Poor Response Research Articles

The Association of Inflammatory Indexes Derived from Peripheral Blood Cell Count and Clinical Signs with Response to Treatment with Dupilumab in Pediatric Patients with Moderate-to-Severe Atopic Dermatitis.

Dupilumab is a safe and effective treatment for moderate to severe atopic dermatitis (AD), but real-world data in pediatric patients in China are limited. Currently, there is no exploration of changes in blood cell counts derived indexes in pediatric patients, especially under 6 years old. To investigate the changes in blood cell counts derived indexes before and after dupilumab treatment in Chinese children with AD, the relationship with clinical scores, and the potential role of these indexes on treatment efficacy. We conducted a retrospective study of 109 children with moderate to severe AD treated with dupilumab. Derived inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR), eosinophil-to-neutrophil Ratio (ENR), monocyte-to-lymphocyte ratio (MLR), inflammation response index (SIRI), systemic inflammation index (SII), and aggregate inflammation systemic index (AISI) were calculated. The correlation between clinical scores and inflammatory indexes at different treatment time points were analyzed. Logistic regression and ROC curve was employed to explore factors associated with treatment efficacy. Baseline ELR and ENR were positively correlated with the baseline Eczema Area and Severity Index (EASI) and the Scoring Atopic Dermatitis (SCORAD). Additionally, baseline ENR levels showed a positive correlation with the baseline Peak Pruritus Numeric Rating Scale (PP-NRS). At 4 and 16weeks of treatment, the percentage reduction in ELR was significantly associated with the percentage reduction in EASI and PP-NRS. Logistic regression results indicated that high baseline ELR could predict a poor response to dupilumab treatment. ELR was significantly correlated with disease severity score during the treatment with dupilumab. Baseline ELR could act as a predictor of the efficacy of dupilumab in the treatment of children with atopic dermatitis under 6 years of age.

Peroxisome Metabolism Pathway and EHHADH Expression are Downregulated in Macrophages in Neutrophilic Asthma.

Neutrophilic asthma (NA) is associated with more severe symptoms and poor responsiveness to inhaled corticosteroid therapy. Macrophages are the most abundant immune cells in the airway, but the role of macrophages in NA pathogenesis has not been fully studied. We hypothesized that dysregulation of peroxisome metabolism in macrophages may drive NA. We retrieved microarray datasets from the GEO Gene Expression Omnibus database by using induced sputum samples from eosinophilic and neutrophilic asthma patients as well as healthy controls. We identified key molecules in NA and validated the expression of the key genes in our cohort of asthma patients using quantitative polymerase chain reaction (PCR). Furthermore, immunofluorescence staining was performed to detect the expression and localization of the key molecule in bronchoalveolar lavage (BAL) cells from asthma patients and the murine model of neutrophilia-dominant allergic airway inflammation. The expression of the key molecule was also examined in mouse bone marrow-derived macrophages (BMDMs) by quantitative PCR and western blotting. Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), sterol carrier protein 2, and peroxisomal biogenesis factor 14 were identified as the key molecules and were downregulated in patients with NA or severe asthma. The peroxisomal fatty acid metabolism pathway was significantly downregulated in NA. In our cohort of asthma patients, the expression of EHHADH, a key enzyme of the peroxisomal fatty acid beta-oxidation, was significantly decreased in non-eosinophilic asthma patients and positively correlated with airflow limitation. EHHADH was primarily expressed in macrophages in BAL cells. EHHADH was downregulated in lipopolysaccharide (LPS)-induced M1-like macrophages in mouse BMDMs. Fenofibrate, an agonist of the peroxisome pathway, significantly inhibits LPS-induced macrophage M1 polarization. EHHADH expression and the peroxisome metabolism pathway are downregulated in macrophages in patients with NA. This downregulation may contribute to macrophage M1 polarization and neutrophilic airway inflammation in asthma.

Monocytic reactive oxygen species-induced T-cell apoptosis impairs cellular immune response to SARS-CoV-2 mRNA vaccine.

