Treatment Period Research Articles

Gut microbial features and dietary fiber intake predict gut microbiota response to resistant starch supplementation

ABSTRACT Resistant starch (RS) consumption can have beneficial effects on metabolic health, but the response, in terms of effects on the gut microbiota and host physiology, varies between individuals. Factors predicting the response to RS are not yet established and would be useful for developing precision nutrition approaches that maximize the benefits of dietary fiber intake. We sought to identify predictors of gut microbiota response to RS supplementation. We enrolled 76 healthy adults into a 7-week crossover study with 59 individuals completing the study. Participants consumed RS type 2 (RS2), RS type 4 (RS4), and digestible starch, for 10 d each with 5-d washout periods in between. We collected fecal and saliva samples and food records during each treatment period. We performed 16S rRNA gene sequencing and measured fecal short-chain fatty acids (SCFAs), salivary amylase (AMY1) gene copy number, and salivary amylase activity (SAA). Dietary fiber intake was predictive of the relative abundance of several amplicon sequence variants (ASVs) at the end of both RS treatments. AMY1-related metrics were not predictive of response to RS. SAA was only predictive of the relative abundance of one ASV after digestible starch supplementation. Interestingly, SCFA concentrations increased the most during digestible starch supplementation. Treatment order (the order of consumption of RS2 and RS4), alpha diversity, and a subset of ASVs were predictive of SCFA changes after RS supplementation. Based on our findings, dietary fiber intake and gut microbiome composition would be informative if assessed prior to recommending RS supplementation because these data can be used to predict changes in specific ASVs and fecal SCFA concentrations. These findings lay a foundation to support the premise that using a precision nutrition approach to optimize the benefits of dietary fibers such as RS could be an effective strategy to compensate for the low consumption of dietary fiber nationwide.

Sustained benefits of onabotulinumtoxinA treatment in chronic migraine: An analysis of the pooled Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) randomized controlled trials.

To characterize the long-term (56-week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among those experiencing CM. Understanding the impact of sustained preventive treatment response in CM can provide important information about the impact of successful therapy. The two Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy trials of onabotulinumtoxinA in adults included a 24-week, randomized, double-blind, placebo-controlled phase and a 32-week open-label phase. Data were pooled to determine proportions of individuals with <15 headache days/month while on treatment during several time periods in the double-blind phase (Weeks 21-24; any 12 consecutive weeks; Weeks 13-24) and the entire study (Weeks 53-56; any 12 consecutive weeks; any 4-week period). We assessed the long-term impact on mean monthly headache days and changes from baseline on the six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2.1). We analyzed 1384 participants with chronic migraine (double-blind: onabotulinumtoxinA, n = 688; placebo, n = 696; open-label: n = 688 [onabotulinumtoxinA]). The discontinuation rates prior to the completion of the full 56-week treatment period for onabotulinumtoxinA and placebo were 25.4% (n = 175) and 29.3% (n = 204), respectively. During Weeks 13-24 of the double-blind phase, significantly more onabotulinumtoxinA-treated (386/688 [56.1%]) than placebo-treated (342/696 [49.1%]) individuals had <15 headache days/month (p = 0.010), with fewer monthly headache days for onabotulinumtoxinA versus placebo responders. The proportions of participants achieving <15 monthly headache days with onabotulinumtoxinA were 60.9% (419/688) at Weeks 25-56, 81.1% (558/688) at Weeks 53-56, and 79.4% (546/688) during any consecutive 12-week period. Mean changes from baseline on the HIT-6 and MSQv2.1 questionnaire surpassed within-group minimal important difference thresholds in all periods. At Week 24, onabotulinumtoxinA-treated participants who achieved <15 monthly headache days during Weeks 21-24 had a greater mean HIT-6 score reduction (-6.5 vs. -1.4) and greater mean MSQv2.1 Role-Function Restrictive score improvements (21.3 vs. 6.4) than those who did not achieve <15 monthly headache days during the same period. Participants who achieved <15 monthly headache days with onabotulinumtoxinA treatment achieved meaningful benefits in headache-related disability and migraine-specific quality of life compared with those who remained at or above the 15-monthly headache days threshold. Sustained benefits observed over 56 weeks support long-term onabotulinumtoxinA use for the prevention of CM.

Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain.

We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7days before). The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID. Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.

A 3D German-designed brace used to treat adolescent idiopathic scoliosis

Introduction Adolescent Idiopathic Scoliosis (AIS) is a condition that affects an otherwise healthy child 10 years of age or older and is the high risk of severe deformity and surgery. Different brace applications include the Milwaukee Brace, Boston Scoliosis Brace, TLSO and others, and the success rates of orthoses vary. With little experience in the use of the Chêneau-type corset, the brace provides an effective means for the active correction of scoliotic spinal deformity.The objective was to demonstrate an outcome with a 3D functional corrective German-designed corset used to treat a patient with AIS in the period from the onset of the curve to the onset of skeletal maturity.Material and methods The medical history of patient S. including anamnestic, clinical and radiological findings recorded 2018 and 2023 when she used a 3D German-designed (3D GD) corset. The corset design was defined as 3CL/B2 according to the Lehnert – Schroth scoliotic classification as modified by Rigo.Results The left-sided thoracolumbar curve of a 9-year-old patient with a Risser sign of 0 and a Cobb angle of 25° at baseline decreased to 12° at the age of 16 years (Risser sign — 5) due to bracing.Discussion The AIS was diagnosed in the patient at the age of 5 years and bracing was initiated at the age of 9. The curve correction using 3D GD brace was based on the principles offered by Chêneau. The patient used the corset for 20 hours per day. The initial brace correction was 90 %. The curve decreased from Cobb angle 25° to 12° over a six-year period of brace treatment with no need for surgery. Three cases with identical outcomes were reported with the use of the Boston and Chêneau braces in AIS.Conclusion The clinical case showed effective use of the 3D GD corset as a new exponent of corsets developed on the principles offered by Chêneau to prevent surgical treatment by the time of skeletal maturity.

Antihypertensive effect of esaxerenone and correlation between brachial and wrist home monitoring devices in patients with nocturnal hypertension: A post hoc analysis of the EARLY-NH study.

Adequate management of nocturnal hypertension is crucial to reduce the risk of organ damage and cardiovascular events. The EARLY-NH study was a prospective, open-label, multicenter study conducted in Japanese patients with nocturnal hypertension who received esaxerenone treatment for 12weeks. This post hoc analysis aimed to assess (1) the relationship between changes in morning home systolic blood pressure (SBP), bedtime home SBP, and nighttime home SBP based on changes in SBP and achievement rates of target SBP levels; and (2) the correlation between nighttime home SBP measurements using brachial and wrist home BP monitoring (HBPM) devices. This analysis evaluated 82 patients who completed the 12-week treatment period. Among those who achieved target morning home SBP (<135mmHg) and target bedtime home SBP (<135mmHg), the brachial HBPM device showed achievement rates of 63.6% and 56.4%, respectively, for target nighttime home SBP (<120mmHg). The wrist device showed achievement rates of 66.7% and 63.4%, respectively, for the same targets. Significant correlations were observed between both devices for nighttime home SBP measurements at baseline (r=0.790), Week 12 (r=0.641), and change from baseline to Week 12 (r=0.533) (all, p<.001). In this patient population, approximately 60% of individuals who reached target morning or bedtime home SBP levels <135mmHg exhibited well-controlled nighttime home SBP. Although nighttime home SBP measurements obtained using both brachial and wrist HBPM devices displayed a significant correlation, the wrist device needs to be examined in more detail for clinical use.

Long-term effects of abomasal infusion of linoleic and linolenic acids on the enrichment of n-6 and n-3 fatty acids into plasma lipid fractions of lactating cows

