Mutations in the photoreceptor transcription factor gene cone-rod homeobox (CRX) lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital ...amaurosis (LCA). Using induced pluripotent stem cells (iPSCs) from a patient with CRX-I138fs48 mutation, we established an in vitro model of CRX-LCA in retinal organoids that showed defective photoreceptor maturation by histology and gene profiling, with diminished expression of visual opsins. Adeno-associated virus (AAV)-mediated CRX gene augmentation therapy partially restored photoreceptor phenotype and expression of phototransduction-related genes as determined by single-cell RNA-sequencing. Retinal organoids derived from iPSCs of a second dominant CRX-LCA patient carrying K88N mutation revealed the loss of opsin expression as a common phenotype, which was alleviated by AAV-mediated augmentation of CRX. Our studies provide a proof-of-concept for developing gene therapy of dominant CRX-LCA and other CRX retinopathies.
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•Leber congenital amaurosis caused by CRX mutations is modeled in retinal organoids•Patient iPSCs-derived organoids show impaired expression of visual opsins•AAV-mediated CRX delivery partially restores expression of phototransduction genes•Gene therapy is applicable to mutations in DNA-binding and transactivation domains
In this article, Swaroop and colleagues show impaired expression of opsin visual pigments in retinal organoids derived from iPSC lines of patients with Leber congenital amaurosis, caused by dominant mutations in the photoreceptor transcription factor gene CRX. AAV-mediated CRX gene augmentation partially restores the expression of phototransduction genes, suggesting a potential therapeutic strategy.
We investigate the anisotropy of the optical response (i.e., dichroism) in the representative ‘parent’ ferropnictide BaFe
2
As
2
. The dichroism is achieved through measurements of the optical ...reflectivity in a broad spectral range, across the tetragonal-to-orthorhombic and spin-density-wave (SDW) phase transitions, from which we extract the real part of the optical conductivity. The collection of data on the specimen with variable degree of detwinning is made possible via our novel pressure device which allows tuning in situ uniaxial stress. Thedichroism bears testimony to an important electronic polarization, reflecting the impact of the nematic phase and its fluctuations on the electronic structure.
Summary
Background Cross‐sectional studies suggest insulin resistance is strongly associated with hepatic steatosis and fibrosis in patients with chronic hepatitis C (CHC), which might affect the ...efficacy of antiviral therapy.
Aim To investigate retrospectively the impact of insulin resistance on treatment response in Chinese genotype 1 CHC patients receiving a 24‐week course therapy with peginterferon α‐2b/ribavirin.
Methods A total of 133 biopsy‐proven CHC patients were enrolled for analyses. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA‐IR). Hepatic fibrosis was graded by the METAVIR scoring system.
Results Mean HOMA‐IR progressively elevated along with the severity of hepatic fibrosis (F1–F2 fibrosis: 2.55 ± 0.16 vs. F3–F4 fibrosis: 3.61 ± 0.20, P < 0.001). Compared with patients with sustained virological response (SVR), patients without SVR had significantly higher percentages of F3–F4 fibrosis (62.2% vs. 21.6%, P < 0.001) and baseline high viral load (≥600 000 IU/mL; 64.4% vs. 35.6%, P = 0.038). In addition, patients without SVR had significantly higher plasma levels of insulin (15.03 ± 0.89 vs. 10.19 ± 0.55 μU/mL, P < 0.001) and HOMA‐IR values (3.76 ± 0.23 vs. 2.50 ± 0.15, P < 0.001). Multivariate analyses showed that F1–F2 fibrosis (odds ratio: 4.49, P = 0.001), HOMA‐IR < 2 (odds ratio: 7.15, P = 0.005) and pre‐treatment hepatitis C virus RNA < 600 000 IU/mL (odds ratio: 3.26, P = 0.012) were the independent factors associated with SVR.
Conclusions Insulin resistance is a major determinant of SVR in genotype 1 CHC patients receiving peginterferon α‐2b/ribavirin. Strategies to modify insulin resistance may be effective in enhancing SVR before or during anti‐viral therapy.
The purpose of this study was to determine the prevalence of psychiatric diagnoses among a sample of breast reconstruction patients and measure the association between these diagnoses and ...reconstruction-related, patient-reported outcomes.
The impact of psychiatric disorders in conjunction with breast cancer diagnosis, treatment, and reconstruction have the potential to cause significant patient distress but remains not well understood.
A retrospective review of postmastectomy breast reconstruction patients from 2007 to 2018 at Memorial Sloan Kettering Cancer Center was conducted. Patient demographics, comorbidities, cancer characteristics, psychiatric diagnoses, and BREAST-Q Reconstruction Module scores (measuring satisfaction with breast, well-being of the chest, psychosocial, and sexual well-being) at postoperative years 1 to 3 were examined. Mixed-effects models and cross-sectional linear regressions were conducted to measure the effect of psychiatric diagnostic class type and number on scores.
