[Applications of native mass spectrometry and ultraviolet photodissociation in protein structure and interaction analysis].

Dynamic changes in the structures and interactions of proteins are closely correlated with their biological functions. However, the precise detection and analysis of these molecules are challenging. Native mass spectrometry (nMS) introduces proteins or protein complexes into the gas phase by electrospray ionization, and then performs MS analysis under near-physiological conditions that preserve the folded state of proteins and their complexes in solution. nMS can provide information on stoichiometry, assembly, and dissociation constants by directly determining the relative molecular masses of protein complexes through high-resolution MS. It can also integrate various MS dissociation technologies, such as collision-induced dissociation (CID), surface-induced dissociation (SID), and ultraviolet photodissociation (UVPD), to analyze the conformational changes, binding interfaces, and active sites of protein complexes, thereby revealing the relationship between their interactions and biological functions. UVPD, especially 193 nm excimer laser UVPD, is a rapidly evolving MS dissociation method that can directly dissociate the covalent bonds of protein backbones with a single pulse. It can generate different types of fragment ions, while preserving noncovalent interactions such as hydrogen bonds within these ions, thereby enabling the MS analysis of protein structures with single-amino-acid-site resolution. This review outlines the applications and recent progress of nMS and UVPD in protein dynamic structure and interaction analyses. It covers the nMS techniques used to analyze protein-small-molecule ligand interactions, the structures of membrane proteins and their complexes, and protein-protein interactions. The discussion on UVPD includes the analysis of gas-phase protein structures and interactions, as well as alterations in protein dynamic structures, and interactions resulting from mutations and ligand binding. Finally, this review describes the future development prospects for protein analysis by nMS and new-generation advanced extreme UV light sources with higher brightness and shorter pulses.

Clinical Characteristics and Outcomes of Generalized Myasthenia Gravis in Malaysia: A Single-Center Experience.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is clinically heterogeneous and can be classified into subgroups according to the clinical presentation, antibody status, age at onset, and thymic abnormalities. This study aimed to determine the clinical characteristics and outcomes of generalized MG (GMG) patients based on these subgroups. METHODS: Medical records of MG patients from 1976 to 2023 were reviewed retrospectively. Patients with pure ocular MG were excluded. Data on demographic, clinical characteristics, laboratory features, and outcomes were analyzed. RESULTS: This study included 120 GMG patients. There was a slight preponderance of female patients over male patients (male:female ratio=1:1.3), with the age at onset exhibiting a bimodal distribution. Female patients peaked at a lower age (21-30 years) whereas male patients peaked at a higher age (61-70 years). Most (92%, 105 of 114) patients had positive anti-acetylcholine receptor antibodies. Five patients were also tested for anti-muscle-specific tyrosine kinase antibodies, with two showing positivity. Thymectomy was performed in 62 (52%) patients, of which 30 had thymoma, 16 had thymic hyperplasia, 7 had an involuted thymus, and 6 had a normal thymus. There were significantly more female patients (68% vs. 45%, p=0.011) with early-onset disease (<50 years old) and thymic hyperplasia (33% vs. 0%, p<0.025). Most (71%) of the patients had a good outcome based on the Myasthenia Gravis Foundation of America postintervention status. GMG patients with early-onset disease had a significantly better outcome than patients with a late onset in univariate (58% vs. 37%, p=0.041) and multivariate (odds ratio=4.68, 95% confidence interval=1.17-18.64, p=0.029) analyses. CONCLUSIONS: Female patients with early-onset MG and thymic hyperplasia had significantly better outcomes, but only early-onset disease was independently associated with a good outcome. These findings are comparable with those of other studies.

Single-cell RNA sequencing elucidated the landscape of breast cancer brain metastases and identified ILF2 as a potential therapeutic target.

