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Background: Safety data sheets (SDSs) are hazard communication materials that accompany chemicals/hazardous products in the workplace. Many SDSs contain dense, technical text, which places considerable comprehension demands on workers, especially those with lower literacy skills. The goal of this study was to assess SDSs for readability, comprehensibility, and suitability (i.e., fit to the target audience). Methods: The Suitability Assessment of Materials (SAM) tool assessed SDSs for suitability and readability. We then amended the SAM tool to further assess SDSs for comprehensibility factors. Both the original and amended SAM tool were used to score 45 randomly selected SDSs for content, literacy demand, graphics, and layout/typography. Results: SDSs performed poorly in terms of readability, suitability, and comprehensibility. The mean readability scores were Flesch–Kincaid Grade Level (9.6), Gunning Fog index (11.0), Coleman–Liau index (13.7), and Simple Measure of Gobbledygook index (10.7), all above the recommended reading level. The original SAM graded SDSs as “not suitable” for suitability and readability. When the amended SAM was used, the mean total SAM score increased, but the SDSs were still considered “not suitable” when adding comprehensibility considerations. The amended SAM tool better identified content-related issues specific to SDSs that make it difficult for a reader to understand the material. Conclusions: In terms of readability, comprehensibility, and suitability, SDSs perform poorly in their primary role as a hazard communication tool, therefore, putting workers at risk. The amended SAM tool could be used when writing SDSs to ensure that the information is more easily understandable for all audiences.

Abstract Immune checkpoint inhibitors (ICI) are increasingly utilized as first‐line treatment for many solid tumour malignancies. One downside of ICI therapy is autoimmune‐mediated organ inflammation, or immune‐related adverse events (irAE). ICI‐related pneumonitis, or non‐infectious inflammation of the lung, is a well‐described irAE. While guidelines surrounding ICI‐related pneumonitis are well established, other ICI‐related pulmonary toxicities, including reactive airways disease, are rarely described in the literature. Here, we present a series of patients without pre‐existing COPD or asthma who developed reactive airways disease with peripheral eosinophilia after ICI therapy and without radiographic evidence of pneumonitis. The patients were treated with typical therapies for reactive airways disease, including– inhaled steroids, bronchodilators, systemic steroids, and in one instance, dupilumab. All experienced symptomatic improvement with these therapies, enabling some of the patients to continue receiving ICI therapy.

IntroductionThe acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS.MethodsWe identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing.ResultsWe first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport.DiscussionThese findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.

Arterial thoracic outlet syndrome (aTOS) is a rare, but potentially, limb-threatening condition that is often misdiagnosed. We present the case of a 29-year-old man who was initially managed under the presumption of primary Raynaud's phenomenon for >1 year before the correct diagnosis of aTOS, and the delay in diagnosis was complicated by substantial distal thromboembolic occlusion. Successful staged treatment included thoracic outlet decompression, subclavian artery aneurysm repair with subclavian-to-axillary bypass, anticoagulation, and an unconventional axillary-to-ulnar artery bypass. This report highlights the diagnostic challenges of aTOS and the importance of considering it in patients with Raynaud's phenomenon and vaso-occlusive symptoms.

Introduction: A large proportion of patients with chronic lateral ankle instability suffer from recurrent ankle sprains and develop concurrent peroneal tendon pathology. This is associated with significant pain, post-traumatic ankle osteoarthritis and severe impairments in quality of life. Currently, evidence-based treatment guidelines for peroneal pathology are lacking despite a high failure rate with nonoperative management of tears or ruptures. This case report details the first cited peroneal L-lengthening tenodesis and modified Brostrom-Gould to date. Case presentation: A 56-year-old male presented with chronic pain, disability and instability following a forced ankle plantarflexion-inversion injury. The patient was diagnosed with a complete rupture of the peroneus brevis tendon at the level of the retro-malleolar groove with 5 cm retraction, marked peroneal tenosynovitis and tendinopathy, and chronic lateral ankle ligament deficiency. Surgical management was successful, involving an L-lengthening peroneal tendon repair and tenodesis, with a concurrent modified Brostrom-Gould procedure. Following 12 months follow-up after” surgical management, the patient returned to activities of normal living and sports with significant improvements in pain levels and reported quality of life. Conclusions: A high index of suspicion is necessary for peroneal tendon injury following inversion ankle trauma, especially in the presence of chronic ankle instability. The reported surgical technique may be considered as a feasible option for patients with chronic ankle instability and concurrent peroneal tendon rupture. Further research is warranted to establish evidence-based guidelines to facilitate clinical decision-making.

