Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.

Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 µM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.

Evaluation of the Addition of Angiotensin II in Patients With Shock After Cardiac Surgery at a Veterans Affairs Medical Center.

BACKGROUND: Vasoplegic shock occurs in up to 37% of cardiac surgery patients. We investigated the use of angiotensin II for treating vasoplegic shock in these patients. OBJECTIVES: We assessed clinical outcomes and mortality in patients undergoing cardiac surgery at our center between March 1, 2018 and October 31, 2020 who developed vasoplegic shock, comparing those who received angiotensin II with those who did not. METHODS: This was a retrospective chart review. Response to angiotensin II was defined as increase in or maintenance of mean arterial pressure (MAP) and decrease in background vasopressor dosage. RESULTS: Angiotensin II was administered to 7 patients (postoperatively in 4 patients [57.1%]) with vasoplegic shock and baseline norepinephrine equivalent (NEE) of 0.49 ± 0.08 µg/kg/min; 12 patients with vasoplegic shock did not receive angiotensin II. Within 3 hours of angiotensin II administration, NEE decreased by 38.0 ± 33.1%. Angiotensin patients were more likely to newly require renal replacement therapy (66.7% vs 9.1%, P = 0.03) and had a longer, although not statistically significant, postoperative stay (23.1 vs 14.0 days, P = 0.16). Despite higher NEE requirements at baseline (0.49 vs 0.30, P = 0.03) and over the next 48 hours in the angiotensin group, no between-group differences in 7-day mortality (14.3% vs 0.0%, P = 0.37) or 30-day mortality (28.6% vs 8.3%, P = 0.52) were noted. CONCLUSION AND RELEVANCE: In patients who developed vasoplegic shock after cardiac surgery, angiotensin II administration allowed immediate dosage reductions of other vasopressors while maintaining MAP. Despite its small sample size, this study adds to the paucity of data in these patients and highlights future research needs.

Novel benzo chromene derivatives: design, synthesis, molecular docking, cell cycle arrest, and apoptosis induction in human acute myeloid leukemia HL-60 cells.

A series of benzo[h]chromenes, benzo[f]chromenes, and benzo[h]chromeno[2,3-d]pyrimidines were prepared. All the newly synthesised compounds were selected by National Cancer Institute for single-dose testing against 60 cell lines. Benzo[h]chromenes 5a and 6a showed promising anti-cancer activity and selected for the five-dose testing. Compounds 5a and 6a suppressed cell growth in HL-60 by the induction of cell cycle arrest, which was confirmed using flow cytometry and Annexin V-FITC/PI assays showed at the G1/S phase by regulating the expression of CDK-2/CyclinD1, triggering cell apoptosis by activating both the extrinsic (Fas/Caspase 8) and intrinsic (Bcl-2/Caspase 3) apoptosis pathways, which were determined by the western blot. Benzo[h]chromenes 5a and 6a decreased the protein expression levels of Bcl-2, CDK-2, and CyclinD1 and increased the expression of caspase 3, caspase 8, and Fas. In silico molecular analysis of compounds 5a and 6a in CDK-2 and Bcl-2 was performed.

Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency.

Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions' intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure-activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers.

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a-c in acid medium (HCl) yielding pyrimidines 4a-c, which in turn were hydrolyzed to carboxylic acid derivatives 5a-c which were chlorinated by SOCl2 to give acyl chlorides 6a-c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a-c, 8a-c, and 9a-c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC50 measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure-activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents.

Novel 2-Thiouracil-5-Sulfonamide Derivatives: Design, Synthesis, Molecular Docking, and Biological Evaluation as Antioxidants with 15-LOX Inhibition.

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4-9) were designed and synthesized. In line with this approach, our target new compounds were prepared from methyl ketone derivative 3, which was used as a blocking unit for further synthesis of a novel series of chalcone derivatives 4a-d, thiosemicarbazone derivatives 5a-d, pyridine derivatives 6a-d and 7a-d, bromo acetyl derivative 8, and thiazole derivatives 9a-d. All compounds were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), lipid peroxidation, and 15-lipoxygenase (15-LOX) inhibition activity. Compounds 5c, 6d, 7d, 9b, 9c, and 9d demonstrated significant RSA in all three techniques in comparison with ascorbic acid and 15-LOX inhibitory effectiveness using quercetin as a standard. Molecular docking of compound 9b endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.

Surgical Reconstruction of Stage 3 and 4 Pressure Injuries: A Literature Review and Proposed Algorithm from an Interprofessional Working Group.

