Measure Of Treatment Efficacy Research Articles

Type 2 diabetes mellitus accelerates brain aging and cognitive decline: Complementary findings from UK Biobank and meta-analyses.

Type 2 diabetes mellitus (T2DM) is known to be associated with neurobiological and cognitive deficits; however, their extent, overlap with aging effects, and the effectiveness of existing treatments in the context of the brain are currently unknown. We characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HCs). We also evaluated in a cohort of T2DM-diagnosed individuals using UK Biobank how disease chronicity and metformin treatment interact with the identified neurocognitive effects. The UK Biobank dataset included cognitive and neuroimaging data (N = 20,314), including 1012 T2DM and 19,302 HCs, aged between 50 and 80 years. Duration of T2DM ranged from 0 to 31 years (mean 8.5 ± 6.1 years); 498 were treated with metformin alone, while 352 were unmedicated. Our meta-analysis evaluated 34 cognitive studies (N = 22,231) and 60 neuroimaging studies: 30 of T2DM (N = 866) and 30 of aging (N = 1088). Compared to age, sex, education, and hypertension-matched HC, T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen, with reorganization of brain activity (decreased in the caudate and premotor cortex and increased in the subgenual area, orbitofrontal cortex, brainstem, and posterior cingulate cortex). The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. Metformin treatment status was not associated with improved neurocognitive outcomes. The neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging; disease duration was associated with increased neurodegeneration. Mechanistically, our results suggest a neurometabolic component to brain aging. Clinically, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects. The research described in this article was funded by the W. M. Keck Foundation (to LRMP), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRMP), and the Baszucki Brain Research Fund (to LRMP). None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. DJW reports serving on data monitoring committees for Novo Nordisk. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this article.

Outcomes Impacting Quality of Life in Advanced Parkinson's Disease Patients Treated with Levodopa-Carbidopa Intestinal Gel.

Background:It is believed that motor symptoms, including dyskinesia, and non-motor symptoms impact health-related quality of life (HRQoL) in patients with Parkinson’s disease (PD), and that improvements in these metrics are correlated.Objective:Investigate the relationship between HRQoL and measures of PD severity and treatment efficacy, including motor and non-motor symptoms.Methods:This was a planned investigation of an international, prospective, single-arm, post-marketing observational study of the long-term effectiveness of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD. Pearson correlation coefficients (PCC) were calculated for baseline and change from baseline at 12 months between HRQoL and motor and non-motor symptoms.Results:A total of 195 patients were included. At baseline, HRQoL was moderately positively correlated with Activities of Daily Living (UPDRS II, PCC = 0.44), non-motor symptoms (0.48), and measures of sleep (0.50 and 0.40); all p < 0.001. After 12 months of treatment with LCIG, improvements in HRQoL were moderately positively correlated with improvement from baseline in non-motor symptoms (PCC = 0.42), sleep (0.54), and daytime sleepiness (0.40; all p < 0.001), and weakly correlated with improvement in dyskinesia signs and symptoms (PCC = 0.23; p = 0.011). Improvement in HRQoL was not correlated with improvements in OFF time or dyskinesia time.Conclusion:Both at baseline and for change from baseline at 12 months, HRQoL was correlated with baseline and change from baseline in dyskinesia, Activities of Daily Living, and non-motor symptoms, including sleep; but not with baseline or change in OFF time.

Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts

BackgroundDespite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a “real-time” measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load.MethodsThe present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen.ResultsRegression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis.ConclusionsOur results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials.Trial registration NexGen EBA study (NCT02371681)

183 A Systematic Review of Sample Size Calculations in High-Profile Surgical Trials That Use Patient-Reported Outcome Measures.

Abstract Background Patient reported outcome measures (PROMs) are increasingly recognised as a measure of treatment efficacy in randomised controlled trials (RCTs). It can be difficult to determine meaningful target differences in PROM scores for sample size calculations and this can risk over-recruitment and/or erroneous trial conclusions. The Difference ELicitation in TriAls (DELTA2) statement sets recommendations for sample size calculations in RCTs including target difference determination. We aimed to evaluate sample size calculations from high-profile surgical RCTs that used PROMs as their primary outcome, against DELTA2 standards, with a focus on target differences. Method Pubmed was systematically searched for surgical RCTs published in the five highest ranking journals, by Thomson Reuters impact factor, for medicine and surgery. Studies were included if surgery was the intervention and/or comparator arm, and a PROM was the primary outcome. Surgery was defined as using instrumentation to change macro-anatomy with the aim of improving health. Data were extracted with a piloted data collection sheet that included the DELTA2 reporting recommendations. Results Most target differences used in sample size calculations were determined with suboptimal techniques and target difference justification was overall poor. In this sample, £28 million of UK public research spending supported trials with poor target difference justification. Conclusions In this sample of trials, sample size calculations were generally not reported to DELTA2 standards. There was frequent use of sub-optimal methods to determine the target difference. This risks over-recruitment and/or erroneous trial conclusions. Clinicians should be aware of these potential pitfalls when interpreting published trials.

Psychological Treatment Effects Unrelated to Hair-Cortisol and Hair-BDNF Levels in Chronic Tinnitus.

BackgroundCurrently, there are no objective markers to measure treatment efficacy in chronic (distressing) tinnitus. This study explores whether stress-related biomarkers cortisol and brain-derived neurotrophic factor (BDNF) measured in hair samples of chronic tinnitus patients change after compact multimodal tinnitus-specific cognitive behavioral therapy.MethodsIn this longitudinal study, hair-cortisol and hair-BDNF levels, self-reported tinnitus-related distress (Tinnitus Questionnaire; TQ), and perceived stress (Perceived Stress Questionnaire; PSQ-20) were assessed before and 3 months after 5 days of treatment in N = 80 chronic tinnitus patients. Linear mixed-effects models with backward elimination were used to assess treatment-induced changes, and a cross-lagged panel model (structural equation model) was used for additional exploratory analysis of the temporal associations between TQ and hair-BDNF.ResultsAt follow-up, a reduction in TQ (p < 0.001) and PSQ-20 scores (p = 0.045) was observed, which was not influenced by baseline hair-cortisol or hair-BDNF levels. No changes in biomarker levels were observed after treatment. The exploratory analysis tentatively suggests that a directional effect of baseline TQ scores on hair-BDNF levels at follow-up (trend; p = 0.070) was more likely than the opposite directional effect of baseline hair-BDNF levels on TQ scores at follow-up (n.s.).DiscussionWhile the treatment effectively reduced tinnitus-related distress and perceived stress in chronic tinnitus patients, this effect was not mirrored in biological changes. However, the lack of changes in hair-cortisol and hair-BDNF levels might have been influenced by the treatment duration, follow-up interval, or confounding medical factors, and therefore must be interpreted with caution. The relationship between tinnitus-related distress and hair-BDNF levels should be explored further to obtain a better understanding of stress-related effects in chronic tinnitus.

Patient-Reported Anxiety/Depression After Endovascular Thrombectomy: A post-hoc Analysis of Direct-MT Trial.

ObjectiveTo analyze the effect of endovascular thrombectomy (EVT) alone vs. EVT after an intravenous (IV) alteplase of ischemic stroke on a patient-reported anxiety/depression, and to identify predictors of patient-reported anxiety/depression by analyzing data from Direct Intraarterial Thrombectomy in Order to Revascularize the patients with Acute Ischemic Stroke with a Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial (DIRECT-MT).MethodsPatients with acute ischemic stroke (AIS), triggered by a large-vessel occlusion in the anterior circulation, were randomly allocated to undergo an EVT after IV alteplase (combination-therapy group) or an EVT alone (EVT-alone group) at a 1:1 ratio in DIRECT-MT. Patients in both groups were followed up for 90 days (±14 days) after stroke using a structured modified Ranking Scale (mRS), a Barthel Index (BI), and a 5-Dimensional European Quality of Life Scale (EQ-5D-5L). Patients who returned EQ-5D-5L were included. The EQ-5D-5L anxiety/depression dimension was used to analyze the patient-reported anxiety/depression. First, differences in patient-reported anxiety/depression were compared between the combination-therapy group and the EVT-alone group. Then, the baseline and influencing factors between the anxiety/depression group and no anxiety/depression group were analyzed using univariate regression analysis. Finally, variables with p < 0.1 in univariate regression were subjected to multivariable binary regression analysis to screen independent predictors for patient-reported anxiety /depression after ischemic stroke.Results: Five hundred fifteen patients returned the EQ-5D-5L in Direct-MT. Of these patients, 226 (43.88%) reported a level of anxiety/depression, and about 7% reported a severe or extremely severe anxiety/depression. The patient-reported anxiety/depression in the EVT-alone group was significantly higher than that in the combination-therapy group (48.26% vs. 39.45%, p = 0.04). The clinical outcomes were significantly different between the no Anxiety/Depression Group and the anxiety/depression group (mRS at 90 days:2 vs 3, p < 0.001; BI of 95 or 100 at 90 days: 73.36% vs 42.04%, p < 0.001; EQ-5D-5l utility indexes at 90 days:0.96 vs.57, p < 0.001). Logistic regression analysis showed that allocation to thrombolysis before EVT strategy was inversely associated with anxiety/depression [0.61(0.40, 0.94), p = 0.03], an insular cortex ischemia, and National Institute of Health Strocke Scale (NIHSS) at 7 days were positively associated with anxiety/depression [2.04(1.07, 3.90), p = 0.03; 1.07(1.03, 1.12), p < 0.001].ConclusionsPatient-reported anxiety/depression may suggest that there is a benefit to administering intravenous alteplase before EVT. It may also indicate that it is better to provide IV alteplase before EVT, rather than EVT alone according to patient-reported anxiety/depression. Future research should consider not only the motor function impairments but also the patient-reported mental problems as measures of treatment efficacy in patients with stroke (DIRECT-MT ClinicalTrials.gov number, NCT03469206).

A head-to-head randomised controlled trial of aripiprazole versus quetiapine as augmenting agents in treatment-resistant depression

Introduction: Almost 30%–50% of the patients with major depressive disorder can be categorised as treatment-resistant depression (TRD). The use of augmenting agents such as aripiprazole (ARI) and quetiapine (QP) to the existing antidepressant (AD) therapy could be a suitable alternative for treating TRD. The superiority of anyone over others is not established in short-term studies. Hence, the present study was performed to compare the safety and efficacy of ARI and QP for the treatment of TRD. Materials and Methods: In the present study, a total of 50 patients with TRD who showed insufficient response to at least two ADs for 12 weeks were enrolled. The participants were assigned randomly in a double-blind trial to receive ARI (10 mg/day; n = 25) or QP (300 mg/day; n = 25) in addition to their standard AD therapy for 12 weeks. Montgomery–Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions (CGI) scale were used to measure treatment efficacy. The safety was evaluated by recording treatment-caused adverse effects (AEF). Results: A significant decrease in MADRS score was observed with ARI groups than in the QP group (‒7.5; ‒4.6, P < 0.001). The CGI scores in the ARI group also exhibit significant improvement compared with the QP group. There was a non-significant change in CGI score recorded in both groups. The AEF was observed in 11% of patients with more incidences in the QP groups. The incidences of AEFs resulting in discontinuation of therapy were found low in both groups (ARI: 1.6%; QP: 3.2%). Conclusion: The findings of this study conclude that TRD patients can be more benefitted by ARI augmentation therapy than QP.