Abstract The traditional indications for lobectomy for resectable Non‐small Cell Lung Cancer (NSCLC) may be set to change. Recently, anatomical segmentectomy (AS) versus lobectomy as an approach for early‐stage NSCLC has been described in phase 3 randomised controlled trials. The demand for methods to facilitate AS may increase as a consequence. We describe three cases of AS using the combination of endobronchial infiltration of indocyanine green (ICG) to identify the intersegmental plane (critical for the performance of AS), and Computed Tomography (CT) guided methylene blue injection for lesion localisation. The operations were completed successfully demonstrating satisfactory post‐operative outcomes including lesion resection with clear surgical margins and acceptable length of stay. We believe that endobronchial instillation of ICG and CT‐guided methylene blue injection for lesion localisation show promise as a technique to complement parenchymal sparing thoracic oncological surgery.

Abstract Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Objective(s): Miltuximab® is a chimeric antibody targeting Glypican-1 (GPC-1), a cell surface antigen which is overexpressed in solid cancers. Miltuximab® has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. This first in human study used Miltuximab® radiolabelled with Gallium-67 ([67Ga]Ga-DOTA-Miltuximab®). The primary study endpoint was to establish safety and tolerability of Miltuximab®. Secondary endpoints were biodistribution, tumour targeting and pharmacokinetic analysis.Methods: Four cohorts of three patients (9 with advanced prostate cancer, 2 with pancreatic and 1 with bladder cancer) were dosed with 1 mg, ~250 MBq of [67Ga]Ga-DOTA-Miltuximab®. Cohort 1 received [67Ga]Ga-DOTA-Miltuximab® alone, while cohorts 2-4 were pre-infused with increasing doses (3.5, 11.5 and 24 mg, respectively) of unlabelled Miltuximab®-DOTA 1 hour prior to [67Ga]Ga-DOTA-Miltuximab®. Safety and tolerability were assessed by clinical and standard laboratory assessments. Patients underwent whole body gamma-camera scans and SPECT/CT scans up to 144 h post-infusion. Total organ radiation exposure was determined by dosimetry of whole-body gamma scans.Results: The dosing regimen was well tolerated, with no drug-related adverse events observed. Liver and spleen uptake of [67Ga]Ga-DOTA-Miltuximab® was observed. Liver uptake was reduced by pre-infusion of unlabelled Miltuximab®-DOTA. Dosimetry analysis showed a favorable exposure profile. [67Ga]Ga-DOTA-Miltuximab® targeting to tumour sites was observed in two prostate cancer patients who had failed enzalutamide treatment. Higher doses of unlabelled antibody achieved lower liver uptake and increased antibody serum half life.Conclusions: This study is the first in human for Miltuximab® a first in class antibody targeting GPC-1. The trial met its primary endpoint of safety, demonstrating its potential as a safe and tolerable monoclonal antibody. This safety data, together with targeting to tumour lesions and biodistribution information supports the further clinical development of Miltuximab® as a theranostic agent in a planned Phase I human trial.Trial registration: ANZCTR, ACTRN12616000787482, https://www.anzctr.org.

Study Design Retrospective cohort study. Purpose To identify the clinical significance of different patterns of intraoperative neuromonitoring (IONM) signal alerts. Overview of Literature IONM is a long-established valuable adjunct to complex spine surgeries. IONM for cervical spine surgery is in the form of somatosensory evoked potential (SSEP) and motor evoked potential (MEP). The efficacy of both modalities (individually or in combination) to detect clinically significant neurological compromise is constantly being debated and requires conclusive suggestions. Methods Clinical and neuromonitoring data of 207 consecutive adult patients who underwent cervical spine surgeries at multiple surgical centers using bimodal IONM were analyzed. Signal changes were divided into three groups. Group 0 had transient signal changes in either MEPs or SSEPs, group 1 had sustained unimodal changes, and group 2 had sustained changes in both MEPs and SSEPs. The incidences of true neurological deficits in each group were recorded. Results A total of 25% (52/207) had IONM signal alerts. Out of these signal drops, 96% (50/52) were considered to be false positives. Groups 0 and 1 had no incidence of neurological deficits, while group 2 had a 29% (2/7) rate of true neurological deficits. The sensitivities of both MEP and SSEP were 100%. SSEP had a specificity of 96.6%, while MEP had a lower specificity at 76.6%. C5 palsy rate was 6%, and there was no correlation with IONM signal alerts (p=0.73). Conclusions This study shows that we can better predict its clinical significance by dividing IONM signal drops into three groups. A sustained, bimodal (MEP and SSEP) signal drop had the highest risk of true neurological deficits and warrants a high level of caution. There were no clear risk factors for false-positive alerts but there was a trend toward patients with cervical myelopathy.

