Search

Purpose: To evaluate the influence of immediate loading on the osseointegration and bone density of implants placed in a healed alveolar bone crest and supporting single crowns. Materials and Methods: Two solid titanium transmucosal mini-implants were placed in the distal regions of the mandible in 14 patients. One mini-implant was immediately functionally loaded, whereas the other was left unloaded. After 2 months of healing, biopsy samples were retrieved and the levels of new bone, old bone, and total bone (new + old) were assessed. Results: Histologic examination was performed on biopsies from 12 patients (n = 12). The new bone-to-implant contact percentage (BIC%) was 40.3% ± 16.8% and 55.1% ± 19.1% (P = .043) at the unloaded and loaded sites, respectively; in addition, the total BIC% was 44.9% ± 17.0% and 59.5% ± 18.8%, respectively (P = .034). The new bone density was 45.9% ± 11.6% for the unloaded implants and 45.9% ± 16.7% for the loaded implants (P = .622). Conclusions: Immediate loading had a positive effect on bone apposition at the implant surface, but no effect on bone density was observed after 2 months of healing. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the clinical accuracy of a robotically assisted implant guidance system in partially edentulous patients without the use of postoperative CBCT. Materials and Methods: A total of 10 implants (7 patients) were placed in partially edentulous patients utilizing a robotically assisted implant guidance system. Following the implant placement, an intraoral scan was performed to register the implant position after attaching a scan body. The virtual plan and the postoperative intraoral scan with the scan bodies were exported as STL files and superimposed, and discrepancies were analyzed using Geomagic Control X software. Positional deviations were measured between the midpoint of the platform and apex of the planned and achieved implant positions. Results: Seven of the 10 implants in this study were defined as fully robotically guided, while 3 were partially robotically guided. For the fully robotic dynamically guided group, the mean deviation at the midpoint of the restorative platform of the implant, the apex of the implant, the top of the scan body, and the mean angular deviation were 1.31 ± 0.46 mm, 1.58 ± 0.61 mm, 1.11 ± 0.57 mm, and 2.34 ± 1.71 degrees, respectively. For the partially robotic dynamically guided cases, these values were 1.31 ± 0.49 mm, 1.45 ± 0.3 mm, 1.74 ± 0.47 mm, and 3.75 ± 2.53 degrees, respectively. Eight of the 10 implants (irrespective of full or partial guidance) showed a buccal displacement. Conclusions: Robotic surgery offers a level of accuracy similar to fully guided implant placement, without the need for a physical template, and allows for changes in the surgical plan at any time. The analytical method described in this study is an effective and radiation-free quality-control tool that can be used in implant dentistry as well as in other areas of dental research. [ABSTRACT FROM AUTHOR]

Purpose: The study evaluated the clinical performance of partial indirect resin composite (PIRC) restorations with "proximal box elevation" (PBE) placed in molars. Materials and Methods: Sixty-three patients received 80 posterior PIRC (SR Nexco, Ivoclar Vivadent) restorations. Large posterior defects with cuspal loss and deep cervical margins were included in the study. PBE was performed priorto preparation and impression making. Two independent observers evaluated the restorations using the FDI criteria (scores 1-5) foresthetic, functional, and biological properties. Patients were recalled at 6 months and 1, 2, and 3 years. Overall success rates were calculated (Kaplan-Meier analysis) and compared (log-rank tests) according to baseline variables. The impact of the baseline variables on the failure of the restorations was analyzed (multiple proportional Cox regression). Results: Seventy-nine (98.7%), 69 (88.4%), 66 (92.9%), 44 (86.2%) and 45 (91.8%) PIRCs completed their follow up at baseline, 6 months, and 1, 2 and 3 years, respectively. In total, 10 failures were observed: 5 with partial loss, 4 with material chipping, and one with secondary caries, yielding an overall success rate of 87.5% and a survival rate of 93.8%, with a mean observation timeof 26.5 ± 13.6 months. Conclusions: PIRCs with PBE demonstrated a high survival rate and satisfactory esthetic properties. Failure was less likelyfor PIRC restorations with partial cuspal coverage (onlay) compared to full cuspal coverage (overlay). [ABSTRACT FROM AUTHOR]

Purpose: To evaluate two pharmacologic antibiotic prophylaxis regimens and a control group of immunocompetent patients undergoing two-stage dental implant placement in a triple-blind randomized controlled clinical trial. Materials and Methods: From a group of 61 immunocompetent patients, 21 were randomly allocated into group 1 (G1) without antibiotic prophylaxis (control), 20 in group 2 (G2) with preoperative antibiotic prophylaxis (1 g amoxicillin 1 hour before the procedure), and 20 in group 3 (G3) with preoperative (1 g amoxicillin) and postoperative (500 mg every 8 hours for 5 days) antibiotic prophylaxis. Pain was assessed with the visual analog scale (VAS) and by considering the number of painkillers patients used. Infection was identified via the presence of pus and fistula. Patients were evaluated after 7, 14, 30, and 120 days. Implant failure (defined as mobility upon the application of manual torque) was evaluated after 120 days during the second surgical stage. Results: At the 7-day follow-up, pain intensity was less severe in the patients who had received antibiotics, with the G3 patients experiencing the least pain (P < .05). Infection was present in groups G1 (2 cases) and G3 (2 cases), but there was no statistically significant intergroup difference. Two implants failed, one in G1 and the other in G3. Conclusions: Based on the results of the present study, although the use of antibiotics reduced pain in the immediate postoperative period, it did not reduce infection rates and implant failure in immunocompetent patients. [ABSTRACT FROM AUTHOR]

For patients with functional mitral regurgitation (FMR) and symptomatic heart failure (HF), randomized trials of mitral transcatheter edge-to-edge repair (M-TEER) have produced conflicting results. This study sought to assess the impact of M-TEER on hospitalization rates, and explore the effects of M-TEER on patients who did or did not have a history of recent HF hospitalizations before undergoing M-TEER. RESHAPE-HF2 (Randomized Investigation of the MitraClip Device in Heart Failure: 2nd Trial in Patients with Clinically Significant Functional Mitral Regurgitation) included patients with symptomatic HF and moderate to severe FMR (mean effective regurgitant orifice area 0.25 cm2; 14% >0.40 cm2, 23% <0.20 cm2) and showed that M-TEER reduced recurrent HF hospitalizations with and without the addition of cardiovascular (CV) death and improved quality of life. We now report the results of prespecified analyses on hospitalization rates and for the subgroup of patients (n = 333) with a HF hospitalization in the 12 months before randomization. At 24 months, the time to first event of CV death or HF hospitalization (HR: 0.65; 95% CI: 0.49-0.85; P = 0.002), the rate of recurrent CV hospitalizations (rate ratio [RR]: 0.75; 95% CI: 0.57-0.99; P = 0.046), the composite rate of recurrent CV hospitalizations and all-cause mortality (RR: 0.74; 95% CI: 0.57-0.95; P = 0.017), and of recurrent CV death and CV hospitalizations (RR: 0.76; 95% CI: 0.58-0.99; P = 0.040), were all lower in the M-TEER group. The RR of recurrent hospitalizations for any cause was 0.82 (95% CI: 0.63-1.07; P = 0.15) for patients in the M-TEER group vs control group patients. Patients randomized to M-TEER lost fewer days due to death or HF hospitalization (13.9% [95% CI: 13.0%-14.8%] vs 17.4% [95% CI: 16.4%-18.4%] of follow-up time; P < 0.0001, and 1,067 vs 1,776 total days lost; P < 0.0001). Patients randomized to M-TEER also had better NYHA functional class at 30 days and at 6, 12, and 24 months of follow-up (P < 0.0001). A history of HF hospitalizations before randomization was associated with worse outcomes and greater benefit with M-TEER on the rate of the composite of recurrent HF hospitalizations and CV death (P interaction = 0.03) and of recurrent HF hospitalizations within 24 months (P interaction = 0.06). These results indicate that a broader application of M-TEER in addition to optimal guideline-directed medical therapy should be considered among patients with symptomatic HF and moderate to severe FMR, particularly in those with a history of a recent hospitalization for HF. [ABSTRACT FROM AUTHOR]

