Comparing Job Satisfaction Among Healthcare Workers at Emergency Departments and Primary Healthcare Units During the COVID-19 Pandemic.

Background The primary healthcare professionals' work description changed during the COVID-19 pandemic, as was the case of all other healthcare departmental operation systems. Objectives This investigation compares job satisfaction between emergency department (ED) and primary healthcare professionals during the COVID-19 pandemic to ascertain the possible effect of the pandemic on healthcare providers. Methods A cross-sectional online self-assessment questionnaire consisting of 36 questions was distributed using available social media to target all frontline healthcare workers (HCWs) in emergency departments and primary healthcare centres in Riyadh. The inclusive criterion was that the respondents should have been frontline HCWs during the pandemic era. The questionnaire was validated by a pre-test of responses of 10 frontline HCWs. This was to ensure the comprehensibility and validity of the questions. Thereafter, necessary corrections were made to the final questionnaire. Responses were collected with an Excel sheet (Microsoft Corp., Redmond, WA), while data were analysed with SPSS version 23 (IBM Corp., Armonk, NY) and GraphPad Prism version 9.2.0 (GraphPad Software, San Diego, CA). Results The targeted sample size was 400; however, 159 HCWs responded to the questionnaire and were thus included in the investigation. There were more male (60.4%) than female (39.6%) respondents, the majority of whom were Saudi nationals (86.6%) while the remaining were non-Saudi nationals working in the Kingdom. Also, 67% of the respondents were emergency medical service professionals while the remaining (23%) were primary healthcare professionals. Significantly, 71.8% of the respondents (p < 0.05) disagreed with adequate enumeration, rewards, and chances of promotion compared to those who agreed (28.2%) during the COVID-19 pandemic. Job satisfaction was not significantly correlated to gender or the work departments (p > 0.05). Respondents significantly (p < 0.05) agreed to the competence of their supervisors, and liked their colleagues and work environment. Conclusion The study has shown that although supervision during the pandemic era was with competence; however, hours of work put in by these frontline emergency professionals were not adequately remunerated. Also, the services they provide seemed not to have been appreciated and hence did not lead to promotion either. Therefore, there was job satisfaction. As expected, the workload was huge while chances of promotion were lacking. These observations could lead to a substandard service should there be another pandemic. There is a need for all stakeholders to look into this more cautiously should there be another pandemic.

Pathway-Based Approaches for Assessing Biological Hazards of Complex Mixtures of Contaminants: A Case Study in the Maumee River.

Assessment of ecological risks of chemicals in the field usually involves complex mixtures of known and unknown compounds. We describe the use of pathway-based chemical and biological approaches to assess the risk of chemical mixtures in the Maumee River (OH, USA), which receives a variety of agricultural and urban inputs. Fathead minnows (Pimephales promelas) were deployed in cages for 4 d at a gradient of sites along the river and adjoining tributaries in 2012 and during 2 periods (April and June) in 2016, in conjunction with an automated system to collect composite water samples. More than 100 industrial chemicals, pharmaceuticals, and pesticides were detected in water at some of the study sites, with the greatest number typically found near domestic wastewater treatment plants. In 2016, there was an increase in concentrations of several herbicides from April to June at upstream agricultural sites. A comparison of chemical concentrations in site water with single chemical data from vitro high-throughput screening (HTS) assays suggested the potential for perturbation of multiple biological pathways, including several associated with induction or inhibition of different cytochrome P450 (CYP) isozymes. This was consistent with direct effects of water extracts in an HTS assay and induction of hepatic CYPs in caged fish. Targeted in vitro assays and measurements in the caged fish suggested minimal effects on endocrine function (e.g., estrogenicity). A nontargeted mass spectroscopy-based analysis suggested that hepatic endogenous metabolite profiles in caged fish covaried strongly with the occurrence of pesticides and pesticide degradates. These studies demonstrate the application of an integrated suite of measurements to help understand the effects of complex chemical mixtures in the field. Environ Toxicol Chem 2021;40:1098-1122. © 2020 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Neural Tube Defects in Pregnancies Among Women With Diagnosed HIV Infection - 15 Jurisdictions, 2013-2017.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services† (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.§ Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.

