Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval

Over the last decade, few novel antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval

Dissociating tinnitus patients from healthy controls using resting-state cyclicity analysis and clustering

Chronic tinnitus is a common and sometimes debilitating condition that lacks scientific consensus on physiological models of how the condition arises as well as any known cure. In this study, we applied a novel cyclicity analysis, which studies patterns of leader-follower relationships between two signals, to resting-state functional magnetic resonance imaging (rs-fMRI) data of brain regions acquired from subjects with and without tinnitus. Using the output from the cyclicity analysis, we were able to differentiate between these two groups with 58–67% accuracy by using a partial least squares discriminant analysis. Stability testing yielded a 70% classification accuracy for identifying individual subjects’ data across sessions 1 week apart. Additional analysis revealed that the pairs of brain regions that contributed most to the dissociation between tinnitus and controls were those connected to the amygdala. In the controls, there were consistent temporal patterns across frontal, parietal, and limbic regions and amygdalar activity, whereas in tinnitus subjects, this pattern was much more variable. Our findings demonstrate a proof-of-principle for the use of cyclicity analysis of rs-fMRI data to better understand functional brain connectivity and to use it as a tool for the differentiation of patients and controls who may differ on specific traits. Chronic tinnitus is a common, yet poorly understood, condition without a known cure. Understanding differences in the functioning of brains of tinnitus patients and controls may lead to better knowledge regarding the physiology of the condition and to subsequent treatments. There are many ways to characterize relationships between neural activity in different parts of the brain. Here, we apply a novel method, called cyclicity analysis, to functional MRI data obtained from tinnitus patients and controls over a period of wakeful rest. Cyclicity analysis lends itself to interpretation as analysis of temporal orderings between elements of time-series data; it is distinct from methods like periodicity analysis or time correlation analysis in that its theoretical underpinnings are invariant to changes in time scales of the generative process. In this proof-of-concept study, we use the feature generated from the cyclicity analysis of the fMRI data to investigate group level differences between tinnitus patients and controls. Our findings indicate that temporal ordering of regional brain activation is much more consistent in the control population than in tinnitus population. We also apply methods of classification from machine learning to differentiate between the two populations with moderate amount of success

Expression Profiling the Temperature-Dependent Amphibian Response to Infection by Batrachochytrium dendrobatidis

Amphibians are experiencing a panzootic of unprecedented proportions caused by the emergence of Batrachochytrium dendrobatidis (Bd). However, all species are not equally at risk of infection, and risk is further modified by environmental variables, specifically temperature. In order to understand how, and when, hosts mount a response to Bd we analysed infection dynamics and patterns of gene expression in the model amphibian species Silurana (Xenopus) tropicalis. Mathematical modelling of infection dynamics demonstrate the existence of a temperature-dependent protective response that is largely independent of the intrinsic growth-rate of Bd. Using temporal expression-profiling by microarrays and qRT-PCR, we characterise this response in the main amphibian lymphoid tissue, the spleen. We demonstrate that clearance of Bd at the host-optimal temperature is not clearly associated with an adaptive immune response, but rather is correlated with the induction of components of host innate immunity including the expression of genes that are associated with the production of the antimicrobial skin peptide preprocareulein (PPCP) as well as inflammatory responses. We find that adaptive immunity appears to be lacking at host-optimal temperatures. This suggests that either Bd does not stimulate, or suppresses, adaptive immunity, or that trade-offs exist between innate and adaptive limbs of the amphibian immune system. At cold temperatures, S. tropicalis loses the ability to mount a PPCP-based innate response, and instead manifests a more pronounced inflammatory reaction that is characterised by the production of proteases and higher pathogen burdens. This study demonstrates the temperature-dependency of the amphibian response to infection by Bd and indicates the influence that changing climates may exert on the ectothermic host response to pathogens

Manganese concentrations in soil and settled dust in an area with historic ferroalloy production

Ferroalloy production can release a number of metals into the environment, of which manganese (Mn) is of major concern. Other elements include lead, iron, zinc, copper, chromium, and cadmium. Manganese exposure derived from settled dust and suspended aerosols can cause a variety of adverse neurological effects to chronically exposed individuals. To better estimate the current levels of exposure, this study quantified metal levels in dust collected inside homes (n=85), outside homes (n=81), in attics (n=6), and in surface soil (n=252) in an area with historic ferroalloy production. Metals contained in indoor and outdoor dust samples were quantified using inductively coupled plasma optical emission spectroscopy while attic and soil measurements were made with a XRF instrument. Mean Mn concentrations in soil (4600 μg/g) and indoor dust (870 μg/g) collected within 0.5 km of a plant exceeded levels previously found in suburban and urban areas, but did decrease outside 1.0 km to the upper end of background concentrations. Mn concentrations in attic dust were approximately 120 times larger than other indoor dust levels, consistent with historical emissions that yielded high airborne concentrations in the region. Considering the potential health effects that are associated with chronic manganese inhalation and ingestion exposure, remediation of soil near the plants and frequent, on-going hygiene indoors may decrease residential exposure and the likelihood of adverse health effects

