RA in Korea by sex. We conducted a nationwide cross-sectional study using data from the Korea National Health and Nutrition Examination Survey. A total of 12 417 men and 15 878 women were included. In this study, RA was defined as physician diagnosed or currently under RA treatment. COPD was defined based on spirometry results, chronic symptoms, and smoking history. Multivariable logistic regression models were employed and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for COPD prevalence in patients with RA. The prevalence of COPD was 15.5% in men with RA, 3.5% in women with RA, 7.8% in men without RA, and 2.2% in women without RA. After adjustment for potential confounding variables, including smoking status, RA was significantly associated with COPD in men (OR 2.16, 95% CI 1.06-4.40), but not in women (OR 1.58, 95% CI 0.81-3.10). In Korea, the prevalence of COPD was high in patients with RA of both sexes; RA and COPD was significantly likely to be associated in men, but not in women.


YAP Promotes VEGFA Expression and Tumor Angiogenesis Though Gli2 in Human Renal Cell Carcinoma.
High vascularization is a major characteristic of renal cell carcinoma (RCC). Thus, exploration of molecules promoting the tumor vascularization in RCC is urgent. Yes-associated Protein (YAP) is an oncogene in many cancer types, and high YAP expression was correlated with worse overall survival of RCC patients according to The Cancer Genome Atlas (TCGA) database. However, whether YAP promotes tumor angiogenesis of RCC is still unknown. Western blotting assay, real-time Quantitive PCR analysis, and ELISA assay were used to detect the related gene expression. The function of YAP on tumor angiogenesis was investigated by HUVEC recruitment, tube formation, and rabbit cornea assay. The clinical relevance of several genes was analyzed in a public database. knockdown of YAP decreased RCC cell-inducing HUVEC recruitment and tube formation. Moreover, tumor angiogenesis ability of 786-O cells was crippled by YAP knockdown in vivo. In addition, the expression of Vascular endothelial growth factors A (VEGFA) was positively correlated with YAP expression in RCC tumor tissues, and YAP promoted expression and secretion of VEGFA in RCC cells. Mechanistically, GLI family zinc finger 2 (Gli2) knockdown in RCC cells reduced both basic and YAP-induced VEGFA expression, HUVECs recruitment, and tube formation, indicating that Gli2 is necessary for YAP to promote expression of VEGFA. Taken together, our results demonstrate that YAP/Gli2 promotes VEGFA expression and tumor angiogenesis in RCC cells, which could provide novel therapeutic targets in RCC treatment.