Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates

Objectives: pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.Methods: DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.Results: increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.Conclusions: PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidate

Just Friends? : Richard Rolle and the Possibility of Christian Friendship Between Men and Women

Tutkimus käsittelee Richard Rollen (k. 1349), englantilaisen erakon ja uskonnollisen kirjailijan, käsityksiä ystävyydestä yleensä ja erityisesti hengellisestä ystävyydestä miesten ja naisten välillä. Rolle kirjoitti useita latinan- ja keskienglanninkielisiä tutkielmia ja hengellisiä oppaita, joissa hän sivusi ystävyyden tematiikkaa sekä omaelämäkerrallisesta että teoreettisesta näkökulmasta. Tutkimuksen pääasiallisina lähteinä käytetään seitsemää Rollen omaa teosta sekä kanonisoinnin toivossa hänestä laadittua pyhimyselämäkertaa. Tutkimus esittelee Rollen ystävyysteoriaa ja suhteuttaa sen 1300-luvun Yorkshiren historialliseen kontekstiin, Rollen kirjallisiin esikuviin sekä hänen ajatteluunsa yleensä. Rolle näyttää tunteneen sekä Ciceron (k. 43 eaa.) että Aelred Rievaulxlaisen (k. 1167) teokset ystävyydestä, mutta sovelsi näiden näkemyksiä omintakeisesti. Rollen maailmankuvalle oli ominaista jyrkkä kaksijakoisuus maailman ja Jumalan rakkauden välillä, minkä vuoksi ero pyhän ja maallisen ystävyyden välillä oli ehdoton. Vääränlainen ystävyys oli vaarallista etenkin kontemplatiivista elämää harjoittaville erakoille ja anakoreeteille, joita Rolle opasti välttämään ihmiskontakteja. Jyrkkyydestään huolimatta Rolle erosi edeltäjistään ja 1300-luvun valtavirrasta puolustamalla sukupuolten välisen pyhän ystävyyden mahdollisuutta. Tutkimuksen keskeinen löytö on, että Rolle määritteli sukupuolten välisen ystävyyden hengelliseksi ohjaukseksi ja perusteli siten sen tarpeellisuutta; naiset tarvitsivat pyhien miesten neuvoja pelastuakseen. Tällainen opetusystävyys ei ollut tasa-arvoinen suhde, vaan miehen tuli opastaa ja oikaista naista tämän omaksi parhaaksi. Toisaalta Rolle uskoi naisten mahdollisuuksiin saavuttaa hengellisen elämän korkeimmat asteet. Lähteet paljastavat, että Rolle tosiasiassa opasti naisia esittämänsä mallin mukaan. Tutkimus osoittaa, että yksittäisille naisille laaditut kansankieliset opaskirjeet sisältävät opetusystävyyden keskeisiä piirteitä ja noudattavat sen hierarkista logiikkaa: Rolle esiintyy välittäjänä Jumalan ja lukijan välillä houkutellen, moittien ja neuvoen lukijaa, jotta tämä saavuttaisi yhä korkeamman pyhyyden asteen. Rollen ja anakoreetti Margaret Kirkebyn välinen suhde, jota on keskiajalla ja myöhemmin pidetty esimerkkinä pyhästä ystävyydestä, näyttää myös muiden lähteiden valossa olleen hierarkkinen opetussuhde. Tutkimuksessa argumentoidaan, että Rollen kirjoittamista motivoi tarve itsepuolustukseen ja toiminnan oikeuttamiseen; hänen kontaktinsa naisiin herättivät epäilyksiä. Rolle halusi olla hengellinen auktoriteetti, mutta hänellä ei ollut luostarisääntökunnan, kerjäläisveljestön tai pappisviran tuomaa virallista tukea, joten hänen paras mahdollisuutensa itsepuolustukseen oli kirjallinen toiminta. Oikeuttaakseen toimintansa naisten parissa Rolle esitti mallin Jumalan rakkauden elävöittämästä pyhästä elämästä, johon kuului velvollisuus opettaa naisia ystävinä. Lisäksi Rollen tuli osoittaa, että hänen oma elämänsä edusti hänen puolustamaansa mallia, jonka edellytyksenä oli välinpitämättömyys maallisia houkutuksia kohtaan. Kaiken tämän takana näyttää olleen toive tasavertaisen ystävän löytämisestä: Rolle ei ollut löytänyt vertaistaan ystävää, joka olisi jakanut hänen hengelliset kokemuksensa, joten hän pyrki hengellisen ohjauksen avulla nostamaan edes yhden oppilaistaan tasolleen. On huomionarvoista, että Rolle näyttää pitäneen naisia kelvollisina kandidaatteina tällaiseen suhteeseen

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

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Vascular findings on FDG PET/CT:a pictorial review

Since its introduction into clinical practice, 2-deoxy-2-[(18)F]flu-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) has become firmly established in the field of oncological imaging, with a growing body of evidence demonstrating its use in infectious and inflammatory vascular pathologies. This pictorial review illustrates the utility of FDG PET/CT as a diagnostic tool in the investigation of vascular disease and highlights some of the more common incidental vascular findings that PET reporters may encounter on standard oncology FDG PET/CTs, including atherosclerosis, large vessel vasculitis, complications of vascular grafts, infectious aortitis and acute aortic syndromes