We have recently shown that during acute severe coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein induces a cascade of events resulting in T-cell apoptosis. Indeed, by neutralizing the protease activity of its receptor, angiotensin-converting enzyme 2, S protein induces an increase in circulating angiotensin II (AngII), resulting in monocytic release of reactive oxygen species (ROS) and programmed T-cell death. Here, we tested whether SARS-CoV-2 mRNA vaccines, known to cause the circulation of the vaccine antigen, S protein receptor binding domain (RBD), might trigger the same cascade. We used ELISA to quantify the presence of RBD and AngII in peripheral blood of participants and the presence of IFN-γ in the supernatant of PBMCs exposed to S protein. Monocytic ROS production, T-cell apoptosis, and S protein-induced T-lymphocyte proliferation were measured by flow cytometry, and DNA damage was measured by immunofluorescence. In most vaccinees, we observed that the presence of circulating RBD peaked on day 14 and was linked to an increase in AngII plasma levels with a peak on day 28. This increase correlated with the ability of monocytes to produce ROS and to induce ROS-mediated DNA damage in neighboring cells, including PBMCs; CD4+ and CD8+ T-lymphocyte apoptosis; and a poor response to protein S invitro from both CD4+ and CD8+ T cells. We observed the same cascade of events triggered by the vaccinal antigen as by SARS-CoV-2 infection. This cascade may account for the suboptimal efficiency of mRNA SARS-CoV-2 vaccines in preventing the infection, the limited vaccine memory, and certain side effects. In this model, AngII receptor antagonists and/or antioxidants might improve the performance of the SARS-CoV-2 vaccine. ClinicalTrials.gov Identifier: NCT05655351.

CXCR4—A Potential Novel Theranostic Target in Adrenocortical Carcinoma

Abstract Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with high recurrence rates and poor prognosis. There are only limited treatment options with poor response rates. ACCs are documented to express chemokine receptor CXCR4, which can be visualized using 68Ga-pentixafor PET/CT. We herein present a case of ACC with local recurrence and peritoneal metastases, which was well visualized on FDG and pentixafor PET/CT. The high expression of CXCR4 offers the potential of theranostics and targeted endoradiotherapy in patients with metastatic ACC. We also observed thymic rebound to illustrate mild to moderate grade uptake of 68Ga-pentixafor in this patient.

How Hospitalizations Can Be Effective in Subsequent Care of Children with Asthma?

Asthma is a prevalent chronic inflammatory disorder in children, and poor therapeutic response in asthmatic children could result from various factors related to the physician, patient, disease, and treatment. This study aimed to evaluate the most important causes of failure in asthma control. One hundred three children referred to the Children’s Medical Center in Tehran, Iran, participated in this study in 2017. A specific questionnaire was organized and completed by telephone interviews with parents. The mean age of participants was 10.30 years, and 68.9% were male. More action plans (45/53) were received from hospitalized patients in the asthma and allergy ward than from hospitalized patients in the emergency department (13/46). Moreover, 85% of admitted patients in the asthma and allergy ward were visited by a specialist compared with 50% in the emergency department (23/46). Hospitalization in the asthma and allergy ward resulted in receiving more action plans, spirometry tests, and visits by an allergist after discharge compared with admission to the emergency department.

S100A4 contributes to colorectal carcinoma aggressive behavior and to chemoradiotherapy resistance in locally advanced rectal carcinoma

To investigate the functional role of S100A4 in advanced colorectal carcinoma (Ad-CRC) and locally advanced rectal carcinoma (LAd-RC) receiving neoadjuvant chemoradiotherapy (NCRT). We analyzed histopathological and immunohistochemical sections from 150 patients with Ad-CRC and 177 LAd-RC patients treated with NCRT. S100A4 knockout (KO) HCT116 cells were also used. S100A4 expression was absent in normal mucosa but increased progressively from colorectal adenoma to carcinoma, suggesting that S100A4 regulation is an early event in colorectal carcinogenesis. In Ad-CRC, high S100A4 expression correlated with high tumor budding and nuclear β-catenin, deep invasion, lymph-vascular involvement, and unfavorable prognosis. In NCRT-treated LAd-RC, high S100A4 expression was associated with poor treatment response and short progression-free survival. S100A4 KO decreased the proliferation of HCT116 cells through activation of the p53/p21waf1 axis, and sensitized cells to adriamycin-induced apoptosis. Levels of the apoptotic marker, cleaved poly (ADP-ribose) polymerase 1, were significantly higher in samples with low S100A4 and wild type p53. Finally, we observed a direct interaction between S100A4 and p53. In conclusion, S100A4 expression engenders aggressive behavior in Ad-CRC through association with β-catenin-driven tumor buddings. S100A4 exerts anti-apoptotic and proliferative effects via inhibition of p53 in LAd-RC patients receiving NCRT, which leads to chemoradioresistance and poor prognosis.

