Ferroptosis Contributes to Microvascular Dysfunction in Diabetic Retinopathy.

Ferroptosis is a new form of cell death characterized by iron-dependent lipid peroxidation. Whether ferroptosis is involved in retinal microvascular dysfunction under diabetic condition is not known. Herein, the expression of ferroptosis-related genes in patients with proliferative diabetic retinopathy and in diabetic mice was determined with quantitative RT-PCR. Reactive oxygen species, iron content, lipid peroxidation products, and ferroptosis-associated proteins in the cultured human retinal microvascular endothelial cells (HRMECs) and in the retina of diabetic mice were examined. The association of ferroptosis with the functions of endothelial cells in vitro was evaluated. After administration of ferroptosis-specific inhibitor, Fer-1, the retinal microvasculature in diabetic mice was assessed. Characteristic changes of ferroptosis-associated markers, including glutathione peroxidase 4, ferritin heavy chain 1, long-chain acyl-CoA synthetase 4, transferrin receptor protein 1, and cyclooxygenase-2, were detected in the retinal fibrovascular membrane of patients with proliferative diabetic retinopathy, cultured HRMECs, and the retina of diabetic mice. Elevated levels of reactive oxygen species, lipid peroxidation, and iron content were found in the retina of diabetic mice and in cultured HRMECs. Ferroptosis was found to be associated with HRMEC dysfunction under high-glucose condition. Inhibition of ferroptosis with specific inhibitor Fer-1 in diabetic mice significantly reduced the severity of retinal microvasculopathy. Ferroptosis contributes to microvascular dysfunction in diabetic retinopathy, and inhibition of ferroptosis might be a promising strategy for the therapy of early-stage diabetic retinopathy.

Broadband linear frequency-modulated waveform generation based on optical frequency comb assisted spectrum stitching.

In this paper, we propose and demonstrate a novel spectrum stitching method for broadband linear frequency-modulated waveform (LFMW) generation. An optical frequency comb (OFC) is modulated by a narrowband LFMW whose bandwidth matches the free spectral range of the OFC. Optical injection locking is employed in extracting one broadband frequency sweeping component from the modulated OFC. In this way, seamless spectrum stitching is realized and a broadband LFMW with a multi-fold time-bandwidth product (TBWP) is obtained. Our scheme has a simple structure, which requires only a single OFC, a modulation module and a baseband waveform generator. An LFMW as broad as 20 GHz is generated from a baseband LFMW with 2GHz bandwidth experimentally. The TBWP is 100 times as large as that of the baseband LFMW. Moreover, the power fluctuation and the phase jumps are both eliminated, ensuring an excellent pulse compression performance. Benefiting from the injection locking technique, the linearity reaches 2.0 × 10-6. The central frequency tuning ability of our scheme is also demonstrated.

Reconfigurable radar signal generator based on phase-quantized photonic digital-to-analog conversion.

A novel, to the best of our knowledge, scheme for reconfigurable radar signal generation is proposed based on the principle of photonic phase-quantized digital-to-analog conversion. Multi-level digital phase modulation with different modulation depths is combined to convert multi-channel digital data to the phase of an optical carrier. Frequency-modulated or phase-modulated radar signals are generated by beating the phase-synthesized optical carrier with a coherent reference light. The proposed radar signal generator features a simple structure, highly reconfigurable modulation format, and flexibly tunable frequency. A 3-bit photonic phase-quantized digital-to-analog converter with a 10-GSa/s sampling rate is constructed experimentally. The generation of linear frequency-modulated, nonlinear frequency-modulated, frequency-stepped, frequency-hopping, binary phase-coded, and polyphase-coded waveforms is demonstrated.

Cost-effectiveness of artificial intelligence screening for diabetic retinopathy in rural China.

BACKGROUND: Diabetic retinopathy (DR) has become a leading cause of global blindness as a microvascular complication of diabetes. Regular screening of diabetic retinopathy is strongly recommended for people with diabetes so that timely treatment can be provided to reduce the incidence of visual impairment. However, DR screening is not well carried out due to lack of eye care facilities, especially in the rural areas of China. Artificial intelligence (AI) based DR screening has emerged as a novel strategy and show promising diagnostic performance in sensitivity and specificity, relieving the pressure of the shortage of facilities and ophthalmologists because of its quick and accurate diagnosis. In this study, we estimated the cost-effectiveness of AI screening for DR in rural China based on Markov model, providing evidence for extending use of AI screening for DR. METHODS: We estimated the cost-effectiveness of AI screening and compared it with ophthalmologist screening in which fundus images are evaluated by ophthalmologists. We developed a Markov model-based hybrid decision tree to analyze the costs, effectiveness and incremental cost-effectiveness ratio (ICER) of AI screening strategies relative to no screening strategies and ophthalmologist screening strategies (dominated) over 35 years (mean life expectancy of diabetes patients in rural China). The analysis was conducted from the health system perspective (included direct medical costs) and societal perspective (included medical and nonmedical costs). Effectiveness was analyzed with quality-adjusted life years (QALYs). The robustness of results was estimated by performing one-way sensitivity analysis and probabilistic analysis. RESULTS: From the health system perspective, AI screening and ophthalmologist screening had incremental costs of $180.19 and $215.05 but more quality-adjusted life years (QALYs) compared with no screening. AI screening had an ICER of $1,107.63. From the societal perspective which considers all direct and indirect costs, AI screening had an ICER of $10,347.12 compared with no screening, below the cost-effective threshold (1-3 times per capita GDP of Chinese in 2019). CONCLUSIONS: Our analysis demonstrates that AI-based screening is more cost-effective compared with conventional ophthalmologist screening and holds great promise to be an alternative approach for DR screening in the rural area of China.

