Lumbar spinal endoscopy has long been mischaracterized by payers as investigational. Such claims conflict with decades of refinement, randomized trials, and policy precedent. We reviewed the historical evolution, prospective trials, meta-analyses, and policy milestones of transforaminal endoscopic lumbar discectomy (TELD), with emphasis on coding, reimbursement, and comparative effectiveness. Evidence demonstrates that TELD, performed with direct visualization, provides durable outcomes with complication, reoperation, and conversion rates equal or superior to open decompression. Meta-analyses confirm comparable effect sizes to microsurgery, while selective integration with motion-preserving adjuncts extends durability in complex cases. TELD has matured into a safe and durable technology. It is not limited to lateral recess disease but is capable of effectively addressing central stenosis, including select cases with low-grade spondylolisthesis. TELD's trajectory mirrors that of other coverage-adopted technologies, and its future impact depends on structured training to ensure reproducibility and broad patient access. This work establishes that transforaminal endoscopy, performed with direct visualization, is not limited to lateral recess disease. TELD can safely and effectively address central stenosis, including selected cases with low-grade spondylolisthesis. Contemporary evidence demonstrates durable outcomes comparable to open decompression. The next step is structured training to ensure reproducibility across the broader surgical community, thereby securing patient access to this established and codified technique within recognized coverage frameworks.
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are primarily driven by activating mutations in KIT or PDGFRA. Although tyrosine kinase inhibitors (TKIs), particularly imatinib, have substantially improved outcomes, most patients with advanced disease eventually develop resistance, resulting in disease progression. Methods: We performed a narrative review with scoping approach of interventional clinical trials registered on ClinicalTrials.gov between January 2020 and July 2025 to characterize the contemporary investigational therapeutic landscape in GIST. Eligible studies included clinical trials evaluating novel agents, combinations, or alternative strategies beyond current regulatory approvals. Trial characteristics, therapeutic classes, endpoints, enrollment, and funding sources were analyzed. Results: A total of 27 ongoing trials were identified. Most studies were phase I/II and focused on metastatic or unresectable disease, predominantly in the second-line or later settings. TKIs remained the dominant therapeutic class, included in over 70% of trials, either as monotherapy or in combination. Emerging strategies comprised antibody-drug conjugates, immune checkpoint inhibitors, HIF inhibitors, FGFR inhibitors, and epigenetic modulators. Only four phase III trials were identified, reflecting the difficulty of conducting large, randomized studies in GIST. No trial used overall survival or quality of life as a primary endpoint. Conclusions: The current investigational landscape in GIST is largely focused on overcoming TKI resistance in advanced disease. Molecular stratification and personalized approaches dominate ongoing research, but evidence generation remains limited by small sample sizes and slow recruitment. Future trials integrating innovative therapeutic platforms and patient-centered outcomes are essential to improve long-term disease control and quality of life.
Premedications used to prevent paclitaxel-associated infusion hypersensitivity reactions (iHSRs) can cause undesirable toxicities, such as sleep disturbance and weight gain. Although phase II data suggest that discontinuing premedications after paclitaxel-associated iHSRs may be safe and feasible in select patients without prior iHSRs, no prospective randomized trials have evaluated this approach. This randomized clinical trial enrolled patients with breast cancer receiving paclitaxel chemotherapy. Those who experienced no iHSRs with the first 2 doses of paclitaxel were randomized to either continue standard premedications (control arm) or to discontinue all premedications (investigational arm). Both arms were followed longitudinally for any subsequent iHSRs requiring parenteral rescue medications. Additionally, changes in weight, drug-related side effects, and quality of life were assessed. A total of 98 patients were randomized; 89 were evaluable (46 in the control arm and 43 in the investigational arm). Only 1 (2.3%) patient in the investigational arm experienced an iHSR, which resolved with rescue medications. No iHSRs occurred in the control arm. The estimated proportion of subjects who experienced a hypersensitivity reaction (exact binomial 95% CI) was 2.3% (95% CI, 0.1%-12.3%) in the investigational arm and 0.0% (95% CI, 0.0%-7.7%) in the control arm. Patients in the investigational arm reported significantly less sleep disruption (0.5 vs 1.7; P=.002) and unwanted appetite increases (1.0 vs 2.5; P=.0018). Discontinuation of premedications after 2 uneventful paclitaxel doses was not associated with a high rate of subsequent iHSRs and resulted in fewer steroid-related side effects. This strategy may reduce unnecessary medication exposure, improve patient experience, and streamline clinical workflows. For patients who do not experience iHSRs during the first 2 paclitaxel treatments, discontinuing premedications appears safe and may improve tolerability.
