Objective: To investigate the clinical characteristics of symptoms and signs of ocular surface lesions in dry eye patients with type 2 diabetes mellitus (T2DM) of different disease durations. Methods: A cross-sectional study was conducted. Consecutive T2DM patients complicated with dry eye who visited the Special Clinic for Diabetic Ocular Surface Diseases at Qingdao Eye Hospital, Shandong First Medical University from January 2020 to December 2024 were enrolled as the T2DM group. Dry eye patients without T2DM from the Dry Eye Clinic and age-and gender-matched healthy volunteers were recruited as the non-T2DM group and control group, respectively. The T2DM group was further divided into four stages according to disease duration: Stage Ⅰ (duration≤5 years), Stage Ⅱ (5 years<duration≤10 years), Stage Ⅲ (10 years<duration≤20 years), and Stage Ⅳ (duration>20 years). Ocular symptoms were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Ocular surface function was assessed by corneal sensitivity (CS), corneal fluorescein staining (CFS) score, Schirmer Ⅰ test (SⅠT), tear meniscus height (TMH), non-invasive first tear film break-up time (NIKf-BUT), non-invasive average tear film break-up time (NIKav-BUT), lipid layer thickness (LLT), and meibomian gland loss (MGL) grading score. Anterior segment optical coherence tomography was used to measure central corneal epithelial thickness (CCET) and central corneal thickness (CCT). In vivo confocal microscopy was performed to detect corneal nerve fiber parameters. Spearman's rank correlation analysis was used to evaluate the correlations between variables. Results: A total of 278 T2DM patients (556 eyes) were enrolled in the T2DM group, with a mean age of (60.25±8.71) years, a male-to-female ratio of 117∶161, and a mean disease duration of (11.09±8.02) years; among them, 84 cases were Stage Ⅰ, 81 cases Stage Ⅱ, 90 cases Stage Ⅲ, and 23 cases Stage Ⅳ. The non-T2DM group included 60 patients (120 eyes), with a mean age of (58.52±7.93) years and a male-to-female ratio of 23∶37. The control group comprised 53 healthy volunteers (106 eyes), with a mean age of (58.79±5.73) years and a male-to-female ratio of 21∶32. There were no statistically significant differences in age and gender distribution among the three groups (all P>0.05). Compared with the control group, the T2DM group showed significantly higher OSDI score (31.58%±20.56%), MGL grading score (3.59±0.95) and CFS score (1.84±3.01) (all P<0.05); while significantly lower SⅠT [(5.79±3.10) mm], NIKf-BUT [(5.81±3.14)s], NIKav-BUT [(9.31±4.85)s], LLT [(60.48±16.6) nm], CCET [(51.95±5.56) μm], CS [(56.9±8.30) mm], corneal endothelial cell density [(2 596±465.38)/mm²], and all corneal nerve parameters (including paracentral corneal nerve fiber density and length, etc.) (all P<0.05). Compared with the non-T2DM group, the T2DM group had significantly lower LLT, CCET, CS, OSDI score and all corneal nerve parameters, along with significantly higher MGL grading score and CFS score (all P<0.05); no statistically significant differences were found in SⅠT, NIKf-BUT and NIKav-BUT between the two groups (all P>0.05). In T2DM patients with disease duration≤5 years, compared with the control group, the OSDI score (23.98%±18.21%) and MGL grading score (3.35±0.91) were significantly increased, while SⅠT [(5.65±2.93) mm], LLT, NIKf-BUT and all corneal nerve parameters were significantly decreased (all P<0.05); meanwhile, compared with the non-T2DM group, this subgroup had significantly lower OSDI score and significantly higher MGL grading score (all P<0.05). When the disease duration exceeded 10 years, the OSDI score further increased to be comparable with that of the non-T2DM group, and NIKf-BUT [(5.44±2.92)s], CFS score (2.75±3.25), CCET [(51.36±4.17) μm], CS [(55.21±8.02) mm] showed statistically significant differences compared with both the control group and non-T2DM group (all P<0.05). Spearman's correlation analysis indicated that disease duration was significantly positively correlated with OSDI score, MGL grading score and CFS score, and significantly negatively correlated with NIKf-BUT, CCET, CS and all corneal nerve parameters (all P<0.05). Conclusions: Ocular surface lesion characteristics vary among dry eye patients with T2DM of different disease durations: decreased tear secretion, meibomian gland dysfunction and corneal nerve structural changes occur when the disease duration is ≤5 years, and corneal hypoesthesia and epithelial thinning develop when the duration exceeds 10 years, with lesions gradually worsening as the disease progresses. Compared with non-diabetic dry eye, significant differences exist in meibomian gland function, corneal nerves and epithelial barrier between the two groups.

