Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

Ancient DNA and deep population structure in sub-Saharan African foragers.

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.

Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus.

Recent genomic data have revealed multiple interactions between Neanderthals and modern humans, but there is currently little genetic evidence regarding Neanderthal behaviour, diet, or disease. Here we describe the shotgun-sequencing of ancient DNA from five specimens of Neanderthal calcified dental plaque (calculus) and the characterization of regional differences in Neanderthal ecology. At Spy cave, Belgium, Neanderthal diet was heavily meat based and included woolly rhinoceros and wild sheep (mouflon), characteristic of a steppe environment. In contrast, no meat was detected in the diet of Neanderthals from El Sidrón cave, Spain, and dietary components of mushrooms, pine nuts, and moss reflected forest gathering. Differences in diet were also linked to an overall shift in the oral bacterial community (microbiota) and suggested that meat consumption contributed to substantial variation within Neanderthal microbiota. Evidence for self-medication was detected in an El Sidrón Neanderthal with a dental abscess and a chronic gastrointestinal pathogen (Enterocytozoon bieneusi). Metagenomic data from this individual also contained a nearly complete genome of the archaeal commensal Methanobrevibacter oralis (10.2× depth of coverage)-the oldest draft microbial genome generated to date, at around 48,000 years old. DNA preserved within dental calculus represents a notable source of information about the behaviour and health of ancient hominin specimens, as well as a unique system that is useful for the study of long-term microbial evolution.

Differentiated experiences of financial precarity and lived precariousness among international students in Australia.

Empirical research on international student migrants has sometimes homogenised this group, framing it as predominantly made up of privileged members of the global middle-class. This has led to calls to acknowledge and address the precarity faced by international students in their respective host countries more comprehensively. This study aims to explore how levels of financial precarity vary among international students in Australia, and how this in turn contributes to varying levels of precariousness in the personal spheres of students' lives. In doing so, we centre and refine the concept of precarity for use in studies of internationally mobile students, arguing for its use as a 'relational nexus', bridging financial precarity and broader lived experiences. Drawing on a large-scale survey and semi-structured interviews with 48 students, we emphasise the linkages between financial precarity and precariousness as a socio-ontological experience, explored through the examples of time poverty, physical and mental wellbeing, and relationships.

Explaining Government Policy Inaction on International Student Housing in Australia: The Perspectives of Stakeholders.

Housing is a major concern for many international students. This is especially so in those countries where students are mostly dependent on the private market for their accommodation. Australia is one such country, and is one of the world's major destinations for international students. This article analyses governmental failure to address problems relating to international student housing affordability and conditions. Using theory on 'policy inaction' to frame the analysis, we draw on 20 interviews with policy stakeholders to explain the Australian government's reliance on: (1) market-based housing provision for international students, and (2) a longstanding policy preference not to provide support. Interviewees were widely critical of the lack of action to address international student housing problems and understood inaction in relation, rather than in opposition, to the dominance of market-based action in housing and higher education. However, analysis of stakeholder perspectives also illuminates how policy-making action benefiting some emerges as inaction for others left behind or overlooked by the status quo. The interview data points to the need for government to overhaul its policy framework, and in doing so, to collaborate with higher education providers in revising the market-based regulatory approach. The main implications for theory and policy are discussed.

High-intensity endurance training is associated with left atrial fibrosis.