Our objective was to compare abomasal infusions of linoleic (18:2n-6) and α-linolenic (18:3n-3) acids on the enrichment of n-6 and n-3 fatty acids (FA) into the plasma lipid fractions of lactating dairy cows and evaluate their potential carryover effects in plasma lipid fractions post-infusion. Six rumen-cannulated multiparous Holstein cows (252 ± 33 d in milk) were fed the same diet and assigned to 1 of 2 treatments in a completely randomized design with repeated measures. Treatments were abomasal infusions (67 g/d total FA) of 1) n-6 FA blend (N6) to provide approximately 43 g/d 18:2n-6 and 8 g/d of 18:3n-3; or 2) n-3 FA blend (N3) providing 43 g/d 18:3n-3 and 8 g/d 18:2n-6. Treatments were dissolved in ethanol, and the daily dose for each treatment was divided into 4 equal infusions, occurring every 6 h. The treatment period lasted from d 1 to 20, and the carryover period lasted from d 21 to 40. Results are presented as FA contents within each of the 4 main plasma lipid fractions: cholesterol esters (CE), phospholipids (PL); triglycerides (TG), and plasma nonesterified fatty acids. Concentrations of individual lipid fractions in plasma were not quantified. Plasma CE and PL had the highest content of polyunsaturated FA (PUFA) during both the treatment and carryover periods. In plasma PL, N3 increased the contents of total n-3 FA (134%), 18:3n-3 (267%), and eicosapentaenoic acid (96.3%, 20:5n-3), and decreased total n-6 FA (8.14%) and 18:2n-6 (8.16%) from d 4 to 20 compared with N6. In plasma CE, N3 increased the contents of total n-3 FA (191%) from d 4 to 20, 18:3n-3 from d 2 to 20 (178%), and 20:5n-3 from d 6 to 20 (59.9%), while N3 decreased total n-6 FA from d 4 to 20 (11.2%) and 18:2n-6 from d 2 to 20 (10.5%) compared with N6. In addition, compared with N6, N3 decreased arachidonic acid (20:4n-6) at d 2 (45%) and from d 10 to 20 (14.7%) in PL and tended to decrease 20:4n-6 without interacting with time for CE. Phospholipids were the only lipid fraction with detectable levels of docosahexaenoic acid (22:3n-6) in all samples, but we did not observe differences between treatments. In plasma TG, N3 increased the contents of total n-3 FA (135%) and 18:3n-3 (146%) from d 4 to 20, increased 20:5n-3 from d 12 to 20 (89%), decreased or tended to decrease total n-6 FA content from d 6 and 8 (26.9%), and tended to decrease 18:2n-6 at d 8 compared with N6. A similar pattern was observed for plasma nonesterified fatty acids. We observed positive carryover effects for both N3 and N6 at different degrees in all lipid fractions, with N3 promoting more consistent outcomes and increasing total n-3 FA throughout the carryover period (from d 22 to 40) in both PL (52.8%) and CE (68.6%) compared with N6. It is important to emphasize that the higher magnitude responses observed for n-3 FA are also influenced by the content of n-3 FA being much lower than those of n-6 FA in all lipid fractions. While these data provide important and robust information, future research quantifying changes in concentrations of individual lipid fractions in plasma and the entry and exit rates of specific FA will further enhance our understanding. In conclusion, abomasally infusing N3 and N6 increased the contents of n-3 and n-6 FA, respectively, in all plasma lipid fractions. These responses were more evident in PL and CE. We also observed positive carryover effects in all lipid fractions, where N3 had more consistent outcomes than N6. Our results indicate that dairy cows have a robust mechanism to conserve essential FA, with a pronounced preference for n-3 FA.

Comparison of the effectiveness of temporomandibular joint osteoarthritis treatment with corticosteroids, hyaluronic acid, and platelet-rich plasma mono-therapy