Pharmacokinetic and pharmacodynamic herb-drug interaction of aspirin with Ijintang (Er Chen Tang) or Cheongsanggyeontongtang (Qing Shang Juan Tong Tang): An exploratory study in healthy adults.

Haploidentical allogeneic hematopoietic stem cell transplantation (h-HSCT) is increasingly used in patients lacking an HLA-matched donor. In this context, the combination of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) effectively prevents graft-versus-host disease, but its impact on the reconstitution of peripheral blood natural killer (NK) cell subsets remains insufficiently characterized. In this study, NK cell subsets were analyzed in depth in 56 adult recipients of unmanipulated h-HSCT with PTCy and ATG. Peripheral blood samples were collected at days +30, +60, and +100 after transplant. NK cell immunophenotype and cytotoxic function were assessed using multiparameter flow cytometry with unsupervised clustering, and degranulation assays against lymphoid and myeloid targets. Data were compared with those from 200 healthy volunteers. In spite of early numerical reconstitution, NK cells exhibited an immature immunophenotype with a low expression of activation markers. Cytotoxic activity against lymphoid targets was preserved, but degranulation against acute myeloid leukemia cell lines was significantly impaired across all NK subsets, including phenotypically mature NK cells. Cytomegalovirus reactivation was associated with an expansion of memory-like NK subsets but did not enhance degranulation. Functional education via killer cell immunoglobulin-like receptors was lost by day +30 and progressively reacquired from day +60 onward, in a pattern primarily influenced by the HLA-C genotype of recipients. These results indicate that, after h-HSCT with PTCy and ATG, NK cell subsets recover in number but fail to achieve early functional competence, particularly against myeloid targets. Strategies aiming at restoring mature NK cell functions warrant prospective investigations, especially in high-risk myeloid malignancies.

The Dutch flagship project Next Generation ImmunoDermatology (NGID) aims to profile five chronic immune-mediated inflammatory skin diseases: atopic dermatitis (AD), plaque psoriasis (PSO), hidradenitis suppurativa (HS), chronic spontaneous urticaria (CSU) and cutaneous lupus erythematosus (CLE) in comparison with cutaneous T-cell lymphoma subtype mycosis fungoides (MF) and healthy volunteers. Within NGID, a clinical study entitled: 'SKIN disease profiling by an Exploratory, pRospective, biomarker study in dermatoloGY practice (SKINERGY)' will be conducted as a multicentre, parallel-cohort, open-label, observational, longitudinal basket study. Objectives include evaluation of disease-related characteristics in comparison to those of healthy volunteers and evaluation of biomarkers for disease stratification and (targeted) treatment response in patients in a real-world clinical setting. Additionally, differences and similarities in disease characteristics between diseases, changes over time, and profiles of responders versus non-responders will be evaluated. Patients with AD (N = 120), PSO (N = 160), HS (N = 80), CSU (N = 120) and CLE (N = 120) will be enrolled in groups of N ≤ 40 patients per treatment. Matched healthy volunteers (N = 120) and the MF cohort (N = 120) will serve as control groups. Assessments include blood sampling, skin punch biopsies, tape stripping, skin swabs, (multimodal) imaging, tele-health and patient- and physician-reported outcomes. This manuscript describes the study protocol prior to data collection and its strategic evaluation of multi-omics profiling. Patient advocacy groups co-defined the research agenda and contributed to study design and informed consent document development, ensuring alignment with patients' needs and real-world relevance. SKINERGY will generate a machine learning-ready dataset with information about changes in various biomarkers over time, including histology, metabolomics, spatial proteomics, transcriptomics, lipidomics, microbiomics, imaging biomarkers, tele-health, patient-reported outcome measures (PROMs) and clinical parameters. Identified biomarker profiles within SKINERGY may guide targeted treatment selection, enhance targeted therapeutic response in clinical practice and improve understanding of disease pathology in chronic immune-mediated skin diseases.

Blood T1 is a key parameter for hemodynamic quantification in both non-contrast- and contrast-enhanced imaging. Individual vessel T1 has been measured using a modified Look-Locker scheme with multi-shot EPI or FLASH in high spatial resolution, requiring ∼1 min. Here, by exploiting the temporal sparsity from the excessive number of inversion delays, we apply Golden Angle rotated Spiral k-t Sparse Parallel imaging (GASSP) to enable blood T1 measurement in a single shot of 10 s. The pulse sequence with single-shot GASSP reconstruction was developed for T1 measurement from the internal jugular vein (IJV) with 1 × 1 mm2 in-plane resolution. On nine healthy volunteers, the single-shot GASSP was compared to the segmented EPI readout and was repeated to assess its intra-scan reproducibility. Another experiment was performed on three patients, during which the 10 s GASSP was obtained at different time points prior to and following the Gadolinium (Gd) administration to assess dynamic changes in blood T1. The blood T1 values measured with the highly undersampled GASSP method were strongly correlated (r = 0.83) with those using the multi-shot EPI readout and exhibited high reproducibility (r = 0.88) within the session. The baseline IJV T1 values measured were 1700-2000 ms. Following the Gd injection, the T1 values of IJVs gradually recovered from ∼300-400 to ∼500 ms within 10-15 min. The feasibility of an ultrafast blood T1 measurement was demonstrated with high spatial resolution in a single shot of 10 s, applicable to both pre- and post-contrast conditions.

Background: Chronic neuropathic low back pain (LBP) is a prevalent health condition and difficult to treat. Conventional therapies often provide limited relief and raise safety concerns. Supplemental palmitoylethanolamide (PEA), an endogenous fatty acid amide with analgesic and anti-inflammatory properties, has shown benefits in neuropathic pain, but its application as a supportive strategy has been limited by poor oral bioavailability. Objectives: This study aimed to investigate a phospholipid-based palmitoylethanolamide formulation (PEA-PL, Cronilief™), developed using Phytosome™ delivery technology, with respect to solubility optimization, systemic exposure, and associated clinical effects in individuals with chronic neuropathic LBP. Methods: PEA-PL solubility was assessed in fasted-state simulated intestinal fluid and compared with unformulated PEA. Plasma PEA concentrations were evaluated in healthy volunteers after 2 weeks of supplementation with unformulated PEA (300 mg/day) or PEA-PL (300 or 600 mg/day). Clinical efficacy was assessed in a double-blind, placebo-controlled randomized, trial in which 120 adults with neuropathic LBP received PEA-PL 600 → 300 mg (n = 40), PEA-PL 450 mg (n = 40), or placebo (n = 40), daily for 8 weeks in addition to Standard of Care. Primary outcomes were effects on neuropathic pain (Douleur Neuropathique 4, DN4) and its intensity (Numeric Pain Rating Scale, NPRS). Secondary outcomes included effect on functional disability (Oswestry Disability Index, ODI), sleep quality (Pittsburgh Sleep Quality Index, PSQI), quality of life (QoL) (SF-12), and concomitant analgesic use. Safety was monitored throughout the 8-week supplementation period. Results: PEA-PL increased PEA solubility approximately eight-fold and resulted in higher plasma PEA concentrations than unformulated PEA. Both PEA-PL regimens significantly improved pain, functional disability, sleep, and QoL outcomes versus placebo (all p &lt; 0.0001), with greater effects for the 600 → 300 mg regimen. Analgesic discontinuation occurred more frequently in PEA-PL groups (65–70%). Supplementation was well tolerated. Conclusions: A phospholipid-based (Phytosome™) PEA formulation (Cronilief™) was developed and associated with optimized systemic exposure and clinically meaningful reductions in pain severity and functional disability in individuals with chronic neuropathic LBP.

Background/Objectives: Hydroxychloroquine (HCQ) is used to manage various autoimmune diseases, including systemic lupus erythematosus. The prolonged use of HCQ is associated with retinopathy and irreversible visual loss due to retinal toxicity. Despite adherence to dosage regimens, patients may develop functional rather than structural changes, without detectable abnormalities on routine examination using visual acuity and optical coherence tomography (OCT). The study aimed to detect early signs of retinopathy in patients with autoimmune diseases treated with HCQ. Methods: This cross-sectional study included patients (n = 36) with autoimmune diseases who were treated with HCQ. The control group (n = 35) comprised healthy volunteers matched for age and sex. All participants were screened using colour vision tests (Ishihara, Konan ColourDX high definition [HD]), and retinal thickness was evaluated using OCT. Results: Our findings suggest a significant reduction in the contrast threshold of the L and M-cone photoreceptors compared with that of the control using Konan ColourDX HD. The OCT measurements revealed no statistically significant difference in retinal thickness between patients and controls; however, the contrast sensitivity test showed a significant reduction at all spatial frequencies (p &lt; 0.0001). Conclusions: The current study suggests that the Konan ColourDX cone contrast test HD and contrast sensitivity testing may be valuable for periodic monitoring of patients receiving HCQ, potentially enabling earlier detection of toxicity. However, longitudinal studies with larger cohorts are needed to confirm these findings and to further establish the clinical value of these functional visual tests.