INTRODUCTION: Endurance athletes are at higher risk for developing atrial fibrillation as compared to the general population. The exact mechanism to explain this observation is incompletely understood. Our study aimed to determine whether degree of left atrial fibrosis detected by late gadolinium-enhancement magnetic resonance imaging (LGE-MRI) differed between Masters athletes and non-athlete controls. METHODS: We recruited 20 endurance healthy Masters athletes and 20 healthy control subjects who underwent cardiac MRI. Healthy controls were recruited during screening colonoscopies and Masters athletes were recruited through word of mouth and at competitions. The two groups were age and gender matched. None of the participants were known to have an arrhythmia. Fibrosis, as measured by late gadolinium-enhancement, was measured in each participant by blinded readers. The degree of left atrial fibrosis was compared between the two groups. All participants were recruited from the Salt Lake City region and scanned at the University of Utah healthcare complex. RESULTS: Left ventricular function was normal in all study participants. Left atrial volumes were significantly larger in the athletes (74.2 ml ±â€¯14.4) as compared to the healthy control subjects (60.8 mL ±â€¯21.4) (P = .02). Mean left atrial fibrosis score, reported as a percentage of the LA, was 15.5% ±â€¯5.9 in the athlete cohort compared to 9.6% ±â€¯4.9 in the controls (P = .002). CONCLUSIONS: To our knowledge this is the first study that describes, characterizes and specifically quantifies fibrotic changes within the left atrium of highly trained endurance athletes. Increased atrial fibrosis seen in this population may be an early indicator for endurance athletes at risk of developing atrial arrhythmias.

Magnetic resonance imaging-guided cryoballoon ablation for left atrial substrate modification in patients with atrial fibrillation.

BACKGROUND: Cryoballoon ablation (CBA) for pulmonary vein isolation (PVI) is an established modality for the treatment of atrial fibrillation (AF). We report feasibility of left atrial (LA) substrate modification in addition to PVI both using the cryoballoon. METHODS: LA substrates and CBA-induced scar were assessed at baseline and 3 months after ablation using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). Common periprocedural data including postablation LGE-MRI for evaluation of esophageal thermal injury, and CBA-associated complications were collected. Freedom from AF recurrence at 12 months was assessed using Holter and 30-day rhythm monitors. RESULTS: In 26 patients (64 ± 11 years, 69% male; 27% persistent AF, CHADSVASC score: 2.3 ± 1.5; left ventricular ejection fraction: 56 ± 10%, oral anticoagulation with warfarin/direct oral anticoagulants: n = 11/15), referred for first-time AF ablation, CBA of the pulmonary veins and extrapulmonary LA substrates was performed (median: 12 [interquartile range {IQR}: 7-14] freezes over 1675 seconds [IQR: 1168-2160]). On LGE-MRI, significant postablation cryoballoon-induced LA scar (median: 19.4% [IQR: 13.4-24.7] in comparison to baseline preablation LA-LGE (median: 10.6% [IQR 3.1-13.1]; P = .01) was found. Freedom from AF recurrence at 12 months was 74.5% with median time-to-recurrence of 242 days (IQR: 172-298). In 15 of 26 (58%) patients, esophageal enhancement on the postablation MRI was present with full recovery after 3 months. No major periprocedural complications were observed. CONCLUSION: LA substrate modification in addition to PVI using LGE-MRI-guided CBA is feasible but still experimental. The efficacy and safety have to be investigated in a prospective randomized trial.

Left atrial fibrosis progression detected by LGE-MRI after ablation of atrial fibrillation.

BACKGROUND: Left atrial (LA) fibrosis is thought to be a substrate for atrial fibrillation (AF) and can be quantified by late gadolinium enhancement magnetic resonance imaging (LGE-MRI). Fibrosis formation in LA is a dynamic process and may either progress or regress following AF ablation. We examined the impact of postablation progression in LA fibrosis on AF recurrence. METHODS: LA enhancement in LGE-MRI was quantified in 127 consecutive patients who underwent first time AF ablation. Serial LGE-MRIs were done prior to AF ablation, 3 months postablation and at least 12 months after second LGE-MRI. Transient postablation lesion (TL) was defined as atrial enhancement caused by ablation lesions that was detected on the first (3 month) but not on the second postablation LGE-MRI. New fibrosis (NF) was defined as atrial enhancement detected on the most recent LGE-MRI, at least 15 months after the ablation procedure. AF recurrence and its correlation with TL and NF was assessed in all patients during the follow-up period. RESULTS: An increase of 1% NF increased the chance of postablation AF recurrence by 3% (hazard ratio [HR] 1.03, 95% CI 1-1.06, P = .05). TL had no significant impact on recurrence (P = .057). After adjusting for cardiovascular risk factors, HR increased as NF became greater. Greater volume of NF (≥21%) corresponded with lower arrhythmia-free survival (37% vs 62%, P = .01). CONCLUSION: NF formation postablation of AF is a novel marker of long-term procedural outcome. Extensive NF is associated with significantly higher risk of atrial arrhythmia recurrence.

