The prognostic value of serum α-klotho in age-related diseases among the US population: A prospective population-based cohort study.

Objective: α-Klotho is a potential biological marker of aging with satisfactory clinical applicability. However, its prognostic significance in age-related diseases has largely been undermined. Therefore, we aimed to report the prognostic value of serum α-klotho levels in age-related diseases. Methods: Participants with available serum α-klotho data from the National Health and Nutrition Examination Survey (2007-2016) were included. Their survival status was collected at 7.62 ± 2.99 years after serum α-klotho data was collected, and the endpoint was all-cause and cardiovascular mortality. A Cox regression model was established to examine the association between serum α-klotho levels and all-cause and cardiovascular mortality. Results: The present study included 13,746 U.S. adults with a survey-weighted mean age of 56.19 ± 10.42 years old. Of these, 52.2 % were female and 72.9 % were non-Hispanic whites. The optimal cutoff value of serum α-klotho for predicting all-cause mortality risk in the general population was 603.5 pg/ml. Individuals with low serum α-klotho (<603.5 pg/ml) had a significantly higher risk of all-cause (adjusted HR: 1.34(1.18-1.52), P < 0.001) and cardiovascular mortality (adjusted HR: 1.63(1.27-2.10), P < 0.001). Subgroup analysis showed that low serum α-klotho level was an independent risk factor for all-cause and cardiovascular mortality in people with hypertension, congestive heart failure, diabetes mellitus, and emphysema, while it was an independent risk factor for all-cause mortality in patients with renal insufficiency. Conclusion: A low serum α-klotho concentration (<603.5 pg/ml) could serve as a marker of all-cause and cardiovascular mortality in the general population and in people with age-related diseases, including hypertension, congestive heart failure, diabetes mellitus, and emphysema.

Optogenetic Stimulation of the Cardiac Vagus Nerve to Promote Heart Regenerative Repair after Myocardial Infarction.

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.

Linking Disulfide Levels and NAD+ Metabolism with Alzheimer's Disease for Diagnostic Modeling and Target Drug Analysis.

BACKGROUND: Alzheimer's disease (AD) is a condition that affects the nervous system and that requires considerably more in-depth study. Abnormal Nicotinamide Adenine Dinucleotide (NAD+) metabolism and disulfide levels have been demonstrated in AD. This study investigated novel hub genes for disulfide levels and NAD+ metabolism in relation to the diagnosis and therapy of AD. METHODS: Data from the gene expression omnibus (GEO) database were analyzed. Hub genes related to disulfide levels, NAD+ metabolism, and AD were identified from overlapping genes for differentially expressed genes (DEGs), genes in the NAD+ metabolism or disulfide gene sets, and module genes obtained by weighted gene co-expression network analysis (WGCNA). Pathway analysis of these hub genes was performed by Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was constructed based on the expression level of hub genes in brain samples. CIBERSORT was used to evaluate immune cell infiltration and immune factors correlating with hub gene expression. The DrugBank database was also used to identify drugs that target the hub genes. RESULTS: We identified 3 hub genes related to disulfide levels in AD and 9 related to NAD+ metabolism in AD. Pathway analysis indicated these 12 genes were correlated with AD. Stepwise regression analysis revealed the area under the curve (AUC) for the predictive model based on the expression of these 12 hub genes in brain tissue was 0.935, indicating good diagnostic performance. Additionally, analysis of immune cell infiltration showed the hub genes played an important role in AD immunity. Finally, 33 drugs targeting 10 hub genes were identified using the DrugBank database. Some of these have been clinically approved and may be useful for AD therapy. CONCLUSION: Hub genes related to disulfide levels and NAD+ metabolism are promising biomarkers for the diagnosis of AD. These genes may contribute to a better understanding of the pathogenesis of AD, as well as to improved drug therapy.

Trends in the global burden of vision loss among the older adults from 1990 to 2019.

