Reduction In Progression Research Articles

Cost‐effectiveness of amyloid‐targeting therapies: modelling based on 5724 biomarker positive AD patients in the Swedish Registry of Cognitive Disorders

AbstractBackgroundLecanemab is an amyloid‐targeting therapy recently approved by the U.S. FDA for treatment of early Alzheimer’s disease. A phase III trial (Clarity AD) demonstrated a reduction of disease progression, however uncertainty remains around the long‐term health outcomes and implications for cost‐effectiveness. Previous economic evaluations have been limited by lack of long‐term follow‐up data on health outcomes and resource utilization in AD patients with biomarker‐confirmed amyloid pathology.Method5724 patients with longitudinal follow‐up data were included from the Swedish Registry of Cognitive Disorders (SveDem), linked to other data sources. Amyloid positivity was determined from the CSF beta amyloid 1‐42/p‐Tau ratio, with optimal cut‐off levels determined from Abeta 40/42 ratios. Patients were followed up to 12.9 years from diagnosis (mean 4.9 years). A disease model model was constructed with states defined by cognitive status (MCI/dementia, MMSE score) and care setting (community/institution). The semi‐Markov design allows transition probabilities to vary with time spend in individual states. Hazard rates for disease progression, institutionalization and mortality were estimated using semiparametric survival models based on SveDem linked to the municipal care and death registries. Costs by disease state were estimated from resource utilization data from the national patient and prescription drug registries on formal medical and community care. Health utility values by disease state were derived from previous observational studies in Sweden.ResultA therapy reducing disease progression to more severe cognitive states by 31% over a treatment period of 18 months (as in Clarity AD) was associated with savings in formal care costs of 41,000 SEK and 0.140 quality‐adjusted life‐years (QALYs) gained. At 1 million SEK per QALY, treatment would be cost‐effective at an annual cost of 121,000 SEK, including costs for diagnosis and monitoring. Almost half of estimated QALY gains were due to reduced mortality; setting survival equal in treated and untreated patients resulted in fewer QALYs gained but higher cost savings.ConclusionThis is the first study to report on the cost‐effectiveness of amyloid‐targeting therapy based on integrated disease progression and cost data from a large, representative cohort of amyloid‐positive early AD patients. Such data is of critical importance to enable cost‐effective introduction of lecanemab.

Therapeutic effects of finasteride: inhibition of disease progression and serum prostate-specific antigen reduction in patients with prostatic intraepithelial neoplasia.

The objective of this study was to evaluate the impact of finasteride on the progression of prostate intraepithelial neoplasia and levels of prostate-specific antigen (PSA) in patients. A total of 120 patients with high-grade prostatic intraepithelial neoplasia were included in this study from January 2013 to January 2018. All patients underwent prostate biopsies. Among them, 60 patients were assigned to the observation group and received a daily dosage of 5mg finasteride for 60 months, while the remaining 60 patients were assigned to the control group and did not receive finasteride. PSA levels were measured every six months, and imaging scans were conducted throughout the five-year study period. Additional biopsies were performed if PSA levels exceeded 10ng/mL or imaging suggested the presence of prostate cancer. Statistical analysis was applied to the collected data. In total, 25 cases of prostate cancer were identified in this study. Of these cases, 7 patients belonged to the observation group, whereas the remaining 18 patients were from the control group. The observation group exhibited significantly lower levels of total serum PSA (p <0.001) and Gleason scores (p <0.001) compared to the control group. Our study, which involved 120 participants, demonstrated that finasteride effectively reduces serum PSA levels and mitigates the severity of prostate cancer. These findings suggest that finasteride holds potential as a treatment option for patients with -high-grade prostatic intraepithelial neoplasia.

Incorporating clinical trial outcomes in health economic evaluations of disease‐modifying therapies for AD

AbstractBackgroundEvidence on cost‐effectiveness of novel therapies for Alzheimer’s disease (AD) is of increasing importance for patient access. Challenges involved in implementing treatment effects in health economic (HE) models is an important source of uncertainty around the value of new AD therapies. HE models are developed from observational studies that often include different patient populations and different endpoints and scales from clinical trials.MethodsThe International Pharmacoeconomic Collaboration on Alzheimer’s Disease (IPECAD) conducted a series of workshops with research groups developing HE models in AD, to systematically characterize methodological approaches to modelling and benchmark results from these models in standardized scenarios. We reviewed published models and contrasted the characteristics of these models with study design specifications of recent late‐stage clinical trials of AD DMT to highlight potential issues with incorporating efficacy data from clinical trials in existing HE models. Identified issues included: need for mapping between different scales used to assess cognition, function and other efficacy domains, incorporating effects on multiple domains, differences in trial populations and expected patient populations treated in routine care, and statistical methods for generating efficacy estimates for use in HE models.ResultsThree options were identified for translating trial efficacy estimates into HE models: 1) use actual trial data and model disease course post trial, 2) assume treatment reduces transition probabilities to more severe states, and 3) implement treatment effect as a proportional reduction of progression on the time scale.ConclusionsThe design of future clinical trials of DMT need to take into account the need to generate data to populate HE models. Pre‐specifying analyses of trial data for HE modeling purposes can reduce uncertainty and improve confidence in results.

Durable Clinical Benefits of Idasanutlin Therapy in Hydroxyurea-Refractory Polycythemia Vera

Background: In phase 1 (NCT02407080) and phase 2 (NCT03287245) clinical trials, idasanutlin, a human double minute 2 homolog (HDM2) antagonist, demonstrated robust clinical activity and rapid reduction in JAK2V617F variant allele frequencies (VAF) in patients with hydroxyurea-intolerant or refractory polycythemia vera (PV). Despite promising disease-targeted clinical efficacy, high rates of discontinuation due to toxicity, and concerns regarding the potential clinical implications of transient TP53 mutations had dampened the enthusiasm for pursuing further development of this class of drugs in PV patients. 1,2,3 Given the significant reduction in JAK2V617F VAF that was documented in the clinical trials, we postulated that idasanutlin may have durable clinical effects in terms of reduction in phlebotomy requirement, splenomegaly, and disease progression, as well as questioned the significance of the transient increments in TP53 mutations. To assess the long-term implications of this therapy on PV patients, we examined the longer-term effects of idasanutlin administration. Methods: We retrospectively evaluated the long-term outcomes of patients enrolled in the phase 1 and 2 clinical trials and used descriptive statistical analysis to evaluate a change in phlebotomy requirements, change in spleen size, and JAK2V617F VAF. Results: Seventy-six percent (29/38) of the patients enrolled in the phase 1 and phase 2 studies continued to be followed at the participating institutions after the end of trial (EOT) visit (Table 1). Median follow-up after EOT to last follow up visit was 40 months (range XX-XX months). There was no increase in 8-week phlebotomy requirements when comparing 8-week phlebotomy requirement prior to EOT to pre-specified time-points of 1, 3, 6, 12, 18, 24, 36 months after idasanutlin discontinuation (P=.50). Six of 29 (21%) participants remained off PV-directed therapy for the duration of follow up. Therapies initiated in the remainder of the patients are listed in Table 1, four of whom received either combination or sequential therapies. Reduction in splenomegaly with idasanutlin was durable with no observed increase in spleen size by palpation from EOT through the 36-month follow up visit (P=.51). Change in hematologic profile of patients throughout follow up is shown in Figure 1 (median, range). There were four (13.7%) documented cases of disease progression. Three progressed to myelofibrosis (MF), one to blast phase (BP). Two participants that progressed to MF went on to receive allogeneic hematopoietic cell transplant. Of those who progressed, median time to progression was 17.5 months (range 14-24 months) after treatment discontinuation. Of those that progressed, mutations by next generation sequencing were noted in JAK2 (4), TET2 (2), DNMT3A (1), SF3B1 (1), and ASXL1 (1). None had a known TP53 mutation at the time of disease progression. There were no documented cases of thrombotic events, or hemorrhagic events within the follow-up period. Changes in JAK2V617F VAF after treatment discontinuation will be presented at the meeting. Conclusion: HDM2 antagonist therapy represents a rational and highly effective treatment approach in PV. The durable effects of idasanutlin on phlebotomy requirements and splenomegaly persist even after treatment discontinuation. Additionally, the lack of appearance of TP53 mutations or loss of TP53 in those who progress suggest that the previously-described transient TP53 mutations do not have long-term clinical implications. Alternative dose and scheduling approaches that are more tolerable may be warranted to safely maintain long-term PV disease control. 1 Mascarenhas J, Passamonti F, Burbury K, et al. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Advances. 2022;6(4):1162-1174. doi:10.1182/bloodadvances.2021006043 2 Mascarenhas J, Lu M, Kosiorek H, et al. Oral idasanutlin in patients with polycythemia vera. Blood. 08 08 2019;134(6):525-533. doi:10.1182/blood.2018893545 3 Marcellino BK, Farnoud N, Cassinat B, et al. Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin. Blood Advances. 2020;4(22):5735-5744. doi:10.1182/bloodadvances.2020002379

Xpo-1 Antagonism Impairs CSF-1R Expression and Depletes Lymphoma-Associated Macrophages in T-Cell Lymphomas

Background: Lymphoma-associated macrophages (LAM) provide ligands for antigen, costimulatory, and cytokine receptors expressed by malignant T cells and directly promote T-cell lymphomagenesis. LAM also play an important role in suppressing host anti-tumor immunity and indirectly promote T-cell lymphomagenesis. Therefore, LAM are a therapeutic vulnerability in T-cell lymphomas (TCL), and their depletion from the tumor microenvironment (TME) is a rational therapeutic goal. Methods: XPO1 and CD163 expression were examined by immunohistochemical staining. In order to determine the extent to which XPO1 antagonism depletes LAM, a pharmacologic strategy was adopted using selinexor. Viability of human monocyte-derived and TCL conditioned macrophages upon selinexor treatment was examined in vitro using standard methods. RNA binding to eIF4e was determined by RNA immunoprecipitation (RIP) using eIF4e and IgG antibodies and quantification performed by qPCR. Nuclear export of eIF4e client mRNA upon XPO1 antagonism with selinexor was examined by qRT-PCR in nuclear and cytoplasmic pools of RNA. LAM depletion upon selinexor treatment was examined in vivo using a previously described GEM ( Smarcb1-deficient) model and CD68-GFP reporter mice. Results: As we had previously demonstrated that CD163 identifies LAM that are alternatively polarized and proliferative, co-staining was performed with CD163 and XPO1, and CD163+XPO-1+ LAM identified in 69% of PTCL cases (n=26) examined. We previously demonstrated that LAM within a PTCL context are resistant to inhibition by selective CSF-1R antagonists. Therefore, we performed an unbiased, high-throughput screen using monocytes cultured in the presence of cell-free conditioned media (CFCM) obtained from T-cell lymphoma cell lines and primary specimens. This screen identified selinexor as a potential therapeutic vulnerability. Therefore, we cultured normal-donor monocytes in RPMI media alone, or in media supplemented with cell free conditioned media (CFCM) obtained from PTCL/CTCL cell lines (n=2) or primary specimens (n=5) and determined cell viability. Consistent with our prior findings, CFCM from PTCL/CTCL cells promoted the growth and survival of monocyte-derived macrophages (MDM), but this effect was abrogated upon selinexor treatment. These findings converged with the observation that CSF-1R transcripts are eIF4e clients in ALCL cells. Therefore, the extent to which transcripts required for macrophage survival (i.e. CSF-1R), proliferation (i.e. PU.1), and polarization (i.e. STAT3) are eIF4e clients was examined by eIF4e-RIP in MDM. These experiments demonstrated that CSF-1R, PU.1 and STAT3 are eIF4e clients, and selinexor treatment significantly decreased their nuclear export in MDM. Given the obvious clinical relevance of CSF-1R as a therapeutic target, CSF-1R expression in MDM following selinexor treatment was examined, and compatible with these results, a significant decrease in CSF-1R expression observed upon selinexor treatment. We previously employed CD68-GFP reporter mice in a Smarcb1-deficient GEM model, demonstrating that GFP+ macrophages in this TCL model are transcriptionally reprogrammed and proliferative. Selective CSF-1R antagonists minimally impair LAM survival in this model. In contrast, selinexor significantly depleted LAM ex vivo in this model and impaired the viability of bone marrow derived macrophages. In order to extend these findings, lymphoma-bearing GEM mice were treated with selinexor and the abundance of CD11b+Ly6G- LAM determined by flow cytometry, whereby a significant reduction in LAM abundance and TCL progression were observed, compatible with our in vitro/ex vivo findings. Conclusions: Therefore, we concluded that XPO1 inhibition indirectly impairs T-cell lymphoma growth and survival by depleting LAM, which are a dependency in these lymphomas.

The Functional Implications of Broad Spectrum Bioactive Compounds Targeting RNA-Dependent RNA Polymerase (RdRp) in the Context of the COVID-19 Pandemic.