Single-pill combinations of 3 or more low-dose blood pressure (BP)–lowering drugs hold promise for initial or early treatment of hypertension. The authors conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety. This international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event. From June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were −7.3 mm Hg (95% CI: −4.5 to −10.2) for GMRx2 ¼ dose and −8.2 mm Hg (95% CI: −5.2 to −11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group. In a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306) [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions This study aimed to assess the safety, pharmacokinetics and pharmacodynamics of noiiglutide (SHR20004), a novel glucagon‐like peptide‐1 receptor agonist, in Chinese obese participants without diabetes mellitus (DM).This phase 1, randomised, double‐blind, placebo‐controlled study enrolled adult participants with body mass index (BMI) ≥28 kg/m2. The study used a titration method, each subject received daily noiiglutide injection for 3–6 weeks, until reaching the final dose of 0.18, 0.24, 0.30 or 0.36 mg per day. Each dose group consisted of 10 participants, with eight receiving noiiglutide and two receiving placebos. Safety assessments were conducted throughout the study, and pharmacokinetics and pharmacodynamics were evaluated.Most treatment‐emergent adverse events were of mild to moderate in severity, with no serious adverse event or adverse event led to withdraw. Blood concentration of noiiglutide reached a steady state after daily administration for 4 days, with no significant accumulation. Mean elimination half‐life (t1/2) was between 9.90 and 11.8 h at steady state. At the end of treatment, the mean weight loss compared to baseline for the placebo group and each treatment group was −1.89, −3.26, −5.45, −4.35 and −7.46 kg respectively. The weight and BMI reductions observed in each noiiglutide treatment group were greater than those in the placebo group and exhibited an increasing trend with extended administration duration.Daily administration of noiiglutide using a titration method was well tolerated by Chinese obese participants without DM and showed potential therapeutic effect for weight loss. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis in high-impact areas, including the scalp, nails, palms, and soles, can disproportionately impair patient quality of life. Here, we evaluate the 2-year efficacy of bimekizumab treatment in patients with moderate to severe plaque psoriasis in post hoc analyses of five phase 3/3b trials. Methods: High-impact area efficacy data were pooled through 2 years across five phase 3/3b trials: BE VIVID, BE READY, BE SURE, their ongoing open-label extension (OLE) BE BRIGHT, and BE RADIANT (including its double-blinded treatment period and the first year of its OLE). Complete clearance of psoriasis in high-impact areas is reported over 2 years using the scalp Investigator's Global Assessment (IGA), palmoplantar IGA, and modified Nail Psoriasis Severity Index (mNAPSI). Patients included in these analyses had baseline moderate to severe scalp or palmoplantar involvement (scalp or palmoplantar IGA score ≥ 3) or mNAPSI score > 10. Results: A total of 1107 patients were randomized to bimekizumab and entered the OLEs. Subsets of 821 patients had scalp IGA ≥ 3 at baseline, 377 had mNAPSI > 10, and 193 had palmoplantar IGA ≥ 3. Complete scalp clearance in patients with baseline scalp IGA ≥ 3 randomized to bimekizumab was achieved rapidly, with high responses sustained from first (86.4%) to second year (85.9%). Nail clearance responses in patients with baseline mNAPSI > 10 increased from 63.4% to 68.5% from first to second year. Palmoplantar clearance in patients with baseline palmoplantar IGA ≥ 3 was sustained from first (88.3%) to second year (89.8%). Similar trends were seen in the 374 patients who received bimekizumab 320 mg every 4 weeks (Q4W)/every 8 weeks (Q8W) initial/maintenance dosing. Conclusion: In these analyses pooled across 2 years, bimekizumab showed sustained efficacy in psoriasis in high-impact areas. Clinicaltrials.gov Trial Registration Numbers: NCT03370133, NCT03410992, NCT03412747, NCT03598790, NCT03536884. Plain Language Summary: Psoriasis in some body areas can have a bigger impact on the self-confidence and well-being of patients. These body areas, called high-impact areas, are often very visible or important for day-to-day activities. They include the scalp, fingernails, palms, and soles of the feet. People with psoriasis often find applying creams or ointments to these areas challenging. The treatment may also not be effective. Therefore, new medications that can clear psoriasis from these areas are needed by patients and physicians. Bimekizumab is a drug given by injection. We examined whether bimekizumab can clear psoriasis in high-impact areas over 2 years in five clinical trials. Psoriasis of the scalp, palms, and soles cleared quickly with bimekizumab. Most patients reported clear skin in these areas after 4 months, and skin remained clear for the rest of the 2-year period. After 2 years, 90% (18 in 20) of patients with psoriasis on their palms and soles saw it clear completely; 86% of patients (around 17 in 20) saw their scalp psoriasis completely cleared. Nail psoriasis took slightly longer to clear, because nails grow more slowly. Nevertheless, 63% of patients (around 13 in 20) had completely clear nails after 1 year and 69% of patients (around 14 in 20) had clear nails after 2 years. Bimekizumab can clear psoriasis in high-impact areas quickly, and this is maintained over the long-term. Bimekizumab can provide a lasting treatment option for areas of the body which are difficult to treat and have a big impact on patients' lives. [ABSTRACT FROM AUTHOR]

The diversity and delicate balance of the oral microbiome contribute to oral health, with its disruption leading to oral and systemic diseases. Toothpaste includes elements like traditional additives such as sodium lauryl sulfate (SLS) as well as novel postbiotics derived from probiotics, which are commonly employed for maintaining oral hygiene and a healthy oral cavity. However, the response of the oral microbiota to these treatments remains poorly understood. In this study, we systematically investigated the impact of SLS, and toothpaste containing postbiotics (hereafter, postbiotic toothpaste) across three systems: biofilms, animal models, and clinical populations. SLS was found to kill bacteria in both preformed biofilms (mature biofilms) and developing biofilms (immature biofilms), and disturbed the microbial community structure by increasing the number of pathogenic bacteria. SLS also destroyed periodontal tissue, promoted alveolar bone resorption, and enhanced the extent of inflammatory response level. The postbiotic toothpaste favored bacterial homeostasis and the normal development of the two types of biofilms in vitro, and attenuated periodontitis and gingivitis in vivo via modulation of oral microecology. Importantly, the postbiotic toothpaste mitigated the adverse effects of SLS when used in combination, both in vitro and in vivo. Overall, the findings of this study describe the impact of toothpaste components on oral microflora and stress the necessity for obtaining a comprehensive understanding of oral microbial ecology by considering multiple aspects. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the study was to evaluate the modulating effects of five commonly used sweetener (glucose, inulin, isomaltulose, tagatose, trehalose) containing mouth rinses on the oral microbiome. Methods: A single-centre, double-blind, parallel randomized clinical trial was performed with healthy, 18–55-year-old volunteers (N = 65), who rinsed thrice-daily for two weeks with a 10% solution of one of the allocated sweeteners. Microbiota composition of supragingival dental plaque and the tongue dorsum coating was analysed by 16S RNA gene amplicon sequencing of the V4 hypervariable region (Illumina MiSeq). As secondary outcomes, dental plaque red fluorescence and salivary pH were measured. Results: Dental plaque microbiota changed significantly for two groups: inulin (F = 2.0239, p = 0.0006 PERMANOVA, Aitchison distance) and isomaltulose (F = 0.67, p = 0.0305). For the tongue microbiota, significant changes were observed for isomaltulose (F = 0.8382, p = 0.0452) and trehalose (F = 1.0119, p = 0.0098). In plaque, 13 species changed significantly for the inulin group, while for tongue coating, three species changed for the trehalose group (ALDEx2, p < 0.1). No significant changes were observed for the secondary outcomes. Conclusion: The effects on the oral microbiota were sweetener dependant with the most pronounced effect on plaque microbiota. Inulin exhibited the strongest microbial modulating potential of the sweeteners tested. Further full-scale clinical studies are required. [ABSTRACT FROM AUTHOR]