Proposed computed tomography severity index for the evaluation of invasive fungal sinusitis: Preliminary results.

Invasive fungal sinusitis (IFS) can present as a mild disease to life-threatening infection. A recent surge in cases was seen due to the coronavirus disease 2019 (COVID-19) pandemic. Many patients require surgical debridement and hence imaging [contrast-enhanced computed tomography (CECT) of the paranasal sinuses (PNS)] to document the extent of the disease. However, there was no scoring system using CECT to describe the severity of IFS. This study proposes a computed tomography (CT) severity index (CTSI) to describe the severity of rhino-orbital-cerebral involvement in symptomatic COVID-19 patients and hypothesizes that higher CTSI correlates with disease severity and thus slow response/non-response to treatment. To propose a scoring system using CECT to describe the severity of IFS and correlate it with clinical outcomes. A prospective study on 66 COVID-19 positive patients with CECT PNS done for IFS was performed. Split-bolus single-phase CT technique was used. Based on the extent of involvement, a CTSI was designed. Disease in four major subsite areas was assessed. Each subsite involvement was given points according to this model and then summated. Based on the final summated CTSI, the disease was classified as mild, moderate, or severe. Two subsets were subsequently analyzed including survival and death; and responders and non-responders. The study cohort was 66 COVID-19-positive patients with suspected IFS with a median age of 48.5 years. Mild disease was noted in 34 (51.52%), moderate in 28 (42.42%), and severe disease in 4 (6.06%) patients. There was a significant association of mortality and poor clinical response (P = 0.02) with disease bilaterality. Laterality and CTSI were significant predictors of response to treatment. The mean CTSI of responders was 6.3, of non-responders was 12.9 and the response to treatment was significantly associated with CTSI (t-test, P < 0.001). Receiver operating characteristic curve analysis (Liu method) to distinguish between responders and non-responders showed that the cut-off value for CTSI of 11 had a sensitivity of 78.26% and a specificity of 95.35% to predict response assessment. CTSI can help in quantification of the disease burden, mapping out disease extent, triaging patients, and response assessment; especially patients with underlying comorbidities. A higher score would alert the clinician to initiate aggressive treatment, as severe disease correlates with slow response/non-response to the treatment.

Poultry farmers’ knowledge, attitudes and practices regarding poultry predation by African wildcats (Felis lybica) in Chiawa Game Management Area, Zambia

African wildcats (Felis lybica) cause considerable poultry losses to poultry farmers in African rural areas through predation, and contribute to human food insecurity, loss of income and livelihood, and social well-being. Unable to manage poultry farmer-wildcat conflicts, the affected poultry farmers reduce their support to wildlife conservation and resort to retaliatory killings of African wildcats and other wildlife, mainly by secretly using poisons and traps. Such a human-carnivore conflict becomes protracted due to poor anti-predator responses implemented by the poultry farmers and wildlife management authorities. In this study, we used 101 semi-structured questionnaires to evaluate poultry predation by African wildcats occurring adjacent (approximately between 7 and 68 km) to Zambia’s Lower Zambezi National Park in Chiawa Game Management Area by focusing on local poultry farmer knowledge, attitudes and practices. The study’s Generalized Linear Model showed that season (i.e., hot-wet season), time (i.e., night) and countermeasures (i.e., absence of wire fences) were the primary predictors of poultry predation by African wildcats, while low tree cover and education attained by the poultry farmers were the secondary factors. The rate of chicken loss per year/poultry farmer was 19.1 ± 1.3 SE. We suggest strengthening farmer-based countermeasures, such as small-mesh fencing to protect poultry from African wildcats, and sensitisation programmes by wildlife managers for poultry farmer transformation towards supporting conservation alongside conservation planning in these human-dominated-wildlife landscapes for improved farmer-African wildcat co-existence, particularly in the hot-wet season and night-time when the poultry losses from attacks by African wildcats spike.

