Pancreatic ductal adenocarcinoma (PDAC) is one of the leading forms of cancer related deaths in the United States. With limited treatment options and unreliable diagnostic methods, long-term survival ...rates following a diagnosis of pancreatic cancer remain poor. Pancreatic intraepithelial neoplasia (PanIN) are precancerous lesions that precede progression towards PDAC. PanIN occur in increasing complexity as the disease progresses and the description of PanIN plays a critical role in describing, staging and diagnosing PDAC. Inconsistencies in PanIN classifications exist even amongst leading pathologists. This has led to debate and confusion among researchers and pathologists involved in pancreatic cancer research, diagnosis and treatment. We have sought to initiate a discussion with leading pathologists with a goal of increasing consensus in the interpretation of PanIN and associated structures within the precancerous pancreas. Toward achieving this goal, we are in the process of conducting an extensive study of over 1000 male and female pancreata in varying stages of PanIN progression isolated from the Ptf1a.sup.Cre/+ ;LSL-Kras.sup.G12D/+ transgenic mouse model of pancreatic cancer. Using this extensive database, we have established the Mouse Model of Pancreatic Cancer Atlas (MMPCA) to serve as a platform for meaningful and interactive discussion among researchers and pathologists who study pancreatic disease. We hope that the MMPCA will be an effective tool for promoting a more consistent and accurate consensus of PanIN classifications in the future.
To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort.
GIEs on risk ...of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study.
GIE reports (odds ratio OR 2.17 95% CI 1.39-3.39) as well as Norwalk viruses found in stool (OR 5.69 1.36-23.7) at <1 year of age were associated with an increased IAA risk at 2-4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 0.35-0.68). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12-23 months prior 1.41-2.96). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 1.54-3.02).
Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.
The ever-increasing human demand for fossil fuels has resulted in the expansion of oil exploration efforts to waters over the continental shelf. These waters are largely utilized by a complex ...biological community. Large baleen whales, in particular, utilize continental shelf waters as breeding and calving grounds, foraging grounds, and also as migration corridors. We developed a dynamic approach to estimate the likelihood that individuals from different populations of blue whales
Balaenoptera musculus
and humpback whales
Megaptera novaeangliae
could be exposed to idealized, simulated seismic surveys as they move over the continental shelf. Animal tracking data for the different populations were filtered, and behaviors (transit and foraging) were inferred from the tracks using hidden Markov models. We simulated a range of conditions of exposure by having the source of noise affecting a circular area of different radii (5, 25, 50 and 100 km), moving along a gridded transect of 270 and 2500 km
2
at a constant speed of 9 km h
-1
, and starting the simulated surveys every week of the year. Our approach allowed us to identify the temporal variability in the susceptibility of the different populations under study, as we ran the simulations for an entire year, allowing us to identify periods when the surveys would have an intensified effect on whales. Our results highlight the importance of understanding the behavior and ecology of individuals in a site-specific context when considering the likelihood of exposure to anthropogenic disturbances, as the habitat utilization patterns of each population are highly variable.
Emergent endotracheal intubation (ETI) is considered the standard of care for patients with severe traumatic brain injury (TBI). However, recent evidence suggests that the procedure may be associated ...with increased mortality, possibly reflecting inadequate training, suboptimal patient selection, or inappropriate ventilation.
To explore prehospital ETI in patients with severe TBI using a novel application of Trauma Score and Injury Severity Score methodology.
Patients with moderate-to-severe TBI (head Abbreviated Injury Scale score 3+) were identified from our county trauma registry. Demographic information, pre-resuscitation vital signs, and injury severity scores were used to calculate a probability of survival for each patient. The relationship between outcome and prehospital ETI, provider type (air vs. ground), and ventilation status were explored using observed survival-predicted survival and the ratio of unexpected survivors/deaths.
A total of 11,000 patients were identified with complete data for this analysis. Observed and predicted survivals were similar for both intubated and nonintubated patients. The ratio of unexpected survivors/deaths increased and observed survival exceeded predicted survival for intubated patients with lower predicted survival values. Both intubated and nonintubated patients transported by air medical crews had better outcomes than those transported by ground. Both hypo- and hypercapnia were associated with worse outcomes in intubated but not in nonintubated patients.
Prehospital intubation seems to improve outcomes in more critically injured TBI patients. Air medical outcomes are better than predicted for both intubated and nonintubated TBI patients. Iatrogenic hyper- and hypoventilations are associated with worse outcomes.
It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way ...to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = 6.93, 25.7, Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = 0.90,8.83,Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest.
While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs ...using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the
gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding
-regulatory elements upon 5' deletions in
. We also observed recurrent intragenic deletions of
, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that
is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
Although early intubation to prevent the mortality that accompanies hypoxia is considered the standard of care for severe traumatic brain injury (TBI), the efficacy of this approach remains unproven.
...Patients with moderate to severe TBI (Head/Neck Abbreviated Injury Scale AIS score 3+) were identified from our county trauma registry. Logistic regression was used to explore the impact of prehospital intubation on outcome, controlling for age, gender, mechanism, Glasgow Coma Scale score, Head/Neck AIS score, Injury Severity Score, and hypotension. Neural network analysis was performed to identify patients predicted to benefit from prehospital intubation.
A total of 13,625 patients from five trauma centers were included; overall mortality was 22.9%, and 19.3% underwent prehospital intubation. Logistic regression revealed an increase in mortality with prehospital intubation (odds ratio, 0.36; 95% confidence interval, 0.32-0.42; p < 0.001). This was true for all patients, for those with severe TBI (Head/Neck AIS score 4+ and/or Glasgow Coma Scale score of 3-8), and with exclusion of patients transported by aeromedical crews. Patients intubated in the field versus the emergency department had worse outcomes. Neural network analysis identified a subgroup of patients with more significant injuries as potentially benefiting from prehospital intubation.
Prehospital intubation is associated with a decrease in survival among patients with moderate-to-severe TBI. More critically injured patients may benefit from prehospital intubation but may be difficult to identify prospectively.
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