Disseminated tuberculosis, CMV viraemia & haemophagocytic-lymphohistiocystosis syndrome in an adult patient with anti- IFNγ autoantibodies - case report and brief review.

We report a case of an adult female with disseminated tuberculosis, cytomegalovirus viraemia and haemophagocytic-lymphohistiocystosis syndrome associated with neutralizing anti- interferon gamma (IFNγ) autoantibodies demonstrated by absent IFNγ stimulated STAT1 phosphorylation in the presence of patient sera. A brief review of immunodeficiency caused by anti-IFNγ autoantibodies is also described.

Comparison of PFAS soil remediation alternatives at a civilian airport using cost-benefit analysis.

Contamination of soil and water systems by per- and polyfluoroalkyl substances (PFAS) due to uncontrolled use of aqueous film-forming foams (AFFFs) at firefighting training sites at civilian and military airports is a universal issue and can lead to significant human health and environmental impacts. Remediation of these sites is often complex but necessary to alleviate the PFAS burden and minimise the risks of exposure by eliminating the hotspot/source from which the PFAS spreads. This study presents a probabilistic cost-benefit analysis (CBA) for evaluating PFAS remediation alternatives, which includes monetisation of both direct costs and benefits as well as externalities. The method is applied for a case study to compare five remediation alternatives for managing PFAS contaminated soil at Stockholm Arlanda Airport in Sweden. The social profitability, or the net present value (NPV), of each remediation alternative was calculated in comparison to two reference alternatives - 'total excavation' of the site (Alt 0) or 'do nothing'. Sensitivity analyses and model scenarios were tested to account for uncertainties, including small or large PFAS spreading and simulating different values for the magnitude of annual avoided cost of inaction (i.e., aggregate benefit) from PFAS remediation. In comparison to total excavation, four of the five studied remediation alternatives resulted in a positive mean NPV. Excavation and stabilization/solidification of the hotspot on-site combined with stabilization using activated carbon for the rest of site (Alt 2) had the highest NPV for both spreading scenarios, i.e., Alt 2 was the most socially profitable alternative. Simulations of the annual avoided cost of inaction enabled estimation of the breakeven point at which a remediation alternative becomes socially profitable (NPV > 0) compared to 'do nothing'. Alt 2 had the lowest breakeven point: 7.5 and 5.75 millions of SEK/year for large and small spreading, respectively.

PM-Scl and Th/To in systemic sclerosis: a comparison of different autoantibody assays.

OBJECTIVE: To compare test characteristics of the Euroimmun line blot assay with other assays for two uncommon autoantibody specificities in systemic sclerosis (SSc). METHODS: Patients from the Johns Hopkins Scleroderma Center were assayed routinely using the Euroimmun platform. Patients positive for anti-Th/To (N = 73) and anti-PM-Scl (PM75 and/or PM100; N = 290) by Euroimmun were compared with SSc patients negative for these autoantibodies. For Th/To antibodies, the comparison assay was immunoprecipitation (IP), performed using 4 Th/To complex components: POP1, RPP40, RPP30, and RPP25. For anti-PM-Scl, IPs were performed with PM100 and PM75. Different Euroimmun cut-offs for assigning antibody positive status (≥ 15/+, ≥ 36/++, ≥ 71/+++) were examined. Kappa statistics were calculated to determine agreement between assays. RESULTS: The best performing thresholds for defining anti-PM-Scl positivity were both PM75 and PM100 ≥ 15/+ on Euroimmun, corresponding to a kappa statistic of 0.79, sensitivity 72% and specificity 100%. For anti-Th/To, kappa values were lower for all comparisons (κ < 0.5). Given the high sensitivity of defining anti-Th/To by ≥ 15/+ (91-95%), a potential approach is to use Euroimmun screening (15/+ cut-off), followed by confirmatory IP. CONCLUSION: Given the increasing utilization of Euroimmun and the importance of comparing data across cohorts, continued use of this platform is warranted, acknowledging discordance with IP for some specificities. For these, using a two-step approach (Euroimmun to maximize sensitivity, confirmatory assay to increase specificity) is suggested. KEY POINTS: • For less common SSc autoantibody specificities, some discordances exist between IP and Euroimmun LIA. • The best performing thresholds for defining anti-PM-Scl positivity were both PM75 and PM100 ≥ 15/+ on Euroimmun. • For Th/To, a two-step approach (Euroimmun to maximize sensitivity, confirmatory assay to increase specificity) is suggested.

