Opioid-induced fragile-like regulatory T cells contribute to withdrawal.

Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms.

Identification of the immune repertoire of γδ T-cell receptors in psoriasis.

The γδ T cells are a subpopulation of T cells that are abundantly found in the skin and mucous membranes. Their reactivity to self-antigens and ability to secrete various cytokines make them a key component in psoriasis development. Although the correlation between the immune repertoire (IR) of γδ T-cell receptors and the occurrence and severity of psoriasis remains incompletely explored, high-throughput sequencing of γδ T cells has led to a deeper understanding of IR in psoriasis. This study investigated the differences between γδ T cells in patients with psoriasis and healthy controls. The γδ T cells were identified via immunofluorescence staining and a correlation analysis was performed according to the psoriasis area and severity index (PASI) scores. The IR sequencing method was used to detect IR in the γδ T-cell receptors. The findings demonstrated more skin γδ T cells in patients with psoriasis, which were positively correlated with the PASI score. There were subtle differences in most variable (V), diversity (D) and joining (J) gene segments and VJ/VDJ combination segments between patients with psoriasis and healthy controls. However, a higher diversity of complementarity-determining region 3 (CDR3) was observed in patients with psoriasis. In summary, the IR of skin γδ T cells was significantly altered in patients with psoriasis, and the diversity in the cell's CDR3 population is a promising biomarker for assessment of psoriasis severity.

Generation of a terahertz quasi-Pearcey beam and its investigation in ptychography.

The terahertz structured beams played a significant role in imaging. We utilized the transmitter with 0.1 THz to generate the quasi-Pearcey beam. The beam is produced by combining the self-designed parabola-slit modulated plate and Fourier lens, showing stripe-shaped pattern and self-focusing property. Based on that, introducing it into the testing of ptychography, we discovered there are decent effects in field reconstruction of the probe and sample with this beam by comparisons both in the simulations and the experiments. The beam has good spatial coherence through the analysis of the spatial frequency spectrums. It suggests that the beam with such features can take advantage of rapid reconstruction in full-field imaging.

Nondestructive measurement of terahertz optical thin films by machine learning based on physical consistency.

Optical scattering measurement is one of the most commonly used methods for non-contact online measurement of film properties in industrial film manufacturing. Terahertz photons have low energy and are non-ionizing when measuring objects, so combining these two methods can enable online nondestructive testing of thin films. In the visible light band, some materials are transparent, and their thickness and material properties cannot be measured. Therefore, a method based on physical consistency modeling and machine learning is proposed in this paper, which realizes the method of obtaining high-precision thin film parameters through single-frequency terahertz wave measurement, and shows good performance. Through the experimental measurement of organic material thin films, it is proved that the proposed method is an effective terahertz online detection technology with high precision and high throughput.

Terahertz fan-beam computed tomography.

A terahertz (THz) fan-beam computed tomography (CT) system using a 0.3 THz continuous-wave sheet beam is proposed. The diffraction-free sheet beam expands in a fan shape in only one direction and provides propagation-invariant focal lines and extended the depth-of-field. The fan-beam CT based on this beam is the second-generation THz CT. It breaks the conventional 4-f symmetric structure of THz CT using the parallel beam. The fan-beam THz CT allows for use with a linear array detector, which reduces the time required to collect data. To demonstrate its feasibility for three-dimensional (3D) imaging, the 3D structure of a metal rod packed in a carton is reconstructed with the support of the system. The results show that the object's internal structure can be obtained by this new THz CT system while retaining the geometrically magnified features of the cross-sectional structure. The results of our research provide a template for the second-generation THz CT system, which provides an additional method for nondestructive testing.

Diagnosis and treatment of diabetic foot ulcer complicated with lower extremity vasculopathy: Consensus recommendation from the Chinese Medical Association (CMA), Chinese Medical Doctor Association (CMDA).

Diabetic foot ulcer complicated with lower extremity vasculopathy is highly prevalent, slow healing and have a poor prognosis. The final progression leads to amputation, or may even be life-threatening, seriously affecting patients' quality of life. The treatment of lower extremity vasculopathy is the focus of clinical practice and is vital to improving the healing process of diabetic foot ulcers. Recently, a number of clinical trials on diabetic foot ulcers with lower extremity vasculopathy have been reported. A joint group of Chinese Medical Association (CMA) and Chinese Medical Doctor Association (CMDA) expert representatives reviewed and reached a consensus on the guidelines for the clinical diagnosis and treatment of this kind of disease. These guidelines are based on evidence from the literature and cover the pathogenesis of diabetic foot ulcers complicated with lower extremity vasculopathy and the application of new treatment approaches. These guidelines have been put forward to guide practitioners on the best approaches for screening, diagnosing and treating diabetic foot ulcers with lower extremity vasculopathy, with the aim of providing optimal, evidence-based management for medical personnel working with diabetic foot wound repair and treatment.