CD200 is a useful diagnostic marker for identifying atypical chronic lymphocytic leukemia by flow cytometry.

INTRODUCTION: Immunophenotyping by flow cytometry is routinely employed in distinguishing between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Inclusion of CD200 has been reported to contribute to more reliable differentiation between CLL and MCL. We investigated the value of CD200 in assessment of atypical CLL cases. METHODS: CD200 expression on mature B cell neoplasms was studied by eight-color flow cytometry in combination with a conventional panel of flow cytometry markers. The study included 70 control samples, 63 samples with CLL or atypical CLL phenotype, 6 MCL samples, and 40 samples of other mature B cell neoplasms. RESULTS: All CLL samples were positive for CD200, whereas MCL samples were dim or negative for CD200. Of the CLL samples, 7 were atypical by conventional flow cytometry, with Matutes scores ≤3. These cases were tested for evidence of a t(11;14) translocation, characteristic of MCL, and all were negative, consistent with their classification as atypical CLL. All these atypical CLL samples were strongly positive for CD200. CONCLUSION: CD200 proved to be a useful marker for differentiation between CLL and MCL by flow cytometry. In particular, CD200 was useful in distinguishing CLL samples with atypical immunophenotypes from MCL.

Primary central nervous system posttransplantation lymphoproliferative disorder after heart and lung transplantation.

Primary central nervous system posttransplantation lymphoproliferative disorder (PCNS-PTLD) is uncommon, especially after heart or lung transplantation. Database analysis from a single heart and lung transplantation centre and a literature review pertaining to PCNS-PTLD was performed. In this study, the prevalence of PCNS-PTLD was 0.18% after heart and/or lung transplants. Of 1674 transplants, three cases of PCNS-PTLD developed 14 months, 9 years and 17 years posttransplant, and all were Epstein-Barr virus driven malignancies. Literature review of the topic revealed predominantly retrospective studies, with most reported cases after renal transplantation. The overall survival is poor, and it may be improved by early diagnosis and treatment. There are no published guidelines on the management of PCNS-PTLD; immune-chemotherapy in conjunction with reduction of immune suppression is preferred based on available evidence.

Hepatosplenic T-cell lymphoma, immunosuppressive agents and biologicals: what are the risks?

We present three cases of the rare hepatosplenic T-cell lymphoma (HSTCL); two patients suffering from Crohn disease who developed HSTCL on azathioprine without exposure to biologicals, and a third patient who had psoriasis treated using etanercept, cyclosporine and methotrexate. The evidence for an association between HSTCL and immunosuppressive drugs and biologicals is reviewed. We argue for improved pharmacovigilance processes to help determine the benefit to risk ratios for the use of these and other new agents.

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients.

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

An especial skill in elite wheelchair basketball players.

We aimed to investigate whether an especial skill is present in elite wheelchair basketball players when taking twenty shots with a regular basketball from five different distances (11 ft, 13 ft, 17 ft, & 19 ft) from the basket including the free throw line (15 ft). Twelve elite male basketball players participated. The results showed that as distance increased shot accuracy decreased in line with force by variability predictions for the 11 ft, 13 ft, 17 ft, & 19 ft distances. However, shot performance at the free throw line where players are more familiar with practicing free throw shots did not follow this trend. A linear regression line was drawn to predict performance at the free throw line based on nearer (11 ft & 13 ft) and farer (17 ft & 19 ft) distances to the basket, this was then compared to actual performance. A significant difference between actual and predicted scores was found (p<.05) supporting the presence of an especial skill. Significant positive correlations were found for the 11 ft and 17 ft distance, age, years of playing, and accumulated practice hours with performance at the 15 ft line (p<.05). These correlations imply the operation of generalization in the especial skill. This observation received support from applying a model in which shot accuracy as a function of distance was approximated by two regression lines.

Acute effects of prostaglandin E1 and E2 on vascular reactivity and blood flow in situ in the chick chorioallantoic membrane.