Distant metastasis remains the primary cause of morbidity in patients with breast cancer. Hence, the development of more efficacious strategies and the exploration of potential targets for patients with metastatic breast cancer are urgently needed. The data of six patients with breast cancer brain metastases (BCBrM) from two centres were collected, and a comprehensive landscape of the entire tumour ecosystem was generated through the utilisation of single-cell RNA sequencing. We utilised the Monocle2 and CellChat algorithms to investigate the interrelationships among each subcluster. In addition, multiple signatures were collected to evaluate key components of the subclusters through multi-omics methodologies. Finally, we elucidated common expression programs of malignant cells, and experiments were conducted in vitro and in vivo to determine the functions of interleukin enhancer-binding factor 2 (ILF2), which is a key gene in the metastasis module, in BCBrM progression. We found that subclusters in each major cell type exhibited diverse characteristics. Besides, our study indicated that ILF2 was specifically associated with BCBrM, and experimental validations further demonstrated that ILF2 deficiency hindered BCBrM progression. Our study offers novel perspectives on the heterogeneity of BCBrM and suggests that ILF2 could serve as a promising biomarker or therapeutic target for BCBrM.

Activation of NOTCH signaling impedes cell proliferation and survival in acute megakaryoblastic leukemia.

The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines and detected frequent genetic mutations in the NOTCH pathway in addition to previously reported alterations in GATA-1 and the JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient-derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis. and NOTCH activation holds the potential for therapeutic application in AMKL.

Checklist of land snail species of Gua Rumbang, Sarawak, Malaysian Borneo (Mollusca, Gastropoda), with a description of a new species, Diplommatinarumbangensis sp. nov.

The current study presents an annotated checklist of the land snail species in the vicinity of the limestone hill of Gua (= cave) Rumbang, an outcrop located at the district of Padawan, Sarawak, Malaysian Borneo. The sampling was conducted at the surrounding areas and near the cave's entrance. A total of 62 species, involving 19 families and 38 genera, were recorded. Comparison with previous surveys made in the Bau limestone hills revealed similarities with respect to the species-rich families Diplommatinidae and Cyclophoridae, and the genera Kaliella and Diplommatina, highlighting the regional consistency of the land snail diversity of the Bau-Padawan-Serian cluster. Possibly because of its smaller size, Gua Rumbang is home to two endemic species, while there are eight endemic species in the Bau limestone karsts. This suggests a potential for a significant species diversity within the areas of the limestone ranges that remain to be explored. Nonetheless, the occurrence of endemic species in Gua Rumbang highlights the need to conserve certain areas within the Padawan limestone range since hitherto no protected areas have been proposed in this region. In this checklist, a new species for science is also described, namely, Diplommatinarumbangensissp. nov.

Evaluation of dry eye disease symptomatology and mental health status among patients with different COVID-19 statuses.

AIM: To evaluate dry eye disease (DED) symptomatology and mental health status in different COVID-19 patients. METHODS: A cross-sectional observational design was used. Totally 123 eligible adults (46.34% of men, age range, 18-59y) with COVID-19 included in the study from August to November, 2022. Ocular Surface Disease Index (OSDI), Five-item Dry Eye Questionnaire (DEQ-5), Hospital Anxiety and Depression Scale (HADS), and Pittsburgh Sleep Quality Index (PSQI) were used in this study. RESULTS: OSDI scores were 6.82 (1.25, 15.91) in asymptomatic carriers, 7.35 (2.50, 18.38) in mild cases, and 16.67 (4.43, 28.04) in recurrent cases, with 30.00%, 35.56%, and 57.89%, respectively evaluated as having DED symptoms (χ2=7.049, P=0.029). DEQ-5 score varied from 2.00 (0, 6.00) in asymptomatic carriers, 3.00 (0, 8.00) in mild cases, and 8.00 (5.00, 10.00) in recurrent cases, with 27.50%, 33.33%, and 55.26%, respectively assessed as having DED symptoms (χ2=8.532, P=0.014). The prevalence of clinical anxiety (50.00%) and depression (47.37%) symptoms were also significantly higher in patients with recurrent infection (χ2=24.541, P<0.001; χ2=30.871, P<0.001). Recurrent infection was a risk factor for high OSDI scores [odds ratio, 2.562; 95% confidence interval (CI), 1.631-7.979; P=0.033] and DEQ-5 scores (odds ratio, 3.353; 95%CI, 1.038-8.834; P=0.043), whereas having a fixed occupation was a protective factor for OSDI scores (odds ratio, 0.088; 95%CI, 0.022-0.360; P=0.001) and DEQ-5 scores (odds ratio, 0.126; 95%CI, 0.039-0.405; P=0.001). CONCLUSION: Patients with recurrent COVID-19 have more severe symptoms of DED, anxiety, and depression.