Of 7414 total patients, 50.1% had at least 1 psychiatric diagnosis. Patients with any psychiatric diagnoses before reconstruction had significantly lower BREAST-Q scores for all domains at all time points. Anxiety (50%) and depression (27.6%) disorders were the most prevalent and had the greatest impact on BREAST-Q scores. Patients with a greater number of psychiatric diagnostic classes had significantly worse patient-reported outcomes compared with patients with no psychiatric diagnosis. Psychosocial (β: -7.29; 95% confidence interval: -8.67, -5.91), and sexual well-being (β: -7.99; 95% confidence interval: -9.57, -6.40) were most sensitive to the impact of psychiatric diagnoses.
Mental health status is associated with psychosocial and sexual well-being after breast reconstruction surgery as measured with the BREAST-Q. Future research will need to determine what interventions (eg, screening, early referral) can help improve outcomes for breast cancer patients with psychiatric disorders undergoing breast reconstruction.
Posted maximum speed limits used by highway agencies worldwide are typically applicable to dry-weather driving conditions. During wet weather, these speed limits may exceed the maximum speed for safe ...traffic operations. More and more highway agencies are employing variable speed limits as a means to improve wet-weather driving safety. For rain-related wet-weather conditions, the variable speed limit systems in use today commonly set speed limits based on either consideration of stopping sight distance, or past experience and engineering judgement. A common shortcoming of the existing systems is that the actual pavement skid resistance characteristics are not considered in setting the speed limits. This paper proposes an improved procedure to derive mechanistically the speed limits from the required safe stopping distance as well as the minimum skid resistance requirement for safe driving, based on the actual skid resistance properties of the pavement considered. The proposed procedure makes use of a finite-element skid resistance computer simulation model to determine both the available skid resistance values and vehicle braking distances at different vehicle speeds of the in-service pavement under specified rain-related wet-weather conditions. The procedure is theoretically sound, and is consistent with the concept of pavement network friction management system. In the analysis, the rain-related wet-weather condition is represented by rainfall intensity, and the road section is characterised by its gradient and cross slope, as well as the skid resistance properties of the pavement. A numerical example is presented to illustrate the working of the proposed procedure.
This study evaluates the seismic reliability of eccentrically braced frame (EBF) and buckling-restrained braced frame (BRBF) systems in comparison with that of moment-resisting frame (MRF) systems. ...In detail, a series of three-dimensional nonlinear time-history analyses was carried out for six example buildings. The effectiveness of braced frames was assessed in 6- and 20-story steel office buildings. Two ensembles of ordinary and near-source earthquake ground motions were evaluated with a vector-valued intensity measure. The results show that the effectiveness of braced frames can vary significantly with ground motions and building rises. The added braced frames help to reduce story drifts, decreasing the probability of failure against ordinary ground motions. The effect is particularly obvious for low-rise buildings. On the other hand, the pulse-like feature of near-source ground motions decreases the drift demands on MRF systems but increases the drift demands on EBF and BRBF systems. As a result, the added braced frames can help to resist near-source ground motions, but only to a limited extent.
Background
Prepectoral implant placement for postmastectomy breast reconstruction has increased in recent years. Benefits of prepectoral reconstruction may include lack of animation deformities and ...reduced postoperative pain, but its complication profile is currently unclear. This study aimed to examine the complication profile of prepectoral tissue expanders (TEs) to determine factors associated with TE loss.
Methods
A retrospective review was performed to identify all patients who underwent immediate prepectoral TE reconstruction from January 2018 to June 2021. The decision to use the prepectoral technique was based on mastectomy skin quality and patient comorbidities. Patient demographics, comorbidities, and operative details were evaluated. Outcomes of interest included TE loss, seroma, hematoma, infection/cellulitis, mastectomy skin flap necrosis requiring revision, and TE exposure. Logistic regression analysis was performed to identify factors associated with TE loss.
Results
The study identified 1225 TEs. The most frequent complications were seroma (8.7%,
n
= 106), infection/cellulitis (8.2%,
n
= 101), and TE loss (4.2%,
n
= 51). Factors associated with TE loss in the univariate analysis included ethnicity, history of smoking, body mass index, mastectomy weight, and neoadjuvant chemotherapy. In the multivariate regression analysis, only mastectomy weight had a positive association with TE loss (odds ratio, 1.001;
p
= 0.016).
Conclusion
Prepectoral two-stage breast reconstruction can be performed safely with an acceptable early complication profile. The study data suggest that increasing mastectomy weight is the most significant factor associated with TE loss. Further research examining the quality of the soft tissue envelope and assessing patient-reported outcomes would prove beneficial.
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