Rapid and Deep Prostate-Specific Antigen Decline is a Prognostic Marker in Metastatic Hormone-Sensitive Prostate Cancer: A Real-World Multi-Intuitional Analysis.

Prostate-specific antigen (PSA) kinetics has been investigated as a prognostic marker in post hoc analyses of clinical trials. This study validated the prognostic value of rapid and deep PSA decline in metastatic hormone-sensitive prostate cancer (mHSPC) using real-world data. In total, 1296 patients with mHSPC were retrospectively reviewed. We assessed the prognostic value of a PSA decline to ≤ 0.2 ng/mL after 12 weeks of treatment and investigated several potential risk factors for a poor PSA response. Of 1296 patients, 714 (cohort 1: 55.1%) were treated with conventional hormonal therapy, while 582 (cohort 2: 44.9%) received androgen signaling inhibitors. There were significant differences in progression-free survival and overall survival between patients with PSA decline to ≤ 0.2 ng/mL by 12 weeks of treatment and others (p < 0.001 for each). In addition, patients with an initial PSA ≥ 200 ng/mL, Clinical T4 and Grade Group 5 were less likely to achieve PSA decline to ≤ 0.2 ng/mL by 12 weeks of treatment, with odds ratios of 0.31 (p < 0.001), 0.67 (p = 0.039) and 0.70 (p = 0.043), respectively. Our findings suggested that PSA decline to ≤ 0.2 ng/mL by 12 weeks of treatment may be a useful prognostic biomarker for mHSPC in the real-world setting. The prognostic value of this should be further investigated in a prospective cohort, and identification of an optimal cutoff value is necessary for its application in clinical trial design or clinical practice.

Super-enhancer Activates Master Transcription Factor NR3C1 Expression and Promotes 5-FU Resistance in Gastric Cancer.

Poor response to 5-fluorouracil (5-FU) remains an obstacle in the treatment of gastric cancer (GC). Super enhancers (SEs) are crucial for determining tumor cell survival under drug pressure. SE landscapes related to 5-FU-resistance are mapped to GC using chromatin immunoprecipitation-sequencing (ChIP-Seq). SiRNA transcription factors (TFs) screen determines master TF Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) activated by SE. High NR3C1 expression driven by SE correlated with 5-FU resistance in patient-derived organoids (PDOs). Phase separation formed by NR3C1 is observed using fluorescence recovery after photobleaching (FRAP). NR3C1 protein and Mediator promoted SE-related gene transcription via phase separation. SEs and NR3C1 co-binding patterns are explored using Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing. 5-FU-related genes driven by NR3C1 are identified using epigenetic reader inhibitor JQ1 and NR3C1 specific inhibitor Cort108297. NR3C1 knockdown increases 5-FU sensitivity and alters the SE landscape through enhancer reprogramming, reducing downstream 5-FU-related target genes. JQ1 and Cort108297 both improve 5-FU efficacy in PDOs and patient-derived xenografts (PDXs) by destroying SEs or inhibiting NR3C1. In conclusion, SE-driven NR3C1 promotes 5-FU resistance in GC. SE destruction and NR3C1 inhibition lead to enhancer reconstruction and reduce 5-FU-related gene transcription, providing alternative therapeutic strategies for improving 5-FU sensitivity.

