Integrated Systems Health Management (ISHM) Toolkit

A framework of software components has been implemented to facilitate the development of ISHM systems according to a methodology based on Reliability Centered Maintenance (RCM). This framework is collectively referred to as the Toolkit and was developed using General Atomics' Health MAP (TM) technology. The toolkit is intended to provide assistance to software developers of mission-critical system health monitoring applications in the specification, implementation, configuration, and deployment of such applications. In addition to software tools designed to facilitate these objectives, the toolkit also provides direction to software developers in accordance with an ISHM specification and development methodology. The development tools are based on an RCM approach for the development of ISHM systems. This approach focuses on defining, detecting, and predicting the likelihood of system functional failures and their undesirable consequences

Enhanced Selection of High Affinity DNA-Reactive B Cells Following Cyclophosphamide Treatment in Mice

A major goal for the treatment of patients with systemic lupus erythematosus with cytotoxic therapies is the induction of long-term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects of cyclophosphamide on the selection of the re-emerging B cell repertoire in wild type mice and transgenic mice that express the H chain of an anti-DNA antibody. The reconstituting B cell repertoire in wild type mice contained an increased frequency of DNA-reactive B cells; in heavy chain transgenic mice, the reconstituting repertoire was characterized by an increased frequency of mature, high affinity DNA-reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in serum levels of BAFF. Treatment of transgene-expressing mice with a BAFF blocking agent or with DNase to reduce exposure to autoantigen limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, not only is negative selection of high affinity DNA-reactive B cells impaired by increased BAFF, but also that B cells escaping negative selection are positively selected by autoantigen. There are significant implications for therapy

Integrated System Health Management (ISHM) Implementation in Rocket Engine Testing

A pilot operational ISHM capability has been implemented for the E-2 Rocket Engine Test Stand (RETS) and a Chemical Steam Generator (CSG) test article at NASA Stennis Space Center. The implementation currently includes an ISHM computer and a large display in the control room. The paper will address the overall approach, tools, and requirements. It will also address the infrastructure and architecture. Specific anomaly detection algorithms will be discussed regarding leak detection and diagnostics, valve validation, and sensor validation. It will also describe development and use of a Health Assessment Database System (HADS) as a repository for measurements, health, configuration, and knowledge related to a system with ISHM capability. It will conclude with a discussion of user interfaces, and a description of the operation of the ISHM system prior, during, and after testing

Monitoring System for Storm Readiness and Recovery of Test Facilities: Integrated System Health Management (ISHM) Approach

Severe weather events are likely occurrences on the Mississippi Gulf Coast. It is important to rapidly diagnose and mitigate the effects of storms on Stennis Space Center's rocket engine test complex to avoid delays to critical test article programs, reduce costs, and maintain safety. An Integrated Systems Health Management (ISHM) approach and technologies are employed to integrate environmental (weather) monitoring, structural modeling, and the suite of available facility instrumentation to provide information for readiness before storms, rapid initial damage assessment to guide mitigation planning, and then support on-going assurance as repairs are effected and finally support recertification. The system is denominated Katrina Storm Monitoring System (KStorMS). Integrated Systems Health Management (ISHM) describes a comprehensive set of capabilities that provide insight into the behavior the health of a system. Knowing the status of a system allows decision makers to effectively plan and execute their mission. For example, early insight into component degradation and impending failures provides more time to develop work around strategies and more effectively plan for maintenance. Failures of system elements generally occur over time. Information extracted from sensor data, combined with system-wide knowledge bases and methods for information extraction and fusion, inference, and decision making, can be used to detect incipient failures. If failures do occur, it is critical to detect and isolate them, and suggest an appropriate course of action. ISHM enables determining the condition (health) of every element in a complex system-of-systems or SoS (detect anomalies, diagnose causes, predict future anomalies), and provide data, information, and knowledge (DIaK) to control systems for safe and effective operation. ISHM capability is achieved by using a wide range of technologies that enable anomaly detection, diagnostics, prognostics, and advise for control: (1) anomaly detection algorithms and strategies, (2) fusion of DIaK for anomaly detection (model-based, numerical, statistical, empirical, expert-based, qualitative, etc.), (3) diagnostics/prognostics strategies and methods, (4) user interface, (5) advanced control strategies, (6) integration architectures/frameworks, (7) embedding of intelligence. Many of these technologies are mature, and they are being used in the KStorMS. The paper will describe the design, implementation, and operation of the KStorMS; and discuss further evolution to support other needs such as condition-based maintenance (CBM)

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington’s disease

Background: Huntington’s disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent ‘incurability’ often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. Methods: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. Results: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n = 81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p < 0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. Conclusions: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570