Risk Of Clinical Progression Research Articles

Anti-spike antibody level is associated with the risk of clinical progression among subjects hospitalized with COVID-19 pneumonia: results from a retrospective cohort study.

Antibodies against SARS-CoV-2 spike (anti-S) may confer protection against symptomatic COVID-19. Whether their level predicts progression among those with COVID-19 pneumonia remains unclear. We conducted a retrospective cohort study to assess predictors of anti-S levels and whether anti-S titer is associated with death or mechanical ventilation (MV). Adults hospitalized for COVID-19 pneumonia between July 2021 and July 2022 were enrolled if anti-S had been measured within 72h of admission. Predictors of anti-S level were explored using multivariable quantile regression. The association between anti-S levels and 30-day death/MV was investigated via multivariable logistic regression. Analyses were stratified by vaccine status. The median anti-S level was 1370 BAU/ml in 328 vaccinated and 15.5 BAU/ml in 206 unvaccinated individuals. Among the vaccinated, shorter symptom duration (p = 0.001), hematological malignancies (p = 0.002), and immunosuppressive therapy (p = 0.004) were associated with lower anti-S levels. In the unvaccinated group, symptom duration was the only predictor of anti-S levels (p < 0.001). After 30days, 134 patients experienced death or MV. Among vaccinated individuals, higher anti-S levels correlated significantly with lower death/MV risk (per log2 increase, OR 0.88, 95%CI 0.81-0.97), irrespective of age and solid malignancies. Among unvaccinated, a marginally protective effect was observed (OR 0.86, 95%CI 0.73-1.01), independent of age, immunosuppressive therapy, and diabetes. Adjustment for monoclonal antibody treatment strengthened the association (OR 0.81, 95%CI 0.68-0.96). This study suggests that levels of anti-S antibodies can predict critical or fatal outcomes in COVID-19 pneumonia patients, regardless of vaccination. Whether anti-S Ab could guide risk assessment and vaccination boosting merits further evaluation.

541. The Effect of Early Remdesivir Administration in COVID-19 Disease Progression

Abstract Background Since the global outbreak of SARS-CoV-2, antiviral drugs have played a major role in the treatment of COVID-19 by reducing complications and mortality. Remdesivir is an effective therapeutic option for hospitalized patients with risk for clinical progression with COVID-19 who cannot receive nirmatrelvir/ritonavir mainly because of kidney &amp; liver disease or issues with drug- interactions. Remdesivir can be administered for as long as 7 days after symptom onset according to treatment recommendations, but antiviral treatment work best when given as early as possible. In this study we investigated the impact of timing of remdesivir administration on clinical outcome. Methods Retrospective clinical data from consecutive PCR-confirmed SARS-CoV-2 patients who received remdesivir and were hospitalized at the department of infectious diseases, Clinic Favoriten (Vienna) from the 1st of July 2021 until the 31st of April 2022 were analyzed. We divided patients into two groups of early (0-3 days since symptom onset) and late (≥ 4) remdesivir administration. The primary outcome was in hospital disease progression measured according to the WHO COVID-19 Clinical Progression Scale (≥1 point). In a multivariable logistic regression adjusted for age, sex, SARS-CoV2 variant, and COVID-19 vaccination status, clinical outcomes were assessed. Results 219 patients who received remdesivir could be included in the analysis. The ratio between early and late group was 67.6% to 32.4%. After adjusting for age, sex, vaccination status, and viral variant, patients who received remdesivir more than 4 days after symptom onset tended to have a higher probability of clinical deterioration (OR 2,13 95% CI 0,98 to 4,64, p= 0,056) including a higher probability for high-flow oxygen therapy (OR 2,52 95% CI 1,40 to 4,52, p= 0,002) or being admitted to ICU (OR 4,34 95% CI 1,38 to 13,67, p= 0,012). There was no significant difference in mortality.Table 1.Demographic and Clinical Characteristics of the PatientsTable 2.Clinical outcomes adjusted to age, sex, virus variant and vaccination status Conclusion Our data show that the risk for complications of COVID19 including a need for high-flow oxygen therapy and ICU admission is elevated when remdesivir is administered after day 4 in hospitalized patients. This may indicate that patients at increased risk for severe disease who cannot take oral options should receive antiviral therapy with remdesivir as early as possible. Disclosures Moritz Platzer, MD, Gilead: Grant/Research Support

