Looking back at genomic medicine in 2011

Genomic medicine, in its broadest sense of being medical developments informed by ‘omic ’ advances, has continued to move towards the clinic in 2011. To mark the end of the year and the beginning of 2012, the editors of the six sections within Genome Medicine were invited to provide their highlights of the past year and to hint at the developments that we are likely to see in the near future. Six different areas of progress are covered here, but the core of genomic medicine continues to be intrinsically linked to improvements in the underlying technology, and two obvious examples are sequencing and mass spectrometry. Technological advances have enabled larger studies and more complex analyses, allowing researchers and clinicians to track changes within a single cell and yet spot patterns across a whole population an

Practice patterns for acute ischemic stroke workup: A longitudinal population‐based study

Background We examined practice patterns of inpatient testing to identify stroke etiologies and treatable risk factors for acute ischemic stroke recurrence. Methods and Results We identified stroke cases and related diagnostic testing from four 1‐year study periods (July 1993 to June 1994, 1999, 2005, and 2010) of the Greater Cincinnati/Northern Kentucky Stroke Study. Patients aged ≥18 years were included. We focused on evaluation of extracranial arteries for carotid stenosis and assessment of atrial fibrillation because randomized controlled trials supported treatment of these conditions for stroke prevention across all 4 study periods. In each study period, we also recorded stroke etiology, as determined by diagnostic testing and physician adjudication. An increasing proportion of stroke patients received assessment of both extracranial arteries and the heart over time (50%, 58%, 74%, and 78% in the 1993–1994, 1999, 2005, and 2010 periods, respectively; P &lt;0.0001 for trend), with the most dramatic individual increases in echocardiography (57%, 63%, 77%, and 83%, respectively). Concurrently, we observed a decrease in strokes of unknown etiology (47%, 48%, 41%, and 38%, respectively; P &lt;0.0001 for trend). We also found a significant increase in strokes of other known causes (32%, 25%, 45% and 59%, respectively; P &lt;0.0001 for trend). Conclusions Stroke workup for treatable causes of stroke are being used more frequently over time, and this is associated with a decrease in cryptogenic strokes. Future study of whether better determination of treatable stroke etiologies translates to a decrease in stroke recurrence at the population level will be essential. </jats:sec

Kasner and Mixmaster behavior in universes with equation of state w \ge 1

We consider cosmological models with a scalar field with equation of state $w\ge 1$ that contract towards a big crunch singularity, as in recent cyclic and ekpyrotic scenarios. We show that chaotic mixmaster oscillations due to anisotropy and curvature are suppressed, and the contraction is described by a homogeneous and isotropic Friedmann equation if $w>1$. We generalize the results to theories where the scalar field couples to p-forms and show that there exists a finite value of $w$, depending on the p-forms, such that chaotic oscillations are suppressed. We show that $Z_2$ orbifold compactification also contributes to suppressing chaotic behavior. In particular, chaos is avoided in contracting heterotic M-theory models if $w>1$ at the crunch.Comment: 25 pages, 2 figures, minor changes, references adde

MyD88 and TRIF mediate the cyclic adenosine monophosphate (cAMP) induced corticotropin releasing hormone (CRH) expression in JEG3 choriocarcinoma cell line

Background: Classically protein kinase A (PKA) and transcription factor activator protein 1 (AP-1) mediate the cyclic AMP (cAMP) induced-corticotrophin releasing hormone (CRH) expression in the placenta. However enteric Gram (-) bacterial cell wall component lipopolysaccharide (LPS) may also induce-CRH expression via Toll like receptor (TLR)4 and its adaptor molecule Myd88. Here we investigated the role of MyD88, TRIF and IRAK2 on cAMP-induced CRH promoter activation in JEG3 cells in the absence of LPS/TLR4 stimulation. Methods: JEG3 cells were transfected with CRH-luciferase and Beta-galactosidase expression vectors and either empty or dominant-negative (DN)-MyD88, DN-TRIF or DN-IRAK2 vectors using Fugene6 (Roche). cAMP-induced CRH promoter activation was examined by using a luminometer and luciferase assay. Calorimetric Beta-galactosidase assays were performed to correct for transfection efficiency. Luciferase expression vectors of cAMP-downstream molecules, CRE and AP-1, were used to further examine the signaling cascades. Results: cAMP stimulation induced AP-1 and CRE promoter expression and led to dose-dependent CRH promoter activation in JEG3 cells. Inhibition of MyD88 signaling blocked cAMP-induced CRE and CRH promoter activation. Inhibition of TRIF signaling blocked cAMP-induced CRH but not CRE expression, while inhibition of IRAK2 did not have an effect on cAMP-induced CRH expression. Conclusion: MyD88 and TRIF exert direct regulatory effect on cAMP-induced CRH promoter activation in JEG3 cells in the absence of infection. MyD88 most likely interacts with molecules upstream of IRAK2 to regulate cAMP-induced CRH expression