OBJECTIVE: Stage 3 and 4 pressure injuries (PIs) present an enormous societal burden with no clearly defined interventions for surgical reconstruction. The authors sought to assess, via literature review and a reflection/evaluation of their own clinical practice experience (where applicable), the current limitations to the surgical intervention of stage 3 or 4 PIs and propose an algorithm for surgical reconstruction. METHODS: An interprofessional working group convened to review and assess the scientific literature and propose an algorithm for clinical practice. Data compiled from the literature and a comparison of institutional management were used to develop an algorithm for the surgical reconstruction of stage 3 and 4 PIs with adjunctive use of negative-pressure wound therapy and bioscaffolds. RESULTS: Surgical reconstruction of PI has relatively high complication rates. The use of negative-pressure wound therapy as adjunctive therapy is beneficial and widespread, leading to reduced dressing change frequency. The evidence for the use of bioscaffolds both in standard wound care and as an adjunct to surgical reconstruction of PI is limited. The proposed algorithm aims to reduce complications typically seen with this patient cohort and improve patient outcomes from surgical intervention. CONCLUSIONS: The working group has proposed a surgical algorithm for stage 3 and 4 PI reconstruction. The algorithm will be validated and refined through additional clinical research.

Novel hit of DPP-4Is as promising antihyperglycemic agents with dual antioxidant/anti-inflammatory effects for type 2 diabetes with/without COVID-19.

DPP-4Is are well recognized therapy for type 2 diabetes. In spite of sharing a common mode of action, the chemical diversity among members of DPP-4Is raised the question whether structural differences may result in distinguished activities. DPP-4Is were recently explored as drug repurposing means for treatment of SARS-CoV-2 due to the urgent need for small molecule drugs for controlling infections. The use of DPP-4Is was not correlated with adverse COVID-19-related consequences among patients with type 2 diabetes. Inspired by these reasons and the importance of pyrimidinone ring as DPP-4I with both antioxidant and anti-inflammatory activities, we succeeded to prepare some novel pyrimidinone and thio-pyrimidinone derivatives, which were then screened for their antidiabetic activity and DPP-4 inhibition. In addition, their anti-inflammatory effect on LPS-stimulated RAW 264.7 cells were evaluated. Furthermore, their antioxidant activities were also tested.

Design, synthesis, ADME, biological evaluation and molecular dynamic studies of natural and synthetic remedy of Herpes simplex virus type-1.

Garlic (known as; Allium sativum) is one of the most widely used medicinal plants in the world. Allicin is the major agent of garlic that gives its known pharmacological activities as anti-inflammatory, antibacterial, antifungal, antiviral and antioxidant agent. It could be extracted from bulbs of Allium sativum by water extraction to give allicin in low yield therefore other better methods were followed for extraction such as ultrasonic-assisted method that gives good yield. Attempts to optimize allicin extraction were found with sliced garlic at 25 °C for 90 minute of extraction for maximum yield (112µg/mL). Allicin was subjected to its evaluation as anti-herpetic against herpes simplex virus 1 (HSV-1) and exhibited a promising activity compared to acyclovir which was used as a reference standard. On the other hand, a novel synthetic amantadine derivative was evaluated as antiherpetic agent and prepared from the reaction of 2-thiouracil-5-sulphonyl chloride with amantadine hydrochloride in pyridine. The synergestic effect of allicin and the amantadine derivative was evaluated against HSV-1, using both in silico molecular docking as for dynamics simulations. Thymidine kinase target enzyme was chosen to analyze any possible interactions, as well as any protein-ligand stability. Furthermore, some of properties of the potential HSV-1 thymidine kinase target inhibitor of the amantadine derivative were analyzed.

Synthesis of novel calcium channel blockers with ACE2 inhibition and dual antihypertensive/anti-inflammatory effects: A possible therapeutic tool for COVID-19.

Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2:SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition.

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking.

In an effort to discover potent anticancer agents, 2-thiouracil-5-sulfonamides derivatives were designed and synthesized. The cytotoxic activity of all synthesized compounds was investigated against four human cancer cell lines viz A-2780 (ovarian), HT-29 (colon), MCF-7 (breast), and HepG2 (liver). Compounds 6b,d-g, and 7b showed promising anticancer activity and significant inhibition of CDK2A. Moreover, they were all safe when tested on WI38 normal cells with high selectivity index for cancer cells. Flow cytometric analysis for the most active compound 6e displayed induction of cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells) and stimulated the apoptotic death of all cancer cells. Moreover, 6e was able to cause cycle arrest indirectly through enhanced expression of cell cycle inhibitors p21 and p27. Finally, molecular docking of compound 6e endorsed its proper binding to CDK2A, which clarifies its potent anticancer activity.

Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents.

Since herpes simplex virus type 1 (HSV-1) infection is so widespread, several antiviral drugs have been developed to treat it, among which are uracil nucleosides. However, there are major problems with the current medications such as severe side-effects and drug resistance. Here we present some newly synthesized cyclic and acyclic uracil nucleosides that showed very promising activity against HSV-1 compared to acyclovir.

Synthesis, biological evaluation and molecular docking studies of novel thiopyrimidine analogue as apoptotic agent with potential anticancer activity.

This study synthesizes novel 6-amino-5-cyano-4-aryl-2-mercapto pyrimidines and condensed pyrimidines analogues in order to investigate their potential activity as anticancer agents. The compounds were synthesized via one-pot condensation of p-nitrobenzaldehyde or p-anisaldehyde with malononitrile and thiourea to prepare 6-amino-5-cyano-4-aryl-2-mercaptopyrimidines series (1-9a,b). The pyrimidine analogues were biologically screened In-vitro in HepG2 and MCF-7 compared to normal WI-38. Compound 8a showed higher antiproliferative activity to MCF-7 cells with sensitivity and minimal cytotoxic effect (IC50 53.3 µM- HepG2, 12.9 µM- MCF-7 and >100 µM- WI-38). Compound 8a was able to induce 40% of total antioxidants and 60% following treatment with 50 µM of H2O2 for 3hrs as external source of oxidative stress in MCF-7. 8a was able to significantly induce early stage apoptosis of 74.37% MCF-7 and cell cycle arrest with cells accumulation in subG0-G1 phase to 69.42% and reduction of cells in G2M phase to 3.6% and high apoptotic index. Compound 8a induced over-expression of Fas receptor and Cyto C genes. Molecular docking studies suggested that 8a can bind to both phosphodiesterase 4B and 4D binding pockets and inhibit their action through network of hydrophobic interactions in Q-P pockets with preferential selectivity to PDE4B through invariant Glu443. The chemical profile and the biological results suggest that 8a can be a promising anticancer agent.

Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors.

Oxidative stress is one of the main causes of significant severe diseases. The discovery of new potent antioxidants with high efficiency and low toxicity is a great demand in the field of medicinal chemistry. Herein, we report the design, synthesis molecular modelling and biological evaluation of novel hybrids containing pyrazole, naphthalene and pyrazoline/isoxazoline moiety. Chalcones 2a-e were synthesized efficiently and were used as starting materials for synthesis of a variety of heterocycles. A novel series of pyrazoline 3a-e, phenylpyrazoline 4a-e, isoxazoline 5a-e and pyrazoline carbothioamide derivatives 6a-e were synthesized and screened for in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide radical scavenging assay as well as 15-lipoxygenase (15-LOX) inhibition activity. Compounds 3a, 4e, 5b, 5c, 6a, 6c, and 6e showed excellent radical scavenging activity in all three methods in comparison with ascorbic acid and 15-LOX inhibition potency using quercetin as standard then were subjected to in vivo study. Catalase (CAT) activity, glutathione (GSH) and malondialdehyde (MDA) levels were assayed in liver of treated rats. Compounds 5b, 5c, and 6e showed significant in vivo antioxidant potentials compared to control group at dose of 100 mg/kg B.W. Molecular docking of compound 6a endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.

Application techniques of a novel hemostat in cardiac operations: HEMOBLAST.

BACKGROUND: Postoperative bleeding complications are associated with less favorable outcomes in cardiac surgery and contribute to excessive overall healthcare costs. HEMOBLAST (Biom'up, Lyon, France) (HB) is a novel ready-to-use hemostatic powder that consists of porcine collagen, bovine chondroitin sulfate, and human pooled plasma thrombin that may help reduce surgical bleeding. AIMS: The aim of this study was to describe the techniques of application for this new combination powder-based hemostat, HB, and demonstrate its use employing photographs of application methods during cardiac procedures. MATERIALS AND METHODS: The initial 24 procedures in which HB was used at our institution included: left ventricular assist device (LVAD) insertions, lung transplants, heart transplants, aortic valve replacements, coronary artery bypass grafting, and mitral valve repair. RESULTS: Hemostasis was achieved in all cases and there were no instances of mediastinitis, sternal infections, allergic reactions, or 30-day mortality. DISCUSSION: This report describes the best methods of application of HB including use for treatment of mediastinal bleeding in a re-operative procedure in a patient on antiplatelet agents and sternal bleeding during an LVAD insertion. Proper application can facilitate excellent hemostasis using this powder. CONCLUSION: HB is a novel powder-based multiple component hemostatic agent that promotes focal or large area hemostasis. We have presented the techniques of use that are important to the successful application of HB to facilitate hemostasis.