Purpose: To quantify the global impact of vision impairment in individuals aged 65 years and older between 1990 and 2019, segmented by disease, age, and sociodemographic index (SDI). Methods: Using the Global Burden of Diseases 2019 (GBD 2019) dataset, a retrospective demographic evaluation was undertaken to ascertain the magnitude of vision loss over this period. Metrics evaluated included case numbers, prevalence rates per 100,000 individuals, and shifts in prevalence rates via average annual percentage changes (AAPCs) and years lived with disability (YLDs). Results: From 1990 to 2019, vision impairment rates for individuals aged 65 years and older increased from 40,027.0 (95% UI: 32,232.9-49,945.1) to 40,965.8 (95% UI: 32,911-51,358.3, AAPC: 0.11). YLDs associated with vision loss saw a significant decrease, moving from 1713.5 (95% UI: 1216.2-2339.7) to 1579.1 (95% UI: 1108.3-2168.9, AAPC: -0.12). Gender-based evaluation showed males had lower global prevalence and YLD rates compared to females. Cataracts and near vision impairment were the major factors, raising prevalence by 6.95 and 2.11%, respectively. Cataract prevalence in high-middle SDI regions and near vision deficits in high SDI regions significantly influenced YLDs variation between 1990 and 2019. Conclusion: Over the past three decades, there has been a significant decrease in the vision impairment burden in individuals aged 65 and older worldwide. However, disparities continue, based on disease type, regional SDI, and age brackets. Enhancing eye care services, both in scope and quality, is crucial for reducing the global vision impairment burden among the older adults.

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data.

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Dual-functional thermosensitive hydrogel for reducing infection and enhancing bone regeneration in infected bone defects.

The contamination of bone defects is a serious therapeutic problem. The treatment of infected bone defects involves rigorous infection control followed by bone reconstruction. Considering these two processes, the development of biomaterials possessing antibacterial and osteogenic properties offers a promising approach for the treatment of infected bone defects. In this study, a dual-functional, thermosensitive, and injectable hydrogel composed of chitosan (CS), quaternized CS (QCS), and nano-hydroxyapatite (nHA) was designed, and the ratio of CS to QCS in the hydrogel was optimized to enhance the antibacterial efficacy of CS while reducing the cytotoxicity of QCS. In vitro studies demonstrated that the hydrogel with an 85 %:15 % ratio of CS to QCS exhibited excellent biocompatibility and antibacterial properties while also possessing suitable mechanical characteristics and degradability. The incorporation of nHA into the hydrogel enhanced MC3T3-E1 proliferation and osteogenic differentiation. Moreover, this hydrogel demonstrated superior in vivo therapeutic effectiveness in a rabbit model of infected bone defect. In summary, this study provides a promising material design and a comprehensive one-step treatment strategy for infected bone defects.

Correction: Structural variation underlies functional diversity at methyl salicylate loci in tomato.

[This corrects the article DOI: 10.1371/journal.pgen.1010751.].

Dual-functional 3D-printed porous bioactive scaffold enhanced bone repair by promoting osteogenesis and angiogenesis.

The treatment of bone defects is a difficult problem in orthopedics. The excessive destruction of local bone tissue at defect sites destroys blood supply and renders bone regeneration insufficient, which further leads to delayed union or even nonunion. To solve this problem, in this study, we incorporated icariin into alginate/mineralized collagen (AMC) hydrogel and then placed the drug-loaded hydrogel into the pores of a 3D-printed porous titanium alloy (AMCI/PTi) scaffold to prepare a bioactive scaffold with the dual functions of promoting angiogenesis and bone regeneration. The experimental results showed that the ACMI/PTi scaffold had suitable mechanical properties, sustained drug release function, and excellent biocompatibility. The released icariin and mineralized collagen (MC) synergistically promoted angiogenesis and osteogenic differentiation in vitro. After implantation into a rabbit radius defect, the composite scaffold showed a satisfactory effect in promoting bone repair. Therefore, this composite dual-functional scaffold could meet the requirements of bone defect treatment and provide a promising strategy for the repair of large segmental bone defects in clinic.

Quantification of soft tissue artifacts using CT registration and subject-specific multibody modeling.