Dual-targeted STAb-T cells secreting BCMA and CD19 T cell engagers for improved control of haematological cancers

ABSTRACT Despite recent advances in immunotherapy against B cell malignancies such as BCMA (B cell maturation antigen) and CD19-targeted treatments using soluble T cell-engaging (TCE) antibodies or chimeric antigen receptor T cells (CAR-T), there is still an important number of patients experiencing refractory/relapsed (R/R) disease. Approaches to avoid tumor-intrinsic mechanisms of resistance such as immune pressure-mediated antigen downmodulation, are being broadly investigated. These strategies include BCMA/CD19 dual-targeting therapies, which may be of particular interest to patients with B cell lymphoma and multiple myeloma, where a specific double-positive immature subpopulation is commonly associated with poor prognosis and poor response to current treatments. In fact, several clinical trials targeting both antigens through different strategies are currently underway. Here, based on the previously validated STAb (in situ secretion of T cell-redirecting bispecific antibodies) concept, we used two different engineering strategies (pool and co-transduction) to generate dual-targeted STAb-T cells simultaneously secreting BCMA TCE and CD19 TCE that outperformed single-targeted STAb-T cells in different in vitro models. These promising results encourage further preclinical clinical testing of dual STAb-T cells in R/R B-cell malignancies.

Limited Efficacy of Anti-EGFR Monoclonal Antibodies in Colorectal Cancer Patients with Rare RAS Variants: Analysis of the C-CAT Database.

Epidermal growth factor receptor (EGFR) inhibition is crucial in treating RAS wild-type metastatic colorectal cancer, yet current testing methods may miss rare RAS variants affecting treatment efficacy. We analyzed 4122 colorectal cancer patients receiving anti-EGFR antibodies from the Center for Cancer Genomics and Advanced Therapeutics database, identifying 54 patients (1.3%) with rare RAS variants undetectable by standard testing. These patients showed significantly lower response rates to anti-EGFR therapy (28.3%) compared to RAS wild-type cases (44.6%, p = 0.003). Disease control rates were also lower in rare variant cases (60.9%) versus wild-type cases (80.0%). Most common rare variants included KRAS Q22K, A59E, and A11_G12insGA. Comprehensive genomic profiling revealed additional alterations in TP53 (90.7%), APC (87.0%), and non-V600E BRAF mutations (25.9%). Our findings suggest that rare RAS variants predict poor anti-EGFR therapy response, highlighting the potential benefit of comprehensive genomic profiling before treatment initiation. This study provides real-world evidence supporting the clinical relevance of rare RAS variants in treatment decision-making for colorectal cancer. Future studies should focus on developing cost-effective comprehensive testing strategies and evaluating alternative treatment approaches for patients with rare RAS variants.

Efficient Input‐Output Feedback Linearizing Control of BLDC Drives

ABSTRACTElectrically driven unmanned aerial vehicles (UAVs) are gaining popularity due to use in industrial, military, and civil applications. The UAVs have to execute complicated maneuvers in the air requires accurate control of the BLDC motor propeller systems. In this study, we propose easy to implement field‐oriented adaptive input‐output feedback linearizing control (AIOFL) for controlling propellers as per demand of flight controller. This study aims to compare the proposed field‐oriented AIOFL with usual six step control architecture with a focus on the typical back‐electromotive force (back‐EMF) shapes featured in the propeller motor. The proposed control architecture that does not only regulate speed and torque of the propeller with acceptable torque ripple but it also estimates the rotor magnetic flux and the stator resistance of the BLDC motor to know about stator/rotor condition monitoring, motor fault detection, and temperature rise. To ensure reliable operation in all operational conditions, closed loop stability of proposed speed controller is analyzed based on the Lyapunov method. Particle swarm optimization (PSO) is utilized to accurately tune the PI controller since the trial‐and‐error technique used to choose the PI controller gains resulted in the low stability and poor transient response of the controller. Finally, comprehensive numerical and experimental tests are performed and compared with conventional field‐oriented control to evaluate the effectiveness and robustness of the proposed control system.

Clinical decision support tool-guided, selective intensive induction strategy of ustekinumab in patients with Crohn's disease: A multicenter cohort study.

