Longer Treatment Duration Research Articles

The evolving treatment landscape of multiple myeloma in Portugal: A nation‐wide retrospective cohort study of real‐world clinical practice

AbstractObjectivesTo characterize variations in real‐world treatment patterns in multiple myeloma (MM) in Portugal over a 5‐year period.MethodsA retrospective cohort multicenter study using secondary data of national hospital drug consumption database from 11 Portuguese public hospitals between 2017 and 2022.ResultsNumber of MM‐treated patients increased 53% over 5 years (from 825 to 1266 patients). Constant slight predominance of male patients (55%), 82% over 60 years old (median age, 70 years), and half of newly diagnosed patients were transplant‐eligible. The highest growth rate was in second‐line treatments, with a sixfold increase in patients in fourth‐line or beyond. First‐line treatment pattern remained stable both in transplant‐eligible (bortezomib, cyclophosphamide and dexamethasone (VCd_, bortezomib, thalidomide and dexamethasone (VTd), and bortezomib, lenalidomide and dexamethasone (VRd)) and noneligible patients (bortezomib, melphalan and prednisolone (VMP), VCd, and lenalidomide, dexamethasone (Rd)). Maintenance therapy increased from 5% to 16%, shifting from thalidomide to lenalidomide. Second and third lines were dominated by daratumumab‐based regimens after 5 years. No standard of care in fourth‐line treatment. Treatment duration increased in transplant‐eligible due to maintenance therapy and in noneligible due to fourth‐line treatments. Patients moved from first‐ to second‐line more rapidly over time.ConclusionsThere was an increase in MM patients reaching advanced treatment lines and significant changes in the treatment patterns, driven by access to more effective frontline treatments and longer duration of treatment.

Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Zibotentan in microvascular angina: a randomized, placebo-controlled, crossover trial

Abstract Background/Introduction Microvascular angina is a chronic condition characterized by abnormal myocardial blood flow leading to ischemic symptoms. Endothelin-1, a peptide secreted by endothelial cells, is a highly potent constrictor of the human coronary arterioles. Microvascular angina is associated with elevated circulating concentrations of endothelin-1, and prolonged exposure to ‘excess’ endothelin causes vasoconstriction and vascular remodelling. The chronic elevation of circulating endothelin-1 in microvascular angina may be influenced by genetic factors. Purpose Zibotentan, the most selective antagonist of the endothelin A receptor with no off-target binding to the endothelin B receptor, was evaluated in oncology trials and did not improve survival. We identified zibotentan as a potential disease-modifying therapy for patients suffering from microvascular angina. We hypothesized that zibotentan 10 mg daily for 12 weeks in addition to background medical therapy could be an efficacious and safe treatment for patients with microvascular angina. We further hypothesized that the SNP regulator of EDN1 gene expression, rs9349379 (G allele), could be a novel theragnostic biomarker. Methods The trial involved a prospective, multicentre, randomized, double-blind, placebo-controlled, sequential crossover design to assess the effects of zibotentan 10 mg or matched placebo, once daily for 12 weeks. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The secondary outcomes included exercise test parameters, health status questionnaires, safety (frequency and severity of severe adverse events (SAEs) and adverse events), feasibility (withdrawal rate), and biomarkers of efficacy (pharmacokinetics, pharmacodynamics). Results The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). There was no effect on the secondary outcomes. However, for exploratory (mechanistic) outcomes, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). Conclusion(s) In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.

Impact of Atezolizumab + Bevacizumab Therapy on Health-Related Quality of Life in Patients with Advanced Hepatocellular Carcinoma

Background/Objectives: Health-related quality of life (HRQoL) is critical in patients with hepatocellular carcinoma (HCC). It has become a key endpoint in the evaluation of new therapies, including atezolizumab + bevacizumab (Atezo + Bev) therapy. Methods: This study explored the factors associated with treatment efficacy, treatment duration, and overall survival (OS) in patients with advanced HCC undergoing Atezo + Bev therapy. We included 58 consecutive patients with HCC receiving Atezo + Bev from 19 November 2020, to 28 December 2023, who were followed up until the end of the study or death. We analyzed the relationships between baseline characteristics, adverse events (AEs), and HRQoL and efficacy, OS, and treatment duration. Results: The demographic (older men) and baseline characteristics (Child–Pugh score of 5, Barcelona Clinic Liver Cancer Stage C) were consistent with those of previous studies. The treatment demonstrated promising efficacy with a disease control rate of 71.2%, but HRQoL scores in five functional domains and seven symptoms worsened significantly within the first 3 months. Notably, better baseline cognitive and physical function scores and absence of severe (grade ≥ 2) hypoalbuminemia were associated with an improved objective response rate, longer treatment duration, and better OS. Conclusions: These findings underscore the importance of monitoring and managing treatment-related AEs and maintaining the HRQoL. They also highlight the crucial and reassuring role of multidisciplinary care in enhancing treatment outcomes in this cohort.