As long as COVID-19 endures, viral surface proteins will keep changing and new viral strains will emerge, rendering prior vaccines and treatments decreasingly effective. To provide durable targets for preventive and therapeutic agents, there is increasing interest in slowly mutating viral proteins, including non-surface proteins like RdRp. A scoping review of studies was conducted describing RdRp in the context of COVID-19 through MEDLINE/PubMed and EMBASE. An iterative approach was used with input from content experts and three independent reviewers, focused on studies related to either RdRp activity inhibition or RdRp mechanisms against SARS-CoV-2. Of the 205 records screened, 43 studies were included in the review. Twenty-five evaluated RdRp activity inhibition, and eighteen described RdRp mechanisms of existing drugs or compounds against SARS-CoV-2. In silico experiments suggested that RdRp inhibitors developed for other RNA viruses may be effective in disrupting SARS-CoV-2 replication, indicating a possible reduction of disease progression from current and future variants. In vitro, in vivo, and human clinical trial studies were largely consistent with these findings. Future risk mitigation and treatment strategies against forthcoming SARS-CoV-2 variants should consider targeting RdRp proteins instead of surface proteins.

Real-world treatment preferences among health care providers in the United States in selecting disease modifying therapies for patients with multiple sclerosis: a discrete choice experiment

AimsHealth care providers (HCPs) treating multiple sclerosis (MS) in clinical practice have numerous disease-modifying therapies (DMTs) to consider when evaluating treatment options. This study assessed the treatment preferences of HCPs in the United States, both direct (explicit) and derived (explicit and implicit), when selecting MS DMTs based on clinical and logistical treatment attributes.Materials and methodsA 45-minute web-enabled questionnaire was administered to HCPs who manage patients with MS to assess the importance of treatment attributes. HCPs were recruited through an online panel. This study examined treatment attributes relevant to treatment decisions in MS, with a focus on the burden to HCPs and their staff, as well as HCP attitudes toward various aspects of MS care such as diagnosis, treatment prioritization, and ease of initiating or switching DMTs. The study also employed a discrete choice experiment (DCE) to assess direct and derived treatment preferences.ResultsThe study recruited 145 HCPs. Direct assessments (a score of greater than 7.0 was considered important) suggested that safety (mean importance rating = 7.8/9) and relative risk reduction in relapses (7.6/9) and disability progression (7.5/9) were most important when selecting DMTs. In contrast, derived importance from the DCE (higher points corresponding to greater importance) suggested that logistical attributes such as dose frequency (mean relative attribute importance = 17.5%), dose titration (10.3%), formulation (9.4%), and volume of calls (9.1%) were important considerations, along with efficacy (16.5%), safety (9.8%), and gastrointestinal tolerability (9.4%).LimitationsThis study may have been subject to selection bias due to the application of eligibility criteria, the convenient sampling recruitment methodology, and recruitment of HCPs with internet access.ConclusionIn the direct assessment, clinical attributes were chosen as the most important treatment attributes by HCPs. However, in the DCE, derived treatment decisions rated logistical attributes as also being as important in treatment choice.

Role of Fisetin in Selected Malignant Neoplasms in Women.

A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3',4',7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid.

β2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting β2-adrenergic receptor (β2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use β2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other β2-AR agonists compared with those with no COPD. These data indicate that β2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of β2-AR agonist intake, compared with those without COPD. These data indicate that β2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

The PKC-β Inhibitor MS-553 Displays Preclinical Efficacy in BTK Inhibitor Resistant Chronic Lymphocytic Leukemia

Background: Treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by usage of targeted therapies against the B-cell receptor (BCR) signaling cascade, specifically Bruton's Tyrosine Kinase (BTK). However, resistance to BTK inhibition occurs through acquisition of various mutations in BTK or its immediate downstream signaling partner, PLCγ2. Clinical outcomes for these patients are poor, emphasizing the need for alternative therapeutics. In the presence of these mutations, BCR signaling remains intact, suggesting that targeting molecules downstream of BTK may be effective. Protein kinase C-β (PKCβ) is a downstream component of the BCR pathway that has been shown to be over-expressed in CLL. Moreover, PKCβ is essential to the development of CLL in the Eμ-TCL1 mouse model and its expression in stromal cells is required for the survival of leukemic B-cells (Holler et al. 2009). This suggests that signaling through PKCβ, in both CLL cells and cells in the microenvironment, is essential to promote leukemogenesis. MS-553 is a potent, ATP competitive, reversible inhibitor of multiple PKC isoforms including PKCβ, with the potential to overcome BTKi mediated resistance. Methods: Primary CLL cells were isolated by negative selection and treated with up to 5 μM MS-553. Cell viability was assessed via Annexin V/PI with and without HS-5 stromal cell co-culture. BCR and canonical WNT signaling changes were evaluated by change in target protein phosphorylation or total protein by immunoblot following drugging. Changes in downstream NFκB and WNT signaling were interrogated by RT-qPCR. Using genetically modified TMD8 cells that express only C481S or T474I mutated BTK, we tested MS-553's effect on cell-viability and BCR signaling. In vivo survival studies were performed using the Eμ-MTCP1 (Walker et al. 2021) adoptive transfer mouse model, an aggressive model of CLL, with subsequent randomization into vehicle or MS-553 treatment arms. Results: Following 72 hours of drugging, 5 μM MS-553 displayed modest cytotoxicity against primary CLL cells both alone (50%, p&amp;lt;0.0001, n=8) and in the presence of HS-5 stromal cells (25%, p=0.0008, n=8). In primary CLL cells harboring the C481S BTK mutation, we observed retained cytotoxicity following 72 hours of drugging (29%, p=0.00029, n=6). At 24 hours, 5 μM MS-553 inhibited downstream BCR and WNT signaling in primary CLL cells, demonstrated by reduced phosphorylation of PKC-β (43%, p=0.0024, n=15) and several of its downstream targets including pGSK3β (45%, p&amp;lt;0.0001, n=15), pIκBα (66%, p&amp;lt;0.0001, n=15), and pERK (17%, p=0.0301, n=15), and reduced total protein of β-Catenin (82%, p&amp;lt;0.0001, n=9), Cyclin D2 (71%, p=0.0011, n=9), and cMyc (85%, p&amp;lt;0.0001, n=9) compared to vehicle treated, stimulated samples. In both treatment naïve and C481S patient samples, mRNA expression of NFκB and WNT pathway targets BCL-2, OCT-2, BFL-1, MYC, CD40, Cyclin D1, and Cyclin D2 were all decreased after 48 hours of treatment with 1 or 5 μM MS-553. MS-553 also showed efficacy in the presence of BTK mutations: viability in TMD8 cells was reduced following 72-hour drugging with MS-553 regardless of BTK mutational status (WT: 22%, p=0.0006, n=3; C481S BTK: 18%, p=0.0032, n=3; T474I BTK: 19%, p=0.0015, n=3). Inflammatory cytokine production is inhibited by MS-553 through its ability to decrease CCL3 and CCL4 cytokine expression in WT and mutant BTK-harboring TMD8 cells (p&amp;lt;0.0001, n=3) (Figure 1A). To validate inhibition of BCR signaling in the C481S BTK setting, we treated primary CLL cells harboring this mutation and observed a reduction in both CCL3 and CCL4 production (61%, p=0.001229, n=5). As proof of concept, we examined MS-553's efficacy in vivo in the Eμ-MTCP1 mouse engraftment model, and found a significant reduction in disease progression and increase in survival (median 117 days) when compared to vehicle control (median 56 days, p=0.0003) (Figure 1B). Conclusion: Our data demonstrate the efficacy of the PKCβ inhibitor MS-553 in preclinical models of CLL including that with BTK mutations conferring BTKi resistance. These findings support continued preclinical and clinical investigation of MS-553 in CLL, and the phase 1 trial of this agent is currently underway (NCT03492125) (Blachly et al. 2022).

Safety and efficacy of 0.01% and 0.1% low-dose atropine eye drop regimens for reduction of myopia progression in Danish children: a randomized clinical trial examining one-year effect and safety

BackgroundTo investigate the efficacy and safety of 0.1% and 0.01% low-dose atropine eye drops in reducing myopia progression in Danish children.MethodsInvestigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months followed by 0.01% for six months (loading dose group, Number (N) = 33), 0.01% for twelve months (0.01% group, N = 32) or vehicle for twelve months (placebo, N = 32). Primary outcomes were axial length and spherical equivalent refraction. Secondary outcomes included adverse events and reactions, choroidal thickness and ocular biometry. Outcomes were measured at baseline and three-month intervals. Data was analyzed with linear-mixed model analysis according to intention-to-treat.ResultsMean axial elongation was 0.10 mm less (95% confidence interval (CI): 0.17; 0.02, adjusted-p = 0.06) in the 0.1% loading dose and 0.07 mm less (95% CI: 0.15; 0.00, adjusted-p = 0.16) in the 0.01% group at twelve months compared to placebo. Mean spherical equivalent refraction progression was 0.24 D (95% CI: 0.05; 0.42) less in the loading dose and 0.19 D (95% CI: 0.00; 0.38) less in the 0.01% groups at twelve months, compared to placebo (adjusted-p = 0.06 and 0.14, respectively). A total of 108 adverse events were reported during the initial six-month loading dose period, primarily in the loading dose group, and 14 were reported in the six months following dose switching, all deemed mild except two serious adverse events, unrelated to the intervention.ConclusionsLow-dose atropine eye drops are safe over twelve months in otherwise healthy children. There may be a modest but clinically relevant reduction in myopia progression in Danish children after twelve months treatment, but the effect was statistically non-significant after multiple comparisons adjustment. After dose-switching at six months the loading dose group approached the 0.01% group, potentially indicating an early “rebound-effect”.Trial registrationthis study was registered in the European Clinical Trials Database (EudraCT, number: 2018-001286-16) 05/11/2018 and first posted at www.clinicaltrials.gov (NCT03911271) 11/04/2019, prior to initiation.