Capabilities of GPT-4 in ophthalmology: an analysis of model entropy and progress towards human-level medical question answering

Background: Evidence on the performance of Generative Pre-trained Transformer 4 (GPT-4), a large language model (LLM), in the ophthalmology question-answering domain is needed. // Methods: We tested GPT-4 on two 260-question multiple choice question sets from the Basic and Clinical Science Course (BCSC) Self-Assessment Program and the OphthoQuestions question banks. We compared the accuracy of GPT-4 models with varying temperatures (creativity setting) and evaluated their responses in a subset of questions. We also compared the best-performing GPT-4 model to GPT-3.5 and to historical human performance. // Results: GPT-4–0.3 (GPT-4 with a temperature of 0.3) achieved the highest accuracy among GPT-4 models, with 75.8% on the BCSC set and 70.0% on the OphthoQuestions set. The combined accuracy was 72.9%, which represents an 18.3% raw improvement in accuracy compared with GPT-3.5 (p<0.001). Human graders preferred responses from models with a temperature higher than 0 (more creative). Exam section, question difficulty and cognitive level were all predictive of GPT-4-0.3 answer accuracy. GPT-4-0.3’s performance was numerically superior to human performance on the BCSC (75.8% vs 73.3%) and OphthoQuestions (70.0% vs 63.0%), but the difference was not statistically significant (p=0.55 and p=0.09). // Conclusion: GPT-4, an LLM trained on non-ophthalmology-specific data, performs significantly better than its predecessor on simulated ophthalmology board-style exams. Remarkably, its performance tended to be superior to historical human performance, but that difference was not statistically significant in our study

No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50

Background: The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging. Methods: Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38–46 years, N=351) and after (54–62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs). Results: As expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course. There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline. There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study – Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores. Conclusions: There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed

Progenitor Cell Therapy for the Treatment of Central Nervous System Injury: A Review of the State of Current Clinical Trials

Recent preclinical work investigating the role of progenitor cell therapies for central nervous system (CNS) injuries has shown potential neuroprotection in the setting of traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. Mechanisms currently under investigation include engraftment and transdifferentiation, modulation of the locoregional inflammatory milieu, and modulation of the systemic immunologic/inflammatory response. While the exact mechanism of action remains controversial, the growing amount of preclinical data demonstrating the potential benefit associated with progenitor cell therapy for neurological injury warrants the development of well-controlled clinical trials to investigate therapeutic safety and efficacy. In this paper, we review the currently active or recently completed clinical trials investigating the safety and potential efficacy of bone marrow-derived progenitor cell therapies for the treatment of TBI, SCI, and ischemic stroke. Our review of the literature shows that while the preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of stem/progenitor cell therapies for CNS injury, a great deal of additional work is needed to ensure the safety, efficacy, and mechanisms of progenitor cell therapy prior to widespread clinical trials

Diminished physical function in older HIV-infected adults in the Southeastern U.S. despite successful antiretroviral therapy

As antiretroviral therapy efficacy improves, HIV is gradually being recognized more as a chronic disease within the aging HIV-infected population. While these individuals are surviving into old age, they may, however, be experiencing “accelerated aging” with greater declines in physical function than that observed among comparably matched individuals free of HIV. This decline is not well understood and it remains unclear if physical decline correlates with the degree of immunosuppression based on CD4 lymphocyte nadir