Exosomes derived from mouse vibrissa dermal papilla cells promote hair follicle regeneration during wound healing by activating Wnt/ß-catenin signaling pathway.

Hair follicle (HF) regeneration during wound healing continues to present a significant clinical challenge. Dermal papilla cell-derived exosomes (DPC-Exos) hold immense potential for inducing HF neogenesis. However, the accurate role and underlying mechanisms of DPC-Exos in HF regeneration in wound healing remain to be fully explained. This study, represents the first analysis into the effects of DPC-Exos on fibroblasts during wound healing. Our findings demonstrated that DPC-Exos could stimulate the proliferation and migration of fibroblasts, more importantly, enhance the hair-inducing capacity of fibroblasts. Fibroblasts treated with DPC-Exos were capable of inducing HF neogenesis in nude mice when combined with neonatal mice epidermal cells. In addition, DPC-Exos accelerated wound re-epithelialization and promoted HF regeneration during the healing process. Treatment with DPC-Exos led to increased expression levels of the Wnt pathway transcription factors ß-catenin and Lef1 in both fibroblasts and the dermis of skin wounds. Specifically, the application of a Wnt pathway inhibitor reduced the effects of DPC-Exos on fibroblasts and wound healing. Accordingly, these results offer evidence that DPC-Exos promote HF regeneration during wound healing by enhancing the hair-inducing capacity of fibroblasts and activating the Wnt/ß-catenin signaling pathway. This suggests that DPC-Exos may represent a promising therapeutic strategy for achieving regenerative wound healing.

Interval estimation of relative risks for combined unilateral and bilateral correlated data.

Measurements are generally collected as unilateral or bilateral data in clinical trials, epidemiology, or observational studies. For example, in ophthalmology studies, the primary outcome is often obtained from one eye or both eyes of an individual. In medical studies, the relative risk is usually the parameter of interest and is commonly used. In this article, we develop three confidence intervals for the relative risk for combined unilateral and bilateral correlated data under the equal dependence assumption. The proposed confidence intervals are based on maximum likelihood estimates of parameters derived using the Fisher scoring method. Simulation studies are conducted to evaluate the performance of proposed confidence intervals with respect to the empirical coverage probability, the mean interval width, and the ratio of mesial non-coverage probability to the distal non-coverage probability. We also compare the proposed methods with the confidence interval based on the method of variance estimates recovery and the confidence interval obtained from the modified Poisson regression model with correlated binary data. We recommend the score confidence interval for general applications because it best controls converge probabilities at the 95% level with reasonable mean interval width. We illustrate the methods with a real-world example.

Activation of Sestrin2 accelerates deep second-degree burn wound healing through PI3K/AKT pathway.

Deep second-degree burns heal slowly, and promoting the healing process is a focus of clinical research. Sestrin2 is a stress-inducible protein with antioxidant and metabolic regulatory effects. However, its role during acute dermal and epidermal re-epithelialization in deep second-degree burns is unknown. In this study, we aimed to explore the role and molecular mechanism of sestrin2 in deep second-degree burns as a potential treatment target for burn wounds. To explore the effects of sestrin2 on burn wound healing, we established a deep second-degree burn mouse model. Then we detected the expression of sestrin2 by western blot and immunohistochemistry after obtaining the wound margin of full-thickness burned skin. The effects of sestrin2 on burn wound healing were explored in vivo and in vitro through interfering sestrin2 expression using siRNAs or the small molecule agonist of sestrin2, eupatilin. We also investigated the molecular mechanism of sestrin2 in promoting burn wound healing by western blot and CCK-8 assay. Our in vivo and in vitro deep second-degree burn wound healing model demonstrated that sestrin2 was promptly induced at murine skin wound edges. The small molecule agonist of sestrin2 accelerated the proliferation and migration of keratinocytes, as well as burn wound healing. Conversely, the healing of burn wounds was delayed in sestrin2-deficient mice and was accompanied by the secretion of inflammatory cytokines as well as the suppression of keratinocyte proliferation and migration. Mechanistically, sestrin2 promoted the phosphorylation of the PI3K/AKT pathway, and inhibition of PI3K/AKT pathway abrogated the promoting role of sestrin2 in keratinocyte proliferation and migration. Therefore, sestrin2 plays a critical role in activation of the PI3K/AKT pathway to promote keratinocyte proliferation and migration, as well as re-epithelialization in the process of deep second-degree burn wound repair.