Participation in a paediatric, complex randomized controlled trial (RCT) might add to the family burden when a child is diagnosed with a severe disease. Although important, there are only a limited number of papers describing this aspect of research from the family point of view. This study explored parents' and children's experiences of participation in a research study shortly after the child had been diagnosed with type 1 diabetes. Sixteen parents (nine mothers, seven fathers) and nine children were interviewed by an independent researcher about their inducement, the decision-making process within the family which led to their participation, and their experience of having done so. The result showed that the parents wanted to contribute to improve treatment for children with diabetes in general but also specifically for their own child. Older children were more involved in the decision making than the younger children. Study information needs to be communicated clearly and effectively since decision-making based on information of a clinical trial directly after the child's diabetes onset proved difficult. Being randomized to the intervention group in this specific study was considered somewhat burdensome. However, parental participants in both intervention and control group claimed that they would recommend participation in research studies to other parents in a similar situation, and so did the children. There was no difference between the mothers' and fathers' experiences. Implications: Parents' expectations: A predominant driving force for the parents was the expectation that the study outcome could lead to something good for both their own child and other children with type 1 diabetes. Children's perspective on participation: Older children appreciated being involved in the decision-making process and valued their role in potentially helping others with diabetes. However, younger children were less involved and often relied on their parents for decision-making. Personal benefits: Both children and parents considered it important to gain something for themselves; by participating, they could benefit from more advanced technology and more rigorous follow-ups. Importance of control group: It was important for the families' motivation for completing the study that the researchers conveyed that the control group was as important for the outcome of the study as the intervention group. Future treatments: The parents felt that participation in the clinical trial could eventually lead to new treatments that could help their own child. Perceived safety: The fact that the clinical trial was considered well-planned and safe and implied no risk for the child made it easier to agree to participation. Effective communication: Since the onset of diabetes is emotionally stressful, and diabetes treatment itself is demanding, effective communication about the content of such a clinical trial is necessary, otherwise families may not understand what they are agreeing to. Burden on the intervention group: This clinical trial was somewhat burdensome for the intervention group to participate in; nevertheless, all of the families remained committed to their reasons for participating and completed the study [ABSTRACT FROM AUTHOR]

The benefit of the delivery of the right form of cancer care, tailored to the right patient, at the right time is increasingly being recognized in the global oncology community. Information on the role and feasible potential of precision oncology during the management of genitourinary cancer in Nigeria, the most populous country in Africa, is limited. This article, therefore, describes the present application of personalized medicine in Nigeria and its barriers and facilitators. It provided granular details on manpower distribution and epidemiological disparities. It also explored the use of clinical and biological markers for screening and early diagnosis, the application of team science to support genomic profiling, cost-effective approaches for image-based phenotypic precision oncology, the emerging role of molecular imaging, access to clinical trials; and their potential to support data driven diagnosis, treatment decision and care availability in order to address gaps in genitourinary cancer management in the country. [ABSTRACT FROM AUTHOR]

Rationale: Neurological conditions like Stroke and Alzheimer's disease (AD) often include inflammatory responses in the nervous system. Stroke, linked to high disability and mortality rates, poses challenges related to organ-related complications. Recent focus on understanding the pathophysiology of ischemic stroke includes aspects like cellular excitotoxicity, oxidative stress, cell death mechanisms, and neuroinflammation. Objective: The objective of this paper is to summarize and explore the pathophysiology of ischemic stroke, elucidates the gut-brain axis mechanism, and discusses recent clinical trials, shedding light on novel treatments and future possibilities. Results: Changes in gut architecture and microbiota contribute to dementia by enhancing intestinal permeability, activating the immune system, elevating proinflammatory mediators, altering blood-brain barrier (BBB) permeability, and ultimately leading to neurodegenerative diseases (NDDs). The gut-brain axis's potential role in disease pathophysiology offers new avenues for cell-based regenerative medicine in treating neurological conditions. Conclusion: In conclusion, the gut microbiome significantly impacts stroke prognosis by highlighting the role of the gut-brain axis in ischemic stroke mechanisms. This insight suggests potential therapeutic strategies for improving outcomes. [ABSTRACT FROM AUTHOR]

Background: Asthma is a leading cause of pediatric hospitalization and morbidity, necessitating the development of educational interventions for its management and control. Objective: To evaluate the effectiveness of an educational intervention in promoting parent/caregiver self-efficacy in the management and control of their children's asthma. Methods: A clinical trial was conducted in Fortaleza, Ceará, Brazil, involving two randomized groups of parents/caregivers of children: the comparison group (CG) (n = 42) and the intervention group (IG) (n = 42). Data collection took place in two phases: the first included face-to-face sessions followed by the educational intervention in the IG, and the second included telephone follow-up. The educational intervention included the use of an educational booklet and a brief motivational interview. Results: The groups were homogeneous at baseline. After the intervention, the mean self-efficacy scores of the IG were significantly higher than those of the CG (p < 0.05), and children whose parents/caregivers were in the CG were 1.43 times more likely to experience an asthma crisis than those in the IG. Conclusions: The educational intervention proved effective in increasing parent/caregiver self-efficacy in asthma management and control. Furthermore, children whose parents/caregivers did not receive the educational intervention were more likely to experience an asthma crisis. Significance: What is Already Known on this Subject?: Asthma is a chronic, non-communicable disease that contributes to morbidity and mortality in children. In addition, the crisis of this disease can be prevented if parents/caregivers are able to manage and control their children's asthma. What does this Study add?: This randomized clinical trial confirms that the use of an educational intervention consisting of an educational booklet and a brief motivational interview increases parent/caregiver self-efficacy to manage and control childhood asthma, thereby reducing the likelihood of an asthma crisis. [ABSTRACT FROM AUTHOR]

Background: Physical therapy seems the most promising treatment for temporomandibular disorders (TMD), although their effectiveness is controversial in general, due to high heterogeneity regarding study designs, applied treatments and outcomes measures. Objectives: The aim of this scoping review is to analyse the methodological characteristics of clinical trials evaluating physical therapy treatments in subjects with TMD. Methods: A systematic search was conducted in Medline/PubMed, SPORTDiscus, Scopus, Web of Science, SciELO, Cochrane, ScienceDirect and EMBASE databases on 31 October 2023. Clinical trials evaluating physical therapy interventions in patients older than 18 years with TMD, published in English or Spanish languages. Data regarding content reporting of study designs, sample characteristics, interventions and outcome measures was extracted. Descriptive summary statistics were reported. Results: The search retrieved 15 322 records, and 136 were included. There were 107 randomised clinical trials, 5 non‐randomised controlled trials and 24 non‐controlled trials. Most studies had moderate to high risk of bias, small sample sizes (median, 44 subjects) and short follow‐up periods (1–3 months). The most common diagnostic criteria used was the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) (48.9%). The most reported experimental interventions were manual therapy (40.4%), exercise (30.2%) and electrotherapy modalities (27.2%), and the most common outcome measure domains were pain (83.8%), range of movement (61.8%), disability (45.6%) and mechanosensitivity (29.4%). There was poor content reporting of experimental interventions. Conclusions: Current literature of clinical trials of physical therapy interventions for TMD has moderate to high risk of bias, poor content reporting, small sample size and short‐term follow‐ups which limit internal and external validity, as well as applicability into clinical practice. [ABSTRACT FROM AUTHOR]

• Meta-analysis covers 2004–2024 data on MSC use in ischemic cardiomyopathy. • Studies assessed the safety and efficacy of MSCs from 3 different tissue origin. • Forty-nine trials with 1408 participants were followed up for 1–10 years. • Eighty deaths (52% of cases) reported post-MSC treatment. • LVEF increase was reported 5.75% (95% CI: 3.38%–8.11%, p < 0.0001) from baseline. This meta-analysis and systematic review compiles comparative data from 2004 to 2024, investigating the safety and efficacy of mesenchymal stem/stromal cells (MSCs) derived from various tissues for the treatment of ischemic cardiomyopathy (ICM) and associated heart failure. In addition, this review highlights the limitations of these interventions and provides valuable insights for future therapeutic approaches. Relevant articles were retrieved from the PubMed® database using targeted keywords. Our inclusion criteria included clinical trials with patients over 18 years of age, case reports and pilot studies. Animal experiments, in vitro studies, correlational and longitudinal studies, and study designs and protocols were excluded. Forty-nine original articles resulted in follow-up reports of 45 trials. MSCs from bone marrow, umbilical cord and adipose tissue were moderately well tolerated. Of the 1408 participants who received MSCs, 33 trials (67.3%) reported the occurrence of death or serious adverse events. These events resulted in 80 deaths (52% of reported cases) following MSC administration. Importantly, 41.3% of these deaths (n = 33) were not considered to be related to the intervention itself, while 40% of these deaths had no reported cause. As the primary outcome, the mean increase in left ventricular ejection fraction (LVEF) from baseline was 5.75% (95% CI: 3.38% –8.11%, p < 0.0001, I2 = 90,9%) in the randomized controlled trials only (n = 24) within the treatment groups and 3.19% (95% CI: 1.63% to 4.75%, p < 0.0001, I2 = 74,17%) in the control groups after the intervention. When the above results were compared using the standardized mean difference (SDM), a significance in favor of the treatment group was also found (SDM = 0.41; 95% CI: 0.19–0.64, p < 0.001, I2 = 71%). Although improvements were also seen in the control groups, 33.3% (n = 15) of the studies showed no significant difference between the control and treatment groups. The 6-minute walking test (6MWT) and New York Heart Association (NYHA) class scores, used for assessing exercise tolerance and quality of life (QoL), respectively, further supported the improvements in the treatment group. These improvements were noted as 62.5% (n = 10) for the 6MWT and 54.5% (n = 12) for the NYHA class scores. According to the risk of bias analysis, 4 trials were of good quality (11.8%), 15 were of fair quality (44.1%), and 15 were of poor quality (44.1%). Major limitations of these studies included small sample size, diagnostic challenges/lack, uncertain cell dosage and potential bias in patient selection. Despite the ongoing debate surrounding cell administration for ICM, there are supporting signs of improved clinical and laboratory outcomes, as well as improved QoL in the MSC-treated groups. However, it is important to recognize the limitations of each study, highlighting the need for larger, controlled trials to validate these findings. [ABSTRACT FROM AUTHOR]