Karoshi May Be a Consequence of Overwork-Related Malignant Arrhythmia.

BACKGROUND Karoshi, which is sudden death associated with overwork, has become a serious problem in China. Many studies have examined the relationship between cardiovascular risks and karoshi, but there is little evidence that explains the exact mechanism by which overwork induces sudden death. In these cases, there are few obvious positive findings from forensic autopsies except for histories of overwork prior to death. Therefore, we assume that abnormalities, such as cardiac arrhythmia, rather than organic changes are the cause of karoshi. MATERIAL AND METHODS In the present study, the forced swim test (FST) was used to establish models of overwork. The myocardial tissues of SD rats taking FST (1 h per day, for 30 consecutive days) were collected. The arrhythmia-related molecule CX43 as well as its upstream regulation molecule Cav-1 and cSrc were tested by Western blot (WB) and immunohistochemistry (IHC). HE staining and Masson's staining were performed in the myocardium tissue section. RESULTS We observed downregulation of caveolin-1 (Cav1) followed by cSrc activation, resulting in the decrease of connexin43 (Cx43) levels in overwork models. Myocardial interstitial fibrosis, which is associated with electrophysiological aberrances that result in arrhythmia, was also found in the overwork models. CONCLUSIONS These data provide a mechanistic explanation for the speculated link between karoshi and cardiac arrhythmias.

Advancing crush syndrome management: the potent role of Sodium zirconium cyclosilicate in early hyperkalemia intervention and survival enhancement in a rat model.

Background: Crush Syndrome (CS), a severe trauma resulting from prolonged muscle compression, is commonly seen in large-scale disasters such as earthquakes. It not only causes localized tissue damage but also triggers electrolyte imbalances, particularly hyperkalemia, increasing the risk of early mortality. This study aims to assess the early intervention effects of Sodium Zirconium Cyclosilicate (SZC) on hyperkalemia in rat CS model. Methods: A rat CS model was established using a self-developed multi-channel intelligent small-animal crush injury platform. Rats in the experimental groups were treated with varying doses of SZC before compression and immediately post-decompression. The efficacy of SZC was evaluated by continuous monitoring of blood potassium levels and survival rates. Serum creatinine (Cre) and blood urea nitrogen (BUN) levels were analyzed, and renal damage was assessed through histopathological examination. Results: SZC treatment significantly reduced blood potassium levels and improved survival rates in rats. Compared to the placebo group, the SZC-treated rats showed a significant decrease in blood potassium levels at 6 and 12 h post-decompression, maintaining lower levels at 24 h. Biochemical analysis indicated no significant impact of SZC on renal function, with no notable differences in Cre and BUN levels between groups. Histopathological findings revealed similar levels of renal damage in both groups. Conclusion: SZC demonstrates significant early intervention effects on hyperkalemia in a rat model of crush injury, effectively improving survival rates without adverse effects on renal function. These results provide a new strategic direction for the clinical treatment of Crush Syndrome and lay the foundation for future clinical applications.

BREAKING NEW GROUND: STANDARDIZING RAT MODELS FOR CRUSH SYNDROME INVESTIGATIONS.

ABSTRACT: Crush syndrome (CS), alternatively termed traumatic rhabdomyolysis, is a paramount posttraumatic complication. Given the infeasibility of conducting direct simulation research in humans, the role of animal models is pivotal. Regrettably, the dearth of standardized animal models persists. The objective of this study was to construct a repeatable standardized rat CS models and, based on this, simulate specific clinical scenarios. Methods: Using a self-developed multichannel intelligent small-animal crush injury platform, we applied a force of 5 kg to the hind limbs of 8-week-old rats (280-300 g), subjecting them to a continuous 12 h compression to establish the CS model. Continuous monitoring was conducted for both the lower limbs and the overall body status. After decompression, biochemical samples were collected at 3, 6, 12, and 24 h. In addition, we created a CS model after resection of the left kidney (UNx-CS), which was conceptualized to simulate a more challenging clinical scenario to investigate the physiological and pathological responses rats with renal insufficiency combined with crush injury. The results were compared with those of the normal CS model group. Results : Our experiments confirm the stability of the crush injury platform. We defined the standardized conditions for modeling and successfully established rats CS model in bulk. After 12 h of compression, only 40% of the rats in the CS group survived for 24 h. Systemically, there was clear evidence of insufficient perfusion, reflecting the progression of CS from localized to generalized. The injured limbs displayed swelling, localized perfusion deficits, and severe pathological alterations. Significant changes were observed in blood biochemical markers: aspartate transaminase, lactate dehydrogenase, K+, creatine kinase, creatinine, and blood urea nitrogen levels rose rapidly after decompression and were significantly higher than the sham group. The kidney demonstrated characteristic pathological changes consistent with established CS diagnostic criteria. Although the UNx-CS rat model did not exhibit significant biochemical differences and pathological scores when compared with the standard CS model, it did yield intriguing results with regard to kidney morphology. The UNx-CS group manifested a higher incidence of cortical and medullary protein casts compared with the NC-CS group. Conclusion: We developed and iteratively refined a novel digital platform, addressing the multiple uncontrollable variables that plagued prior models. This study validated the stability of the platform, defined the standardized conditions for modeling and successfully established the CS model with good repeatability in bulk. In addition, our innovative approach to model a clinically challenging scenario, the UNx-CS rat model. This offers an opportunity to delve deeper into understanding the combined effects of preexisting renal compromise and traumatic injury. In summary, the development of a standardized, reproducible CS model in rats represents a significant milestone in the study of Crush syndrome. This study is of paramount significance as it advances the standardization of the CS model, laying a solid foundation for subsequent studies in related domains, especially in CS-AKI.

