A digital microfluidic system for serological immunoassays in remote settings

Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system’s analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Somatotopy of nociceptive responses in the human spinal cord

This Letter to the Editor of the journal Pain addresses the study by Nash and colleagues (Pain 2013;154:776-781), reporting fMRI somatotopic responses to noxious stimulations within the human spinal cord. Spinal cord fMRI, although a rapidly expanding field, is still hampered by significant technical shortcomings. This paper is welcome, in that it introduces significant technical novelty. However, more details are needed about the methods followed, in order to grasp the procedures and to assess their actual efficacy. Moreover, the spatial specificity of the responses is not fully supported by the results, both regarding the spinal cord site and side

Multi-shot turbo spin-echo for 3D vascular space occupancy imaging

Vascular space occupancy (VASO) is a magnetic resonance imaging technique sensitive to cerebral blood volume, and is a potential alternative to the blood oxygenation level dependent (BOLD) sensitive technique as a basis for functional mapping of the neurovascular response to a task. Many implementations of VASO have made use of echo-planar imaging strategies that allow rapid acquisition, but risk introducing potentially confounding BOLD effects. Recently, multi-slice and 3D VASO techniques have been implemented to increase the imaging volume beyond the single slice of early reports. These techniques usually rely, however, on advanced scanner software or hardware not yet available in many centers. In the present study, we have implemented a short-echo time, multi-shot 3D Turbo Spin-Echo (TSE) VASO sequence that provided 8-slice coverage on a routine clinical scanner. The proposed VASO sequence was tested in assessing the response of the human motor cortex during a block design finger tapping task in 10 30 healthy subjects. Significant VASO responses, inversely correlated with the task, were found at both individual and group level. The location and extent of VASO responses were in close correspondence to those observed using a conventional BOLD acquisition in the same subjects. Although the spatial coverage and temporal resolution achieved were limited, robust and consistent VASO responses were observed. The use of a susceptibility insensitive volumetric TSE VASO sequence may have advantages in locations where conventional BOLD and echo-planar based VASO imaging is compromised

Functional exploration of the human spinal cord during voluntary movement and somatosensory stimulation

Demonstrations of the possibility of obtaining functional information from the spinal cord in humans using fMRI have been growing in number and sophistication, but the technique and the results that it provides are still perceived by the scientific community with a greater degree of scepticism than fMRI investigations of brain function. Here we review the literature on spinal fMRI in humans during voluntary movements and somatosensory stimulation. Particular attention is given to study design, acquisition and statistical analysis of the images, and to the agreement between the obtained results and existing knowledge regarding spinal cord anatomy and physiology.A striking weakness of many spinal fMRI studies is the use of small numbers of subjects and of time-points in the acquired functional image series. In addition, spinal fMRI is characterised by large physiological noise, and the recorded functional responses are poorly characterised. For all these reasons, spinal fMRI experiments risk of having low statistical power, and few spinal fMRI studies have yielded physiologically relevant information.Thus, while available evidence indicates that spinal fMRI is feasible, we are only approaching the stage at which the technique can be considered to have been rigorously established as a viable means of non-invasively investigating spinal cord functioning in humans

Alterations in cortical gray matter volume, thickness and surface area in women with fibromyalgia syndrome.

Aim of Investigation: Recent neuroimaging studies using voxel-based morphometry (VBM) demonstrated reductions in brain gray matter (GM) volume in Fibromyalgia (FS), a chronic pain syndrome thought to result from altered central pain processing. Little is known about the relative contribution of the two components of cortical GM volume – thickness and surface area – to these structural alterations. Our aim was to assess alterations in GM morphology (volume, thickness, area) in FS compared to a control group, and to correlate GM morphology with clinical variables of pain, namely duration, intensity (VAS), and tender point count, and with depression score (Center for Epidemiology Studies-Depression Scale). Methods: Twenty-three women with FS and 26 healthy pain-free women matched for age and educational level participated in the study. Pressure pain thresholds were measured with an algometer applied to the 18 defining tender points and to 10 additional points to obtain a total positive tender point count. A high-resolution structural T1-weighted brain scan (360 sagittal slices without gap; isotropic voxel size 0.5mm; FOV 240 x 240 x 180mm; TR 35ms; flip angle 50°; TE 5.7ms) was acquired for each subject, using a 3T Philips Achieva MR scanner. GM volume was assessed applying VBM to modulated data in SPM8 using an individualised DARTEL template for inter-subject alignment. Surface-based measures of cortical thickness and area were obtained using the Freesurfer 4.5.0 software. Both the VBM and Freesurfer data were spatially smoothed using an 8mm FWHM Gaussian kernel. The statistical analysis of the surface-based data was performed both on vertex-wise values and on values averaged within 64 anatomical Regions of Interest (ROIs). Nuisance influences of age, total intracranial volume (TIV), handedness and menopause were removed. Results: Compared to the control group, FS patients showed i) reduced GM volume in the left medial and superior frontal gyrus (BA 6; a trend that became significant after controlling for depression score), ii) reduced surface area in the left pericalcarine cortex, and iii) increased thickness in the left fusiform gyrus and in the right rostral middle frontal cortex. Pain intensity was negatively correlated with thickness in the bilateral paracentral lobule (BA 6); however, brain morphology was correlated neither with pain duration nor with positive tender point count. The only significant age-by-group interaction consisted in the fact that the age-related loss in GM thickness and area in the left lateral occipital cortex was less steep in patients compared to controls, because the patients had lower values already at a younger age. Conclusions: The present results provide further evidence for altered brain morphology in FS, including brain areas in which this had not been previously demonstrated, and show a relationship of specific structural changes with the severity of specific symptoms