Short Treatment Period Research Articles

Experience of abrocitinib in atopic dermatitis

Atopic dermatitis is an autoinflammatory, genetically determined, itchy disease characterized by a long, relapsing course and a sharp decrease in the patient’s quality of life. Atopic dermatitis is caused by a complex interaction of immune dysregulation, epidermal gene mutations, and multi-environmental factors that affect the skin, causing intense itchy rashes. The disease often occurs among young children and subsequently has age-related clinical features. Currently, the treatment of atopic dermatitis has a wide range of options, including drugs from the group of small molecules recently registered in the Russian Federation. The drugs are intended for patients with moderate to severe atopic dermatitis. Baricitinib, abrocitinib and upadacitinib as Janus kinase inhibitors from the small molecule group have already demonstrated good tolerability, safety and a pronounced clinical effect in the vast majority of patients with atopic dermatitis in available clinical trials. The first clinical experience with the use of abrocitinib in adult patients with atopic dermatitis is presented. The interest of the presented clinical cases lies in the demonstration of high clinical efficacy and safety of mono- and combination therapy with the Janus kinase inhibitor abrocitinib. Despite the short period of treatment and observation (4 weeks), objective severity of atopic dermatitis manifestations (SCORAD index 60 points) and sharp decrease in the patients' quality of life (DLQI index 20 points), a reduction of clinical parameters exceeding 60% was achieved at a dose of 200 mg daily. During the whole observation period no adverse clinical reactions or changes in laboratory parameters were registered against the background of abrocitinib administration. The pilot results of abrocitinib use are encouraging and provide grounds for conducting longer and larger-scale studies to investigate the efficacy of the drug for its inclusion in the combination therapy of patients with moderate to severe atopic dermatitis.

Psychotherapy use among migrants: a register-based longitudinal study

BackgroundMigrants use less mental health services compared with non-migrant populations, but there is very little information on the use of long-term psychotherapy among migrants. Finnish register data allow for studying...

An interdisciplinary treatment to reshape upper anterior displaced teeth by using dynamic occlusal recording with an intraoral scanner.

This article describes an interdisciplinary treatment that helped a patient with displaced upper anterior teeth. A gingivectomy, root canal therapies, digital smile design, digital wax-up, and guided tooth preparations were applied. A patient with pathologically migrated teeth asked for treatment without orthodontic involvement due to a primary failed orthodontic treatment history. A smile photo was taken and superimposed with the dentition in a CAD software to accomplish a digital smile design. The jaw movements were recorded with two different methods, a mechanical articulator and an intraoral scanner with Patient-Specific-Motion function. The occlusal contacts during protrusive and lateral movements were compared and the digital wax-up was designed according to the later occlusal data. An aesthetic crown lengthening and pre-op root canal treatment were carried out in advance accordingly. After guided tooth preparation with a silicone index, the final fixed restorations were manufactured and cemented. A 2-year follow-up showed that our prosthesis functions well. This clinical report revealed that an intraoral scanner with Patient-Specific-Motion function can effectively record individual dynamic occlusal patterns and these data can be integrated into the CAD/CAM process to enhance the fulfillment of clinical requirements. This clinical procedure with a 2-year follow-up demonstrated that a prosthodontic-based interdisciplinary treatment of pathologically migrated teeth using dynamic occlusal recording with an intraoral scanner could achieve satisfactory esthetics in a relatively short treatment period. The Patient Specific Motion module may be used to record a personalized functional movement and the data can be integrated into the design process of the final restorations.

Comparative Analysis of Braces and Aligners: Long-Term Orthodontic Outcomes.