Background and purpose: Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre‐specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT‐2) was assessed. Methods: RIGHT‐2 was a pre‐hospital‐initiated multicentre randomized sham‐controlled blinded‐endpoint trial that randomized patients with presumed ultra‐acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2). Results: In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre‐morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70–3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09–13.59). Conclusions: Pre‐hospital ultra‐acute transdermal GTN did not improve overall functional outcome in patients with investigator‐diagnosed TIA compared with sham treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: This study evaluated associations of brain amyloid with 2‐year objective and subjective cognitive measures in a trial‐ready older general population at risk for dementia. Methods: Forty‐eight participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability underwent 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET) scans and assessment of cognition (modified Neuropsychological Test Battery [NTB]) and subjective memory complaints (Prospective and Retrospective Memory Questionnaire). Results: Mean age was 71.4 ± 5.06 years, and 20 participants (42%) had positive baseline PiB‐PET scans. Amyloid positivity was associated with lower NTB executive function at baseline and less favorable 2‐year NTB total score and memory trajectories, but not with other objective or subjective cognitive measures. Overall, there was little cognitive decline during 2 years. Conclusions: Amyloid accumulation may affect objective but not necessarily subjective cognition from a very early at‐risk stage, although substantial decline likely requires >2 years to occur. [ABSTRACT FROM AUTHOR]

Aim: To investigate the blood pressure (BP) and ductal calibre patterns associated with early ductal closure in very low gestational age (<32 weeks) infants. Methods: Blood pressure was continuously measured intra‐arterially among 43 infants participating in a randomised, double‐blind trial of 4 days prophylactic intravenous paracetamol. Early closure of the ductus was verified by daily ultrasound examinations. The BP recordings, before and after the verified ductal closure, were examined and compared to control infants without ductal closure. In the 24‐h preceding the ultrasound‐verified ductal closure, periods of increased BP were searched and identified as suggestive ductal closure time points. In control infants without ductal closure, BP trends were examined during the corresponding age. Results: Mean arterial BP increased significantly before ductal closure (p < 0.001) and stayed higher than in the control group. Mean BP during the 8 h preceding closure significantly predicted the ductal closure [OR 2.094 (95% CI 1.209–3.630), p = 0.008], and multiple potential confounders failed to abolish this association. A linear decrease pattern in ductal calibre was significantly associated with the ductal closure. Conclusion: Blood pressure increased and stabilised before the early ductal closure, offering potential implications on treatment strategies of very premature infants. [ABSTRACT FROM AUTHOR]

Introduction: Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing–remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. Methods: Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years. Results: Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0–7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. Conclusions: These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. Trial registration: NCT02282826, NCT02977533, NCT02313285. [ABSTRACT FROM AUTHOR]

Background: Inadequate health literacy in people with chronic kidney disease is associated with poorer disease management and greater complications. Adherence to the renal diet is known to be suboptimal and patient feedback about the renal diet suggests that patients leave nephrology clinics feeling confused. The present study aimed to evaluate the impact of a health literacy sensitive model of care (MOC) in outpatient nephrology dietetic clinics. Methods: This quasi‐experimental non‐randomised pre‐post study recruited adults attending three renal dietitian clinics. The revised MOC consisted of a renal diet question prompt sheet, teachback, and plain language materials and instructions. Outcomes assessed included clinical, dietary, patient‐reported satisfaction and quality of life. Differences between and within groups were analysed using paired t‐tests, independent sample t‐tests (or non‐parametric equivalent), chi‐squared and McNemar's tests. Linear mixed models evaluated change in total diet quality score, fruit, vegetable, protein and dairy intake with time as a fixed effect and a random subject specific effect. Results: Fail to attend rates at the initial appointments were lower in the revised MOC (21.5% vs. 9.1%). The revised MOC was associated with significantly improved fruit (p = 0.03) and vegetable (p = 0.003) intake and an improved proportion with adequate diet quality (p = 0.03). These impacts were of moderate effect size (d = 0.5, 95% confidence interval = 0.0–1.0). The revised MOC was also associated with greater satisfaction at baseline (p = 0.04) and higher acceptability scores for all questions at the review appointments. Quality of life improved clinically but not significantly in the revised MOC (p = 0.92). Conclusions: This low‐cost health literacy sensitive intervention is a promising strategy to improve fruit and vegetable intake in adults attending renal dietitian clinics. Further research to determine fidelity of teachback use and cost utility analysis would be beneficial. Larger scale trials powered to detect changes in quality of life would also be informative. Key points: There was no improvement in overall adherence to the renal diet in the usual care or revised model of care.However, the revised model of care was associated with a significant improvement in fruit and vegetable intake and diet qualityPatient satisfaction was high in both models of dietetic care, however, the revised model of care was associated with greater satisfaction at baseline. [ABSTRACT FROM AUTHOR]

Aim: To explore the efficacy and safety of once‐weekly insulin icodec (icodec) in Japanese adults (≥20 years old) with type 2 diabetes from the global ONWARDS 1, 2 and 4 trials. Materials and Methods: Insulin‐naive (ONWARDS 1) and insulin‐experienced (ONWARDS 2 and 4) individuals were randomized to icodec or a once‐daily insulin comparator: insulin glargine U100 [ONWARDS 1 (basal insulin only) and 4 (basal–bolus regimen)] or insulin degludec [ONWARDS 2 (basal insulin only)]. The primary outcome was change in glycated haemoglobin from baseline to end of treatment (EOT) (ONWARDS 1: Week 52; ONWARDS 2 and 4: Week 26). Here, we present the Japanese subgroup results. Results: Similar reductions in glycated haemoglobin from baseline to EOT were observed in each trial for icodec and comparators. The proportion of time in range (blood glucose 3.9–10.0 mmol/L) at EOT was also comparable across treatment groups (time in range: 58%–68%), as was time spent with blood glucose below 3.0 mmol/L (<1.0%). Combined clinically significant (blood glucose <3.0 mmol/L) or severe (requiring external assistance for recovery) hypoglycaemia rates were low, with no severe events (ONWARDS 1 and 2) or a single severe event (ONWARDS 4; icodec group) reported. These results generally aligned with findings from the respective global populations. No new safety issues were identified. Conclusions: Icodec improved glycaemic control to a similar degree as once‐daily basal insulin comparators while maintaining low levels of clinically significant or severe hypoglycaemia. The findings support icodec use in Japanese individuals with different levels of type 2 diabetes progression. [ABSTRACT FROM AUTHOR]

Aims: The combination of cagrilintide and semaglutide (CagriSema) is being developed for the treatment of obesity and type 2 diabetes. The objective of this thorough QT study was to confirm that cagrilintide does not result in a clinically relevant prolongation in cardiac repolarization compared with placebo. Materials and Methods: This was a double‐blind study (NCT05804162) in which healthy participants were randomized to cagrilintide, administered as a once‐weekly subcutaneous injection dose escalated to 4.5 mg, or a placebo. The primary end point was the time‐matched change from baseline in Fridericia heart rate–corrected QT interval (QTcF) at 12‐, 24‐, 48‐ and 72 h after the last cagrilintide 4.5‐mg dose. To conclude that cagrilintide does not induce a clinically relevant prolongation, the upper limit of the two‐sided 90% confidence interval (CI) for the treatment difference at each of the four time points must fall below 10 ms. To establish QT assay sensitivity, participants in the placebo arms received a single 400‐mg oral moxifloxacin dose as a positive control and moxifloxacin placebo in a nested cross‐over fashion. Results: A total of 105 participants received cagrilintide (n = 53) or placebo (n = 52). No clinically relevant QTcF prolongation occurred after the last cagrilintide 4.5‐mg dose; the upper limits of the two‐sided 90% CIs of the placebo‐adjusted QTcF changes from baseline were below 10 ms at all time points. QT assay sensitivity was demonstrated with moxifloxacin as a positive control. Conclusions: Cagrilintide did not result in clinically relevant QTcF prolongation, indicating no increased risk of ventricular tachyarrhythmias. [ABSTRACT FROM AUTHOR]