Efficacy of dotinurad in patients with severe renal dysfunction.

Although hyperuricemia is associated with the progression of chronic kidney disease (CKD), a reduction in CKD progression by uric acid (UA)-lowering therapy has been controversial. Recently, dotinurad, a uricosuric drug with selective urate reabsorption inhibitory properties, has been developed. However, its efficacy in lowering serum UA levels and its effects on renal function in patients with severe renal dysfunction are unclear. Thus, this study aimed to determine the effects of dotinurad on renal function in patients with severe renal dysfunction. Data from 53 outpatients with hyperuricemia who newly received dotinurad between December 2020 and October 2022 were retrospectively analyzed. The mean baseline estimated glomerular filtration rate (eGFR) was 38.7 ± 17.0mL/min/1.73m2. The patients were divided into three groups based on their baseline eGFR: eGFR < 30 (n = 17), 30 ≤ eGFR < 45 (n = 17), and eGFR ≥ 45 (n = 19). The mean follow-up period was 9.8 ± 4.5 (range, 3-21) months. Serum UA levels significantly decreased in all groups. Although eGFR did not significantly change in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45 (P = 0.918 and P = 0.535, respectively), it improved significantly in patients with eGFR < 30 (P = 0.032). The proportion of patients with improved eGFR was significantly higher in patients with eGFR < 30 (P = 0.038) than in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45. In the multivariate logistic regression analysis, baseline eGFR < 30 and achieving a serum UA level of ≤ 6.0mg/dL were significantly associated with improved eGFR (P = 0.033 and P = 0.015, respectively). Dotinurad may have UA-lowering effects and the potential to improve kidney function in patients with severe renal dysfunction.

Probiotics, as Adjuvant Therapy and Preventive Measure on Progression, and Complications of Head and Neck Cancer.

Preclinical and clinical evidence implies that destructive therapies in local and malignant tissue are frequently used on patients with head and neck cancer. Consequently, the microbiome of the treated and adjacent regions is affected. Disruption of the normal microbiome plays an important role not only in the disease progression but also in its emergence, therefore new therapies involving probiotics, prebiotics, and synbiotics have been developed to control or regulate this microbial disruption. This review aims to describe the current and potential uses of probiotics at different stages of development of head and neck squamous cell carcinoma, as an adjuvant therapy to prevent common complications such as radiation-induced oral mucositis (RIOM) and its role in other areas. Currently, there is no widely effective strategy to treat or prevent this kind of cancer. Surgery, radiation therapy, and chemotherapy are the three main treatments for head and neck cancer. Some therapies can also cause long-term health problems, or complications which might change the way you eat, talk, hear and breathe. The main uses for which probiotics have been studied are: Prevention and reduction of severity of RIOM, change in dental plaque to reduce dysbiosis, and reduction of complications in post-operated patients. Potential uses of probiotics include the reduction of disease initiation and progression by reducing local inflammation caused by bacteria and other organisms. The incidence and severity of RIOM may be lessened by probiotics. To establish its uses in additional clinical settings, though, more studies are necessary.

Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis.

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA. To explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression. Our findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression. In conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.

Evaluating the Effects of C3 Inhibition on Geographic Atrophy Progression from Deep-Learning OCT Quantification: A Split-Person Study.