The prevalence of temporomandibular joint (TMJ) osteoarthritis is 18–85 % of all TMJ dysfunctional conditions. Most patients are elderly, especially women. Today, intra-articular injections are often used for treatment, so it is necessary to study the effectiveness of drug administration on the course of the disease. The number of studies on the effectiveness of certain drugs most commonly used to treat TMJ osteoarthritis is limited, that does not allow correct treatment planning in each individual case. Aim: to evaluate the effectiveness of TMJ osteoarthritis treatment with monotherapy with hyaluronic acid, corticosteroids, and platelet-rich plasma. Materials and methods. We included 90 patients who received intra-articular injections. Patients were randomly divided into 3 groups: group I, which received platelet-rich plasma (PRP, n = 30), group II, which received hyaluronic acid (HA, n = 30), group III, which received corticosteroids (CS, n = 30). To objectively evaluate the effectiveness of TMJ osteoarthritis treatment with monotherapy of hyaluronic acid, corticosteroids and platelet-rich plasma, the following indicators were used: filling in the visual analogue pain scale, maximum mouth opening (mm) and cortical plate density of the articular head of the mandible according to the Hounsfield scale using CBCT. Results. PRP therapy demonstrated the highest efficacy in the form of monotherapy for all study parameters (p &lt; 0.05). The fastest pain reduction was achieved with the use of corticosteroids (p &lt; 0.05). In general, during the treatment period, the reduction of pain according to the visual analogue scale in group I was 85.71 %. In patients of group II (HA) and group III (CS) – by 71.42 %. Maximum mouth opening after treatment in group I increased by 24.32 %, in group II – by 15.79 %, in group III – by 18.92 %. The density of the articular head according to the Hounsfield scale after treatment in group I increased by 12.56 %, in group II – by 6.97 %, in group III – by 4.87 %. Conclusions. All of the studied drugs demonstrated a positive effect on the treatment of TMJ osteoarthritis, but monotherapy with intra-articular PRP injections demonstrated the highest effectiveness according to the studied parameters (p &lt; 0.05).

Green synthesis and characterization of AgNPs, liposomal loaded AgNPs and ZnPcS4 photosensitizer for enhanced photodynamic therapy effects in MCF-7 breast cancer cells

Breast cancer remains a formidable challenge in oncology despite significant advancements in treatment modalities. Conventional therapies such as surgery, chemotherapy, radiation therapy, and hormonal therapy have been the mainstay in managing breast cancer for decades. However, a subset of patient's experiences treatment failure, leading to disease recurrence and progression. Therefore, this study investigates the therapeutic potential of green-synthesized silver nanoparticles (AgNPs) using an African medicinal plant (Dicoma anomala methanol root extract) as a reducing agent for combating breast cancer. AgNPs were synthesized using the bottom-up approach and later modified with liposomes (Lip) loaded with photosensitizer (PS) zinc phthalocyanine tetrasulfonate (Lip@ZnPcS4) using thin film hydration method. The successful formation and Lip modification of AgNPs, alongside ZnPcS4, were confirmed through various analytical techniques including UV–Vis spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), high-resolution transmission electron microscopy (HR-TEM), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). Following a 24 h treatment period, MCF-7 cells were assessed for viability using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT viability assay), cell death analysis using mitochondrial membrane potential (MMP) (ΔΨm), Annexin V-fluorescein isothiocyanate (FITC)-propidium iodide (PI) kit, and caspase- 3, 8 and 9 activities. The experiments were repeated four times (n = 4), and the results were analyzed using SPSS statistical software version 27, with a confidence interval set at 0.95. The synthesized nanoparticles and nanocomplex, including AgNPs, AgNPs-Lip, Lip@ZnPcS4, and AgNPs-Lip@ZnPcS4, exhibited notable cytotoxicity and therapeutic efficacy against MCF-7 breast cancer cells. Notably, the induction of apoptosis, governed by the upregulation of apoptotic proteins i.e., caspase 8 and 9 activities. In addition, caspase 3 was not expressed by MCF-7 cells in both control and experimental groups. Given the challenging prognosis associated with breast cancer, the findings underscore the promise of liposomal nanoformulations in cancer photodynamic therapy (PDT), thus warranting further exploration in clinical settings.

Comparison of the effectiveness of temporomandibular joint osteoarthritis treatment with corticosteroids, hyaluronic acid, and platelet-rich plasma mono-therapy