Candidozyma (Candida) auris has emerged as a global health threat because of its ability to persist on skin and environmental surfaces and its frequent resistance to multiple antifungal agents. We describe a rare but clinically significant case of C. auris-associated central nervous system (CNS) infection in a postoperative neurosurgical patient. A 60-year-old woman developed a postoperative cerebrospinal fluid (CSF) leak following intradural lumbar tumor resection and was readmitted with headaches, neck pain, and nausea. CSF and wound cultures grew C. auris, while blood cultures remained negative, suggesting localized CNS involvement. Combination antifungal therapy with liposomal amphotericin B, flucytosine, and micafungin, later supplemented with posaconazole, was initiated but was complicated by significant toxicities requiring dose adjustments and stepwise discontinuation. Antifungal susceptibility testing demonstrated reduced susceptibility to amphotericin B, and C. auris was repeatedly isolated from CSF despite therapy. Given persistent recovery of the organism, the clinical team initiated the US Food and Drug Administration Single Patient IND process to obtain fosmanogepix, an investigational antifungal agent, although the request was ultimately discontinued as the patient clinically stabilized. She was discharged on long-term oral voriconazole for antifungal suppression because of persistent CSF isolation of C. auris, multidrug resistance, and limited CNS penetration of previously administered antifungals. This case highlights diagnostic uncertainty, therapeutic challenges, and antifungal decision-making complexities following isolation of C. auris from CSF.
Alzheimer's disease (AD) is an irreversible neurodegenerative syndrome that affects memory, cognitive abilities and behaviour. Detecting AD in the early stage is crucial to improve the quality of life. However, traditional diagnostic approaches and manual analysis of neuroimaging data are slow, subjective and lead to human mistakes. Existing machine learning techniques often have difficulty in identifying complex patterns in high-dimensional biomedical data. These drawbacks emphasize the necessity for a more efficient and automated diagnostic system. This study introduced a new deep learning based hybrid framework for classifying and predict progression of AD. The method comprises three main steps: data acquisition, feature extraction and classification. Initially, EEG signals are collected from the CAU-EEG dataset. Then, features such as time domain features, frequency domain features and time frequency domain features are extracted. Finally, classification is performed by dilated convolutions attention based long short term memory (DC-ALSTM). Investigational results show that the proposed model outperforms existing baseline methods. DC-ALSTM achieved a classification 99.26% accuracy, 99.21% precision, recall at 99.23% and 99.22% F1-score, which indicates outstanding diagnostic capability.
Early detection of Alzheimer's disease (AD) and related dementias is critical for timely intervention and disease management. Mild cognitive impairment represents a transitional state between normal aging and dementia, but diagnosis remains challenging. Biomarkers offer promising tools for identifying early neurodegenerative changes, potentially years before clinical symptoms appear. This systematic review examined studies published between 2012 and 2025 from PubMed and Ovid MEDLINE, focusing on the role of biomarkers in the early diagnosis of AD. Search terms included "biomarkers," "Alzheimer's disease," "early diagnosis," and "early detection." Included studies were systematic reviews that had been peer-reviewed and emphasized early-stage diagnostic utility. Observational studies, meta-analyses, and systematic reviews were included and screened using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Biomarkers identified included cerebrospinal fluid (CSF) markers (amyloid beta, total tau, phosphorylated tau), genetic markers (ApoE4, presenilin mutations), and neuroimaging techniques (MRI, PET, fNIRS). Novel biomarkers such as miRNAs and biosensors, while still largely investigational, also show emerging potential. Phosphorylated tau, particularly p-tau 217, and the amyloid beta 42:40 ratio demonstrate high sensitivity in some studies for early AD pathology. In certain experimental studies, genetic and imaging biomarkers can detect risk or structural changes well before symptom onset. While biomarkers cannot currently replace clinical diagnosis, they significantly enhance early detection and risk stratification. Further research is needed to establish standardized thresholds and to evaluate the ethical implications of widespread biomarker testing. Non-invasive, cost-effective tools such as CSF (minimally invasive) and plasma-based (non-invasive) assays and biosensors represent the future of early dementia diagnostics.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an exceptionally high global prevalence that is projected to continue rising in the near future. MASLD is strongly associated with a spectrum of cardiometabolic risk factors, and may itself, in turn, contribute to cardiovascular morbidity and mortality. This interconnection warrants the development of integrated treatment strategies targeting shared pathophysiological processes and addressing both hepatic, metabolic, and cardiovascular outcomes. In this work, we review the modern MASLD clinical development pipeline and highlight the most prominent drug candidates with known or purported cardiovascular benefits, discussing mechanistic links and supporting evidence ranging from preclinical experiments to real-world data. Although the drug development pipeline is extensive and diverse, evidence supporting cardiovascular benefits for most candidate molecules remains limited. Both of the FDA-approved therapies, resmetirom and semaglutide, have been found to significantly reduce the risk of major adverse cardiovascular events as well as cardiovascular and all-cause mortality in patients with MASH. In addition, significant improvements were observed in patients with heart failure with preserved ejection fraction treated with semaglutide, highlighting incretin mimetics as a promising class for managing cardiovascular disease concomitant with MASLD/MASH. Other investigational compounds, targeting the farnesoid X receptor, peroxisome proliferator-activated receptors, de novo lipogenesis enzymes, and fibroblast growth factors, have demonstrated improvements in blood lipid spectrum and glycemic control; however, their clinical effectiveness in patients at cardiovascular risk has yet to be established.
Meralgia paresthetica is a sensory mononeuropathy of the lateral femoral cutaneous nerve that remains frequently underdiagnosed despite its characteristic clinical presentation. Burning pain, paresthesia, and numbness over the anterolateral thigh may mimic hip, lumbar, or pelvic disorders, contributing to diagnostic delay. Imaging has gained increasing relevance in the evaluation of meralgia paresthetica, both for confirming neuropathy and for identifying contributory anatomical factors. High-resolution ultrasound enables direct visualization of the lateral femoral cutaneous nerve, characterization of its anatomical variants, and detection of focal changes at typical entrapment sites. Quantitative ultrasound parameters, particularly cross-sectional area, provide additional objective information and may help distinguish symptomatic nerves from normal variants, while elastography offers preliminary insight into chronic stiffness alterations. Magnetic resonance imaging complements ultrasound by allowing assessment of deeper nerve segments and by differentiating intrinsic signal abnormalities from extrinsic compression. Advanced techniques such as diffusion tensor imaging, although still investigational for this small sensory nerve, may eventually provide microstructural information beyond the capabilities of conventional sequences. This review summarizes current knowledge on the anatomy of the lateral femoral cutaneous nerve, outlines qualitative and quantitative ultrasound approaches, and discusses how multimodal imaging can support a more comprehensive and confident evaluation of patients with meralgia paresthetica.