Abstract Coronavirus disease 2019 (COVID‐19) has transformed very quickly into a world pandemic with severe and unexpected consequences on human health. Concerted efforts to generate better diagnostic and prognostic tools have been ongoing. Research, thus far, has primarily focused on the virus itself or the direct immune response to it. Here, we propose extracellular vesicles (EVs) from serum liquid biopsies as a new and unique modality to unify diagnostic and prognostic tools for COVID‐19 analyses. EVs are a novel player in intercellular signalling particularly influencing immune responses. We herein show that innate and adaptive immune EVs profiling, together with SARS‐CoV‐2 Spike S1+ EVs provide a novel signature for SARS‐CoV‐2 infection. It also provides a unique ability to associate the co‐existence of viral and host cell signatures to monitor affected tissues and severity of the disease progression. And provide a phenotypic insight into COVID‐associated EVs.

A cellular fibrous histiocytoma (CFH) is a variant of fibrous histiocytomas with increased cellularity with a fascicular growth pattern and increased frequency to extend into the subcutis. CFH is a benign nodular growth with a high recurrence rate of 26%. It is regularly confused with dermatofibrosarcoma protuberans and leiomyosarcoma due to their morphological similarities, hence emphasizing the importance of proper diagnosis. In this article, we discuss the case of a 50-year-old male who presents with a recurrence of CFH 30 years post-excision. The 15mm lesion on the right fourth toe was previously excised and misdiagnosed as a granuloma. In regard to the current case, a surgical excision was performed without complications, and histopathology testing confirmed the diagnosis of CFH . To date, there is no occurrence of a CFH on the toe reported in literature.

A below knee amputation (BKA) requires sufficient stump length for the fitting of a modern prosthesis. In cases of trauma where the levels of injury are unpredictable, achieving sufficient stump length can be a challenge. We described a case report of using the Ilizarov technique for bone lengthening at the residual BKA stump for a patient who sustained a mangled limb following a road traffic accident. Using this technique, we have successfully lengthened the tibial stump adequately for a functioning prosthesis. As shown in this case, we believe that this technique could attain an excellent outcome for a selected group of patients with short residual BKA stump. Keywords: Below knee amputation, Stump lengthening, Ilizarov technique

Objectives: Soluble suppression of tumorigenicity 2 (sST2) is a member of the interleukin-1 receptor family. It is raised in various cardiovascular diseases, but its value in predicting disease severity or mortality outcomes has been controversial. Therefore, we conducted a systematic review and meta-analysis to determine whether sST2 levels differed between survivors and non-survivors of patients with cardiovascular diseases, and whether elevated sST2 levels correlated with adverse outcomes. Methods: PubMed and Embase were searched until 23rd June 2021 for studies that evaluated the relationship between sST2 levels and cardiovascular disease severity or mortality. Results: A total of 707 entries were retrieved from both databases, of which 14 studies were included in the final meta-analysis. In acute heart failure, sST2 levels did not differ between survivors and non-survivors (mean difference [MD]: 24.2 ± 13.0 ng/ml; P = 0.06; I2: 95%). Elevated sST2 levels tend to be associated with increased mortality risk (hazard ratio [HR]: 1.12, 95 %CI: 0.99–1.27, P = 0.07; I2: 88%). In chronic heart failure, sST2 levels were higher in non-survivors than in survivors (MD: 0.19 ± 0.04 ng/ml; P = 0.001; I2: 0%) and elevated levels were associated with increased mortality risk (HR: 1.64, 95% CI: 1.27–2.12, P

Incisional hernia represents a common and potentially serious complication of open abdominal surgery, with up to 20% of all patients undergoing laparotomy subsequently developing an incisional hernia. This incidence increases to as much as 35% for laparotomies performed in high-risk patients and emergency procedures. A rarely used technique for enabling closure of large ventral hernias with loss of domain is preoperative progressive pneumoperitoneum (PPP), which uses intermittent insufflation to gradually stretch the contracted abdominal wall muscles, increasing the capacity of the abdominal cavity and allowing viscera to re-establish right of domain. This assists in tension-free closure of giant hernias which may otherwise be considered inoperable. This technique may be used on its own, or in conjunction with preoperative Botulinum Toxin A to confer paralysis to the lateral oblique muscles. These two complementary techniques, are changing the way complex hernias are managed.

Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.