The prevalence of temporomandibular joint (TMJ) osteoarthritis is 18–85 % of all TMJ dysfunctional conditions. Most patients are elderly, especially women. Today, intra-articular injections are often used for treatment, so it is necessary to study the effectiveness of drug administration on the course of the disease. The number of studies on the effectiveness of certain drugs most commonly used to treat TMJ osteoarthritis is limited, that does not allow correct treatment planning in each individual case. Aim: to evaluate the effectiveness of TMJ osteoarthritis treatment with monotherapy with hyaluronic acid, corticosteroids, and platelet-rich plasma. Materials and methods. We included 90 patients who received intra-articular injections. Patients were randomly divided into 3 groups: group I, which received platelet-rich plasma (PRP, n = 30), group II, which received hyaluronic acid (HA, n = 30), group III, which received corticosteroids (CS, n = 30). To objectively evaluate the effectiveness of TMJ osteoarthritis treatment with monotherapy of hyaluronic acid, corticosteroids and platelet-rich plasma, the following indicators were used: filling in the visual analogue pain scale, maximum mouth opening (mm) and cortical plate density of the articular head of the mandible according to the Hounsfield scale using CBCT. Results. PRP therapy demonstrated the highest efficacy in the form of monotherapy for all study parameters (p &lt; 0.05). The fastest pain reduction was achieved with the use of corticosteroids (p &lt; 0.05). In general, during the treatment period, the reduction of pain according to the visual analogue scale in group I was 85.71 %. In patients of group II (HA) and group III (CS) – by 71.42 %. Maximum mouth opening after treatment in group I increased by 24.32 %, in group II – by 15.79 %, in group III – by 18.92 %. The density of the articular head according to the Hounsfield scale after treatment in group I increased by 12.56 %, in group II – by 6.97 %, in group III – by 4.87 %. Conclusions. All of the studied drugs demonstrated a positive effect on the treatment of TMJ osteoarthritis, but monotherapy with intra-articular PRP injections demonstrated the highest effectiveness according to the studied parameters (p &lt; 0.05).

Subsequent Complications of Pediatric Patients With Osteomyelitis and Accompanying Subperiosteal Abscess.

Subperiosteal abscesses (SAs) are a complication of osteomyelitis that requires surgical intervention. This study aimed to characterize the occurrence of subsequent complications in pediatric patients with osteomyelitis and accompanying SA. Fourteen pediatric patients with SAs were included. We recorded clinical information, including age at diagnosis, interval (days) between the onset of symptoms and diagnosis, location of SAs (long/flat bone), pathogens [methicillin-resistant Staphylococcus aureus (MRSA)/non-MRSA], treatment period (days) and any subsequent complications. Patients were classified based on SAs with or without complications. Mann-Whitney U and Fisher exact tests were used for statistical analyses, and data are expressed as median and interquartile range. Six patients (42.9%) had subsequent complications. There were significant differences in location of SAs between these two groups (long/flat bone, with versus without complication = 6/0 versus 3/5; P = 0.031). No significant differences were observed between the groups in terms of age [with versus without complication = 13.8 (9.7-24.5) versus 556.3 (5.0-107.8) months; P = 0.491], the interval (days) between symptoms onset and diagnosis [with versus without complications = 5 (1-10) versus 5 (3-6.5) days; P = 0.950], pathogenesis (MRSA/non-MRSA, with versus without complication = 4/2 versus 2/6; P = 0.277) and treatment period [with versus without complication = 50.5 (31-57) versus 29 (24.5-41.5) days; P = 0.108]. Pediatric patients with SAs in the long bones have a higher likelihood of experiencing subsequent complications than those with SAs in flat bones. Physicians should carefully manage this vulnerable patient group.

Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients.

Despite the efficacy of efgartigimod demonstrated in ADAPT phase 3 trial, data specifically derived from Chinese participants are not available. Therefore, we aimed to evaluate the efficacy and safety of efgartigimod in Chinese patients with generalized myasthenia gravis (gMG). This is a prospective cohort study conducted in 8 hospitals across China. gMG patients received weekly intravenous infusions of efgartigimod (10 mg/kg) under a named patient program (NPP). The present study is an 8-week study, consisting of 4 consecutive doses of efgartigimod administered over 3 weeks (one cycle), followed by a 5-week follow-up period to assess the tolerability of efgartigimod's therapeutic effects. The primary outcome was the mean change in MG activities of daily living (MG-ADL) total score from baseline to 4 weeks. MG-ADL responder was defined as a ≥ 2-point improvement that persisted for 4 weeks, starting by week 4. Safety evaluations encompassed the monitoring of adverse events (AE) and serious AE (SAE) throughout the study. Between 5 July 2022 and 25 August 2023, a total of 14 gMG patients were included. The mean age was 57.7 years, with a mean MG-ADL score of 10.86 ± 3.32. At week 4, MG-ADL scores showed a mean reduction of 6 points, reaching a maximum decline of 13 points. Among the patients, 85.7% (12/14) achieved MG-ADL responder status after one cycle of treatment. The most significant reduction in quantitative MG (QMG) scores also occurred at week 4, with a mean decrease of 7 points. Notably, the improvements in MG-ADL and QMG scores persisted until week 8. During treatment and follow-up period, only two mild neck rashes occurred and resolved promptly. No infections or SAE were reported. A single cycle of efgartigimod treatment demonstrates effectiveness and the tolerability through week 8, with no new safety signals observed in Chinese gMG patients.

