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1.  Lung Protective Ventilation Induces Immunotolerance and Nitric Oxide Metabolites in Porcine Experimental Postoperative Sepsis 
PLoS ONE  2013;8(12):e83182.
Low tidal volume ventilation is beneficial in patients with severe pulmonary dysfunction and would, in theory, reduce postoperative complications if implemented during routine surgery. The study aimed to investigate whether low tidal volume ventilation and high positive end-expiratory pressure (PEEP) in a large animal model of postoperative sepsis would attenuate the systemic inflammatory response and organ dysfunction. Thirty healthy pigs were randomized to three groups: Group Prot-7h, i.e. protective ventilation for 7 h, was ventilated with a tidal volume of 6 mL x kg-1 for 7 h; group Prot-5h, i.e. protective ventilation for 5 h, was ventilated with a tidal volume of 10 mL x kg-1 for 2 h, after which the group was ventilated with a tidal volume of 6 mL x kg-1; and a control group that was ventilated with a tidal volume of 10 mL x kg-1 for 7 h. In groups Prot-7h and Prot-5h PEEP was 5 cmH2O for 2 h and 10 cmH2O for 5 h. In the control group PEEP was 5 cmH2O for the entire experiment. After surgery for 2 h, postoperative sepsis was simulated with an endotoxin infusion for 5 h. Low tidal volume ventilation combined with higher PEEP led to lower levels of interleukin 6 and 10 in plasma, higher PaO2/FiO2, better preserved functional residual capacity and lower plasma troponin I as compared with animals ventilated with a medium high tidal volume and lower PEEP. The beneficial effects of protective ventilation were seen despite greater reductions in cardiac index and oxygen delivery index. In the immediate postoperative phase low VT ventilation with higher PEEP was associated with reduced ex vivo plasma capacity to produce TNF-α upon endotoxin stimulation and higher nitrite levels in urine. These findings might represent mechanistic explanations for the attenuation of systemic inflammation and inflammatory-induced organ dysfunction.
doi:10.1371/journal.pone.0083182
PMCID: PMC3861481  PMID: 24349457
2.  Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease 
PLoS Genetics  2014;10(12):e1004801.
Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10−7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
Author Summary
Non-targeted metabolomic profiling of large population-based studies has become feasible only in the past 1–2 years and this hypothesis-free exploration of the metabolome holds a great potential to fuel the discovery of novel biomarkers for coronary heart disease (CHD). Such biomarkers are not only important for risk stratification and treatment decisions, but can also improve understanding of cardiovascular disease pathophysiology to identify new drug targets. In this study, we investigated the metabolic profiles of more than 3,600 individuals from three population-based studies, and discovered four metabolites that are consistently associated with incident CHD. We integrate genetic and metabolomic analysis to delineate the underlying biological mechanisms and evaluate potential causal effects of the novel biomarkers. Specifically, we found one metabolite to be strongly associated with single nucleotides polymorphisms previously reported for association with CHD, and consistent with a potential causal role in CHD development, as suggested by Mendelian randomization analysis.
doi:10.1371/journal.pgen.1004801
PMCID: PMC4263376  PMID: 25502724
3.  Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Kassebaum, Nicholas J | Bertozzi-Villa, Amelia | Coggeshall, Megan S | Shackelford, Katya A | Steiner, Caitlyn | Heuton, Kyle R | Gonzalez-Medina, Diego | Barber, Ryan | Huynh, Chantal | Dicker, Daniel | Templin, Tara | Wolock, Timothy M | Ozgoren, Ayse Abbasoglu | Abd-Allah, Foad | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie E | Akena, Dickens | Alasfoor, Deena | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Al Kahbouri, Mazin J | Alla, François | Allen, Peter J | AlMazroa, Mohammad A | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzmán, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Antonio, Carl A T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asad, Majed Masoud | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Basu, Arindam | Basu, Sanjay | Beardsley, Justin | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku J | Bhutta, Zulfiqar | Abdulhak, Aref Bin | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Breitborde, Nicholas | Cárdenas, Rosario | Castañeda-Orjuela, Carlos A | Castro, Ruben Estanislao | Catalá-López, Ferrán | Cavlin, Alanur | Chang, Jung-Chen | Che, Xuan | Christophi, Costas A | Chugh, Sumeet S | Cirillo, Massimo | Colquhoun, Samantha M | Cooper, Leslie Trumbull | Cooper, Cyrus | da Costa Leite, Iuri | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Degenhardt, Louisa | De Leo, Diego | del Pozo-Cruz, Borja | Deribe, Kebede | Dessalegn, Muluken | deVeber, Gabrielle A | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Dorrington, Rob E | Driscoll, Tim R | Ermakov, Sergei Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Felicio, Manuela Mendonca | Fereshtehnejad, Seyed-Mohammad | de Lima, Graça Maria Ferreira | Forouzanfar, Mohammad H | França, Elisabeth B | Gaffikin, Lynne | Gambashidze, Ketevan | Gankpé, Fortuné Gbètoho | Garcia, Ana C | Geleijnse, Johanna M | Gibney, Katherine B | Giroud, Maurice | Glaser, Elizabeth L | Goginashvili, Ketevan | Gona, Philimon | González-Castell, Dinorah | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rahul | Gupta, Rajeev | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Havmoeller, Rasmus | Hay, Simon I | Heredia Pi, Ileana B | Hoek, Hans W | Hosgood, H Dean | Hoy, Damian G | Husseini, Abdullatif | Idrisov, Bulat T | Innos, Kaire | Inoue, Manami | Jacobsen, Kathryn H | Jahangir, Eiman | Jee, Sun Ha | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kan, Haidong | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazanjan, Konstantin | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kulkarni, Chanda | Kulkarni, Veena S | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Kwan, Gene | Lai, Taavi | Lalloo, Ratilal | Lam, Hilton | Lansingh, Van C | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Xiaohong | Li, Yichong | Li, Yongmei | Liang, Juan | Liang, Xiaofeng | Lim, Stephen S | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | London, Stephanie J | Lotufo, Paulo A | Ma, Jixiang | Ma, Stefan | Machado, Vasco Manuel Pedro | Mainoo, Nana Kwaku | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Mason-Jones, Amanda J | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | de la Cruz Monis, Jonathan | Hernandez, Julio Cesar Montañez | Moore, Ami R | Moradi-Lakeh, Maziar | Mori, Rintaro | Mueller, Ulrich O | Mukaigawara, Mitsuru | Naheed, Aliya | Naidoo, Kovin S | Nand, Devina | Nangia, Vinay | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nieuwenhuijsen, Mark J | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Park, Jae-Hyun | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pesudovs, Konrad | Petzold, Max | Poenaru, Dan | Polanczyk, Guilherme V | Polinder, Suzanne | Pope, Dan | Pourmalek, Farshad | Qato, Dima | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad ur | Raju, Murugesan | Rana, Saleem M | Refaat, Amany | Ronfani, Luca | Roy, Nobhojit | Sánchez Pimienta, Tania Georgina | Sahraian, Mohammad Ali | Salomon, Joshua A | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Sayinzoga, Felix | Schneider, Ione J C | Schumacher, Austin | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Shakh-Nazarova, Marina | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Sreeramareddy, Chandrashekhar T | Stroumpoulis, Konstantinos | Sturua, Lela | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tan, Feng | Teixeira, Carolina Maria | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thorne-Lyman, Andrew L | Tirschwell, David L | Towbin, Jeffrey A | Tran, Bach X | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Undurraga, Eduardo A | Uzun, Selen Begüm | Vallely, Andrew J | van Gool, Coen H | Vasankari, Tommi J | Vavilala, Monica S | Venketasubramanian, N | Villalpando, Salvador | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vos, Theo | Waller, Stephen | Wang, Haidong | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Woldeyohannes, Solomon Meseret | Wong, John Q | Wordofa, Muluemebet Abera | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa Z | Yu, Chuanhua | Jin, Kim Yun | El SayedZaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Naghavi, Mohsen | Murray, Christopher J L | Lozano, Rafael
Lancet  2014;384(9947):980-1004.
Summary
Background
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
Methods
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
Findings
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Interpretation
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60696-6
PMCID: PMC4255481  PMID: 24797575
4.  Elective orthopedic and cardiopulmonary bypass surgery causes a reduction in serum endostatin levels 
Background
Endostatin is an endogenous inhibitor of angiogenesis that inhibits neovascularisation. The aim of the study was to evaluate the effect of elective surgery on endostatin levels.
Methods
Blood samples were collected prior to elective surgery and 4 and 30 days postoperatively in 2 patient groups: orthopedic surgery (n =27) and coronary bypass patients (n =21). Serum endostatin levels were measured by ELISA.
Results
Serum endostatin was significantly reduced 30 days after surgery in comparison with presurgical values in both the orthopedic (P =0.03) and cardiopulmonary surgery (P =0.04) group.
Conclusion
Serum endostatin is reduced 30 days after surgery. This reduction would favor angiogenesis and wound-healing.
doi:10.1186/s40001-014-0061-9
PMCID: PMC4230358  PMID: 25380724
Angiogenesis; CRP; ELISA; Endostatin; Elective surgery
5.  Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Murray, Christopher J L | Ortblad, Katrina F | Guinovart, Caterina | Lim, Stephen S | Wolock, Timothy M | Roberts, D Allen | Dansereau, Emily A | Graetz, Nicholas | Barber, Ryan M | Brown, Jonathan C | Wang, Haidong | Duber, Herbert C | Naghavi, Mohsen | Dicker, Daniel | Dandona, Lalit | Salomon, Joshua A | Heuton, Kyle R | Foreman, Kyle | Phillips, David E | Fleming, Thomas D | Flaxman, Abraham D | Phillips, Bryan K | Johnson, Elizabeth K | Coggeshall, Megan S | Abd-Allah, Foad | Ferede, Semaw | Abraham, Jerry P | Abubakar, Ibrahim | Abu-Raddad, Laith J | Abu-Rmeileh, Niveen Me | Achoki, Tom | Adeyemo, Austine Olufemi | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie Elisabet | Akena, Dickens | Al Kahbouri, Mazin J | Alasfoor, Deena | Albittar, Mohammed I | Alcalá-Cerra, Gabriel | Alegretti, Miguel Angel | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Alla, Francois | Allen, Peter J | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzman, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Anderson, Benjamin O | Antonio, Carl Abelardo T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Banerjee, Amitava | Basu, Sanjay | Beardsley, Justin | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku Jibat | Bhala, Neeraj | Bhalla, Ashish | Bhutta, Zulfiqar A | Abdulhak, Aref Bin | Binagwaho, Agnes | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Brainin, Michael | Breitborde, Nicholas | Castañeda-Orjuela, Carlos A | Catalá-López, Ferrán | Chadha, Vineet K | Chang, Jung-Chen | Chiang, Peggy Pei-Chia | Chuang, Ting-Wu | Colomar, Mercedes | Cooper, Leslie Trumbull | Cooper, Cyrus | Courville, Karen J | Cowie, Benjamin C | Criqui, Michael H | Dandona, Rakhi | Dayama, Anand | De Leo, Diego | Degenhardt, Louisa | Del Pozo-Cruz, Borja | Deribe, Kebede | Jarlais, Don C Des | Dessalegn, Muluken | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Driscoll, Tim R | Durrani, Adnan M | Ellenbogen, Richard G | Ermakov, Sergey Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Forouzanfar, Mohammad H | Paleo, Urbano Fra. | Gaffikin, Lynne | Gamkrelidze, Amiran | Gankpé, Fortuné Gbètoho | Geleijnse, Johanna M | Gessner, Bradford D | Gibney, Katherine B | Ginawi, Ibrahim Abdelmageem Mohamed | Glaser, Elizabeth L | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rajeev | Gupta, Rahul | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Haro, Josep Maria | Havmoeller, Rasmus | Hay, Simon I | Hedayati, Mohammad T | Pi, Ileana B Heredia | Hoek, Hans W | Hornberger, John C | Hosgood, H Dean | Hotez, Peter J | Hoy, Damian G | Huang, John J | Iburg, Kim M | Idrisov, Bulat T | Innos, Kaire | Jacobsen, Kathryn H | Jeemon, Panniyammakal | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kan, Haidong | Kankindi, Ida | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Keren, Andre | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Khonelidze, Irma | Kinfu, Yohannes | Kinge, Jonas M | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, S | Defo, Barthelemy Kuate | Kulkarni, Veena S | Kulkarni, Chanda | Kumar, Kaushalendra | Kumar, Ravi B | Kumar, G Anil | Kwan, Gene F | Lai, Taavi | Balaji, Arjun Lakshmana | Lam, Hilton | Lan, Qing | Lansingh, Van C | Larson, Heidi J | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Yichong | Li, Yongmei | De Lima, Graça Maria Ferreira | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | Lotufo, Paulo A | Machado, Vasco Manuel Pedro | Maclachlan, Jennifer H | Magis-Rodriguez, Carlos | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Masci, Joseph R | Mashal, Mohammad Taufiq | Mason-Jones, Amanda J | Mayosi, Bongani M | Mazorodze, Tasara T | Mckay, Abigail Cecilia | Meaney, Peter A | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Melaku, Yohannes Adama | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Mori, Rintaro | Moturi, Wilkister Nyaora | Mukaigawara, Mitsuru | Murthy, Kinnari S | Naheed, Aliya | Naidoo, Kovin S | Naldi, Luigi | Nangia, Vinay | Narayan, K M Venkat | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nowaseb, Vincent | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pervaiz, Aslam | Pesudovs, Konrad | Petzold, Max | Pourmalek, Farshad | Qato, Dima | Quezada, Amado D | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad Ur | Raju, Murugesan | Rana, Saleem M | Razavi, Homie | Reilly, Robert Quentin | Remuzzi, Giuseppe | Richardus, Jan Hendrik | Ronfani, Luca | Roy, Nobhojit | Sabin, Nsanzimana | Saeedi, Mohammad Yahya | Sahraian, Mohammad Ali | Samonte, Genesis May J | Sawhney, Monika | Schneider, Ione J C | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Shivakoti, Rupak | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Simard, Edgar P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soneji, Samir | Soshnikov, Sergey S | Sreeramareddy, Chandrashekhar T | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Swaminathan, Soumya | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thomson, Alan J | Thorne-Lyman, Andrew L | Towbin, Jeffrey A | Traebert, Jefferson | Tran, Bach X | Dimbuene, Zacharie Tsala | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Uzun, Selen Begüm | Vallely, Andrew J | Vasankari, Tommi J | Venketasubramanian, N | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Waller, Stephen | Wallin, Mitchell T | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | White, Richard A | Wilkinson, James D | Williams, Thomas Neil | Woldeyohannes, Solomon Meseret | Wong, John Q | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | El Sayed Zaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Vos, Theo
Lancet  2014;384(9947):1005-1070.
Summary
Background
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.
Methods
To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets.
Findings
Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.
Interpretation
Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS’s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60844-8
PMCID: PMC4202387  PMID: 25059949
6.  Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Wang, Haidong | Liddell, Chelsea A | Coates, Matthew M | Mooney, Meghan D | Levitz, Carly E | Schumacher, Austin E | Apfel, Henry | Iannarone, Marissa | Phillips, Bryan | Lofgren, Katherine T | Sandar, Logan | Dorrington, Rob E | Rakovac, Ivo | Jacobs, Troy A | Liang, Xiaofeng | Zhou, Maigeng | Zhu, Jun | Yang, Gonghuan | Wang, Yanping | Liu, Shiwei | Li, Yichong | Ozgoren, Ayse Abbasoglu | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Alemu, Zewdie Aderaw | Allen, Peter J | AlMazroa, Mohammad AbdulAziz | Alvarez, Elena | Amankwaa, Adansi A | Amare, Azmeraw T | Ammar, Walid | Anwari, Palwasha | Cunningham, Solveig Argeseanu | Asad, Majed Masoud | Assadi, Reza | Banerjee, Amitava | Basu, Sanjay | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bhutta, Zulfiqar | Blore, Jed | Basara, Berrak Bora | Boufous, Soufiane | Breitborde, Nicholas | Bruce, Nigel G | Bui, Linh Ngoc | Carapetis, Jonathan R | Cárdenas, Rosario | Carpenter, David O | Caso, Valeria | Castro, Ruben Estanislao | Catalá-Lopéz, Ferrán | Cavlin, Alanur | Che, Xuan | Chiang, Peggy Pei-Chia | Chowdhury, Rajiv | Christophi, Costas A | Chuang, Ting-Wu | Cirillo, Massimo | Leite, Iuri da Costa | Courville, Karen J | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Deribe, Kebede | Dharmaratne, Samath D | Dherani, Mukesh K | Dilmen, Uğur | Ding, Eric L | Edmond, Karen M | Ermakov, Sergei Petrovich | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Foigt, Nataliya | Forouzanfar, Mohammad H | Garcia, Ana C | Geleijnse, Johanna M | Gessner, Bradford D | Goginashvili, Ketevan | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Green, Mark A | Greenwell, Karen Fern | Gugnani, Harish Chander | Gupta, Rahul | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Harb, Hilda L | Hay, Simon | Hedayati, Mohammad T | Hosgood, H Dean | Hoy, Damian G | Idrisov, Bulat T | Islami, Farhad | Ismayilova, Samaya | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kazi, Dhruv S | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khang, Young-Ho | Kim, Daniel | Kinfu, Yohannes | Kinge, Jonas M | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Lai, Taavi | Lan, Qing | Larsson, Anders | Lee, Jong-Tae | Leinsalu, Mall | Lim, Stephen S | Lipshultz, Steven E | Logroscino, Giancarlo | Lotufo, Paulo A | Lunevicius, Raimundas | Lyons, Ronan Anthony | Ma, Stefan | Mahdi, Abbas Ali | Marzan, Melvin Barrientos | Mashal, Mohammad Taufiq | Mazorodze, Tasara T | McGrath, John J | Memish, Ziad A | Mendoza, Walter | Mensah, George A | Meretoja, Atte | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Moschandreas, Joanna | Msemburi, William T | Mueller, Ulrich O | Muszynska, Magdalena M | Naghavi, Mohsen | Naidoo, Kovin S | Narayan, KM Venkat | Nejjari, Chakib | Ng, Marie | Ngirabega, Jean de Dieu | Nieuwenhuijsen, Mark J | Nyakarahuka, Luke | Ohkubo, Takayoshi | Omer, Saad B | Caicedo, Angel J Paternina | Wyk, Victoria Pillay-van | Pope, Dan | Prabhakaran, Dorairaj | Rahman, Sajjad UR | Rana, Saleem M | Reilly, Robert Quentin | Rojas-Rueda, David | Ronfani, Luca | Rushton, Lesley | Saeedi, Mohammad Yahya | Salomon, Joshua | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Schmidt, Jürgen C | Nazarova, Marina Shakh | She, Jun | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shishani, Kawkab | Shiue, Ivy | Sigfusdottir, Inga Dora | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Tabb, Karen M | Talongwa, Roberto Tchio | Teixeira, Carolina Maria | Terkawi, Abdullah Sulieman | Thomson, Alan J | Lyman, Andrew L Thorne | Toyoshima, Hideaki | Dimbuene, Zacharie Tsala | Uwaliraye, Parfait | Uzun, Selen Begüm | Vasankari, Tommi J | Vasconcelos, Ana Maria Nogales | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Vos, Theo | Waller, Stephen | Wan, Xia | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Williams, Hywel C | Yang, Yang C | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | Zaki, Maysaa El Sayed | Zhu, Shankuan | Lopez, Alan D | Murray, Christopher J L
Lancet  2014;384(9947):957-979.
Summary
Background
Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.
Methods
We generated updated estimates of child mortality in early neonatal (age 0–6 days), late neonatal (7–28 days), postneonatal (29–364 days), childhood (1–4 years), and under-5 (0–4 years) age groups for 188 countries from 1970 to 2013, with more than 29 000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.
Findings
We estimated that 6·3 million (95% UI 6·0–6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1–18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6–177·4) in Guinea-Bissau to 2·3 (1·8–2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from −6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000–13 than during 1990–2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only −1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.
Interpretation
Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.
Funding
Bill & Melinda Gates Foundation, US Agency for International Development.
doi:10.1016/S0140-6736(14)60497-9
PMCID: PMC4165626  PMID: 24797572
7.  Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation 
Critical Care  2014;18(5):505.
Introduction
When alveoli collapse the traction forces exerted on their walls by adjacent expanded units may increase and concentrate. These forces may promote its re-expansion at the expense of potentially injurious stresses at the interface between the collapsed and the expanded units. We developed an experimental model to test the hypothesis that a local non-lobar atelectasis can act as a stress concentrator, contributing to inflammation and structural alveolar injury in the surrounding healthy lung tissue during mechanical ventilation.
Methods
A total of 35 rats were anesthetized, paralyzed and mechanically ventilated. Atelectasis was induced by bronchial blocking: after five minutes of stabilization and pre-oxygenation with FIO2 = 1.0, a silicon cylinder blocker was wedged in the terminal bronchial tree. Afterwards, the animals were randomized between two groups: 1) Tidal volume (VT) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH2O (VT10/PEEP3); and 2) VT = 20 ml/kg and PEEP = 0 cmH2O (VT20/zero end-expiratory pressure (ZEEP)). The animals were then ventilated during 180 minutes. Three series of experiments were performed: histological (n = 12); tissue cytokines (n = 12); and micro-computed tomography (microCT; n = 2). An additional six, non-ventilated, healthy animals were used as controls.
Results
Atelectasis was successfully induced in the basal region of the lung of 26 out of 29 animals. The microCT of two animals revealed that the volume of the atelectasis was 0.12 and 0.21 cm3. There were more alveolar disruption and neutrophilic infiltration in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. Edema was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in the VT20/ZEEP than VT10/PEEP3 group. The volume-to-surface ratio was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. We did not find statistical difference in tissue interleukin-1β and cytokine-induced neutrophil chemoattractant-1 between regions.
Conclusions
The present findings suggest that a local non-lobar atelectasis acts as a stress concentrator, generating structural alveolar injury and inflammation in the surrounding lung tissue.
doi:10.1186/s13054-014-0505-1
PMCID: PMC4172813  PMID: 25200702
8.  Influence of a prudent diet on circulating cathepsin S in humans 
Nutrition Journal  2014;13(1):84.
Background
Increased circulating cathepsin S levels have been linked to increased risk of cardiometabolic diseases and cancer. However, whether cathepsin S is a modifiable risk factor is unclear. We aimed to investigate the effects of a prudent diet on plasma cathepsin S levels in healthy individuals.
Findings
Explorative analyses of a randomized study were performed in 88 normal to slightly overweight and hyperlipidemic men and women (aged 25 to 65) that were randomly assigned to ad libitum prudent diet, i.e. healthy Nordic diet (ND) or a control group (habitual Western diet) for 6 weeks. Whereas all foods in the ND were provided, the control group was advised to consume their habitual diet throughout the study. The ND was in line with dietary recommendations, e.g. low in saturated fats, sugars and salt, but high in plant-based foods rich in fibre and unsaturated fats.
The ND significantly decreased cathepsin S levels (from 20.1 (+/-4.0 SD) to 19.7 μg/L (+/-4.3 SD)) compared with control group (from 18.2 (+/-2.9 SD) to 19.1 μg/L (+/-3.8 SD)). This difference remained after adjusting for sex and change in insulin sensitivity (P = 0.03), and near significant after adjusting for baseline cathepsin S levels (P = 0.06), but not for change in weight or LDL-C. Changes in cathepsin S levels were directly correlated with change in LDL-C.
Conclusions
Compared with a habitual control diet, a provided ad libitum healthy Nordic diet decreased cathepsin S levels in healthy individuals, possibly mediated by weight loss or lowered LDL-C. These differences between groups in cathepsin S were however not robust and therefore need further investigation.
doi:10.1186/1475-2891-13-84
PMCID: PMC4155124  PMID: 25128296
Nordic prudent diet; Cathepsin S; Weight loss; Cardiometabolic risk factors
9.  AliView: a fast and lightweight alignment viewer and editor for large datasets 
Bioinformatics  2014;30(22):3276-3278.
Summary: AliView is an alignment viewer and editor designed to meet the requirements of next-generation sequencing era phylogenetic datasets. AliView handles alignments of unlimited size in the formats most commonly used, i.e. FASTA, Phylip, Nexus, Clustal and MSF. The intuitive graphical interface makes it easy to inspect, sort, delete, merge and realign sequences as part of the manual filtering process of large datasets. AliView also works as an easy-to-use alignment editor for small as well as large datasets.
Availability and implementation: AliView is released as open-source software under the GNU General Public License, version 3.0 (GPLv3), and is available at GitHub (www.github.com/AliView). The program is cross-platform and extensively tested on Linux, Mac OS X and Windows systems. Downloads and help are available at http://ormbunkar.se/aliview
Contact: anders.larsson@ebc.uu.se
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu531
PMCID: PMC4221126  PMID: 25095880
10.  Outcome predictors of intra-articular glucocorticoid treatment for knee synovitis in patients with rheumatoid arthritis – a prospective cohort study 
Arthritis Research & Therapy  2014;16(3):R129.
Introduction
Intra-articular glucocorticoid treatment (IAGC) is widely used for symptom relief in arthritis. However, knowledge of factors predicting treatment outcome is limited. The aim of the present study was to identify response predictors of IAGC for knee synovitis in patients with rheumatoid arthritis (RA).
Methods
In this study 121 RA patients with synovitis of the knee were treated with intra-articular injections of 20 mg triamcinolone hexacetonide. They were followed for six months and the rate of clinical relapse was studied. Non-responders (relapse within 6 months) and responders were compared regarding patient characteristics and knee joint damage as determined by the Larsen-Dale index. In addition, matched samples of serum and synovial fluid were analysed for factors reflecting the inflammatory process (C-reactive protein, interleukin 6, tumour necrosis factor alpha, vascular endothelial growth factor), joint tissue turnover (cartilage oligomeric matrix protein, metalloproteinase 3), and autoimmunity (antinuclear antibodies, antibodies against citrullinated peptides, rheumatoid factor).
Results
During the observation period, 48 knees relapsed (40%). Non-responders had more radiographic joint damage than responders (P = 0.002) and the pre-treatment vascular endothelial growth factor (VEGF) level in synovial fluid was significantly higher in non-responders (P = 0.002).
Conclusions
Joint destruction is associated with poor outcome of IAGC for knee synovitis in RA. In addition, higher levels of VEGF in synovial fluid are found in non-responders, suggesting that locally produced VEGF is a biomarker for recurrence of synovial hyperplasia and the risk for arthritis relapse.
doi:10.1186/ar4586
PMCID: PMC4095577  PMID: 24950951
11.  Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations 
Critical Care  2014;18(3):R124.
Introduction
While non-invasive ventilation aimed at avoiding intubation has become the modality of choice to treat mild to moderate acute respiratory acidosis, many severely acidotic patients (pH <7.20) still need intubation. Extracorporeal veno-venous CO2 removal (ECCO2R) could prove to be an alternative. The present animal study tested in a systematic fashion technical requirements for successful ECCO2R in terms of cannula size, blood and sweep gas flow.
Methods
ECCO2R with a 0.98 m2 surface oxygenator was performed in six acidotic (pH <7.20) pigs using either a 14.5 French (Fr) or a 19Fr catheter, with sweep gas flow rates of 8 and 16 L/minute, respectively. During each experiment the blood flow was incrementally increased to a maximum of 400 mL/minute (14.5Fr catheter) and 1000 mL/minute (19Fr catheter).
Results
Amelioration of severe respiratory acidosis was only feasible when blood flow rates of 750 to 1000 mL/minute (19Fr catheter) were used. Maximal CO2-elimination was 146.1 ± 22.6 mL/minute, while pH increased from 7.13 ± 0.08 to 7.41 ± 0.07 (blood flow of 1000 mL/minute; sweep gas flow 16 L/minute). Accordingly, a sweep gas flow of 8 L/minute resulted in a maximal CO2-elimination rate of 138.0 ± 16.9 mL/minute. The 14.5Fr catheter allowed a maximum CO2 elimination rate of 77.9 mL/minute, which did not result in the normalization of pH.
Conclusions
Veno-venous ECCO2R may serve as a treatment option for severe respiratory acidosis. In this porcine model, ECCO2R was most effective when using blood flow rates ranging between 750 and 1000 mL/minute, while an increase in sweep gas flow from 8 to 16 L/minute had less impact on ECCO2R in this setting.
doi:10.1186/cc13928
PMCID: PMC4095596  PMID: 24942014
12.  The association between glomerular filtration rate and left ventricular function in two independent community-based cohorts of elderly 
Nephrology Dialysis Transplantation  2014;29(11):2069-2074.
Background
The cardiorenal syndrome, the detrimental bi-directional interplay between symptomatic heart failure and chronic kidney disease, is a major clinical challenge. Nonetheless, it is unknown if this interplay begins already at an asymptomatic stage. Therefore we investigated whether the glomerular filtration rate (GFR) is associated with left ventricular function in participants free from clinical heart failure and with a left ventricular ejection fraction (LVEF) >40% and with pre-specified sub-group analyses in individuals with a GFR >60 mL/min/m2.
Methods
Two independent community-based cohorts were used; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 911; 50% women; mean age: 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 538; mean age: 71 years). We investigated cross-sectional association between cystatin C-based GFR (estimated glomerular function [eGFR]) and systolic (LVEF), diastolic- (isovolumic relaxation time [IVRT]) and global left ventricular function (myocardial performance index [MPI]) determined by echocardiography.
Results
In both PIVUS and ULSAM, higher eGFR was significantly associated with higher LVEF (P = 0.004 [PIVUS] and P = 0.005 [ULSAM]). In PIVUS, higher eGFR was significantly associated with lower IVRT (P = 0.001) and MPI (P = 0.006), in age- and sex-adjusted models. After further adjustment for cardiovascular risk factors, the association between higher eGFR and higher LVEF was still statistically significant (P = 0.008 [PIVUS] and P = 0.02 [ULSAM]). In PIVUS, the age- and sex-adjusted association between eGFR and left ventricular function was similar in participants with eGFR >60 mL/min/m2.
Conclusions
Our data suggest that the interplay between kidney and heart function begins prior to the development of symptomatic heart failure and kidney disease.
doi:10.1093/ndt/gfu199
PMCID: PMC4209878  PMID: 24916339
chronic kidney disease; cystatin C; glomerular filtration rate; left ventricular dysfunction; heart failure
13.  A nationwide postal questionnaire survey: the presence of airway guidelines in anaesthesia department in Sweden 
BMC Anesthesiology  2014;14:25.
Background
In Sweden, airway guidelines aimed toward improving patient safety have been recommended by the Swedish Society of Anaesthesia and Intensive Care Medicine. Adherence to evidence-based airway guidelines is known to be generally poor in Sweden. The aim of this study was to determine whether airway guidelines are present in Swedish anaesthesia departments.
Methods
A nationwide postal questionnaire inquiring about the presence of airway guidelines was sent out to directors of Swedish anaesthesia departments (n = 74). The structured questionnaire was based on a review of the Swedish Society of Anaesthesia and Intensive Care voluntary recommendations of guidelines for airway management. Mean, standard deviation, minimum/maximum, percentage (%) and number of general anaesthesia performed per year as frequency (n), were used to describe, each hospital type (university, county, private). For comparison between hospitals type and available written airway guidelines were cross tabulation used and analysed using Pearson’s Chi-Square tests. A p- value of less than 0 .05 was judged significant.
Results
In total 68 directors who were responsible for the anaesthesia departments returned the questionnaire, which give a response rate of 92% (n 68 of 74). The presence of guidelines showing an airway algorithm was reported by 68% of the departments; 52% reported having a written patient information card in case of a difficult airway and guidelines for difficult airways, respectively; 43% reported the presence of guidelines for preoperative assessment; 31% had guidelines for Rapid Sequence Intubation; 26% reported criteria for performing an awake intubation; and 21% reported guidelines for awake fibre-optic intubation. A prescription for the registered nurse anaesthetist for performing tracheal intubation was reported by 24%. The most frequently pre-printed preoperative elements in the anaesthesia record form were dental status and head and neck mobility.
Conclusions
Despite recommendations from the national anaesthesia society, the presence of airway guidelines in Swedish anaesthesia departments is low. From the perspective of safety for both patients and the anaesthesia staff, airway management guidelines should be considered a higher priority.
doi:10.1186/1471-2253-14-25
PMCID: PMC3996174  PMID: 24708670
Airway guidelines; Airway management; Patient safety
14.  Serum pentraxin 3 concentrations in neonates 
doi:10.3109/03009734.2013.878770
PMCID: PMC3916723  PMID: 24438192
15.  Beneficial Antimicrobial Effect of the Addition of an Aminoglycoside to a β-Lactam Antibiotic in an E. coli Porcine Intensive Care Severe Sepsis Model 
PLoS ONE  2014;9(2):e90441.
This study aimed to determine whether the addition of an aminoglycoside to a ß-lactam antibiotic increases the antimicrobial effect during the early phase of Gram-negative severe sepsis/septic shock. A porcine model was selected that considered each animal’s individual blood bactericidal capacity. Escherichia coli, susceptible to both antibiotics, was given to healthy pigs intravenously during 3 h. At 2 h, the animals were randomized to a 20-min infusion with either cefuroxime alone (n = 9), a combination of cefuroxime+tobramycin (n = 9), or saline (control, n = 9). Blood samples were collected hourly for cultures and quantitative polymerase chain reaction (PCR). Bacterial growth in the organs after 6 h was chosen as the primary endpoint. A blood sample was obtained at baseline before start of bacterial infusion for ex vivo investigation of the blood bactericidal capacity. At 1 h after the administration of the antibiotics, a second blood sample was taken for ex vivo investigation of the antibiotic-induced blood killing activity. All animals developed severe sepsis/septic shock. Blood cultures and PCR rapidly became negative after completed bacterial infusion. Antibiotic-induced blood killing activity was significantly greater in the combination group than in the cefuroxime group (p<0.001). Growth of bacteria in the spleen was reduced in the two antibiotic groups compared with the controls (p<0.01); no difference was noted between the two antibiotic groups. Bacterial growth in the liver was significantly less in the combination group than in the cefuroxime group (p<0.05). High blood bactericidal capacity at baseline was associated with decreased growth in the blood and spleen (p<0.05). The addition of tobramycin to cefuroxime results in increased antibiotic-induced blood killing activity and less bacteria in the liver than cefuroxime alone. Individual blood bactericidal capacity may have a significant effect on antimicrobial outcome.
doi:10.1371/journal.pone.0090441
PMCID: PMC3938751  PMID: 24587365
16.  Serum Cathepsin S Is Associated With Decreased Insulin Sensitivity and the Development of Type 2 Diabetes in a Community-Based Cohort of Elderly Men 
Diabetes Care  2012;36(1):163-165.
OBJECTIVE
To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.
RESEARCH DESIGN AND METHODS
Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.
RESULTS
After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase −0.09 [95% CI −0.14 to −0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08–2.01], P = 0.01).
CONCLUSIONS
Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.
doi:10.2337/dc12-0494
PMCID: PMC3526243  PMID: 22923671
17.  Brain death due to fat embolism — could moderate hypercapnia and prone position be blamed for the tonsillar herniation? 
Upsala Journal of Medical Sciences  2013;118(4):276-278.
Fat embolism to the systemic circulation in polytrauma patients is very common. The fat embolism syndrome (FES), however, is a rare condition. We describe a case of traumatic femur fracture with FES that was presented as acute tonsillar herniation (coning) and brain death postoperatively. We believe that in this case the prone position and moderate hypercapnia contributed to the acute coning.
doi:10.3109/03009734.2013.818600
PMCID: PMC4190893  PMID: 23977867
Fat embolism; hypercapnia; prone position; trauma
18.  Transcriptome-Mining for Single-Copy Nuclear Markers in Ferns 
PLoS ONE  2013;8(10):e76957.
Background
Molecular phylogenetic investigations have revolutionized our understanding of the evolutionary history of ferns—the second-most species-rich major group of vascular plants, and the sister clade to seed plants. The general absence of genomic resources available for this important group of plants, however, has resulted in the strong dependence of these studies on plastid data; nuclear or mitochondrial data have been rarely used. In this study, we utilize transcriptome data to design primers for nuclear markers for use in studies of fern evolutionary biology, and demonstrate the utility of these markers across the largest order of ferns, the Polypodiales.
Principal Findings
We present 20 novel single-copy nuclear regions, across 10 distinct protein-coding genes: ApPEFP_C, cryptochrome 2, cryptochrome 4, DET1, gapCpSh, IBR3, pgiC, SQD1, TPLATE, and transducin. These loci, individually and in combination, show strong resolving power across the Polypodiales phylogeny, and are readily amplified and sequenced from our genomic DNA test set (from 15 diploid Polypodiales species). For each region, we also present transcriptome alignments of the focal locus and related paralogs—curated broadly across ferns—that will allow researchers to develop their own primer sets for fern taxa outside of the Polypodiales. Analyses of sequence data generated from our genomic DNA test set reveal strong effects of partitioning schemes on support levels and, to a much lesser extent, on topology. A model partitioned by codon position is strongly favored, and analyses of the combined data yield a Polypodiales phylogeny that is well-supported and consistent with earlier studies of this group.
Conclusions
The 20 single-copy regions presented here more than triple the single-copy nuclear regions available for use in ferns. They provide a much-needed opportunity to assess plastid-derived hypotheses of relationships within the ferns, and increase our capacity to explore aspects of fern evolution previously unavailable to scientific investigation.
doi:10.1371/journal.pone.0076957
PMCID: PMC3792871  PMID: 24116189
19.  Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study 
Introduction
While microvascular disease is well described in systemic sclerosis (SSc), it is still unclear whether the occurrence of ischemic macrovascular events and atherosclerosis is enhanced among patients with SSc.
Methods
In this study, 111 SSc patients (74% of prevalent cases in Stockholm County) and 105 age- and sex-comparable population controls were investigated. Previous ischemic arterial events were tabulated. As surrogate measures of atherosclerosis, plaque occurrence and intima-media thickness (IMT) were determined with carotid ultrasound and the ankle-brachial index (ABI) was calculated. Traditional cardiovascular risk factors were recorded and we also measured biomarkers indicating systemic inflammation and endothelial activation/dysfunction.
Results
Mean age was 62 ± 12 years for patients and controls. Ischemic arterial events were more common, due to increased occurrence of ischemic heart disease (IHD) and ischemic peripheral vascular disease (IPVD), in the patient group (12% vs. 4%, P = 0.03 and 9% vs. 0%, P = 0.003 respectively). On a group level, there was no difference regarding the occurrence of ischemic cerebrovascular disease, the frequency of plaques, IMT or ABI between SSc patients and controls. Subgroup analyses revealed that patients with anticentromere antibodies (ACA+) had more plaques and more ischemic arterial events compared to other SSc patients (67% vs. 39% and 32% vs. 11%; P = 0.006 and P = 0.01, respectively) and compared to controls (67% vs. 41% and 32% vs. 7%, P = 0.02 and P = 0.0003, respectively). Biomarkers of inflammation/endothelial activation were generally increased among SSc patients.
Conclusions
Patients with SSc are at enhanced risk for IHD and IPVD. The ACA+ SSc subgroup was particularly affected with both ischemic arterial events and premature atherosclerosis. The microvascular vulnerability of ACA+ patients is previously well documented. We demonstrate that ACA+ SSc patients have an enhanced risk of macrovascular injury as well. This group should be followed closely and modifiable cardiovascular risk factors should be treated at an early stage.
doi:10.1186/ar4267
PMCID: PMC3979018  PMID: 23945149
20.  Lifestyle intervention is associated with decreased concentrations of circulating pentraxin 3 independent of CRP decrease 
Upsala Journal of Medical Sciences  2013;118(3):165-168.
Objectives
Pentraxin 3 (PTX3) is an acute phase marker, which is produced at the site of infection or inflammation in contrast to CRP that is mainly synthesized by the liver. The aim of the present study was to see if lifestyle interventions/weight loss would lead to decreased blood plasma concentrations of PTX3.
Methods
Study subjects (n = 31) were recruited to a lifestyle intervention program aiming at increased physical activity, improved eating habits, and weight loss. High-sensitivity C-reactive protein (CRP) and PTX3 methods were used for analysis of CRP and PTX3 in plasma samples collected at inclusion and after 4 and 8 weeks of treatment.
Results
Wilcoxon paired samples test showed a significant decrease in PTX3 concentrations from 2068 pg/mL at start to 2007 pg/mL at 4 weeks (P = 0.002) and 1748 pg/mL at 8 weeks (P = 0.003). The PTX3 decrease was not significantly correlated with a corresponding decrease in CRP or weight reduction.
Conclusions
The lifestyle intervention program resulted in a significant reduction of circulating concentrations of pentraxin 3 already after 4 and 8 weeks of treatment.
doi:10.3109/03009734.2013.801540
PMCID: PMC3713381  PMID: 23837595
Adult; body weight; CRP; human; inflammation; pentraxin 3; plasma
21.  Ruling out cardiac failure: Cost-benefit analysis of a sequential testing strategy with NT-proBNP before echocardiography 
Objectives
To estimate the possible economic benefit of a sequential testing strategy with NT-proBNP to reduce the number of echocardiographies.
Methods
Retrospective study in a third-party payer perspective. The costs were calculated from three Swedish counties: Blekinge, Östergötland, and Uppland. Two cut-off levels of NT-proBNP were used: 400 and 300 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies.
Results
The estimated costs for NT-proBNP tests and echocardiographies per county were reduced by 33%–36% with the 400 pg/mL cut-off and by 28%–29% with the 300 pg/mL cut-off. This corresponded to a yearly cost reduction of approximately €2–5 million per million inhabitants in these counties.
Conclusion
The use of NT-proBNP as a screening test could substantially reduce the number of echocardiographies in the diagnostic work-up of patients with suspected cardiac failure, as well as the associated costs.
doi:10.3109/03009734.2012.751471
PMCID: PMC3633333  PMID: 23230860
Cost; echocardiography; health economics; heart failure; laboratory test; NT-proBNP
22.  Endotoxin Tolerance Variation over 24 h during Porcine Endotoxemia: Association with Changes in Circulation and Organ Dysfunction 
PLoS ONE  2013;8(1):e53221.
Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.
doi:10.1371/journal.pone.0053221
PMCID: PMC3542331  PMID: 23326400
23.  Optimizing positive end-expiratory pressure by oscillatory mechanics minimizes tidal recruitment and distension: an experimental study in a lavage model of lung injury 
Critical Care  2012;16(6):R217.
Introduction
It is well established that during mechanical ventilation of patients with acute respiratory distress syndrome cyclic recruitment/derecruitment and overdistension are potentially injurious for lung tissues. We evaluated whether the forced oscillation technique (FOT) could be used to guide the ventilator settings in order to minimize cyclic lung recruitment/derecruitment and cyclic mechanical stress in an experimental model of acute lung injury.
Methods
We studied six pigs in which lung injury was induced by bronchoalveolar lavage. The animals were ventilated with a tidal volume of 6 ml/kg. Forced oscillations at 5 Hz were superimposed on the ventilation waveform. Pressure and flow were measured at the tip and at the inlet of the endotracheal tube respectively. Respiratory system reactance (Xrs) was computed from the pressure and flow signals and expressed in terms of oscillatory elastance (EX5). Positive end-expiratory pressure (PEEP) was increased from 0 to 24 cm H2O in steps of 4 cm H2O and subsequently decreased from 24 to 0 in steps of 2 cm H2O. At each PEEP step CT scans and EX5 were assessed at end-expiration and end-inspiration.
Results
During deflation the relationship between both end-expiratory and end-inspiratory EX5 and PEEP was a U-shaped curve with minimum values at PEEP = 13.4 ± 1.0 cm H2O (mean ± SD) and 13.0 ± 1.0 cm H2O respectively. EX5 was always higher at end-inspiration than at end-expiration, the difference between the average curves being minimal at 12 cm H2O. At this PEEP level, CT did not show any substantial sign of intra-tidal recruitment/derecruitment or expiratory lung collapse.
Conclusions
Using FOT it was possible to measure EX5 both at end-expiration and at end-inspiration. The optimal PEEP strategy based on end-expiratory EX5 minimized intra-tidal recruitment/derecruitment as assessed by CT, and the concurrent attenuation of intra-tidal variations of EX5 suggests that it may also minimize tidal mechanical stress.
doi:10.1186/cc11858
PMCID: PMC3672594  PMID: 23134702
24.  Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study 
BMC Research Notes  2012;5:537.
Background
The role of inflammation and oxidative stress in mild renal impairment in the elderly is not well studied. Accordingly, we aimed at investigating the associations between estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR), and markers of different inflammatory pathways and oxidative stress in a community based cohort of elderly men.
Findings
Cystatin C-based GFR, ACR, and biomarkers of cytokine-mediated inflammation (interleukin-6, high-sensitivity C-reactive protein[CRP], serum amyloid A[SAA]), cyclooxygenase-mediated inflammation (urinary prostaglandin F2α [PGF2α]), and oxidative stress (urinary F2 isoprostanes) were assessed in the Uppsala Longitudinal Study of Adult Men(n = 647, mean age 77 years).
Results
In linear regression models adjusting for age, BMI, smoking, blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, and treatment with statins, ACE-inhibitors, ASA, and anti-inflammatory agents, eGFR was inversely associated with CRP, interleukin-6, and SAA (β-coefficient −0.13 to −0.19, p < 0.001 for all), and positively associated with urinary F2-isoprostanes (β-coefficient 0.09, p = 0.02). In line with this, ACR was positively associated with CRP, interleukin-6, and SAA (β- coefficient 0.09-0.12, p < 0.02 for all), and negatively associated with urinary F2-isoprostanes (β-coefficient −0.12, p = 0.002). The associations were similar but with lower regression coefficients in a sub-sample with normal eGFR (>60 ml/min/1.73 m2, n = 514), with the exception that F2-isoprostane and SAA were no longer associated with eGFR.
Conclusion
Our data indicate that cytokine-mediated inflammation is involved in the early stages of impaired kidney function in the elderly, but that cyclooxygenase-mediated inflammation does not play a role at this stage. The unexpected association between higher eGFR/lower albuminuria and increased F2-isoprostanes in urine merits further studies.
doi:10.1186/1756-0500-5-537
PMCID: PMC3527356  PMID: 23016573
Inflammation; Oxidative stress; Glomerular filtration rate and albuminuria
25.  Reference values of thirty-one frequently used laboratory markers for 75-year-old males and females 
Upsala Journal of Medical Sciences  2012;117(3):264-272.
Background
We have previously reported reference values for common clinical chemistry tests in healthy 70-year-old males and females. We have now repeated this study 5 years later to establish reference values also at the age of 75. It is important to have adequate reference values for elderly patients as biological markers may change over time, and adequate reference values are essential for correct clinical decisions.
Methods
We have investigated 31 frequently used laboratory markers in 75-year-old males (n = 354) and females (n = 373) without diabetes. The 2.5 and 97.5 percentiles for these markers were calculated according to the recommendations of the International Federation of Clinical Chemistry.
Results
Reference values are reported for 75-year-old males and females for 31 frequently used laboratory markers.
Conclusion
There were minor differences between reference intervals calculated with and without individuals with cardiovascular diseases. Several of the reference intervals differed from Scandinavian reference intervals based on younger individuals (Nordic Reference Interval Project).
doi:10.3109/03009734.2011.644873
PMCID: PMC3410285  PMID: 22300333
Clinical chemistry; geriatrics; immunoassays; laboratory tests

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