Historic tobacco legislation in Israel: a moment to celebrate.

BACKGROUND: Israel was once a leader in tobacco control, but fell behind other countries, particularly during the past decade, as smoking rates stagnated. TEXT: Landmark tobacco control legislation, which banned advertising (with the exception of the print press) and limited marketing, was passed in Israel on Dec. 31rst, 2018. The changes occurred following years of attempts which culminated in successful last-minute efforts to promote the legislation just before the early disbanding of the 20th Knesset (Israeli Parliament). Regulations concerning marketing and advertising were substantially strengthened to address all tobacco, nicotine and smoking products. Digital media was included for the first time. Electronic cigarettes, which were previously largely unregulated, now fall under existing tobacco legislation. The changes overcame intense opposition from the tobacco lobby, and occurred despite the fact that the basic elements for prevention policy postulated by the Richmond model were not in place. CONCLUSIONS: This legislation represents an important and long-awaited change in Israeli tobacco control policy. Many deficiencies in existing tobacco control regulation were overcome, and some measures went beyond current international regulations. The cohesive partnership between legislators, public health organizations and professionals, advocacy groups, academia, and leading journalists was critical to this success. The progress was lauded by the World Health Organization with its highest award for tobacco control, which was presented to Smoke Free Israel. This case study provides important lessons for up-to-date tobacco control policy, in the age of rapid global changes in the tobacco, vaping and nicotine landscape.

Is moving from targeted culling to BCG-vaccination of badgers (Meles meles) associated with an unacceptable increased incidence of cattle herd tuberculosis in the Republic of Ireland? A practical non-inferiority wildlife intervention study in the Republic of Ireland (2011-2017).

Bovine tuberculosis (BTB) remains as a costly disease of cattle-herds in the Republic of Ireland (ROI). This persistence is partially attributable to the presence of M. bovis infection in a wildlife reservoir, the European badger (Meles meles). Thus, both area-wide and limited-area targeted-badger-culling have been part of the ROI-BTB control/eradication program to help reduce the future incidence of a cattle-herd BTB breakdown (i.e. a "new herd-level occurrence of BTB"). However, neither badger-culling practice can be sustained as a major component in the ongoing BTB eradication program in the ROI. Vaccination of badgers with Bacille Calmette-Guérin (BCG) has been proposed as an alternative to badger culling. Thus, in 2011, a five-year non-inferiority study was implemented in seven counties in the ROI. This study was designed to compare and contrast the cattle-herd-BTB-incidence in areas where intramuscular badger vaccination would be implemented versus the cattle-herd-BTB-incidence in the remaining area of the same county where targeted-badger-culling was maintained as the standard treatment response to probable badger-sourced BTB breakdowns. Our outcome of interest was a new cattle-herd-BTB-episode (breakdown) with a total of >2 standard skin-test (SICTT) reactors detected during the episode. Treatments (badger vaccination or targeted badger culling) were cluster allocated based on where the majority of the herd owner's land was located. To assess the impact of the two treatments, we compared the incidence-risk, of our defined outcome, for cattle herds in the area under vaccination to the outcome incidence-risk for cattle herds in the remainder of the same county after 4 and 5 years of having implemented badger vaccination. A random-effects logit model with adjustment for clustering by treatment, and statistical control of herd-type, herd-size and five-year prior-BTB-episode history was used for our analyses. Although not included in the logistic model, a relative badger density metric based on the annual number of badgers captured-per-sett-night of capturing effort was developed for each treatment area; this metric indicated that relative badger density was approximately 40 % higher in vaccination areas than in the targeted badger-culling areas during our study. Overall, our study results indicated that vaccination was not inferior to targeted badger-culling in four counties and badger vaccination was deemed to produce ambivalent results in one (County Cork North) of the seven study sites in the ROI. A post-study investigation, in County Galway, where vaccination was deemed inferior to target culling, revealed that widespread purchases of cattle from a nearby cattle mart, by herd owners in the vaccination-area, was associated with the increased herd and vaccination-area risk of BTB. No single "biasing hypothesis" was evident for the apparent vaccine inferiority in the second study site (County Monaghan) where vaccination was deemed inferior to targeted culling; hence no further investigations were conducted.