Total hip arthroplasty (THA) is the gold standard for treating Crowe IV developmental dysplasia of the hip (DDH). However, its long-term effects on lower limb alignment, gait biomechanics, and plantar force in these patients remain underexplored, which is discussed in this article. We conducted a retrospective cohort study that included 43 DDH Crowe IV patients who underwent THA between February 2008 and October 2019 and a control group of 43 matched healthy volunteers. Postoperative functional outcomes and quality of life were assessed using the Harris Hip Score, KOOS, AOFAS, and WOMAC scores. Lower limb alignment parameters (MAD, HKA, aTFA, mLDFA, mMPTA, and FO), knee alignment (HMFC, HLFC), and ankle alignment (mLDTA, FACO, and TT) were measured preoperatively, postoperatively, and at follow-up. Gait analysis and plantar force measurements were performed at the final follow-up. With an average follow-up of 10.2 years, patients showed significant improvement in functional and quality of life scores compared to pre-surgery. Preoperatively, all patients had knee valgus and ankle varus on the affected side. After THA, most parameters showed reduced valgus alignment, except for HKA and HLFC. On the unaffected side, MAD, aTFA, and HKA indicated preoperative valgus, which was fully corrected post-THA. Gait analysis revealed restricted lower limb motion and abnormal plantar force distribution that persisted postoperatively in Crowe IV DDH patients. THA partially corrected abnormal lower limb alignment, gait parameters, and plantar force distribution in DDH Crowe IV patients over long-term follow-up.

Current reference standards for measuring gastric emptying and motility are not considered optimal due to the time required, ionizing radiation, invasiveness, and spatial resolution. To assess gastric motility using novel real-time dynamic magnetic resonance imaging in combination with static measurements for gastric emptying and training of an automated deep-learning-based segmentation pipeline. Prospective. The study included 36 healthy volunteers (20 female, mean 24 ± 3 years) and three patients with diagnosed Crohn's disease. Participants ingested water to assess fasting motility and pineapple juice for the postprandial state. 3 T, 3D spoiled gradient echo (GRE) sequence and real-time spoiled GRE. Gastric emptying was measured by using the gastric volume, while motility was analyzed by tracking changes in the antrum's cross-sectional area and applying Fast Fourier Transformation. Segmentations were performed using a trained semantic segmentation model. Linear Mixed Model with continuous dependent variables and fixed effects. Models included a random intercept for participants. Statistical significance was defined as p = 0.05. The method enabled volumetric analysis of gastric content from 3D breath-hold static acquisition and time-resolved quantification of peristaltic parameters from real-time FLASH2 imaging at high temporal resolution (here 6.24 fps). Water emptied rapidly and exponentially (t1/2 = 14.77 ± 10.55 min), while juice showed slower emptying (t1/2 = 64.24 ± 11.87 min). Contraction frequencies (fasted: 2.76 ± 0.43 cpm, fed: 2.89 ± 0.43 cpm) and velocities (fasted: 1.67 ± 0.38 mm/s, fed: 1.72 ± 0.37 mm/s) were within physiological ranges, with fasting conditions characterized by stronger occlusion compared to the fed. Measurements taken from three patients proved that the workflow could be used in a clinical context. Real-time MRI with AI-based analysis enabled quantitative assessment of gastric emptying and motility, revealing physiological peristaltic parameters and state-dependent differences in occlusion. 2. Stage 1.

The role of T-cell-mediated immune responses is recognized as pivotal in achieving functional cure in chronic hepatitis B (CHB) patients. We aimed to assess safety and T-cell responses induced by JNJ-6430535 (JNJ-0535); a hepatitis B virus (HBV)-specific therapeutic DNA vaccine administered via electroporation-mediated intramuscular injection. JNJ-0535 comprises 2 plasmids, encoding HBV core and polymerase (pol) proteins, respectively. We describe the safety, tolerability, and immunogenicity results of JNJ-0535 from an open-label, single arm phase 1 study in healthy volunteers (HVs) (64300535HPB1003, NTC04736147) and a randomized, placebo controlled phase 1 study in CHB patients (64300535HPB1001, NTC03463369). HBV-specific T-cell responses were evaluated using enzyme-linked immunospot (ELISpot) and intracellular cytokine staining (ICS). We performed baseline single-cell RNA sequencing (scRNA-seq) to explore immune correlates associated with vaccine response in HVs, and baseline serum proteomics (Olink Explore® 3072) to explore differences in soluble immune markers between responders and non-responders in both HVs and CHB patients. JNJ-0535 was safe and well tolerated in both HVs and CHB patients. Compared to CHB patients, HVs showed a higher proportion of participants with vaccine-induced HBV-specific T-cell responses (92% versus 50%), a greater increase from baseline (24× [interquartile range=40×;9×] versus 4.8× [interquartile range=5×;6×]) and a broader response in terms of number of antigens. Serum proteomics revealed few differential circulating host biomarkers between CHB and HVs, but these could not be linked to differences in immunogenicity. In addition, whole-blood scRNA-seq was performed in HVs to explore differences between participants with a strong vaccine response and those with low or no response. Our research showed a decrease in vaccine-induced responses in CHB patients compared to HVs and may provide preliminary insights into immune-related biomarkers that could influence vaccine immunogenicity but require further confirmation in future larger studies. trial numbers: 64300535HPB1001 (NCT03463369) First posted: 18. April 2018; ULR: https://clinicaltrials.gov/study/NCT03463369?term=JNJ-64300535&rank=2 and 64300535HPB1003 (NCT04736147) First posted: 03. Feb. 2021; URL: https://clinicaltrials.gov/study/NCT04736147?term=JNJ-64300535&rank=1.

Mirogabalin besylate is a selective α2δ-1 ligand approved for diabetic peripheral neuropathic pain. This study evaluated the pharmacokinetic (PK) bioequivalence and safety of generic 5 mg and 10 mg mirogabalin formulations compared with the reference product (Tarlige®) under both fasting and fed conditions among healthy Chinese volunteers. This pooled analysis comprised two independent, randomized, open-label, two-period crossover trials: one evaluating the 5 mg formulation (24 participants/group) and another evaluating the 10 mg formulation (36 participants/group). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays have been validated over ranges of 1.00-200 ng/mL (5-mg study) and 0.50-500 ng/mL (10-mg study) for plasma mirogabalin quantification. Primary endpoints were peak plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t), and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞). Bioequivalence was determined if the 90% confidence intervals (CIs) of geometric mean ratios (GMRs) fell within the 80.00-125.00% range, evaluated via analysis of variance (ANOVA) on log-transformed parameters. For the 5 mg formulation, the fasting study demonstrated bioequivalence with a Cmax GMR of 99.10% (90% CI 91.23-107.64), AUC0-t of 99.50% (97.14-101.91), and AUC0-∞ of 99.29% (96.96-101.68). Under fed conditions, Cmax showed higher variability (GMR: 88.61%, 80.48-97.55), while AUC0-t (98.55%, 96.42-100.73) and AUC0-∞ (99.03%, 97.00-101.10) remained within equivalence bounds. The 10 mg formulation exhibited robust bioequivalence in both fasting and fed states: fasting Cmax GMR was 97.07% (91.84-102.60), AUC0-t 100.61% (98.52-102.74), and AUC0-∞ 100.55% (98.61-102.53); fed Cmax was 97.14% (89.64-105.26), AUC0-t 101.04% (99.26-102.86), and AUC0-∞ 100.53% (99.03-102.05). An exploratory analysis of the two dose levels suggested a linear PK for mirogabalin within the 5-10 mg range. The intrasubject variability was generally low (CVW%: 3.76-20.36%), with the 10 mg formulation showing numerically lower variability for Cmax (13.79%) compared with the 5 mg formulation (16.39%) in the fasting state. Adverse event incidence ranged from 13.0% to 25.0% across groups, with no severe events reported. Both generic formulations met bioequivalence criteria to Tarlige® across studied doses. While both formulations showed acceptable PK profiles, the 10 mg dose exhibited more consistent exposure characteristics, as evidenced by a lower within-subject variability. The PK data are consistent with linear PK for mirogabalin within the studied dose range. Comparable safety profiles support the pharmaceutical equivalence in the studied population. These findings provide critical PK evidence for China's first generic mirogabalin products. ( http://www.chinadrugtrials.org.cn ): 5 mg: CTR20232783; 10 mg: CTR20242717.

Safety, Pharmacokinetics, and Sex Hormone Suppression of LY01021 versus Relugolix: A Single- and Multiple-Dose Escalation Study.

Storage-induced spectral changes of human platelet-rich plasma revealed by SERS.

Objective Insomnia is the most common type of sleep disorder; however, the neurobiological causes and correlates of hyperarousal in insomnia remain to be fully determined, and the levels of cerebral metabolites in patients with insomnia remain unclear. This study aimed to quantify changes in cerebral metabolite levels in patients with insomnia and to explore their relationship with fatigue, anxiety, and subjective sleepiness. Methods Twenty unmedicated patients with insomnia disorder and 21 age- and sex-matched healthy volunteers were included. The concentrations of metabolites including γ -aminobutyric acid (GABA+), glutamate (Glu), glycerophosphocholine (GPC), creatine (Cr), and phosphocreatine (PCr) were obtained by magnetic resonance spectroscopy, and the differences in metabolites between the two groups were compared. Sleep quality, sleepiness, anxiety, and fatigue were assessed using the Pittsburgh Sleep Quality Index (PSQI), Karolinska Sleepiness Scale (KSS), Beck Anxiety Inventory (BAI), and Fatigue Severity Scale (FSS), respectively. Correlations between the changes in GABA+, Glu, and GPC levels and the PSQI, KSS, FSS, and BAI scores were evaluated in patients with insomnia. Results GABA+ levels were significantly lower in patients with insomnia than in healthy controls ( p = 0.027), whereas GPC and Cr+PCr levels were significantly higher ( p &amp;lt; 0.001 and p = 0.003, respectively). However, Glu levels were comparable between the groups ( p = 0.962). Furthermore, GABA+ levels were significantly negatively correlated with FSS (r = −0.656, p = 0.003) and BAI (r = −0.467, p = 0.038) scores; a trend-level negative association with KSS was also observed (r = −0.419, p = 0.066). Conclusion Our results revealed alterations in the levels of GABA+ and GPC in the thalamus of patients with insomnia. These findings provide objective neurochemical evidence for the pathophysiological mechanisms of insomnia.

Trace amine-associated receptor 1 (TAAR1) is a novel target for antipsychotic and potentially mood-stabilizing and anti-addictive drugs, offering a new mechanism by modulating dopaminergic, serotonergic, and glutamatergic neurotransmission. TAAR1 agonists from a prior amino oxazolines series were studied preclinically and clinically, but development of partial agonist RO5263397 was halted due to poor metabolization by N-glucuronidation in individuals with UGT2B10 splice site mutations. A medicinal chemistry program subsequently identified new potent and selective TAAR1 ligands from the morpholine series. Two selective partial agonists, RO6799477 and RO6889450, were advanced and showed antipsychotic, stress-response-modulating, and anti-addictive-like activity in rodent models. They reduced PCP- and cocaine-induced hyperlocomotion, potentiated olanzapine's effect, partially reversed cocaine-induced facilitation of intracranial self-stimulation and demonstrated anxiolytic-like properties in the stress-induced hyperthermia test. Neural activation profiles, measured by pharmacological MRI, differed from first and second-generation antipsychotics. Non-clinical drug abuse liability studies with RO6889450 indicated a favorable low abuse liability profile and suggested a lack of reinforcing effects. Preclinical safety studies indicated a favorable profile with clinically monitorable and reversible findings. Both compounds progressed into Phase I single and multiple ascending dose studies in healthy volunteers. RO6799477 was well tolerated, with rapid absorption and dose-proportional pharmacokinetics, though higher doses led to nervous system and cardiovascular adverse events. RO6889450 was well tolerated up to 300 mg; at 450 mg, dose-limiting adverse events included postural tachycardia and erythema. Together, these results indicate the translational potential and support further clinical exploration of TAAR1 agonists as a novel therapeutic option for neuropsychiatric disorders, particularly schizophrenia and substance use disorder.

A method for simultaneous mapping of static (B0) and transmit (B1 +) field inhomogeneities at ultra-high field (UHF) was developed and validated. The utility of accelerating the proposed sequence using deep learning (DL) and joint low-rank tensor completion (TxLR) reconstruction methods was evaluated to enable rapid online implementation. A 3D sequence, Combined caLculation of UHF Biases (CLUB)-Sandwich, was developed by incorporating a multi-echo readout into the unsaturated segment of the Sandwich B1 + mapping sequence, enabling simultaneous B0 estimation. Data from 11 healthy volunteers were acquired at 7 T. Estimated ΔB0 and B1 + maps were compared with established, separate reference scans. Retrospectively and prospectively undersampled data were reconstructed using TxLR and a DL-based algorithm. The resulting maps were compared with fully sampled data. CLUB-Sandwich maps showed strong agreement with reference methods. A strong correlation (r > 0.97) and low mean volumetric root mean squared errors were found for both ΔB0 (9.5 ± 1.8 Hz) and absolute B1 + (3.5° ± 0.3°). Both reconstruction methods enabled acquisitions in under 10 s of acquisition time. DL reconstruction was found to be substantially faster (5 s) than the TxLR algorithm (4 min) while producing comparable map quality. Prospective validation confirmed the feasibility of online mapping with acceptable accuracy. The CLUB-Sandwich method was developed for fast, accurate, and simultaneous ΔB0 and B1 + mapping. When combined with a DL-based reconstruction, the proposed framework provides maps in under 10 s of acquisition time, presenting a feasible solution for rapid online inhomogeneity estimation in UHF applications.

The clearance of brain metabolites increases during sleep, in association with increased spectral power of the three main cerebrospinal fluid (CSF) flow drivers: cardiovascular, respiratory, and vasomotor brain pulsations. However, little is known about how the increased power of these pulsations affects the velocity and direction of fluid flow in the sleeping brain. To address this knowledge gap, we mapped the CSF oscillatory flow velocity in relation to the changing physiological pulsations in the brains of 22 healthy volunteers during sleep and waking. We used the ultrafast magnetic resonance imaging sequence known as magnetic resonance encephalography (MREG) for tracing the pulsatile movement of water molecules inside the cranium. First, we conducted a phantom validation study with optical flow analysis to confirm that MREG accurately tracks pulsatile water molecule flow in a porous tissue medium. Next, we obtained MREG recordings for mapping the three physiological pulsations without aliasing in the human brain across the awake and sleep states; we thereby quantified the brain-wide 3D velocity vectors (i.e., the velocity vs and 3D direction ) of each pulsation band, using comprehensive dense optical flow analysis during EEG-verified sleep in comparison to the awake state. Finally, we assessed relationships among the spectral power of the physiological pulsations, their 3D velocity , and slow-delta EEG power, which is known to depict the increased interstitial volume during sleep. In our phantom study, dense optical flow analysis reliably detected water flow in tissue driven by external pulsations. In healthy volunteers, sleep increased flow velocities ( ) of the pulsations by more than 20% in concert with elevations in respiratory pulsations and vasomotor waves, while the velocity of cardiovascular pulsations (vs) declined by the same percentage. There was a significant anticorrelation between cardiac mean spectral power and slow delta EEG mean power, and a significant correlation between vasomotor mean spectral power and slow delta EEG mean power over the whole brain. Phantom studies validated the optic flow analysis of fast MREG recordings. Sleep altered the 3D velocity dynamics of all neurofluidic brain pulsations in a manner consistent with increased interstitial space and greater fluid exchange, thus supporting the glymphatic model wherein physiological pulsations drive bulk flow during sleep.