Biliary reconstructive techniques and associated anatomic variants in adult living donor liver transplantations: The adult‐to‐adult living donor liver transplantation cohort study experience

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140020/1/lt24872.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140020/2/lt24872_am.pd

Zebrafish TRPA1 Channels Are Required for Chemosensation But Not for Thermosensation or Mechanosensory Hair Cell Function

Transient receptor potential (TRP) ion channels have been implicated in detecting chemical, thermal, and mechanical stimuli in organisms ranging from mammals to Caenorhabditis elegans. It is well established that TRPA1 detects and mediates behavioral responses to chemical irritants. However, the role of TRPA1 in detecting thermal and mechanical stimuli is controversial. To further clarify the functions of TRPA1 channels in vertebrates, we analyzed their roles in zebrafish. The two zebrafish TRPA1 paralogs are expressed in sensory neurons and are activated by several chemical irritants in vitro. High-throughput behavioral analyses of trpa1a and trpa1b mutant larvae indicate that TRPA1b is necessary for behavioral responses to these chemical irritants. However, TRPA1 paralogs are not required for behavioral responses to temperature changes or for mechanosensory hair cell function in the inner ear or lateral line. These results support a role for zebrafish TRPA1 in chemical but not thermal or mechanical sensing, and establish a high-throughput system to identify genes and small molecules that modulate chemosensation, thermosensation, and mechanosensation

Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy. Lossos et al. describe a family with an early-onset Pelizaeus-Merzbacher disease-like phenotype that slowly evolves into complicated hereditary spastic paraplegia, affecting both the CNS and PNS. Exome sequencing reveals a causative homozygous missense mutation in MAG, which encodes myelin associated glycoprotei

The LIGO HET Response (LIGHETR) Project to Discover and Spectroscopically Follow Optical Transients Associated with Neutron Star Mergers

The LIGO HET Response (LIGHETR) project is an enterprise to follow up optical transients (OT) discovered as gravitational wave merger sources by the LIGO/Virgo collaboration (LVC). Early spectroscopy has the potential to constrain crucial parameters such as the aspect angle. The LIGHETR collaboration also includes the capacity to model the spectroscopic evolution of mergers to facilitate a real-time direct comparison of models with our data. The principal facility is the Hobby-Eberly Telescope. LIGHETR uses the massively-replicated VIRUS array of spectrographs to search for associated OTs and obtain early blue spectra and in a complementary role, the low-resolution LRS-2 spectrograph is used to obtain spectra of viable candidates as well as a densely-sampled series of spectra of true counterparts. Once an OT is identified, the anticipated cadence of spectra would match or considerably exceed anything achieved for GW170817 = AT2017gfo for which there were no spectra in the first 12 hours and thereafter only roughly once daily. We describe special HET-specific software written to facilitate the program and attempts to determine the flux limits to undetected sources. We also describe our campaign to follow up OT candidates during the third observational campaign of the LIGO and Virgo Scientific Collaborations. We obtained VIRUS spectroscopy of candidate galaxy hosts for 5 LVC gravitational wave events and LRS-2 spectra of one candidate for the OT associated with S190901ap. We identified that candidate, ZTF19abvionh = AT2019pip, as a possible Wolf-Rayet star in an otherwise unrecognized nearby dwarf galaxy.Comment: 26 pages, 15 figure

Accuracy of CT Colonography for Detection of Large Adenomas and Cancers

Background Computed tomographic (CT) colonography is a noninvasive option in screening for colorectal cancer. However, its accuracy as a screening tool in asymptomatic adults has not been well defined. Methods We recruited 2600 asymptomatic study participants, 50 years of age or older, at 15 study centers. CT colonographic images were acquired with the use of standard bowel preparation, stool and fluid tagging, mechanical insufflation, and multidetector-row CT scanners (with 16 or more rows). Radiologists trained in CT colonography reported all lesions measuring 5 mm or more in diameter. Optical colonoscopy and histologic review were performed according to established clinical protocols at each center and served as the reference standard. The primary end point was detection by CT colonography of histologically confirmed large adenomas and adenocarcinomas (10 mm in diameter or larger) that had been detected by colonoscopy; detection of smaller colorectal lesions (6 to 9 mm in diameter) was also evaluated. Results Complete data were available for 2531 participants (97%). For large adenomas and cancers, the mean (±SE) per-patient estimates of the sensitivity, specificity, positive and negative predictive values, and area under the receiver-operating-characteristic curve for CT colonography were 0.90±0.03, 0.86±0.02, 0.23±0.02, 0.99± Conclusions In this study of asymptomatic adults, CT colonographic screening identified 90% of subjects with adenomas or cancers measuring 10 mm or more in diameter. These findings augment published data on the role of CT colonography in screening patients with an average risk of colorectal cancer. (ClinicalTrials.gov number, NCT00084929; American College of Radiology Imaging Network [ACRIN] number, 6664.