The purpose of this retrospective study was to evaluate the long-term results of orthodontic treatment with traditional braces and Invisalign, with a particular emphasis on treatment length, patient satisfaction, correction of malocclusion, and long-term stability. Between 2020 and 2022, individuals who had orthodontic treatment at a tertiary care center had their data analysed. Patients with mild to severe malocclusions treated with conventional braces or Invisalign between the ages of 12 and 18 met the inclusion criteria. Assessments were done on results, length of treatment, degree of malocclusion, and long-term stability. With significance set at P < 0.05, statistical analyses comprised t-tests for treatment duration and Chi-square testing for malocclusion correction. The mean treatment time for Invisalign was much shorter (18 months) than for conventional braces (24 months) (P < 0.001). With 88-90% success rates, both techniques demonstrated remarkable success rates in malocclusion treatment. Even though Invisalign was associated with a somewhat greater percentage of relapse instances, the difference was not statistically significant (P > 0.05). In conclusion, Invisalign showed a much shorter treatment period than conventional braces, yet both showed excellent malocclusion correction. The choice of modality should be based on patient satisfaction, treatment objectives, and case complexity, taking into account the trade-offs between treatment length and potential variations in long-term stability.

State and trait characteristics of attachment as predictors of outcome in inpatient psychotherapy.

Attachment has mostly been investigated as a stable characteristic of individuals, although theoretical considerations and recent empirical findings suggest that attachment styles are also subject to change. When attachment is investigated as a treatment factor in psychotherapy, state and trait characteristics need to be differentiated, as they warrant different conclusions. This study examined the trait- and statelike characteristics of attachment styles over the course of inpatient psychotherapy as predictors of treatment outcome. A total of N = 419 patients provided weekly measurements of attachment styles and symptoms for up to 8 weeks of inpatient psychotherapy. Data were analyzed in multilevel longitudinal models controlling for rolling admissions and weekly changes in group membership. Over the course of treatment, patients' attachment styles became more secure and less fearful-avoidant. Trait attachment security as well as gains in attachment security predicted better outcomes, while trait preoccupied and fearful-avoidant attachment as well as increases in attachment preoccupation and anxiety predicted worse outcomes. Findings imply that attachment security may grow during a relatively short inpatient treatment period and both trait attachment styles as well as changes in attachment styles predict outcome. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

Anabolic Signaling After Withdrawl of AMPK-Activating Drugs in C2C12 Cells

Adenosine monophosphate-activated protein kinase (AMPK) is a master metabolic regulator that is activated under low-energy conditions, which generally promotes catabolic processes, including an increase of ATP synthesis and inhibiting anabolic processes that consume ATP. Indeed, acute AMPK activation potently inhibits anabolic pathways, including Akt/mTORC1 signaling. However, recent research reported that withdrawal of the AMPK-activating drug AICAR after a short treatment period results in enhanced anabolic signaling through Akt/mTORC1. This work aims to extend those findings using a more specific AMPK activator since AICAR is well-known to have numerous AMPK-independent effects. To do so, we treated differentiated C2C12 cells with either 2 mM AICAR, 5uM MK8722 (a pan-AMPK activator), or vehicle control (DMSO) for 60 minutes. After 60 minutes of incubation with the drugs, the treatment media was removed, the cells were rinsed and lysed immediately or incubated with media without drug treatment for 30, 60, 120, or 180 minutes, and then lysed. Phosphorylation of ACC (as an indicator of AMPK activity) and anabolic markers Akt, p70 ribosomal protein S6 kinase (S6k), and eIF4E-binding protein (4EBP1) were measured by western blotting. ACC phosphorylation (reflective of AMPK activity) remained elevated through 180 minutes after drug withdrawal for both AICAR and MK8722. Both AKT and S6k phosphorylation remained suppressed for at least 60 minutes after withdrawal of both AICAR and MK8722 and were not elevated at any time point up to 3 hours after withdrawal of the drugs. In contrast to previously reported data, we conclude that anabolic signaling remains inhibited in skeletal muscle myotubes for up to 3 hours after 1 hour of pharmacological activation of AMPK. This work was funded by a BYU Gerontology Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dynamics of Dental Enamel Surface Remineralization under the Action of Toothpastes with Substituted Hydroxyapatite and Birch Extract.

To address tooth enamel demineralization resulting from factors such as acid erosion, abrasion, and chronic illness treatments, it is important to develop effective daily dental care products promoting enamel preservation and surface remineralization. This study focused on formulating four toothpastes, each containing calcined synthetic hydroxyapatite (HAP) in distinct compositions, each at 4%, along with 1.3% birch extract. Substitution elements were introduced within the HAP structure to enhance enamel remineralization. The efficacy of each toothpaste formulation was evaluated for repairing enamel and for establishing the dynamic of the remineralization. This was performed by using an in vitro assessment of artificially demineralized enamel slices. The structural HAP features explored by XRD and enamel surface quality by AFM revealed notable restorative properties of these toothpastes. Topographic images and the self-assembly of HAP nanoparticles into thin films on enamel surfaces showcased the formulations' effectiveness. Surface roughness was evaluated through statistical analysis using one-way ANOVA followed by post-test Bonferroni's multiple comparison test with a p value < 0.05 significance setting. Remarkably, enamel nanostructure normalization was observed within a short 10-day period of toothpaste treatment. Optimal remineralization for all toothpastes was reached after about 30 days of treatment. These toothpastes containing birch extract also have a dual function of mineralizing enamel while simultaneously promoting enamel health and restoration.

Safety and tolerability of phenylbutyrate in inclusion body myositis

Introduction&#x0D; Phenylbutyrate (PBA) showed positive effect on the muscle cell model of Inclusion Body Myositis (IBM) by improving lysosomal activity, ameliorating consequences of impaired autophagy, and decreasing vacuolization. This provides rationale to study this medication in patients with IBM.&#x0D; Objectives&#x0D; To evaluate the safety and tolerability of phenylbutyrate in IBM, and monitor for any early signal of effectiveness.&#x0D; Methods&#x0D; Open-label study of 10 subjects with IBM who received treatment with PBA for 3 months after a 3-month run-in period. The PBA dose was 3 gm twice daily. The primary outcome measure was adverse event reporting. Secondary outcome measures included manual muscle testing, timed up and go test, IBM functional rating scale, and grip strength, along with exploratory biomarkers evaluating the mitochondrial function, stress response, degenerative process, and apoptosis.&#x0D; Results&#x0D; Ten subjects completed the study. PBA was well tolerated with no serious adverse events related to it. The most common adverse events were gastrointestinal related and did not require stopping treatment. One of the biomarkers (MitoTracker) showed a statistically significant drop over the treatment period of the study (p-value of 0.02 for the mean change). There were no statistically significant changes in other secondary outcome measures, but the study was limited by a small sample size and short treatment period.&#x0D; Conclusions&#x0D; Phenylbutyrate was safe and well tolerated in patients with IBM in this pilot study. The change in the MitoTracker suggests target engagement, but a Phase II study is needed to confirm and study the efficacy of PBA in IBM

Efficacy of cranial electrotherapy stimulation in patients with burning mouth syndrome: a randomized, controlled, double-blind pilot study.

The Burning mouth syndrome (BMS) is a chronic pain syndrome characterized by a burning sensation in the oral mucous membranes. The etiology and pathophysiology of BMS is largely unexplained. To date, there is no evidence-based treatment strategy for BMS. Cranial electrical stimulation (CES) represents a non-invasive treatment option with a low side effect profile that is approved for the treatment of pain, depression, anxiety disorder and insomnia. It has shown efficacy in studies for chronic pain such as fibromyalgia and neuropathic pain after spinal cord injury. This study aimed to investigate the therapeutic effectiveness of CES in combination with local transcutaneous electrical nerve stimulation (TENS) as an adjunct therapy in patients with BMS compared to sham stimulation. This randomized, double-blind, sham-controlled pilot study enrolled 22 patients, aged 18 years and over, with the diagnosis of BMS meeting the ICHD-3 criteria from August 2020 to June 2021. The study duration was 4 weeks (28 days) per participant. After randomization, the active group participants (n = 11) received a 100 μA CES treatment for 60 min a day whereas the devices in the Sham group did not emit electricity. Simple linear regression was used to determine whether the interventions promoted significant differences in pain intensity. The linear regression showed that the period of stimulation significantly predicted decrease in the intensity of pain in the active group [β = -0.036; t(26) = -7.219; p < 0.001] as in the sham group [β = -0.026; t(26) = -2.56; p < 0.017]. With the applied cutoff of 30% pain reduction within the stimulation period, both the active and sham groups had 36% responders (n = 4) (Fisher's exact test, p = 1.00). In both groups (active stimulation and sham group), a significant decrease in the intensity of pain, somatic symptoms and an improvement in sleep quality over the study period was observed. Subjects reported no adverse events during the study. Although CES is an easily applicable and safe therapeutic option for chronic facial pain, active stimulation was not superior to sham stimulation. Among other reasons, this could be due to the short double-blinded treatment period, duration of the daily stimulation session or the small sample size.

Short-term and long-term efficacy of accelerated transcranial magnetic stimulation for depression: a systematic review and meta-analysis

BackgroundIn recent years, accelerated transcranial magnetic stimulation (aTMS) has been developed, which has a shortened treatment period. The aim of this study was to evaluate the efficacy and long-term maintenance effects of aTMS in patients with major depressive disorder (MDD).MethodsWe systematically searched online databases for aTMS studies in patients with MDD published before February 2023 and performed a meta-analysis on the extracted data.ResultsFour randomized controlled trials (RCTs) and 10 before-and-after controlled studies were included. The findings showed that depression scores significantly decreased following the intervention (SMD = 1.80, 95% CI (1.31, 2.30), p < 0.00001). There was no significant difference in antidepressant effectiveness between aTMS and standard TMS (SMD = -0.67, 95% CI (-1.62, 0.27), p = 0.16). Depression scores at follow-up were lower than those directly after the intervention based on the depression rating scale (SMD = 0.22, 95% CI (0.06, 0.37), p = 0.006), suggesting a potential long-term maintenance effect of aTMS. Subgroup meta-analysis results indicated that different modes of aTMS may have diverse long-term effects. At the end of treatment with the accelerated repetitive transcranial magnetic stimulation (arTMS) mode, depressive symptoms may continue to improve (SMD = 0.29, 95% CI (0.10, 0.49), I2 = 22%, p = 0.003), while the accelerated intermittent theta burst stimulation (aiTBS) mode only maintains posttreatment effects (SMD = 0.01, 95% CI (-0.45, 0.47), I2 = 66%, p = 0.98).ConclusionsCompared with standard TMS, aTMS can rapidly improve depressive symptoms, but there is no significant difference in efficacy. aTMS may also have long-term maintenance effects, but longer follow-up periods are needed to assess this possibility.Trial registrationThis article is original and not under simultaneous consideration for publication. The study was registered on PROSPERO (https://www.crd.york.ac.uk/prospero/) (number: CRD42023406590).

Clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan: Comparison of single and multiple OTC product abusers.

To examine the clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan. We examined the attributes, ICD-10 subcategory, and comorbid mental disorders of patients who mainly abuse OTC products and compared the clinical characteristics of single product and multiple products abusers, using the database of the "2022 Nationwide Mental Hospital Survey of Drug-related Disorders." Among the 2468 subjects included in this survey, 273 (11.1%) used OTC products as main drugs. Of these, 209 (78.3%) and 58 (21.7%) were classified into the single product group and the multiple products group, respectively. Six were excluded for unknown ingredients. By comparing these groups, we found that many of the multiple products group consisted of young women who were recently treated for drug problems. Many subjects in the group also had a short treatment period. No differences were observed between the groups regarding the ICD-10 F1 subcategory, but many subjects in the multiple products group fulfilled the criteria of F6 "disorders of adult personality and behavior." OTC products are easily accessible drugs of abuse for young women in Japan. The results of this study indicate the necessity to reconsider the educational approach for preventing drug abuse, which has focused on illicit drugs. The study also indicates that some OTC products, which contain ingredients banned overseas due to their harmful effects, are still sold in Japan and that abusers for those products exist. Measures by the government are considered urgently needed.