Test‐retest variability of relative tracer delivery rate as measured by [11C]PiB

AbstractBackgroundIn Alzheimer’s disease (AD), reductions in cerebral blood flow (CBF) have been reported and these may be used as proxy for measuring treatment efficacy or disease progression. The gold standard technique for measuring CBF is [15O]H2O positron emission tomography (PET). Recent studies, however, have reported high correlations between [11C]PiB PET derived relative tracer delivery rate R 1 and [15O]H2O derived relative CBF, suggesting that [11C]PiB R 1 may be a good proxy of relative CBF. As longitudinal PET studies become more common for measuring disease progression, it is important to know the intrinsic variability of R 1. The purpose of the present study was to determine R 1 test‐retest (TRT) variability.MethodPreviously, TRT variability of [11C]PiB binding potential has been reported for a group of twelve participants (five cognitively unimpaired (CU), one with mild cognitive impairment and six with AD dementia), in which all participants underwent two 90 min [11C]PiB PET scans using a Siemens ECAT EXACT HR+ scanner1. This dataset was reanalysed to also determine TRT variability of [11C]PiB R1. The voxel‐based implementation of the two‐step simplified reference tissue model with cerebellar grey matter as reference tissue was used to generate R1 images. Next, TRT variability was calculated both globally and regionally, and global R1 measures were compared between diagnostic groups using a non‐parametric Mann‐Whitney U test. Next, correlation analysis was used to assess the relationship between TRT variability and regional volume. Finally, regional test and retest R1 measures were compared using Linear Mixed Effect Models and Bland‐Altman analysis.ResultGlobal relative tracer delivery (R1) was significantly lower in AD patients (test R1:0.82±0.04, retest R1:0.82±0.03) compared with CU participants (test R1:0.93±0.04 retest R1:0.91±0.03, p&lt;0.01). TRT variability was low across regions (range:1.5‐5.8%), with a trend effect towards smaller TRT for larger regions (R2=0.14, p=0.09). Furthermore, test and retest measures showed high, significant correlations (R2=0.92, slope=0.98) and negligible bias (0.69±3.07%).ConclusionThe high precision of [11C]PiB R1 suggests suitable applicability for cross‐sectional and longitudinal studies. This finding further demonstrates the utility of dynamic [11C]PiB PET scans for dual‐biomarker imaging in AD research. Reference: Tolboom et al.(2009) Eur J Nucl Med Mol Imaging 36:1629‐38.

Plasma and serum neurofilament-light levels increase in an age- and pathology-dependent manner in the Arctic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia of the elderly in the US. No disease-modifying drugs have been approved, indicating a need for novel targets and relevant biomarkers to follow treatment efficacy. Neurofilament-light (NfL) is an intermediate filament protein in neurons that increases in plasma after injury and neurodegeneration, suggesting it may be a biomarker of neurodegeneration before other symptoms are evident. Here, we measured blood NfL levels in the Arctic AD mouse and compared levels to a neuroprotective Arctic model in which C5aR1 was genetically ablated (C5aR1KO) and to levels of a microglial activation marker CD11c and fibrillar plaque load in brain. Blood was collected via cardiac puncture from WT, Arctic, C5aR1KO, and ArcticC5aR1KO at 5, 7, 10, and 13 months of age and processed for plasma or serum isolation. The MSD NfL kit was used to detect NfL. Immunohistochemical detection of CD11c-positive microglia and ThioS-stained plaques were analyzed by Imaris. Comparison of NfL in both WT and Arctic mice demonstrated increased levels in Arctic and WT with increasing age (p=0.02 and 0.01, respectively) and a trend for greater levels in Arctic vs WT at 7 (p=0.1) and 13 (p=0.08) months. In ArcticC5aR1KO mice, there was a 44% reduction in NfL compared to Arctic mice at 7 months. Interestingly, by 10 months, NfL levels in ArcticC5aR1KO plasma was 35% higher than in Arctic mice, suggesting that the protective effect observed at 7 months in the ArcticC5aR1KO mice is superseded by 10 months. Similarly, the increase in CD11c and ThioS levels were lower (44%, 37% respectively) in the hippocampus of ArcticC5aR1KO CONCLUSION: This study demonstrated that NfL modulation can be detected with therapeutic intervention (i.e. C5aR1KO), and that changes in NfL paralleled changes in CD11c-positive microglia and fibrillar plaque load. These data suggest that blood levels of NfL can be used in the Arctic mouse model of AD as a biomarker of age and disease progression, which may serve as a noninvasive tool to measure treatment efficacy.

Efficacy of Dupilumab in Atopic Dermatitis: The Patient's Perspective.