8 Perspectives of Self, Stigma, and the Future Following Alzheimer's Disease Biomarker Disclosure in Cognitively Symptomatic Older Adults

AbstractObjective:In the absence of treatments to halt or reverse symptoms of Alzheimer's disease, early detection may extend the window for meaningful treatment, advanced planning, and coping. Positron emission tomography (PET) scans for amyloid and tau are validated biomarkers of AD, yet results are rarely disclosed to participants due to concerns about negative impacts. While prior studies suggest limited anxiety, depression, or suicidality following biomarker disclosure, no study to date has examined broader psychological impacts of PET amyloid/tau disclosure to symptomatic individuals. Therefore, we explored post-disclosure changes in future time perspective (perceptions of limited time or possibilities left in the future), self-efficacy for managing symptoms, and perceived stigma as a function of result received.Participants and Methods:Forty-three older adults (age = 72.0±6.2 years; education = 16.5±2.6; 88.4% White Non-Hispanic; 48.8% female) participated in the study, of whom 62.8% were diagnosed with mild cognitive impairment (MCI) and the remainder with Dementia of the Alzheimer's type. All participants underwent pre-disclosure biomarker education and decisional capacity assessment, followed by baseline measures. Participants demonstration decisional capacity completed an interactive disclosure session during which they received dichotomous results of their research positron emission tomography (PET) scans for amyloid and tau (elevated versus not elevated for each biomarker). Findings were discussed in relation to presence/absence of Alzheimer's disease, the etiology of their cognitive difficulties, and risk for conversion or further decline. At baseline, immediately following disclosure, and at 1-week follow-up, participants completed several questionnaires: the Future Time Perspective (FTP) scale, a measure of how much the participant sees time as limited, the Self Efficacy for Managing Chronic Disease scale (SECD), and the Stigma Scale for Chronic Illness (SSCI-8), all of which were modified to apply to Alzheimer's disease and associated experiences.Results:The main effects of time (F=1.10, p=.334, A?p2=.026), biomarker status (F(1)=3.10, p=.086, Ajp2=.070), and the time by biomarker status interaction (F=0.39, p=.661, Ajp2=.009) on FTP score was not significant. Though neither time (F=0.07, p=.933, A?p2=.002) nor the time by biomarker status interaction (F=2.16, p=.122, Ajp2=.050) effect on SECD was significant, being biomarker positive (A+T-/A+T+) was associated with lower self-efficacy (F(1)=5.641, p=.022, Ajp2=.121). Neither main effect for time (F=0.15, p=.853, Ajp2=.004) or biomarker status (F(1)=0.35, p=.558, A?p2=.009) on SSCI-8 was significant. The time by biomarker status interaction was significant (f=4.27, p=.018, =.096), such that biomarker negative participants experience a transient increase in perceived stigma directly after disclosure that resolves one week later, and biomarker negative participants experience the opposite pattern.Conclusions:Findings suggest that individuals who receive biomarker positive results may feel less competent to manage their symptoms compared to those who are biomarker negative, emphasizing the need for post-disclosure interventions targeting self-efficacy. The effect of disclosure on perceptions of time being limited and on perceived stigma were minimal, even when those results indicate evidence of Alzheimer's disease and risk for clinical progression. These results further support the safety of biomarker disclosure procedures. Future studies should provide longer-term assessment of psychological, behavioral, and clinical outcomes following Alzheimer's disease biomarker disclosure.

Evaluation of risk factors for the development of bacteremia and complications in patients with brucellosis: Is it possible to predict the clinical course?

