Nailfold capillaroscopy by smartphone-dermatoscope for connective tissue disease diagnosis in interstitial lung disease: a prospective observational study.

Nailfold capillaroscopy (NFC) is a non-invasive tool validated for systemic sclerosis diagnosis. The role and interpretation of NFC in interstitial lung disease (ILD) patients for the diagnosis of connective tissue disease associated ILD (CTD-ILD) remains undefined. In a prospective study, quantitative and qualitative NFC by smartphone-dermatoscope (3M Dermlite-DL4ΤΜ attached to iPhone-6plusΤΜ) was performed in 96 patients with well-defined CTD-ILD (n=27) and non-CTD ILD (n=69; idiopathic interstitial pneumonia n=42, interstitial pneumonia with autoimmune features n=27) by ILD-multidisciplinary meeting. NFC scoring was performed by two independent, blinded specialist rheumatologists. Comprehensive baseline clinical, serological, physiological and radiological data were included. Multivariable models for CTD diagnosis in ILD, comprising nailfold characteristics at empirical thresholds determined by receiver operating characteristic curve analysis and clinical variables, were explored. In 94 patients with complete NFC data (total 687 images, median eight images per patient from eight digits), low capillary density (<6 capillaries/millimetre), increased giant capillaries (≥3), avascular areas (≥2) and microhaemorrhages all strongly enhanced the discrimination of CTD-ILD from non-CTD ILD (OR 5.00-7.47) independent of clinical covariates. In multivariable analysis, low capillary density and microhaemorrhages were independent predictors of CTD in ILD additional to the risk conferred by serology and radiology. Microhaemorrhages were also a strong predictor of CTD (adjusted OR 13.45, p=0.006) independent of clinical manifestations. All pre-specified qualitative NFC classification schemes identified CTD-ILD (OR range 3.27-8.47). NFC performed by smartphone-dermatoscope is an accessible, clinically feasible tool that may improve the identification of CTD further to routine clinical assessment of the ILD patient.

Phybrata Sensors and Machine Learning for Enhanced Neurophysiological Diagnosis and Treatment.

Concussion injuries remain a significant public health challenge. A significant unmet clinical need remains for tools that allow related physiological impairments and longer-term health risks to be identified earlier, better quantified, and more easily monitored over time. We address this challenge by combining a head-mounted wearable inertial motion unit (IMU)-based physiological vibration acceleration ("phybrata") sensor and several candidate machine learning (ML) models. The performance of this solution is assessed for both binary classification of concussion patients and multiclass predictions of specific concussion-related neurophysiological impairments. Results are compared with previously reported approaches to ML-based concussion diagnostics. Using phybrata data from a previously reported concussion study population, four different machine learning models (Support Vector Machine, Random Forest Classifier, Extreme Gradient Boost, and Convolutional Neural Network) are first investigated for binary classification of the test population as healthy vs. concussion (Use Case 1). Results are compared for two different data preprocessing pipelines, Time-Series Averaging (TSA) and Non-Time-Series Feature Extraction (NTS). Next, the three best-performing NTS models are compared in terms of their multiclass prediction performance for specific concussion-related impairments: vestibular, neurological, both (Use Case 2). For Use Case 1, the NTS model approach outperformed the TSA approach, with the two best algorithms achieving an F1 score of 0.94. For Use Case 2, the NTS Random Forest model achieved the best performance in the testing set, with an F1 score of 0.90, and identified a wider range of relevant phybrata signal features that contributed to impairment classification compared with manual feature inspection and statistical data analysis. The overall classification performance achieved in the present work exceeds previously reported approaches to ML-based concussion diagnostics using other data sources and ML models. This study also demonstrates the first combination of a wearable IMU-based sensor and ML model that enables both binary classification of concussion patients and multiclass predictions of specific concussion-related neurophysiological impairments.

Diagnosis of myositis-associated interstitial lung disease: Utility of the myositis autoantibody line immunoassay.