Tuberculosis serosurveillance and management practices of captive African elephants (Loxodonta africana) in the Kavango-Zambezi Transfrontier Conservation Area.

Transfrontier conservation areas represent an international effort to encourage conservation and sustainable development. Their success faces a number of challenges, including disease management in wildlife, livestock and humans. Tuberculosis (TB) affects humans and a multitude of non-human animal species and is of particular concern in sub-Saharan Africa. The Kavango-Zambezi Transfrontier Conservation Area encompasses five countries, including Zimbabwe, and is home to the largest contiguous population of free-ranging elephants in Africa. Elephants are known to be susceptible to TB; thus, understanding TB status, exposure and transmission risks to and from elephants in this area is of interest for both conservation and human health. To assess risk factors for TB seroprevalence, a questionnaire was used to collect data regarding elephant management at four ecotourism facilities offering elephant-back tourist rides in the Victoria Falls area of Zimbabwe. Thirty-five working African elephants were screened for Mycobacterium tuberculosis complex antibodies using the ElephantTB Stat-Pak and the DPP VetTB Assay for elephants. Six of 35 elephants (17.1%) were seropositive. The risk factor most important for seropositive status was time in captivity. This is the first study to assess TB seroprevalence and risk factors in working African elephants in their home range. Our findings will provide a foundation to develop guidelines to protect the health of captive and free-ranging elephants in the southern African context, as well as elephant handlers through simple interventions. Minimizing exposure through shared feed with other wildlife, routine TB testing of elephant handlers and regular serological screening of elephants are recommended as preventive measures.

Expert elicitation for deriving input data for probabilistic risk assessment of shipwrecks.

The necessity of having a process in place for adequate risk assessment of shipwrecks that pose a threat to the marine environment is today internationally acknowledged. However, retrieving the desired data for such a risk assessment can prove challenging. One means of addressing this problem is to make use of experts' knowledge and experience. The purpose of this paper is therefore to present and analyse data for risk assessment of shipwrecks derived by expert elicitation. The main outcome is the experts' estimations of (i) the generic probability of an opening in a shipwreck due to the occurrence of a number of activities and (ii) estimations of the degree to which site-specific and wreck-specific indicators affect the probability of opening. Results show that the derived information is applicable in probabilistic shipwreck risk assessment and that the VRAKA framework now contains needed information for integrating generic and site-specific information using Bayesian updating.

Bayesian updating in a fault tree model for shipwreck risk assessment.

Shipwrecks containing oil and other hazardous substances have been deteriorating on the seabeds of the world for many years and are threatening to pollute the marine environment. The status of the wrecks and the potential volume of harmful substances present in the wrecks are affected by a multitude of uncertainties. Each shipwreck poses a unique threat, the nature of which is determined by the structural status of the wreck and possible damage resulting from hazardous activities that could potentially cause a discharge. Decision support is required to ensure the efficiency of the prioritisation process and the allocation of resources required to carry out risk mitigation measures. Whilst risk assessments can provide the requisite decision support, comprehensive methods that take into account key uncertainties related to shipwrecks are limited. The aim of this paper was to develop a method for estimating the probability of discharge of hazardous substances from shipwrecks. The method is based on Bayesian updating of generic information on the hazards posed by different activities in the surroundings of the wreck, with information on site-specific and wreck-specific conditions in a fault tree model. Bayesian updating is performed using Monte Carlo simulations for estimating the probability of a discharge of hazardous substances and formal handling of intrinsic uncertainties. An example application involving two wrecks located off the Swedish coast is presented. Results show the estimated probability of opening, discharge and volume of the discharge for the two wrecks and illustrate the capability of the model to provide decision support. Together with consequence estimations of a discharge of hazardous substances, the suggested model enables comprehensive and probabilistic risk assessments of shipwrecks to be made.