Magnesium and Potassium Supplementation for Systolic Blood Pressure Reduction in the General Normotensive Population: A Systematic Review and Subgroup Meta-Analysis for Optimal Dosage and Treatment Length

Background/Objectives: Studies have shown that consistent reductions of 2 mm Hg in systolic blood pressure (SBP) for the general normotensive population can result in significant decreases in mortality from heart disease and stroke. The purpose of this meta-analysis was to determine the optimal dose and duration of treatment for magnesium and potassium supplementation, having previously discovered that both reduce SBP by −2.79 and −2.10 mm Hg, respectively. Methods: Placebo-controlled, randomized clinical trials examining the effects of magnesium and potassium supplementation on SBP were identified. Pairwise meta-analyses with subgroups for dosage and treatment duration were run. Results: Magnesium at dosages of ≤360 mg/day and durations greater than 3 months reduced SBP by −3.03 and −4.31 mm Hg, respectively. Potassium at dosages of ≤60 mmol/day and durations greater than 1 month reduced SBP by −2.34 and −2.80 mm Hg, respectively. Conclusions: Both supplements demonstrated greater reductions in SBP for the general population at lower dosages and longer treatment durations. Future studies are needed to validate these findings and provide tailored recommendations. These studies could investigate varying dosages over long-term follow-up to provide robust data on optimal dosages and treatment durations, as our findings were limited due to reliance on previously published trials.

Prevalence of Vitamin B12 Deficiency in Patients With Type 2 Diabetes Mellitus on Metformin Therapy: A Cross-Sectional Study.

Background Metformin is frequently prescribed as a first-line oral hypoglycemic drug to treat insulin resistance-causing type 2 diabetesmellitus (T2DM). Long-term metformin use results in vitamin B12 deficiency, which is frequently overlooked and undiagnosed. A severe deficit may cause severe anemiaand gastrointestinal, or neurological issues. Studies are scarce onthis issue in Pakistani patients with T2DM. The current study aimed to estimate the prevalence of metformin-induced vitamin B12 deficiency in T2DM patients and to explore how it relates to metformin dosage or duration of therapy. Methodology A descriptive cross-sectional study was conducted on 260 T2DM patients using metformin therapy for more than a year and attending the outpatient diabetes clinic and the medicine department of Sheikh Zayed Hospital, Rahim Yar Khan, Pakistan, from August 2022 to October 2023. All socio-demographic, clinical, and general characteristics were collected. Blood samples were taken to measure the serum vitamin B12 levels, and based on these levels, deficient and normal group characteristics were compared. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York, United States). Results Based on the serum levels of vitamin B12 of the studied T2DM on the metformin regimen, the overall prevalence of vitamin B12 deficiency was found to be 36.54% (95). The B12 deficiency was higher among the age group of 41-50 years (109, 41.9%), female gender (150, 57.7%, p-value=0.0035), urban residents (194, 74.6%), non-smokers (197, 75.8%), and with a history of chronic disease (131, 50.4%). There was a statistically significant difference in vitamin B12 levels based on T2DM duration (p=0.012), with a higher prevalence in patients with a longer diabetes history of more than two years. There was no discernible statistical relationship between patients receiving different dosages of metformin (odds ratio (OR)=0.8627; 95% confidence interval (CI) (0.5195, 1.4326); p-value=0.568), durations of metformin (OR=0.7400; 95% CI (0.442, 1.2325); p-value=0.247), or intake of vitamin B12 (OR=0.8532; 95% CI (0.5073, 1.4351); p-value=0.549). Conclusion The prevalence of vitamin B12 deficiency impacted more than one-third of T2DM patients using metformin (36.54%). The risk of vitamin B12 deficiency may increase in females with higher metformin dosages and longer durations of treatment. Furthermore, a statistically significant correlation exists between vitamin B12 deficiency and the longer duration of T2DM. These findings highlight the relevance of routinely monitoring serum levels of vitamin B12 among those with T2DM, especially when metformin is being given for over a year or at doses greater than 1000 mg per day. These preventive strategies will aid in the early detection of vitamin B12 deficiency, allowing patients to be treated with supplementation before problems such as anemia or neuropathies arise, resulting in improved quality of life and a lower socioeconomic burden.

Decoding the variability in clinical and laboratory profiles of Chronic Inducible Urticaria vs. Chronic Spontaneous Urticaria - a retrospective study from a tertiary care center.

Chronic inducible urticaria (CIndU) is characterized by wheals and/or angioedema for longer than 6 weeks induced by specific triggers. The data regarding epidemiology of CIndU is scarce with limited available literature on urticaria severity, investigations, and treatment responses in CIndU compared to CSU. We performed a retrospective chart review of all CIndU patients(cases) enrolled in our Urticaria clinic, past seven years between January 2017 to December 2023. Equal number of CSU patients enrolled during study period were taken as controls. Patients with absence of weals and both CSU and CIndU were excluded from the study. Urticaria severity was assessed by Urticaria activity score over 7 days (UAS7). Statistical analyses were performed using SPSS V29 with P < 0.05 as significant. Out of all records screened, 222 CIndU (cases) and 226 CSU (controls) were eligible based on complete availability of data. Both groups were comparable in terms of age and gender with slight female preponderance. Mean UAS7 at baseline was comparable(p = 0.619) between two groups [(11.49 ± 10.37 in CIndU vs. 10.9 ± 12.2 in CSU)]. The mean CRP (mg/dl) levels for CIndU vs. CSU patients was 2.8 ± 4.2 vs. 6.9 ± 11.2 (p < 0.001). Serum D-dimer levels (mg/dl) were also significant between cases(167 ± 220) and controls(265 ± 452) (p = 0.020). The quality of life assessed by CU-QOL score was 9.39 ± 9.5 in CIndU vs. 16 ± 14.8 in CSU (p < 0.001). 80% of CIndU patients and 52% of CSU patients required updosing of antihistamines upto 4 times and the difference was statistically significant between two groups(p = < 0.001). The mean time taken to achieve remission i.e. UAS7 = 0 (T0) was 60 ± 42 days amongst CIndU while it was shorter in CSU (27.77 ± 27 days) (p < 0.001).Amongst all CIndU cases, commonest subtypes were symptomatic dermographism (SD) (39.5%) followed by cholinergic urticaria(4.2%) and cold urticaria(1.8%). Our study underscores the distinct clinical and laboratory profiles between CIndU and CSU patients. CIndU patients exhibit poorer response to standard antihistamine doses, requiring more frequent updosing and longer treatment duration. The time to attain remission as assessed by UAS7 score was also longer in CIndU patients than CSU patients (mean difference of 33 days). Further research is warranted to elucidate the underlying mechanisms and explore targeted treatment approaches for CIndU.

Enzalutamide versus abiraterone acetate in the development of new-onset or worsening type 2 diabetes mellitus in patients with metastatic castration-resistant prostate cancer: EVADE study

PurposeTo determine new-onset or worsening T2DM risk in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone acetate (AA) vs. enzalutamide (ENZA) in England.MethodsRecords of patients on AA and/or ENZA (2015−2021) were analysed retrospectively from UK- or England-wide databases and data sets. The primary endpoint was new-onset or worsening T2DM, analysed using a Cox model.ResultsOf 1382 patients, 84 (6.1%) met the primary endpoint; 42 of 826 patients (5.1%) received ENZA and 42 of 556 patients (7.6%) received AA. Among patients without baseline T2DM (n = 1049), 50 developed new-onset T2DM: 24 (3.9%) on ENZA and 26 (5.9%) on AA. Among patients with baseline T2DM (n = 333), 34 (10.2%) had worsening T2DM: 18 (8.3%) on ENZA and 16 (13.8%) on AA. Patients on ENZA had longer median follow-up (445 vs. 408 days) and treatment duration (164 vs. 139 days) than those on AA, who were also more likely to have new-onset or worsening T2DM than those on ENZA (HR: 1.8; 95% CI: 1.4–2.7; P = 0.0101). The number needed to harm for an additional patient to experience new-onset or worsening T2DM when receiving AA instead of ENZA was 40 overall, 50 in patients without baseline T2DM, and 18 in patients with baseline T2DM.ConclusionPatients with mCRPC receiving AA were more likely to experience new-onset or worsening T2DM than those on ENZA, despite having a shorter treatment duration. Further research is required to substantiate these findings in earlier disease settings with longer treatment duration.