We aimed to evaluate the effectiveness and safety of clinical decision support tool (CDST)-guided initial selective intensive induction therapy (IIT) for patients with Crohn's disease (CD) who were treated with ustekinumab (UST) and to identify those most likely to benefit from IIT. Patients with active CD were included in this multicenter retrospective study and were categorized as low-, intermediate-, and high-probability responders according to the UST-CDST. IIT was defined as intensive induction by two or three initial doses of weight-based intravenous UST administration. Patients treated with standard therapy (ST) served as controls. The primary end-point was corticosteroid-free clinical remission (CFCR) at Week 24. Secondary end-points included clinical remission, clinical response, endoscopic remission, endoscopic response, and C-reactive protein (CRP) normalization at Week 24. Propensity score adjustments was conducted to ensure comparability. A total of 296 patients were included. At Week 24, IIT was associated with higher rates of CFCR (72.3% vs 43.0%, p < 0.001), clinical remission (77.3% vs 47.1%, p < 0.001), clinical response (78.1% vs 60.1%, p = 0.001), endoscopic remission (26.1% vs 9.9%, p = 0.024), and endoscopic response (58.6% vs 36.9%, p = 0.018) in low-intermediate-probability responders compared with ST. CRP normalization was comparable between groups. No significant differences were found in any end-points in high-probability responders. No serious adverse events were observed. The efficacy of IIT was superior to that of ST in patients with predicted poor response to UST, which may be regarded as a novel strategy for stratifying patients at baseline.

Effect of pyridostigmine on growth hormone and IGF-1 levels and outcomes of controlled ovarian stimulation cycle in women with poor ovarian response.

This study aimed to evaluate the effect of Pyridostigmine on IGF-1 and GH levels and the outcomes of COS cycles in women with POR. A total of 110 eligible women were randomly allocated to Pyridostigmine (n: 55) and control (n: 55) groups. COS outcomes, including gonadotrophin doses, COS duration, cycle cancellation rate, number of retrieved oocytes, number of MII oocytes, and fertilization rate, were compared between the groups. Also, IGF-1 and GH levels were measured at three time points: baseline, on the 5thday of the cycle, and on the trigger day. A total of 92 participants (Pyridostigmine: 44, Control: 48) were included in the final analysis. The Pyridostigmine group required significantly lower gonadotrophin doses (P < 0.0022) and had a shorter COS duration (P = 0.0019). No significant differences were observed in cycle cancellation rate, number of retrieved oocytes, number of MII oocytes, or fertilization rate. Pyridostigmine significantly accelerated GH levels over time compared to the Control group, with larger mean differences observed at each time point. The interaction between time and group indicated that the effect of the intervention on GH levels varied over the course of the COS cycle. Specifically, the intervention augmented the effect of COS agents on GH levels, as evidenced by the higher GH levels observed in the intervention group compared to the control group. For IGF-1 levels, time had a highly significant effect (P < 0.0001), but the interaction between Time and Group was not significant (P = 0.5067). Mean IGF-1 levels were higher in the Pyridostigmine group, though not statistically significant. Pyridostigmine improved COS efficiency by reducing gonadotrophin doses and COS duration. Further research is needed to explore its potential benefits in enhancing ovarian response in women with POR. Iranian Registry of Clinical Trials (IRCT). Registration date: 2023-08-05, Registration number: IRCT20100518003950N8.

Multimodality Treatment Outcome in Adult Patients with Head and Neck Rhabdomyosarcoma.

Head and neck rhabdomyosarcoma (HNRMS) is a rare malignant tumor in adults. No standard treatment for adults with HNRMS currently exists. A retrospective study of 72 newly diagnosed consecutive adult patients with HNRMS was conducted at one institution between November 2010 and April 2023. The log-rank tests were used to compare the differences in survival between treatment groups, and overall survival (OS), local recurrence-free survival (LRFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. We used restricted cubic spline models fitted for Cox proportional hazards models to determine the association between chemotherapy cycles/radiotherapy dose and mortality. The 2-year OS, PFS, LRFS, and DMFS rates for the entire cohort were 51.0%, 39.2%, 44.3%, and 47.3%, respectively. Radiotherapy significantly improved the OS (p < 0.01), PFS (p < 0.01), LRFS (p < 0.01), and DMFS (p < 0.01). Surgery had no effect on OS (49.3% vs. 53.0%, p = 0.62), PFS (36.9% vs. 41.8%, p = 0.31), LRFS (41.6% vs. 47.4%, p = 0.27), or DMFS (44.4% vs. 50.2%, p = 0.43). The restricted cubic spline showed that eight (HR = 1.002, 95% CI: 0.996-1.007) cycles of chemotherapy and 62.5Gy radiation therapy resulted in the lowest mortality. For HNRMS, eight cycles of chemotherapy and 62.5Gy of radiation might be sufficient. Poor response to chemotherapy predicted an extreme worse outcome. Surgery played a limited role in the treatment. III Laryngoscope, 2024.