The article "Representation of women in randomized controlled trials of novel antidiabetic drugs: A cohort study" published in Diabetes, Obesity & Metabolism highlights the underrepresentation of women in clinical trials for diabetes drugs, impacting the precision of medical interventions. The study focused on trials with primary outcomes related to cardiac and renal events, revealing a significant lack of female participants. Despite efforts to reduce gender disparities in clinical research, women were notably underrepresented, affecting the accuracy of treatment practices. The study recommends future research prioritize recruiting women in proportions reflective of their representation in the population to enhance the relevance of medical interventions. [Extracted from the article]

Aim: Automated insulin delivery (AID) systems have demonstrated improved glycaemic outcomes in people with type 1 diabetes (T1D), yet limited data exist on these systems in very young children and their impact on caregivers. We evaluated psychosocial outcomes following use of the tubeless Omnipod® 5 AID System in caregivers of very young children. Materials and Methods: This 3‐month single‐arm, multicentre, pivotal clinical trial enrolled 80 children aged 2.0–5.9 years with T1D to use the Omnipod 5 AID System. Caregivers completed questionnaires assessing psychosocial outcomes—diabetes distress (Problem Areas in Diabetes), hypoglycaemia confidence (Hypoglycemia Confidence Scale), well‐being (World Health Organization 5 Well‐Being Index), sleep quality (Pittsburgh Sleep Quality Index), insulin delivery satisfaction (Insulin Delivery Satisfaction Survey) and system usability (System Usability Scale) at baseline with standard therapy and after 3 months of AID use. Results: Following 3 months of Omnipod 5 use, caregivers experienced significant improvements across all measures, including diabetes‐related psychosocial outcomes (Problem Areas in Diabetes; p < 0.0001, Hypoglycemia Confidence Scale; p < 0.01), well‐being (World Health Organization 5 Well‐Being Index; p < 0.0001) and perceived system usability (System Usability Scale; p < 0.0001). Significant improvements were seen in the Pittsburgh Sleep Quality Index total score and the overall sleep quality, sleep duration and efficiency subscales (all p < 0.05). Insulin Delivery Satisfaction Survey scores improved on all subscales (greater satisfaction, reduced burden and reduced inconvenience; all p < 0.0001). Conclusions: Caregivers face unique challenges when managing T1D in very young children. While glycaemic metrics have unquestioned importance, these results evaluating psychosocial outcomes reveal additional meaningful benefits and suggest that the Omnipod 5 AID System alleviates some of the burdens caregivers face with diabetes management. [ABSTRACT FROM AUTHOR]

Unblinded interim analyses in clinical trials with adaptive designs are gaining increasing popularity. Here, the type I error rate is controlled by defining an appropriate conditional error function. Since various approaches to the selection of the conditional error function exist, the question of an optimal choice arises. In this article, we extend existing work on optimal conditional error functions by two results. Firstly, we prove that techniques from variational calculus can be applied to derive existing optimal conditional error functions. Secondly, we answer the question of optimizing the conditional error function of an optimal promising zone design and investigate the efficiency gain. [ABSTRACT FROM AUTHOR]

Background: Valid measurement of drug use in patients enrolled in clinical trials that treat substance use disorder is vital to determine the trial's outcome. Self-reports are often used but their validity has been studied with mixed results. Urinalysis may sometimes be employed as an alternative or supplement to self-reports. Objectives: This study examined how estimating drug use by either method would affect the results from a randomized clinical trial conducted in a methadone treatment program. At the initial Baseline interview and four follow-up interviews, participants were asked about their drug use history and provided a urine specimen for drug testing. Results: In most cases, the urinalyses detected more drugs than the patients had reported using. A major exception was heroin, whose use was an eligibility criterion for enrollment in the study and methadone treatment. Conclusions: The patients' self-reports would have led us to conclude that the use of heroin and fentanyl had declined from the initial Baseline interview to the final follow-up interview, while the urinalysis results indicated no change in exposure to heroin and an increase in exposure to fentanyl. Clinical trials would be well served to employ the use of biological tests in addition to self-reports to measure recent drug use and to accurately estimate the efficacy of the experimental protocols and patients' exposure to drugs. [ABSTRACT FROM AUTHOR]

The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345). [ABSTRACT FROM AUTHOR]

In plaque psoriasis, palmoplantar areas are more difficult to treat. Evaluate the safety and efficacy of risankizumab (RZB) versus placebo (PBO) for the treatment of palmoplantar psoriasis. Patients were randomized to RZB or PBO for 16 weeks followed by RZB through week 52. The primary and secondary end points were achievement of palmoplantar Investigator's Global Assessment of "clear" or "almost clear" with ≥2-point reduction from baseline (ppIGA 0/1), achievement of ≥75%, ≥90%, and 100% improvement in Palmoplantar Psoriasis Area and Severity Index (PPASI 75, PPASI 90, PPASI 100) and achievement of static Physician Global Assessment of "clear" or "almost clear" with ≥2-point reduction from baseline (sPGA 0/1) at week 16. Safety was based on treatment-emergent adverse events. RZB demonstrated significant efficacy compared to PBO at week 16 in the patients achieving ppIGA 0/1 (33.3% vs 16.1% [ P =.006]), PPASI 75 (42.5% vs 14.9% [ P <.001]), PPASI 90 (27.6% vs 5.7% [ P <.001]), sPGA 0/1 (32.2% vs 11.5% [ P <.001]), and PPASI 100 (17.2% vs 1.1% [ P <.001]). Results improved through week 52 with no new safety signals. No biologic comparator. RZB demonstrated good tolerance and efficacy in palmoplantar psoriasis. [ABSTRACT FROM AUTHOR]

Response‐adaptive randomization (RAR) procedures have been extensively studied in the literature, but most of the procedures rely on updating the randomization after each response, which is impractical in many clinical trials. In this article, we propose a new family of RAR procedures that dynamically update based on the responses of a group of individuals, either when available or at fixed time intervals (weekly or biweekly). We show that the proposed design retains the essential theoretical properties of Hu and Zhang's doubly adaptive biased coin designs (DBCD), and performs well in scenarios involving delayed and randomly missing responses. Numerical studies have been conducted to demonstrate that the new proposed group doubly adaptive biased coin design has similar properties to the Hu and Zhang's DBCDs in different situations. We also apply the new design to a real clinical trial, highlighting its advantages and practicality. Our findings open the door to studying the properties of other group response adaptive designs, such as urn models, and facilitate the application of response‐adaptive randomized clinical trials in practice. [ABSTRACT FROM AUTHOR]

Background: A 12-week randomized controlled trial demonstrated that brexpiprazole is efficacious for treating agitation in patients with dementia due to Alzheimer's disease. Objective: To assess the long-term safety and tolerability of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease. Methods: This 12-week, active-treatment (oral brexpiprazole 2 or 3 mg/day) extension trial ran from October 2018–September 2022 at 66 sites in Europe/US. Patients with agitation in dementia due to Alzheimer's disease in a care facility/community-based setting who completed the randomized trial were eligible (N = 259 enrolled/analyzed for safety; 88.4% completed). Stable Alzheimer's disease medications were permitted. The primary safety endpoint was the frequency and severity of treatment-emergent adverse events (TEAEs). Change in Cohen-Mansfield Agitation Inventory (CMAI) total score was an exploratory efficacy endpoint. Results: Mean (SD) age was 74.3 (7.6) years, 145 patients (56.0%) were female, and 248 (95.8%) were White. TEAEs were reported by 67 patients (25.9%), most commonly headache (3.5%) and fall (2.3%). Most TEAEs were mild or moderate in severity; 5 patients (1.9%) reported a severe TEAE, including 3 severe falls attributed to tripping, misjudging sitting, or dehydration. Twelve patients (4.6%) discontinued due to TEAEs. No patients died. Mean CMAI total score improved by 9.1 points over 12 weeks. Conclusions: Considering the randomized and extension trials together, brexpiprazole 2 or 3 mg was generally well tolerated for up to 24 weeks in elderly patients with agitation associated with dementia due to Alzheimer's disease. Patients showed continued improvement in agitation. ClinicalTrials.gov identifier: NCT03594123 (registration date: July 11, 2018). [ABSTRACT FROM AUTHOR]