Near-infrared fluorescence (NIRF) can deliver high-contrast, video-rate, non-contact imaging of tumor-targeted contrast agents with the potential to guide surgeries excising solid tumors. However, it has been met with skepticism for wide-margin excision due to sensitivity and resolution limitations at depths larger than ~ 5 mm in tissue. To address this limitation, fast-sweep photoacoustic-ultrasound (PAUS) imaging is proposed to complement NIRF. In an exploratory in vitro feasibility study using dark-red bovine muscle tissue, we observed that PAUS scanning can identify tozuleristide, a clinical stage investigational imaging agent, at a concentration of 20 µM from the background at depths estimated to be of up to ~ 34 mm, highly extending the capabilities of NIRF alone. The capability of spectroscopic PAUS imaging was tested by direct injection of 20 µM tozuleristide into bovine muscle tissue at a depth of ~ 8 mm. Experimental results demonstrate that multi-point laser fluence compensation and strong clutter suppression enabled by the unique capabilities of the fast-sweep approach greatly improve spectroscopic accuracy and the PA detection limit and strongly reduce image artifacts. Thus, the complementary NIRF-PAUS approach can be promising for comprehensive pre- (with PA) and intra- (with NIRF) operative solid tumor detection and wide-margin excision in optically guided solid tumor surgery.
(Z)-endoxifen is the tamoxifen metabolite that possesses the highest affinity to the estrogen receptor and is evolving as an alternative to tamoxifen. Mammographic breast density (MBD) change has been shown to be a proxy for tamoxifen therapy response. The objective was to measure the effect of 2 different doses of (Z)-endoxifen on MBD, safety, and side effects in healthy women. Healthy premenopausal women included in the national Swedish screening program in Stockholm were invited to KARISMA Endoxifen, a proof of principle, dose determining, double-blinded, randomized, placebo-controlled trial. Women were randomly assigned to placebo or 1 or 2 mg of (Z)-endoxifen daily for 6 months. In all, 240 women were randomly assigned. There was a significant relative change in MBD in both (Z)-endoxifen arms compared to placebo: -19.3% (95% confidence interval [CI] = -6.15% to -32.4%) in the 1 mg arm and -26.5% (95% CI = -14.1% to -38.9%) in the 2 mg arm. The number of participants discontinuing because of adverse events related to the investigational medicinal product was 4 (placebo), 5 (1 mg), and 11 (2 mg), respectively. Participants on 2 mg of (Z)-endoxifen reported significantly higher scores of vasomotor symptoms, compared with placebo. No clinically significant changes in hematological safety tests or vital signs were noted. Both 1 and 2 mg of (Z)-endoxifen significantly reduced MBD to a degree comparable to the established 20 mg dose of tamoxifen. The 1 mg dosage of (Z)-endoxifen indicated superior tolerability. Future studies are necessary to confirm impact on breast cancer incidence. ClinicalTrials.gov ID: NCT05068388.
Background/Objectives: Platelet-rich plasma (PRP) is an autologous blood-derived biologic enriched in platelets and bioactive mediators. In urology and sexual medicine, PRP has been promoted for erectile dysfunction (ED) and a growing range of urogenital disorders on the premise that it may support angiogenesis, neuroregeneration, immune modulation, and tissue remodeling. However, clinical uptake has outpaced high-quality evidence, while heterogeneity in PRP preparation, characterization, and delivery limits interpretability and reproducibility. This structured narrative review aims to critically integrate mechanistic, preclinical, and clinical evidence regarding PRP use in ED, Peyronie's disease (PD), stress urinary incontinence (SUI), interstitial cystitis/bladder pain syndrome (IC/BPS), and selected emerging indications. We further aim to identify sources of heterogeneity and propose an actionable minimum reporting framework (PRP-Uro Checklist) to guide future research. Methods: A structured search of PubMed/MEDLINE was conducted for studies published between 2021 and 2025. The relevant literature on PRP use in ED, PD, SUI, IC/BPS, and related indications was included for critical narrative synthesis. Emphasis was placed on PRP classification and preparation variables, outcome measure validity, and sources of heterogeneity across studies. Results: Mechanistic and preclinical evidence supports PRP's potential to modulate nerve repair, angiogenesis, extracellular matrix remodeling, and immune polarization through a complex secretome of growth factors, cytokines, and extracellular vesicles (EVs). Clinical evidence suggests that intracavernosal PRP may improve erectile function in selected populations, but effect size, durability, and superiority over placebo remain uncertain due to small trials, substantial placebo effects, short follow-up, and incomplete biologic characterization. Evidence for PRP in PD, SUI, and IC/BPS remains preliminary and is derived largely from small cohorts, proof-of-concept studies, or uncontrolled designs, although early findings suggest potential symptom benefit and acceptable short-term tolerability. Across indications, inconsistent PRP reporting, particularly the absence of absolute platelet dose, leukocyte quantification, activation method, and standardized treatment protocols, represents a major barrier to reproducibility and evidence synthesis. Conclusions: PRP is biologically plausible and appears broadly safe, but its role in urology and sexual medicine remains investigational and is not yet supported by guideline-level evidence. To enhance reproducibility and interpretation, we propose a Minimum PRP Reporting Checklist for Urology and Sexual Medicine Trials (PRP-Uro Checklist). Future progress requires rigorous standardized reporting, indication-specific biologic characterization, rigorously designed sham-controlled trials, clinically meaningful endpoints, and longer-term follow-up.