The chick chorioallantoic membrane (CAM) subserves gas exchange in the developing embryo and shell-less culture affords a unique opportunity for direct observations over time of individual blood vessels to pharmacologic interventions. We tested a number of lipids including prostaglandins PGE(1&2) for vascular effects and signaling in the CAM. Application of PGE(1&2) induced a decrease in the diameter of large blood vessels and a concentration-dependent, localized, reversible loss of blood flow through small vessels. The loss of flow was also mimicked by misoprostol, an agonist for 3 of 4 known PGE receptors, EP(2-4), and by U46619, a thromboxane mimetic. Selective receptor antagonists for EP(3) and thromboxane each partially blocked the response. This is a first report of the effects of prostaglandins on vasoreactivity in the CAM. Our model allows the unique ability to examine simultaneous responses of large and small vessels in real time and in vivo.

The association between sports participation and athletic identity with eating pathology among college-aged males and females.

The current study examined associations among sports participation (SP), athletic identity (AI), weight status, and eating pathology, and whether these relations differed by gender. Data come from male and female first-year college students who participated in the Tufts Longitudinal Health Study (TLHS) between 1999-2007 (N=712). Relations among SP, AI, actual and perceived weight statuses, Eating Disorders Inventory (EDI) subscale scores, and indices of body shape concern and restrictive eating were examined with hierarchical ordinary least squares (OLS) regression. Associations between SP and eating pathology among females were moderated by perceived weight status. By contrast, relations between males' EDI subscales scores and SP were moderated by ethnicity, as well as by actual weight status. Our findings support that sports participation alone neither promotes nor protects against eating pathology among males and females.

Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach.

Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.

Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function.

PtdIns(3,5)P(2) is one of the seven regulatory PPIn (polyphosphoinositides) that are ubiquitous in eukaryotes. It controls membrane trafficking at multiple points in the endosomal/lysosomal system and consequently regulates the size, shape and acidity of at least one endo-lysosomal compartment. PtdIns(3,5)P(2) appears to exert this control via multiple effector proteins, with each effector specific for a subset of the various PtdIns(3,5)P(2)-dependent processes. Some putative PtdIns(3,5)P(2) effectors have been identified, including Atg18p-related PROPPIN [beta-propeller(s) that bind PPIn] proteins and the epsin-like proteins Ent3p and Ent5p, whereas others remain to be defined. One of the principal functions of PtdIns(3,5)P(2) is to regulate the fission/fragmentation of endo-lysosomal sub-compartments. PtdIns(3,5)P(2) is required for vesicle formation during protein trafficking between endo-lysosomes and also for fragmentation of endo-lysosomes into smaller compartments. In yeast, hyperosmotic stress accelerates the latter process. In the present review we highlight and discuss recent studies that reveal the role of the HOPS-CORVET complex and the vacuolar H(+)-ATPase in the process of endo-lysosome fission, and speculate on connections between these machineries and the Fab1p pathway. We also discuss new evidence linking PtdIns(3,5)P(2) and PtdIns5P to the regulation of exocytosis.

Children's understanding of promising, lying, and false belief.

Understanding promising and lying requires an understanding of intention and the ability to interpret mental states. The author examined (a) the extent to which 4- to 6-year-olds focus on the sincerity of the speaker's intention when the 4-to 6-year-olds make judgments about promises and lies and (b) whether false-belief reasoning skills are related to understanding promising and lying. Participants watched videotaped stories and made promise and lie judgments from their own perspective and from the listener-character's perspective. Children also completed false-belief reasoning tasks. Older children made more correct promise judgments from both perspectives. All children made correct lie judgments from the listener's perspective. The author found that Ist-order false-belief reasoning was related to making judgments from the participant's perspective; 2nd-order false-belief reasoning was related to making judgments from the listener-character's perspective. Results suggest that children's understanding of promising and lying moves from a focus on outcome toward a focus on the belief that each utterance is designed to create.

Absolute quantification of human uridine-diphosphate glucuronosyl transferase (UGT) enzyme isoforms 1A1 and 1A6 by tandem LC-MS.