Background: Acute mountain sickness (AMS) is a debilitating condition that individuals may develop on ascent to high altitude. It is characterized by headache, nausea, vomiting, dizziness, and fatigue with the potential to progress to fatal disease. Although the pathophysiology of AMS remains unclear, proposed mechanisms are hypothesized to be similar to migraine. Prochlorperazine, a first-line treatment for acute migraine, has been shown to abort migraine early and thus may be effective in preventing AMS. Its action as a respiratory stimulant additionally makes it a promising novel agent for AMS prevention. Methods: In this randomized double-blinded trial, participants will be randomized to receive oral prochlorperazine maleate or placebo for 24 h of three times daily dosing on a rapid ascent to 4348 m. Participants will be adults, aged 18, and older who are unacclimatized. Participants will remain at this elevation overnight. The Lake Louise Questionnaire will be utilized to define the primary outcome and presence of AMS and will be assessed the evening of and morning after ascent to peak altitude. Discussion: Currently, acetazolamide is the preferred option for the chemoprophylaxis of AMS, which has been studied and utilized since the 1970s and involves potential prohibitive side effects. Other more efficacious options with more tolerable side effects are needed. Preventing AMS has the potential to limit both the morbidity and mortality associated with developing AMS and more serious diseases (notably high-altitude cerebral edema). Additionally, there is a substantial economic and environmental impact of AMS that could be prevented. Trial registration: Clinicaltrial.gov, NCT06450899. Registered on June 2024. [ABSTRACT FROM AUTHOR]

Background: Recruiting a sufficient number of patients is often a challenge for conducting clinical trials. Published data reveal that only 10% of eligible patients according to inclusion and exclusion criteria are enrolled in clinical trials. Consequentially, identifying barriers and facilitators may improve enrollment. These factors may differ in the pediatric population, for example, due to the involvement of parents in the decision-making process. We aimed to conduct an overview of systematic reviews to summarize the barriers and facilitators influencing the enrollment of pediatric participants in clinical trials. Methods: A systematic literature search in PubMed and Epistemonikos of published systematic reviews focusing on barriers and facilitators influencing the enrollment of pediatric patients in clinical trials was conducted. Study selection, data extraction, and quality assessment were performed by two authors independently. The methodological quality was judged using a critical appraisal tool. Finally, data were narratively synthesized. Results: Of 283 identified systematic reviews, four met the inclusion criteria and were included in the overview. Parents belonging to an ethnic minority or having low socioeconomic status were identified as barriers to enrollment whereas higher parental education and higher age served as facilitators. Additionally, existing expectations, previous treatment experiences and preferences, study duration, type of control group, and the child's attitude toward study participation could favor or hinder participation. Furthermore, physicians' opinions of study-related treatments may also influence the enrollment process. Conclusion: This overview provides a summary of barriers and facilitators to the enrollment of pediatric patients in clinical trials. Taking into account this information may enhance the enrollment of this hard-to-reach population. [ABSTRACT FROM AUTHOR]

Background: Consensus on what outcomes should be included in trials of psychological therapies on acute psychiatric inpatient wards is currently lacking. Inclusion of different viewpoints, including service user perspectives, is crucial in ensuring that future trials measure outcomes which are meaningful and important. Development of a Core Outcome Set (COS), a minimum standardised set of outcomes to be measured and reported, would help improve synthesis and interpretation of clinical trial data in this area. Methods: Stage 1 of the COS development involved compiling a comprehensive long-list of outcomes from key sources including i) a systematic review of outcomes from published trials, ii) online survey of key stakeholders (service users, carers, healthcare professionals, researchers, and end users of research), iii) qualitative interviews with service users and carers. Stage 2 involved stakeholder groups short-listing the outcomes using consensus methods (e-Delphi survey). The final outcome set was derived from the short-list at a consensus meeting of stakeholders, facilitated by an Independent Chair. Results: A long-list of 68 outcomes was compiled from the systematic review (n = 30 trials), online stakeholder survey (n = 100 participants) and qualitative interviews (n = 15 participants). Fifty stakeholders took part in the e-Delphi study, where the long-list was cut down to a short-list of 12 outcomes over 2 rounds. Nine stakeholders took part in the final consensus meeting, and after some outcomes were removed and/or amalgamated, a final set of 6 outcomes was recommended for inclusion in the COS. These were Ability to Cope, Hopefulness, Quality of Life, Psychosis Symptoms, Mood, and Self-Harm Behaviours. Conclusions: Widespread future adoption of the COS will reduce research waste by ensuring that outcomes are more easily comparable across trials, and that the full range of stakeholder priorities are represented in trial outcomes. This makes it more likely that effective therapies will be identified in a timely fashion and successfully implemented in routine clinical practice. The final 6-outcome COS should be feasible to implement given the need keep participant burden to a minimum in inpatient trials. Further work is needed to make recommendations for the best outcome measurement instruments to use, including the use of patient-reported outcomes alongside clinician-rated measures. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions X‐linked Charcot‐Marie‐Tooth disease type 1 (CMTX1) ranks as the second most prevalent hereditary neuropathy and, currently, has no definitive cure. Emerging preclinical trials offer hope for potential clinical studies in the near future. While it is widely accepted that experimental groups in these trials should be balanced for age and gender, there is a current shortfall in data regarding phenotype–genotype correlations. Our aim was to provide a more detailed understanding of these correlations to facilitate the formation of well‐matched patient groups in upcoming clinical trials.We conducted a retrospective evaluation of CMTX1 patients from 13 designated reference centers in France. Data on genetics, clinical features, and nerve conduction were systematically gathered.We analyzed the genotype–phenotype correlations in 275 CMTX1 patients belonging to 162 families and carrying 87 distinct variants. Patients with variants affecting the transmembrane domains demonstrated significantly greater severity, as evidenced by a Charcot‐Marie‐Tooth Examination Score of 10.5, compared to 7.1 for those with intracellular domain variants and 8.7 for extracellular domain variants (p < 0.000). These patients also experienced an earlier age of onset, showed slower ulnar nerve conduction velocities and had more substantial loss of motor amplitude.This study confirms the presence of a correlation between the mutated protein domain and the clinical phenotype. Patients with a variant in the transmembrane domains demonstrated a more severe clinical and electrophysiological profile. Consequently, the genotype could play a prognostic role in addition to its diagnostic role, and it will be essential to consider this in future clinical trials. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Beta‐blockers may inhibit neprilysin activity and conversely, neprilysin inhibition may have a sympatho‐inhibitory action. Consequently, sacubitril/valsartan may have a greater effect in patients not receiving a beta‐blocker compared to those treated with a beta‐blocker.We examined the effect of sacubitril/valsartan compared to enalapril on outcomes according to background beta‐blocker treatment in the 8399 patients with heart failure with reduced ejection fraction enrolled in PARADIGM‐HF. The primary outcome was time to first heart failure hospitalization or cardiovascular death. Compared to the 7811 patients taking a beta‐blocker, the 588 patients not receiving a beta‐blocker were older, more frequently female, but had a similar mean left ventricular ejection fraction and New York Heart Association class distribution, with little difference in N‐terminal pro‐B‐type natriuretic peptide. Patients not taking beta‐blockers had a higher rate of the primary endpoint than those taking beta‐blockers. The benefit of sacubitril/valsartan on the primary endpoint was evident in both the no beta‐blocker subgroup (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.45–0.82) and the beta‐blocker subgroup (HR 0.82, 95% CI 0.75–0.90; p‐interaction = 0.06). The respective HRs for cardiovascular death were 0.47 (95% CI 0.32–0.69) versus 0.84 (95% CI 0.75–0.95; p‐interaction <0.01) and for HF hospitalization 0.76 (95% CI 0.51–1.12) versus 0.80 (95% CI 0.71–0.90; p‐interaction = 0.73). For all‐cause death, the HR in the no beta‐blocker group was 0.50 (95% CI 0.36–0.71) compared to 0.89 (95% CI 0.80–0.99) in the beta‐blocker group (p‐interaction <0.01). Safety outcomes related to sacubitril/valsartan versus enalapril did not differ according to background beta‐blocker use.Sacubitril/valsartan may be more effective than enalapril in reducing the risk of death in patients not treated with a beta‐blocker compared to those treated with a beta‐blocker, but is effective regardless of beta‐blocker use.Clinical Trial Registration: ClinicalTrials.gov NCT01035255. [ABSTRACT FROM AUTHOR]

The meta-analysis study examines the association between glucagon-like peptide 1 (GLP1) receptor agonists and the risk of ischemic optic neuropathy. The study includes data from randomized controlled trials on GLP1 receptor agonists approved for obesity and type 2 diabetes. Results show no significant difference in the risk of optic ischemic neuropathy between GLP1-RA therapy and control groups. The study suggests that while rare, the potential risk increase of optic neuropathy should be further investigated, especially for semaglutide. [Extracted from the article]