To quantify bladder wall relaxation times in men without and with lower urinary tract symptoms (LUTS) using three-dimensional (3D) magnetic resonance fingerprinting (MRF). Following informed consent, 51 men (mean age 68.2 years, range 46-80) on active surveillance for prostate cancer underwent multiparametric MRI that included an investigational 3D MRF sequence. Anterior bladder wall T1 and T2 relaxation times were measured from the quantitative maps. Anterior bladder wall thickness (BWT) was measured and prostate and transition zone (TZ) volumes were estimated, from the conventional T2w images. Body mass index (BMI), LUTS scores (AUA-SI), risk factors for metabolic syndrome, history of diabetes (DM), and medications prescribed for LUTS were documented from the electronic medical record. The Kruskal-Wallis rank sum test, Wilcoxon rank sum exact test, and Fisher's exact test were used to assess the associations between clinical variables, categorical imaging data, and mean T1 and T2 relaxation times. Native bladder wall T1 relaxation times were longer in men with higher AUA-SI scores [AUA-SI 0-7: 1,496 ms vs. AUA-SI 8-20: 1,787 ms vs. AUA-SI 21-35: 2,063 ms, p = 0.03] while native bladder wall T2 relaxation times were similar [AUA-SI 0-7: 67 ms vs. AUA-SI 8-20: 78 ms vs. AUA-SI 21-35: 122 ms, p = 0.3]. Native bladder wall T1 relaxation times were shorter in diabetic men compared to non-diabetic men (1239 ms vs. 1633 ms, p < 0.001), while T2 relaxation times were similar (86 ms vs. 62 ms, p = 0.4). Prostate and TZ volume, and BWT were similar in men without and with LUTS and DM. 3D MRF of the bladder is feasible, provides in-vivo tissue characterization of the bladder wall in men with LUTS.
Preserving a very small proximal gastric remnant (SRS), often referred to as Laparoscopic Near-Total Gastrectomy (LNTG), is an emerging function-preserving strategy for upper-third gastric cancer. This systematic review and meta-analysis evaluates its evolution, clinical outcomes, and oncological safety. Following PRISMA guidelines (PROSPERO: CRD420251062548), we systematically searched PubMed, Embase, MEDLINE, and SCI databases up to May 2025 for observational studies on LsTG with SRS. Methodological quality was assessed using the Newcastle-Ottawa Scale. Key short-term outcomes were quantitatively synthesized using a random-effects model. Ten studies were included for qualitative review. Pooled analysis of non-overlapping cohorts revealed that LsTG with SRS was associated with significantly shorter operative time (Weighted Mean Difference [WMD] = -60.53 min), reduced intraoperative blood loss (WMD = -37.80 ml), and shorter postoperative hospital stay (WMD = -2.53 days) compared to conventional gastrectomies. Qualitative synthesis indicated favorable nutritional recovery and comparable short-term survival, largely attributed to fundus preservation. LsTG with SRS is a safe, feasible procedure offering significant short-term surgical advantages and nutritional benefits. While promising, careful patient selection is paramount; current evidence supports this approach primarily for non-infiltrative, early-stage gastric cancers, while its use in diffuse-type or signet ring cell histology remains investigational and requires extreme caution. Future research must prioritize standardizing the SRS definition (e.g., 2-3 cm stump) and validating long-term oncological safety through prospective trials.
Post-kidney transplantation hypertension is common and is frequently driven by calcineurin inhibitor (CNI)-mediated sodium retention and vasoconstriction, producing a salt-sensitive phenotype in which sodium-chloride cotransporter (NCC) inhibition remains the mechanistically aligned cornerstone of therapy. This opinion piece examines aldosterone synthase inhibitors (ASIs) as an emerging drug class that may have adjunctive relevance in selected resistant phenotypes after kidney transplantation. We summarize the class rationale, distinguish older less selective compounds from newer CYP11B2-selective agents, and position baxdrostat within the broader ASI landscape alongside lorundrostat, vicadrostat, and earlier-stage dexfadrostat data. In non-transplant populations, baxdrostat and lorundrostat have lowered blood pressure in uncontrolled or resistant hypertension, whereas vicadrostat has shown cardiorenal promise in chronic kidney disease, including combination development with empagliflozin. However, no ASI has been studied in kidney transplant recipients. This gap is especially important because transplant recipients have reduced nephron reserve, frequent CNI exposure, narrow potassium margins, and a hypertensive phenotype often dominated by NCC activation rather than uniform aldosterone excess. Accordingly, ASIs should be viewed in transplantation as hypothesis-generating investigational agents rather than therapeutic recommendations. Any transplant-specific trial should incorporate rigorous hyperkalemia monitoring, comparator arms that reflect optimized NCC-directed therapy, and formal assessment of drug-drug interactions with immunosuppressants.
Targeted radioligand therapy (TRT) is an emerging theranostic modality in oncology. While well established in neuroendocrine and prostate cancers, its role in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) remains investigational. This systematic review summarizes current evidence evaluating TRT in lung cancer. A Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-guided systematic review of PubMed, Embase, and Scopus (2000-November 2025) was conducted. Original studies evaluating TRT in SCLC or NSCLC were included. Primary outcomes were tumor response, disease-control rate, and treatment-related toxicity. Secondary outcomes included progression-free survival, overall survival, and dosimetry. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool. From 2,453 records, 15 studies were included, reporting 358 lung cancer patients, of whom 105 received TRT. Disease-control rates reached up to 78% in mixed NSCLC/SCLC cohorts. In SCLC, somatostatin receptor-targeted peptide receptor radionuclide therapy demonstrated heterogeneous disease control (0-50%), with [177Lu]Lu-labeled agents showing more favorable outcomes than [90Y]Y-based therapy. The most favorable outcomes were a median progression-free survival of 11.9 months and an overall survival of 16 months in responders. In NSCLC, fibroblast activation protein (FAP)-targeted agents such as [177Lu]Lu-FAP-2286 demonstrated partial metabolic responses, including a 44.4% response rate and 78% disease control in a mixed cohort. Severe toxicities were infrequent. TRT is a promising but experimental option for advanced lung cancer. Early efficacy signals exist for strong somatostatin receptor (SSTR)-targeted therapy in SCLC and FAP-targeted therapy in NSCLC, but evidence remains limited. Prospective trials with standardized protocols and dosimetry are needed to define TRT's role in lung cancer treatment.
Antimicrobial resistance (AMR) is an urgent global health threat. Timely and complete antimicrobial agent clinical trial results reporting is essential to evaluate the safety and efficacy of investigational therapies. The Food and Drug Administration Amendments Act (FDAAA) of 2007 mandated results reporting to ClinicalTrials.gov. After nearly ten years of underreporting, the U.S. Department of Health and Human Services issued the Final Rule, requiring a designated responsible party to submit results to ClinicalTrials.gov. The Final Rule clarified that trials meeting "applicable clinical trial" (ACT) criteria must adhere to the federal reporting requirements. ACTs and probable ACTs (pACTs) are interventional studies regulated by the FDA with at least one site based in the United States. However, pACTs were initiated prior to January 2017, thus the Final Rule requirements do not apply to these trials. This study investigates the effectiveness of the Final Rule by analyzing compliance and timeliness of results reporting of ACTs and pACTs for antimicrobial agents. We extracted data from ClinicalTrials.gov for trials involving antimicrobial agents with primary completion dates between May 1, 2013, and May 1, 2023. We analyzed the time from primary completion to results reporting and estimated the hazard ratio to compare timeliness between ACTs and pACTs. Additionally, we assessed delays in reporting across different study types and funding sources. Our search resulted in 2629 NCT records. After exclusion of ineligible trials, we included 2525 trials. We found 1769 pACTs (70.1%; 95% CI, 68.2%-71.8%) and 756 ACTs (29.9%; 95% CI, 28.2%-31.8%). Among the 2525 eligible trials, 2288 trials (90.6%; 95% CI, 89.5%-91.7%) were reported on ClinicalTrials.gov and 74 out of the 237 (31.2%) missing records were found in journals. Overall, 79.4% (95% CI, 77.7%-81.0%) of trials were reported late (71.3% of ACTs vs 82.6% of pACTs). ACTs were more likely to report results earlier than pACTs, with a hazard ratio of 1.3 (95% CI, 1.2-1.4). ACTs demonstrated greater reporting compliance and shorter delays in the reporting of overdue results. While this analysis provides initial insights, limitations related to timeline and sample scope suggest that broader investigations are needed to fully evaluate the impact of the Final Rule.
Parkinsonian disorders, including Parkinson's disease, Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy, are progressive neurodegenerative conditions with no treatment options to slow disease progression. This systematic review provides an overview of evidence of disease-modifying therapies that have been evaluated in clinical studies across these disorders, based on a comprehensive literature search up to May 2025. Eligible studies included clinical trials investigating pharmacological interventions aimed at slowing disease progression. Most clinical development has focused on Parkinson's disease, with limited progress in other Parkinsonian disorders. Therapies targeting alpha-synuclein, such as monoclonal antibodies and small molecules, have shown target engagement but limited clinical efficacy. Glucocerebrosidase-enhancing agents, particularly ambroxol, demonstrated promising biomarker and clinical signals in early-phase trials. Glucagon-like peptide-1 receptor agonists and kinase inhibitors have yielded mixed results, with some agents progressing to phase 3 trials. Neurotrophic factors, cell survival and neuroprotective therapies, stem cell therapies, and anti-inflammatory agents remain largely investigational, with limited evidence of efficacy. Repurposed drugs, including memantine and riluzole, have shown preliminary signals of benefit, though confirmatory trials are lacking. Despite substantial research efforts, no disease-modifying therapy has been approved for any Parkinsonian disorder. The heterogeneity of disease mechanisms and the limitations of current clinical endpoints, such as the Unified Parkinson's Disease Rating Scale, underscore the need for biomarker-driven approaches and stratified trial designs. Future success will likely depend on improved patient selection, mechanistic targeting, and the integration of fluid and imaging biomarkers to demonstrate disease modification.
Cone beam computed tomography (CBCT) provides morphological details of the dental hard tissues and bone. However, the relationship between object density and CBCT grey values is unreliable and limits application of CBCT for quantitative evaluation of bone density. This single center, open-label clinical trial investigated the validity of novel dual-energy CBCT device (DE-CBCT) to assess jaw bone density. The study analyses comprised 24 subjects who were examined with DE-CBCT and multidetector CT (MDCT)-an established standard for bone density assessment. MDCT and DE-CBCT scans of each subject were analyzed in the vendor's software application for assessment of bone density at 10 discrete sites in the jaws. Two independent assessments were made. The mean bone density assessed by DE-CBCT and MDCT were not significantly different (0.46 ± 0.36 g/cc versus 0.48 ± 0.31 g/cc, respectively). Bone density assessments from DE-CBCT correlated well with MDCT assessments (Pearson's correlation r = 0.92, p < 0.0001). Bland-Altman analyses demonstrated higher agreement between the two techniques at densities great than 0.6 g/cm3. However, at lower densities the limits of agreement were broad. DE-CBCT is a promising approach to assess bone density in the jaw bones. The investigational device performs best in well-trabeculated and cortical bone, with reduced reliability in sparsely trabeculated regions. Future refinements in this technology will be needed to expand the range of reliability for reliable assessment of bone density. The study is registered in clinical trials.gov, NCT04686084.
