Impact of the COVID-19 pandemic on clinical research in hospitals: observational study in the first epicenter of the epidemic during the general lockdown in France.

OBJECTIVE: The COVID-19 epidemic has had a strong impact on the entire healthcare sector in France with priority being given to research for new therapeutic options for COVID-19. Nevertheless, continuity of care for patients suffering from other diseases represents a crucial challenge, and clinical research is no exception in this respect. This study aims to assess the impact of the strict Covid-19 lockdown on non-Covid-19 clinical research in the French University Hospital of Strasbourg. MATERIALS AND METHODS: Clinical research activity (non-Covid-19) from the point of view of pharmacy department was estimated and compared to the pre-lockdown period. The impact of lockdown was assessed through five indicators: site initiation visits, the initiation of experimental therapies in non-Covid-19 patients, the delivery of non-Covid-19 investigational medical products, the number of drug shipments to patients' homes, and the number of monitoring or closure visits. RESULTS: During the study period, the number of site initiation visits decreased by 90%, total inclusions by 72%, and delivery of investigational medical products by 30%. During the lockdown period, 15 treatments were sent to patients' homes. Monitoring activity decreased by 98%. CONCLUSIONS: Although the COVID-19 outbreak has created an incredible momentum in the field of clinical research, research not focused on SaRS-CoV-2 has suffered greatly from this situation. The impact on patients is difficult to estimate but should be further investigated.

Genome-wide analysis of p53-regulated transcription in Myc-driven lymphomas.

The tumour suppressor p53 is a transcription factor that controls cellular stress responses. Here, we dissected the transcriptional programmes triggered upon restoration of p53 in Myc-driven lymphomas, based on the integrated analysis of p53 genomic occupancy and gene regulation. p53 binding sites were identified at promoters and enhancers, both characterized by the pre-existence of active chromatin marks. Only a small fraction of these sites showed the 20 base-pair p53 consensus motif, suggesting that p53 recruitment to genomic DNA was primarily mediated through protein-protein interactions in a chromatin context. p53 also targeted distal sites devoid of activation marks, at which binding was prevalently driven by sequence recognition. In all instances, the relevant motif was the canonical unsplit consensus element, with no clear evidence for p53 recruitment by split motifs. At promoters, p53 binding to the consensus motif was associated with gene induction, but not repression, indicating that the latter was most likely indirect. Altogether, our data highlight key features of genome recognition by p53 and provide unprecedented insight into the pathways associated with p53 reactivation and tumour regression, paving the way for their therapeutic application.

Improving physical and mental health in frontline mental health care providers: Yoga-based stress management versus cognitive behavioral stress management.

The need for brief, low-cost, easily disseminable and effective interventions to promote healthy lifestyles is high. This is especially true for mental health providers. We developed two studies to compare the impacts of Cognitive Behavioral Stress Management (CBSM) and Yoga Based Stress Management (YBSM) interventions for healthcare professionals. Study 1 offered an 8-week YBSM intervention to 37 mental healthcare participants and collected health data pre and post. Study 2 offered YBSM and CBSM classes to 40 randomly assigned mental healthcare providers and collected mental and physical health data at four time points. In Study 1, using t-tests, the YBSM intervention affected a number of mental and physical wellbeing indices pre to post. In Study 2, using linear mixed modeling, both YBSM and CBSM groups improved significantly (p <.05) in fruit and vegetable intake, heart rate, alcohol consumption, relaxation and awareness, professional quality of life, compassion satisfaction, burnout, depression, and stress levels. There was a group by time effect for coping confidence (CBSM increased more, p<.05, F = 4.34), physical activity (YBSM increased more, p<.05, F = 3.47), overall mental health (YBSM increased more, p<.10, F =5.32), and secondary traumatic stress (YBSM decreased more, p<.10, F = 4.89). YBSM and CBSM appear to be useful for healthcare professionals' mental and physical health. YBSM demonstrates some benefit above and beyond the extremely well-studied and empirically supported CBSM, including increased physical activity, overall mental health, and decreased secondary traumatic stress benefits.

Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors.

Inhibition of bromodomain and extraterminal motif (BET) proteins such as BRD4 bears great promise for cancer treatment and its efficacy has been frequently attributed to Myc downregulation. Here, we use B-cell tumors as a model to address the mechanism of action of JQ1, a widely used BET inhibitor. Although JQ1 led to widespread eviction of BRD4 from chromatin, its effect on gene transcription was limited to a restricted set of genes. This was unlinked to Myc downregulation or its chromatin association. Yet, JQ1-sensitive genes were enriched for Myc and E2F targets, were expressed at high levels, and showed high promoter occupancy by RNAPol2, BRD4, Myc and E2F. Their marked decrease in transcriptional elongation upon JQ1 treatment, indicated that BRD4-dependent promoter clearance was rate limiting for transcription. At JQ1-insensitive genes the drop in transcriptional elongation still occurred, but was compensated by enhanced RNAPol2 recruitment. Similar results were obtained with other inhibitors of transcriptional elongation. Thus, the selective transcriptional effects following JQ1 treatment are linked to the inability of JQ1-sensitive genes to sustain compensatory RNAPol2 recruitment to promoters. These observations highlight the role of BET proteins in supporting transcriptional elongation and rationalize how a general suppression of elongation may selectively affects transcription.

[Eye lens radiation exposure during ureteroscopy with and without a face protection shield: Investigations on a phantom model]. / Strahlenbelastung der Augenlinse bei ureterorenoskopischen Eingriffen ohne und mit Strahlenschutzvisier : Untersuchungen an einem Phantommodell.

BACKGROUND AND OBJECTIVES: Eye lens radiation exposure during radiologically-guided endoscopic procedures may result in radiation-induced cataracts; therefore, we investigated the ocular radiation exposure during ureteroscopy on a phantom model. MATERIALS AND METHODS: Using an Alderson phantom model and eye lens dosimeters, we measured the ocular radiation exposure depending on the number of X-ray images and on the duration of fluoroscopic imaging. The measurements were done with and without using a face protection shield. RESULTS: We could demonstrate that a significant ocular radiation exposure can occur, depending on the number of X-ray images and on the duration time of fluoroscopy. Eye lens doses up to 0.025 mSv were recorded even using modern digital X-ray systems. Using face protection shields this ocular radiation exposure can be reduced to a minimum. CONCLUSION: The International Commission on Radiological Protection (ICRP) recommendations of a mean eye lens dosage of 20 mSv/year may be exceeded during repeated ureteroscopy by a high volume surgeon. Using a face protection shield, the eye lens dose during ureteroscopy could be reduced to a minimum in a phantom model. Further investigations will show whether these results can be transferred to real life ureteroscopic procedures.

Industrial hemp decreases intestinal motility stronger than indian hemp in mice.

BACKGROUND: Indian hemp has shown beneficial effects in various gastrointestinal conditions but it is not widely accepted due to high content of tetrahydrocannabinol resulting in unwanted psychotropic effects. AIM: Since industrial hemp rich in cannabidiol lacks psychotropic effects the aim of research was to study the effects of industrial hemp on intestinal motility. MATERIALS AND METHODS: Animals were randomly divided in six groups (each group consisting of 6 animals): Control group, Cind group - receiving indian hemp infuse for 20 days, Cids group-receiving industrial hemp infuse for 20 days, M group - treated with single dose of morphine (5 mg/kg i.m.) Cind+M group - treated with indian hemp infuse and single dose of morphine (5 mg/kg i.m.), Cids+M - treated with industrial hemp infuse and single dose of morphine (5 mg/kg i.m.). On the 20th day of the study animals were administered charcoal meal, and were sacrificed 35 minutes after administration. Intestinal motility was estimated according to distance between carbo medicinalis and cecum in centimeters. RESULTS: Decrease of intestinal motility in animals treated with indian hemp infuse was not significant compared to controls and it was smaller compared to animals treated with morphine (Indian hemp =15.43±10.5 cm, morphine = 20.14±5.87 cm). Strongest decrease of intestinal motility was recorded in animals treated with industrial hemp infuse, and it was significant compared to controls and morphine (industrial hemp = 26.5±9.90 cm, morphine = 20.14±5.87 cm; p < 0.005). CONCLUSIONS: Although not completely without psychotropic activity cannabidiol could be a potential replacement for tetrahydrocannabinol. Since industrial hemp infuse rich in cannabidiol reduces intestinal motility in healthy mice cannabidiol should be further evaluated for the treatment of intestinal hypermotility.

Beta-lactam antibiotics during pregnancy: a cross-sectional comparative study Zagreb-Novi Sad.

BACKGROUND AND OBJECTIVES: During pregnancy, a number of changes occur in women's body, and some medications are safe and some are not. The aim of our study was to establish the possible correlation between use of beta-lactam antibiotics in pregnancy and occurrence of congenital malformations. MATERIAL AND METHODS: The study included 893 pregnant women from Zagreb and 6099 pregnant women from Novi Sad. 527 pregnant women used beta-lactams. First part of the study (one month study) was performed at four maternity hospitals in Zagreb, Croatia. Second part were collected as a part of the study analysing the teratogenicity of drugs used in pregnancy, a longitudinal study performed in Novi Sad district. RESULTS: Pregnant women most frequently used antibacterial agents in the first trimester of pregnancy. They used 15 different antibacterial medications, most often beta-lactams. In Zagreb arm, out of the total number of pregnant women that used medications during pregnancy (859), 231 (26.9%) used beta-lactam antibiotics. Malformations were detected in 8 (3.5%) cases. The prevalence of malformations in newborns whose mothers did not take beta-lactam antibiotics in pregnancy (662) was 2.7% (18 newborns with malformations). In Novi Sad arm, out of the total number of pregnant women that used medications during pregnancy (2013), 296 (14.7%) used beta-lactam antibiotics. Malformations were detected in 14 (4.7%) cases. The prevalence of malformations in newborns whose mothers did not take beta-lactam antibiotics in pregnancy (5803) was 1.7% (99 newborns with malformations). DISCUSSION: The results show possible teratogenic potential even with those antibacterials which are considered safe (amoxicillin) but as those are usually minor malformations they often pass undetected. International pharmacoepidemiological studies of drug use in pregnancy could substantially contribute to the improvement of pharmacotherapy, and could be of great help in assessing the fetal risks.

Tolerability and toxicity of lipidosterolic extract of American dwarf palm Serenoa repens in Wistar rats: well-known extract, new insight.

BACKGROUND AND OBJECTIVES: Serenoa repens extracts (SrE) have been used for centuries in the treatment of benign prostatic hyperplasia (BPH). According to recommendations that each product should be examined separately, including its tolerability and toxicity, we conducted this study in order to broaden the current cognition about tolerability and toxicity of SrE, in particular of German brand ProstamolunoR. MATERIALS AND METHODS: Twenty-four adult male Wistar rats were randomly distributed into 4 groups of 6 animals. The first control group (O) received water (1 ml/kgBW) and second control group (OO) received olive oil (1 ml/kgb.w.) every day for 30 days. The third and fourth group of rats (SR5 and SR10) were treated with SrE (150 and 300 mg/kgb.w. daily) dissolved in olive oil. Tolerability and toxicity of SrE were estimated on the basis of daily monitoring of behavior, body weight gain (BWG), relative weight of liver, left kidney, prostate and left testis, and values of general biochemical parameters. Total liver proteins (TLP) and glutathione content in hepatocyte suspension were also determined. RESULTS: BWG was significantly unchanged in SR5 and SR10 compared to both controls in all intervals of measurement and at the end of treatment (p > 0.05). LW/BW ratio was significantly higher in SR10 compared with O (p < 0.01). Creatinine and potassium were significantly higher in SR5 compared to O (p < 0.05), but in SR10 were significantly higher compared to both control groups (p < 0.01). TLP content was significantly higher in SR5 compared to OO (p < 0.01). The content of glutathione in homogeneous suspension of hepatocytes didn't alter significantly. CONCLUSIONS: Obtained results have expanded the current state of knowledge about the tolerability and toxicity of SrE, in particular of Prostamol-unoR. For the adoption of a more precise conclusion about its tolerability and toxicity, it should be excluded possible limiting factors that we identified in this study.

Pharmacodynamic action of a commercial preparation of the mushroom Coprinus comatus in rats.

The pharmacodynamic effect of a 7-day oral treatment with a suspension of Coprinus comatus at doses of 0.835 and 1.670 g/kg in rats was studied. Changes in body weight, bile secretion and hypoglycaemic action were examined together with antipyretic activity and paw oedema tests. Such treatments resulted in a significantly lower increase in the body weight of tested animals (15.73 ± 8.36 g/rat in the untreated group, 8.44 ± 8.23 g/rat (p < 0.05) and 3.18 ± 7.93 g/rat (p < 0.05), for C. comatus 0.835 and 1.67 g/kg, respectively). Hypoglycaemic action was evident only in the glucose load test (6.79 ± 0.61 to 9.70 ± 1.16 (p < 0.05) in the untreated group and 6.47 ± 0.35 to 7.27 ± 0.76 for C. comatus 1.67 g/kg). Histological examination of pancreas cross-sections suggested certain protective functions of the mushroom suspension in alloxan poisoning. In the antipyretic test, a significantly lower increase in body temperature was observed in the mushroom-pretreated rats. In the paw oedema test, no decrease in oedema induced by formalin injection was observed following treatment with C. comatus.

Interaction of diclofenac and ketoprofen with cardioactive drugs in rats.

The interaction of diclofenac and ketoprofen, both applied intraperitoneally in a dose of 8 mg/kg for twenty-eight days, was assessed with cardioactive drugs in rats. Interaction was assessed on the basis of ECG records after the infusion of adrenaline, verapamil or lidocaine to the rats treated with diclofenac or ketoprofen vs control. The infusion time was measured in seconds to the moment of the appearance of the first heart reaction to the infusion of the cardioactive drug, then to the appearance of more frequent changes in the ECG record, and finally, to the occurrence of the toxic effect. It was also measured the plasma concentrations of sodium and potassium ions. As well as diclofenac and ketoprofen concentration, 2 hours after single and 28th dose. ECG patterns revealed no occurrence of cardiotoxic action of diclofenac and ketoprofen. The treatment with diclofenac caused significantly lower sodium plasma concentrations whereas the concentration of potassium was increased. Diclofenac concentrations were the same after a single and multiple doses, whereas concentrations of ketoprofen were significantly higher after a single dose than after its multiple applications.

The effect of early administration of glucocorticoids on learning and spatial memory.

Synthetic glucocorticoids are commonly administered to early low-birth weight infants to prevent the onset of chronic lung disease. During this period, the brain is undergoing significant structural and functional changes and is therefore particularly vulnerable to external influences. It has been observed that steroids administered postnatally may have transient retarding effect on learning and memory functions, and that animal age and sex may modify such effects. This study aims to illustrate the effect of early administration of glucocorticoids on learning and spatial memory. Wistar rat pups were grouped into two [control and treatment] of six pups each. 0.5 mg/kg of dexamethasone was administered to four day old pups for a period of three days. At 35 days the pups were subjected to spatial memory testing. Spatial memory was assessed using a Y-Maze. It was observed that the animals in the treatment group preferred to return to the start arm or explore the other arm. This is indicative of impaired spatial memory. Steroids administered postnatally may have transient retarding effect on learning and memory functions.

Anti-nociceptive and anti-inflammatory properties of 5alpha-reductase inhibitor finasteride in experimental animals.

Finasteride is a potent drug which has been prescribed for the management of benign prostatic hyperplasia (BPH) for more than 20 years. Recent studies indicate that finasteride, as 5alpha-reductase inhibitor, can influence some central effects such as analgesia, neurosteroidogeneses and behavior. The purpose of this study was to investigate the analgesic effect of finasteride, to determine whether finasteride interact with morphine analgesia in tail-flick test and to examine the anti-inflammatory effect of this drug. Adult male Wistar rats (280-330 g) were used for the both of experiments. Tests were assessed on groups of 6 animals. The first control group (O) received water (1 ml/kg, p.o.), the second control group (OO) received the vehicle (olive oil, 1 ml/kg, p.o.) and the third group (F) received finasteride (0.5 mg/kg, p.o.) suspended in olive oil, every morning for 30 days. After 30 days of treatment, tail-flick test and formalin-induced foot paw edema test were performed. Finasteride increased the average latency in seconds in comparison to both controls (10.06 vs. 9.16 and 8.66 s). It was 9.83% higher depression of pain in group F in comparison to O and 16.17% in comparison to OO, but the anti-nociceptive effect of finasteride at applied dose didn't significantly differ compared to both controls (p > 0.05). Chronic pre-treatment with finasteride didn't interact with analgesic effect of morphine compared to O (p > 0.05), but compared to OO finasteride fastened, increased and prolonged the analgesic effect of morphine at all measuring intervals, achiving statistical significance in 60 min (p < 0.01). Finasteride also exhibited significant anti-inflammatory action (p < 0.05) in comparison to OO, but It was not significantly different from the control O. Finasteride didn't exert analgesic action, it increased morphine antinociception and showed chronic anti-inflammatory effect to some extent. This might be a useful contribution to highlight the pathogenesis of BPH. There is the need for further studies in order to confirm these results with more details.

Thyroid hormone: a "prime suspect" in human immunodeficiency virus (HIV/AIDS) patients?

Acquired Immunodeficiency Syndrome (AIDS) is the final and most serious stage of the disease caused by human immunodeficiency virus. The Immune system is the target of AIDS. We investigate presently any possible involvement of thyroid hormone, the deficiency of which gives rise to oedema and susceptibility to nonspecific infections; with a view to finding the primary factor seeding the disease. It has been reported that circumcision reduced the incidence of HIV/AIDS infection. Beyond circumcision however there might be some constitutional factor that comprises HIV infection to clinical AIDS. It is against this background that our research team turned to possible dyshormonopoisis and to thyroid hormone as a prime suspect among other possible factors that cause clinical AIDS. Moreover the hormone has been reported to be crucial for optimum immune function. A population of 200 seropositive AIDS patients were investigated against a control of 50 subjects made up of 25 healthy circumcised males and 25 healthy females; all of who were seronegative for the disease. The parameters investigated include thyrotropin (TSH), Thyroxine (T4), Total protein (TP), Albumin (Alb), Globulin (Glob), Immune complex (IC3) and Bence Jones proteins (BJP) levels in serum or urine. All seropositive clinically HIV/AIDS patients were hypothyroid. Seronegatives had significantly higher T4, TP, and Alb levels at P < 0.001 and P < 0.05 for Glob than seropositives. Seropositive females exhibited significant (P < 0.001) higher levels of IC3 than seronegative males. The globulin levels of all HIV patients were significantly (P < 0.05) higher than control. BJP was also isolated in the urine of patients. The findings suggest that thyroid hormone deficiency is a primary culprit for the other inert or dormant factors to be activated.

Ketoprofen is superior to metamizole in relieving postoperative pain after head and neck tumor operation.

PURPOSE: Recently, nonsteroidal analgoantipyretics are recommended in the management of postoperative pain, with great attention to their safety. We conducted a randomized, single blind study to compare the analgesic efficacy and safety of ketoprofen and dipyrone (metamizole) after major head and neck surgery. PATIENTS AND METHODS: 60 patients received postoperatively 100 mg ketoprofen or 2.5 g metamizole i.v. every 8h over 72h with additional administration of tramadol in case of inadequate analgesia. Pain was assessed by visual numeric scale every 2h during the 72h. RESULTS: Patients in both groups had similar pain score during the first 2 postoperative days, while on the 3rd postoperative day patients in the ketoprofen group had significantly lower pain score (p <0.05). CONCLUSION: The efficacy of ketoprofen to achieve postoperative analgesia was comparable to metamizole during the first 48h, while ketoprofen was superior to metamizole during the 3rd postoperative day.

Influence of pregnancy on ceftriaxone, cefazolin and gentamicin pharmacokinetics in caesarean vs. non-pregnant sectioned women.

OBJECTIVE: To study the effect of pregnancy on postoperative ceftriaxone, cefazolin and gentamicin elimination rate constant, half-life, volume of distribution and systemic clearance. METHODS: Fifty-four patients undergoing caesarean section and 12 undergoing gynaecological surgery were given intravenous dose of ceftriaxone, cefazolin or gentamicin immediately before the operation, for chemoprophylaxis. The levels of antibiotics were measured in blood plasma, amniotic fluid and umbilical cord blood plasma by HPLC for the cephalosporins and by fluorescence polarization immunoassay for gentamicin. Pharmacokinetic parameters were estimated using a one-compartment model. RESULTS: Pregnancy significantly influenced the pharmacokinetics of ceftriaxone and gentamicin, but not that of cefazolin. Ceftriaxone constant of elimination decreased statistically significantly in caesarean-sectioned women relative to the non-pregnant subjects. Gentamicin constant of elimination increased significantly in caesarean-sectioned women relative to the controls. The concentrations of antibiotics in umbilical cord blood were higher, whereas they were substantially lower in amniotic fluid than in maternal plasma. Six hours after antibiotic administration, only the cefazolin concentrations exceeded the MIC for sensitive bacteria both in pregnant and in non-pregnant patients. CONCLUSION: Analysis of the pharmacokinetic data suggests that a single-dose of cefazolin may well be the optimal preoperative prophylactic treatment for obstetrical and gynaecological surgical procedures.

The influence of dexamethasone in the decrease of chemotherapy-induced nausea and vomiting.

PURPOSE: The aim of this study was to determine the influence of dexamethasone in the decrease of cisplatin and etoposide-induced nausea and vomiting in patients treated for lung cancer during and after 2 chemotherapy cycles. PATIENTS AND METHODS: The analysis included 60 patients with histologically proven lung cancer, who were divided in two groups. Group A consisted of 30 patients who received cisplatin and etoposide with standard antiemetic drugs: ondansetron [serotonin receptor antagonist (5-HT(3) antagonist)] and metoclopramide (dopamine receptor antagonist). Group B consisted of 30 patients who received the same chemotherapy regimen with the previous antiemetic therapy plus dexamethasone 8 mg intravenously (i.v.) per day during the 3 days of chemotherapy. During and after the 3-day therapy, patients filled in a questionnaire issuing adverse effects of chemotherapy concerning many symptoms including nausea and vomiting. The results were statistically processed. RESULTS: There was a significant decrease in the frequency and toxicity of nausea, acute and delayed vomiting in the group of patients who received antiemetic treatment with ondansetron, metoclopramide plus dexamethasone. CONCLUSION: Dexamethasone administered with 5-HT(3) antagonists and dopamine receptor antagonists significantly decreases the chemotherapy-induced nausea and vomiting.