The role of the notch signalling pathway in vascular smooth muscle cell apoptosis

The Notch signalling system is a highly conserved method of cell-to-cell communication involved in cell fate decisions in many cell types. Until recently, the importance of the Notch signalling pathway was recognized in the embryonic but not in the adult vasculature. This project has successfully identified the presence of components of this pathway in adult vascular smooth muscle cells (VSMC). The effect of this pathway on serum deprivation- and cyclic strain-induced VSMC apoptosis has also been determined. This study reports that over-expression of components of the Notch signalling pathway results in a decrease in serum deprivation-induced VSMC apoptosis, whereas endogenous inhibition of the pathway increases apoptosis in these cells. The effect of the Notch signalling pathway on VSMC apoptosis is mediated, at least in part, in a CBF-1-dependent manner. A possible mechanism of the Notch signalling pathway regulation of apoptosis is through interaction with members of the Bcl-2 family of apoptotic proteins. Notch over-expression decreases pro-apoptotic bax, and increases anti-apoptotic bcl-xi expression in VSMC in a CBF-1-dependent manner. In addition, this study has shown previously unreported interaction of the Notch and NFkB signalling pathways in VSMC. Additionally, the effect of cyclic strain, a biomechanical force increased in many vascular disease states, was determined on components of the Notch signalling pathway and also on VSMC apoptosis. Increased cyclic strain results in decreased Notch signalling pathway component expression, and increased apoptosis. Over-expression of the Notch receptor, Notch 3, attenuates the cyclic strain-induced apoptosis in a bcl-xi-caspase 3-dependent manner. In vivo validation of the effects of altered biomechanical forces was performed through analysis of carotid artery, and hepatic portal vein, ligation models. In correlation with the in vitro results obtained, increased alterations in cyclic strain results in an inverse relationship between the Notch signalling pathway and apoptosis in the vessel. These findings may be relevant in the future management of vascular diseases

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Developing a Diagnostic Multivariable Prediction Model for Urinary Tract Cancer in Patients Referred with Haematuria: Results from the IDENTIFY Collaborative Study

377siBackground: Patient factors associated with urinary tract cancer can be used to risk stratify patients referred with haematuria, prioritising those with a higher risk of cancer for prompt investigation. Objective: To develop a prediction model for urinary tract cancer in patients referred with haematuria. Design, setting, and participants: A prospective observational study was conducted in 10 282 patients from 110 hospitals across 26 countries, aged ≥16 yr and referred to secondary care with haematuria. Patients with a known or previous urological malignancy were excluded. Outcome measurements and statistical analysis: The primary outcomes were the presence or