7831 Unveiling Drug Resistance Mechanisms In Triple-Positive Breast Cancer: Insights From Long-Term Estrogen Deprivation Models And Innovative Mutation Detection Strategies

Abstract Disclosure: S. Bahnassy: None. H.S. Andrews: None. L. Jin: None. B.F. Kohrn: None. S. Tam: None. D. Mobin: None. Y.J. Dunn: None. M. Balachandran: None. M. Podar: None. W. He: None. M.D. McCoy: None. R.A. Beckman: Consulting Fee; Self; AstraZeneca, Boehringer Ingelheim. Other; Self; Chief Scientific Officer of OncoMind, LLC, which owns patents on dynamic precision medicine. R.B. Riggins: None. Compelling evidence from preclinical and clinical data suggests that triple-positive (TP; HER2+/HR+) breast cancer (BC) has lower response rates to HER2-targeted therapy and a higher risk of recurrence to endocrine therapy (ET) than HER2+/HR−. Molecular mechanisms underpinning drug resistance in TP-BC are poorly understood, thereby limiting our ability to improve patient outcomes and prevent metastatic progression. In our recent publication, we established and characterized long-term estrogen deprivation (LTED) ET-resistant (ETR) TP-BC models that mimic resistance to aromatase inhibitors without using genetic manipulation approaches. We reported intrinsic subtype shifts towards non-luminal phenotypes, metabolic reprogramming, and acquiring mutations in genes encoding for transcription factors and chromatin modifiers, as potential mechanisms of ETR in our LTED models. The emergence of drug-resistant mutator subclones under treatment-induced selective pressures, coupled with limitations in shallow-depth whole genome sequencing coverage, highlight an unmet need to develop a strategy for visually monitoring, capturing, and mapping resistant subclones through a mutational phenotypic screen, an approach offering valuable insights for optimizing treatment schedules. To address this, we developed and applied an innovative dual fluorescence mutation detection system to detect mutator cells expressing both mCherry and green fluorescence protein (GFP). First, we validated if our system is working properly. Compared to parental cells, transduced BT-474 and MDA-MB-361 LTEDs showed a drastic increase in GFP+ cells, suggesting the presence of resistant mutator cells. Consistent with the increase in GFP signal, TP-LTEDs showed increased mutation number and frequency in two Duplex Sequencing targeted capture panels (neutral loci and DNA polymerase-focused), used to perform ultra-deep, highly accurate sequencing. We then treated parental cells with single, dual, and triple combinations of anti-HER2, ET and CDK4/6 inhibitors to track the emergence of GFP+ mutator cells. Nine-day treatments with triple combinatorial therapies were best at inhibiting the growth of both BT-474 and MDA-MB-361 parental cell lines, compared to single- and double-agent targeted therapies. However, no GFP signal was detected within treated cells, suggesting that longer treatment durations are needed for drug-resistance mutator subclones to be discovered. Ongoing studies monitoring TP-drug resistance mutator subclones with long-term conventional targeted-therapies will improve our understanding of drug resistance mechanisms in this understudied subtype of BC. Importantly, these studies will enable dynamic precision medicine simulations to empower for a more tailored and effective therapeutic administration to prevent drug resistance and metastatic progression of TP-BC. Presentation: 6/3/2024

7831 Unveiling Drug Resistance Mechanisms in Triple-Positive Breast Cancer: Insights from Long-Term Estrogen Deprivation Models and Innovative Mutation Detection Strategies

Abstract Disclosure: S. Bahnassy: None. H.S. Andrews: None. L. Jin: None. B.F. Kohrn: None. S. Tam: None. D. Mobin: None. Y.J. Dunn: None. M. Balachandran: None. M. Podar: None. W. He: None. M.D. McCoy: None. R.A. Beckman: Consulting Fee; Self; AstraZeneca, Boehringer Ingelheim. Other; Self; Chief Scientific Officer of OncoMind, LLC, which owns patents on dynamic precision medicine. R.B. Riggins: None. Compelling evidence from preclinical and clinical data suggests that triple-positive (TP; HER2+/HR+) breast cancer (BC) has lower response rates to HER2-targeted therapy and a higher risk of recurrence to endocrine therapy (ET) than HER2+/HR−. Molecular mechanisms underpinning drug resistance in TP-BC are poorly understood, thereby limiting our ability to improve patient outcomes and prevent metastatic progression. In our recent publication, we established and characterized long-term estrogen deprivation (LTED) ET-resistant (ETR) TP-BC models that mimic resistance to aromatase inhibitors without using genetic manipulation approaches. We reported intrinsic subtype shifts towards non-luminal phenotypes, metabolic reprogramming, and acquiring mutations in genes encoding for transcription factors and chromatin modifiers, as potential mechanisms of ETR in our LTED models. The emergence of drug-resistant mutator subclones under treatment-induced selective pressures, coupled with limitations in shallow-depth whole genome sequencing coverage, highlight an unmet need to develop a strategy for visually monitoring, capturing, and mapping resistant subclones through a mutational phenotypic screen, an approach offering valuable insights for optimizing treatment schedules. To address this, we developed and applied an innovative dual fluorescence mutation detection system to detect mutator cells expressing both mCherry and green fluorescence protein (GFP). First, we validated if our system is working properly. Compared to parental cells, transduced BT-474 and MDA-MB-361 LTEDs showed a drastic increase in GFP+ cells, suggesting the presence of resistant mutator cells. Consistent with the increase in GFP signal, TP-LTEDs showed increased mutation number and frequency in two Duplex Sequencing targeted capture panels (neutral loci and DNA polymerase-focused), used to perform ultra-deep, highly accurate sequencing. We then treated parental cells with single, dual, and triple combinations of anti-HER2, ET and CDK4/6 inhibitors to track the emergence of GFP+ mutator cells. Nine-day treatments with triple combinatorial therapies were best at inhibiting the growth of both BT-474 and MDA-MB-361 parental cell lines, compared to single- and double-agent targeted therapies. However, no GFP signal was detected within treated cells, suggesting that longer treatment durations are needed for drug-resistance mutator subclones to be discovered. Ongoing studies monitoring TP-drug resistance mutator subclones with long-term conventional targeted-therapies will improve our understanding of drug resistance mechanisms in this understudied subtype of BC. Importantly, these studies will enable dynamic precision medicine simulations to empower for a more tailored and effective therapeutic administration to prevent drug resistance and metastatic progression of TP-BC. Presentation: 6/3/2024

7548 Final adult height in children with idiopathic growth hormone deficiency after growth hormone treatment

Abstract Disclosure: H. Lee: None. S. An: None. M. Cho: None. H. Nam: None. Objective: The aim of this study was to assess the final adult height (FAH) achieved through recombinant human growth hormone (GH) treatment and the factors influencing FAH. Methods: We retrospectively reviewed the charts of all patients diagnosed with IGHD who were prepubertal when they began GH treatment since August 2007. FAH was determined in 41 patients (28 males and 13 females) by July 2023. Results: 41 patients started treatment at an average age of 9.1 years and continued for 6.5 years. The mean initial height was -2.6 standard deviation scores (SDS) and the mean FAH was -0.6 SDS. GH treatment was initiated at a significantly younger age in females than in males (7.2±1.9 vs 10.0±3.2; p=0.01). The mean FAH was 169.9±4.5cm for males and 156.1±3.2cm for females. Differences between initial height and final height SDS were not significant between males and females. The mean of FAH SDS was higher compared to their mid-parental height -1.0 SDS (p=0.017). In multiple regression analysis, FAH showed a positive correlation with initial height, duration of treatment, and growth rate in the first year of treatment, and a negative correlation with BMI SDS at the start of GH (r2=0.59; p=0.000). FAH SDS was positively related to initial height SDS and growth rate in the first year of treatment. (r2=0.3; p=0.001) Conclusions: The mean FAH SDS after GH treatment was significantly higher than the mean MPH SDS in IGHD patients. Moreover, the good response of GH treatment was associated with longer treatment duration, greater height at the start of treatment, better treatment response at 1 year, and lower initial BMI SDS. Presentation: 6/3/2024

Birth Traits Associated with Pre-Adulthood Disease Manifestations in Calves.

The objective of this study was to explore the relationship between calf birth traits and their susceptibility to diseases before reaching adulthood. A total of 5253 birth traits of Chinese Holstein calves were examined, including gestation length (GL), calf weight at birth (CW), and calving ease score (CES), which ranges from 1 (easy) to 5 (very difficult). Furthermore, monthly medical records were scrutinized for pneumonia and diarrhea in these calves. The study assessed five aspects of disease manifestation in calves: age at first onset, frequency of illness, longest duration of treatment, and total duration of treatment. The link between age at onset and disease manifestation prior to adulthood was analyzed using general linear models and regression models. The GL of calves significantly correlated with the risk of pneumonia, with the risk decreasing as the GL increases. A higher CES was associated with a later onset of diarrhea in calves. Furthermore, the CES was significantly negatively correlated with the duration of diarrhea treatment in calves. These results suggest that implementing different preventive measures for calves with different birth traits and modifying treatment protocols for affected calves could enhance the productivity of dairy cows and reduce losses on farms.

Neurofilament heavy chain and chitinase 3-like 1 as markers for monitoring therapeutic response in multiple sclerosis

AimsThe aim of this study was to evaluate the association of serum neurofilament heavy chain (sNfH) and chitinase 3-like 1 (sCHI3L1) with treatment response and disease activity in multiple sclerosis (MS). MethodsThis single-center, prospective, observational cohort study was conducted at the MS Centre, University Hospital Ostrava, Czech Republic, from May 2020 to August 2023. sNfH and sCHI3L1 were determined using ELISA. A mixed-effects linear model with a log-transformed outcome variable was applied. ResultsWe analyzed 459 samples from 57 people with MS. Patients were sampled an average of 8.05 times during 21.9 months of follow-up. Those experiencing a relapse at sampling had a sNfH concentration 50 % higher than those in remission (exp(β) 1.5, 95 % CI 1.15–1.96). A longer duration of treatment was associated with lower sNfH (exp(β) 0.95, 95 % CI 0.94–0.96). Patients switched from low- to high-efficacy disease-modifying therapies (DMTs) had higher sNfH than patients treated with low-efficacy DMTs only (exp(β) 1.95, 95 % CI 1.35–2.81). Higher sCHI3L1 was associated with older age (exp(β) 1.01, 95 % CI 1.00–1.02) and longer DMT use (exp(β) 1.01, 95 % CI 1.00–1.02). sCHI3L1 values were not associated with relapse at the time of sampling, renal function, sex, or type of DMT. ConclusionIn contrast to sCHI3L1, sNfH may be a potential biomarker for monitoring treatment response and confirming clinical relapse in MS. Further research is needed to determine the long-term dynamics of sNfH and develop related treatment strategies.

The impact of plasma-activated water on the process of nickel bioremediation by Neowestiellopsis persica A1387

Cyanobacteria provide an economical, feasible, and environmentally friendly solution for heavy metal removal. In addition, plasma can facilitate the removal of heavy metals across various time frames. In this study, we applied plasma-activated water (PAW) to prepare Neowestiellopsis persica A1387 strain medium culture for 0, 10, 15, and 20 min via an Atmospheric Cold Plasma Jet device (ACPJ-17A). Nickel removal efficiency was evaluated after 48 hours of cultivation under controlled conditions at 0, 10, 30, 60, and 90 min. Further investigation was performed through FTIR, GC-MS, and XRD techniques. Statistical analysis of ANOVA and Tukey's test indicated that the samples treated for 15 min had the highest biomass dry weight, polysaccharide content, and nickel removal rate (p ≤ 0.05). The GC-MS analysis presented elevated concentrations of ethanol, 1,3-dimethylbenzene, acetic acid, 3-methylbutyl ester, aromatic chemicals, 2-methyl-1-propanol, and 3-octen-2-ol in all samples treated with plasma. The functional group analysis using the FT-IR approach showed increased peak intensities with more extended treatment periods, indicating the addition of methyl, methylene, and hydroxyl groups to the cyanobacterium cell wall. Furthermore, a peak at 468 cm⁻¹ wavelength was observed, correlating to the Ni-O stretching mode after absorption of Ni on the cyanobacterium surface. The XRD data exhibited prominent peaks in all diffraction patterns angles below 20 degrees, suggesting the presence of amorphous and non-crystalline chemical structures within the cyanobacterial structures. The peak intensity increased with longer treatment durations. The 15-min plasma treatment optimized Ni removal, but the efficiency decreased with prolonged exposure due to adverse effects such as increased reactive oxygen species (ROS) production.

The Impact of Loneliness and Social Relationship Dissatisfaction on Clinical and Functional Outcomes in Dutch Mental Health Service Users

The relationship between reduced social connectedness and mental health outcomes is increasingly acknowledged. Yet, relatively little is known about how two crucial subjective aspects of social disconnectedness - loneliness and social relationship dissatisfaction (SRD) - are related to clinical and functional recovery. This cohort study aimed to investigate the association of loneliness and SRD with various mental health outcomes among 15,512 outpatients from a Dutch mental health service. Demographics and data on loneliness, SRD, symptomatic distress, suicidal ideation, and role functioning, as well as treatment duration, and mortality, were collected. The study analyzed the association between these factors overall and by diagnostic group, gender, and age, using cross-sectional and longitudinal regression, while controlling for relevant covariates. Findings revealed significant, independent, associations between loneliness, SRD, symptomatic distress, and role functioning across different diagnostic groups. Particularly strong associations were noted in bipolar and psychosis-related disorders. Gender did not significantly influence the strength of associations. In older patients, lower levels of loneliness and SRD were observed, but the impact on clinical and functional outcomes was consistent across ages. Higher loneliness and SRD were associated with longer treatment durations, regardless of age, gender or diagnosis. This study indicates the wide-reaching effects of perceived social disconnectedness on recovery and emphasizes interventions targeting loneliness and SRD to enhance outcomes.

Treatment patterns of goserelin 3.6 mg once monthly and 10.8 mg every three months in women with breast cancer: A real-world analysis.

391 Background: Goserelin is a gonadotropin-releasing hormone agonist used for ovarian function suppression in the treatment of pre- and peri-menopausal patients with breast cancer. Goserelin, administered as a subcutaneous implant, is available in doses of 3.6 mg once monthly or 10.8 mg every three months; goserelin 3.6 mg is approved in the US, and both the 3.6 mg and 10.8 mg doses are approved by Health Canada and the European Medicines Agency. A study utilizing US real-world evidence was conducted to characterize treatment patterns of patients treated with goserelin 3.6 mg and/or 10.8 mg. Methods: Electronic health record data of adult patients with a history of breast cancer and with ≥2 prescriptions of goserelin between 1 January 2017 – 31 December 2022 were identified through TriNetX. Index date was the initiation of goserelin administration. Patients were followed until 15 March 2024. Patient demographics, treatment adherence, and healthcare resource utilization (HCRU) were examined and summarized using descriptive analytics. Results: Overall, 3,620 patients were identified: 2,870 treated with goserelin 3.6 mg, 410 with goserelin 10.8 mg, and 340 who switched from goserelin 3.6 mg to 10.8 mg. Peak utilization of goserelin 10.8 mg (36.6%) and peak dosage switching (26.5%) occurred in 2020. Across groups, mean age at index date was 42.2–44.4 years, and patients were white (64.1–67.6%), black (11.8%–13.9%), Asian (8.0%–11.8%), and American Indian and/or Alaskan native (0.3%–2.9%). Of patients with known BMI, BMI mostly ranged between 18.5–24.9 kg/m 2 in all groups. Patients who switched from goserelin 3.6 mg to 10.8 mg had the longest median treatment duration (776 days) (Table). Patients treated with goserelin 10.8 mg remained on treatment for a median of 426 days; 74.4% of these patients were treatment-adherent (Table). In comparison, patients treated with goserelin 3.6 mg had a shorter median treatment duration (226 days) and were less adherent (56.4%) (Table). HCRU during the 12 months after index date was broadly similar across groups. Conclusions: Treatment with goserelin 10.8 mg every three months is associated with greater adherence and longer treatment duration, compared with 3.6 mg once monthly, in patients with a history of breast cancer. Patients who switched from goserelin 3.6 mg to 10.8 mg were treatment-adherent for nearly two years, consistent with clinical recommendations. Goserelin 3.6 mg (n = 2,870) Goserelin 10.8 mg (n = 410) Switched from goserelin 3.6 mg to 10.8 mg (n = 340) Median duration of treatment (days) 264 429 776 Median time to switch (days) — — 218 Patients adherent* to dosing schedule 1,608 (56.4%) 306 (74.4%) — Status as of March 15, 2024 Discontinued goserelin 2,018 (70.8%) 261 (64.3%) 173 (50.9%) Death 88 (3.1%) 10 (2.5%) 3 (0.9%) *Defined as: ≤36 days between prescriptions (3.6 mg) or ≤108 days between prescriptions (10.8 mg).

Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.

Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters. In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p= 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups. Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration. National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.

Therapeutic effect analysis of non-invasive ear moldings on correcting congenital auricular deformity in 435 ears

Objective:To evaluate the therapeutic effect of non-invasive ear moldings on correcting congenital auricular deformity of infants. Methods:A total of 435 ears with congenital auricular deformity were treated in the department of Otorhinolaryngology of Chengdu Women and Children's Central Hospital from December 2019 to July 2023. The infants were divided into 3 groups according to the initial treatment age, i. e. , 0-30 days（group A, n=106, 175 ears）, 31-90 days（group B, n=124, 202 ears） and ≥91 days（group C, n=37, 58 ears）. All infants were corrected with Chinese ear moldings. The efficacy, complication rate and treatment duration were compared among the three groups, and the treatments of different types of auricle deformity was analyzed. Results:Through comparison of three groups, the results showed that the markedly effective and cured rate of group A was the highest, and group C was the lowest. The difference was statistically significant（P=0.008）. Specially, there was a significant decrease of after 5 months in Group C. There was no significant difference in the complication rate among the three groups（P=0.232）, and the occurrence of complications has no significant impact on treatment. Group C has the longest treatment duration and group A has the shortest. The difference was statistically significant（P<0.001）. Conclusion:Congenital auricle deformity should be early detected and intervened. The younger the age of children, the better efficacy and shorter treatment duration can be acquired. Children under 5 months still will receive a good treatment. Nevertheless, for children older than 5 months, corrective treatment may also be considered. The efficacy for malformations was significantly lower than that of deformations. The number of cases, efficacy and complication rate for different types of deformations were significantly different.

Duration of antimicrobial treatment for uncomplicated streptococcal bacteraemia: another example of shorter is better

ObjectivesDuration of treatment for uncomplicated streptococcal bacteraemia is unknown. The study aims to assess clinical outcomes of patients with uncomplicated streptococcal bacteraemia receiving a short course (5-10 days) of antimicrobial treatment compared to those receiving the traditional, longer duration (11-18 days). MethodsThis retrospective study was conducted at the Lausanne University Hospital, Switzerland and included episodes of uncomplicated streptococcal bacteraemia among adult patients from 2015 to 2023. Clinical failure was defined as mortality, recurrence of bacteraemia by the same streptococcal species and development in bone and joint infection within 120 days. ResultsDuring the study period, 336 episodes of uncomplicated streptococcal bacteraemia were included. The median duration of antimicrobial treatment was 10 days (interquartile range: 7-14); 184 (55%) and 152 (45%) episodes received a short (5-10 days) and long (11-18 days) duration of antimicrobial treatment, respectively. Forty-three (13%) episodes had clinical failure; 120-day mortality was 11% (36 episodes); recurrence of bacteraemia by the same streptococcal species was observed in 8 episodes (2%). No difference in clinical failure was observed between episodes receiving short and long courses of antimicrobial treatment (10% versus 16%; P 0.143). The Cox multivariable regression model found that a Charlson comorbidity index >4 (aHR 4.87, 95% CI 3.08-7.71), and septic shock (1.67, 1.04-2.67) were associated with clinical failure; a short course of antimicrobial treatment was not associated with clinical failure (0.90, 0.57-1.12). ConclusionsThis study has shown that a short duration of antimicrobial treatment for cases of streptococcal bacteraemia is effective and safe.

Effects of 12-Week Supplementation with Coffee Diterpene Cafestol in Healthy Subjects with Increased Waist Circumference: A Randomized, Placebo-Controlled Trial.

Background: Coffee consumption is inversely associated with type 2 diabetes. Cafestol, a bioactive compound in coffee, has demonstrated glucose-lowering and insulin-secretory properties in cell and animal studies. The acute effects of cafestol on glucose metabolism in humans have only been briefly investigated, and longer-term effects have not been explored. This study aimed to assess the effects of purified cafestol on insulin sensitivity and other metabolic parameters in healthy individuals with increased waist circumference at risk of developing type 2 diabetes. Methods: A 12-week randomized, placebo-controlled, parallel trial was conducted with 40 participants. Insulin suppression tests, mixed meal tests, and MRI scans were performed before and after the intervention. Results: Administering 6 mg of cafestol twice daily did not alter insulin sensitivity or glucose tolerance but led to significant reductions in body weight (2%), visceral fat volume (5%), and gamma-glutamyl transferase levels (15%) compared to the placebo. Conclusions: Cafestol may hold promise for weight and visceral fat reduction. Cafestol did not improve insulin sensitivity or glucose tolerance in this study but might still contribute to the observed inverse association between coffee consumption and type 2 diabetes. Future research should explore higher dosages and longer treatment durations, particularly in individuals with impaired glucose metabolism and type 2 diabetes.