Disrupted mitochondrial transcription factor A expression promotes mitochondrial dysfunction and enhances ocular surface inflammation by activating the absent in melanoma 2 inflammasome.

PURPOSE: Severe dry eye disease causes ocular surface damage, which is highly associated with mitochondrial dysfunction. Mitochondrial transcription factor A (TFAM) is essential for packaging mitochondrial DNA (mtDNA) and is crucial for maintaining mitochondrial function. Herein, we aimed to explore the effect of a decreased TFAM expression on ocular surface damage. METHODS: Female C57BL/6 mice were induced ocular surface injury by topical administrating benzalkonium chloride (BAC). Immortalized human corneal epithelial cells (HCECs) were stimulated by tert-butyl hydroperoxide (t-BHP) to create oxidative stress damage. HCECs with TFAM knockdown were established. RNA sequencing was employed to analyze the whole-genome expression. Mitochondrial changes were measured by transmission electron microscopy, Seahorse metabolic flux analysis, mitochondrial membrane potential, and mtDNA copy number. TFAM expression and inflammatory cytokines were determined using RT-qPCR, immunohistochemistry, immunofluorescence, and immunoblotting. RESULTS: In both the corneas of BAC-treated mice and t-BHP-induced HCECs, we observed impaired TFAM expression, accompanied by mitochondrial structure and function defects. TFAM downregulation in HCECs suppressed mitochondrial respiratory capacity, reduced mtDNA content, induced mtDNA leakage into the cytoplasm, and led to inflammation. RNA sequencing revealed the absent in melanoma 2 (AIM2) inflammasome was activated in the corneas of BAC-treated mice. The AIM2 inflammasome activation was confirmed in TFAM knockdown HCECs. TFAM knockdown in t-BHP-stimulated HCECs aggravated mitochondrial dysfunction and the AIM2 inflammasome activation, thereby further triggering the secretion of inflammatory factors such as interleukin (IL) -1ß and IL-18. CONCLUSIONS: TFAM reduction impaired mitochondrial function, activated AIM2 inflammasome and promoted ocular surface inflammation, revealing an underlying molecular mechanism for ocular surface disorders.

Efficacy of repeated low-level red-light therapy in the prevention and control of myopia in children.

OBJECTIVE: In this study, we aimed to determine how different factors influence the effectiveness of repeated low-level red-light (RLRL) therapy in preventing and treating myopia in children. METHODS: Between June 2022 and April 2023, 336 children who visited our hospital due to myopia or significant decreases in hyperopia reserve were enrolled. The children were treated twice daily for three minutes with a head-mounted low-level red-light (single wavelength of 650 nm) therapeutic device. Each of the two treatment sessions was separated by at least four hours. The axial lengths and diopters of the children's eyes were compared before and three months after treatment, and the effects of gender, age, and baseline diopter on the efficacy of RLRL therapy were analyzed. RESULTS: Following three months of treatment, the average axial length of the eyes decreased by 0.031 mm. The condition was better for the boys than for girls, but the difference was not statistically significant. As age increased (F = 8.112, P = 0.000) or as the absolute value of baseline myopia degree increased (F = 10.51, P = 0.000), axial lengths of the eyes tended to decrease. The spherical equivalent refraction (SER) of children decreased by an average of 0.012 ± 0.355D. The condition was better for the boys than for girls, but the difference was not statistically significant. SER increased in the direction of hyperopic drift as age increased (F = 2.48, P = 0.031), or as the absolute value of baseline myopia degrees increased (F = 6.835, P = 0.000). There were no obvious side effects following the treatment. CONCLUSION: This study showed that RLRL therapy is a potential efficient, easily operable, and practically feasible method for the prevention and control of myopia.

Cognitive load in tele-robotic surgery: a comparison of eye tracker designs.

PURPOSE: Eye gaze tracking and pupillometry are evolving areas within the field of tele-robotic surgery, particularly in the context of estimating cognitive load (CL). However, this is a recent field, and current solutions for gaze and pupil tracking in robotic surgery require assessment. Considering the necessity of stable pupillometry signals for reliable cognitive load estimation, we compare the accuracy of three eye trackers, including head and console-mounted designs. METHODS: We conducted a user study with the da Vinci Research Kit (dVRK), to compare the three designs. We collected eye tracking and dVRK video data while participants observed nine markers distributed over the dVRK screen. We compute and analyze pupil detection stability and gaze prediction accuracy for the three designs. RESULTS: Head-worn devices present better stability and accuracy of gaze prediction and pupil detection compared to console-mounted systems. Tracking stability along the field of view varies between trackers, with gaze predictions detected at invalid zones of the image with high confidence. CONCLUSION: While head-worn solutions show benefits in confidence and stability, our results demonstrate the need to improve eye tacker performance regarding pupil detection, stability, and gaze accuracy in tele-robotic scenarios.

The ROCK inhibitor netarsudil in the treatment of corneal endothelial decompensation caused by corneal endotheliitis: A case report and literature review.

Proper hydration and the clarity of the cornea are maintained through the crucial function of the corneal endothelium. Inflammation of the corneal endothelium, known as endotheliitis, can disrupt endothelial function, resulting in alterations to vision. Corneal endotheliitis is characterised by corneal oedema, the presence of keratic precipitates, inflammation within the anterior chamber, and occasionally, limbal injection, neovascularisation, and the concurrent or overlapping presence of uveitis. The aetiology of this condition is diverse, predominantly viral, but it may also be drug-induced, result from bacterial or fungal infections, be associated with systemic diseases and procedures, or remain idiopathic with no identifiable cause. To date, no standardised protocol for the treatment of this ocular disease exists, and in severe cases, corneal transplantation may be required. A 31-year-old male was transferred to our hospital for the management of corneal endothelial decompensation resulting from corneal endotheliitis. Hormonal therapy and antiviral medications proved ineffective, rendering the patient a candidate for corneal transplantation. As a final measure, treatment with the ROCK inhibitor netarsudil was initiated. The patient demonstrated significant improvement in symptoms, and the inflammation was successfully managed after nine months. In this study, a novel approach employing ROCK inhibitor therapy was utilised for the treatment of corneal endotheliitis, leading to marked recovery during patient follow-up. This case report represents the inaugural application of the ROCK inhibitor netarsudil in managing corneal endothelial decompensation attributed to corneal endotheliitis. These findings suggest that this method warrants consideration as a potential novel treatment option for similar conditions.

ASSIST-U: A system for segmentation and image style transfer for ureteroscopy.

Kidney stones require surgical removal when they grow too large to be broken up externally or to pass on their own. Upper tract urothelial carcinoma is also sometimes treated endoscopically in a similar procedure. These surgeries are difficult, particularly for trainees who often miss tumours, stones or stone fragments, requiring re-operation. Furthermore, there are no patient-specific simulators to facilitate training or standardized visualization tools for ureteroscopy despite its high prevalence. Here a system ASSIST-U is proposed to create realistic ureteroscopy images and videos solely using preoperative computerized tomography (CT) images to address these unmet needs. A 3D UNet model is trained to automatically segment CT images and construct 3D surfaces. These surfaces are then skeletonized for rendering. Finally, a style transfer model is trained using contrastive unpaired translation (CUT) to synthesize realistic ureteroscopy images. Cross validation on the CT segmentation model achieved a Dice score of 0.853 ± 0.084. CUT style transfer produced visually plausible images; the kernel inception distance to real ureteroscopy images was reduced from 0.198 (rendered) to 0.089 (synthesized). The entire pipeline from CT to synthesized ureteroscopy is also qualitatively demonstrated. The proposed ASSIST-U system shows promise for aiding surgeons in the visualization of kidney ureteroscopy.

Intraoperative gaze guidance with mixed reality.