Detection of KRAS mutation using plasma samples in non-small-cell lung cancer: a systematic review and meta-analysis.

Background: The aim of this study was to investigate the diagnostic accuracy of KRAS mutation detection using plasma sample of patients with non-small cell lung cancer (NSCLC). Methods: Databases of Pubmed, Embase, Cochrane Library, and Web of Science were searched for studies detecting KRAS mutation in paired tissue and plasma samples of patients with NSCLC. Data were extracted from each eligible study and analyzed using MetaDiSc and STATA. Results: After database searching and screening of the studies with pre-defined criteria, 43 eligible studies were identified and relevant data were extracted. After pooling the accuracy data from 3341 patients, the pooled sensitivity, specificity and diagnostic odds ratio were 71%, 94%, and 59.28, respectively. Area under curve of summary receiver operating characteristic curve was 0.8883. Subgroup analysis revealed that next-generation sequencing outperformed PCR-based techniques in detecting KRAS mutation using plasma sample of patients with NSCLC, with sensitivity, specificity, and diagnostic odds ratio of 73%, 94%, and 82.60, respectively. Conclusion: Compared to paired tumor tissue sample, plasma sample showed overall good performance in detecting KRAS mutation in patients with NSCLC, which could serve as good surrogate when tissue samples are not available.

Dispersion-less Kerr solitons in spectrally confined optical cavities.

Solitons are self-reinforcing localized wave packets that manifest in the major areas of nonlinear science, from optics to biology and Bose-Einstein condensates. Recently, optically driven dissipative solitons have attracted great attention for the implementation of the chip-scale frequency combs that are decisive for communications, spectroscopy, neural computing, and quantum information processing. In the current understanding, the generation of temporal solitons involves the chromatic dispersion as a key enabling physical effect, acting either globally or locally on the cavity dynamics in a decisive way. Here, we report on a novel class of solitons, both theoretically and experimentally, which builds up in spectrally confined optical cavities when dispersion is practically absent, both globally and locally. Precisely, the interplay between the Kerr nonlinearity and spectral filtering results in an infinite hierarchy of eigenfunctions which, combined with optical gain, allow for the generation of stable dispersion-less dissipative solitons in a previously unexplored regime. When the filter order tends to infinity, we find an unexpected link between dissipative and conservative solitons, in the form of Nyquist-pulse-like solitons endowed with an ultra-flat spectrum. In contrast to the conventional dispersion-enabled nonlinear Schrödinger solitons, these dispersion-less Nyquist solitons build on a fully confined spectrum and their energy scaling is not constrained by the pulse duration. Dispersion-less soliton molecules and their deterministic transitioning to single solitons are also evidenced. These findings broaden the fundamental scope of the dissipative soliton paradigm and open new avenues for generating soliton pulses and frequency combs endowed with unprecedented temporal and spectral features.

Progress in the Diagnostic and Predictive Evaluation of Crush Syndrome.

Crush syndrome (CS), also known as traumatic rhabdomyolysis, is a syndrome with a wide clinical spectrum; it is caused by external compression, which often occurs in earthquakes, wars, and traffic accidents, especially in large-scale disasters. Crush syndrome is the second leading cause of death after direct trauma in earthquakes. A series of clinical complications caused by crush syndrome, including hyperkalemia, myoglobinuria, and, in particular, acute kidney injury (AKI), is the main cause of death in crush syndrome. The early diagnosis of crush syndrome, the correct evaluation of its severity, and accurate predictions of a poor prognosis can provide personalized suggestions for rescuers to carry out early treatments and reduce mortality. This review summarizes various methods for the diagnostic and predictive evaluation of crush syndrome, including urine dipstick tests for a large number of victims, traditional and emerging biomarkers, imaging-assisted diagnostic methods, and developed evaluation models, with the aim of providing materials for scholars in this research field.