UGT enzymes catalyze the formation of glucuronic acid conjugates. Specifically selected representative stable isotope (C(13), N(15)) labeled peptide internal standards of each enzyme were employed to quantify UGTs 1A1 and 1A6 by LC-MS/MS using isotope dilution techniques. Inter day variability (n=5) for human liver microsomes was

Decrease in N-methyl-D-aspartic acid receptor-NR2B subunit levels by intrathecal short-hairpin RNA blocks group I metabotropic glutamate receptor-mediated hyperalgesia.

The present study characterizes the involvement of the N-methyl-D-aspartic acid receptors (NMDARs) in mediating thermal hyperalgesia induced by activation of group I metabotropic glutamate receptors (mGluRs). Intrathecal administration of the mGluR1/5 agonist (S)-3,5-DHPG [(S)-3,5-dihydroxyphenylglycine] to mice resulted in significant hyperalgesia as assessed by the tail immersion test. The pretreatment of mice i.t. with CGS 19755 (selective antagonist of the NMDAR), CGP 78608 [[(1S)-1-[[(7-bromo-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]amino]ethyl]phosphonic acid] (selective antagonist at the glycine-binding site of the NMDAR), ifenprodil and Ro 25-6981 (selective antagonists of the NR2B subunit of the NMDAR), bisindolylmaleimide I and Go-7874 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] (inhibitors of protein kinase C), or PKI-(14-22)-amide [Myr-N-Gly-Arg-Thr-Gly-Arg-Arg-Asn-Ala-Ile-NH(2)] (inhibitor of protein kinase A) dose-dependently inhibited the hyperalgesia induced by i.t. administration of the mGluR1/5 receptor agonist (S)-3,5-DHPG. In contrast, i.t. pretreatment of mice with NVP-AAM077 [[(R)-[(S)-1-(4-bromophenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid] (selective antagonist of the NR2A subunit of the NMDAR) or DT-3 [H-Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-Leu-Arg-Lys-Lys-Lys-Lys-Lys-His-OH] (inhibitor of protein kinase G) had no effect on (S)-3,5-DHPG-mediated hyperalgesia. We also show for the first time that i.t. injection of pSM2 (pShag Magic version 2)-grin2b (coding for an short-hairpin RNA to the NR2B subunit of the NMDAR) resulted in a dose-dependent decrease in the NR2B protein and blockade of hyperalgesia induced by activation of the mGluR1/5 in (S)-3,5-DHPG-treated mice. Taken together, our results suggest the hypothesis that mGluRs are coupled to the NMDAR channels through the NR2B subunit in the spinal cord and that this coupling involves the activation of protein kinase C and protein kinase A.

The contribution of intestinal UDP-glucuronosyltransferases in modulating 7-ethyl-10-hydroxy-camptothecin (SN-38)-induced gastrointestinal toxicity in rats.

Life-threatening diarrhea afflicts a considerable percentage of patients treated with irinotecan, an anticancer agent with effects elicited through its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The primary detoxification pathway for SN-38 is glucuronidation. The purpose of this study was to evaluate the role that intestinal UDP-glucuronosyltransferases (UGTs) have from hepatic UGTs in modulating this diarrhea. To investigate this, Gunn rats devoid of UGT1A activity were injected with recombinant adenoviral vectors expressing UGT1A1, 1A6, and 1A7, resulting in reconstituted hepatic UGT expression comparable to a heterozygote. Hepatic microsome studies indicated that 4 to 7 days after adenoviral injection, transfected Gunn rats (j/jAV) had SN-38 glucuronide (SN-38G) formation rates three times higher than control heterozygote rats (j+AV). The adenovirus did not impart any glucuronidating capacity to the intestine in j/jAV rats, whereas j+AV rats possessed intestinal UGT function. After the administration of 20 mg/kg/day irinotecan i.p. to j/jAV rats 4 days after adenovirus injection, diarrhea ensued before the fourth irinotecan dose. j+AV rats were spared the diarrhea, and the toxicity was mild compared with the j/jAV rats, as measured by diarrhea scores, weight loss, and histological assessments of the cecum and colon. The pharmacokinetics of irinotecan, SN-38, and SN-38G indicate that the systemic exposure of SN-38 and SN-38G was higher and lower, respectively, in j/jAV rats. Despite this, the biliary excretion of irinotecan and metabolites was similar. Because intestinal UGTs are the main discriminating factor between j/jAV and j+AV rats, their presence seems to be critical for the gastrointestinal protection observed in j+AV rats.