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent difficulties in social communication together with restricted, repetitive patterns of behaviour and sensory-processing differences. Growing evidence suggests that ASD is shaped by complex interactions among genetic susceptibility, epigenetic regulation, immune signalling, maternal and early-life exposures and gut microbiome-related pathways. However, many of these associations remain biologically plausible rather than definitively causal, particularly when findings from experimental models are considered alongside human clinical data. This narrative review examines recent advances across these interconnected domains, with particular emphasis on maternal immune activation, prenatal nutrition, gut microbial imbalance, epigenetic and molecular mechanisms, emerging therapeutic directions and developing biomarker platforms. We also discuss current diagnostic limitations and evaluate the potential of salivary microRNAs, perinatal metabolic and epigenetic markers, oxidative stress-related measures and microbiome-based profiles as early and biologically informative indicators of ASD risk. Special attention is given to the need for biologically informed stratification, although current subgrouping frameworks remain preliminary and not yet sufficiently validated for routine clinical use. Likewise, candidate biomarkers remain investigational and require stronger evidence for reproducibility, external validation, longitudinal performance and clinically meaningful sensitivity and specificity before they can be considered for screening or precision-guided care. Emerging therapeutic strategies targeting immune, epigenetic and microbiome-related pathways are also reviewed, but most remain preclinical or early-stage and face substantial translational barriers. The convergence of epigenomics, microbiome research and early diagnostic science may help advance a more personalized medicine framework for ASD, provided that future studies improve cross-cohort reproducibility, clarify brain relevance of peripheral signals and develop practical multiomics models that can support clinically meaningful integration.
Racial and ethnic inequities persist in medication treatment initiation and adherence for pregnant and postpartum people with opioid use disorder (OUD). Our objective was to understand the experiences of "positive outliers," specifically pregnant and postpartum people of color with OUD who utilized medication treatment and engaged in a randomized clinical trial for buprenorphine despite historical, cultural, and structural barriers. We conducted two sets of semi-structured qualitative interviews. First, trained peers with lived expertise as mothers in recovery interviewed individuals who identified with a non-white race and/or ethnicity and enrolled in the Medication Treatment for OUD in Expectant Mothers (MOMs) trial (NCT03918850). Second, we interviewed principal investigators, clinicians, and research coordinators from the 13 MOMs trial sites. We used an inductive thematic approach informed by the Social Ecological Model of Racism and Anti-Racism. Transcripts were double-coded and reviewed until consensus was reached. Preliminary findings from participant and staff interviews were merged and triangulated with peers to inform theme development. We completed 17 interviews with MOMs trial participants from 7 sites. Participants identified as Hispanic (29%), Black non-Hispanic (24%), multi-racial Hispanic (18%), multi-racial non-Hispanic (18%), and American Indian, Native Hawaiian, or Pacific Islander (12%). Thirty-two interviews with trial staff were also completed. Three themes emerged: (1) Although some participants expected racist treatment and research exploitation, all participants interviewed reported non-discriminatory, non-judgmental care within the MOMs trial; (2) Compassionate care, frequent, personalized, and integrated encounters, and emotional support helped counteract prior stigmatizing and discriminatory health care interactions, enabling participants of color to feel particularly supported, trusted, and empowered during the MOMs trial; and (3) Despite pervasive cultural stigma around addiction and concerns about taking an investigational drug while pregnant, participants expressed that pregnancy status, care team trust, and transparent communication with MOMs trial staff encouraged medication utilization and adherence. Facilitators of successful engagement in the MOMs trial and retention in medication treatment among pregnant and postpartum people of color with OUD included non-judgmental care, sustained trust, and frequent contact. Key perinatal OUD clinical interventions and trial improvements include personalized communication and scheduling flexibility to promote engagement of marginalized populations.