P510 Relapse rate following withdrawal of vedolizumab and ustekinumab in patients with inflammatory bowel disease. The VEDUST-EXIT study

Abstract Background Approximately half of patients with IBD in clinical remission (CR) flare within 12 months of withdrawing anti-TNF therapy. However, the outcomes of vedolizumab (VDZ) or ustekinumab (UST) cessation in terms of CR in routine practice are unknown. There is a need for more data to establish the relapse rates following treatment cessation. Methods This was a retrospective observational multicenter study. We included adult IBD patients who had withdrawn from either VDZ or UST after achieving CR and had available follow-up data for one year following treatment discontinuation or until relapse occurred. The control arm comprised patients discontinuing anti-TNFs after achieving CR. The primary objectives of this study are to assess the clinical relapse rates after discontinuing VDZ or UST and to identify potential predictors of sustained remission and relapse after therapy discontinuation. Results A total of 133 patients were included (48.1% Crohn’s disease and 51.9% ulcerative colitis). Sixty out of the 133 (45%) patients discontinued anti-TNF, 54 (40%) VDZ and 19 (15%) UST. All patients were in CR prior to drug discontinuation. The most common cause for drug discontinuations was patients’ preferences (80%) followed by cost and administrative issues. Duration of remission before drug discontinuation was 11 (IQR 7.5-10), 8.5 (6-12.2), and 12 (8-27) months, for anti-TNF, VDZ, and UST, respectively. The median follow-up duration was 14 months (5.5-20), with an overall relapse rate of 78.9% (105/133). Relapse rates in each cohort were 71.6%, 83.3%, and 89.4%, respectively, p=0.5. The median time to relapse was 10 months (3-9), 9 (6-16.5), and 8 (5-16.5), respectively. There was no significant difference in the relapse rates between the different drugs (anti-TNF vs VDZ, anti-TNF vs UST, and VDZ vs UST, (hazard ratio, HR 1.2, confidence interval, CI 95% 0.2-1.8; P = 0.35), HR 1.2, CI 95% 0.9-1.6; p=0.13, HR 1.2, CI 95% 0.6-2.1; P=0.5, respectively). Predictors of relapse after drug withdrawal were a short treatment period (HR 0.98, CI 95% 0.96-0.99; P = 0.04), shorter remission period (HR 0.9, CI 95% 0.95-0.99, P =0.03), multiple prior biologics (HR 1.2, CI 95% 1.04-1.44, P= 0.013), perianal disease (HR 5.5, CI 95% 1.6-1.8, P=0,006) and lower hemoglobin level (HR 1.95, CI 95% 1.1-3.1, P= 0.008). The following factors were not associated with an increased risk of relapse: IBD type, disease phenotype, extraintestinal manifestations, active smoking status, prior IBD-related surgery, elevated CRP or calprotectin, and endoscopic or radiologic signs of active disease. Conclusion In IBD patients that discontinue biologics after achieving clinical remission, relapse rates following withdrawal of VDZ and UST are comparable with those of anti-TNF.

Long-term efficacy and safety of perampanel as an add-on therapy in patients with epilepsy