Adenovirus-mediated gene therapy to restore expression and functionality of multiple UDP-glucuronosyltransferase 1A enzymes in Gunn rat liver.

The Gunn rat has been a valuable model for investigating the effect of UDP-glucuronosyltransferase 1A (UGT1A) deficiencies on drug metabolism and toxicity, but it is limited in some aspects. For example, the native Gunn rat model cannot distinguish between hepatic and extrahepatic UGT1A deficiencies in toxicological mechanisms. To extend the model's utility, we investigated the use of replication-defective recombinant UGT1A adenoviruses for the purpose of selectively restoring hepatic UGT1A function. Mycophenolic acid, the active metabolite of the anti-transplant rejection drug mycophenolate mofetil and suspected gastrointestinal toxicant, was used as a model UGT1A-dependent substrate. Treatment with UGT1A adenoviruses normalized the plasma mycophenolic acid and 7-O-mycophenolate glucuronide (MPAG) (concentration-time curves after mycophenolic acid administration (80 mg/kg intraperitoneally). Functional reconstitution was also apparent in the correction of the mycophenolic acid t(1/2alpha) and the area under the curve (AUC)(MPA,0-8 h)/AUC(MPAG,0-8 h) ratio. Twenty-four hours after administration of mycophenolic acid, severe signs of toxicity were noted in the naive Gunn group, including reduced food consumption. The effect on food consumption was reduced but not completely prevented in the UGT adenovirus-treated Gunn rats. In vitro analyses indicated adenovirus dose-dependent reconstitution of mycophenolic acid UGT activities and UGT1A contents in liver but not intestinal microsomes. In the highest adenovirus dose group, the liver microsomal UGT1A markers exceeded those of the heterozygote controls. The ability to selectively manipulate multiple hepatic UGT1A enzymes in Gunn rats should provide a novel way to assess the importance of intestinal or other extrahepatic UGT1A enzymes in toxicities induced by mycophenolic acid and other cytotoxic drugs and dietary agents.

Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid.

Mycophenolic acid (MPA) is the active immunosuppressive metabolite of the anti-organ rejection drug mycophenolate mofetil (MMF) and is implicated in the gastrointestinal toxicity associated with MMF therapy. Intestinal UDP-glucuronosyltransferases (UGT) have been proposed to provide intrinsic resistance against MMF-induced gastrointestinal toxicity by converting MPA to the inactive MPA 7-O-glucuronide. Using an optimized intestinal microsome preparation method that stabilized the intestinal MPA UGT activity, the MPA UGT activity of male Sprague-Dawley rat intestinal microsomes was characterized. A longitudinal gradient similar to that described for other phenolic compounds was observed, with the activity decreasing from the duodenum to the distal small intestine and colon. The catalytic efficiency of MPA glucuronidation decreased from the proximal to distal intestine as a result of decreasing Vmax and increasing Km. The finding that homozygous Gunn rats lack detectable intestinal MPA UGT activity indicates exclusive roles of UGT1A1, UGT1A6, and/or UGT1A7. Quantitative immunoblotting revealed a parallel between the MPA UGT activity and the content of UGT1A7-like immunoreactivity (18.7 and 7.3 microg/mg for duodenum and colon, respectively). In contrast, the lesser MPA-metabolizing UGT, UGT1A1 and UGT1A6, were lower in abundance (1.6-2.1 and 1.7-2.9 microg/mg, respectively), and their patterns of longitudinal distribution were distinct from the MPA UGT activity. These data suggest a dominant role of a UGT1A7-like enzyme, presumably UGT1A7 itself, in the catalysis of rat intestinal MPA glucuronidation. Studies are ongoing to investigate the relationship between intestinal UGT1A enzymes and susceptibility to MMF-induced gastrointestinal toxicity.