Romiplostim use in pregnant women with immune thrombocytopenia.

Treatment for immune thrombocytopenia (ITP) in pregnancy is hampered by the lack of fetal safety evidence of maternally-administered medications. The Pregnancy Surveillance Program (PSP) collected patient information from 2017-2020 for pregnancy, birth outcomes, and adverse events (AEs) for 186 women exposed to romiplostim from 20 days before pregnancy to the end of pregnancy. Timing of exposure was available in 128 women. Seventy-one mothers (38%) had prepregnancy exposure to romiplostim; intrapartum exposure was known for the first (for many mothers when they discovered their pregnancy), second, and third trimesters for 74 (40%), 22 (12%), and 44 (24%) mothers, respectively, with 15 mothers exposed during >1 trimester. Among the 86 mothers with known pregnancy outcomes, 46 (53%) had at least one pregnancy-related serious AE (SAE); approximately 2/3 of SAEs were due to underlying ITP. Of 92 mothers with known birth outcomes, 60 (65%) had a normal pregnancy and 16 (17%) had complications, with both categories including term and preterm births; there were 12 (14%) spontaneous miscarriages/stillbirths, 3 (3%) ectopic pregnancies, and 1 (1%) molar pregnancy. Most abnormal births resulted from abnormal pregnancies. There were five neonatal/postnatal AEs of note: inguinal hernia, cytomegalovirus infection, trisomy 8 (third trimester single-dose romiplostim exposure), single umbilical artery without known anomalies, and development of autism at age 2 years. Seven of 12 infants with neonatal thrombocytopenia had resolution of thrombocytopenia before discharge; all 12 were discharged. Review of pregnancies in women exposed to romiplostim did not reveal any specific safety concerns for mothers, fetuses, or infants.

Altered local spontaneous brain activity pattern in children with right-eye amblyopia of varying degrees: evidence from fMRI.

PURPOSE: To investigate the abnormal changes of local brain activity in children with right-eye amblyopia of varying degrees. METHODS: Data of resting-state functional magnetic resonance imaging were collected from 16 children with severe amblyopia, 17 children with mild to moderate amblyopia, and 15 children with normal binocular vision. Local brain activity was analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo). RESULTS: There were extensive ALFF differences among the three groups in 10 brain regions. There were extensive differences in ReHo among the three groups in 11 brain regions. The ALFF and ReHo of the right orbital part of the middle frontal gyrus displayed a significantly positive correlation with the best-corrected visual acuity of the right eye, respectively. The ALFF value and ReHo value of the right orbital part of the middle frontal gyrus followed the pattern of normal control < mild to moderate amblyopia < severe amblyopia. CONCLUSION: This study demonstrated that there were changes in specific patterns of ALFF and ReHo in children with right-eye amblyopia of different degrees in brain regions performing visual sensorimotor and attentional control functions.

Extracellular vesicles from Lactobacillus druckerii inhibit hypertrophic scar fibrosis.

BACKGROUND: Hypertrophic scars (HS) affect millions of people each year and require better treatment strategies. Bacterial extracellular vesicles (EVs) are advantaged by low cost and high yield which was commonly used in the treatment of diseases. Here, we investigated the therapeutic efficacy of EVs obtained from Lactobacillus druckerii in hypertrophic scar. In vitro, the effects of Lactobacillus druckerii-derived EVs (LDEVs) on Collagen I/III and α-SMA in fibroblasts obtained from HS. In vivo, a scleroderma mouse model was used to investigate the effects of LDEVs on fibrosis. The impact of LDEVs on excisional wound healing was explored. The different proteins between PBS and LDEVs treated fibroblasts derived from hypertrophic scar were studied by untargeted proteomic analysis. RESULTS: In vitro, LDEVs treatment significantly inhibited the expression of Collagen I/III and α-SMA and cell proliferation of fibroblasts derived from HS. In vivo, LDEVs withdrawn the hypertrophic scar formation in scleroderma mouse model and decreased the expression of α-SMA. LDEVs promoted the proliferation of skin cells, new blood vessel formation and wound healing in excisional wound healing mice model. Moreover, proteomics has shown that LDEVs inhibit hypertrophic scar fibrosis through multiple pathways. CONCLUSIONS: Our results indicated that Lactobacillus druckerii-derived EVs has the potential application in the treatment of hypertrophic scars and any other fibrosis diseases.

High Satisfaction with Patient-Centered Telemedicine for Hepatitis C Virus Delivered to Substance Users: A Mixed-Methods Study.