IntroductionAtopic dermatitis (AD), a predominantly type 2 inflammatory skin disease, affects approximately 2–5% of adults, with a high burden of disease. In moderate-to-severe AD, lesions can be extensive and pruritus intense with patients experiencing skin pain, sleep and mental health disturbances, and diminished quality of life (QoL).MethodsThe objective of this study was to evaluate the efficacy of dupilumab for the treatment of AD from the patients’ perspective using patient-reported outcome data from four clinical trials (CHRONOS, SOLO 1&2, and CAFÉ) in patients (N = 1553) receiving either the approved 300 mg q2w dupilumab with/without topical corticosteroids (TCS) dose or control (placebo or placebo + TCS). Patient Global Assessment of Disease Status (PGADS) was used to measure patients’ well-being and Patient Global Assessment of Treatment Effect (PGATE) was used to measure treatment efficacy. Patients were asked “Considering all the ways in which your eczema affects you, indicate how well you are doing” to assess their perception of well-being and “How would you rate the way your eczema responded to the study medication?” to assess their perception of treatment effect. Possible responses for both metrics included poor, fair, good, very good, and excellent.ResultsIn all four studies, a significantly higher proportion of dupilumab-treated patients reported “Good”/”Very Good”/”Excellent” disease status from week 2 through study end versus control (CHRONOS, 52 weeks: 69.8% vs. 25.1%; SOLO 1&2, 16 weeks: 59.5% vs. 24.6%; CAFÉ, 16 weeks: 84.1% vs. 45.4%; all P < 0.0001), and significantly more dupilumab-treated patients reported “Good”/”Very Good”/”Excellent” treatment efficacy versus control (CHRONOS: 72.6% vs. 24.8%; SOLO 1&2: 65.0% vs. 21.1%; CAFÉ, 16 weeks: 85.0% vs. 36.1%; all P < 0.0001).ConclusionAdult patients with AD perceived that dupilumab with/without concomitant TCS was highly efficacious and improved overall disease status and well-being as early as week 2 and throughout treatment periods up to 1 year. Video (MP4 90521 kb)Electronic Supplementary MaterialThe online version of this article (10.1007/s13555-021-00621-w) contains supplementary material, which is available to authorized users.

Real-World Single-Center Comparison of the Safety and Efficacy of Entecavir, Tenofovir Disoproxil Fumarate, and Tenofovir Alafenamide in Patients with Chronic Hepatitis B

Introduction: Chronic hepatitis B (CHB) is a major cause of chronic liver diseases and tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and entecavir (ETV) are recommended as primary treatments. This study aimed to evaluate the efficacy and safety of ETV, TDF, and TAF in a real-world clinical setting. Methods: In this retrospective cohort study, a total of 363 CHB patients who were treated with ETV (n = 163), TDF (n = 154), or TAF (n = 46) from July 2007 to September 2019 were enrolled. Results: Median patient age was 51 years and 66.4% of patients were male. Median duration of treatment with ETV, TDF, or TAF was 49.0 months (interquartile range, 27.0–74.0 months). In terms of safety, cholesterol was mildly increased in the ETV and TAF groups and significantly lowered in the TDF group than baseline (p < 0.001). There was no significant difference in liver cirrhosis-related complications among the 3 groups at 48 weeks (p = 0.235). Hepatitis B e antigen seroconversion, complete virological response, and alanine aminotransferase normalization at 48 weeks as measures of treatment efficacy were not significantly different among the 3 groups (p = 0.142, 0.538, and 0.520, respectively). There was also no significant difference in cumulative incidence rate of hepatocellular carcinoma (HCC) between the ETV and TDF groups (p = 0.894). Conclusions: ETV, TDF, and TAF were safe antiviral agents and showed similar antiviral effect for CHB at 48 weeks. Cirrhosis-related complications and annual HCC incidence rates did not differ significantly between the ETV and TDF groups over the 48 week follow-up period.

226 Non-invasive skin-surface biomarkers for psoriasis monitoring

In clinical dermatology there is a need for non-invasive efficient and accurate diagnostic tools that can objectively measure psoriasis (PS) activity and can be used to monitor therapeutic effects of PS treatment. This exploratory study aimed to determine whether non-invasive measurements of proteins from PS lesional skin can be used to assess disease severity and measure treatment efficacy. BM measurements from skin were performed using non-invasive Transdermal Analysis Patch (TAP) capture antibody microarrays detecting IL-1α, IL-1RA, CXCL-1/2, hBD-1 (ng/ml). Captured BM were visualised using spot-ELISA.TAPs were applied to non-lesional (NL) and lesional (L) skin of PS patients (N=30). PASI and local inflammation scores of lesions were documented; thickness of epidermis, dermis, subepidermal lowechogenic band (SLEB) was analysed using ultrasound (US) at the same skin site as TAP measurements and clinical scores. Potential of these skin-surface BM was further studied by monitoring skin lesions of PS patients (N=14) undergoing UVB (311nm) therapy using TAP together with clinical scores for PS severity. Skin surface measurements of PS patients revealed clear differences of IL-1a, IL-1RA, CXCL-1/2 on L skin when compared to NL. Comparing BM expression patterns with clinical scores of PS skin following correlations were observed: between CXCL-1/2 and lesion thickness (p<0.05), between CXCL-1/2 and SLEB thickness (p<0.001) on L; IL-1RA and SLEB thickness (p<0.05) of analysed NL skin. During UVB treatment, clear patterns towards normalisation of IL-1RA and CXCL-1/2 levels were noted on L which was in accordance with clinical parameters. Skin surface analysis of IL-1RA and CXCL-1/2 displayed a different profile than achieved by visual scoring of local inflammation or US - confirming that measuring the ‘molecular root’ of inflammation appears to have value as an objective, non-invasive BM measurement for scoring disease severity in its own right.

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies.

Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.

Clinical characteristics and outcomes of adult patients with acquired thrombotic thrombocytopenic purpura: a single center retrospective study.

Thrombotic thrombocytopenic purpura (TTP) is a rare disease and a potentially life-threatening thrombotic microangiopathy. Although the diagnostic and therapeutic techniques have improved, it is still difficult for clinicians to identify early due to different initial clinical manifestations and the incidence and survival rate are reported inconsistently. This study investigated the clinical characteristics, treatment strategies, and treatment outcomes of adult patients with acquired TTP. A retrospective analysis of 55 patients (35 females and 20 males) treated for acquired TTP from January 1, 2013 to December 31, 2017 was conducted. The analysis included clinical manifestations at onset, treatment efficacy measures, survival, cause of death, and the APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (sequential organ failure assessment) scores. At onset, in addition to thrombocytopenia and hemolysis, 50 patients (90.91%) presented with neurological abnormalities, but only 19 (34.55%) showed the classic TTP pentad of symptoms. The overall mortality rate was 34.55%. Plasma exchange (PEX) was performed in 49 patients. The most effective treatment was PEX with a normal dose of corticosteroid and rituximab which showed a response rate of 81.25%. The main cause of death was cerebral hemorrhage. The APACHE II and SOFA scores were higher in non-survivors compared to survivors (APACHE II: 20.12±7.83 vs. 11.50±4.49, P<0.05; SOFA: 12.06±3.27 vs. 7.74±2.10, P<0.05). Non-survivors had higher levels of lactic dehydrogenase (LDH; 1,646.94±1,269.48 vs. 942.76±740.58 IU/L, P=0.015), and higher numbers of schistocytes (6.18%±4.69% vs. 3.44%±3.13%, P=0.035) compared to survivors. TTP progressed rapidly, and its clinical manifestations varied between patients. The diagnosis depended on the clinical features and laboratory tests. Combination therapy with PEX, immunosuppressive therapy, and rituximab may be useful. Higher APACHE II and SOFA scores, higher LDH levels, and a greater degree of schistocytosis were associated with the severity and outcome of TTP.

Use of a Collar-Mounted Triaxial Accelerometer to Predict Speed and Gait in Dogs.

Simple SummaryAccelerometers have been used for several years to monitor activity in free-moving dogs. The technique has particular utility for measuring the efficacy of treatments for osteoarthritis when changes to movement need to be monitored over extended periods. While collar-mounted accelerometer measures are precise, they are difficult to express in widely understood terms, such as gait or speed. This study aimed to determine whether measurements from a collar-mounted accelerometer made while a dog was on a treadmill could be converted to an estimate of speed or gait. We found that gait could be separated into two categories—walking and faster than walking (i.e., trot or canter)—but we could not further separate the non-walking gaits. Speed could be estimated but was inaccurate when speed exceeded 3 m/s. We conclude that collar-mounted accelerometers only allowing limited categorisation of activity are still of value for monitoring activity in dogs.Accelerometry has been used to measure treatment efficacy in dogs with osteoarthritis, although interpretation is difficult. Simplification of the output into speed or gait categories could simplify interpretation. We aimed to determine whether collar-mounted accelerometry could estimate the speed and categorise dogs’ gait on a treadmill. Eight Huntaway dogs were fitted with a triaxial accelerometer and then recorded using high-speed video on a treadmill at a slow and fast walk, trot, and canter. The accelerometer data (delta-G) was aligned with the video data and records of the treadmill speed and gait. Mixed linear and logistic regression models that included delta-G and a term accounting for the dogs’ skeletal sizes were used to predict speed and gait, respectively, from the accelerometer signal. Gait could be categorised (pseudo-R2 = 0.87) into binary categories of walking and faster (trot or canter), but not into the separate faster gaits. The estimation of speed above 3 m/s was inaccurate, though it is not clear whether that inaccuracy was due to the sampling frequency of the particular device, or whether that is an inherent limitation of collar-mounted accelerometers in dogs. Thus, collar-mounted accelerometry can reliably categorise dogs’ gaits into two categories, but finer gait descriptions or speed estimates require individual dog modelling and validation. Nonetheless, this accelerometry method could improve the use of accelerometry to detect treatment effects in osteoarthritis by allowing the selection of periods of activity that are most affected by treatment.

Test-Retest Variability of Relative Tracer Delivery Rate as Measured by [11C]PiB

PurposeModerate-to-high correlations have been reported between the [11C]PiB PET-derived relative tracer delivery rate R1 and relative CBF as measured using [15O]H2O PET, supporting its use as a proxy of relative CBF. As longitudinal PET studies become more common for measuring treatment efficacy or disease progression, it is important to know the intrinsic variability of R1. The purpose of the present study was to determine this through a retrospective data analysis.ProceduresTest-retest data belonging to twelve participants, who underwent two 90 min [11C]PiB PET scans, were retrospectively included. The voxel-based implementation of the two-step simplified reference tissue model with cerebellar grey matter as reference tissue was used to compute R1 images. Next, test-retest variability was calculated, and test and retest R1 measures were compared using linear mixed effect models and a Bland-Altman analysis.ResultsTest-retest variability was low across regions (max. 5.8 %), and test and retest measures showed high, significant correlations (R2=0.92, slope=0.98) and a negligible bias (0.69±3.07 %).ConclusionsIn conclusion, the high precision of [11C]PiB R1 suggests suitable applicability for cross-sectional and longitudinal studies.

Time-To-Event Data: An Overview and Analysis Considerations

In oncology, overall survival and progression-free survival are common time-to-event end points used to measure treatment efficacy. Analyses of this type of data rely on a complex statistical framework and the analysis results are only valid when the data meet certain assumptions. This article provides an overview of time-to-event data, the basic mechanics of common analysis methods, and issues often encountered when analyzing such data. Our goal is to provide clinicians and other lung cancer researchers with the knowledge to choose the appropriate time-to-event analysis methods and to interpret the outcomes of such analyses appropriately. We strongly encourage investigators to seek out statisticians with expertise in survival analysis when embarking on studies that include time-to-event data to ensure that their data are collected and analyzed using the appropriate methods.

Serum HER2 levels predict treatment efficacy and prognosis in patients with HER2-positive breast cancer undergoing neoadjuvant treatment.