Abstract Background Tak Province, at the Thai–Myanmar border, is one of three high malaria incidence areas in Thailand. This study aimed to describe and identify possible factors driving the spatiotemporal trends of disease incidence from 2012 to 2015. Methods Climate variables and forest cover were correlated with malaria incidence using Pearson’s r. Statistically significant clusters of high (hot spots) and low (cold spots) annual parasite incidence per 1000 population (API) were identified using Getis-Ord Gi* statistic. Results The total number of confirmed cases declined by 76% from 2012 to 2015 (Plasmodium falciparum by 81%, Plasmodium vivax by 73%). Incidence was highly seasonal with two main annual peaks. Most cases were male (62.75%), ≥ 15 years (56.07%), and of Myanmar (56.64%) or Thai (39.25%) nationality. Median temperature (1- and 2-month lags), average temperature (1- and 2-month lags) and average relative humidity (2- and 3-month lags) correlated positively with monthly total, P. falciparum and P. vivax API. Total rainfall in the same month correlated with API for total cases and P. vivax but not P. falciparum. At sub-district level, percentage forest cover had a low positive correlation with P. falciparum, P. vivax, and total API in most years. There was a decrease in API in most sub-districts for both P. falciparum and P. vivax. Sub-districts with the highest API were in the Tha Song Yang and Umphang Districts along the Thai–Myanmar border. Annual hot spots were mostly in the extreme north and south of the province. Conclusions There has been a large decline in reported clinical malaria from 2012 to 2015 in Tak Province. API was correlated with monthly climate and annual forest cover but these did not account for the trends over time. Ongoing elimination interventions on one or both sides of the border are more likely to have been the cause but it was not possible to assess this due to a lack of suitable data. Two main hot spot areas were identified that could be targeted for intensified elimination activities.

One of the most accurate and non-invasive prostate imaging methods is magnetic resonance imaging (MRI). Segmentation is needed to find the boundary of the prostate, either automatically or semi-automatically. Recently, fully convolutional neural networks (FCNN) are being used for this purpose. In this paper, to improve the FCNN performance for prostate MRI segmentation, we analyze various structures of shortcut connections together with the size of a deep network and suggest eight different FCNNs-based deep 2D network structures for automatic MRI prostate segmentation. Our evaluations on the PROMISE12 dataset with ten-fold cross-validation indicate improved and competitive results. We analyze the results in detail, considering MRI slices, MRI volumes, test folds, and also the impact on prostate segmentation of using an EndoRectal Coil to capture the prostate MRI. Our best 2D network outperforms the state-of-the-art 3D FCNN-based methods for prostate MRI segmentation on publicly available data, without any further post-processing.

Large-scale intracellular signaling during developmental growth or in response to environmental alterations are largely orchestrated by chromatin within the cell nuclei. Chemical and conformational modifications of the chromatin architecture are critical steps in the regulation of differential gene expression and ultimately cell fate determination. Therefore, establishing chemical properties of the nucleus could provide key markers for phenotypic characterization of cellular processes on a scale of individual cells. Raman microscopy is a sensitive technique that is capable of probing single cell chemical composition—and sub-cellular regions—in a label-free optical manner. As such, it has great potential in both clinical and basic research. However, perceived limitations of Raman spectroscopy such as low signal intensity and the difficulty in linking alterations in vibrational signals directly with ensuing biological effects have hampered advances in the field. Here we use immune B lymphocyte development as a model to assess chromatin and transcriptional changes using confocal Raman microscopy in combination with microfluidic devices and correlative transcriptomics, thereby linking changes in chemical and structural properties to biological outcomes. Live B lymphocytes were assessed before and after maturation. Multivariate analysis was applied to distinguish cellular components within each cell. The spectral differences between non-activated and activated B lymphocytes were then identified, and their correlation with known intracellular biological changes were assessed in comparison to conventional RNA-seq analysis. Our data shows that spectral analysis provides a powerful tool to study gene activation that can complement conventional molecular biology techniques and opens the way for mapping the dynamics in the biochemical makeup of individual cells.