OBJECTIVES: The detection of myositis autoantibodies (MA) in patients with interstitial lung disease (ILD) has major implications for diagnosis and management, especially amyopathic and forme frustes of idiopathic inflammatory myositis-associated ILD (IIM-ILD). Use of the MA line immunoblot assay (MA-LIA) in non-rheumatological cohorts remains unvalidated. We assessed the diagnostic performance of the MA-LIA and explored combined models with clinical variables to improve identification of patients with IIM-ILD. METHODS: Consecutive patients referred to a specialist ILD clinic, with ILD-diagnosis confirmed at multidisciplinary meeting, and MA-LIA performed within six months of baseline were included. Pre-specified MA-LIA thresholds were evaluated for IIM-ILD diagnosis. RESULTS: A total 247 ILD patients were included (IIM-ILD n = 12, non-IIM connective tissue disease-associated ILD [CTD-ILD] n = 52, idiopathic interstitial pneumonia [IIP] n = 115, other-ILD n = 68). Mean age was 64.8 years, with 45.3% female, mean FVC 75.5% and DLCO 59.2% predicted. MA were present in 13.8% overall and 83.3% of IIM-ILD patients. The most common MA in IIM-ILD and non-IIM ILD patients were anti-Jo-1 (prevalence 40%) and anti-PMScl (29.2%) autoantibodies respectively. The pre-specified low-positive threshold (>10 signal intensity) had the highest discriminative capacity for IIM-ILD (AUC 0.86). Combining MA-LIA with age, gender, clinical CTD-manifestations and an overlap non-specific interstitial pneumonia/organising pneumonia pattern on HRCT improved discrimination for IIM-ILD (AUC 0.96). CONCLUSION: The MA-LIA is useful to support a diagnosis of IIM-ILD as a complement to multi-disciplinary ILD assessment. Clinical interpretation is optimised by consideration of the strength of the MA-LIA result together with clinical and radiological features of IIM-ILD.

Baseline Characteristics and Survival of an Australian Interstitial Pneumonia with Autoimmune Features Cohort.

BACKGROUND AND OBJECTIVE: The research term "interstitial pneumonia with autoimmune features" (IPAF) encompasses interstitial lung disease (ILD) patients with autoimmune features not meeting diagnostic criteria for a defined connective tissue disease (CTD). It remains unclear if IPAF is a distinct disease entity with implications for management and prognosis. We describe an Australian IPAF population and compare their baseline characteristics and outcomes with distinct cohorts of idiopathic interstitial pneumonia (IIP), CTD-ILD, and unclassifiable ILD. METHODS: Review of 291 consecutive patients attending a specialist ILD clinic was performed. Patients with a diagnosis of IIP, CTD-ILD, and unclassifiable ILD by ILD-multidisciplinary meeting (ILD-MDM) were included. Patients meeting the IPAF criteria were identified. Baseline clinical data, survival, and progression were compared between ILD groups. RESULTS: 226 patients were included, 36 meeting the IPAF criteria. IPAF patients demonstrated a high prevalence of autoantibodies to tRNA synthetase (35.3%), Ro52 (27.8%), and neutrophilic cytoplasmic antigens (ANCA; 20.0%). IPAF and CTD-ILD patients demonstrated similar clinical characteristics (mean age 66.6 and 63.7 years, respectively, female predominant, frequent CTD-manifestations). Lung function did not differ between ILD groups. Disease severity, pulmonary hypertension (PH), and ILD-MDM diagnosis were strong predictors of worse transplant-free survival (TFS). Meeting the IPAF criteria was not associated with TFS. CONCLUSIONS: We identified IPAF as a heterogeneous phenotype that overlaps considerably with CTD-ILD. Disease severity, PH, and ILD-MDM diagnosis were more powerful predictors of survival outcomes than meeting the IPAF criteria.

Diagnosis and management of connective tissue disease-associated interstitial lung disease in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand.

Pulmonary complications in CTD are common and can involve the interstitium, airways, pleura and pulmonary vasculature. ILD can occur in all CTD (CTD-ILD), and may vary from limited, non-progressive lung involvement, to fulminant, life-threatening disease. Given the potential for major adverse outcomes in CTD-ILD, accurate diagnosis, assessment and careful consideration of therapeutic intervention are a priority. Limited data are available to guide management decisions in CTD-ILD. Autoimmune-mediated pulmonary inflammation is considered a key pathobiological pathway in these disorders, and immunosuppressive therapy is generally regarded the cornerstone of treatment for severe and/or progressive CTD-ILD. However, the natural history of CTD-ILD in individual patients can be difficult to predict, and deciding who to treat, when and with what agent can be challenging. Establishing realistic therapeutic goals from both the patient and clinician perspective requires considerable expertise. The document aims to provide a framework for clinicians to aid in the assessment and management of ILD in the major CTD. A suggested approach to diagnosis and monitoring of CTD-ILD and, where available, evidence-based, disease-specific approaches to treatment have been provided.