Controversy remains regarding the predictive and prognostic value of serum human epidermal growth factor receptor 2 (HER2) in breast cancer. The purpose of this retrospective study was to determine the clinical utility and efficacy of serum HER2 (sHER2) in predicting treatment response and prognosis in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy and trastuzumab treatment. A total of 309 HER2-positive breast cancer patients diagnosed at Fudan University Shanghai Cancer Center from July 2015 to January 2019 were analyzed. Baseline sHER2 levels were obtained for all patients and sHER2 levels were collected after 2 cycles of treatment in 208 patients. A sHER2 level ≥15 ng/mL was regarded as "high expression" and sHER2 <15 ng/mL was regarded as "low expression". Outcome measures of treatment efficacy and prognosis were pathological complete response (pCR) and invasive disease-free survival (iDFS), respectively. In patients with high baseline sHER2, more were ER-negative (P=0.029), had larger tumor size (P=0.006), more advanced clinical stage (P=0.002), higher Miller-Payne grade (P=0.024) and higher likelihood of iDFS events (P=0.015). Patients with high sHER2 levels after 2 cycles of treatment had lower pCR rates (P=0.038), higher Miller-Payne grade (P=0.013) and higher likelihood of iDFS events (P=0.003). Kaplan-Meier analysis showed significant differences in iDFS between patients with high and low sHER2 levels at baseline (P=0.019) and after 2 cycles of treatment (P=0.000). Further analyses according to cancer subtypes found baseline sHER2 to be significantly correlated with the iDFS of Luminal B patients (p=0.002), while sHER2 levels after 2 cycles of treatment was significantly correlated with the iDFS of HER2-enriched patients (P=0.000). Univariate analysis showed significant association between iDFS and tumor size (P=0.026), lymph node status (P=0.008), clinical stage (P=0.031), baseline sHER2 (P=0.024), overall tumor response (P=0.011), pCR (P=0.043) and Miller-Payne grade (P=0.001). Multivariate analysis found Miller-Payne grade (P=0.037) to be significantly associated with iDFS. Our results demonstrate the clinical value of sHER2 in a population of Chinese breast cancer patients, suggesting that sHER2 levels after 2 cycles of neoadjuvant therapy may be more predictive of treatment outcomes and that the prognostic value of sHER2 may be time point and subtype dependent.

Apnea-hypopnea index supplied by CPAP devices: time for standardization?

Background/objectiveFor obstructive sleep apnea (OSA) patients on continuous positive airway pressure (CPAP) treatment, the apnea-hypopnea index (AHI) is a key measure of treatment efficacy. However, the residual AHI is CPAP brand specific. Here, we studied changes in residual AHI in patients who used two different brands over their treatment history. Patients/methodsUsing our CPAP telemonitoring database of 3102 patients, we compared the residual AHI of 69 patients before and after change in their CPAP device. ResultsA paired Wilcoxon signed-rank test revealed a significant difference between brands in the reported AHI, which might be clinically misleading. ConclusionsThese findings suggest that physicians should be alerted to the differences between brands and learned societies should push for standardization of AHI reporting.

Hypoglossal Nerve Stimulation in Veterans With Comorbid Insomnia and Sleep Apnea.

Insomnia and sleep apnea frequently co-occur, with additive effects of both disorders presenting clinicians with unique treatment challenges compared to one disorder alone. The hypoglossal nerve stimulator (HNS) is a promising treatment for patients with comorbid insomnia and sleep apnea (COMISA), many of whom have positive airway pressure (PAP) intolerance. Our aim was to determine adherence to and efficacy of HNS in veterans with COMISA refractory to PAP therapy compared to those with obstructive sleep apnea alone (OSA only). Retrospective case series. A single, academic Veterans Affairs medical center. Review of clinical records, pre- and postoperative polysomnography, and clinical measures of obstructive sleep apnea (OSA), sleepiness, and insomnia was conducted in 53 consecutive cases of veterans with OSA undergoing HNS implantation. HNS adherence was obtained at postoperative visits. HNS adherence and efficacy were compared between individuals with COMISA and OSA only. COMISA was noted in 30 of 53 (56.6%) veterans studied. There was no significant difference between HNS adherence in patients with COMISA and OSA only (5.6 vs 6.4 h/night, P = .17). HNS implantation improved polysomnographic and clinical measures of OSA and sleepiness in both COMISA and OSA only, and 56.5% (13/23) of patients with COMISA self-reported improvement in insomnia after surgery. HNS was successful in treating a complex veteran population with COMISA refractory to PAP when examining measures of treatment adherence and efficacy. Future studies of patients with COMISA undergoing HNS will examine effective combination therapy targeting insomnia and a multidisciplinary effort to optimize treatment adherence.