absence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC], and renal cancer). Mixed-effect multivariable logistic regression was performed with site and country as random effects and clinically important patient-level candidate predictors, chosen a priori, as fixed effects. Predictors were selected primarily using clinical reasoning, in addition to backward stepwise selection. Calibration and discrimination were calculated, and bootstrap validation was performed to calculate optimism. Results and limitations: The unadjusted prevalence was 17.2% (n = 1763) for bladder cancer, 1.20% (n = 123) for UTUC, and 1.00% (n = 103) for renal cancer. The final model included predictors of increased risk (visible haematuria, age, smoking history, male sex, and family history) and reduced risk (previous haematuria investigations, urinary tract infection, dysuria/suprapubic pain, anticoagulation, catheter use, and previous pelvic radiotherapy). The area under the receiver operating characteristic curve of the final model was 0.86 (95% confidence interval 0.85-0.87). The model is limited to patients without previous urological malignancy. Conclusions: This cancer prediction model is the first to consider established and novel urinary tract cancer diagnostic markers. It can be used in secondary care for risk stratifying patients and aid the clinician's decision-making process in prioritising patients for investigation. Patient summary: We have developed a tool that uses a person's characteristics to determine the risk of cancer if that person develops blood in the urine (haematuria). This can be used to help prioritise patients for further investigation.noneopenKhadhouri, Sinan; Gallagher, Kevin M.; MacKenzie, Kenneth R.; Shah, Taimur T.; Gao, Chuanyu; Moore, Sacha; Zimmermann, Eleanor F.; Edison, Eric; Jefferies, Matthew; Nambiar, Arjun; Anbarasan, Thineskrishna; Mannas, Miles P.; Lee, Taeweon; Marra, Giancarlo; Gómez Rivas, Juan; Marcq, Gautier; Assmus, Mark A.; Uçar, Taha; Claps, Francesco; Boltri, Matteo; La Montagna, Giuseppe; Burnhope, Tara; Nkwam, Nkwam; Austin, Tomas; Boxall, Nicholas E.; Downey, Alison P.; Sukhu, Troy A.; Antón-Juanilla, Marta; Rai, Sonpreet; Chin, Yew-Fung; Moore, Madeline; Drake, Tamsin; Green, James S.A.; Goulao, Beatriz; MacLennan, Graeme; Nielsen, Matthew; McGrath, John S.; Kasivisvanathan, Veeru; Chaudry, Aasem; Sharma, Abhishek; Bennett, Adam; Ahmad, Adnan; Abroaf, Ahmed; Suliman, Ahmed Musa; Lloyd, Aimee; McKay, Alastair; Wong, Albert; Silva, Alberto; Schneider, Alexandre; MacKay, Alison; Knight, Allen; Grigorakis, Alkiviadis; Bdesha, Amar; Nagle, Amy; Cebola, Ana; Dhanasekaran, Ananda Kumar; Kondža, Andraž; Barcelos, André; Galosi, Andrea Benedetto; Ebur, Andrea; Minervini, Andrea; Russell, Andrew; Webb, Andrew; de Jalón, Ángel García; Desai, Ankit; Czech, Anna Katarzyna; Mainwaring, Anna; Adimonye, Anthony; Das, Arighno; Figueiredo, Arnaldo; Villers, Arnauld; Leminski, Artur; Chippagiri, Arvinda; Lal, Asim Ahmed; Yıldırım, Asıf; Voulgaris, Athanasios Marios; Uzan, Audrey; Oo, Aye Moh Moh; Younis, Ayman; Zelhof, Bachar; Mukhtar, Bashir; Ayres, Ben; Challacombe, Ben; Sherwood, Benedict; Ristau, Benjamin; Lai, Billy; Nellensteijn, Brechtje; Schreiter, Brielle; Trombetta, Carlo; Dowling, Catherine; Hobbs, Catherine; Benitez, Cayo Augusto Estigarribia; Lebacle, Cédric; Ho, Cherrie Wing Yin; Ng, Chi-Fai; Mount, Chloe; Lam, Chon Meng; Blick, Chris; Brown, Christian; Gallegos, Christopher; Higgs, Claire; Browne, Clíodhna; McCann, Conor; Plaza Alonso, Cristina; Beder, Daniel; Cohen, Daniel; Gordon, Daniel; Wilby, Daniel; Gordon, Danny; Hrouda, David; Lau, David Hua Wu; Karsza, Dávid; Mak, David; Martin-Way, David; Suthaharan, Denula; Patel, Dhruv; Carrion, Diego M; Nyanhongo, Donald; Bass, Edward; Mains, Edward; Chau, Edwin; Canelon Castillo, Elba; Day, Elizabeth; Desouky, Elsayed; Gaines, Emily; Papworth, Emma; Yuruk, Emrah; Kilic, Enes; Dinneen, Eoin; Palagonia, Erika; Xylinas, Evanguelos; Khawaja, Faizan; Cimarra, Fernando; Bardet, Florian; Kum, Francesca; Peters, Francesca; Kovács, Gábor; Tanasescu, Geroge; Hellawell, Giles; Tasso, Giovanni; Lam, Gitte; La Montagna, Giuseppe; Pizzuto, Giuseppe; Lenart, Gordan; MacLennan, Graeme; Özgür, Günal; Bi, Hai; Lyons, Hannah; Warren, Hannah; Ahmed, Hashim; Simpson, Helen; Burden, Helena; Gresty, Helena; Rios Pita, Hernado; Clarke, Holly; Serag, Hosam; Kynaston, Howard; Crawford-Smith, Hugh; Mostafid, Hugh; Otaola-Arca, Hugo; Koo, Hui Fen; Ibrahim, Ibrahim; Ouzaid, Idir; Puche-Sanz, Ignacio; Tomašković, Igor; Tinay, Ilker; Sahibzada, Iqbal; Thangasamy, Isaac; Cadena, Iván Revelo; Irani, Jacques; Udzik, Jakub; Brittain, James; Catto, James; Green, James; Tweedle, James; Hernando, Jamie Borrego; Leask, Jamie; Kalsi, Jas; Frankel, Jason; Toniolo, Jason; Raman, Jay D.; Courcier, Jean; Kumaradeevan, Jeevan; Clark, Jennifer; Jones, Jennifer; Teoh, Jeremy Yuen-Chun; Iacovou, John; Kelly, John; Selph, John P.; Aning, Jonathan; Deeks, Jon; Cobley, Jonathan; Olivier, Jonathan; Maw, Jonny; Herranz-Yagüe, José Antonio; Nolazco, Jose Ignacio; Cózar-Olmo, Jose Manuel; Bagley, Joseph; Jelski, Joseph; Norris, Joseph; Testa, Joseph; Meeks, Joshua; Hernandez, Juan; Vásquez, Juan Luis; Randhawa, Karen; Dhera, Karishma; Gronostaj, Katarzyna; Houlton, Kathleen; Lehman, Kathleen; Gillams, Kathryn; Adasonla, Kelvin; Brown, Kevin; Murtagh, Kevin; Mistry, Kiki; Davenport, Kim; Kitamura, Kosuke; Derbyshire, Laura; Clarke, Laurence; Morton, Lawrie; Martinez, Levin; Goldsmith, Louise; Paramore, Louise; Cormier, Luc; Dell'Atti, Lucio; Simmons, Lucy; Martinez-Piñeiro, Luis; Rico, Luis; Chan, Luke; Forster, Luke; Ma, Lulin; Moore, Madeline; Gallego, Maria Camacho; Freire, Maria José; Emberton, Mark; Feneley, Mark; Antón-Juanilla, Marta; Rivero, Marta Viridiana Muñoz; Pirša, Matea; Tallè, Matteo; Crockett, Matthew; Liew, Matthew; Trail, Matthew; Peters, Max; Cooper, Meghan; Kulkarni, Meghana; Ager, Michael; He, Ming; Li, Mo; Omran Breish, Mohamed; Tarin, Mohamed; Aldiwani, Mohammed; Matanhelia, Mudit; Pasha, Muhammad; Akalın, Mustafa Kaan; Abdullah, Nasreen; Hale, Nathan; Gadiyar, Neha; Kocher, Neil; Bullock, Nicholas; Campain, Nicholas; Pavan, Nicola; Al-Ibraheem, Nihad; Bhatt, Nikita; Bedi, Nishant; Shrotri, Nitin; Lobo, Niyati; Balderas, Olga; Kouli, Omar; Capoun, Otakar; Oteo Manjavacas, Pablo; Gontero, Paolo; Mariappan, Paramananthan; Marchiñena, Patricio Garcia; Erotocritou, Paul; Sweeney, Paul; Planelles, Paula; Acher, Peter; Black, Peter C.; Osei-Bonsu, Peter K; Østergren, Peter; Smith, Peter; Willemse, Peter-Paul Michiel; Chlosta, Piotr L.; Ul Ain, Qurrat; Barratt, Rachel; Esler, Rachel; Khalid, Raihan; Hsu, Ray; Stamirowski, Remigiusz; Mangat, Reshma; Cruz, Ricardo; Ellis, Ricky; Adams, Robert; Hessell, Robert; Oomen, Robert J.A.; McConkey, Robert; Ritchie, Robert; Jarimba, Roberto; Chahal, Rohit; Andres, Rosado Mario; Hawkins, Rosalyn; David, Rotimi; Manecksha, Rustom P.; Agrawal, Sachin; Hamid, Syed Sami; Deem, Samuel; Goonewardene, Sanchia; Swami, Satchi Kuchibhotla; Hori, Satoshi; Khan, Shahid; Mohammud Inder, Shakeel; Sangaralingam, Shanthi; Marathe, Shekhar; Raveenthiran, Sheliyan; Horie, Shigeo; Sengupta, Shomik; Parson, Sian; Parker, Sidney; Hawlina, Simon; Williams, Simon; Mazzoli, Simone; Grzegorz Kata, Slawomir; Pinheiro Lopes, Sofia; Ramos, Sónia; Rai, Sonpreet; Rintoul-Hoad, Sophie; O'Meara, Sorcha; Morris, Steve; Turner, Stacey; Venturini, Stefano; Almpanis, Stephanos; Joniau, Steven; Jain, Sunjay; Mallett, Susan; Nikles, Sven; Shahzad, null; Yan, Sylvia; Lee, Taeweon; Uçar, Taha; Drake, Tamsin; Toma, Tarq; Cabañuz Plo, Teresa; Bonnin, Thierry; Muilwijk, Tim; Wollin, Tim; Chu, Timothy Shun Man; Appanna, Timson; Brophy, Tom; Ellul, Tom; Austin, Tomas; Smrkolj, Tomaž; Rowe, Tracey; Sukhu, Troy; Patel, Trushar; Garg, Tullika; Çaşkurlu, Turhan; Bele, Uros; Haroon, Usman; Crespo-Atín, Víctor; Parejo Cortes, Victor; Capapé Poves, Victoria; Gnanapragasam, Vincent; Gauhar, Vineet; During, Vinnie; Kumar, Vivek; Fiala, Vojtech; Mahmalji, Wasim; Lam, Wayne; Fung Chin, Yew; Filtekin, Yigit; Chyn Phan, Yih; Ibrahim, Youssed; Glaser, Zachary A; Abiddin, Zainal Adwin; Qin, Zijian; Zotter, Zsuzsanna; Zainuddin, ZulkifliKhadhouri, Sinan; Gallagher, Kevin M.; Mackenzie, Kenneth R.; Shah, Taimur T.; Gao, Chuanyu; Moore, Sacha; Zimmermann, Eleanor F.; Edison, Eric; Jefferies, Matthew; Nambiar, Arjun; Anbarasan, Thineskrishna; Mannas, Miles P.; Lee, Taeweon; Marra, Giancarlo; Gómez Rivas, Juan; Marcq, Gautier; Assmus, Mark A.; Uçar, Taha; Claps, Francesco; Boltri, Matteo; La Montagna, Giuseppe; Burnhope, Tara; Nkwam, Nkwam; Austin, Tomas; Boxall, Nicholas E.; Downey, Alison P.; Sukhu, Troy A.; Antón-Juanilla, Marta; Rai, Sonpreet; Chin, Yew-Fung; Moore, Madeline; Drake, Tamsin; Green, James S. A.; Goulao, Beatriz; Maclennan, Graeme; Nielsen, Matthew; Mcgrath, John S.; Kasivisvanathan, Veeru; Chaudry, Aasem; Sharma, Abhishek; Bennett, Adam; Ahmad, Adnan; Abroaf, Ahmed; Suliman, Ahmed Musa; Lloyd, Aimee; Mckay, Alastair; Wong, Albert; Silva, Alberto; Schneider, Alexandre; Mackay, Alison; Knight, Allen; Grigorakis, Alkiviadis; Bdesha, Amar; Nagle, Amy; Cebola, Ana; Dhanasekaran, Ananda Kumar; Kondža, Andraž; Barcelos, André; Galosi, Andrea Benedetto; Ebur, Andrea; Minervini, Andrea; Russell, Andrew; Webb, Andrew; de Jalón, Ángel García; Desai, Ankit; Czech, Anna Katarzyna; Mainwaring, Anna; Adimonye, Anthony; Das, Arighno; Figueiredo, Arnaldo; Villers, Arnauld; Leminski, Artur; Chippagiri, Arvinda; Lal, Asim Ahmed; Yıldırım, Asıf; Voulgaris, Athanasios Marios; Uzan, Audrey; Oo, Aye Moh Moh; Younis, Ayman; Zelhof, Bachar; Mukhtar, Bashir; Ayres, Ben; Challacombe, Ben; Sherwood, Benedict; Ristau, Benjamin; Lai, Billy; Nellensteijn, Brechtje; Schreiter, Brielle; Trombetta, Carlo; Dowling, Catherine; Hobbs, Catherine; Benitez, Cayo Augusto Estigarribia; Lebacle, Cédric; Ho, Cherrie Wing Yin; Ng, Chi-Fai; Mount, Chloe; Lam, Chon Meng; Blick, Chris; Brown, Christian; Gallegos, Christopher; Higgs, Claire; Browne, Clíodhna; Mccann, Conor; Plaza Alonso, Cristina; Beder, Daniel; Cohen, Daniel; Gordon, Daniel; Wilby, Daniel; Gordon, Danny; Hrouda, David; Lau, David Hua Wu; Karsza, Dávid; Mak, David; Martin-Way, David; Suthaharan, Denula; Patel, Dhruv; Carrion, Diego M; Nyanhongo, Donald; Bass, Edward; Mains, Edward; Chau, Edwin; Canelon Castillo, Elba; Day, Elizabeth; Desouky, Elsayed; Gaines, Emily; Papworth, Emma; Yuruk, Emrah; Kilic, Enes; Dinneen, Eoin; Palagonia, Erika; Xylinas, Evanguelos; Khawaja, Faizan; Cimarra, Fernando; Bardet, Florian; Kum, Francesca; Peters, Francesca; Kovács, Gábor; Tanasescu, Geroge; Hellawell, Giles; Tasso, Giovanni; Lam, Gitte; La Montagna, Giuseppe; Pizzuto, Giuseppe; Lenart, Gordan; Maclennan, Graeme; Özgür, Günal; Bi, Hai; Lyons, Hannah; Warren, Hannah; Ahmed, Hashim; Simpson, Helen; Burden, Helena; Gresty, Helena; Rios Pita, Hernado; Clarke, Holly; Serag, Hosam; Kynaston, Howard; Crawford-Smith, Hugh; Mostafid, Hugh; Otaola-Arca, Hugo; Koo, Hui Fen; Ibrahim, Ibrahim; Ouzaid, Idir; Puche-Sanz, Ignacio; Tomašković, Igor; Tinay, Ilker; Sahibzada, Iqbal; Thangasamy, Isaac; Cadena, Iván Revelo; Irani, Jacques; Udzik, Jakub; Brittain, James; Catto, James; Green, James; Tweedle, James; Hernando, Jamie Borrego; Leask, Jamie; Kalsi, Jas; Frankel, Jason; Toniolo, Jason; Raman, Jay D.; Courcier, Jean; Kumaradeevan, Jeevan; Clark, Jennifer; Jones, Jennifer; Teoh, Jeremy Yuen-Chun; Iacovou, John; Kelly, John; Selph, John P.; Aning, Jonathan; Deeks, Jon; Cobley, Jonathan; Olivier, Jonathan; Maw, Jonny; Herranz-Yagüe, José Antonio; Nolazco, Jose Ignacio; Cózar-Olmo, Jose Manuel; Bagley, Joseph; Jelski, Joseph; Norris, Joseph; Testa, Joseph; Meeks, Joshua; Hernandez, Juan; Vásquez, Juan Luis; Randhawa, Karen; Dhera, Karishma; Gronostaj, Katarzyna; Houlton, Kathleen; Lehman, Kathleen; Gillams, Kathryn; Adasonla, Kelvin; Brown, Kevin; Murtagh, Kevin; Mistry, Kiki; Davenport, Kim; Kitamura, Kosuke; Derbyshire, Laura; Clarke, Laurence; Morton, Lawrie; Martinez, Levin; Goldsmith, Louise; Paramore, Louise; Cormier, Luc; Dell'Atti, Lucio; Simmons, Lucy; Martinez-Piñeiro, Luis; Rico, Luis; Chan, Luke; Forster, Luke; Ma, Lulin; Moore, Madeline; Gallego, Maria Camacho; Freire, Maria José; Emberton, Mark; Feneley, Mark; Antón-Juanilla, Marta; Rivero, Marta Viridiana Muñoz; Pirša, Matea; Tallè, Matteo; Crockett, Matthew; Liew, Matthew; Trail, Matthew; Peters, Max; Cooper, Meghan; Kulkarni, Meghana; Ager, Michael; He, Ming; Li, Mo; Omran Breish, Mohamed; Tarin, Mohamed; Aldiwani, Mohammed; Matanhelia, Mudit; Pasha, Muhammad; Akalın, Mustafa Kaan; Abdullah, Nasreen; Hale, Nathan; Gadiyar, Neha; Kocher, Neil; Bullock, Nicholas; Campain, Nicholas; Pavan, Nicola; Al-Ibraheem, Nihad; Bhatt, Nikita; Bedi, Nishant; Shrotri, Nitin; Lobo, Niyati; Balderas, Olga; Kouli, Omar; Capoun, Otakar; Oteo Manjavacas, Pablo; Gontero, Paolo; Mariappan, Paramananthan; Marchiñena, Patricio Garcia; Erotocritou, Paul; Sweeney, Paul; Planelles, Paula; Acher, Peter; Black, Peter C.; Osei-Bonsu, Peter K; Østergren, Peter; Smith, Peter; Willemse, Peter-Paul Michiel; Chlosta, Piotr L.; Ul Ain, Qurrat; Barratt, Rachel; Esler, Rachel; Khalid, Raihan; Hsu, Ray; Stamirowski, Remigiusz; Mangat, Reshma; Cruz, Ricardo; Ellis, Ricky; Adams, Robert; Hessell, Robert; Oomen, Robert J. A.; Mcconkey, Robert; Ritchie, Robert; Jarimba, Roberto; Chahal, Rohit; Andres, Rosado Mario; Hawkins, Rosalyn; David, Rotimi; Manecksha, Rustom P.; Agrawal, Sachin; Hamid, Syed Sami; Deem, Samuel; Goonewardene, Sanchia; Swami, Satchi Kuchibhotla; Hori, Satoshi; Khan, Shahid; Mohammud Inder, Shakeel; Sangaralingam, Shanthi; Marathe, Shekhar; Raveenthiran, Sheliyan; Horie, Shigeo; Sengupta, Shomik; Parson, Sian; Parker, Sidney; Hawlina, Simon; Williams, Simon; Mazzoli, Simone; Grzegorz Kata, Slawomir; Pinheiro Lopes, Sofia; Ramos, Sónia; Rai, Sonpreet; Rintoul-Hoad, Sophie; O'Meara, Sorcha; Morris, Steve; Turner, Stacey; Venturini, Stefano; Almpanis, Stephanos; Joniau, Steven; Jain, Sunjay; Mallett, Susan; Nikles, Sven; Shahzad, Null; Yan, Sylvia; Lee, Taeweon; Uçar, Taha; Drake, Tamsin; Toma, Tarq; Cabañuz Plo, Teresa; Bonnin, Thierry; Muilwijk, Tim; Wollin, Tim; Chu, Timothy Shun Man; Appanna, Timson; Brophy, Tom; Ellul, Tom; Austin, Tomas; Smrkolj, Tomaž; Rowe, Tracey; Sukhu, Troy; Patel, Trushar; Garg, Tullika; Çaşkurlu, Turhan; Bele, Uros; Haroon, Usman; Crespo-Atín, Víctor; Parejo Cortes, Victor; Capapé Poves, Victoria; Gnanapragasam, Vincent; Gauhar, Vineet; During, Vinnie; Kumar, Vivek; Fiala, Vojtech; Mahmalji, Wasim; Lam, Wayne; Fung Chin, Yew; Filtekin, Yigit; Chyn Phan, Yih; Ibrahim, Youssed; Glaser, Zachary A; Abiddin, Zainal Adwin; Qin, Zijian; Zotter, Zsuzsanna; Zainuddin, Zulkifl

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0â5·5) with an incidence of respiratory critical events of 3·1% (2·9â3·3). Cardiovascular instability occurred in 1·9% (1·7â2·1), with an immediate poor outcome in 5·4% (3·7â7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86â0·90; p<0·0001), medical history, and physical condition (1·60, 1·40â1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981â0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97â0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. Funding European Society of Anaesthesiology

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry

Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Background: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. Methods: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60&nbsp;years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions: Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death.&nbsp;The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death