The win ratio method for analysing a composite clinical hierarchy of outcomes is growing in popularity especially in cardiovascular trials. This article gives a perspective on its use so far and the issues derived from that experience. Specifically, it focuses on the limitations of a conventional composite outcome; how does the win ratio work, what does it mean, and how to display its findings; guidance on choosing an appropriate clinical hierarchy of outcomes including clinical events, quantitative outcomes, and other options; the additional value of the win difference as a measure of absolute benefit: extension to stratified win ratio, subgroup analysis, matched win ratio, and covariate adjustment; determining trial size for a win ratio outcome; specific insights such as adaptive designs, use of repeat events, and use of margins and time averages for quantitative outcomes; a critique of potential misuses; availability of statistical software; and a statistical appendix on the methodological details. Throughout, each principle is illustrated by examples from specific cardiology trials. The article concludes with a set of recommendations for future use of the win ratio. [ABSTRACT FROM AUTHOR]

Background: Conformal proctectomy with sphincter preservation (CPSP) is designed to preserve the rectal wall as much as possible in very low rectal cancer patients. Evaluations of anal function and quality of life outcomes are lacking. Methods: This study included male patients with very low (≤ 5 cm from the anal verge) rectal adenocarcinoma between January 1, 2020, and January 1, 2022. A LARS score questionnaire survey and EORTC-QLQ-CR38 questionnaire survey were administered. Results: A total of 21 very low rectal cancer patients were enrolled in follow-up. The average age of the patients was 56.7 years, the tumors were 1.9 ± 0.6 cm in size, and the distance from the anal verge was 4.8 ± 0.5 cm. All patients were followed up, and the mean follow-up period was 2.7 ± 0.5 years. The LARS score increased significantly from 4.1 ± 2.8 before surgery to 19.1 ± 6.0 at the 1st year after surgery (P < 0.001) and then decreased to 13.1 ± 4.2 (P < 0.001) at the 2nd year. The quality of life of patients was also lower at the 1st year after surgery (61.1 ± 9.6 vs. 74.2 ± 11.2, P < 0.001) and was restored at the 2nd year after surgery (80.6 ± 11.9 vs. 74.2 ± 11.2, P = 0.029). During standard follow-up at the outpatient department, no rectal tumor relapse was confirmed in these patients, although 2 patients were found to have suspected recurrence of local lymph node metastasis. Conclusions: These results suggest that the CPSP technique preserves acceptable defecation function and is a safe and feasible option for male patients with very low rectal cancer. Clinical trial registration: https://www.chictr.org.cn/ , identifier ChiCTR2100052094. [ABSTRACT FROM AUTHOR]

Summary Primary immune thrombocytopenia (ITP) is an antiplatelet‐antibody‐mediated disorder with accelerated platelet clearance and decreased platelet production. Rozanolixizumab, a monoclonal IgG4 anti‐FcRn antibody, blocks IgG recycling and decreases IgG levels. We report efficacy and safety of rozanolixizumab in adults with persistent/chronic ITP in 24‐week phase 3 studies (TP0003; TP0006), and their 52‐week open‐label extension (OLE). Primary end‐point was durable clinically meaningful platelet response (DCMPR) of ≥50 × 109/L for 8/12 weeks during Weeks 13–25 in the double‐blind studies. Operational delays and evolving ITP treatment landscape led the sponsor to terminate these studies early; thus, only 21 and 12 (TP0003) and 20 and 10 (TP0006) patients were randomised to rozanolixizumab or placebo. Forty‐three patients enrolled in the OLE: 42 started on every 2‐week dosing; 21 later switched to weekly dosing. More rozanolixizumab‐treated than placebo‐treated patients achieved DCMPR: 4/21 versus 0 (TP0003) and 1/20 versus 0 (TP0006). Platelet increases to ≥50 × 109/L were observed on Day 8 in 52.4% (TP0003; 2/12 placebo) and 45.0% (TP0006; 1/10 placebo) of rozanolixizumab‐treated patients. OLE platelet increases were maintained while on weekly dosing. The most frequent treatment‐emergent adverse events overall were headache, pyrexia and nausea, as seen previously. Weekly dosing appears more efficacious than every 2‐week dosing. [ABSTRACT FROM AUTHOR]

Background: Chronic insomnia increases the risk of various health problems and mental illness. Existing research suggests promise for both transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in treating chronic insomnia individually. However, the combined effects of tDCS and rTMS on this condition remain unclear. This study aimed to verify the efficacy and safety of tDCS combined with rTMS for the treatment of adult patients with chronic insomnia. Methods: This was a randomised double-blind parallel-group controlled study. Overall, 157 participants with chronic insomnia were randomly assigned to one of three neurotherapy regimens: tDCS + rTMS, sham tDCS + rTMS, or tDCS + sham rTMS. All groups received 20 treatment sessions over 4 consecutive weeks. The primary outcome was the change in patients' sleep as assessed by the Pittsburgh Sleep Quality Index (PSQI) at 2 weeks, 4 weeks, and 3 months of follow-up. The secondary outcome was the assessment of different dimensions of depression and anxiety in patients through the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), as well as the occurrence of adverse events. Results: Throughout the intervention and after the 3-month follow-up, the tDCS + rTMS group had significantly reduced total PSQI scores compared with the other two groups [tDCS + rTMS, 9.21 vs. sham tDCS + rTMS, 10.03; difference − 1.10; 95% confidence interval (CI), − 1.82 to − 0.38; p = 0.003; tDCS + rTMS, 9.21 vs. tDCS + sham rTMS, 10.76; difference − 2.14; 95% CI, − 2.90 to − 1.38; p < 0.001; sham tDCS + rTMS, 10.03 vs. tDCS + sham rTMS, 10.76; difference − 1.04; 95% CI, − 1.82 to − 0.26; p = 0.010), indicating improved overall sleep quality. Total HAMD and insomnia factor scores were significantly lower in the tDCS + rTMS group than in the other two groups after treatment (p < 0.05). Notably, no adverse events or serious adverse reactions were observed during the study period. Conclusions: Combining tDCS with rTMS effectively relieved insomnia symptoms, achieving a significant therapeutic effect after 2-week of intervention, and demonstrating the persistence of treatment effects in later follow-up, emphasising the advantages of combination therapy in improving treatment stability and long-term benefits, reflecting the rapid and effective augmentation of combination therapy. This combined therapy may serve as a safe and effective treatment for adults with chronic insomnia. Trial registration: This study was registered as a clinical trial with the China Clinical Trial Registration Center (ChiCTR2100052681). [ABSTRACT FROM AUTHOR]

ABSTRACT Results from randomized control trials (RCTs) may not be representative when individuals refuse to be randomized or are excluded for having a preference for which treatment they receive. If trial designs do not allow for participant treatment preferences, trials can suffer in accrual, adherence, retention, and external validity of results. Thus, there is interest surrounding clinical trial designs that incorporate participant treatment preferences. We propose a Partially Randomized, Patient Preference, Sequential, Multiple Assignment, Randomized Trial (PRPP‐SMART) which combines a Partially Randomized, Patient Preference (PRPP) design with a Sequential, Multiple Assignment, Randomized Trial (SMART) design. This novel PRPP‐SMART design is a multi‐stage clinical trial design where, at each stage, participants either receive their preferred treatment, or if they do not have a preferred treatment, they are randomized. This paper focuses on the clinical trial design for PRPP‐SMARTs and the development of Bayesian and frequentist weighted and replicated regression models (WRRMs) to analyze data from such trials. We propose a two‐stage PRPP‐SMART with binary end of stage outcomes and estimate the embedded dynamic treatment regimes (DTRs). Our WRRMs use data from both randomized and non‐randomized participants for efficient estimation of the DTR effects. We compare our method to a more traditional PRPP analysis which only considers participants randomized to treatment. Our Bayesian and frequentist methods produce more efficient DTR estimates with negligible bias despite the inclusion of non‐randomized participants in the analysis. The proposed PRPP‐SMART design and analytic method is a promising approach to incorporate participant treatment preferences into clinical trial design. [ABSTRACT FROM AUTHOR]