To evaluate the effect pegcetacoplan, a C3 and C3b inhibitor, on the rate of progression of geographic atrophy (GA) as assessed by spectral domain optical coherence tomography (SD-OCT) using a split-person study design and deep-learning quantification. A post hoc analysis of phase 2 FILLY trial data comparing study (treated monthly, treated every other month and sham-treated) and fellow (untreated) eyes in a split-person study design was performed. This analysis included 288 eyes from 144 patients with bilateral GA from the FILLY phase 2 trial (Clinical Trials identifier: NCT02503332). Only patients with bilateral GA and without evidence of choroidal neovascularisation in either eye were included. Patient study eyes were treated with sham injections or with pegcetacoplan monthly (PM) or every other month (PEOM) for 12months. SD-OCT scans of study and fellow eyes taken at baseline and 12months were used for the analysis. The main outcomes were the annual change in the area of retinal pigment epithelial and outer retinal atrophy (RORA), its constituent features (photoreceptor degeneration [PRD], retinal pigment epithelium [RPE] loss, hypertransmission) and intact macula as compared to the untreated fellow eye. Annual GA growth was reduced in eyes treated with PM versus untreated fellow eyes for OCT features, including RORA (study eye 0.792 vs. fellow eye 1.13 mm2; P = 0.003), PRD (0.739 vs. 1.23 mm2; P = 0.015), RPE-loss (0.789 vs. 1.17 mm2; P = 0.007) and intact macula (- 0.735 vs. - 1.29 mm2; P = 0.011). Similar (but not statistically significant) trends were observed with the PEOM treatment or when GA was quantified with fundus autofluorescence (FAF). The sham treatment demonstrated no effect. Pearson correlation coefficients showed concordance in the enlargement rate of GA between the study and fellow eyes in the sham (R = 0.64) and PEOM (R = 0.68) groups, but not in the PM group (R = 0.21). Pegcetacoplan-treated eyes demonstrated a reduction in spatial GA progression compared to their untreated counterparts. This effect was more evident on OCT than with FAF. Clinical Trials identifier: NCT02503332.

Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors

Insulin signaling often plays a role in the regulation of cancer, including tumor initiation, progression, and response to treatment. In addition, the insulin-regulated PI3K-Akt-mTOR pathway plays an important role in the regulation of islet cell proliferation, and this pathway is hyperactivated in human non-functional pancreatic neuroendocrine tumors (PanNETs). We, therefore, investigated the effect of a very low carbohydrate diet (ketogenic diet) on a mouse model that develops non-functional PanNETs to ask how reduced PI3K-Akt-mTOR signaling might affect the development and progression of non-functional PanNET. We found that this dietary intervention resulted in lower PI3K-Akt-mTOR signaling in islet cells and a significant reduction in PanNET formation and progression. We also found that this treatment had a significant effect on the suppression of pituitary NET development. Furthermore, we found that non-functional PanNET patients with lower blood glucose levels tend to have a better prognosis than patients with higher blood glucose levels. This preclinical study shows that a dietary intervention that results in lower serum insulin levels leads to lower insulin signals within the neuroendocrine cells and has a striking suppressive effect on the development and progression of both pancreatic and pituitary NETs.

Prevention of Radiographic Progression in Higher-Risk Patients with Rheumatoid Arthritis Using Filgotinib in PhaseIII Studies: Narrative Review of PostHoc Analyses.

Filgotinib is an oral preferential Janus kinase1 inhibitor that demonstrated significant reductions in radiographic progression, with an acceptable tolerability and safety profile, vs placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR; FINCH1) and vs MTX in MTX-naïve patients with RA (FINCH3). International treatment guidelines identify multiple poor prognostic factors (PPFs) associated with worse disease outcomes among patients with RA. However, questions remain both about the clinical utility of considering PPFs and about which PPFs should drive treatment decisions. Additionally, the role of radiographic findings in clinical practice continues to be discussed and to evolve. This review examines radiographic results from posthoc analyses of phase3 trials of filgotinib that examined subgroups with 4PPFs or with baseline estimated rapid radiographic progression (e-RRP). In MTX groups, there were trends toward greater progression among patients with 4PPFs or e-RRP, suggesting these subgroups may comprise a higher-risk population. Results show general consistency for the efficacy of filgotinib 200mg plus MTX vs placebo plus MTX/MTX monotherapy on radiographic assessments, including change from baseline in modified total Sharp score and proportions without radiographic progression, even among MTX-IR or MTX-naïve patients with 4PPFs or e-RRP who may be at higher risk of bone damage. Multivariate analysis identified multiple factors associated with baseline e-RRP status. This summary of the current understanding of benefits associated with filgotinib on radiographic progression and the relevance of baseline factors to these benefits may help inform treatment decisions for patients facing high risk of radiographic progression.

Risk Assessment of Kidney Disease Progression and Efficacy of SGLT2 Inhibition in Patients With Type 2 Diabetes.

To develop a risk assessment tool to identify patients with type 2 diabetes (T2D) at higher risk for kidney disease progression and who might benefit more from sodium-glucose cotransporter 2 (SGLT2) inhibition. A total of 41,204 patients with T2D from four Thrombolysis In Myocardial Infarction (TIMI) clinical trials were divided into derivation (70%) and validation cohorts (30%). Candidate predictors of kidney disease progression (composite of sustained ≥40% decline in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney death) were selected with multivariable Cox regression. Efficacy of dapagliflozin was assessed by risk categories (low: <0.5%; intermediate: 0.5 to <2%; high: ≥2%) in Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58. There were 695 events over a median follow-up of 2.4 years. The final model comprised eight independent predictors of kidney disease progression: atherosclerotic cardiovascular disease, heart failure, systolic blood pressure, T2D duration, glycated hemoglobin, eGFR, urine albumin-to-creatinine ratio, and hemoglobin. The c-indices were 0.798 (95% CI, 0.774-0.821) and 0.798 (95% CI, 0.765-0.831) in the derivation and validation cohort, respectively. The calibration plot slope (deciles of predicted vs. observed risk) was 0.98 (95% CI, 0.93-1.04) in the validation cohort. Whereas relative risk reductions with dapagliflozin did not differ across risk categories, there was greater absolute risk reduction in patients with higher baseline risk, with a 3.5% absolute risk reduction in kidney disease progression at 4 years in the highest risk group (≥1%/year). Results were similar with the 2022 Chronic Kidney Disease Prognosis Consortium risk prediction model. Risk models for kidney disease progression can be applied in patients with T2D to stratify risk and identify those who experience a greater magnitude of benefit from SGLT2 inhibition.

Randomized controlled study to evaluate the safety and clinical impact of percutaneous auricular vagus nerve stimulation in patients with severe COVID-19.

Introduction: A severe course of COVID-19 is characterized by a hyperinflammatory state resulting in acute respiratory distress syndrome or even multi-organ failure along a derailed sympatho-vagal balance. Methods: In this prospective, randomized study, we evaluate the hypothesis that percutaneous minimally invasive auricular vagus nerve stimulation (aVNS) is a safe procedure and might reduce the rate of clinical complications in patients with severe course of COVID-19. In our study, patients with SARS-CoV-2 infection admitted to the intensive care unit with moderate-to-severe acute respiratory distress syndrome, however without invasive ventilation yet, were included and following randomization assigned to a group receiving aVNS four times per 24h for 3h and a group receiving standard of care (SOC). Results: A total of 12 patients were included (six in the aVNS and six in the SOC group). No side effects in aVNS were reported, especially no significant pain at device placement or during stimulation at the stimulation site or significant headache or bleeding after or during device placement or lasting skin irritation. There was no significant difference in the aVNS and SOC groups between the length of stay in the intensive care unit and at the hospital, bradycardia, delirium, or 90-day mortality. In the SOC group, five of six patients required invasive mechanical ventilation during their stay at hospital and 60% of them venovenous extracorporeal membrane oxygenation, compared to three of six patients and 0% in the aVNS group (p = 0.545 and p = 0.061). Discussion: Vagus nerve stimulation in patients with severe COVID-19 is a safe and feasible method. Our data showed a trend to a reduction of progression to the need of invasive ventilation and venovenous extracorporeal membrane oxygenation which encourages further research with larger patient samples.

Use of chip seal treatments to mitigate pavement roughness progression in cold regions

ABSTRACT Chip Seals are a type of pavement preservation treatment characterised by its ability to reduce pavement deterioration and restore surface condition. Chip seal performance, like other pavement preservation treatments, depends on several factors such as environmental conditions, traffic level and the condition of the existing pavement structure prior to treatment application. In cold regions, the presence of freeze and thaw cycles promotes the generation of thermal cracks and possible tenting distresses, consequently, pavement roughness has been a prominent parameter to assess treatment performance. The objective of this study was to evaluate the roughness progression on several chip seal configurations in a cold climate region, utilising a set of field performance data from the Pavement Preservation Group Study, a broader research study conducted by the National Center for Asphalt Technology and the Minnesota Department of Transportation’s Road Research Facility. The main findings indicate that chip seals provide a negligible effect on immediate roughness improvement; however, on a long-term basis, they provide a reduction in IRI progression over time. The magnitude of the IRI benefit is dependent on the type of chip seal implemented and the traffic level experienced.