Background: While telemedicine may increase health care access for vulnerable populations, data are limited on whether people with opioid use disorder (PWOUD) are satisfied with telemedicine. We assessed PWOUD satisfaction with telemedicine and identified factors that increase telemedicine satisfaction. Methods: We conducted a mixed-methods study among hepatitis C virus (HCV)-infected persons enrolled at 12 opioid treatment programs (OTPs) throughout New York State. Participants successfully completed HCV treatment either through telemedicine integrated into OTPs (N = 238) or through offsite referral (N = 106). We evaluated Patient Satisfaction Questionnaire (PSQ) response scores at the initial and final health care encounters and subsequently interviewed telemedicine study participants (N = 25) to assess their experiences with telemedicine. Results: All participants (N = 344) successfully completed HCV treatment. We observed no differences in PSQ scores between telemedicine and in-person encounters (98.3% and 98.7% of telemedicine participants provided PSQ scores of satisfied or highly satisfied at each timepoint, respectively). Study participants indicated that attributes associated with high telemedicine encounter satisfaction included: (1) communicating study information, (2) gaining trust, and (3) delivering patient-centered care. Participants weighted "General Satisfaction" and "Time Spent with Doctor" higher than "Accessibility and Convenience," and female participants were significantly more satisfied than males. Satisfaction with health care delivery among all participants increased significantly comparing timepoints. Conclusions: Participants were highly satisfied with HCV telemedicine encounters equivalent to in-person encounters. Communication augments trust facilitating delivery of patient-centered care through telemedicine. Participants value empathy and trust with providers over accessibility and convenience. In summary, PWOUD are highly satisfied with the facilitated telemedicine model and value empathetic and trusting providers. ClinicalTrials.gov Identifier: NCT02933970.

Feasibility, comparability and outcomes of three acquainted facial island flaps for periorbital defects reconstruction.

Severe coloboma of ocular malignant neoplasms post-resection poses a reconstructive challenge to surgeons. To compare the practicability, manipulability and outcomes of temporal (myocutaneous) flaps (TFs), forehead (supratrochlear artery/supraorbital artery) flaps (FFs) and buccal (facial artery) flaps (BFs) for periorbital defects reconstruction, a retrospective case series was conducted and evaluated between March 2014 and March 2021. Patient demographics and clinical parameters including age, gender, pathological diagnosis, operative methods, flap selection, operation time, aesthetic satisfaction and follow-up period were collected. The differences in complications were compared and assessed of the three flaps, including flap survival, venous congestion and donor site healing. Totally, 68 patients who underwent periorbital reconstructive operations because of common ocular malignant tumours were reviewed in this study. As for aesthetic satisfaction, a score more than "moderately dissatisfied" was obtained in 21 patients with TFs (95.5%), and of which the scores in FFs group were 12 cases (60%) and 16 cases with BFs reconstruction (61.5%) (P < .05). Severe microvascular complications underwent re-exploration operation occurred in one patient with FFs (1.5%) (P > .05). Notable flap necrosis was observed in two patients with BFs repair (2.9%) and in one case with FFs repair (1.5%), with no statistical difference between the three flap selections (P > .05). Moderate venous congestion occurred in one patient with TFs (1.5%), which was fully meliorated non-surgically. The three familiar facial island flaps are considered as minor trauma and time-saving process for reconstructing the extensive periorbital defects with comparable ranks of complications.

The intrarenal landscape of T cell receptor repertoire in clear cell renal cell cancer.

BACKGROUND: Clear cell renal cell cancer (ccRCC) is accompanied by T-cell infiltration. In this study, we sought to determine the difference in T-cell infiltration and the T-cell receptor (TCR) immune repertoire between ccRCC and peritumour tissue. METHODS: T-cell infiltration was examined using immunohistochemistry (IHC) and haematoxylin and eosin (HE) staining. The chi-squared test and Pearson correlation analysis were applied to evaluate the relationship between clinical traits and CD3, CD4, and CD8 expression. Immune repertoire sequencing (IR-Seq) was used to describe the profile of the TCR repertoire. RESULTS: The adjacent tissue showed increased expression of CD3, CD4 and CD8 compared with ccRCC tissue (PCD3 = 0.033; PCD4 = 0.014; PCD8 = 0.004). Indicated CD3+ T-cell density in ccRCC tissue was positively correlated with that in peritumour tissue (P = 0.010, r = 0.514), which implied the T cells in peritumour tissue directly infect the number of cells infiltrating in ccRCC tissue. Moreover, there was a positive correlation between Vimentin expression and indicated positive T-cell marker in ccRCC tissue (PCD3 = 0.035; PCD4 = 0.020; PCD8 = 0.027). Advanced stage revealed less CD4+ T-cell infiltration in ccRCC tissue (PCD4 = 0.023). The results from IR-Seq revealed an obvious increase in VJ and VDJ segment usage, as well as higher complementarity-determining region 3 (CDR3) amino acid (aa) clonotypes in ccRCC. The matched antigen recognized by the TCR of ccRCC may be potential targets. CONCLUSIONS: The current study collectively demonstrates diminished T-cell infiltration and increased CDR3 aa diversity in ccRCC, which may be associated with immunotherapeutic targets for ccRCC patients.