The performance of the European League Against Rheumatism/American College of Rheumatology idiopathic inflammatory myopathies classification criteria in an expert-defined 10 year incident cohort.

OBJECTIVES: To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria in a cohort of incident IIM cases and examine how criteria-assigned IIM subtype correlates with expert opinion. METHODS: Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust were identified over a 10 year period. A retrospective review of all putative cases was performed and those fulfilling a consensus expert opinion diagnosis of IIM were included. Clinical, serological and histological data were collected and each case was assigned a single IIM subtype. The EULAR/ACR classification criteria were then applied and sensitivity, specificity and positive and negative predictive values were calculated, presented with 95% CIs. RESULTS: A total of 1637 cases were screened, with 255 consensus expert opinion IIM cases ultimately identified. Applying the EULAR/ACR classification criteria, the sensitivity to diagnose an IIM was 99.6% (95% CI 97.2, 100) and 80.9% (95% CI 76.0, 85.8) for the criteria cut-points of probable and definite diagnoses, respectively. In 94/255 cases the IIM subtype differed between consensus expert opinion and classification criteria, most strikingly in the group subtyped as PM by the EULAR/ACR criteria, where there was discrepancy in the majority (i.e. in 87/161). CONCLUSION: The EULAR/ACR criteria performed with high sensitivity in identifying IIM in this external cohort of incident IIM. However, substantial disagreements arose between consensus expert opinion and the criteria regarding IIM subtype assignments, resulting in a large proportion of criteria-assigned cases of PM having heterogeneous features. These results may have important implications for future use of these criteria in subsequent research.

Increasing incidence of adult idiopathic inflammatory myopathies in the City of Salford, UK: a 10-year epidemiological study.

OBJECTIVES: The aim was to identify and characterize all incident adult cases of idiopathic inflammatory myopathies (IIM) between 1 January 2007 and 31 December 2016 in the City of Salford, UK. METHODS: Adults first diagnosed with IIM within the study period were identified by: a Salford Royal NHS Foundation Trust (SRFT) inpatient episode IIM-specific ICD-10 coding search; all new patient appointments to SRFT neuromuscular outpatient clinics; and all Salford residents enrolled within the UKMYONET study. All patients with definite IIM by the 2017 EULAR/ACR classification criteria were included, as were probable cases if consensus expert opinion agreed. Cases were excluded if <18 years of age at disease onset, if they did not meet probable criteria or when probable but expert opinion concluded a non-IIM diagnosis. RESULTS: The multimodal case ascertainment identified 1156 cases which, after review and application of exclusion criteria, resulted in 32 incident cases during the study period. Twenty-three of 32 were female, with a mean age of 58.1 years. The mean incidence of adult IIM was 17.6/1 000 000 person years, and higher for females than for males (25.2 vs 10.0/1 000 000 person years, respectively). A significant incidence increase over time was apparent (13.6 vs 21.4/1 000 000 person years; P = 0.032). Using EULAR/ACR classification criteria, the largest IIM subtype (21/32) was PM, followed by DM (8/32), IBM (2/32) and amyopathic DM (1/32). Expert opinion subtype differed from EULAR/ACR classification criteria in 19/32 cases. CONCLUSION: The incidence of adult IIM in Salford is 17.6/1 000 000 person years, higher in females, and is increasing over time. Disagreement exists between EULAR/ACR-derived and expert opinion-derived IIM subtype assignments.

An evaluation of two novel capillaroscopy techniques in suspected scleroderma-spectrum disorders: A single-centre cross-sectional study.