Clinicopathologic Features of a Rare and Underrecognized Variant of Early-stage Primary Biliary Cholangitis With Ductopenia.

Primary biliary cholangitis (PBC) with early cholestasis and extensive bile duct loss but no significant fibrosis or cirrhosis is rare and underrecognized. We aimed to clarify the clinicopathology features and prognosis of these variants of patients with early-stage PBC with ductopenia. From January 2009 to January 2023, we retrospectively collected the laboratory and pathologic data of patients with early-stage PBC and recorded their liver-related events with a median follow-up of 4.5 years. Finally, a total of 141 patients with PBC in the early stage were included and divided into 2 groups: one with ductopenia (n = 36) and the other without ductopenia (n = 105). The median age of the participants was 50 years, with 90.8% being female. The ductopenia group exhibited significantly elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, total bile acid, and total cholesterol (CHOL). Conversely, they showed a reduced biochemical response to ursodeoxycholic acid according to the Paris II, Barcelona, and Rotterdam criteria. A relatively poorer prognosis was observed in patients with early-stage PBC with ductopenia but with no statistical difference (11.8% vs 4.9%, P = 0.352). Baseline total CHOL levels were identified as an independent factor for the presence of ductopenia in early-stage PBC (odds ratio = 1.771, 95% CI: 1.264-2.479, P = 0.001). In conclusion, ductopenia was a significant risk factor for worse biochemical profiles and poor treatment response in patients with early-stage PBC. High levels of total CHOL at baseline are associated with the presence of ductopenia in early-stage PBC.

Long-term outcomes of Gamma Knife radiosurgery for trigeminal neuralgia patients with or without concomitant continuous pain.

The effectiveness of Gamma Knife radiosurgery (GKRS) in treating trigeminal neuralgia (TN) has been demonstrated by a number of previous studies. However, there is a lack of research specifically documenting the initial and long-term outcomes of paroxysmal and persistent pain respectively following GKRS for TN with concomitant continuous pain (CCP). This study retrospectively analyzed pain outcomes and complications in 46 TN patients with CCP and 112 patients without CCP who underwent GKRS as initial surgical intervention at our institution from January 2019 to January 2024. Pain outcomes were classified as excellent (BNI I), good (BNI II-IIIa), and poor (BNI IIIb-V). Demographic and clinical data, pain outcomes, and complications were compared between patients with and without CCP. Subsequently, risk factors for poor outcomes after GKRS were evaluated using univariate and multivariate Cox regression analysis. The initial rate of poor outcomes in TN patients with CCP was similar to that of patients without CCP (15.8% vs 14.4%, P = .878). Following a minimum 6-month follow-up, the rate of poor pain outcomes increased to 37.0% in patients with CCP, compared to 38.4% in those without CCP (P = .968). Notably, the rate of long-term complete pain relief in patients without CCP was significantly higher than in those with CCP (35.7% vs 15.2%, P < .001). Poor response to medication (P < .001) was identified as an independent risk factors for poor outcomes after GKRS. While most TN patients with or without CCP can achieve favorable pain outcomes after GKRS, individuals with CCP were less likely to achieve complete pain relief compared to those without CCP.

Lung Function Recovery from Pulmonary Exacerbations Treated with Oral Antibiotics in Primary Ciliary Dyskinesia.

Patients with Primary Ciliary Dyskinesia (PCD) experience acute pulmonary exacerbations (PEx). In Cystic Fibrosis (CF), PEx treated with oral antibiotics (oPEx) were found to be related to short and long-term lung function deficits, however the impact oPEx on lung function in patients with PCD has not yet been assessed. To assess the impact of oPEx on lung function recovery in PCD and determine the factors associated with poorer response. This was a retrospective study of pediatric patients with PCD followed between 2000 to 2022 at SickKids (Toronto, Canada). PEx were defined as an increase in baseline symptoms with a physician decision to treat with systemic (intravenous (IV) or oral antibiotics. Lung function recovery was defined as a forced expiratory volume in 1 second (FEV1) measurement ≥90% of a stable baseline within 12 months before the PEx. Univariate and multivariate analyses were completed to identify risk factors for nonresponse. 337 PEx events in 85 patients were included in this analysis, of which 297 (88%) were treated with oral antibiotics. The mean (SD) follow up time for patients was 6.7 years (3.5) and the mean age of oPEx was 12.5 years (3.2). Patients with oPEx had a significant drop from baseline in mean FEV1 values at time of PEx (85.1% to 69.5%) with absolute and relative changes of -10.4% and -12.9%, respectively. At follow up (3 months post PEx) and up to 12 months post PEx, the mean FEV1 was 79.6% and 84.1%, respectively. 73.2% of the patients had lung function recovery at follow up visit which increased to 84.2% within one year post event. We identified two risk factors for nonresponse: being a non responder on the last PEx and younger age at time of oPEx. Conclusions oPEx in PCD show a similar pattern previously seen in CF patients with a decrease in FEV1 during exacerbation and an improvement post therapy. Most oPEx events recover to baseline FEV1 within the year post-exacerbation, with younger age and being non responder in the last PEx identified as risk factors for nonresponse.

Predictive value of a self-administered frailty screening questionnaire for the effectiveness of functional rehabilitation evaluated with the locomotor functional independence measure in a geriatric rehabilitation unit: a multicentre cohort study

BackgroundPatient Reported Outcome Measures (PROMs) are questionnaires that collect health data directly from the patient, without any intervention from a third party. The aim of rehabilitation units is to restore function. Functional gain can be evaluated with classic scales, such as the locomotor subscale of the Functional Independence Measure. This study aimed to assess the accuracy of a new self-assessment questionnaire pertaining to physical, sensory and cognitive ability (abbreviated SEPCO) for the prediction of functional prognosis in older patients admitted to a rehabilitation unit.MethodsIn this multicentre observational study including patients admitted to 12 rehabilitation centres in France, all included patients completed the SEPCO on admission. Poor response to rehabilitation was defined as relative effectiveness < 40% on the evolution of the locomotor FIM subscale. Components of the questionnaire potentially associated with the outcome of rehabilitation were confirmed for inclusion upon expert review and summed to form an overall score. The final score had five components: the depression score of the HADS, the SOFRESC vision score, the SOFRESC balance score, the stress urinary incontinence subscale of the USP, and the EPICES socio-economic deprivation score. A logistic regression model adjusted for baseline characteristics assessed the performance of the SEPCO score to predict change in functional status, defined by the relative functional gain for the locomotion subscale of the Functional Independence Measure (FIM).ResultsA total of 153 patients (mean age 79.2 ± 8.1 years, 72.5% women) were included. By multivariate analysis, a 5-scale SEPCO score ≥ 1.1 predicted worse functional improvement with an odds ratio (OR) of 2.575, 95% Confidence Interval (CI) 1.081 to 6.133, p = 0.03. Sensitivity for this threshold was 67.4% (95% CI 52.0–80.5%), with a specificity of 58.8% (95% CI 46.2–70.6%). Having a SEPCO ≥ 1.1 almost doubled the probability of poor response to rehabilitation (from 27.3 to 52.5%).ConclusionThe SEPCO score can predict poor functional gain from rehabilitation. Future studies should validate this score on an external cohort. The SEPCO could serve as a complement to the initial clinical evaluation performed by physicians, and assist physicians in setting each patient’s rehabilitation goals.