Brucellosis is often confused with other diseases or accompanies the conditions it imitates. It causes treatment delays, failure, relapse, and complications. This study aimed to investigate bacteremia and complication predictors in Brucellosis patients. Early detection may help reduce relapse rates, length of hospital stay, and surgical intervention rates by providing appropriate treatment. We examined 220 adult patients diagnosed with Brucellosis in our tertiary care hospital in the Black Sea Region between January 01, 2010, and January 01, 2022. Patients with and without bacteremia and complications were compared regarding demographic characteristics, clinical features, and laboratory parameters. The mean age was 46.4 ± 15.8 years (18-96 years), and 61% were male. Low back pain and absence of muscle pain were independent risk factors for predicting bacteremia (p = 0.049, p = 0.043, respectively). Weakness /fatigue, weight loss, and 1/320 Standard Tube Agglutination Test (STAT) or Brucella Coombs Gel Test (BCGT) titers were independent risk factors that reduced the risk of complications; in contrast, low back pain and splenomegaly were independent risk factors for development of complications. (p = 0.025, p = 0.007, p = 0.008, p = 0.003, p = 0.021 respectively). Thrombocytopenia was related to complications. When the platelet cut-off value was taken as 160,000/µL in predicting complications, the sensitivity was 31.30%, and the specificity was 97.73% (p = 0.011). The risk of clinical progression and complications could be predicted with symptoms and signs such as myalgia, low back pain, weakness/fatigue, weight loss, splenomegaly, and easily accessible laboratory parameters such as serum STAT/BCGT titer and platelet level.

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

Abstract 5839: Novel stroma-derived prostate cancer subtypes are associated with risk of clinical progression

Abstract The tumor microenvironment influences prostate cancer aggressiveness, and by focusing on how different changes to the microenvironment can affect the cancer, we aimed to identify novel stromal subtypes in localized prostate cancer (LPC), characterize these subtypes, and utilize subtypes to increase accuracy in prostate cancer risk stratification. Subtype identification was conducted using non-negative matrix factorization with consensus clustering on a stroma-specific expression signature in RNA sequencing data. A discovery cohort (127 LPC patients) and two independent validation cohorts (406 LPC &amp; 126 LPC patients) were used for subtype identification. All three cohorts were subsequently used for subtype characterization and prognostic evaluation. Identified subtypes were characterized by evaluation of clinical characteristics, by gene set enrichment analysis, and by cell-type deconvolution analysis. Survival differences between subtypes were assessed using Kaplan-Meier and univariate Cox regression analyses with biochemical recurrence (BCR) as endpoint. Lastly, a high-risk stromal subtype was investigated for its ability to improve risk stratification for intermediate risk prostate cancer using hazard ratio changes from univariate Cox regression analysis. We identified three stromal subtypes (S1-S3) in prostate cancer. Of these, subtype S3 showed characteristics of a highly reactive stromal environment with significantly (adj. p &amp;lt; 0.05) decreased cell polarity and stroma related functions, significantly (adj. p &amp;lt; 0.05) reduced fibroblast infiltration, and a significantly (adj. p &amp;lt; 0.05) increased immune cells infiltration compared to the other subtypes. Survival analysis also revealed significant (p &amp;lt; 0.05) association of S3 with BCR in all three cohorts (HR = 3.2, 2.1, and 3.4 in cohorts 1, 2 and 3 respectively). Lastly, S3 significantly (p &amp;lt; 0.05) improved the risk prediction for patients with intermediate recurrence risk according to the clinical nomogram CAPRA-S (cohort 1, delta HR = 1.4; cohort 2, delta HR = 2.3; cohort 3, delta HR = 4.2). In conclusion, by focusing on the stromal alteration in prostate cancer, this study sheds new light on the influence of tumor microenvironment on LPC aggressiveness. A stromal subtype characterized by dysregulated stromal functions and changes in stroma and immune cells infiltration predicted adverse outcome in patients with a high prognostic ambiguity. This utilization of stromal information to improve risk assessment for clinically intermediate risk PC indicates a potential use in future evaluation of PC aggressiveness. Citation Format: Martin Rasmussen, Jacob Fredsøe, Paul V. Salachan, Marcus P. Blanke, Benedicte P. Ulhøi, Michael Borre, Karina D. Sørensen. Novel stroma-derived prostate cancer subtypes are associated with risk of clinical progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5839.

Outcomes after biochemical or clinical progression in patients with multiple myeloma.

