The ligational behavior of a phenolic quinolyl hydrazone towards copper(II)- ions

<p>Abstract</p> <p>Background</p> <p>The heterocyclic hydrazones constitute an important class of biologically active drug molecules. The hydrazones have also been used as herbicides, insecticides, nematocides, redenticides, and plant growth regulators as well as plasticizers and stabilizers for polymers. The importance of the phenolic quinolyl hydrazones arises from incorporating the quinoline ring with the phenolic compound; 2,4-dihydroxy benzaldehyde. Quinoline ring has therapeutic and biological activities whereas, phenols have antiseptic and disinfectants activities and are used in the preparation of dyes, bakelite and drugs. The present study is planned to check the effect of the counter anions on the type and geometry of the isolated copper(II)- complexes as well as the ligational behavior of the phenolic hydrazone; 4-[(2-(4,8-dimethylquinolin-2-yl)hydrazono)methyl] benzene-1,3-diol; (H₂L).</p> <p>Results</p> <p>A phenolic quinolyl hydrazone (H₂L) was allowed to react with various copper(II)- salts (Cl‾, Br‾, NO₃‾, ClO₄‾, AcO‾, SO₄^2-). The reactions afforded dimeric complexes (ClO₄‾, AcO‾ ), a binuclear complex (NO₃‾ ) and mononuclear complexes (the others; Cl‾, Br‾, SO₄^2-). The isolated copper(II)- complexes have octahedral, square pyramid and square planar geometries. Also, they reflect the strong coordinating ability of NO₃‾, Cl‾, Br‾, AcO‾ and SO₄^2-anions. Depending on the type of the anion, the ligand showed three different modes of bonding <it>viz</it>. (NN)⁰for the mononuclear complexes (<b>3, 4, 6</b>), (NO)^-with O- bridging for the dimeric complexes (<b>1, 5</b>) and a mixed mode [(NN)⁰+ (NO)^-with O- bridging] for the binuclear nitrato- complex (<b>2</b>).</p> <p>Conclusion</p> <p>The ligational behavior of the phenolic hydrazone (H₂L) is highly affected by the type of the anion. The isolated copper(II)- complexes reflect the strong coordinating power of the SO₄^2-, AcO‾, Br‾, Cl‾ and NO₃‾ anions. Also, they reflect the structural diversity (octahedral, square pyramid and square planar) depending on the type of the counter anion.</p

Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts

Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K+) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K+) hearts (P < 0.01): this was prevented by treatment with lidocaine (10 μM, P < 0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P < 0.05) maximal gradients (from 0.55 ± 0.14 to 2.35 ± 0.67 in the epicardium and from 0.67 ± 0.13 to 1.87 ± 0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from −2.14 ± 0.52 ms to 50.93 ± 14.45 ms in the epicardium and from 8.14 ± 1.49 ms to 44.64 ± 5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P > 0.05) on either maximal gradients (0.78 ± 0.27 in the epicardium and 0.83 ± 0.45 in the endocardium) or critical DIs (6.06 ± 2.10 ms and 7.04 ± 3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P < 0.05) both these parameters (1.05 ± 0.30 in the epicardium and 0.89 ± 0.36 in the endocardium and 30.38 ± 8.88 ms in the epicardium and 31.65 ± 4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children &lt;18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p&lt;0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p&lt;0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p&lt;0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

C9orf72 Expansion Disrupts ATM-mediated Chromosomal Break Repair

A hexanucleotide repeat expansion represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which the expansion cause neurodegeneration are poorly understood. We report elevated levels of DNA/RNA hybrids (R-loops) and double-strand breaks (DSBs) in rodent neurons, human cells, and in C9orf72-ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signalling and accumulation of protein-linked DNA breaks. We further reveal that defective ATM-mediated DNA repair is a consequence of p62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signalling. Adeno-associated virus- mediated expression of C9orf72-related RNA and dipeptide repeats in the murine central nervous system causes elevated DSBs, ATM defects, and triggers neurodegeneration. These findings identify R-Loops, DSBs, and defective ATM-mediated repair as pathological consequences of C9orf72 expansions, and suggest that C9orf72-linked neurodegeneration is driven, at least in part, by genomic instability

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication