Integrative Proteomic Characterization of Human Lung Adenocarcinoma.

Genomic studies of lung adenocarcinoma (LUAD) have advanced our understanding of the disease's biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD remain poorly understood. We carried out a comprehensive proteomics analysis of 103 cases of LUAD in Chinese patients. Integrative analysis of proteome, phosphoproteome, transcriptome, and whole-exome sequencing data revealed cancer-associated characteristics, such as tumor-associated protein variants, distinct proteomics features, and clinical outcomes in patients at an early stage or with EGFR and TP53 mutations. Proteome-based stratification of LUAD revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Further, we nominated potential drug targets and validated the plasma protein level of HSP 90ß as a potential prognostic biomarker for LUAD in an independent cohort. Our integrative proteomics analysis enables a more comprehensive understanding of the molecular landscape of LUAD and offers an opportunity for more precise diagnosis and treatment.

Ferroptosis-Related lncRNA to Predict the Clinical Outcomes and Molecular Characteristics of Kidney Renal Papillary Cell Carcinoma.

Kidney renal papillary cell carcinoma (KIRP) is a highly heterogeneous type of kidney cancer, resulting in limited effective prognostic targets for KIRP patients. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the regulation of ferroptosis and iron metabolism, making them potential targets for the treatment and prognosis of KIRP. In this study, we constructed a ferroptosis-related lncRNA risk score model (FRM) based on the TCGA-KIRP dataset, which represents a novel subtype of KIRP not previously reported. The model demonstrated promising diagnostic accuracy and holds potential for clinical translation. We observed significant differences in metabolic activities, immune microenvironment, mutation landscape, ferroptosis sensitivity, and drug sensitivity between different risk groups. The high-risk groups exhibit significantly higher fractions of cancer-associated fibroblasts (CAFs), hematopoietic stem cells (HSC), and pericytes. Drugs (IC50) analysis provided a range of medication options based on different FRM typing. Additionally, we employed single-cell transcriptomics to further analyze the impact of immune invasion on the occurrence and development of KIRP. Overall, we have developed an accurate prognostic model based on the expression patterns of ferroptosis-related lncRNAs for KIRP. This model has the potential to contribute to the evaluation of patient prognosis, molecular characteristics, and treatment modalities, and can be further translated into clinical applications.

Biochemical, biomechanical and imaging biomarkers of ischemic stroke: Time for integrative thinking.

Stroke is one of the leading causes of adult disability affecting millions of people worldwide. Post-stroke cognitive and motor impairments diminish quality of life and functional independence. There is an increased risk of having a second stroke and developing secondary conditions with long-term social and economic impacts. With increasing number of stroke incidents, shortage of medical professionals and limited budgets, health services are struggling to provide a care that can break the vicious cycle of stroke. Effective post-stroke recovery hinges on holistic, integrative and personalized care starting from improved diagnosis and treatment in clinics to continuous rehabilitation and support in the community. To improve stroke care pathways, there have been growing efforts in discovering biomarkers that can provide valuable insights into the neural, physiological and biomechanical consequences of stroke and how patients respond to new interventions. In this review paper, we aim to summarize recent biomarker discovery research focusing on three modalities (brain imaging, blood sampling and gait assessments), look at some established and forthcoming biomarkers, and discuss their usefulness and complementarity within the context of comprehensive stroke care. We also emphasize the importance of biomarker guided personalized interventions to enhance stroke treatment and post-stroke recovery.

Clinical outcome and peripheral immune profile of myasthenic crisis with omicron infections: A prospective cohort study.

The impact of Omicron infections on the clinical outcome and immune responses of myasthenia gravis (MG) remained largely unknown. From a prospective multicenter MG cohort (n = 189) with 197 myasthenic crisis (MC), we finally included 41 independent MG patients to classify into two groups: the Omicron Group (n = 13) and the Control Group (n = 28). In this matched cohort study, all-cause mortality was 7.69% (1/13) in Omicron Group and 14.29% (4/28) in Control Group. A higher proportion of elevated serum IL-6 was identified in the Omicron Group (88.89% vs 52.38%, P = 0.049). In addition, the proportions of CD3+CD8+T in lymphocytes and Tregs in CD3+CD4+ T cells were significantly elevated in the Omicron Group (both P = 0.0101). After treatment, the Omicron Group exhibited a marked improvement in MG-ADL score (P = 0.026) and MG-QoL-15 (P = 0.0357). MCs with Omicron infections were associated with elevated serum IL-6 and CD3+CD8+T response. These patients tended to present a better therapeutic response after fast-acting therapies and anti-IL-6 treatment.

Clinical and genomic characteristics of IMP-producing Enterobacter cloacae complex and Klebsiella pneumoniae.

Carbapenemase-producing Enterobacterales (CPEs) are one of the top priority antimicrobial-resistant pathogens. Among CPEs, those producing acquired metallo-ß-lactamases (MBLs) are considered particularly problematic as few agents are active against them. Imipenemase (IMP) is the most frequently encountered acquired MBL in Japan, but comprehensive assessment of clinical and microbiological features of IMP-producing Enterobacterales infection remains scarce. Here, we retrospectively evaluated 62 patients who were hospitalized at a university hospital in Japan and had IMP-producing Enterobacterales from a clinical culture. The isolates were either Enterobacter cloacae complex or Klebsiella pneumoniae, and most of them were isolated from sputum. The majority of K. pneumoniae, but not E. cloacae complex isolates, were susceptible to aztreonam. Sequence type (ST) 78 and ST517 were prevalent for E. cloacae complex and K. pneumoniae, respectively, and all isolates carried blaIMP-1. Twenty-four of the patients were deemed infected with IMP-producing Enterobacterales. Among the infected patients, therapy varied and largely consisted of conventional ß-lactam agents, fluoroquinolones, or combinations. Three (13%), five (21%), and nine (38%) of them died by days 14, 30, and 90, respectively. While incremental mortality over 90 days was observed in association with underlying comorbidities, active conventional treatment options were available for most patients with IMP-producing Enterobacterales infections, distinguishing them from more multidrug-resistant CPE infections associated with globally common MBLs, such as New Delhi metallo-ß-lactamase (NDM) and Verona integron-encoded metallo-ß-lactamase (VIM).

Effectiveness and toxicity of five-fraction prone accelerated partial breast irradiation.

PURPOSE: Our institution was an early adopter of 5-fraction accelerated partial breast irradiation (ABPI) to treat women with early-stage breast cancer. This study reports long-term oncologic and cosmetic outcomes. METHODS: We included patients receiving APBI 600 cGy × 5 fx delivered every other day or every day between 2010 and 2022. Logistic regression models were used to identify factors associated with development of late toxicities, clinician, and patient-rated cosmesis. Kaplan-Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free survival (LR-RFS). RESULTS: 442 patients received APBI either daily (56%) or every other day (44%) in the prone position (92%). At a median follow-up of 48 months (range: 5.96-155 months), 12 (2.7%) patients developed a local recurrence (LR). Out of 258 patients with > 3-month toxicity data available, the most common late grade ≥ 2 adverse event was breast fibrosis (6.2%). On multivariate analysis, daily APBI treatment (vs every other day) did not correlate with an increased risk of any late grade ≥ 2 toxicity though it did correlate with a lower risk of any late grade ≥ 2 fibrosis. Overall, at a median follow-up of 80 months, the rates of good-excellent physician and patient-rated cosmesis were 95% and 85%, respectively, with no difference between patients treated on consecutive vs. every other day. On multivariate analysis, patients who did not receive any adjuvant therapy were at increased risk of developing a LR. Five-year OS, LRFS, and DFS were 97.2%, 97.7%, and 89.5%, respectively. CONCLUSIONS: Five-fraction APBI delivered primarily in the prone position either daily or every other day was effective with low rates of local recurrence, minimal toxicity, and excellent cosmesis at long-term follow-up.

Clinical outcome assessments of disease burden and progression in late-onset GM2 gangliosidoses.

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials.

Increased human papillomavirus viral load is correlated to higher severity of cervical disease and poorer clinical outcome: A systematic review.

Cervical cancer is the fourth most common cancer in women worldwide and is caused by persistent infection with high-risk types of human papillomavirus (HPV). HPV viral load, the amount of HPV DNA in a sample, has been suggested to correlate with cervical disease severity, and with clinical outcome of cervical cancer. In this systematic review, we searched three databases (EMBASE, PubMed, Web of Science) to examine the current evidence on the association between HPV viral load in cervical samples and disease severity, as well as clinical outcome. After exclusion of articles not on HPV, cervical cancer, or containing clinical outcomes, 85 original studies involving 173 746 women were included. The vast majority (73/85 = 85.9%) reported that a higher viral load was correlated with higher disease severity or worse clinical outcome. Several studies reported either no correlation (3/85 = 3.5%), or the opposite correlation (9/85 = 10.6%); possible reasons being different categorization of HPV viral load levels, or the use of specific sampling methods. Despite variations in study design and populations, the above findings suggest that HPV viral load is correlated to clinical outcome, and may become an important biomarker for treatment selection and response monitoring for cervical cancer.

Clinical outcomes of transcarotid artery revascularization vs carotid endarterectomy from a large single-center experience.

BACKGROUND: Transcarotid artery revascularization (TCAR) has been practiced as an alternative for both carotid endarterectomy (CEA) and transfemoral carotid artery stenting, specifically in high-risk patients. More recently, the Centers for Medicare and Medicaid Services expanded coverage for TCAR in standard surgical risk patients if done within the Society for Vascular Surgery Vascular Quality Initiative TCAR surveillance project. A few registry studies (primarily from the Society for Vascular Surgery Vascular Quality Initiative) compared the early and up to 1-year outcomes of TCAR vs CEA or transfemoral carotid artery stenting. There is no large single-center study that reported late clinical outcomes. The present study compares intermediate clinical outcomes of TCAR vs CEA. METHODS: This study retrospectively analyzed collected data from TCAR surveillance project patients enrolled in our institution and compare it with CEA patients done by the same providers at the same time period. The primary outcome was combined perioperative stroke/death and late stroke/death. Secondary outcomes included combined stroke, death, and myocardial infarction, cranial nerve injury (CNI), and bleeding. Propensity matching was done to analyze outcome. Kaplan-Meier analysis was used to estimate freedom from stroke, stroke/death, and ≥50% and ≥80% restenosis. RESULTS: We analyzed 646 procedures (637 patients) (404 CEA, 242 TCAR). There was no significant difference in the indications for carotid intervention. However, TCAR patients had more high-risk criteria, including hypertension, coronary artery disease, congestive heart failure, and renal failure. There was no significant differences between CEA vs TCAR in 30-day perioperative stroke (1% vs 2%), stroke/death rate (1% vs 3%; P = .0849), or major hematomas (2% vs 2%). The rate of CNI was significantly different (5% for CEA vs 1% for TCAR; P = .0138). At late follow-up (2 years), the rate of stroke was 1% vs 4% (P = .0273), stroke/death 8% vs 15% (P = .008), ≥80 % restenosis 0.5% vs 3% (P = .0139) for CEA patients vs TCAR patients, respectively. After matching 242 CEAs and 242 TCARs, the perioperative stroke rate was 1% for CEA vs 2% for TCAR (P = .5037), the stroke/death rate was 2% vs 3% (P = .2423), and the CNI rate was 3% vs 1% (P = .127). At late follow-up, rates of stroke were 1% for CEA vs 4% for TCAR (P = .0615) and stroke/death were 8% vs 15% (P = .0345). The rate of ≥80% restenosis was 0.9% for CEA vs 3% for TCAR (P = .099). The rates of freedom from stroke at 6, 12, 18, and 24 months for CEA vs TCAR were 99%, 99%, 99%, and 99% vs 97%, 95%, 93% and 93%, respectively (P = .0806); stroke/death were 94%, 90%, 87%, and 86% vs 93%, 87%, 76%, and 75%, respectively (P = .0529); and ≥80% restenosis were 100%, 99%, 98%, and 98% vs 97%, 95%, 93%, and 93%, respectively (P = .1132). CONCLUSIONS: In a propensity-matched analysis, both CEA and TCAR have similar perioperative clinical outcomes. However, CEA was superior to TCAR for the rates of late stroke/death and had a somewhat lower rate of ≥80% restenosis at 2 years, but this difference was not statistically significant.

Metabolic imaging of human cumulus cells reveals associations with pregnancy and live birth.

STUDY QUESTION: Can fluorescence lifetime imaging microscopy (FLIM) detect associations between the metabolic state of cumulus cell (CC) samples and the clinical outcome of the corresponding embryos? SUMMARY ANSWER: FLIM can detect significant variations in the metabolism of CC associated with the corresponding embryos that resulted in a clinical pregnancy versus those that did not. WHAT IS KNOWN ALREADY: CC and oocyte metabolic cooperativity are known to be necessary for the acquisition of developmental competence. However, reliable CC biomarkers that reflect oocyte viability and embryo developmental competency have yet to be established. Quantitative measures of CC metabolism could be used to aid in the evaluation of oocyte and embryo quality in ART. STUDY DESIGN, SIZE, DURATION: A prospective observational study was carried out. In total, 223 patients undergoing IVF with either conventional insemination or ICSI at a tertiary care center from February 2018 to May 2020 were included, with no exclusion criteria applied. PARTICIPANTS/MATERIALS, SETTING, METHODS: This cohort had a mean maternal age of 36.5 ± 4.4 years and an average oocyte yield of 16.9 (range 1-50). One to four CC clusters from each patient were collected after oocyte retrieval and vitrified. CC metabolic state was assessed using FLIM to measure the autofluorescence of the molecules NAD(P)H and FAD+, which are essential for multiple metabolic pathways. CC clusters were tracked with their corresponding oocytes and associated embryos. Patient age, Day 3 and Day 5/6 embryo morphological grades, and clinical outcomes of embryos with traceable fate were recorded. Nine FLIM quantitative parameters were obtained for each CC cluster. We investigated associations between the FLIM parameters and patient maternal age, embryo morphological rank, ploidy, and clinical outcome, where false discovery rate P-values of <0.05 were considered statistically significant. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 851 CC clusters from 851 cumulus-oocyte complexes from 223 patients were collected. Of these CC clusters, 623 were imaged using FLIM. None of the measured CC FLIM parameters were correlated with Day 3 morphological rank or ploidy of the corresponding embryos, but FAD+ FLIM parameters were significantly associated with morphological rank of blastocysts. There were significant differences for FAD+ FLIM parameters (FAD+ fraction engaged and short lifetime) from CC clusters linked with embryos resulting in a clinical pregnancy compared with those that did not, as well as for CC clusters associated with embryos that resulted in a live birth compared those that did not. LIMITATIONS, REASONS FOR CAUTION: Our data are based on a relatively low number of traceable embryos from an older patient population. Additionally, we only assessed CCs from 1 to 4 oocytes from each patient. Future work in a younger patient population with a larger number of traceable embryos, as well as measuring the metabolic state of CCs from all oocytes from each patient, would provide a better understanding of the potential utility of this technology for oocyte/embryo selection. WIDER IMPLICATIONS OF THE FINDINGS: Metabolic imaging via FLIM is able to detect CC metabolic associations with maternal age and detects variations in the metabolism of CCs associated with oocytes leading to embryos that result in a clinical pregnancy and a live birth versus those that do not. Our findings suggest that FLIM of CCs may be used as a new approach to aid in the assessment of oocyte and embryo developmental competence in clinical ART. STUDY FUNDING/COMPETING INTEREST(S): National Institutes of Health grant NIH R01HD092550-03 (to C.R., and D.J.N.). Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. and C.R. are inventors on patent US20170039415A1. TRIAL REGISTRATION NUMBER: N/A.

The impact of implementing a non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) embryo culture protocol on embryo viability and clinical outcomes.

STUDY QUESTION: Are modifications in the embryo culture protocol needed to perform non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) affecting clinical reproductive outcomes, including blastocyst development and pregnancy outcomes? SUMMARY ANSWER: The implementation of an embryo culture protocol to accommodate niPGT-A has no impact on blastocyst viability or pregnancy outcomes. WHAT IS KNOWN ALREADY: The recent identification of embryo cell-free (cf) DNA in spent blastocyst media has created the possibility of simplifying PGT-A. Concerns, however, have arisen at two levels. First, the representativeness of that cfDNA to the real ploidy status of the embryo. Second, the logistical changes that need to be implemented by the IVF laboratory when performing niPGT-A and their effect on reproductive outcomes. Concordance rates of niPGT-A to invasive PGT-A have gradually improved; however, the impact of culture protocol changes is not as well understood. STUDY DESIGN, SIZE, DURATION: As part of a trial examining concordance rates of niPGT-A versus invasive PGT-A, the IVF clinics implemented a specific niPGT-A embryo culture protocol. Briefly, this involved initial culture of fertilized oocytes following each laboratory standard routine up to Day 4. On Day 4, embryos were washed and cultured individually in 10 µl of fresh media. On Day 6 or 7, blastocysts were then biopsied, vitrified, and media collected for the niPGT-A analysis. Six IVF clinics from the previously mentioned trial were enrolled in this analysis. In the concordance trial, Clinic A cultured all embryos (97 cycles and 355 embryos) up to Day 6 or 7, whereas in the remaining clinics (B-F) (379 cycles), nearly a quarter of all the blastocysts (231/985: 23.5%) were biopsied on Day 5, with the remaining blastocysts following the niPGT-A protocol (754/985: 76.5%). During the same period (April 2018-December 2020), the IVF clinics also performed standard invasive PGT-A, which involved culture of embryos up to Days 5, 6, or 7 when blastocysts were biopsied and vitrified. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 428 (476 cycles) patients were in the niPGT-A study group. Embryos from 1392 patients underwent the standard PGT-A culture protocol and formed the control group. Clinical information was obtained and analyzed from all the patients. Statistical comparisons were performed between the study and the control groups according to the day of biopsy. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age, number of oocytes, fertilization rates, and number of blastocysts biopsied were not significantly different for the study and the control group. Regarding the overall pregnancy outcomes, no significant effect was observed on clinical pregnancy rate, miscarriage rate, or ongoing pregnancy rate (≥12 weeks) in the study group compared to the control group when stratified by day of biopsy. LIMITATIONS, REASONS FOR CAUTION: The limitations are intrinsic to the retrospective nature of the study, and to the fact that the study was conducted in invasive PGT-A patients and not specifically using niPGT-A cases. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that modifying current IVF laboratory protocols to adopt niPGT-A has no impact on the number of blastocysts available for transfer and overall clinical outcomes of transferred embryos. Whether removal of the invasive biopsy step leads to further improvements in pregnancy rates awaits further studies. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Igenomix. C.R., L.N.-S., and D.V. are employees of Igenomix. D.S. was on the Scientific Advisory Board of Igenomix during the study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03520933).

Quantitative evaluation of lesion response heterogeneity for superior prognostication of clinical outcome.

PURPOSE: Standardized reporting of treatment response in oncology patients has traditionally relied on methods like RECIST, PERCIST and Deauville score. These endpoints assess only a few lesions, potentially overlooking the response heterogeneity of all disease. This study hypothesizes that comprehensive spatial-temporal evaluation of all individual lesions is necessary for superior prognostication of clinical outcome. METHODS: [18F]FDG PET/CT scans from 241 patients (127 diffuse large B-cell lymphoma (DLBCL) and 114 non-small cell lung cancer (NSCLC)) were retrospectively obtained at baseline and either during chemotherapy or post-chemoradiotherapy. An automated TRAQinform IQ software (AIQ Solutions) analyzed the images, performing quantification of change in regions of interest suspicious of cancer (lesion-ROI). Multivariable Cox proportional hazards (CoxPH) models were trained to predict overall survival (OS) with varied sets of quantitative features and lesion-ROI, compared by bootstrapping with C-index and t-tests. The best-fit model was compared to automated versions of previously established methods like RECIST, PERCIST and Deauville score. RESULTS: Multivariable CoxPH models demonstrated superior prognostic power when trained with features quantifying response heterogeneity in all individual lesion-ROI in DLBCL (C-index = 0.84, p < 0.001) and NSCLC (C-index = 0.71, p < 0.001). Prognostic power significantly deteriorated (p < 0.001) when using subsets of lesion-ROI (C-index = 0.78 and 0.67 for DLBCL and NSCLC, respectively) or excluding response heterogeneity (C-index = 0.67 and 0.70). RECIST, PERCIST, and Deauville score could not significantly associate with OS (C-index < 0.65 and p > 0.1), performing significantly worse than the multivariable models (p < 0.001). CONCLUSIONS: Quantitative evaluation of response heterogeneity of all individual lesions is necessary for the superior prognostication of clinical outcome.

FARS-ADL across Ataxias: Construct Validity, Sensitivity to Change, and Minimal Important Change.

BACKGROUND: Patient-focused outcomes present a central need for trial-readiness across all ataxias. The Activities of Daily Living part of the Friedreich Ataxia Rating Scale (FARS-ADL) captures functional impairment and longitudinal change but is only validated in Friedreich Ataxia. OBJECTIVE: Validation of FARS-ADL regarding disease severity and patient-meaningful impairment, and its sensitivity to change across genetic ataxias. METHODS: Real-world registry data of FARS-ADL in 298 ataxia patients across genotypes were analyzed, including (1) cross-correlation with FARS-stage, Scale for the Assessment and Rating of Ataxia (SARA), Patient-Reported Outcome Measure (PROM)-ataxia, and European Quality of Life 5 Dimensions visual analogue scale (EQ5D-VAS); (2) sensitivity to change within a trial-relevant 1-year median follow-up, anchored in Patient Global Impression of Change (PGI-C); and (3) general linear modeling of factors age, sex, and depression (nine-item Patient Health Questionnaire [PHQ-9]). RESULTS: FARS-ADL correlated with overall disability (rhoFARS-stage = 0.79), clinical disease severity (rhoSARA = 0.80), and patient-reported impairment (rhoPROM-ataxia = 0.69, rhoEQ5D-VAS = -0.37), indicating comprehensive construct validity. Also at item level, and validated within genotype (SCA3, RFC1), FARS-ADL correlated with the corresponding SARA effector domains; and all items correlated to EQ5D-VAS quality of life. FARS-ADL was sensitive to change at a 1-year interval, progressing only in patients with worsening PGI-C. Minimal important change was 1.1. points based on intraindividual variability in patients with stable PGI-C. Depression was captured using FARS-ADL (+0.3 points/PHQ-9 count) and EQ5D-VAS, but not FARS-stage or SARA. CONCLUSION: FARS-ADL reflects both disease severity and patient-meaningful impairment across genetic ataxias, with sensitivity to change in trial-relevant timescales in patients perceiving change. It thus presents a promising patient-focused outcome for upcoming ataxia trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Atopy Does Not Influence the Clinical Outcome of Acute Urticaria: A Retrospective Study.