BackgroundPerampanel (PER) is a newly developed amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist that has been globally approved for the treatment of both focal and generalized seizures. The efficacy and safety of PER have only been reported over short periods of treatment so far. This study aims to clarify the long-term efficacy and safety of PER as an add-on therapy. MethodThis retrospective observational study investigated 176 epilepsy patients who received PER as add-on medical therapy in two Japanese epilepsy centers between June 2016 and July 2022. The adherence, seizure frequency, and plasma concentration of PER were evaluated at three time points: 6 months, 12 months, and 24 months or longer after the start of adjunctive PER treatment. Results112 patients undergoing PER treatment were evaluated at 6 months, 86 were evaluated at 12 months, and 52 were evaluated at 24 months or longer. Overall, 42.9 % (48/112), 45.4 % (40/86), and 44.2 % (23/52) of the patients were seizure-free at 6, 12, and 24 months or longer, respectively. The rate of PER tolerance was 78.3 %, 69.9 %, and 54.7 % at 6, 12, and 24 months or longer, respectively. At the latest timepoint, the seizure-free group was taking a significantly lower dose of PER than the seizure-remnant group, and the number of anti-seizure medications (ASMs) was associated with seizure outcomes. In addition, the seizure-free rate was significantly higher in patients who received PER as a first add-on than in those who received it as a late add-on. No significant difference was found in the plasma concentration of PER between the seizure-free and seizure-remnant groups at 24 months or longer. Among the patients receiving PER at dose of 2 mg, however, the plasma concentrations were significantly higher in the seizure-free group than in the seizure-remnant group (282.7 ± 109.8 μg/ml vs 94.7 ± 54.9 μg/ml, p = 0.0024). ConclusionThis long-term retrospective observational study provides evidence of the efficacy and safety of PER over 2 years treatment period in Japan. Notably, patients who started on PER as the first add-on showed a better seizure outcome than those who received it as a late add-on over the long term. Measured plasma concentrations may provide valuable guidance for the management of patients. Higher plasma concentration at low dose PER may suggest the better seizure control.

Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection.

Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (1) untreated hamsters, and (2) from hamsters receiving effective and suboptimal doses of treatment. We identify a broadly linear relationship between drug dose and the extent of variation in treated viral populations, with a high proportion of this variation being composed of variants at frequencies of less than 1 per cent, below typical thresholds for variant calling. Treatment with an effective dose of antiviral drug was associated with a gain of between 7 and 10 variants per viral genome relative to drug-free controls: even after a short period of treatment a population founded by a transmitted virus could contain multiple sequence differences to that of the original host. Treatment with a suboptimal dose of drug showed intermediate gains of variants. No dose-dependent signal was identified in the numbers of single-nucleotide variants reaching frequencies in excess of 5 per cent. We did not find evidence to support the emergence of drug resistance or of novel immune phenotypes. Our study suggests that where onward transmission occurs, a short period of treatment with mutagenic drugs may be sufficient to generate a significant increase in the number of viral variants transmitted.

Zeolitic imidazolate framework-90 loaded with methylprednisolone sodium succinate effectively reduces hypertrophic scar in vivo.

Hypertrophic scar (HS) is characterized by an abnormal fibroblast-myofibroblast transformation; non-apoptosis of fibroblasts; and redundant expression of TGF-β1, VEGF, α-SMA, and collagen I/III. An HS affects patients' physical and psychological quality of life, leading to joint dysfunction and skin cancer. However, there is currently no satisfactory drug to treat this disorder. In this study, we constructed methylprednisolone sodium succinate (MPSS) encapsulated ZIF-90 (MPSS@ZIF-90) for the effective treatment of an HS. The encapsulation of MPSS in ZIF-90 can achieve the controllable drug release of MPSS and prolong its effective treatment time. MPSS@ZIF-90 enhanced the apoptosis of human hypertrophic scar fibroblasts and downregulated the overexpression of TGF-β1, VEGF, α-SMA, and collagen I/III both in vitro and in vivo. The instant injection of MPSS@ZIF-90 effectively intervened with the formation of the HS after 28 days. On the contrary, MPSS@ZIF-90 greatly reduced the HS with two injections and 14 days of treatment after the HS was formed. This work provides evidence of effective intervention in the formation of an HS and the therapeutic effectiveness of MPSS@ZIF-90 with short treatment periods in vivo. It suggests that MPSS@ZIF-90 can be used as a biomedical option in the treatment of skin wounds and may reveal the potential molecular basis for promising future antifibrotic agents against scarring.

Two-dimensional directed lamellar assembly in silicon- and fluorine-containing block copolymer with identical surface energies

A block copolymer (BCP) with specific monomer structures of fluoroacrylate polymers was designed by exploiting the inorganic superhydrophobicity and low glass transition temperature of polydimethylsiloxane (PDMS). With the use of a fluorine-containing block providing a surface tension as low as that of PDMS (19.9 < γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma$$\\end{document} < 21.5 mN/m), PDMS-b-poly(2,2,3,3,3-pentafluoropropyl acrylate) (PDMS-b-PPeFPA) copolymer was synthesized to create a volume-symmetric lamellar structure. The compositional randomness of the BCP chains adsorbed onto the substrates provided well-balanced interfacial interactions toward the overlaid PDMS-b-PPeFPA (γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma$$\\end{document}PDMS-ads ≈ γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma$$\\end{document}PPeFPA-ads). Under this symmetric confinement with simultaneous dual neutral interfaces, lamellar microdomains with a sub-10 nm half-pitch feature size were successfully oriented perpendicular to the interfaces at room temperature. We showed the response of the BCP films to a lateral electric field, demonstrating that the perpendicular lamellae were adaptively aligned along the electric vector within a short treatment period. Furthermore, the PDMS-b-PPeFPA system exhibited a remarkable etch contrast for O2 reactive ion etching, yielding unidirectionally aligned air–inorganic nanoarrays emanating from the perpendicular lamellae between the electrodes. This study reports a system engineering approach for conceiving highly immiscible, silicon- and fluorine-containing BCP whose components exhibit identical surface tensions (γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma$$\\end{document}PDMS ≈ γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma$$\\end{document}PPeFPA) and for generating perpendicularly oriented lamellar microdomains due to substrate neutrality.

Preliminary Results of a Phase 2a Clinical Trial to Evaluate Safety, Tolerability and Antiviral Activity of Intravenous Brincidofovir (BCV IV) in Immunocompromised Patients with Adenovirus Infection

Background: Adenovirus (AdV) may cause life threatening or fatal infections in immunosuppressed patients including recipients of allogeneic hematopoietic cell transplant (allo-HCT). Brincidofovir (BCV) is a lipid conjugate of cidofovir, that crosses target cell membranes by means of facilitated and passive diffusion and has a long intracellular half-life. The safety, tolerability and antiviral activity of intravenous BCV (BCV IV) were evaluated in a dose ascending Phase 2a study (BCV-PA01: ATHENA study, NCT04706923) in sequential cohorts. Methods: Eligible patients aged 2 months or older who were immunocompromised due to allo-HCT, organ transplant, immunosuppressive medications, or congenital immunodeficiency, and had AdV viremia or disseminated AdV disease were included. AdV viremia was defined as 1) AdV viral load in the blood &amp;gt; 10,000 copies/mL OR 2) two samples greater than 48 hours apart with the second result higher than the first and both greater than 1000 copies/mL, within 7 days prior to initiation of BCV IV treatment. BCV IV was administered intravenously twice weekly for 4 weeks or until resolution of AdV viremia up to 14 weeks, whichever occurred later. The dose escalation was as follows: 0.2 mg/kg (Cohort 1), 0.3 mg/kg (Cohort 2), or 0.4 mg/kg (Cohort 3) for patients weighing &amp;lt; 50 kg and 10 mg/dose, 15 mg/dose, or 20 mg/dose, respectively for patients weighing ≥ 50 kg. The patients were subsequently followed up for 30 days after the last BCV IV dosing. AdV viral loads in blood were monitored weekly by quantitative real-time polymerase chain reaction tests (lower limit of detection (LOD) 25 copies/mL, lower limit of quantification 190 copies/mL, upper limit of quantification 1 x 10 9 copies/mL). Viral clearance was defined as two consecutive plasma viral load test results below the LOD. Results: Of 27 patients treated with BCV IV, 8 were in Cohort 1, 9 in Cohort 2 and 10 in Cohort 3. Baseline characteristics of patients are shown in Table 1. Treatment-related adverse events (TRAE) were observed in 7 patients, as shown in Table 2. No serious TRAEs including gastrointestinal and hepatic toxicities were observed. All TRAEs were reversible and resolved after the completion of the treatment. AE-related discontinuations of treatment were observed in 3 of 8 patients in Cohort 1; 2 of 9 patients in Cohort 2; and 1 of 10 patients in Cohort 3 (Table 2). The reason for discontinuation of treatment beyond 4 weeks of treatment in Cohort 3 was successful clearance of AdV viremia. Antiviral activity was dose-dependent, and viral clearance was achieved in 25% (2/8) in Cohort 1; 56 % (5/9) in Cohort 2; and 100% (10/10) in Cohort 3. The duration of treatment with BCV IV and viral responses are summarized in Table 2. In Cohort 3, it is notable that 90 % of patients achieved AdV viremia clearance in ≤ 4 weeks of treatment with BCV IV. In Cohorts 2 and 3, all patients who achieved AdV viremia clearance maintained undetectable AdV in the blood through the follow-up period. Conclusions: BCV IV was found to be safe and well tolerated in immunocompromised patients. Notably, the potentially serious gastrointestinal and hepatic toxicities described with the oral BCV formulation were not observed. BCV IV was highly effective in a dose-dependent manner, led to rapid clearance of AdV viremia within a short treatment period and provided sustained virologic response. In view of promising results and in the absence of any other approved treatments for AdV infection, our results support the need for further exploration and additional clinical trials of BCV IV as a treatment for AdV infection.