Almost all patients with multiple myeloma (MM) eventually relapse, either asymptomatically or with end-organ damage. However, it remains unclear whether initiating therapy at the time of biochemical progression (BP) improves the outcomes compared with initiating therapy at the clinical progression (CP) stage. Here, we retrospectively assessed 1347 patients with relapsed MM. Most progressions were BP (60.4%); 39.6% had CP. The most prevalent symptoms at relapse were new or evolving bone disease (80.9%), anemia (38.0%), and renal failure (12.7%). Patients with BP had longer median time from second-line treatment to the next treatment compared with patients who had CP (17.0 vs 9.6 months; P< .001) as well as longer median overall survival from first relapse (59.4 vs 26.2 months; P< .001). Male sex (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02-2.18; P= .04), plasma cell labeling index ≥2% (OR, 1.58; 95% CI, 1.02-2.45; P= .04), and extramedullary disease at diagnosis (OR, 1.84; 95% CI, 1.08-3.13; P= .03) were associated with higher risk of CP, whereas very good partial remission or better had decreased risk of CP (OR, 0.62; 95% CI, 0.43-0.91; P= .02). To conclude, patients with CP have inferior postprogression outcomes compared with patients who have BP. Patients with deeper response to first-line therapy are less likely to develop CP. The presence of a specific CRAB (C, hypercalcemia; R, renal failure; A, anemia; B, bone disease) symptom at diagnosis predicts for the development of similar CRAB symptoms at relapse.

Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues.

Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.

Clinical, pathological and long-term oncologic outcomes of papillary type I vs. type II renal cell carcinoma.

Despite papillary renal cell carcinoma (pRCC) subtype represents the second most common histological renal tumor, controversial findings have been shown regarding its prognosis. Thus, we investigated the natural history of patients harbouring pRCC, focusing on its clinicopathological characteristics and long-term oncologic outcomes among pRCC subtypes. We identified 447 patients treated with either partial (PN) or radical nephrectomy (RN) for pRCC at a single tertiary centre, between 1994 and 2019. First, we explored differences in baseline and clinicopathological characteristics. Second, Kaplan-Meier plots investigated progression-free survival (PFS) and cancer-specific survival (CSS) differences among pRCC subtypes. Third, multivariable Cox-regression analyses (MVA) were used to assess predictors of clinical progression (CP) and cancer-specific mortality (CSM). Overall, 120 (27%) patients had symptoms at time of diagnosis. 263 (58.8%) vs. 184 (41.2%) patients underwent PN vs. RN. At histopathological evaluation, 243 (54.4%) harboured pRCC type I vs. 204 (45.6%) type II. pRCC type II more frequently showed higher tumor grade, tumor necrosis or lymphovascular invasion (all P<0.001). After a median follow-up of 51 months, 2.5% and 11% of patients had local relapse and CP, respectively. Kaplan-Meier plots revealed 93 vs. 83% 5-year PFS (P<0.001) and 96 vs. 89% 5-year CSS (P=0.01) for non-metastatic pRCC type I vs. II, respectively. At MVA, pRCC type II predicted higher risk of CP (Hazard ratio [HR]: 3.03, 95%CI 1.42-6.44; P=0.01), as well as of CSM (HR: 2.60, 95%CI 1.05-6.29; P=0.02), relative to pRCC type I. PRCC type II harbour more unfavorable tumor characteristics, such as higher tumor grade, more frequent tumor necrosis or lymphvascular invasion, which translates into worse long-term oncologic outcomes, compared with pRCC type I. Thus, patients harbouring pRCC type II may benefit from stricter follow-up, as well as earlier risk-based adjuvant therapies, based on potential worse oncologic outcomes in this patient population.

Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma

Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma

Inflammation and microbial translocation measured prior to combination antiretroviral therapy (cART) and long-term probability of clinical progression in people living with HIV