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

Bioequivalence Study of Velpatasvir/Sofosbuvir Oral Coated Tablets in Healthy Volunteers Under Fasting Conditions.

This study was conducted as a single-site, open-label, randomized, replicated crossover trial with 4 treatment periods. The aim was to evaluate the bioequivalence of a generic test drug containing velpatasvir and sofosbuvir compared to an established brand-name medication in healthy White subjects under fasting conditions. Blood samples were collected at specified intervals up to 72hours after dosing to measure the concentrations of velpatasvir and sofosbuvir using a certified high-performance liquid chromatography with tandem mass spectrometry method. The bioequivalence of the 2 formulations was confirmed when statistical analysis showed that confidence intervals for the log-transformed peak concentration and area under the concentration-time curve from time 0 to the last quantifiable sample were within an acceptable range from 80% to 125%. Criteria for bioequivalence were met for both area under the concentration-time curve from time 0 until the last quantifiable sample and peak concentration parameters. No adverse effects were reported during this trial in both groups.

Acute Kidney and Liver Injury Associated With Low-Dose Liraglutide in an Obese Adolescent Patient.

In 2020, the US Food and Drug Administration approved liraglutide (glucagon-like-peptide-1-receptor-agonist) as an adjunctive therapy for weight management in adolescents aged 12 to 18 years in combination with a reduced-calorie diet and increased physical activity. The 2023 American Academy of Pediatrics guidelines recommend pharmacotherapy with glucagon-like-peptide-1-receptor-agonist as a second-line therapy in obesity management. Although reports in adults have suggested a link between liraglutide and adverse effects including hepatic injury and acute kidney injury (AKI), these effects have not previously been reported among adolescents treated with liraglutide for weight loss. We present a 17-year-old male who developed AKI and evidence of hepatic injury (significant elevation of hepatic transaminases) after 3 months administration of the lowest dosage of liraglutide (0.6 mg/day) for management of class III obesity. The patient experienced significant loss of appetite, weight loss, and melancholy during the treatment period. One month after discontinuing liraglutide, his mood had improved, his liver enzymes had returned to normal, and AKI had resolved. The Adverse Drug Reaction Probability Scale suggested a high likelihood of a causative association between liraglutide and his symptoms. Our report highlights the importance of vigilance in monitoring for these potential adverse effects among adolescents treated for obesity with any dose of liraglutide.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. isrctn.org Identifier: ISRCTN59757862.

Preventive effect of naldemedine for opioid-induced constipation in patients with cancer starting opioids: A multicenter, double-blinded, randomized, placebo-controlled, phase 3 trial.