Factores asociados al fracaso virológico en pacientes VIH con tratamiento antirretroviral

ObjectiveTo determine the factors associated with virologic failure in HIV patients on antiretroviral treatment treated in a Colombian health institution. MethodThis was a cross-sectional observational retrospective analytical study of HIV patients receiving antiretroviral treatment between 2007-2020. Sociodemographic, pharmacological and clinical variables were collected, including viral load, adherence, and the medication possession ratio. For statistical analysis, crude and adjusted odds ratios and confidence intervals were obtained. ResultsIn a population of 5,406 patients, the proportion of virologic failure was 16.7%. Moreover, in the adjusted model, an association was found between virologic failure and time on treatment greater than one year, medication possession ratio under 80%, failure to claim medications from the pharmacy due to dose omission or discontinuation, adherence under 85%, CD4 count under 500, total cholesterol levels above 201 mg/dL, high density lipoproteins under 39 mg/dL and presence of mycosis. ConclusionsIn our cohort of HIV patients, short treatment periods, CD4 counts under 200, a low medication possession ratio, failure to timely claim medications from the pharmacy due to omission or discontinuation, and a lower degree of adherence were factors related to virologic failure.

Characteristics, management, and healthcare resources of patients with advanced non–small-cell lung cancer surviving 5 years after nivolumab treatment initiation: A national database analysis

BackgroundData on long-term survivors with advanced non-small-cell lung cancer (NSCLC) treated with nivolumab are available from randomized trials. Characteristics, management, and healthcare resources of those patients need to be confirmed with real-world data. MethodsThe UNIVOC retrospective observational study included all patients with advanced NSCLC recorded in the French national hospital database starting nivolumab in 2015 and followed them until December 2020. The Kaplan-Meier method estimated the overall survival (OS). A machine learning approach identified patients with similar treatment sequences. ResultsWithin the 3,050 patients who had nivolumab initiation,5-year OS rate was 14.6 % (95 %CI 13.3 %–16.2 %). In total, data covering at least 5 years of follow-up were retrieved for 231 surviving patients. Survivors were younger, often female and had fewer comorbidities than non-survivors. Three clusters of patients with different nivolumab treatment durations were identified: 1/ Continuous nivolumab treatment; 2/ Long period of nivolumab treatment followed by chemotherapy or no treatment; 3/ Short period of nivolumab treatment then chemotherapy or no treatment. At 5 years, 61.0 % of survivors were no longer receiving systemic therapy, 26.4 % were treated with nivolumab, 8.7 % chemotherapy, and 3.9 % other immunotherapies. Among 5-y survivor patients, the average number of hospitalisations per patient decreased from 23.4 to 12.8 between the 1st and the 5th year. In the 5th year, 46 % of patients had no more hospitalization for lung cancer. ConclusionsThis large nationwide study confirms the long-term benefit of nivolumab treatment for advanced NSCLC patients in the real-world setting, with a 5-year survival rate similar to that reported in clinical trials.