Aims: This study aims to investigate the long-term results of vascularized iliac bone grafting (VIBG) for osteonecrosis of the femoral head (ONFH). The primary outcome is the long-term survivorship of VIBG, using conversion to total hip arthroplasty as an end-point. Secondly, this study will also analyse the patient or disease factors influencing the long-term survivorship of VIBG. Methods: Forty-two patients (50 hips) underwent VIBG for ONFH in our institute between September 1995 and November 2013. Only patients with a follow-up of at least 5 years were included. The risk factors, surgical complications and VIBG survivorship were recorded. The stage of ONFH was classified according to the Ficat staging of the pre-operative radiographs. VIBG was only performed to patients with ONFH of Ficat stage II and stage III. Patients with hip arthritis (Ficat stage IV) did not receive VIBG and thus excluded from the study. Long-term survivorship of VIBG is measured by conversion to total hip arthroplasty. Results: Twenty-eight hips (56%) had surviving VIBG for the duration of follow-up. The overall mean graft survival was 12.2 ± 7.8 years (0.4–24.0). Steroid and alcohol-induced osteonecrosis were more predominant in the graft-failure group, which had a hazard ratio of 2.33 and 2.07 respectively for graft failure ( p = 0.047). In terms of complication, there was one case of groin wound infection which required surgical debridement. Conclusion: At a long-term follow-up of 17 years, our results showed that VIBG is effective in treating patients with pre-collapse (Ficat Stage II) and early post-collapse (Ficat stage III) in ONFH. Alcoholics and patients with steroid are at a higher risk of graft failure, so VIBG should be performed cautiously in these patients. VIBG is an intermediate operation until osteoarthritis sets in, either by the progression of ONFH or natural degenerative change.

This paper introduces a framework for conducting and disseminating mixed methods research on positive outlier countries that successfully improved their health outcomes and systems. We provide guidance on identifying exemplar countries, assembling multidisciplinary teams, collecting and synthesising pre-existing evidence, undertaking qualitative and quantitative analyses, and preparing dissemination products for various target audiences. Through a range of ongoing research studies, we illustrate application of each step of the framework while highlighting key considerations and lessons learnt. We hope uptake of this comprehensive framework by diverse stakeholders will increase the availability and utilisation of rigorous and comparable insights from global health success stories.

We report a case of Marfan syndrome (MFS) in a South African patient, which is extraordinary because of the large constellation of clinical, radiological and vascular anomalies in a single patient. A literature search from 1950 to date did not show a similar report of such extensive clinical characteristics of MFS.

The in vitro efficacy of cancer prodrugs varies significantly between malignant cell lines. The most commonly identified problems relate to delivery: uptake mechanism, endosomal entrapment, and drug release. Here we present the study of collagen/cell penetrating hybrid (COL/CPP) peptide carriers intended to deliver paclitaxel to the hypopharyngeal carcinoma (FaDu) cells. Confocal microscopy imaging revealed the surprising response of FaDu cell to COL/CPP in comparison to previously studied cancer cell lines: hybrid peptides that carry both COL and CPP domain adsorb on the FaDu cell surface. While the CPP domain was design to facilitate the cellular uptake, in the case of FaDu cells, it also induced detrimental interactions with the cell membrane. Despite surface adsorption, the colocalization study with endosomal markers EEA1 and LAMP1 reveals that COL/CPP is internalized via endosomal pathway, peptides are able to escape before lysosome formation and release paclitaxel. Therefore, the main obstacle for paclitaxel delivery to FaDu cells appears to be related to cell surface properties. This behavior seems specific to FaDu cells, and could be linked to previously reported overexpression of T5, heparanase splice variants that produces protein lacking enzymatic activity of heparanase. This results in increased concentration of HSPG on FaDu cell surface, and possibly creates a barrier for cellular uptake of highly charged COL/CPP.

The analysis of protein biomarkers in urine is expected to lead to advances in a variety of clinical settings. Several characteristics of urine including a low-protein matrix, ease of testing and a demonstrated proteomic stability offer distinct advantages over current widely used biofluids, serum and plasma. Improvements in our understanding of the urine proteome and in methods used in its evaluation will facilitate the clinical development of urinary protein biomarkers. Multiplexed bead-based immunoassays were utilized to evaluate 211 proteins in urines from 103 healthy donors. An additional 25 healthy donors provided serial urine samples over the course of two days in order to assess temporal variation in selected biomarkers. Nearly one-third of the evaluated biomarkers were detected in urine at levels greater than 1 ng/ml, representing a diverse panel of proteins with respect to structure, function and biological role. The presence of several biomarkers in urine was confirmed by western blot. Several methods of data normalization were employed to assess impact on biomarker variability. A complex pattern of correlations with urine creatinine, albumin and beta-2-microglobulin was observed indicating the presence of highly specific mechanisms of renal filtration. Further investigation of the urinary protein biomarkers identified in this preliminary study along with a consideration of the underlying proteomic trends suggested by these findings should lead to an improved capability to identify candidate biomarkers for clinical development.

The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies.