Genetically predicted causal effects of gut microbiota on spinal pain: a two-sample Mendelian randomization analysis.

Background: Observational studies have hinted at a correlation between the gut microbiota and spinal pain (SP). However, the impact of the gut microbiota on SP remains inconclusive. Methods: In this study, we employed a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between the gut microbiota and SP, encompassing neck pain (NP), thoracic spine pain (TSP), low back pain (LBP), and back pain (BP). The compiled gut microbiota data originated from a genome-wide association study (GWAS) conducted by the MiBioGen consortium (n = 18,340). Summary data for NP were sourced from the UK Biobank, TSP from the FinnGen Biobank, and LBP from both the UK Biobank and FinnGen Biobank. Summary data for BP were obtained from the UK Biobank. The primary analytical approach for assessing causal relationships was the Inverse Variance Weighted (IVW) method, supplemented by various sensitivity analyses to ensure result robustness. Results: The IVW analysis unveiled 37 bacterial genera with a potential causal relationship to SP. After Benjamini-Hochberg corrected test, four bacterial genera emerged with a strong causal relationship to SP. Specifically, Oxalobacter (OR: 1.143, 95% CI 1.061-1.232, P = 0.0004) and Tyzzerella 3 (OR: 1.145, 95% CI 1.059-1.238, P = 0.0007) were identified as risk factors for LBP, while Ruminococcaceae UCG011 (OR: 0.859, 95% CI 0.791-0.932, P = 0.0003) was marked as a protective factor for LBP, and Olsenella (OR: 0.893, 95% CI 0.839-0.951, P = 0.0004) was recognized as a protective factor for low back pain or/and sciatica. No significant heterogeneity or horizontal pleiotropy was observed through alternative testing methods. Conclusion: This study establishes a causal relationship between the gut microbiota and SP, shedding light on the "gut-spine" axis. These findings offer novel perspectives for understanding the etiology of SP and provide a theoretical foundation for potential interventions targeting the gut microbiota to prevent and treat SP.

Gene association analysis to determine the causal relationship between immune cells and juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a type of chronic childhood arthritis with complex pathogenesis. Immunological studies have shown that JIA is an acquired self-inflammatory disease, involving a variety of immune cells, and it is also affected by genetic and environmental susceptibility. However, the precise causative relationship between the phenotype of immune cells and JIA remains unclear to date. The objective of our study is to approach this inquiry from a genetic perspective, employing a method of genetic association analysis to ascertain the causal relationship between immune phenotypes and the onset of JIA. METHODS: In this study, a two-sample Mendelian randomization (MR) analysis was used to select single nucleotide polymorphisms (SNPs) significantly associated with immune cells as instrumental variables to analyze the bidirectional causal relationship between 731 immune cells and JIA. There were four types of immune features (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)). Finally, the heterogeneity and horizontal reproducibility of the results were verified by sensitivity analysis, which ensured more robust results. RESULTS: We found that CD3 on CM CD8br was causally associated with JIA at the level of 0.05 significant difference (95% CI = 0.630 ~ 0.847, P = 3.33 × 10-5, PFDR = 0.024). At the significance level of 0.20, two immunophenotypes were causally associated with JIA, namely: HLA DR on CD14+ CD16- monocyte (95% CI = 0.633 ~ 0.884, P = 6.83 × 10-4, PFDR = 0.16) and HLA DR on CD14+ monocyte (95% CI = 0.627 ~ 0.882, P = 6.9 × 10-4, PFDR = 0.16). CONCLUSION: Our study assessed the causal effect of immune cells on JIA from a genetic perspective. These findings emphasize the complex and important role of immune cells in the pathogenesis of JIA and lay a foundation for further study of the pathogenesis of JIA.

Association between dermatology follow-up and melanoma survival: A population-based cohort study.

BACKGROUND: Guidelines recommend that patients with melanoma undergo dermatologic examination at least annually. Adherence to follow-up and its impact on survival are unclear. OBJECTIVE: To determine the level of adherence to annual dermatologic follow-up in patients with primary cutaneous melanoma, identify predictors for better adherence, and evaluate whether adherence was associated with melanoma-related mortality. METHODS: Retrospective inception cohort analysis of adults with primary invasive melanoma in Ontario, Canada from 2010 to 2013 with follow-up until December 31, 2018. RESULTS: Adherence to dermatologic follow-up was variable with only 28.0% of patients seeing a dermatologist at least annually (median follow-up 5.0 years). Younger age, female sex, higher income, greater access to dermatology care, stage 2/3 melanoma, prior keratinocyte carcinoma, fewer comorbidities, and any outpatient visit in the 12 months prior to melanoma diagnosis were predictors for adherence. Greater adherence to annual dermatology visits was associated with reduced melanoma-specific mortality compared with lower levels of adherence (adjusted hazard ratio 0.64, 95% CI 0.52-0.78). LIMITATIONS: Observational study design and inability to identify skin examinations performed by non-dermatologists. CONCLUSION: Adherence to annual dermatology visits after melanoma diagnosis was low. Greater adherence may promote better patient survival but warrants confirmation in further research including randomized trials.

Comparing the ocular surface temperature and dry eye condition of keratoconus with normal eyes using infrared thermal imaging.

PURPOSE: This study was conducted to compare the ocular surface temperature in keratoconus eyes with that in normal eyes. METHODS: A total of 27 participants were enrolled, with 10 and 17 participants in the keratoconus and control groups, respectively. Participants in the control group underwent an ophthalmic slit lamp examination and ocular thermography, while an additional corneal tomography was performed for those in the keratoconus group. RESULTS: For patients with keratoconus, the mean upper eyelid temperature (UET) was 32.36 ± 1.02 °C, inner canthus temperature (ICT) was 34.25 ± 0.83 °C, outer canthus temperature (OCT) was 33.62 ± 0.96 °C, initial central corneal temperature (initial CCT) was 33.04 ± 1.03 °C, sixth-second CCT (6 s-CCT) was 32.67 ± 1.19 °C, and the mean change in CCT measured within 6 s (change in CCT within 6 s) was 0.36 ± 0.26 °C. For controls, the values for UET, ICT, OCT, initial CCT, 6 s-CCT, and change in CCT within 6 s were 32.35 ± 1.13 °C, 34.14 ± 0.91 °C, 33.51 ± 1.02 °C, 33.22 ± 1.01 °C, 32.99 ± 1.01 °C, and 0.22 ± 0.17 °C, respectively. Except for the change in CCT within 6 s (p = 0.022), no significant differences were observed in UET (p = 0.973), ICT (p = 0.659), OCT (p = 0.697), initial CCT (p = 0.556) or 6 s-CCT (p = 0.310) between the two groups. CONCLUSION: The keratoconus eyes showed faster changes in CCT and evaporation of tear film after opening the eyes. Therefore, the keratoconus eyes had a higher incidence of dry eye conditions.

Immunohistochemistry analysis reveals lysyl oxidase-like 3 as a novel prognostic marker for primary melanoma.

Lysyl oxidase-like 3 (LOXL3) is an extracellular enzyme involved in the synthesis of collagen and elastin, and it has been reported to promote melanoma cell proliferation and invasion in vitro. However, the expression level of LOXL3 at different stages of melanocytic lesions and the role of LOXL3 in melanoma pathogenesis remain unknown. Immunohistochemical staining of LOXL3 in a tissue microarray of 373 biopsies at different melanocytic stages was conducted. The correlation between LOXL3 expression and patient survival was examined using Kaplan-Meier survival analysis. Univariate and multivariate Cox regression analyses were conducted to study the hazard ratios. The tissue microarray study revealed that stronger expression of LOXL3 protein was found at more advanced melanocytic stages (P < 0.0001; χ2 test). Increased LOXL3 expression was associated with enhanced tumor thickness and mitosis. Survival analysis showed significantly worsened prognosis in primary melanoma patients when the LOXL3 expression level was higher (P = 0.043; log-rank test). Multivariate Cox regression analysis further showed that LOXL3 expression is a prognostic factor for primary melanoma patient survival (P = 0.04). LOXL3 expression is positively correlated with tumor progression and invasion, and its overexpression is associated with worse prognosis of primary melanoma patients. LOXL3 can serve as a prognostic marker to help identify primary melanoma patients at higher risks of death.

A nomogram predicting subclinical extension of cutaneous squamous cell carcinoma in Chinese individuals: A retrospective study.

ABSTRACT: Cutaneous squamous cell carcinoma usually extends beyond the visible margin. Little is known about the predictors for cutaneous squamous cell carcinoma with subclinical extension in Chinese individuals. This study aimed to construct a nomogram for predicting the probability of subclinical extension of cutaneous squamous cell carcinoma in Chinese patients.A retrospective analysis was conducted using data from Mohs micrographic surgery-treated cutaneous squamous cell carcinoma patients at a single institution between December 1, 2009 and October 31, 2019. Subclinical extension was defined as a lesion requiring ≥ 2 Mohs stages or with final safe margins of ≥ 5 mm. A nomogram predicting the probability of subclinical extension was constructed using the predictors identified in multivariable analysis.Of 274 patients included, 119 (43.4%) had subclinical extension. In multivariable analysis, male sex (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.40-4.29; P = .002), lesions on mucocutaneous areas (OR, 3.71; 95% CI, 1.34-10.32; P = .012) and extremities (OR, 2.40; 95% CI, 1.20-4.78; P = .013), maximum diameter of 10 to 19 mm (OR, 14.15; 95% CI, 4.24-47.28; P < .001), and 20 to 29 mm (OR, 9.21; 95% CI, 2.80-30.29; P < .001) were associated with subclinical extension. A nomogram incorporating these 3 variables demonstrated promising predictive ability (C statistics = 0.78; 95% CI, 0.67-0.89).The nomogram incorporating sex, tumor location, and maximum diameter can provide individualized prediction for subclinical extension in Chinese patients with cutaneous squamous cell carcinoma. This information may help surgeons determine appropriate margins at the first Mohs stage.

Two-dimensional stretchable blazed wavelength-tunable grating based on PDMS.

This paper reports a two-dimensional stretchable blazed wavelength-tunable grating based on polydimethylsiloxane (PDMS). In the elastic range, stretch the grating along (Y-axis) and perpendicular to (X-axis) the grating line, fix the position of the +1st-order spot to maintain the grating period, and only change the groove angle to tune the blazed wavelength. By stretching the grating up to 20% of the Y-axis, and 5.2% of the X-axis, the groove angle is reduced by 1.33°, and the blazed wavelength of the first-order diffraction shifts toward the short-wave direction by 42.3 nm. The sensitivity of a spectrometer can be enhanced by tuning the blazed wavelength of the PDMS grating to the wavelength of the spectrum peak under observation in the bands from 460.8 nm to 503.1 nm.

Analytical design of a high-performing +1st order diffraction convex grating imaging spectrometer.

A novel concentric spectrometer having one convex grating and one concave mirror, working at ${+}{1}$+1st order diffraction, and with a small size, high resolution, and high diffraction efficiency, is proposed. It can simultaneously achieve high resolution and compactness by increasing the grating groove density. A compact spectrometer operating at a wavelength of 740-790 nm with an excellent imaging quality is designed. Its spectral resolution reaches 0.049 nm, and its diffraction efficiency improves by 27% compared to the conventional Offner spectrometer with convex grating working at ${-}{1}$-1st order diffraction. This is suitable for small, light, and low-cost atmospheric gas monitoring satellites.

Low-stray-light concave holographic gratings processed by combining the methods of photoresist hot-melting and oxygen-ion ashing.

The principal motivation for this paper is to reduce stray light and line roughness in concave holographic gratings (CHG). Compared with other previously reported line-smoothing grating techniques such as dynamic-exposure near-field holography, we successfully improve the line smoothing of CHG to approximately 10 nm from 2 nm. Our method uses optimization technologies and a combination of photoresist hot-melting (PHM) and oxygen-ion ashing (OIA), thereby improving the degree of stray light before and after optimization by one order of magnitude; the level processed by OIA, PHM, and OIA successively is ${7.85} \times {{10}^{ - 5}}$7.85×10-5. Combining the two technologies, we achieve lower stray light and straighter groove lines for the concave gratings, which is more effective, easy to implement, and incurs a low cost.

Highly Sensitive Graphene/Polydimethylsiloxane Composite Films near the Threshold Concentration with Biaxial Stretching.

Uniformly dispersed graphene effectively improves the strain-sensing capability of the composite film under a low graphene load in nanocomposites prepared with polydimethylsiloxane (PDMS) and graphene (GNP) monolayer powder. The threshold concentration of graphene was determined by loading nanocomposites at different temperatures. For different concentrations, when using traditional uniaxial stretching, the rate of resistance change of films near the threshold concentration is five times higher than the rate of films with a high concentration. Compared with traditional uniaxial stretching, the biaxial stretching we introduced can effectively improve the sensitivity of the film by an order of magnitude. The change in the resistance of the film near the threshold concentration is due to the change of the tunnel length and the cross-section of the tunnel, whereas the high concentration of the film is due to the change of the conductive path inside the film. Biaxial stretching has different effects on films with different concentrations, but the final effect of increasing sensitivity is the same. This study provides guidance for improving the strain-sensing sensitivity of GNP/PDMS composite films and the application of biaxial tension in detecting human motions.

Optimized multielement accommodative intraocular lens with a four-freeform-surface Alvarez lens and a separate aspheric lens.

This paper proposes an accommodative intraocular lens (IOL), which consists of a two-element Alvarez lens and an aspheric lens for changing focal power and refractive power, respectively. The four-freeform-surface Alvarez lens is optimized for a multiple field of view; further, the aspheric lens also corrects the aberrations induced by the corneal asphericity of the human eye over the whole range of accommodation. A simulation using optical design software demonstrates its excellent performance in that the values of the modulation transfer function at 100 cycles/mm all reach ∼0.4 with a ±5° field of view for 3 and 5 mm pupils.

Computer-Aided Discovery of Small Molecule Inhibitors of Thymocyte Selection-Associated High Mobility Group Box Protein (TOX) as Potential Therapeutics for Cutaneous T-Cell Lymphomas.

Cutaneous T-cell lymphomas (CTCL) are the most common primary lymphomas of the skin. We have previously identified thymocyte selection-associated high mobility group (HMG) box protein (TOX) as a promising drug target in CTCL; however, there are currently no small molecules able to directly inhibit TOX. We aimed to address this unmet opportunity by developing anti-TOX therapeutics with the use of computer-aided drug discovery methods. The available NMR-resolved structure of the TOX protein was used to model its DNA-binding HMG-box domain. To investigate the druggability of the corresponding protein-DNA interface on TOX, we performed a pilot virtual screening of 200,000 small molecules using in silico docking and identified 'hot spots' for drug-binding on the HMG-box domain. We then performed a large-scale virtual screening of 7.6 million drug-like compounds that were available from the ZINC15 database. As a result, a total of 140 top candidate compounds were selected for subsequent in vitro validation. Of those, 18 small molecules have been characterized as selective TOX inhibitors.

Multifacet echelle grating for intensity broadening on spectral plane fabricated by rotating ion-beam etching.

This paper describes a new type of multifacet echelle grating (MFEG) for use in an echelle spectrometer. This new type of echelle grating broadens the spectral distribution on the spectral plane. We built a geometric model of MFEG to analyze the influence of the blaze angle and number of facet shapes on the spectral evolution. A dual-facet echelle grating and a four-facet echelle grating with different parameters were fabricated by rotating ion-beam etching with a self-shadowing rotating mask, based on the existing single-facet echelle grating (SFEG) with a line density of 52.7 g/mm and a blaze angle of 63.5°. The distributions of diffraction efficiency for different orders were measured with a He-Ne laser (632.8 nm); furthermore, these echelle gratings were applied in an echelle spectrometer (ICP-OES, Plasma2000), and testing spectra were obtained. The experimental results demonstrate that the MFEG can broaden the intensity distribution on the spectral plane, overcoming the weak spectral margin signal of SFEG spectrometers.

Flexible and Optical Fiber Sensors Composited by Graphene and PDMS for Motion Detection.

A stretchable optical sensor can quantify the strain generated by human movement, which has been widely studied in the development of health monitoring systems, human-machine interfaces and wearable devices. This paper reports a graphene-added polydimethylsiloxane (PDMS) fiber, which has high tensile properties and good light transmittance suitable for detecting human movement. When the graphene-added PDMS fiber is stretched, the concentration of graphene per unit volume is constant, and the sensor uses the optical loss of the beam through the graphene PDMS fiber to detect the tensile strain. The fiber has excellent strain-sensing performance, outstanding sensitivity, a tensile property of 150%, and an excellent waterproofing performance. The linear response and repeated response in large dynamic range could reach 100% stability. The results show that the sensor can be used to detect human motion detection. These excellent properties indicate that the fiber has potential applications in wearable devices, soft robots and electronic skin.

IL-10 is overexpressed in human cutaneous T-cell lymphoma and is required for maximal tumor growth in a mouse model.

A crucial question pertains to a role of IL-10 as a tumorigenic factor, or just a marker of advanced disease in cutaneous T-cell lymphoma (CTCL). Herein, we measured significantly elevated IL-10 mRNA in a cohort of skin samples of patients with CTCL. Increased IL-10 was also detected in the tumor microenvironment of an established inflammation-dependent murine model of using MBL2 T lymphoma cells. Conditioned media from MBL2 cells was able to stimulate IL-10 production in bone marrow-derived macrophages in an IL-4-dependent manner. Implanted MBL2 T-cell lymphomas in IL-10KO mice were 50% smaller, accompanied by decreased numbers of infiltrating macrophages and reduced efficiency of M2-polarization compared with wild-type mice. With anti-IL-10R mAb treatment, both wild-type tumor-bearing mice and IL-10KO mice exhibited a further growth inhibition. Our data indicate that targeting IL-10 signaling with neutralizing antibodies to IL-10 or its receptor may have a great potential for advanced CTCL therapy.

Ring Wrinkle Patterns with Continuously Changing Wavelength Produced Using a Controlled-Gradient Light Field.

We report a facile method to prepare gradient wrinkles using a controlled-gradient light field. Because of the gradient distance between the ultraviolet (UV) lamp and polydimethylsiloxane (PDMS) substrate during UV/ozone treatment, the irradiance reaching the substrate continuously changed, which was transferred into the resulting SiOx film with a varying thickness. Therefore, wrinkles with continuously changing wavelength were fabricated using this approach. It was found that the wrinkle wavelength decreased as the distance increased. We fabricated 1-D wrinkle patterns and ring wrinkles with a gradient wavelength. The ring wrinkles were prepared using radial stresses, which were achieved by pulling the center of a freely hanging PDMS film. The resulting wrinkles with changing wavelength can be used in fluid handling systems, biological templates, and optical devices.