Simple Summary: The impacts of biological sex on cancer treatment outcomes are understudied, but differences in immune-related adverse events and oncologic outcomes have been associated with biological sex for patients with melanoma receiving checkpoint blockade therapy. In a recent trial, we also identified a difference in clinical outcomes between biological female and male patients with metastatic melanoma who received an experimental melanoma vaccine. Here, we examine whether treatment-related adverse events with the vaccine differ by biological sex. Background/Objective: Biological females experience more autoimmune disease than males and more treatment-related adverse events (TRAEs) after immune checkpoint blockade therapy. However, little is known about sex-related differences in TRAEs after cancer vaccines. Methods: The Mel44 clinical trial (NCT00118274) enrolled 167 eligible patients with high-risk melanoma to treatment with either of two melanoma multipeptide vaccines. We hypothesized that females would experience higher rates and grades of TRAEs. TRAE rates and grades were compared between sexes, with adjustment for multiple comparisons, and with mixed-effects models. Results: Multiple sex-related differences in TRAE rate and grade were observed in unadjusted comparisons, but only hyperglycemia and hypopigmentation were significantly higher-grade by sex after correcting for multiple comparisons: they were increased in males. In mixed-effect models, vaccination strategy, but not patient sex, was independently associated with TRAE rates and grades. Conclusions: These data do not support our hypothesis that TRAEs would be increased in females. Vaccine safety was supported for both males and females. [ABSTRACT FROM AUTHOR]

Simple Summary: Cellular immunotherapy represents a rapidly advancing field in cancer treatment, particularly for multiple myeloma (MM). Notably, two approved chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) have demonstrated substantial clinical efficacy, offering renewed hope for patients with this hitherto incurable disease. However, achieving sustained remission across a wider patient population remains challenging. This review examines the landscape of current clinical trials in MM cellular immunotherapy, highlighting key challenges and opportunities. It also explores recent innovations aimed at overcoming existing barriers, including broadening the spectrum of used cell types, optimizing manufacturing processes and targeting novel antigens. Together, these strategies could improve clinical outcomes, paving the way to push immunotherapy to earlier lines of MM treatment. Multiple myeloma (MM) treatment remains challenging due to its relapsed/refractory disease course as well as intra- and inter-patient heterogeneity. Cellular immunotherapies, especially chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA), mark a major breakthrough, achieving long-lasting remissions and instilling hope for a potential cure. While ongoing clinical trials are increasingly driving approved cellular products towards earlier lines of therapy, novel targets as well as advanced approaches employing natural killer (NK) cells or dendritic cell (DC) vaccines are currently under investigation. Treatment resistance, driven by tumor-intrinsic factors such as antigen escape and the intricate dynamics of the tumor microenvironment (TME), along with emerging side effects such as movement and neurocognitive treatment-emergent adverse events (MNTs), are the major limitations of approved cellular therapies. To improve efficacy and overcome resistance, cutting-edge research is exploring strategies to target the microenvironment as well as synergistic combinatorial approaches. Recent advances in CAR-T cell production involve shortened manufacturing protocols and "off-the-shelf" CAR-T cells, aiming at decreasing socioeconomic barriers and thereby increasing patient access to this potential lifesaving therapy. In this review, we provide an extensive overview of the evolving field of cellular therapies for MM, underlining the potential to achieve long-lasting responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal cancer type. Despite recent progress in our understanding of DLBCL biology, the translation of this knowledge into clinical initiatives has lagged, and the first-line treatment for this tumor type, the immunochemotherapy R-CHOP, has been the same for more than two decades. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as a critical modulator of B-cell receptor (BCR) signals and PI3K activity in DLBCL. Pre-clinically and clinically, we confirmed that PDE4 inhibition suppressed PI3K activity, and downstream to it, angiogenesis in the lymphoma microenvironment. Here, we report on a phase 1 clinical trial that combines the PDE4 inhibitor roflumilast with R-CHOP in treatment-naïve DLBCL patients. We show that this combination is safe, active, and inhibits PI3K activity and VEGF-A levels. Further, we preliminarily identified the genetic subtypes of DLBCL that may be especially vulnerable to this new drug combination. Background: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. The standard-of-care immunochemotherapy, R-CHOP, cures only about 60% of DLBCL patients. Improving this cure rate will likely require the effective translation of basic biology knowledge into clinical activities. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as an important modulator of lymphomagenic processes. We also showed that the FDA-approved PDE4 inhibitor roflumilast can suppress B-cell receptor (BCR) signals, phosphoinositide 3-kinase (PI3K) activity and angiogenesis. These data suggested that combining roflumilast with R-CHOP may be beneficial in DLBCL. Methods: We conducted a single-center, single-arm, open-label, phase 1 study of roflumilast in combination with the standard of care, R-CHOP (Ro+R-CHOP), in pathologically proven, treatment-naïve, high-risk DLBCL patients. Results: Ro+R-CHOP was safe, and at a median follow-up time of 44 months, 70% of patients were alive and disease free (median OS not reached, PFS 44% (95% CI, 21–92). In this pilot series, we found that the addition of roflumilast suppressed PI3K activity in peripheral blood mononuclear cells, and VEGF-A secretion in the urine. We also encountered preliminary evidence to suggest that the Ro+R-CHOP combination may be particularly beneficial to patients diagnosed with high-risk genetic subtypes of DLBCL, namely MCD and A53. Conclusions: These initial findings suggest that roflumilast may be an alternative agent able to inhibit BCR/PI3K activity and angiogenesis in DLBCL, and that the testing of Ro+R-CHOP in a larger series of genetically characterized tumors is warranted. This study was registered at ClinicalTrials.gov, number NCT03458546. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the progressive loss of dopaminergic (DAnergic) neurons in the substantia nigra and decreased dopamine (DA) levels, which lead to both motor and non-motor symptoms. Conventional PD treatments aim to alleviate symptoms, but do not delay disease progression. PD gene therapy offers a promising approach to improving current treatments, with the potential to alleviate significant PD symptoms and cause fewer adverse effects than conventional therapies. DA replacement approaches and DA enzyme expression do not slow disease progression. However, DA replacement gene therapies, such as adeno-associated virus (AAV)–glutamic acid decarboxylase (GAD) and L-amino acid decarboxylase (AADC) gene therapies, which increase DA transmitter levels, have been demonstrated to be safe and efficient in early-phase clinical trials. Disease-modifying strategies, which aim to slow disease progression, appear to be potent. These include therapies targeting downstream pathways, neurotrophic factors, and midbrain DAnergic neuronal factors, all of which have shown potential in preclinical and clinical trials. These approaches focus on maintaining the integrity of DAnergic neurons, not just targeting the DA transmitter level itself. In particular, critical midbrain developmental and maintenance factors, such as Nurr1 and Foxa2, can interact synergistically with neighboring glia, in a paracrine mode of action, to protect DAnergic neurons against various toxic factors. Similar outcomes could be achieved by targeting both DAnergic neurons and glial cells with other candidate gene therapies, but in-depth research is needed. Neurotrophic factors, such as neurturin, the glial-cell-line-derived neurotrophic factor (GDNF), the brain-derived neurotrophic factor (BDNF), and the vascular endothelial growth factor (VEGF), are also being investigated for their potential to support DAnergic neuron survival. Additionally, gene therapies targeting key downstream pathways, such as the autophagy–lysosome pathway, mitochondrial function, and endoplasmic reticulum (ER) stress, offer promising avenues. Gene editing and delivery techniques continue to evolve, presenting new opportunities to develop effective gene therapies for PD. [ABSTRACT FROM AUTHOR]

The most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed. [ABSTRACT FROM AUTHOR]

Background: Trigeminal neuralgia (TN) is a disease that causes severe pain that can seriously affect the quality of life. This study aimed to compare the effectiveness of two different low-level laser therapies (LLLT) as alternatives to medical treatment to reduce pain and improve the quality of life in patients with TN. Methods: A total of 45 patients were randomly divided into 3 groups. In the first group, a new-generation diode laser (GRR laser) was applied at predetermined points in the trigeminal nerve line. In the second group, a low-level neodymium-doped yttrium aluminum garnet (Nd:YAG) laser was applied along the affected nerve line. The placebo group received the same protocol with a Nd:YAG laser without the device switched on. The scores were recorded pre- and post-treatment using the Brief Pain Inventory-Facial (BPI-facial) scale. Results: A statistically significant difference was found between the pre- and post-treatment values of all four variables in the GRR laser, Nd:YAG laser, and placebo groups. When the post-treatment values were compared, statistically significant differences were found between the groups in pain frequency, pain intensity, and interference in facial-specific activities, but no differences were found in general activities. Conclusions: Both LLLTs can be considered alternative treatment modalities for TN, but the GRR laser treatment was more effective than the Nd:YAG laser treatment in reducing pain and improving the quality of life in patients with TN. [ABSTRACT FROM AUTHOR]