BACKGROUND: Acute urticaria (AU) may be associated with atopy, but the relationship between atopic status and the clinical features of the disease has not been fully described. OBJECTIVES: The aim of the study was to determine the proportion of atopy in AU patients and to see whether atopy is related to the clinical characteristics of AU and whether it has an impact on the outcome of the disease. MATERIALS AND METHOD: A retrospective analysis of patients with AU was performed. Demographic data, clinical features, and laboratory results were compared and analyzed between the atopic and non-atopic AU (napAU). RESULTS: In total, 139 participants were included. 54 (38.8%) patients were atopic AU (apAU) and 85 (61.2%) were napAU. Compared with napAU patients, apAU patients were more likely to have anaphylaxis, higher levels of C4, and lower levels of antistreptolysin. There were no significant differences between the two groups in terms of other clinical features, laboratory tests, the natural course of the disease, or disease outcomes. CONCLUSION: Atopy does exist in some patients with AU, and AU patients with an atopic background are at higher risk for anaphylaxis. Atopy does not influence the clinical outcome of AU and is not correlated with other clinical features and laboratory results of AU.

Content Validity of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Instrument in Spinocerebellar Ataxia.

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.TI software. Individuals with SCA1 and 3 reported 85 symptoms, signs, and impacts of SCA. All indicated difficulties with walking, stance, balance, speech, fatigue, emotions, and work. All individuals with SCA1 and 3 considered Gait, Stance, and Speech relevant f-SARA concepts; 3 considered Sitting relevant (42.9%). All HCPs considered Gait and Speech relevant; 5 (62.5%) indicated Stance was relevant. Sitting was considered a late-stage disease indicator. Most HCPs suggested inclusion of appendicular items would enhance clinical relevance. Cognitive debriefing supported clarity and comprehension of f-SARA. Maintaining current abilities on f-SARA items for 1 year was considered meaningful for most individuals with SCA1 and 3. All HCPs considered meaningful changes as stability in f-SARA score over 1-2 years, 1-2-point change in total f-SARA score, and deviation from natural history. These results support content validity of f-SARA for assessing SCA disease progression in clinical trials.

Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder.

OBJECTIVE: The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability. METHODS: Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability. RESULTS: CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups. SIGNIFICANCE: This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

Lower serum uric acid to serum creatinine ratio as a predictor of poor functional outcome after mechanical thrombectomy in acute ischaemic stroke.

BACKGROUND AND PURPOSE: The ratio of serum uric acid (SUA) to serum creatinine (SCr), representing normalized SUA for renal function, is associated with functional outcome in acute ischaemic stroke (AIS) patients. However, its effect on AIS patients undergoing mechanical thrombectomy (MT) remains unknown. This study aimed to investigate the influence of the SUA/SCr ratio on clinical outcome in MT-treated AIS patients. METHODS: Acute ischaemic stroke patients who underwent MT were continuously enrolled from January 2018 to June 2023. Upon admission, SUA and SCr levels were recorded within the initial 24 h. Stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS) score. Clinical outcome included poor functional outcome (modified Rankin Scale score >2) at 90 days, symptomatic intracranial haemorrhage and death. RESULTS: Amongst 734 patients, 432 (58.8%) exhibited poor functional outcome at 90 days. The SUA/SCr ratio exhibited a negative correlation with NIHSS score (ρ = -0.095, p = 0.010). Univariate analysis revealed a significant association between SUA/SCr ratio and poor functional outcome. After adjusting for confounders, the SUA/SCr ratio remained an independent predictor of functional outcome (adjusted odds ratio 0.348, 95% confidence interval 0.282-0.428, p < 0.001). Receiver operating characteristic curve analysis highlighted the ability of the SUA/SCr ratio to predict functional outcome, with a cutoff value of 3.62 and an area under the curve of 0.757 (95% confidence interval 0.724-0.788, p < 0.001). CONCLUSION: The SUA/SCr ratio is correlated with stroke severity and may serve as a predictor of 90-day functional outcome in AIS patients undergoing MT.