Environmental factors controlling potentially toxic element behaviour in urban soils, El Tebbin, Egypt.

This study focuses on the assessment of surface soils from industrially polluted region (El Tebbin) of southern Cairo, Egypt. The impact of agricultural, residential and industrial land use on soils developed from Nile river sediments has significantly compromised their function. Previous evidence has shown that the food chain is contaminated and enhances risk of contaminant exposure of the residential communities. This study investigates factors controlling potentially toxic element (PTE) distribution (Co, Ni, Pb, Cd, Zn, Cr and Cu) in El Tebbin soils and provide estimates of their mobility and bioavailability. The PTE concentrations are characterised by high variability as result of the variety of natural and anthropogenic influences. Highest spatial variability is found for Zn, Cd, Pb and Cu (C.V = 260.0%, 280.4%, 140.8% and 159.6% respectively) and enrichment factors indicate strong anthropogenic inputs. For Co and Ni, relatively low spatial variability (C.V = 65.8% and 45.0% respectively) with depletion in Ni suggests a relatively minor contribution from anthropogenic sources. For Cr, a more uniform distribution pattern showing depletion to minimal enrichment across the study area (C.V = 19.2%) reflects almost exclusive lithogenic control. Using principle component analysis (PCA) to explore concentration data reveals that the major inputs affecting PTE distribution are modified by primary soil properties (texture and pH). Their relative bioavailability (identified through sequential chemical extraction) relates strongly to local input sources. Those elements dominated by lithogenic input (Ni and Co) were found predominantly in soil residual fractions (95.6% and 90.5% respectively), while elements with stronger anthropogenic contributions (Cd, Zn, Pb and Cu) showed much higher portion in the more mobile and bioavailable fractions obtained from sequential chemical extraction, with average proportions of the totals being 62.6%, 57%, 40.7% and 39.2% respectively. Those PTEs with strong anthropogenic influence are potentially much more mobile for bioaccumulation in food chain with increased health risk for exposed residents and are confirmed by elevated concentrations of Cd, Zn, Pb and Cu recorded in local plant species. The main pollution sources were further highlighted by cluster analysis and showed vehicle traffic and specific industrial activities but which varied significantly from site to site. The identification of sources through the approach developed here allows prioritisation of monitoring and regulatory decisions by the local government to reduce further environmental exposure of the local population.

Hospital Minimally Invasive Surgery Utilization for Gastrointestinal Cancer.

OBJECTIVE: The aim of the study was to evaluate the impact of receiving care at high minimally invasive surgery (MIS)-utilizing hospitals BACKGROUND:: MIS techniques are used across surgical specialties. The extent of MIS utilization for gastrointestinal (GI) cancer resection and impact of receiving care at high utilizing hospitals is unclear. METHODS: This is a retrospective cohort study of 137,581 surgically resected esophageal, gastric, pancreatic, hepatobiliary, colon, and rectal cancer patients within the National Cancer Data Base (2010-2013). Disease-specific, hospital-level, reliability-adjusted MIS utilization rates were calculated to evaluate perioperative outcomes. Among patients for whom adjuvant chemotherapy (AC) was indicated, the association between days to AC and hospital MIS utilization was examined using generalized estimating equations. Association with risk of death was evaluated using multivariable Cox regression. RESULTS: Disease-specific MIS use increased significantly [42.0%-68.3% increase; trend test, P < 0.001 for all except hepatobiliary (P = 0.007)] over time. Most hospitals [range-30.3% (colon); 92.9% (pancreatic)] were low utilizers (≤30% of cases). Higher MIS utilization is associated with increased lymph nodes examined (P < 0.001, all) and shorter length of stay (P < 0.001, all). Each 10% increase in MIS utilization is associated with fewer days to AC [3.3 (95% confidence interval, 1.2-5.3) for MIS gastric; 3.3 ([0.7-5.8) for open gastric; 1.1 (0.3-2.0) days for open colon]. An association between MIS utilization and risk of death was observed for colon [Q2-hazard ratio (HR) 0.96 (0.89-1.02); Q3-HR 0.91 (0.86-0.98); Q4-HR 0.87 (0.82-0.93)] and rectal cancer [Q2-HR 0.89 (0.76-1.05); Q3-HR 0.84 (0.82-0.97); Q4-HR 0.86 (0.74-0.98)]. CONCLUSIONS: Most hospitals treating GI malignancies are low MIS utilizers. Our findings may reflect real-world MIS effectiveness for oncologic resection and could be useful for identifying hospitals with infrastructure and/or processes beneficial for multimodality cancer care.