Efficient communication and collaboration are essential in the operating room for successful and safe surgery. While many technologies are improving various aspects of surgery, communication between attending surgeons, residents, and surgical teams is still limited to verbal interactions that are prone to misunderstandings. Novel modes of communication can increase speed and accuracy, and transform operating rooms. A mixed reality (MR) based gaze sharing application on Microsoft HoloLens 2 headset that can help expert surgeons indicate specific regions, communicate with decreased verbal effort, and guide novices throughout an operation is presented. The utility of the application is tested with a user study of endoscopic kidney stone localization completed by urology experts and novice surgeons. Improvement is observed in the NASA task load index surveys (up to 25.23%), in the success rate of the task (6.98% increase in localized stone percentage), and in gaze analyses (up to 31.99%). The proposed application shows promise in both operating room applications and surgical training tasks.

Development of an augmented reality guidance system for head and neck cancer resection.

The use of head-mounted augmented reality (AR) for surgeries has grown rapidly in recent years. AR aids in intraoperative surgical navigation through overlaying three-dimensional (3D) holographic reconstructions of medical data. However, performing AR surgeries on complex areas such as the head and neck region poses challenges in terms of accuracy and speed. This study explores the feasibility of an AR guidance system for resections of positive tumour margins in a cadaveric specimen. The authors present an intraoperative solution that enables surgeons to upload and visualize holographic reconstructions of resected cadaver tissues. The solution involves using a 3D scanner to capture detailed scans of the resected tissue, which are subsequently uploaded into our software. The software converts the scans of resected tissues into specimen holograms that are viewable through a head-mounted AR display. By re-aligning these holograms with cadavers with gestures or voice commands, surgeons can navigate the head and neck tumour site. This workflow can run concurrently with frozen section analysis. On average, the authors achieve an uploading time of 2.98 min, visualization time of 1.05 min, and re-alignment time of 4.39 min, compared to the 20 to 30 min typical for frozen section analysis. The authors achieve a mean re-alignment error of 3.1 mm. The authors' software provides a foundation for new research and product development for using AR to navigate complex 3D anatomy in surgery.

The protective effect of vitamin A palmitate eye gel on the ocular surface during general anaesthesia surgery: a randomized controlled trial.

PURPOSE: To investigate the change in tear production associated with general anesthesia and the protective effect of vitamin A palmitate eye gel on the ocular surface during general anesthesia. METHODS: This double-blind, randomized clinical trial included patients undergoing non-ophthalmic surgery under general anesthesia who randomly received vitamin A palmitate eye gel and taping for one eye (Group A, n = 60) or taping alone for the other eye (Group B, n = 60). Symptom assessment in dry eye (SANDE) score, tear film break-up time (TBUT), corneal fluorescein staining (CFS) score, and Schirmer tear test I (STT-1) were analyzed under a hand-held slit lamp before anesthesia (T0), 0.5 h postoperatively (T1), and 24 h postoperatively (T2). RESULTS: At 0.5 h postoperatively, an increase in CFS score was observed in both groups (P < 0.05 in Group A and P < 0.01 in Group B), and the participants in Group A had less corneal abrasions than those in Group B. STT-1 significantly increased in Group A (P < 0.05), while it significantly decreased in Group B (P < 0.001). The changes between the two groups were statistically significant (P < 0.001). At 24 h postoperatively, both CFS score and STT-1 almost returned to baseline levels in the two groups. In both groups, the SANDE score and TBUT showed little change at 0.5 h and 24 h postoperatively (all P > 0.05). CONCLUSION: Vitamin A palmitate eye gel effectively protected the ocular surface and aqueous supplementation during general anesthesia. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2100052140) on 20/10/2021.

Association between sleep quality and dry eye disease: a literature review and meta-analysis.

OBJECTIVE: The purpose of this article is to systematically review the association between dry eye and sleep quality. METHODS: PubMed, EMBASE, Cochrane, Web of Science, and grey literature databases were searched for observational studies published before April 2023. Meta-analysis was performed using STAT15 software. RESULTS: A total of 21 studies with 419,218 participants were included. The results showed that the dry eye subjects had a worse sleep quality than the healthy population, with poorer subjective sleep quality, longer sleep latency, and a higher risk of unhealthy sleep duration such as insufficient sleep or excessive sleep. The Pittsburgh Sleep Quality Index (PSQI) scores of the dry eye subjects were significantly higher than those of the control subjects (WMD = 1.78, 95%CI: 1.06, 2.50, P < 0.001). The dry eye subjects scored higher than the control subjects in sleep quality, sleep latency, and sleep disturbance in PSQI; there was no difference between the dry eye individuals and control subjects in sleep duration, sleep efficiency, daytime dysfunction, and sleep medication scores. The risk of sleep disorders in the dry eye subjects was significantly higher than that in the non-dry eye subjects (RR = 2.20, 95%CI: 1.78, 2.72, P < 0.001); the risk of insufficient sleep in the dry eye subjects was higher than that in the control subjects (RR = 3.76, 95%CI: 3.15, 4.48, P < 0.001), and the prevalence of excessive sleepiness in dry eye subjects was higher than that in the control subjects (RR = 5.53, 95%CI: 3.83, 7.18, P < 0.001). The ESS scores of the dry eye subjects were significantly higher than those of the control subjects (WMD = 3.02, 95%CI: 2.43, 3.60, P < 0.01). CONCLUSION: Our meta-analysis suggests that individuals with dry eye have a worse sleep quality than the healthy population, with poorer subjective sleep quality, longer sleep latency, and higher risk of unhealthy sleep duration such as insufficient sleep or excessive sleepiness.

Towards navigation in endoscopic kidney surgery based on preoperative imaging.

Endoscopic renal surgeries have high re-operation rates, particularly for lower volume surgeons. Due to the limited field and depth of view of current endoscopes, mentally mapping preoperative computed tomography (CT) images of patient anatomy to the surgical field is challenging. The inability to completely navigate the intrarenal collecting system leads to missed kidney stones and tumors, subsequently raising recurrence rates. A guidance system is proposed to estimate the endoscope positions within the CT to reduce re-operation rates. A Structure from Motion algorithm is used to reconstruct the kidney collecting system from the endoscope videos. In addition, the kidney collecting system is segmented from CT scans using 3D U-Net to create a 3D model. The two collecting system representations can then be registered to provide information on the relative endoscope position. Correct reconstruction and localization of intrarenal anatomy and endoscope position is demonstrated. Furthermore, a 3D map is created supported by the RGB endoscope images to reduce the burden of mental mapping during surgery. The proposed reconstruction pipeline has been validated for guidance. It can reduce the mental burden for surgeons and is a step towards the long-term goal of reducing re-operation rates in kidney stone surgery.

Cytisine eye drops for benzalkonium chloride-induced dry eye: safety and efficacy evaluation.

This experiment aimed to investigate the feasibility of cytisine (CYT) in treating eye diseases with ocular topical application. An in vitro cytotoxicity test, a hen's egg test-chorioallantoic membrane (HET-CAM), and a mouse eye tolerance test were used to fully reveal the ocular safety profiles of CYT. For the efficacy evaluations, CYT's effects on cell wound healing, against H2O2-induced oxidative stress damages on cells, and on benzalkonium chloride (BAC)-induced dry eye disease (DED) in mice were evaluated. Results showed that CYT did not show any cytotoxicities at concentrations no higher than 250 µg/ml, while lipoic acid (α-LA) at 250 µg/ml and BAC at 1.25 µg/ml showed significant cytotoxicities within 48 h incubation. The HET-CAM and mouse eye tolerance test confirmed that 0.5% CYT eye drops demonstrated good safety characteristics. Efficacy evaluations showed that CTY significantly promoted cell migration and wound healing. CYT significantly improved cell survival against H2O2-induced oxidative stress damage by reversing the imbalance between the reactive oxygen species (ROS) and antioxidant defense mechanisms. The animal evaluation of the BAC-induced dry eye model revealed that CYT demonstrated a strong treatment effect, including reversing ocular surface damages, recovering corneal sensitivity, and inhibiting neovascularization; HMGB1/NF-κB signaling was involved in this DED treatment by CTY. In conclusion, CYT had strong experimental treatment efficacy against DED with good ocular safety profiles, and it might be a novel and promising drug for DED.

Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children With Myopia: A Randomized Clinical Trial.

Importance: Treatments are needed to slow progression of or reduce incidence of myopia. Objective: To evaluate the efficacy and safety of daily 650-nm low-level red light (LLRL) for myopia treatment. Design, Setting, and Participants: Single-masked, randomized clinical trial at 1 site in China. Baseline measurements were completed from August to September 2021. Participants were children aged 6 to 12 years with spherical equivalent error (SER) of -6 diopters (D) to 3 D. Data were analyzed from March to July 2023. Interventions: Irradiation daily with 650-nm LLRL for 3 minutes twice daily 4 or more hours apart or no intervention. Main Outcomes and Measures: Primary outcomes were changes in cycloplegia SER and axial length (AL) at 6- and 12-month follow-up visits. Safety was assessed on masked fundus photograph evaluations. Results: A total of 336 children were randomly allocated into the LLRL group or control group in a 1:1 ratio. The control group contained 86 female patients (51.2%), and the treatment group contained 90 female patients (53.6%). The mean (SD) age, SER, and AL were 9.0 (1.9) years, -1.3 (1.5) D, and 23.8 (1.0) mm for all patients. A total of 161 (95.8%) in the LLRL group and 159 (94.6%) in the control group returned for the 6-month follow-up. A total of 157 (93.5%) in the LLRL group and 152 (90.5%) in the control group returned for the 12-month follow-up. Mean (SD) changes in SER were 0.15 (0.16) D and -0.26 (0.21) D for the LLRL group and the control group, respectively (difference, -0.41 D; 95% CI, -0.48 to -0.34 D; P < .001), at 6 months and 0.24 (0.27) D and -0.65 (0.33) D for the LLRL group and the control group, respectively (difference, -0.89 D; 95% CI, -0.95 to -0.83 D; P < .001), at 12 months. Mean (SD) changes in AL were -0.06 (0.08) mm and 0.13 (0.12) mm for the LLRL group and control group, respectively (difference, 0.19 mm; 95% CI, 0.16 to 0.22 mm; P < .001), at 6 months and -0.11 (0.10) mm and 0.26 (0.16) mm for the LLRL group and control group, respectively (difference, 0.37 mm; 95% CI, 0.34 to 0.40 mm; P < .001). Masked fundus photograph review did not identify retinal changes in either group. Conclusions and relevance: These findings suggest daily use of 650-nm LLRL for 1 year can slow progression of SER and AL without safety concerns identified. Confirmation of these findings at independent sites seems warranted, as well as determining whether these effects can be sustained with or without continued treatment and whether LLRL has any effect on pathological myopia. Trial Registration: ChiCTR2200058963.

Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice.

Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10LKO) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10LTG) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.

Cognitive effort detection for tele-robotic surgery via personalized pupil response modeling.

PURPOSE: Gaze tracking and pupillometry are established proxies for cognitive load, giving insights into a user's mental effort. In tele-robotic surgery, knowing a user's cognitive load can inspire novel human-machine interaction designs, fostering contextual surgical assistance systems and personalized training programs. While pupillometry-based methods for estimating cognitive effort have been proposed, their application in surgery is limited by the pupil's sensitivity to brightness changes, which can mask pupil's response to cognitive load. Thus, methods considering pupil and brightness conditions are essential for detecting cognitive effort in unconstrained scenarios. METHODS: To contend with this challenge, we introduce a personalized pupil response model integrating pupil and brightness-based features. Discrepancies between predicted and measured pupil diameter indicate dilations due to non-brightness-related sources, i.e., cognitive effort. Combined with gaze entropy, it can detect cognitive load using a random forest classifier. To test our model, we perform a user study with the da Vinci Research Kit, where 17 users perform pick-and-place tasks in addition to auditory tasks known to generate cognitive effort responses. RESULTS: We compare our method to two baselines (BCPD and CPD), demonstrating favorable performance in varying brightness conditions. Our method achieves an average true positive rate of 0.78, outperforming the baselines (0.57 and 0.64). CONCLUSION: We present a personalized brightness-aware model for cognitive effort detection able to operate under unconstrained brightness conditions, comparing favorably to competing approaches, contributing to the advancement of cognitive effort detection in tele-robotic surgery. Future work will consider alternative learning strategies, handling the difficult positive-unlabeled scenario in user studies, where only some positive and no negative events are reliably known.