Fifty years devoted to anaerobes: historical, lessons, and highlights.

Renew interest and enthusiasm for anaerobes stem from both technological improvements (culture media, production of an adequate anaerobic atmosphere, identification methods) and greater awareness on the part of clinicians. Anaerobic infections were historically treated empirically, targeting the species known to be involved in each type of infection. Prevotella, fusobacteria, and Gram-positive cocci (GPAC) were considered responsible for infections above the diaphragm whereas for intra-abdominal infections, Bacteroides of the fragilis group (BFG), GPAC and clostridia were predominantly implicated. The antibiotic susceptibility of anaerobes was only taken into consideration by the clinician in the event of treatment failure or when faced with infections by multidrug-resistant bacteria (MDR). The evolution of antibiotic resistance together with clinical failures due to the absence of detection of hetero-resistant clones has resulted in a greater need for accessible antibiotic susceptibility testing (AST) and disc diffusion method. Improved isolation and identification of anaerobes, along with the availability of accessible and robust methods for performing AST, will ensure that treatment, whether empirical or guided by an antibiogram, will lead to better outcomes for anaerobic infections.

Psychometric Evaluation of the Diary for Irritable Bowel Syndrome Symptoms-Constipation in a Prospective Observational Study.

OBJECTIVES: To evaluate the psychometric properties of the Diary for Irritable Bowel Syndrome Symptoms-Constipation (DIBSS-C), which was developed to support primary and secondary endpoints in irritable bowel syndrome (IBS) with predominant constipation (IBS-C) clinical trials. METHODS: Observational data were collected from 108 adults with IBS-C using a smartphone-type device for 17 days. DIBSS-C data regarding bowel movements (BMs) were collected for each event (along with the Bristol Stool Form Scale); abdominal symptoms were rated each evening. Global status items and the Gastrointestinal Symptom Rating Scale-IBS were completed on day 10 and day 17 and the IBS-Symptom Severity Scale on day 17. Item-level performance, internal consistency reliability, test-retest reliability, and construct validity were evaluated. RESULTS: The Abdominal Symptoms Domain score demonstrated high internal consistency reliability (Cronbach's alpha week 1 = 0.98; week 2 = 0.96) and test-retest reliability (intraclass correlation coefficient [ICC] = 0.93). Test-retest reliability was stronger for abdominal symptoms (ICC = 0.91-0.94) than for the frequency-based BM-related outcomes (ICC = 0.54-0.66). Key construct validity hypotheses were supported by moderate to strong correlations with the corresponding Gastrointestinal Symptom Rating Scale-IBS, IBS-Symptom Severity Scale, and Bristol Stool Form Scale items. All known-groups comparisons were statistically significant for the abdominal symptom items and domain score; evidence for known-groups validity of BM-related outcomes was supportive when based on constipation severity. CONCLUSIONS: The results of this study provided key psychometric evidence for the DIBSS-C, ultimately contributing to its qualification by the US Food and Drug Administration for use in IBS-C clinical trials.

Best Practices for the Electronic Implementation and Migration of Patient-Reported Outcome Measures.

While the use of electronic methods to collect patient-reported outcome data in clinical trials continues to increase, it remains the case that many patient-reported outcome measures (PROMs) have originally been developed and validated on paper. Careful consideration during the move from paper PROMs to electronic format is required to preserve the integrity of the measure and ensure a "faithful migration." Relevant literature has long called out the importance of following migration best practices during this process; nevertheless, such best practices are distributed across multiple documents. This article consolidates and builds upon existing electronic PROM implementation best practice recommendations to provide a comprehensive, up-to-date, single point of reference. It reflects the current consensus based on the significant advances in technology capabilities and knowledge gleaned from the growing evidence base on electronic migration and implementation, to balance the need for maintaining the integrity of the measure while optimizing respondent usability. It also specifies whether the practice is rooted in evidence or expert consensus, to enable those using these best practices to make informed and considered decisions when conducting migration.