BackgroundDespite the effectiveness of cART, people living with HIV still experience an increased risk of serious non-AIDS events, as compared to the HIV negative population. Whether pre-cART microbial translocation (MT) and systemic inflammation might predict morbidity/mortality during suppressive cART, independently of other known risk factors, is still unclear. Thus, we aimed to investigate the role of pre-cART inflammation and MT as predictors of clinical progression in HIV+ patients enrolled in the Icona Foundation Study Cohort.MethodsWe included Icona patients with ≥2 vials of plasma stored within 6 months before cART initiation and at least one CD4 count after therapy available. Circulating biomarker: LPS, sCD14, EndoCab, hs-CRP. Kaplan-Meier curves and Cox regression models were used. We defined the endpoint of clinical progression as the occurrence of a new AIDS-defining condition, severe non-AIDS condition (SNAEs) or death whichever occurred first. Follow-up accrued from the data of starting cART and was censored at the time of last available clinical visit. Biomarkers were evaluated as both binary (above/below median) and continuous variables (logescale).ResultsWe studied 486 patients with 125 clinical events: 39 (31%) AIDS, 66 (53%) SNAEs and 20 (16%) deaths. Among the analyzed MT and pro-inflammatory markers, hs-CRP seemed to be the only biomarker retaining some association with the endpoint of clinical progression (i.e. AIDS/SNAEs/death) after adjustment for confounders, both when the study population was stratified according to the median of the distribution (1.51 mg/L) and when the study population was stratified according to the 33% percentiles of the distribution (low 0.0–1.1 mg/L; intermediate 1.2–5.3 mg/L; high > 5.3 mg/L). In particular, the higher the hs-CRP values, the higher the risk of clinical progression (p = 0.056 for median-based model; p = 0.002 for 33% percentile-based model).ConclusionsOur data carries evidence for an association between the risk of disease progression after cART initiation and circulating pre-cART hs-CRP levels but not with levels of MT. These results suggest that pre-therapy HIV-driven pro-inflammatory milieu might overweight MT and its downstream immune-activation.

Determinants of loss to care and risk of clinical progression in PLWH who are re-engaged in care after a temporary loss

The risk of developing AIDS is elevated not only among those with a late HIV diagnosis but also among those lost to care (LTC). The aims were to address the risk of becoming LTC and of clinical progression in LTC patients who re-enter care. Patients were defined as LTC if they had no visit for ≥ 18 months. Of these, persons with subsequent visits were defined as re-engaged in care (RIC). Factors associated with becoming LTC and RIC were investigated. The risk of disease progression was estimated by comparing RIC with patients continuously followed. Over 11,285 individuals included, 3962 became LTC, and of these, 1062 were RIC. Older age, presentation with AIDS and with higher HIV-RNA were associated with a reduced risk of LTC. In contrast, lower education level, irregular job, being an immigrant and injecting-drug user were associated with an increased LTC probability. Moreover, RIC with HIV-RNA > 200 copies/mL at the re-entry had a higher risk of clinical progression, while those with HIV-RNA ≤ 200 copies/mL had a higher risk of only non-AIDS progression. Patients re-entering care after being LTC appeared to be at higher risk of clinical progression than those continuously in care. Active strategies for re-engagement in care should be promoted.

Should We Use Clinical Tools to Identify Disease Progression?

The presence of disability progression in multiple sclerosis (MS) is an important hallmark for MS patients in the course of their disease. The transition from relapsing remitting (RRMS) to secondary progressive forms of the disease (SPMS) represents a significant change in their quality of life and perception of the disease. It could also be a therapeutic key for opportunities, where approaches different from those in the initial phases of the disease can be adopted. The characterization of structural biomarkers (e.g., magnetic resonance imaging or neurofilament light chain) has been proposed to differentiate between both phenotypes. However, there is no definite threshold between them. Whether the risk of clinical progression can be predicted by structural markers at early disease phases is still a focus of clinical research. However, several theories and pathological evidence suggest that both disease phenotypes are part of a continuum with common pathophysiological mechanisms. In this case, the clinical evaluation of the patients would play a preponderant role above destruction biomarkers for the early identification of disability progression and SPMS. For this purpose, the use of clinical tools beyond the Expanded Disability Status Scale (EDSS) should be considered. Besides established functional tests such as the Multiple Sclerosis Functional Composite (MSFC), patient's neurological history or digital resources may help neurologists in the decision-taking. In this article, we discuss arguments for the use of clinical markers in the detection of secondary progressive MS and the characterization of progressive disease activity.

Using advanced analysis of multifocal visual-evoked potentials to evaluate the risk of clinical progression in patients with radiologically isolated syndrome

This study aimed to assess the role of multifocal visual-evoked potentials (mfVEPs) as a guiding factor for clinical conversion of radiologically isolated syndrome (RIS). We longitudinally followed a cohort of 15 patients diagnosed with RIS. All subjects underwent thorough ophthalmological, neurological and imaging examinations. The mfVEP signals were analysed to obtain features in the time domain (SNRmin: amplitude, Latmax: monocular latency) and in the continuous wavelet transform (CWT) domain (bmax: instant in which the CWT function maximum appears, Nmax: number of CWT function maximums). The best features were used as inputs to a RUSBoost boosting-based sampling algorithm to improve the mfVEP diagnostic performance. Five of the 15 patients developed an objective clinical symptom consistent with an inflammatory demyelinating central nervous system syndrome during follow-up (mean time: 13.40 months). The (SNRmin) variable decreased significantly in the group that converted (2.74 ± 0.92 vs. 4.07 ± 0.95, p = 0.01). Similarly, the (bmax) feature increased significantly in RIS patients who converted (169.44 ± 24.81 vs. 139.03 ± 11.95 (ms), p = 0.02). The area under the curve analysis produced SNRmin and bmax values of 0.92 and 0.88, respectively. These results provide a set of new mfVEP features that can be potentially useful for predicting prognosis in RIS patients.

Occupational influences on Spondylolysis and Spondylolisthesis in a cohort of 18-year-old male military conscripts

BackgroundThe reported prevalence of spondylolysis (SL) in the adult population is 6–7%. Data concerning adolescent-onset spondylolisthesis (SLS) and the impact of certain activities on it is scarce. We examined the risk of clinical progression of SL and SLS as a function of primary severity and occupational strain among military recruits.MethodsBased on the Israel defense Force (IDF) central human resources database, we identified 1521 18-year-old males inducted to the IDF with SL/SLS between the late nineteen nineties and early two-thousands. We followed changes in the SL/SLS status during the 3 years of obligatory military service. Disease severity was classified as Cat2: radiological findings of SL without clinical findings; Cat3: painful SL or asymptomatic grade 1 SLS; Cat4: grade 1 SLS with pain; Cat5: Grade 2 SLS. The soldiers were subdivided into the following occupational categories: administrative, combat, maintenance, and driving. The purpose was to compare the progression rates in different medical categories and job assignments.ResultsThere were 162 recruits in Cat2, 961 in Cat3, and 398 recruits in Cat4. The overall progression rate to Cat5 (grade 2 SLS) was 1.02%. Significant progression rates were seen amongst administrative soldiers with a relatively higher risk of progression from Cat4 (painful-grade-1 SLS: 2.2%) vs. Cat3 (asymptomatic SLS: 0.5%, relative risk = 4.7, p < 0.02). Other occupational categories did not exhibit significant progression rates.ConclusionProgression of SL/SLS was highest in Cat4, i.e. for recruits already diagnosed with painful SLS (i.e. with a more severe baseline disorder). Progression did not correlate with military occupation. We recommend further follow-up studies that include, aside from progression rates, incidence rates of newly diagnosed grade 2 SL during military service.

Computer Extracted Features from Initial H&E Tissue Biopsies Predict Disease Progression for Prostate Cancer Patients on Active Surveillance.

Simple SummaryActive surveillance (AS) prostate cancer patients suffer from a lower quality of life, increased risk of anxiety and depression, and an increased risk of disease progression compared to patients who opt for curative treatment. The current inclusion criteria for AS patients is unable to accurately identify patients with increased risk of progression, and therefore there is a need for a risk stratification technique that can identify patients with a higher risk of disease progression. In this work, we leverage quantitative histomorphometric (QH) features describing nuclear position, shape, orientation, and clustering from initial H&E biopsy images to accurately identify AS-eligible patients who are at high risk for disease progression. Our findings indicate that QH features were correlated with the risk of clinical progression in AS-eligible patients and was able to out-perform judgements based on clinical variables such as Gleason score and pro-PSA.In this work, we assessed the ability of computerized features of nuclear morphology from diagnostic biopsy images to predict prostate cancer (CaP) progression in active surveillance (AS) patients. Improved risk characterization of AS patients could reduce over-testing of low-risk patients while directing high-risk patients to therapy. A total of 191 (125 progressors, 66 non-progressors) AS patients from a single site were identified using The Johns Hopkins University’s (JHU) AS-eligibility criteria. Progression was determined by pathologists at JHU. 30 progressors and 30 non-progressors were randomly selected to create the training cohort D1 (n = 60). The remaining patients comprised the validation cohort D2 (n = 131). Digitized Hematoxylin & Eosin (H&E) biopsies were annotated by a pathologist for CaP regions. Nuclei within the cancer regions were segmented using a watershed method and 216 nuclear features describing position, shape, orientation, and clustering were extracted. Six features associated with disease progression were identified using D1 and then used to train a machine learning classifier. The classifier was validated on D2. The classifier was further compared on a subset of D2 (n = 47) against pro-PSA, an isoform of prostate specific antigen (PSA) more linked with CaP, in predicting progression. Performance was evaluated with area under the curve (AUC). A combination of nuclear spatial arrangement, shape, and disorder features were associated with progression. The classifier using these features yielded an AUC of 0.75 in D2. On the 47 patient subset with pro-PSA measurements, the classifier yielded an AUC of 0.79 compared to an AUC of 0.42 for pro-PSA. Nuclear morphometric features from digitized H&E biopsies predicted progression in AS patients. This may be useful for identifying AS-eligible patients who could benefit from immediate curative therapy. However, additional multi-site validation is needed.

Cognitive reserve and midlife vascular risk: Cognitive and clinical outcomes.

ObjectiveExamine whether cognitive reserve moderates the association of 1) vascular risk factors and 2) white matter hyperintensity burden with risk of clinical progression and longitudinal cognitive decline.MethodsBIOCARD Study participants were cognitively normal and primarily middle‐aged (M = 57 years) at baseline and have been followed with annual cognitive and clinical assessments (M = 13 years). Baseline cognitive reserve was indexed with a composite score combining education with reading and vocabulary scores. Baseline vascular risk (N = 229) was assessed with a composite risk score reflecting five vascular risk factors. Baseline white matter hyperintensity load (N = 271) was measured with FLAIR magnetic resonance imaging. Cox regression models assessed risk of progression from normal cognition to onset of clinical symptoms of Mild Cognitive Impairment. Longitudinal mixed effects models measured the relationship of these variables to cognitive decline, using a global composite score, and executive function and episodic memory sub‐scores.ResultsBoth vascular risk and white matter hyperintensities were associated with cognitive decline, particularly in executive function. Higher vascular risk, but not white matter hyperintensity burden, was associated with an increased risk of progression to Mild Cognitive Impairment. Higher cognitive reserve was associated with a reduced risk of symptom onset and higher levels of baseline cognition but did not modify the associations between the vascular risk score and white matter hyperintensities with clinical progression or cognitive decline.InterpretationAlthough cognitive reserve has protective effects on clinical and cognitive outcomes, it does not mitigate the negative impact of vascular risk and small vessel cerebrovascular disease on these same outcomes.

A novel predictor of clinical progression in patients on active surveillance for prostate cancer.

Active surveillance (AS) is standard of care in low-risk prostate cancer (PCa). This study describes a novel total cancer location (TCLo) density metric and aims to determine its performance in predicting clinical progression (CP) and grade progression (GP). This was a retrospective study of patients on AS after confirmatory biopsy (CBx). We excluded patients with Gleason ≥7 at CBx and <2 years followup. TCLo was the number of locations with positive cores at diagnosis (DBx) and CBx. TCLo density was TCLo/prostate volume (PV). CP was progression to any active treatment while GP occurred if Gleason ≥7 was identified on repeat biopsy or surgical pathology. Independent predictors of time to CP or GP were estimated with Cox regression. Kaplan-Meier analysis compared progression-free survival (PFS) curves between TCLo density groups. Test characteristics of TCLo density were explored with receiver operating characteristic (ROC) curves. We included 181 patients who had CBx from 2012-2015 and met inclusion criteria. The mean age of patients was 62.58 years (standard deviation [SD] 7.13) and median followup was 60.9 months (interquartile range [IQR] 23.4). A high TCLo density score (>0.05) was independently associated with time to CP (hazard ratio [HR] 4.70; 95% confidence interval [CI] 2.62-8.42; p<0.001) and GP (HR 3.85; 95% CI 1.91-7.73; p<0.001). ROC curves showed TCLo density has greater area under the curve than number of positive cores at CBx in predicting progression. TCLo density is able to stratify patients on AS for risk of CP and GP. With further validation, it could be added to the decision-making algorithm in AS for low-risk localized PCa.