Robotic port-site hernias after general surgical procedures.

BACKGROUND: With the increasing use of the robotic platform in general surgery, whether 8-mm ports should be closed comes into question. We sought to characterize the incidence of port-site hernias (PSHs) among patients undergoing robotic-assisted general surgery. METHODS: A retrospective chart review of a single institutional database identified patients who underwent robotic-assisted general surgery from July 2010 to December 2016. For each patient, the number, type, location, and size of all ports were collected. Twelve-millimeter port sites were routinely closed, whereas 5-mm and 8-mm port sites were not. PSH was detected on review of documented physical examination and of postoperative cross-sectional imaging, when available, in which case it was defined as a disruption of the fascia with or without eventration of tissue at a site of prior port placement. RESULTS: One hundred and seventy-eight patients underwent robotic-assisted general surgery, with 725 total ports: 433 8-mm working ports, 72 12-mm working ports, 178 12-mm camera ports, and 42 5-mm assistant ports. Ninety-four percent of the patients were men, the mean age was 63 ± 12, body mass index was 29 ± 7 kg/m2, and the median American Society of Anesthesiologists score was 3. Types of cases included 68 rectal (38.2%), 36 colon (20.2%), 25 hepatopancreatobiliary (14.0%), 21 inguinal hernia (11.8%), and 28 "other" (15.7%) operations. At a median follow-up of 193 d, there were three PSHs through 8-mm port sites (0.7%), two PSHs through 12-mm port sites (0.8%), and no PSH through 5-mm port sites. Two of the three 8-mm PSHs occurred in the early postoperative period and required emergent repair due to small bowel incarceration. CONCLUSIONS: PSHs through 8-mm robotic port sites occur infrequently but can cause significant morbidity. Further investigation with longer follow-up is warranted to better understand the true incidence of robotic PSH.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents.

Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel. There are two hydrophobic side chains directed towards the oxygen atom in the C-4 position of the thiouracil ring. In the current study, the structural activity relationship (SAR) was performed on the thiouracil nucleus of PTU to target these hydrophobic side chains and gain more favorable interactions and, in return, more antithyroid activity. Most of the designed compounds show superiority over PTU in reducing the mean serum T4 levels of hyperthyroid rats by 3% to 60%. In addition, the effect of these compounds on the levels of serum T3 was found to be comparable to the effect of PTU treatment. The designed compounds in this study showed a promising activity profile in reducing levels of thyroid hormones and follow up experiments will be needed to confirm the use of the designed compounds as new potential antithyroid agents.

Variation and Impact of Multiple Complications on Failure to Rescue After Inpatient Surgery.

OBJECTIVE: To examine the extent to which multiple, sequential complications impacts variation in institutional postoperative mortality rates. BACKGROUND: Failure to rescue (FTR) has been proposed as an underlying factor in hospital variation in surgical mortality. However, little is currently known about hospital variation in FTR after multiple complications or the contribution of sequential complications to variation. METHODS: Retrospective cohort study of 266,101 patients within the Veterans Affairs Surgical Quality Improvement Program (2000-2014) who underwent a subset of high-mortality inpatient general, vascular, or thoracic procedures. The association between number of postoperative complications (0, 1, 2, or ≥3) and 30-day mortality across quintiles of hospital risk-adjusted mortality was evaluated with multivariable, multilevel mixed-effects models. RESULTS: Among patients who had a complication, over half (60.9%) had 1, but those with more than 1 accounted for the majority of the deaths (63.1%). Across hospital quintiles, there were no differences in complications (23.5% very low mortality vs 23.6% very high mortality; trend test P = 0.15). FTR increased significantly (12.0% vs 18.1%; trend test P < 0.001) with an incremental impact as complications accrued (6.7% 1 complication vs 26.1% ≥3, lowest quintile; 11.7% 1 complication vs 33.0% ≥3, highest quintile). However, the risk of FTR associated with increasing complications remained relatively constant across hospital quintiles and was not explained by differences in patients presenting with multiple complications on the index complicated day. CONCLUSIONS: FTR occurs predominantly among patients who have more than 1 complication with a dose-response relationship as complications accrue. As this dose-response relationship is observed across hospitals, surgical quality improvement efforts may benefit by shifting focus to broader interventions designed to prevent subsequent complications at all hospitals.