OBJECTIVES: The primary aim was to evaluate the diagnostic performance of digital photographs taken with a smartphone camera using both a lens attachment and, separately, a dermatoscope. The secondary aims were to assess the influence of prior capillaroscopy experience and familiarity with the novel techniques on diagnostic accuracy. METHODS: All patients referred for capillaroscopy between May 2016 and January 2017 were eligible for inclusion. Nailfolds were classified by widefield microscopy before proceeding double-blinded to nailfold photography using both novel techniques. Randomised photographs were assessed by three independent investigators and results were compared to widefield microscopy. Sensitivity, specificity, inter- and intra-observer variability were calculated. RESULTS: Sixty-five participants contributed over 1000 digital photographs for assessment. The 'smartphone-lens' technique performed with moderate sensitivity (65%; 58-72) and high specificity (90%; 84-96). The 'smartphone-dermatoscope' technique performed with higher sensitivity (74%; 66-82) and excellent specificity (95%; 88-100) and was used more accurately by a novice. Prior assessor experience with nailfold capillaroscopy in general and prior experience with the novel techniques positively modulated the diagnostic accuracy. CONCLUSION: New technologies, in this case utilising a smartphone camera, could help to improve accessibility to nailfold capillaroscopy, an important diagnostic tool and putative biomarker in scleroderma-spectrum disorders, whilst retaining accurate results.

Molecular Basis for Recognition of the Cancer Glycobiomarker, LacdiNAc (GalNAc[ß1→4]GlcNAc), by Wisteria floribunda Agglutinin.

Aberrant glycosylation and the overexpression of specific carbohydrate epitopes is a hallmark of many cancers, and tumor-associated oligosaccharides are actively investigated as targets for immunotherapy and diagnostics. Wisteria floribunda agglutinin (WFA) is a legume lectin that recognizes terminal N-acetylgalactosaminides with high affinity. WFA preferentially binds the disaccharide LacdiNAc (ß-d-GalNAc-[1→4]-d-GlcNAc), which is associated with tumor malignancy in leukemia, prostate, pancreatic, ovarian, and liver cancers and has shown promise in cancer glycobiomarker detection. The mechanism of specificity for WFA recognition of LacdiNAc is not fully understood. To address this problem, we have determined affinities and structure of WFA in complex with GalNAc and LacdiNAc. Affinities toward Gal, GalNAc, and LacdiNAc were measured via surface plasmon resonance, yielding KD values of 4.67 × 10-4 m, 9.24 × 10-5 m, and 5.45 × 10-6 m, respectively. Structures of WFA in complex with LacdiNAc and GalNAc have been determined to 1.80-2.32 Å resolution. These high resolution structures revealed a hydrophobic groove complementary to the GalNAc and, to a minor extent, to the back-face of the GlcNAc sugar ring. Remarkably, the contribution of this small hydrophobic surface significantly increases the observed affinity for LacdiNAc over GalNAc. Tandem MS sequencing confirmed the presence of two isolectin forms in commercially available WFA differing only in the identities of two amino acids. Finally, the WFA carbohydrate binding site is similar to a homologous lectin isolated from Vatairea macrocarpa in complex with GalNAc, which, unlike WFA, binds not only αGalNAc but also terminal Ser/Thr O-linked αGalNAc (Tn antigen).

Structural basis for selective cross-reactivity in a bactericidal antibody against inner core lipooligosaccharide from Neisseria meningitidis.

The structure of a antigen-binding fragment (Fab) from the bactericidal monoclonal antibody LPT3-1 specific to lipooligosaccharide (LOS) inner cores from Neisseria meningitidis has been solved in complex with an eight-sugar inner core fragment NmL3 galE lpt3 KOH to 2.69 Å resolution. The epitope is centered about an inner core N-acetylglucosamine residue unique to N. meningitidis and does not include the lipid A moiety, which is disordered in the structure, but is positioned to allow the binding of free and membrane-anchored full-length LOS. All the amino acid residues that contact antigen are of germline origin but, remarkably, two consecutive somatic mutations of serine to glycine in the heavy chain at residues 52 and 52a are positioned to deprive the antibody of advantageous interactions and so weaken binding. However, these mutations are key to allowing selective cross-reactivity with the HepII-3-PEtn inner core variant expressed by 70% of strains. Neisseria meningitidis is a leading cause of disease in the developed world and is especially dangerous to children, who lack the necessary protective antibodies. The structure of Fab LPT3-1 in complex with LOS provides insight into the antibody's selective ability to recognize multiple clinically relevant variations of the LOS inner core from N. meningitidis.

Trans-jugular intrahepatic porto-systemic shunt placement for refractory ascites: a 'real-world' UK health economic evaluation.