LBA12014 Background: A peripherally acting μ-opioid receptor antagonist (PAMORA), such as naldemedine, could alleviate OIC in cancer patients. However, the evidence of PAMORA on OIC prevention in cancer patients starting opioid analgesia is limited. This clinical trial aimed to confirm the preventive effect of naldemedine for OIC in cancer patients who start daily strong opioid administration compared with placebo. Methods: We conducted a multicenter, double-blinded, randomized, placebo-controlled trial between July 2021 and May 2023 with four academic hospital in Japan (jRCTs031200397). Patients with cancer starting regular strong opioid for the first time for cancer pain, and age 20 years or older were included. The eligible patient was randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio. The protocol treatment period was 14 days after the start of naldemedine (or placebo) and the naldemedine group had Symproic at 0.2 mg once a day after breakfast for 14 days. The placebo group had the placebo once a day after breakfast for 14 days. The primary endpoint was the proportion of patients with a Bowel Function Index (BFI) of less than 28.8 on Day 14. We conducted the safety assessments with the number of all adverse events occurring during the protocol treatment period using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Japanese translation of Japan Clinical Oncology Group. Results: Of the 103 patients were assessed for eligibility, 99 patients were randomly assigned on a 1:1 basis to receive naldemedine (n = 49) or placebo (n = 50). The BFI score at Day 1 was 18.3±19.8 with naldemedine group and 18.2±20.0 with placebo. The proportion of patients with a BFI of less than 28.8 on Day 14 was significantly greater with naldemedine group (64.6% [31 of 48 patients]; 95% CI, 51.1% to 78.1%) than with placebo (17.0% [8 of 47 patients]; 95% CI, 6.3% to 27.8%) with a difference of 47.6% (95% CI, 30.3% to 64.8%, p&lt; 0.0001). There was no statistical difference in the proportion of adverse events; abdominal distention, abdominal pain, diarrhea, bowel obstruction, and nausea. However, there was a significantly lower proportion of vomiting in patients treated with naldemedine. During the treatment period, none of patients treated with naldemedine had diarrhea, nausea, or vomiting as adverse events causally related to protocol treatment (0.0% [0 of 48 patients] v.s 34.0% [16 of 47 patients]. Conclusions: Naldemedine is a valuable option with proven efficacy in preventing OIC in cancer patients starting regular strong opioids. Clinical trial information: 031200397 .

A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.

To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS. In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 106 IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally. CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants. The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial. ClinicalTrials.gov, NCT06307301.

Superoxide dismutase-contained solid lipid nanoparticles: Formulation development and In-vivo evaluation for second-degree burn wound healing in rats

IntroductionSuperoxide dismutase (SOD), a natural enzyme with high antioxidant activity, reduces injury and accelerates wound healing by scavenging superoxide radicals. This enzyme plays an important role in cellular defense against oxidative stress such as burn injury. The aim of this study was to load SOD into solid lipid nanoparticles for the treatment of rat burn wounds. MethodsSolid lipid nanoparticles were prepared by Solvent Emulsification Diffusion method and evaluated for particle size, enzyme activity and enzyme entrapment efficiency. Twenty-seven rats in 3 different groups were induced with deep second-degree burns and then treated with SOD-loaded solid lipid nanoparticles, solid lipid nanoparticles without enzyme, or SOD solution. After the treatment period, the wounds were evaluated macroscopically for the area of healing and microscopically for indices of re-epithelialization, granulation tissue and angiogenesis. ResultsThe optimized SOD-loaded solid lipid nanoparticles showed a particle size of 35–85 ± 2.41 nm, 78.4 ± 4.31 % entrapment efficiency and 90 % initial enzyme activity. Macroscopic examination showed that the best recovery rate belonged to the solid lipid nanoparticle group. Pathological studies also showed that angiogenesis and granulation tissue were significantly better in this group. Compared to the other two groups, SOD-loaded solid lipid nanoparticles showed a significant improvement in pathological factors, particularly angiogenesis and granulation tissue, as well as a faster reduction in the number of inflammatory cells. ConclusionBased on this study, solid lipid nanoparticles could be used as an effective delivery system for SOD in the treatment of second-degree burns.

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis

AbstractThe ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non–transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542.

Metabolic dynamics in chronic gastritis: Examining urinary profiles post Helicobacter pylori eradication

Chronic gastritis is the persistent and insidious inflammation of the gastric lining. Helicobacter pylori (H. pylori ) has been identified as the most common cause of chronic gastritis and consequently elimination of H. pylori can lead to its cure. This editorial explores the use of urinary metabolic profiles before and after eradication to identify biomarkers that can aid in prognosis and treatment. Despite providing promising insights, there are limitations such as a small sample size (17 patients), a narrow treatment period of 2 wk, and treatment heterogeneity, which raise concerns. Nevertheless, these findings have opened a gateway to enhancing the treatment and prognosis of chronic gastritis through urinary metabolomics.