Personalized risk for clinical progression in cognitively normal subjects\u2014the ABIDE project

BackgroundBiomarkers such as cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) have predictive value for progression to dementia in patients with mild cognitive impairment (MCI). The pre-dementia stage takes far longer, and the interpretation of biomarker findings is particular relevant for individuals who present at a memory clinic, but are deemed cognitively normal. The objective of the current study is to construct biomarker-based prognostic models for personalized risk of clinical progression in cognitively normal individuals presenting at a memory clinic.MethodsWe included 481 individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort. Prognostic models were developed by Cox regression with patient characteristics, MRI, and/or CSF biomarkers to predict clinical progression to MCI or dementia. We estimated 5- and 3-year individualized risks based on patient-specific values. External validation was performed on Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an European dataset.ResultsBased on demographics only (Harrell’s C = 0.70), 5- and 3-year progression risks varied from 6% [3–11] and 4% [2–8] (age 55, MMSE 30) to 38% [29–49] and 28% [21–37] (age 70, MMSE 27). Normal CSF biomarkers strongly decreased progression probabilities (Harrell’s C = 0.82). By contrast, abnormal CSF markedly increased risk (5 years, 96% [56–100]; 3 years, 89% [44–99]). The CSF model could reclassify 58% of the individuals with an “intermediate” risk (35–65%) based on the demographic model. MRI measures were not retained in the models.ConclusionThe current study takes the first steps in a personalized approach for cognitively normal individuals by providing biomarker-based prognostic models.

Biomechanical factors related to clinical vs. structural progression of knee OA

Purpose: The purpose of this presentation is to provide an overview of the in vivo human gait studies investigating biomechanical factors related to clinical (i.e. evidence of structural damage and symptoms) versus structural severity/progression in knee osteoarthritis (OA). Background: Biochemical responses, commonly triggered by biomechanical factors, are related to changes in the homeostatic balance of articular cartilage synthesis and degradation associated with OA. Historically, cartilage degradation has been the hallmark for OA; however, its effects on other structures such as muscles, ligaments, synovium and nerves are gaining recognition. The presence of symptoms is also fundamental in diagnosing OA (e.g. pain, stiffness, swelling, etc.), with pain as the most common symptom for seeking clinical care. Importantly, the level of pain and degree of structural damage are not well correlated in individuals with knee OA and suggest that each component may progress using different pathways. Much of our existing knowledge about OA mechanisms comes from fundamental in vitro or animal model studies that link biomechanical loading to biochemical responses related to OA processes (i.e. cartilage damage, inflammation and pain). In human models, gait (i.e. walking) studies have been the primary source of information for understanding knee joint-level loading in knee OA, and much of the work to date has examined joint moments from biomechanical models. Over the past 10 years an increasing number of studies have examined muscle activation patterns, including the contribution of muscles when modelling joint contact loads associated with OA processes. Summary: Differences in joint moment and muscle activation patterns have been associated with the level of structural severity, and evidence exists that associates specific pattern features with increased risk of structural progression defined using radiography and magnetic resonance imaging. Although fewer studies have focused on biomechanical and muscle activation patterns associated with clinical severity and risk of clinical progression, interesting trends are emerging and differ from features observed for structural outcomes. These gait studies provide information related to the magnitude, distribution, pattern and duration of joint loading. Features associated with the magnitude of joint moments are related to structural processes, whereas muscle function features and patterns of loading are linked with clinical outcomes such as joint replacement surgery. A critical evidence gap exists among these human studies related to the effect of loading frequency on OA progression. Aerobic exercise, particularly increasing walking frequency, is recommended across international non-surgical, non-pharmacological knee OA management guidelines based on pain relief, improved general health (i.e. cardiovascular outcomes), and the response of healthy cartilage to physical activity and exercise, but less on the effects on damaged tissue. The few human studies that link joint loading features during locomotion to biomarkers related to cartilage damage and pain processes in individuals with knee OA provide early evidence of a causal effect. Conclusions: Collectively, the work to date suggests that different biomechanical targets exist for structural versus clinical OA processes and should be considered when tailoring person-specific interventions.