Two simple, rapid, cost-effective, and environmentally friendly chromatographic methods were developed and validated for the simultaneous determination of metformin (MEF), linagliptin (LIN), and empagliflozin (EMP) in human plasma, with successful application to pharmacokinetic study. Plasma sample preparation was performed using a straightforward protein precipitation technique employing acetonitrile: methanol: trichloroacetic acid (50:49:1, by volume), which provided high extraction recovery and minimal matrix interference. The first method was based on high-performance liquid chromatography with diode array detection (HPLC-DAD) using an ODS Hypersil C18 column and isocratic elution with a mobile phase consisting of acetonitrile, methanol, and phosphate buffer (pH 3) in a ratio of (40:40:20, by volume), at a flow rate of 1.3 mL/min, with detection at 230nm. The second method employed high-performance thin-layer chromatography (HPTLC) with densitometric detection at 225nm, using silica gel 60 F254 plates and n-hexane: methanol: glacial acetic acid (6:3:1, by volume) as the developing system. Excellent linearity was achieved over concentration ranges of 85-1650 ng/mL for MEF, 50-1100 ng/mL for EMP, and 45-950 ng/mL for LIN using the HPLC method, and 500-2800, 100-800, and 50-550 ng/band, respectively, using the HPTLC method, with correlation coefficients exceeding 0.998. The lower limits of quantitation for the HPLC method were 85, 50, and 45 ng/mL for MEF, EMP, and LIN, respectively. Both methods demonstrated satisfactory accuracy, precision, recovery (> 92%), stability, and negligible matrix effects in accordance with European Medicines Agency guidelines. The validated methods were successfully applied to a pharmacokinetic study in healthy volunteers, yielding mean Cmax values of 877.5 ± 162.2 ng/mL (MEF), 576 ± 87.5 ng/mL (EMP), and 680.8 ± 7.9 ng/mL (LIN), with Tmax values of 2.42 ± 0.38, 1.5 ± 0.61, and 5.3 ± 0.52h, respectively. The obtained pharmacokinetic parameters were consistent with reported literature, confirming the reliability and clinical applicability of the proposed green bioanalytical methods.

Humans exposed to cold environments for leisure or occupational activities may experience cold stress. Cold-related physical and mental stress can negatively affect cognitive performance. A recent literature review has pointed out that a single acute exposure to cold under controlled laboratory conditions (e.g., cold air or cold water) induces cognitive impairment with attention, processing speed, memory, and executive function being the most affected cognitive domains. Males and females seem to respond differently to short-term cold exposure, although results are not consistent. The aim of the study was to investigate the effect of acute and brief (15min) exposure to low ambient temperatures of -10°C compared with 5°C and 20°C on selected cognitive performance (reaction time, processing speed, and risky decision-making). We hypothesized that cognitive performance decreases at low temperatures with a sex difference, before core temperature changes. This randomized, controlled, crossover study was conducted in an environmental chamber (terraXcube) under controlled, replicable, and safe conditions in twenty-four healthy volunteers, females and males, aged between 18 and 60 years. Measurements included Psychomotor Vigilance Test (PVT), Balloon Analogue Risk Task (BART), and Digit Symbol Substitution Test (DSST). Cognitive performance, stress, and cold were subjectively rated with a visual analogue scale (VAS). Physiological data (including core and skin temperatures) were continuously recorded with a physiological monitoring system. Data were analysed using repeated measures analysis of variance (ANOVA), Friedman test, Generalised Estimating Equations (GEE), and correlation analysis. We identified transient impairments in cognitive performance in individuals wearing appropriate clothing. Cold exposure (-10°C) affected attention by slowing response times and increasing the lapses, and decision-making by reducing risky behaviour. Heart rate, cold sensation, and stress, as well as thermal sensation and comfort, but not core temperature were different in the three experimental temperature exposures. No differences were found between male and female subjects in their cognitive performance. Our data support the distraction theory in the decline of cognitive performance even during a short exposure to cold temperatures. Such impairment should be carefully considered in people performing different activities in cold environments, even for a short time.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants, though their mechanisms of action beyond serotonin transporter (SERT) blockade remain unclear [1]. As previous work on BOLD signal changes remain equivocal, pharmacological multimodal neuroimaging of energy demands and blood flow (CBF) holds promise due to increased specificity of these signals. This may advance the understanding of the involved pharmacodynamic mechanisms and guide treatment strategies of highly prevalent neuropsychiatric disorders. We combine new techniques of functional positron emission tomography (fPET) with high temporal resolution (3 seconds) using [18F]FDG and simultaneously acquired pseudo-continuous arterial spin labelling (pcASL). Thus, we aimed for a highly quantitative assessment of changes in brain activation following an intravenous SSRI challenge using a randomized, placebo-controlled, double-blind study design. We demonstrate acute drug induced changes in glucose metabolism (Ki) in serotonergic projections, i.e. the striatum and the occipital cortex in 16 healthy volunteers (7 females). In an exploratory analysis, acute effects were observed in the dorsal raphe nucleus. We did not observe corresponding changes in CBF, which suggests that observed SSRI effects are specific to brain energy demands. Our results complement the existing literature on the acute pharmacological effects of SSRIs by providing insights in specific aspects of neuronal activation. Moreover, our findings expand upon the results of existing BOLD fMRI studies and, thus, support the application of this pharmacological neuroimaging protocol in psychopharmacological research.