Relationship Between Neuromyelitis Optica Spectrum Disorder and Sjögren's Syndrome: Central Nervous System Extraglandular Disease or Unrelated, Co-Occurring Autoimmunity?

OBJECTIVE: Sjögren's syndrome (SS) patients may be affected by the neuromyelitis optica spectrum disorder (NMOSD), a severe demyelinating syndrome associated with anti-aquaporin 4 antibodies (anti-AQP-4 antibodies). The relationship between SS and NMOSD has been a sustained focus of investigation. Among SS patients, anti-AQP-4 antibodies have been detected exclusively in those with NMOSD. It has therefore been speculated that NMOSD is not a neurologic complication of SS. However, such studies evaluated small numbers of SS patients, often mixed with other inflammatory disorders. METHODS: We compared frequencies of anti-AQP-4 and SS-associated antibodies in 109 SS patients, including 11 with NMOSD, 8 with non-NMOSD demyelinating syndromes, and 90 without demyelinating syndromes. RESULTS: When assessed using a fluorescence-activated cell sorting (FACS) assay, anti-AQP-4 antibodies were seen exclusively in those SS patients with NMOSD (72.7%), but not in SS patients without NMOSD (P < 0.01). In contrast, anti-Ro 52, anti-Ro 60, and other autoantibodies were not more prevalent in SS patients with NMOSD versus those without. Anti-AQP-4 antibodies were detected more frequently among NMOSD patients by FACS assay than with a commercial immunohistochemical assay (72.7% versus 54.5%), despite assessment after a more prolonged period of immunosuppressive therapy (median 38 months versus 5 months; P < 0.01). CONCLUSION: The syndrome-specificity of anti-AQP-4 antibodies, along with an otherwise similar antibody profile in SS NMOSD patients, indicates that NMOSD is not a direct central nervous system manifestation of SS. Anti-AQP-4 antibodies can persist and be refractory to prolonged immunosuppressive therapy.

Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI.

OBJECTIVE: To compare different semiquantitative and quantitative methods using both non-enhanced and gadolinium-enhanced MRI techniques for the assessment of synovitis in knee osteoarthritis (OA). METHODS: Knees with end-stage clinical OA in patients undergoing total knee replacement surgery were included in this cross-sectional study. MRI was performed on all knees. Standard non-enhanced and gadolinium-enhanced sequences were acquired. Using non-enhanced MRI, we semiquantitatively assessed two features widely used as surrogates for synovitis: effusion-synovitis and Hoffa-synovitis. Using gadolinium-enhanced sequences, we semiquantitatively assessed synovial thickness. We quantitatively evaluated the total synovial volume on the gadolinium-enhanced sequences as well. We assessed the correlations of effusion-synovitis and Hoffa-synovitis with synovial thickness and volume, applying Spearman correlation analysis. The diagnostic performance of both synovitis features on non-enhanced MRI was assessed using synovial thickness on gadolinium-enhanced MRI as the reference. RESULTS: A total of 104 subjects (one knee per subject) were included. Correlations of effusion-synovitis with synovial thickness and volume were r = 0.41 and r = 0.43 (P < .001) r = 0.32 and r = 0.39 (P < .0001). CONCLUSION: Using synovial thickness assessed on gadolinium-enhanced sequences as the reference, effusion-synovitis showed superior correlations and sensitivity. Effusion-synovitis should be preferred over Hoffa-synovitis as a surrogate marker for synovial thickening, in studies of knee OA for which gadolinium-enhanced sequences are not available.

Survival following salvage abdominoperineal resection for persistent and recurrent squamous cell carcinoma of the anus: do these disease categories affect survival?