OBJECTIVE: To assess the benefit of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement for refractory ascites. DESIGN: A retrospective observational study of all patients undergoing TIPS for refractory ascites in our hospital between 2003 and 2012. SETTING: Secondary care. PATIENTS: Cirrhotic patients with refractory ascites. MAIN OUTCOME MEASURES: We examined direct real-world (National Health Service) health related costs in the year before and after the TIPS procedure took place. Data were collected relating to the need for reintervention and hepatic encephalopathy. RESULTS: Data were available for 24 patients who underwent TIPS for refractory ascites (86% of eligible patients). TIPS was technically successful in all cases. Mean number of bed days in the year prior to TIPS was 30.3 and 14.3 in the year following (p=0.005). No patient had ascites at the end of the year after the TIPS with less requirement for paracentesis over the course of the year (p<0.001). Mean reduction in cost was £2759 per patient. TIPS was especially cost-effective in patients requiring between 6 and 12 drains per year with a mean saving of £9204 per patient. CONCLUSIONS: TIPS is both a clinically effective and economically advantageous therapeutic option for selected patients with refractory ascites.

Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice.

OBJECTIVE: The autoimmune destruction of beta-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS: Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or beta-cell area. RESULTS: Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic beta-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS: In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

Modeling dispersion from toxic gas released after a train collision in Graniteville, SC.

The Savannah River National Laboratory (SRNL) Weather Information and Display System was used to provide meteorological and atmospheric modeling/consequence assessment support to state and local agencies after the collision of two Norfolk Southern freight trains on the morning of January 6, 2005. This collision resulted in the release of several toxic chemicals to the environment, including chlorine. The dense and highly toxic cloud of chlorine gas that formed in the vicinity of the accident was responsible for 9 fatalities and caused injuries to more than 500 others. Transport model results depicting the forecast path of the ongoing release were made available to emergency managers in the county's Unified Command Center shortly after SRNL received a request for assistance. Support continued over the ensuing 2 days of the active response. The SRNL also provided weather briefings and transport/consequence assessment model results to responders from the South Carolina Department of Health and Environmental Control, the Savannah River Site (SRS) Emergency Operations Center, Department of Energy headquarters, and hazard material teams dispatched from the SRS. Operational model-generated forecast winds used in consequence assessments conducted during the incident were provided at 2-km horizontal grid spacing during the accident response. High-resolution Regional Atmospheric Modeling System (RAMS, version 4.3.0) simulation was later performed to examine potential influences of local topography on plume migration in greater detail. The detailed RAMS simulation was used to determine meteorology using multiple grids with an innermost grid spacing of 125 m. Results from the two simulations are shown to generally agree with meteorological observations at the time; consequently, local topography did not significantly affect wind in the area. Use of a dense gas dispersion model to simulate localized plume behavior using the higher-resolution winds indicated agreement with fatalities in the immediate area and visible damage to vegetation.

The creation of an historical meteorological database for environmental dose assessment.

The focus of this study is to develop wind data for the Savannah River Site (SRS) between 1955 and 1961 to be used in an assessment of estimates of atmospheric dispersion and downwind risk at the Savannah River Site. In particular, a study of the uncertainties of radioiodine dosimetry from the late 1950s provides the underlying motivation for developing historical windroses at the Savannah River Site (SRS). Wind measurement towers did not exist at the SRS until the early 1970s. Three relatively simple methods were used to create a 1955-1961 meteorological database for the SRS for a dose reconstruction project. The winds were estimated from onsite measurements in the 1990s and National Weather Service (NWS) observations in the 1990s and 1950s using (1) a linear regression method, (2) a similarity theory approach, and (3) a simple statistical differences method. The criteria for determining success were based on (1) how well the mean values and standard deviations of the predicted wind speed agree with the known SRS values from the 1990s, (2) the shape of the predicted frequency distribution functions for wind speed, and (3) how closely the predicted windroses resembled the SRS windrose for the 1990s. The linear regression model's wind speed distribution function was broad, flat, and skewed too much toward higher wind speeds. The similarity theory approach produced a wind speed distribution function that contained excess predicted speeds in the range 0-1.54 m s(-1) (0-3 kts) and had 'excluded' bins caused by predictions being made from integer values of knots in the NWS data. The distribution function from the mean difference method was smooth with a shape like a Weibull distribution with a shape parameter of 2 and appeared to resemble closely the SRS 1992-1996 distribution. The wind directions for all three methods of approach were successfully based on the mean difference method. It was difficult to discern differences among the wind roses produced by the three methods so the wind speed distribution functions need to be examined in order to make an informed choice for dose reconstruction.