Left atrial shape predicts recurrence after atrial fibrillation catheter ablation.

INTRODUCTION: Multiple markers left atrium (LA) remodeling, including LA shape, correlate with outcomes in atrial fibrillation (AF). Catheter ablation is an important treatment of AF, but better tools are needed to determine which patients will benefit. In this study, we use particle-based modeling to quantitatively assess LA shape, and determine to what degree it predicts AF recurrence after catheter ablation. METHODS AND RESULTS: There were 254 patients enrolled in the DECAAF study who underwent cardiac magnetic resonance imaging of the LA prior to AF ablation and were followed for recurrence for up to 475 days. We performed particle-based shape modeling on each patient's LA shape. We selected shape parameters using the LASSO method and factor analysis, and then added them to a Cox regression model, which included multiple clinical parameters and LA fibrosis. We computed Harrell's C-statistic with and without shape in the model. We used the model to stratify patients into recurrence risk classes by both shape and shape and fibrosis combined. Three shape parameters were selected for inclusion. The C-statistic increased from 0.68 to 0.72 when shape was added to the model (P < 0.05). Visualized shapes showed that a more round LA shape with a shorter, more laterally rotated appendage was predictive of recurrence. CONCLUSION: LA shape is an independent predictor of recurrence after AF ablation. When combined with LA fibrosis, shape analysis using PBM may improve patient selection for ablation.

Durable lesion formation while avoiding esophageal injury during ablation of atrial fibrillation: Lessons learned from late gadolinium MR imaging.

INTRODUCTION: Adequate catheter/atrial tissue contact is critical for lesion formation during radiofrequency (RF) ablation of atrial fibrillation (AF). Late gadolinium enhancement magnetic resonance imaging (LGE-MRI) is a unique tool for the evaluation of lesion formation and detection of acute esophageal injury. METHODS: LGE-MRIs were obtained prior, within 24 hours of, and at 115 ± 62 days after first AF ablation in 36 patients. The Visitag module of CARTO3 was used to collect contact force (CF) and duration from a CF sensing ablation catheter for each registered ablation point. The minimum CF resulting in permanent lesions was determined. Esophageal enhancement detected by acute LGE-MRI was classified as mild, moderate, and severe. The CF resulting in esophageal enhancement was determined. RESULTS: A total of 4,642 registered ablation tags at 50 W power were analyzed. The mean RF duration (5.9 ± 3.7 vs. 5.6 ± 3.2 seconds, P < 0.05), CF (11.5 ± 5.6 vs. 10.9 ± 5.4 g, P < 0.001), and force time integral (FTI) (67.3 ± 54.5 vs. 62.2 ± 52.7 gs, P < 0.01) were significantly higher between ablation tags with and without associated LGE-MRI detected scar. The mean CF (15.7 ± 6.1 vs. 12.6 ± 5.9 g, P < 0.05, n  =  17 patients) in areas of esophageal enhancement was greater than areas without. CONCLUSION: Left atrial short duration ablation lesions with a CF greater than 12 g are more likely to be associated with permanent lesion formation. Ablating on top of the esophagus, CF less than 15 g would help minimize esophageal wall injury.

Vascular basement membrane alterations and ß-amyloid accumulations in an animal model of cerebral small vessel disease.

Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of ß-amyloid (Aß) transport and degradation. We analyzed BM changes and the pattern of deposition of Aß in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immunostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular Aß was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous Aß deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular ß-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous Aß. Impaired ß-amyloid clearance along perivascular and endothelial pathways and failure of extracellular Aß degradation may be the key mechanisms connecting non-amyloid CSVD and CAA.

Comparison of NHANES III and ERS/GLI 12 for airway obstruction classification and severity.

The diagnosis and severity categorisation of obstructive lung disease is determined using reference values. The American Thoracic Society/European Respiratory Society in 2005 recommended the National Health and Nutrition Examination Survey (NHANES) III spirometry prediction equations for patients in USA aged 8-80 years. The Global Lung Initiative 2012 (GLI 12) provided spirometry prediction equations for patients aged 3-95 years. Comparison of the NHANES III and GLI 12 prediction equations for diagnosing and categorising airway obstruction in patients in USA has not been made.We aimed to quantify the differences between NHANES III and GLI 12 predicted values in Caucasians aged 18-95 years, using both mathematical simulation and clinical data. We compared predicted forced expiratory volume in 1 s (FEV1) and lower limit of normal (LLN) FEV1/forced vital capacity (FVC) % for NHANES III and GLI 12 prediction equations by applying both a simulation model and clinical spirometry data to quantify differences in the diagnosis and categorisation of airway obstruction.Mathematical simulation revealed significant similarities and differences between prediction equations for both LLN FEV1/FVC % and predicted FEV1 There are significant differences when using GLI 12 and NHANES III to diagnose airway obstruction and severity in Caucasian patients aged 18-95 years.Similarities and differences exist between NHANES III and GLI 12 for some age and height combinations. The differences in LLN FEV1/FVC % and predicted FEV1 are most prominent in older taller/shorter individuals. The magnitude of the differences can be large and may result in differences in clinical management.

The role of APOE in cerebrovascular dysfunction.

The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.

Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aß, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aß was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases.

The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (Aß). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer's disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that Aß is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of Aß in the glia limitans in Alzheimer's disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of Aß. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance.

Spirometric reference values for Malagasy adults aged 18-73 years.

The American Thoracic Society (ATS) and European Respiratory Society (ERS) recommend that spirometry prediction equations be derived from samples of similar race/ethnicity. Malagasy prediction equations do not exist. The objectives of this study were to establish prediction equations for healthy Malagasy adults, and then compare Malagasy measurements with published prediction equations. We enrolled 2491 healthy Malagasy subjects aged 18-73 years (1428 males) from June 2006 to April 2008. The subjects attempted to meet the ATS/ERS 2005 guidelines when performing forced expiratory spirograms. We compared Malagasy measurements of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with predictions from the European Community for Steel and Coal (ECSC), the third National Health and Nutrition Examination Survey (NHANES III) and the ERS Global Lung Function Initiative (GLI) 2012 study. A linear model for the entire population, using age and height as independent variables, best predicted all spirometry parameters for sea level and highland subjects. FEV1, FVC and FEV1/FVC were most accurately predicted by NHANES III African-American male and female, and by GLI 2012 black male and black and South East Asian female equations. ECSC-predicted FEV1, FVC and FEV1/FVC were poorly matched to Malagasy measurements. We provide the first spirometry reference equations for a healthy adult Malagasy population, and the first comparison of Malagasy population measurements with ECSC, NHANES III and GLI 2012 prediction equations.

Fluid management with a simplified conservative protocol for the acute respiratory distress syndrome*.

OBJECTIVES: In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols. DESIGN: Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock. SETTING: ICUs of Acute Respiratory Distress Syndrome Network participating hospitals. PATIENTS: Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite. INTERVENTIONS: Fluid management by protocol. MEASUREMENTS AND MAIN RESULTS: Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p < 0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p < 0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite). CONCLUSIONS: FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

Polymorphisms in key pulmonary inflammatory pathways and the development of acute respiratory distress syndrome.

PURPOSE/AIM: Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown. MATERIALS AND METHODS: We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of ≤ 5%. In a secondary analysis we evaluated associations with mortality. RESULTS: Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15). CONCLUSIONS: Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort.

Clinical study replicability and the pursuit of excellence.

Comparisons of processes of care are common in critical care research. Often, these processes are neither explicit nor replicable and this can result in seemingly irreconcilable results. Here, we briefly review the article by Taniguchi and colleagues, who studied liberation from mechanical ventilation by using either a computerized weaning protocol or one driven by respiratory therapists. We discuss the implications of explicit protocols increasing replicability in clinical research.