Single optical element to generate a meter-scale THz diffraction-free beam.

Diffraction-free electromagnetic beam propagates in free space without change in its two-dimensional transverse profile. Elongating diffraction-free length can benefit the practical application of this beam. Here, we demonstrate that a THz diffraction-free beam with meter-scale length can be achieved by using only one optical element. By circumscribing the line-shape of spherical harmonic function on a traditional axicon, such optical element is designed, and then can be fabricated by 3D-printing technique. Simulated, experimental, and theoretical results all show that the diffraction-free length of generated beam is over 1000 mm. Further analysis based on Fourier optics theory indicates that the spatial frequency of this beam has a comb distribution, which plays a key role during the beam generation process. Moreover, such distribution also demonstrates the beam generated by our invented optical element is not the Bessel beam, but a new diffraction-free beam. It is believed that this meter-scale THz diffraction-free beam can be useful in a non-contact and non-destructive THz imaging system for large objects.

Optical element to generate zero-order quasi-Bessel beam with "focal length".

An optical element has been invented to generate a zero-order quasi-Bessel beam with a certain distance to the element, which does not exist in the zero-order quasi-Bessel beam by using a traditional axicon. The cross section of designed element is an isosceles triangle whose equal sides are circumscribed by two semi-ellipses. Using a well-developed three-dimensional (3D)-printing technique, we have fabricated a series of elements working at terahertz (THz) frequency. Both simulated and experimental results clearly show that there is a certain distance between the generated quasi-Bessel beam and this element. A physical analysis based on geometric optics theory is performed to explain the obtained results. Because it is a refractive transmitted optical element, we propose that it can be also realized at another frequency band if the relevant processing techniques are available.

Terahertz ptychography using a long-distance diffraction-free beam as the probe.

We have implemented a terahertz (THz) ptychographic technique using a long-distance diffraction-free beam (DFB) instead of traditional low-energy pinhole-defined illumination as the probe. The DFB generating system containing two lens-axicon doublets is very easily realized. Measured transverse intensities of such a DFB display an Airy-pattern-like distribution. Based on the well-developed extended ptychographic iterative engine, we simultaneously reconstruct a phase object and the DFB probe with both simulated and real data. Further calculation shows that the DFB has abundant spatial high-frequency components that guarantee high coherence of the illuminating probe beam in our THz ptychographic system. In addition, we firmly believe that the proposed approach can be easily transplanted to the ptychography at other frequency bands as both lens and axicon are very common optical elements.

Structuring a terahertz beam by using a 3D-printed n-faced pyramid lens.

Using 3D-printed n-faced pyramid lenses, we generate a series of structured diffraction free terahertz (THz) beams. Based on angular spectrum theory, analytical solutions of the output THz beams from these lenses can be obtained. Furthermore, we experimentally realize these non-diffraction THz beams, showing that the measured results are consistent with theory. It is believed that our structured non-diffraction THz beams can be used in THz imaging with large depth of focus.

Nonlinear error correction for Terahertz FMCW System by a new beat frequency estimation method.

Terahertz (THz) frequency modulated continuous wave (FMCW) technology is a means of nondestructive testing. The signal's nonlinearity is an unavoidable problem in the daily application of THz FMCW technology. The signal's nonlinearity will lead to the spectrum broadening of the FMCW's beat frequency (BF) signal, which degrades the range resolution and result in distance-measuring error. Traditional methods require additional hardware or require a lot of computation, which are not conducive to the miniaturization of the system and real-time measurement. A novel method for correcting the nonlinear error of THz FMCW technology has been proposed and demonstrated in this article. In the proposed method, the windowed Fourier transform (WFT) is introduced to estimate the BF corresponding to the measured target, according to the linearity distribution of voltage-controlled oscillator (VCO). In this way, the measured target's BF can be accurately estimated from the unprocessed BF signal with a poor linearity. From the estimated BF of the reference target, the non-linear compensation coefficients are calculated. With the non-linear compensation coefficients, the non-linearity of the output BF signal can be calibrated. The results of simulations and experiments show that the proposed method allows the range resolution of an FMCW system to reach the theoretical limit.