Improving recognition of early clinical decline: Determining reliability and validity of the Garvey clinical warning curves.

BACKGROUND: New graduate nurses have difficulty recognizing and managing the early signs of clinical decline, resulting in a Failure to Rescue (FTR) event and preventable patient death. To address this gap, Garvey developed a series of Clinical Warning Curves as an instructional tool for new graduate nurses in an academic medical center. The Garvey Clinical Warning Curve models depict the progression of clinical changes in six body systems that occur before cardiac arrest. AIMS: The purpose of this study was to establish the content validity, reliability, and usability of the Garvey Clinical Warning Curves among healthcare experts and new-graduate nurses. METHODS: The current study was a cross-sectional, observational, validation survey design. Content experts used the content validity index (CVI) to evaluate the Curves. RESULTS: All but the temperature curves were rated as "acceptable" (CVI >0.60) for relevance, clarity, and ambiguity. The new graduate nurses who reviewed the case studies and placed patients onto the Clinical Warning Curves did so similarly, generating high intraclass correlation (ICC) scores. The usability survey components measured the perceptions of acceptability, appropriateness, and feasibility for the use of the six Clinical Warning Curves in practice settings. All components of the Curves had an average score of 4.0 or greater except for the level of complexity which scored 3.88. LINKING EVIDENCE TO ACTION: The Garvey Clinical Warning Curves emerged as valid and reliable tools that aid new graduate nurses in recognizing subtle signs of clinical decline. Because timely recognition and communication of clinical decline are key to preventing FTR events and avoiding patient deaths, it would be beneficial to provide the Clinical Warning Curves as a bedside resource for new graduate nurses during their orientation to the unit or within a nurse residency program.

Implications of fatherhood in cystic fibrosis.

Advances in fertility treatment mean that men with CF are increasingly able to become fathers. Here we report clinical outcomes in 22 men with CF who have become fathers for the first time. Overall mean (SD) FEV1% predicted declined from 60.1(18.0)% to 57.4(20.2)% from baseline to 1 year (p = 0.15). Weight declined from mean (SD) 70.6 kg (10.4) to 68.3 kg (10.2), p = 0.0001. Six men had an FEV1% predicted ≤40% at the time of birth: 50% died or received lung transplantation within the 12-15 month follow up period. Becoming a parent is a major life event, and as with new mothers, fathers with CF may be at risk of significant decline.

Amyloid status imputed from a multimodal classifier including structural MRI distinguishes progressors from nonprogressors in a mild Alzheimer's disease clinical trial cohort.

INTRODUCTION: Mild-Alzheimer's disease (AD) subjects without significant Aß pathology represent a confounding finding for clinical trials because they may not progress clinically on the expected trajectory, adding variance into analyses where slowing of progression is being measured. METHODS: A prediction model based on structural magnetic resonance imaging (MRI) in combination with baseline demographics and clinical measurements was used to impute Aß status of a placebo-treated mild-AD sub-cohort (N = 385) of patients participating in global phase 3 trials. The clinical trajectories of this cohort were evaluated over 18 months duration of the trial, stratified by imputed Aß status within a mixed-model repeated measures statistical framework. RESULTS: In the imputed Aß-positive cohort, both cognitive (ADAS-Cog14 and MMSE) and functional (ADCS-iADL) measures declined more rapidly than in the undifferentiated population. DISCUSSION: Our results demonstrate imputing Aß status from MRI scans in mild-AD subjects may be a useful screening tool in global clinical trials if amyloid measurement is not available.

Plasma Interleukin-6 Predicts Clinical Decline After Completion of Dexamethasone Therapy in Severe COVID-19.

To identify and characterize clinical decline after completion of dexamethasone in severe COVID-19 and determine whether interleukin (IL)-6 and other inflammatory biomarkers predict the occurrence of clinical decline. DESIGN: Prospective observational cohort. SETTING: ICUs in three University of Washington affiliated hospitals between July 2020 and April 2021. PATIENTS: Patients admitted to an ICU with COVID-19 who completed a course of dexamethasone. MEASUREMENTS AND MAIN RESULTS: We identified 65 adult patients with severe COVID-19 who completed a 10-day course of dexamethasone, of whom 60 had plasma samples collected within 3 days of dexamethasone completion. We measured IL-6 with a clinical-grade electrochemiluminescent assay and a larger panel of inflammatory biomarkers (IL-8, Monocyte Chemoattractant Protein-1, Monocyte Inflammatory Protein-1 alpha, interferon gamma, C-X-C Motif Chemokine Ligand 10, WBC, bicarbonate) with a research immunoassay. We defined clinical decline by the occurrence of incident severe kidney injury, incident or escalating shock or fever, worsening hypoxemia, or death within 5 days of completion of dexamethasone. We estimated risk for clinical decline by standardized log2 transformed biomarker concentration using multivariable logistic regression. Clinical decline post-dexamethasone was common, occurring in 49% of patients (n = 32). Among all biomarkers, IL-6 levels were most strongly associated with clinical decline. After adjustment for age, sex, and study site, the odds of post-dexamethasone clinical decline were 7.33 times higher per one sd increase in log2 transformed IL-6 concentrations (adjusted odds ratio, 7.33; CI, 2.62-20.47; p < 0.001). The discriminatory power of IL-6 for clinical decline was high (cross-validated mean area under the receiver operating characteristic curve, 0.90; 95% CI, 0.79-0.95). CONCLUSIONS: Clinical decline after completion of dexamethasone for severe COVID-19 is common. IL-6 concentrations obtained prior to completion of dexamethasone may have utility in identifying those at highest risk for subsequent worsening. If validated, future work might test whether plasma IL-6 could be used as a tool for a personalized approach to duration of dexamethasone treatment in severe COVID-19.

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death.

BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. OBJECTIVE: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. METHODS: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-ß (Aß), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline. RESULTS: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aß burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. CONCLUSION: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals.

The biological mechanisms that link Beta-amyloid (Aß) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aß-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aß-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aß burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aß burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage.

Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease.

Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.