AIM: This study aimed to investigate the results of salvage abdominoperineal excision (APR) in patients with persistent or recurrent squamous cell carcinoma of the anus (SCCA). METHOD: Patients with anal neoplasia were identified from a prospective database. Patients with invasive SCCA with demonstrated failure of chemoradiation therapy (CRT) who underwent salvage APR for one of three disease categories (persistent, < 6 months post-CRT; early recurrent, 6-24 months post-CRT; late recurrent, > 24 months post-CRT) were included. The primary outcome was overall survival after salvage APR. Tumour size, metastatic lymph nodes (LN), circumferential resection margin positivity (CRM) and neurolymphovascular invasion (NLVI) were correlated with the outcome. RESULTS: Thirty-six patients with a median 3-year overall survival of 46% (median follow-up 24 months) underwent salvage APR due to persistent or recurrent SCCA (14 men, mean age 59 years). Eleven (31%) patients were diagnosed with persistent disease, 17 (47%) with early and 8 (22%) with late recurrence. Two-year overall survival of Stage 0/I/II and III/IV disease was 81.5% and 33.74%, respectively (P = 0.022). Overall disease stage was associated with disease categorization (P = 0.009): patients with persistent disease or early recurrence had a significantly higher disease stage than patients with late recurrence (OR = 20.9 and 17.2). Despite apparently improved survival in patients with late disease recurrence on live table analysis, no significant difference was identified in overall survival when stratified by disease category on log-rank test analysis. CONCLUSION: Persistent and recurrent disease does not show any significant difference in survival, but patients with late recurrence may have a better prognosis.

Measures of user experience in a streptococcal pharyngitis and pneumonia clinical decision support tools.

OBJECTIVE: To understand clinician adoption of CDS tools as this may provide important insights for the implementation and dissemination of future CDS tools. MATERIALS AND METHODS: Clinicians (n=168) at a large academic center were randomized into intervention and control arms to assess the impact of strep and pneumonia CDS tools. Intervention arm data were analyzed to examine provider adoption and clinical workflow. Electronic health record data were collected on trigger location, the use of each component and whether an antibiotic, other medication or test was ordered. Frequencies were tabulated and regression analyses were used to determine the association of tool component use and physician orders. RESULTS: The CDS tool was triggered 586 times over the study period. Diagnosis was the most frequent workflow trigger of the CDS tool (57%) as compared to chief complaint (30%) and diagnosis/antibiotic combinations (13%). Conversely, chief complaint was associated with the highest rate (83%) of triggers leading to an initiation of the CDS tool (opening the risk prediction calculator). Similar patterns were noted for initiation of the CDS bundled ordered set and completion of the entire CDS tool pathway. Completion of risk prediction and bundled order set components were associated with lower rates of antibiotic prescribing (OR 0.5; CI 0.2-1.2 and OR 0.5; CI 0.3-0.9, respectively). DISCUSSION: Different CDS trigger points in the clinician user workflow lead to substantial variation in downstream use of the CDS tool components. These variations were important as they were associated with significant differences in antibiotic ordering. CONCLUSIONS: These results highlight the importance of workflow integration and flexibility for CDS success.

Clinical and pathologic differences in interstitial lung disease based on antisynthetase antibody type.

BACKGROUND: Interstitial lung disease (ILD) is a common extramuscular manifestation of the idiopathic inflammatory myopathies (IIMs), dermatomyositis (DM) and polymyositis (PM). Patients with antisynthetase antibodies (ASA) demonstrate some or all of the features of the antisynthetase syndrome including IIM and ILD. It has been hypothesized that the clinical expression of antisynthetase syndrome varies between specific ASAs. OBJECTIVE: We sought to determine whether the myositis-associated ILD (MA-ILD) phenotype differs based on the presence of ASAs and by ASA subtype. METHODS: A cross-sectional and longitudinal analysis of consecutive patients enrolled at the Johns Hopkins Myositis Center with ILD in the setting of clinically diagnosed autoimmune myositis was conducted. RESULTS: Seventy-seven subjects were included; 36 were ASA negative, 28 were anti-Jo1 positive, and 13 were non-Jo1 ASA positive (5 anti-PL-12, 4 anti-PL-7, 2 anti-EJ, and 2 anti-OJ). Non-Jo1 ASA positive participants were more likely to be African-American than Caucasian as compared to both the anti-Jo1 positive (p = 0.01) and ASA negative groups (p < 0.01). ASA negative participants had better mean forced vital capacity percent predicted (FVC%) and total computed tomography scores over time compared to those with anti-Jo1 after controlling for potential confounders. CONCLUSIONS: ASA status was significantly different by race. Those with anti-Jo1 antibodies had worse lung function and CT scores over time compared to those without detectable antisynthetase antibodies. Further prospective study in a larger cohort is needed to determine whether these apparent antibody-specific differences in demographics and manifestations of disease translate into meaningful disparities in clinical outcomes.

Anti-MDA5 positive clinically amyopathic dermatomyositis presenting with severe cardiomyopathy.

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated gene 5) positive dermatomyositis is a new variant of clinically amyopathic dermatomyositis that presents with characteristic mucocutaneous findings and is associated with a higher risk of developing rapidly progressive interstitial lung disease. Because its presentation differs from that of classical dermatomyositis, this entity can be a diagnostic challenge for the clinician. METHODS & RESULTS: We present the case of a 55-year-old male with a 7-month history of chill sensation, constitutional symptoms and polyarthralgia. Within 3 months, the patient developed progressive heart failure with dyspnoea and orthopnoea, together with characteristic cutaneous lesions. Skin biopsies demonstrated thrombosis of small and medium-sized arteries in the reticular dermis, together with an evolved lobular panniculitis and prominent mucin deposits. CONCLUSIONS: Clinicians should be aware of the characteristic clinical and histopathologic presentation of this variant of dermatomyositis to establish an early diagnosis. Further evidence is needed to clarify the risk of cardiac involvement in this subset of patients.

A fault tree model to assess probability of contaminant discharge from shipwrecks.

Shipwrecks on the sea floor around the world may contain hazardous substances that can cause harm to the marine environment. Today there are no comprehensive methods for environmental risk assessment of shipwrecks, and thus there is poor support for decision-making on prioritization of mitigation measures. The purpose of this study was to develop a tool for quantitative risk estimation of potentially polluting shipwrecks, and in particular an estimation of the annual probability of hazardous substance discharge. The assessment of the probability of discharge is performed using fault tree analysis, facilitating quantification of the probability with respect to a set of identified hazardous events. This approach enables a structured assessment providing transparent uncertainty and sensitivity analyses. The model facilitates quantification of risk, quantification of the uncertainties in the risk calculation and identification of parameters to be investigated further in order to obtain a more reliable risk calculation.

Effect of rifampin on the pharmacokinetics, safety and tolerability of navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-XL , in patients with cancer.

WHAT IS KNOWN AND OBJECTIVE: Navitoclax, a first-in-class small molecule Bcl-2 family inhibitor, is metabolized in vitro by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4. Drugs that affect CYP3A4 may therefore have an impact on the pharmacological profile of navitoclax. This study evaluated the effects of co-administration of a potent CYP3A4 inducer rifampin on the pharmacokinetic and safety profiles of navitoclax. METHODS: This open-label, fixed-sequence, 2-period study was performed in twelve subjects with non-haematologic or haematologic malignancy that was relapsed or refractory to standard therapy. A 7-day washout period separated the two treatment periods. On Study Day 1 and Day 8, subjects received a single 250 mg oral dose of navitoclax. Rifampin 600 mg was administrated once daily (QD) on Study Day 4 through Day 10. Blood samples for navitoclax assay were collected prior to dosing (0 h) and at a series of time points through 72 h after dosing on Study Day 1 and Day 8. RESULTS AND DISCUSSION: Co-administration of a single 250 mg dose of navitoclax with 600 mg QD doses of rifampin had a negligible effect on the maximum plasma concentration (Cmax ) of navitoclax [ratio of geometric least square means: 0·84 (90% CI: 0·61-1·16)] but moderately decreased the area under the plasma concentration-time curve (AUC) of navitoclax [ratio of geometric least square means: 0·59 (90% CI: 0·44-0·80)]. Rifampin did not affect the half-life of navitoclax. Co-administration of rifampin did not appear to significantly change the safety profile of navitoclax in the limited number of patients evaluated in this study. WHAT IS NEW AND CONCLUSION: Co-administration navitoclax with rifampin moderately decreased navitoclax AUC, which could be partly due to the induction effect of rifampin on CYP3A4. Further assessment on the mechanism of drug interaction is warranted.