Dopamine Agonists Modify the Development of Brain D1 and D2 Receptor Responsiveness

Dopamine (DA) agonist-induced behavioral supersensitivity in the adult rat has served as the standard model for certain of the motor and behavioral side effects associated with long-term exposure to DA agonists in humans. The mechanisms relating receptor events with behavior mediation, however, remain unclear. The striatum of rats progresses through a prolonged and varied postnatal developmental period. In order to examine the relative contribution of D1 and D2 receptor-mediated mechanisms to behavioral changes which follow chronic dopamine agonist exposure, developing rats were treated daily from birth with a D1 agonist, SKF 38393 hydrochloride (3.0 mg/kg $\times$ 32d, i.p.), or a D2 agonist, LY 171555 hydrochloride (3.0 mg/kg $\times$ 32d, i.p.), and/or 6-OHDA (134 $\mu$g, i.c.v., at 3 d after birth). Following a drug-free interval, behavioral responses to selective DA agonists were evaluated. The results indicate that (1) prolonged LY 171555 treatments in development produced a supersensitive animal model for yawning and eating behaviors. (2) Perioral movements of high frequency could be produced by a very low dose of the DA D2 antagonist spiroperidol in rats treated neonatally with 6-OHDA, thereby providing a useful animal model to study tardive dyskinesia. (3) The priming phenomenon described by Breese and co-workers which was thought to be produced by D1 agonists only has been found in this study to be produced by a D2 agonist as well. This model provides a means for studying specific stereotypic behaviors in animals. (4) (3H) SCH 23390 and (3H) spiroperidol binding to striatal tissue was not altered in rats treated in development with specific agonists or antagonists for the D1 and D2 receptors. A neonatal 6-OHDA lesion did not modify binding in any of the agonist- or antagonist-treated groups. In conclusion, DA D1 and D2 agonist treatments during postnatal development are effective means of producing new animal models that are potentially useful for studying clinical disorders in man

Dopamine Agonists Modify the Development of Brain D1 and D2 Receptor Responsiveness

Dopamine (DA) agonist-induced behavioral supersensitivity in the adult rat has served as the standard model for certain of the motor and behavioral side effects associated with long-term exposure to DA agonists in humans. The mechanisms relating receptor events with behavior mediation, however, remain unclear. The striatum of rats progresses through a prolonged and varied postnatal developmental period. In order to examine the relative contribution of D1 and D2 receptor-mediated mechanisms to behavioral changes which follow chronic dopamine agonist exposure, developing rats were treated daily from birth with a D1 agonist, SKF 38393 hydrochloride (3.0 mg/kg $\times$ 32d, i.p.), or a D2 agonist, LY 171555 hydrochloride (3.0 mg/kg $\times$ 32d, i.p.), and/or 6-OHDA (134 $\mu$g, i.c.v., at 3 d after birth). Following a drug-free interval, behavioral responses to selective DA agonists were evaluated. The results indicate that (1) prolonged LY 171555 treatments in development produced a supersensitive animal model for yawning and eating behaviors. (2) Perioral movements of high frequency could be produced by a very low dose of the DA D2 antagonist spiroperidol in rats treated neonatally with 6-OHDA, thereby providing a useful animal model to study tardive dyskinesia. (3) The priming phenomenon described by Breese and co-workers which was thought to be produced by D1 agonists only has been found in this study to be produced by a D2 agonist as well. This model provides a means for studying specific stereotypic behaviors in animals. (4) (3H) SCH 23390 and (3H) spiroperidol binding to striatal tissue was not altered in rats treated in development with specific agonists or antagonists for the D1 and D2 receptors. A neonatal 6-OHDA lesion did not modify binding in any of the agonist- or antagonist-treated groups. In conclusion, DA D1 and D2 agonist treatments during postnatal development are effective means of producing new animal models that are potentially useful for studying clinical disorders in man

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Prevalence of Antibody to Hepatitis C Virus in Saudi Blood Donors

The prevalence of antibodies to hepatitis C virus (anti-HCV) was retrospectively determined using a second generation enzyme immunoassay in 3868 blood donors from the southern part of Saudi Arabia in an area with high prevalence of hepatitis B virus (HBV) infection. Of 3354 Saudis, 48 (1.43%) were seropositive for anti-HCV. A high prevalence (43 of 204, 21.08%) of anti-HCV was observed among Egyptian donors compared with Saudis (1.43%) and other nationalities (eight of 310, 2.58%). Furthermore, the prevalence of anti-HCV antibodies was observed to increase with age, peaking in the 25 to 34 year age group. From this and other studies conducted in different regions of Saudi Arabia, the prevalence of anti-HCV among Egyptian donors appears to range from 19.2 to 24.5%, and among Saudi donors appears to range from 1.00 to 1.7%, a rate similar to that reported from western countries; this latter rate does not seem to be influenced by the high prevalence of HBV infection in this region

Solvent-Dependent Excited-State Hydrogen Transfer and Intersystem Crossing in 2‑(2′-Hydroxyphenyl)-Benzothiazole

The excited-state intramolecular hydrogen transfer (ESIHT) of 2-(2′-hydroxyphenyl) benzothiazole (HBT) has been investigated in a series of nonpolar, polar aprotic, and polar protic solvents. A variety of state-of-the-art experimental methods were employed, including femto- and nanosecond transient absorption and fluorescence upconversion spectroscopy with broadband capabilities. We show that the dynamics and mechanism of ESIHT of the singlet excited HBT are strongly solvent-dependent. In nonpolar solvents, the data demonstrate that HBT molecules adopt a closed form stabilized by O–H···N chelated hydrogen bonds with no twisting angle, and the photoinduced H transfer occurs within 120 fs, leading to the formation of a keto tautomer. In polar solvents, owing to dipole–dipole cross talk and hydrogen bonding interactions, the H transfer process is followed by ultrafast nonradiative deactivation channels, including ultrafast internal conversion (IC) and intersystem crossing (ISC). This is likely to be driven by the twisting motion around the C–C bond between the hydroxyphenyl and thiazole moieties, facilitating the IC back to the enol ground state or to the keto triplet state. In addition, our femtosecond time-resolved fluorescence experiments indicate, for the first time, that the lifetime of the enol form in ACN is approximately 280 fs. This observation indicates that the solvent plays a crucial role in breaking the H bond and deactivating the excited state of the HBT. Interestingly, the broadband transient absorption and fluorescence up-conversion data clearly demonstrate that the intermolecular proton transfer from the excited HBT to the DMSO solvent is about 190 fs, forming the HBT anion excited state

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia:Novel Mutations in PHEX and SLC34A3

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood