Identifying SARS-CoV-2 main protease inhibitors by applying the computer screening of a large database of molecules.

The outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019 affected global health. Its infection agent was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Wearing a mask, maintaining social distance, and vaccination are effective ways to prevent infection of SARS-CoV-2, but none of them help infected people. Targeting the enzymes of SARS-CoV-2 is an effective way to stop the replication of the virus in infected people and treat COVID-19 patients. SARS-CoV-2 main protease is a therapeutic target which the inhibition of its enzymatic activity prevents from the replication of SARS-CoV-2. A large database of molecules has been searched to identify new inhibitors for SARS-CoV-2 main protease enzyme. At the first step, ligand screening based on similarity search was used to select similar compounds to known SARS-CoV-2 main protease inhibitors. Then molecules with better predicted pharmacokinetic properties were selected. Structure-based virtual screening based on the application of molecular docking and molecular dynamics simulation methods was used to select more effective inhibitors among selected molecules in previous step. Finally two compounds were considered as SARS-CoV-2 main protease inhibitors.

Optimal management of severe symptomatic gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a common disorder, and empirical proton pump inhibitor (PPI) treatment is often the first step of management; however, up to 40% of patients remain symptomatic despite PPI treatment. Refractory reflux refers to continued symptoms despite an adequate trial of PPI, and management remains challenging. The differential diagnosis is important; other oesophageal (e.g. eosinophilic oesophagitis) and gastroduodenal disorders (e.g. functional dyspepsia) should be ruled out, as this changes management. A combination of clinical assessment, endoscopic evaluation and in selected cases oesophageal function testing can help characterize patients with refractory reflux symptoms into oesophageal phenotypes so appropriate therapy can be more optimally targeted. Medical options then may include adding a H2 receptor antagonist, alginates, baclofen or antidepressant therapy, and there is emerging evidence for bile acid sequestrants and diaphragmatic breathing. The demonstration of a temporal association of symptoms with reflux events on pH-impedance testing (reflux hypersensitivity) serves to focus the management on modulating oesophageal perception and reducing the reflux burden, or identifies those with no obvious pathophysiologic abnormalities (functional heartburn). Anti-reflux surgery based on randomized controlled trial evidence has a role in reflux hypersensitivity or continued pathological acid reflux despite PPI in carefully considered, fully worked up cases that have failed medical therapy; approximately two of three cases will respond but there is a small risk of complications. In patients with persistent volume reflux despite medical therapy, given the lack of alternatives, anti-reflux surgery is a consideration. Promising newer approaches include endoscopic techniques. This review aims to summarize current diagnostic approaches and critically evaluates the evidence for the efficacy of available treatments.

No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies.

STUDY QUESTION: Does ovarian stimulation affect embryo euploidy rates or live birth rates (LBRs) after transfer of euploid embryos? SUMMARY ANSWER: Euploidy rates and LBRs after transfer of euploid embryos are not significantly influenced by gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger or number of oocytes retrieved, regardless of a woman's age. WHAT IS KNOWN ALREADY: Aneuploidy rates increase steadily with age, reaching >80% in women >42 years old. The goal of ovarian stimulation is to overcome this high aneuploidy rate through the recruitment of several follicles, which increases the likelihood of obtaining a euploid embryo that results in a healthy conceptus. However, several studies have suggested that a high response to stimulation might be embryotoxic and/or increase aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis. Furthermore, a recent study demonstrated a remarkable difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors in 42 fertility centres, potentially suggesting an iatrogenic etiology resulting from different stimulation methods. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study that included 2230 in vitro fertilisation (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) cycles and 930 frozen-thawed single euploid embryo transfer (FET) cycles, performed in our centre between 2013 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 12 298 embryos were analysed for ploidy status. Women were divided into five age groups (<35, 35-37, 38-40, 41-42 and >42 years old). Outcomes were compared between different durations of stimulation (<10, 10-12 and ≥13 days), total gonadotropin dosages (<4000, 4000-6000 and >6000 IU), numbers of oocytes retrieved (<10, 10-19 and ≥20 oocytes), peak estradiol levels (<2000, 2000-3000 and >3000 pg/mL), and sizes of the largest follicle on the day of trigger (<20 and ≥20 mm). MAIN RESULTS AND THE ROLE OF CHANCE: Within the same age group, both euploidy rates and LBRs were comparable between cycles regardless of their differences in total gonadotropin dosage, duration of stimulation, number of oocytes harvested, size of the largest follicles or peak estradiol levels. In the youngest group, (<35 years, n = 3469 embryos), euploidy rates were comparable between cycles with various total gonadotropin dosages (55.6% for <4000 IU, 52.9% for 4000-6000 IU and 62.3% for >6000 IU; P = 0.3), durations of stimulation (54.4% for <10 days, 55.2% for 10-12 days and 60.9% for >12 days; P = 0.2), number of oocytes harvested (59.4% for <10 oocytes, 55.2% for 10-19 oocytes and 53.4% for ≥20 oocytes; P = 0.2), peak estradiol levels (55.7% for E2 < 2000 pg/mL, 55.4% for E2 2000-3000 pg/mL and 54.8% for E2 > 3000 pg/mL; P = 0.9) and sizes of the largest follicle (55.6% for follicles <20 mm and 55.1% for follicles ≥20 mm; P = 0.8). Similarly, in the oldest group (>42 years, n = 1157 embryos), euploidy rates ranged from 8.7% for gonadotropins <4000 IU to 5.1% for gonadotropins >6000 IU (P = 0.3), from 10.8% for <10 days of stimulation to 8.5% for >12 days of stimulation (P = 0.3), from 7.3% for <10 oocytes to 7.4% for ≥20 oocytes (P = 0.4), from 8.8% for E2 < 2000 pg/mL to 7.5% for E2 > 3000 pg/mL (P = 0.8) and from 8.2% for the largest follicle <20 mm to 8.9% for ≥20 mm (P = 0.7). LBRs after single FET were also comparable between these groups. LIMITATIONS, REASONS FOR CAUTION: Although this large study (2230 IVF/PGT-A cycles, 12 298 embryos and 930 single FET cycles) demonstrates the safety of ovarian stimulation in terms of aneuploidy and implantation potential of euploid embryos, a multi-centre study may help to prove the generalisability of our single-centre data. WIDER IMPLICATIONS OF THE FINDINGS: These findings reassure providers and patients that gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger and number of oocytes retrieved, within certain ranges, do not appear to significantly influence euploidy rates or LBRs, regardless of the woman's age. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received and there are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Differential frontal alpha oscillations and mechanisms underlying loss of consciousness: a comparison between slow and fast propofol infusion rates.

Mechanisms underlying loss of consciousness following propofol administration remain incompletely understood. The objective of this study was to compare frontal lobe electroencephalography activity and brainstem reflexes during intravenous induction of general anaesthesia, in patients receiving a typical bolus dose (fast infusion) of propofol compared with a slower infusion rate. We sought to determine whether brainstem suppression ('bottom-up') predominates over loss of cortical function ('top-down'). Sixteen ASA physical status-1 patients were randomly assigned to either a fast or slow propofol infusion group. Loss of consciousness and brainstem reflexes were assessed every 30 s by a neurologist blinded to treatment allocation. We performed a multitaper spectral analysis of all electroencephalography data obtained from each participant. Brainstem reflexes were present in all eight patients in the slow infusion group, while being absent in all patients in the fast infusion group, at the moment of loss of consciousness (p = 0.010). An increase in alpha band power was observed before loss of consciousness only in participants allocated to the slow infusion group. Alpha band power emerged several minutes after the loss of consciousness in participants allocated to the fast infusion group. Our results show a predominance of 'bottom-up' mechanisms during fast infusion rates and 'top-down' mechanisms during slow infusion rates. The underlying mechanisms by which propofol induces loss of consciousness are potentially influenced by the speed of infusion.

Assessment of Coagulase-Negative Staphylococci and Lactic Acid Bacteria Isolated from Portuguese Dry Fermented Sausages as Potential Starters Based on Their Biogenic Amine Profile.

The aim of this study was to evaluate the decarboxylase activity of coagulase-negative staphylococci (CNS) and lactic acid bacteria (LAB) involved in meat products fermentation, in order to characterize and select the strains most suitable to be used as safe starter cultures. Isolates were obtained from traditional Portuguese dry fermented meat sausages, identified by PCR and characterized according to their technological properties. Lactobacilli and enterococci were assessed for their bacteriocinogenic potential. Biogenic amines (BA) were screened by culture method and analyzed by RP-HPLC/UV. The screening method, compared with chromatographic analysis, was not reliable for CNS and LAB strains selection. Tyramine decarboxylase activity was present in CNS strains, with a slight production of amines. No other hazardous BA were produced. Among lactobacilli, moderate production of tyramine was related only to Lactobacillus curvatus, with some strains producing putrescine or 2-phenylethylamine. Enterococci were high and moderate producers of tyramine and 2-phenylethylamine, respectively. Staphylococcus xylosus, Staphylococcus equorum, and Staphylococcus carnosus, independent of their genetic and technological profiles and BA production, were adequate for use in meat products, according to the data. Lactobacillus plantarum and Lactobacillus sakei strains could also be selected for starters. PRACTICAL APPLICATION: The selection of coagulase-negative staphylococci and lactic acid bacteria (LAB) isolates were based on their production of biogenic amines in order to avoid this potential hazard production in meat products. The most suitable isolates could be used as safe starter cultures in meat products industry. The staphylococci and LAB selected will achieve particular organoleptic characteristics in meat products and bioprotection from pathogens.

A rationale for biopsying embryos reaching the morula stage on Day 6 in women undergoing preimplantation genetic testing for aneuploidy.

STUDY QUESTION: Is there a benefit to assessing ploidy in delayed embryos reaching the morula stage on Day 6 of development? SUMMARY ANSWER: Day-6 morulae should be considered for biopsy in women <40 years old undergoing preimplantation genetic testing for aneuploidy (PGT-A) because they are associated with acceptable, albeit reduced, euploidy and implantation rates (IRs). WHAT IS KNOWN ALREADY: Embryo development and morphology have been shown to correlate with aneuploidy and pregnancy rates. During PGT-A cycles, embryos are biopsied if they reach the blastocyst stage by Day 5 or 6, whereas slow-developing embryos are typically deselected and discarded. Determining the viability of slow-developing embryos is particularly relevant for women undergoing PGT-A who have diminished ovarian reserve and a relatively low blastocyst yield. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study that was performed at an academic medical center. Patients who underwent IVF with PGT-A were reviewed for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1615 cycles were reviewed. All cycles which involved a biopsy of a cavitating or compacted morula on Day 6 were included (n = 763). PGT-A was performed using array comparative genomic hybridization. The aneuploidy and implantation of morulae were compared to those of blastocysts originating from the same couples. MAIN RESULTS AND THE ROLE OF CHANCE: The study included 763 cycles in which 1260 morulae and 3014 blastocysts were biopsied. Women were divided into four age groups (<35, 35-37, 38-39 and ≥40 years): the prevalence of aneuploidy was consistently lower among blastocysts (40.3, 50.8, 56 and 78.3%, respectively) than among compacted morulae (68.7, 75.5, 88.9 and 98.1%, respectively) and cavitating morulae (57, 66.4, 81 and 91.6%, respectively) throughout the different age groups (P < 0.001). Of note, the majority of compacted morulae (98.1%) and cavitating morulae (91.6%) were aneuploid in women aged ≥40 years. Compacted and cavitating morulae had significantly higher rates of complex aneuploidy, which involves ≥3 chromosomes, compared with blastocysts (P < 0.001). Furthermore, euploid morulae were associated with a significantly lower IR (28.2 versus 54.6%; P = 0.002) and live birth rate (23.1 versus 55.0%; P = 0.001) compared to euploid blastocysts. LIMITATIONS REASONS FOR CAUTION: This study confirms that Day-6 morulae should not be discarded in young women undergoing PGT-A. However, a potential drawback of biopsying embryos at the morula stage is the inability to distinguish between inner cell mass and trophectoderm cell origin. The sample size of euploid morula transfer cycles in this study was limited. Thus, a larger cohort would be beneficial to validate the reassuring live birth and spontaneous abortion rates reported here. Furthermore, the reproducibility of our findings should be determined at different centers. WIDER IMPLICATIONS OF THE FINDINGS: Although Day-6 morulae are associated with higher aneuploidy rates and lower IRs compared to blastocysts, they still yielded successful pregnancies. Therefore, testing Day-6 morulae should be considered, especially for women <40 years old who are undergoing PGT-A with a small cohort of available blastocysts for biopsy. STUDY FUNDING/COMPETING INTEREST(S): The authors have nothing to disclose. They received no specific funding for this work. TRIAL REGISTRATION NUMBER: N/A.

Urinary retention and syndrome of inappropriate antidiuretic hormone secretion (SIADH) secondary to impacted gravid uterus.

Urinary retention is an emergency that rarely occurs during pregnancy. Previous case reports have suggested multiple risk factors that can cause the gravid uterus to become impacted in the pelvis leading to lower bladder or urethral compression with subsequent urinary retention. However, no cases of urinary obstruction in a pregnancy that was complicated with severe electrolyte imbalance have been reported. To our knowledge, we report the first case of a 31-year-old woman presenting at 8 weeks' gestation with acute urinary retention caused by a retroflexed, retroverted uterus with a 6-cm posterior uterine fibroid leading to syndrome of inappropriate antidiuretic hormone secretion and severe hyponatremia requiring intensive care unit admission. The cornerstones of effective management of urinary retention should include: (i) urgent bladder catheterization; (ii) assessment of sodium levels to rule out syndrome of inappropriate antidiuretic hormone secretion, and prompt treatment before neurological damage occurs; (iii) reduction of the impacted uterus; and (iv) monitoring for post-obstructive diuresis.

Space-time super-resolution.

We propose a method for constructing a video sequence of high space-time resolution by combining information from multiple low-resolution video sequences of the same dynamic scene. Super-resolution is performed simultaneously in time and in space. By "temporal super-resolution," we mean recovering rapid dynamic events that occur faster than regular frame-rate. Such dynamic events are not visible (or else are observed incorrectly) in any of the input sequences, even if these are played in "slow-motion." The spatial and temporal dimensions are very different in nature, yet are interrelated. This leads to interesting visual trade-offs in time and space and to new video applications. These include: 1) treatment of spatial artifacts (e.g., motion-blur) by increasing the temporal resolution and 2) combination of input sequences of different space-time resolutions (e.g., NTSC, PAL, and even high quality still images) to generate a high quality video sequence. We further analyze and compare characteristics of temporal super-resolution to those of spatial super-resolution. These include: How many video cameras are needed to obtain increased resolution? What is the upper bound on resolution improvement via super-resolution? What is the temporal analogue to the spatial "ringing" effect?

Evidence-based medicine: putting theory into practice.

Evidence-based medicine is an essential tool to ensure the effective and efficient management of patients. A practical and unbiased assessment of clinical evidence can be achieved by asking simple questions about the data. Undertaking this process can reveal a new perspective on traditional treatment approaches.

[Electrical injuries during laparoscopy]. / Les accidents électriques en coelioscopie.

Electrical injury is uncommon during surgical laparoscopy, but may be serious. Following a comprehensive literature review, we describe five mechanisms of burn injuries: direct contact, electric arc, insulation failure, direct or capacitive coupling. We discuss these mechanisms and suggest simple preventive measures designed to ensure optimal safety.

Myocardial revascularization in a hemophiliac.

The case of a mild hemophiliac who underwent a successful and uncomplicated myocardial revascularization is presented. The procedures was safely performed while the patient was receiving factor VIIIC.

Medication use review process and information systems utilized for oncology chemotherapy quality improvement.

Fatal chemotherapy overdoses at prestigious institutions have prompted extensive reviews of policies and procedures in medical centers throughout the country. Improving medication use systems for chemotherapy requires a comprehensive multidisciplinary approach. A process to develop a medical center policy on chemotherapy based on the medication use model adopted by the Joint Commission on Accreditation of Healthcare Organizations will be discussed. This will include the prescribing, preparing, dispensing, administering, and monitoring process as well as quality improvement systems. Pharmacy information systems enhancements that safeguard patients are also discussed including maximum dose checks and specific dosing algorithms for bone marrow transplant patients.

Platelet function, coagulation tests, and cardiopulmonary bypass: lack of correlation between pre-operative and intra-operative whole blood lumiaggregometry and peri-operative blood loss in patients receiving autologous platelet-rich plasma.

Platelet function and blood coagulation were studied and correlated with the post-operative red blood cell (RBC) loss in 41 patients that underwent cardiopulmonary bypass surgery. Before and after surgery, whole blood platelet aggregation and secretion were tested with different agonists, and the platelet count, prothrombin time, and activated partial thromboplastin time measured simultaneously. Post-operatively, RBC loss in chest fluid was also calculated. Platelet aggregation and secretion with different agonists (except with ristocetin and adenosine diphosphate (ADP)) were decreased significantly after protamine and platelet-rich plasma administration. There were no significant differences in aggregation and secretion immediately after cardiopulmonary bypass compared with after platelet-rich plasma administration With ADP, adenosine triphosphate (ATP) release was decreased significantly after the platelet-rich plasma infusion compared with post-protamine. Platelet count decreased significantly during surgery and remained low after platelet-rich plasma infusion. The clotting times were increased significantly after surgery, and after platelet-rich plasma infusion, the prothrombin time decreased significantly relative to the post-protamine value, the activated partial thromboplastin time being essentially unchanged. Postoperatively, the total volume of RBC collected after 36 h was 158 +/- 13 ml and there was no significant correlation with the above parameters. We conclude that pre-operative or intra-operative whole blood lumi-aggregometry is not a predictor of post-operative blood loss in patients receiving platelet-rich plasma intra-operatively.

[Early reoperation in chylothorax after thoracic surgery]. / La réintervention précoce dans les chylothorax après chirurgie thoracique.

Chylothorax is a rare complication of thoracic surgery. The chyle leak can induce serious metabolic and immunological disorders. The ideal treatment of chylothorax has not been clearly established, and opinions are still divided between medical treatment and early or late surgical reoperation after prolonged medical treatment. Out of a total of 1.750 thoracic operations performed at the Centre Chirurgical du Val d'Or over the last 10 years, six cases of chylothorax were reoperated early, an average of five days after the initial operation. The chyle leak was easy to localize in every case. The second operation was performed via the same initial incision. All six patients has an uneventful postoperative course and only one case had a persistent chyle leak which gradually resolved. The mean total hospital stay was 18 days. No systemic infections or deaths were recorded. Early reoperation avoids the complications of prolonged medical treatment, is technically easy and decreases the length of hospital stay.