The potential use of gait analysis for quantitative preoperative planning in total hip arthroplasty (THA) has previously been demonstrated. However, the joint kinematic data measured through this process tend to be unreliable for surgical planning due to distortions caused by soft tissue artifacts (STAs). In this study, we developed a novel motion capture framework by combining computed tomography (CT)-based postural calibration and subject-specific multibody dynamics modeling to prevent the effect of STAs in measuring hip kinematics. Three subjects with femoroacetabular impingement syndrome were recruited, and CT data for each patient were collected by attaching marker clusters near the hip. A subject-specific multibody hip joint model was developed based on reconstructed CT data. Spring-dashpot network calculations were performed to minimize the distance between the anatomical landmark and its corresponding infrared reflective marker. The STAs of the thigh was described as six degrees of freedom viscoelastic bushing elements, and their parameter values were identified via smooth orthogonal decomposition. Least squares optimization was used to modify the pelvic rotations to compensate for the rigid components of STAs. The results showed that CT-assisted motion tracking enabled the successful identification of STA influences in gait and squat positions. Furthermore, STA effects were found to alter maximal pelvis tilt and hip rotations during a squat. Compared to other techniques, such as dual fluoroscopic imaging, the adopted framework does not require additional medical imaging for patients undergoing robot-assisted THA surgery and is thus a practical way of evaluating hip joint kinematics for preoperative surgical planning.

Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP).

Background: Prior studies using the ADSP data examined variants within presenilin-2 ( PSEN2 ), presenilin-1 ( PSEN1 ), and amyloid precursor protein ( APP ) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer's Disease Sequencing Project (ADSP). Objective: To characterize previously-reported clinically-relevant variants and DM variants in PSEN2, PSEN1, APP within the participants from the ADSP. Methods: We identified rare variants (MAF <1%) previously-reported in PSEN2 , PSEN1, and APP in the available ADSP sample of 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available for research-use (N total = 31,490). We additionally curated variants in these three genes from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes. Results: We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in PSEN2 , 25 in PSEN1 , and 2 in APP . The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with non-carriers (p-value=7.8×10 -57 ). Conclusion: A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to non-carriers.

Identification of New Diterpenoids from the Pulp of Coffea arabica and Their α-Glucosidase Inhibition Activity.

Six new (1, 2, 3, 5, 6, and 8) and seven known (4, 7, 9, 10, 11, 12, and 13) diterpenoids have been identified in the pulp of Coffea arabica. The structures of new diterpenoids were elucidated by extensive spectroscopic analysis, including 1D, 2D NMR (HSQC, HMBC, 1H-1H COSY, and ROESY), HRESIMS, IR, DP4+, electronic circular dichroism, and X-ray crystallography analysis. Compound 1 is ent-labdane-type diterpenoid, whereas compounds (2-13) are ent-kaurane diterpenoids. The result of α-glucosidase inhibitory assay demonstrated that compounds (1, 3, 5, 7, and 10) have moderate inhibitory activity with IC50 values of 55.23 ± 0.84, 74.02 ± 0.89, 66.46 ± 1.05, 49.70 ± 1.02, and 76.34 ± 0.46 µM, respectively, compared to the positive control (acarbose, 51.62 ± 0.21 µM). Furthermore, molecular docking analysis has been conducted to investigate the interaction between the compounds and the receptors of α-glucosidase to interpret their mechanism of activity. This study is the first investigation that successfully discovered the presence of diterpenoids within the coffee pulp.

Influence of targeted nursing-guided bladder filling on embryo transfer outcomes and patient comfort: A prospective open randomized controlled study.

BACKGROUND: The success of assisted pregnancy relies heavily on the effectiveness of the embryo transfer process. Currently, embryo transfer is typically conducted with the assistance of abdominal ultrasound. OBJECTIVE: The primary aim of this study was to evaluate the influence of targeted nursing interventions on the embryo transfer procedure, its impact on pregnancy outcomes, and the level of patient comfort concerning bladder management throughout the procedure. METHODS: A total of 247 patients who underwent embryo transfer at the Reproductive Center of Peking University People's Hospital from December 2019 to August 2020 were included in this study. These patients were categorized into two groups: the control group (n= 124) and the experimental group (n= 123). Within the control group, patients received conventional preoperative education, whereas those within the experimental group were subjected to targeted nursing interventions. Furthermore, patients in the experimental group were furnished with explicit instructions pertaining to the volume and timing of water intake. Multiple factors were assessed in this study, encompassing bladder filling, the quality of uterine imaging, the utilization of assistive devices during the surgical procedure, and pregnancy outcomes. Additionally, a post-operative questionnaire was administered to both groups to gauge their comfort levels regarding urinary retention. RESULTS: Following the targeted nursing intervention, ultrasound scans indicated an increase in bladder depth (5.91 ± 1.76 vs. 5.40 ± 1.61, P= 0.02), resulting in clearer endometrial imaging (96.74% vs. 88.71%, P= 0.02). Additionally, the experimental group reported significantly higher levels of comfort with urine retention (P= 0.01) compared to the control group, and these differences held statistical significance. Furthermore, the pregnancy rate in the experimental group was greater than that in the control group (52.85% vs. 50.8%, P> 0.05). CONCLUSION: Based on the premise that pregnancy rates remain unaffected, the implementation of targeted nursing care has the potential to augment bladder filling, enhance the quality of endometrial imaging, reduce the requirement for instrument-assisted embryo transfers, and notably enhance the comfort of patients in relation to urine retention.

Surgical flip-dislocation of the bicolumnar approach without olecranon osteotomy versus olecranon osteotomy in type AO 13C3 distal humeral fracture: a matched-cohort study.

BACKGROUND: Our experience with the surgical flip-dislocation of the bicolumnar (SFDB) approach for type AO 13C3 humeral fractures indicates that this surgical approach can be performed safely and effectively in appropriately selected patients. We aimed to evaluate the clinical outcomes of the SFDB approach without olecranon osteotomy (OO) for type AO 13C3 distal humeral fractures. METHODS: We retrospectively reviewed 65 cases of type AO 13C3 distal humeral fractures treated between April 2008 and July 2018; 33 patients were treated with the SFDB approach, and the remaining were treated with OO. Propensity score matching was used to control for sex, age, and the American Society of Anesthesiology score. Elbow pain, range of motion, stability, and function were assessed using the Mayo Elbow Performance Index (MEPI) and the Disabilities of the Arm, Shoulder, and Hand questionnaire. Clinical complications, reoperation rates, and radiographic results were compared between the groups. RESULTS: Operative time and blood loss were significantly lower in the SFDB group than in the OO group (P = 0.001, P = 0.002, respectively). At the final follow-up, the mean postoperative MEPI did not significantly differ between the groups (P = 0.628). According to Morrey's criteria, a typical functional range of elbow motion was achieved in 12 and 15 patients in the SFDB and OO groups, respectively. CONCLUSIONS: The SFDB approach achieves superior exposure of the articular surface without injury to the extensor mechanism in type 13C3 articular surface fracture treatment. This approach also results in good early functional recovery and clinical outcomes, with a low risk of complications.

Form and contour: breeding and genetics of organ shape from wild relatives to modern vegetable crops.

Shape is a primary determinant of consumer preference for many horticultural crops and it is also associated with many aspects of marketing, harvest mechanics, and postharvest handling. Perceptions of quality and preference often map to specific shapes of fruits, tubers, leaves, flowers, roots, and other plant organs. As a result, humans have greatly expanded the palette of shapes available for horticultural crops, in many cases creating a series of market classes where particular shapes predominate. Crop wild relatives possess organs shaped by natural selection, while domesticated species possess organs shaped by human desires. Selection for visually-pleasing shapes in vegetable crops resulted from a number of opportunistic factors, including modification of supernumerary cambia, allelic variation at loci that control fundamental processes such as cell division, cell elongation, transposon-mediated variation, and partitioning of photosynthate. Genes that control cell division patterning may be universal shape regulators in horticultural crops, influencing the form of fruits, tubers, and grains in disparate species. Crop wild relatives are often considered less relevant for modern breeding efforts when it comes to characteristics such as shape, however this view may be unnecessarily limiting. Useful allelic variation in wild species may not have been examined or exploited with respect to shape modifications, and newly emergent information on key genes and proteins may provide additional opportunities to regulate the form and contour of vegetable crops.

Inguinal draining-lymph node in 18F-FDG PET/CT images could be a new indicator for the diagnosis of fracture-related infection in the lower extremities.

Purpose: The imaging diagnosis of fracture-related infection is often challenging. The aim of this study was to evaluate the value of 18F-FDG PET/CT for the diagnosis of fracture-related infection (FRI) with internal fixation after orthopedic surgery in lower extremities. Methods: A total of 254 consecutive patients who underwent 18F-FDG PET/CT scans with suspected FRI with internal fixation in lower extremities were retrospectively investigated 18F-FDG PET/CT images were semiquantitatively evaluated with multiple metabolic parameters. Additionally, morphological information of the inguinal draining lymph nodes (DLN) with the highest SUV value was also collected and analyzed. Results: Patients were divided into two groups according to final diagnosis: the infected (N=197) and the non-infected group (N=57). The differences in the inguinal DLN-related parameters, including the long diameter, short diameter, maximum cross-sectional area, maximum standardized uptake value (SUVmax), metabolic volume (MV) 60%, MV70%, MV80%, total lesional glycolysis (TLG) 60%, TLG70%, TLG80%, and the infection suspected area related parameters, including SUVmax, MV25%, MV30%, MV35%, MV40%, MV50%, and TLG70%, between the two groups were statistically significant. We then compared the highest area under the curves (AUCs) among the morphological parameters of DLN, metabolic parameters of DLN, and metabolic parameters of the suspected infection area. The result demonstrated that SUVmax of the inguinal DLN showed the best diagnostic performance with an AUC of 0.939 (P<0.05). Conclusion: Semiquantitative analysis (especially SUVmax) of the inguinal DLN in 18F-FDG PET/CT images could be a promising method for the diagnosis of suspected FRI with internal fixation after orthopedic surgery in lower extremities.

Key variants via Alzheimer's Disease Sequencing Project whole genome sequence data.

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases=2,184, N controls=2,383) and targeted analyses in sub-populations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Bisphosphonate-incorporated coatings for orthopedic implants functionalization.

Bisphosphonates (BPs), the stable analogs of pyrophosphate, are well-known inhibitors of osteoclastogenesis to prevent osteoporotic bone loss and improve implant osseointegration in patients suffering from osteoporosis. Compared to systemic administration, BPs-incorporated coatings enable the direct delivery of BPs to the local area, which will precisely enhance osseointegration and bone repair without the systemic side effects. However, an elaborate and comprehensive review of BP coatings of implants is lacking. Herein, the cellular level (e.g., osteoclasts, osteocytes, osteoblasts, osteoclast precursors, and bone mesenchymal stem cells) and molecular biological regulatory mechanism of BPs in regulating bone homeostasis are overviewed systematically. Moreover, the currently available methods (e.g., chemical reaction, porous carriers, and organic material films) of BP coatings construction are outlined and summarized in detail. As one of the key directions, the latest advances of BP-coated implants to enhance bone repair and osseointegration in basic experiments and clinical trials are presented and critically evaluated. Finally, the challenges and prospects of BP coatings are also purposed, and it will open a new chapter in clinical translation for BP-coated implants.

Assessment of Ocular Deformation in Pathologic Myopia Using 3-Dimensional Magnetic Resonance Imaging.

IMPORTANCE: Ocular deformation in pathologic myopia can affect the entire globe. However, few studies have investigated the equatorial pattern of ocular shape. In addition, the correlation between equatorial and posterior morphology needs to be further explored. OBJECTIVE: To assess global ocular deformation in pathologic myopia. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based, cross-sectional study included 180 pathologic myopic eyes with atrophic maculopathy grading C2 (diffuse chorioretinal atrophy) or more from 180 participants who underwent comprehensive ophthalmic examination, including high-resolution 3-dimensional magnetic resonance imaging. In addition, 10 nonpathologic myopic eyes of 10 participants were set as the control group. Main Outcomes and Measures: According to the cross-sectional view of equator, equatorial shape was classified as round, rectangular, pyriform (noncircular and more protruded in 1 direction), vertical-elliptical, or horizontal-elliptical; according to the nasal and inferior views, the posterior shape was categorized as spheroidal, conical, bulb-shaped, ellipsoidal, multidistorted, and barrel-shaped. Equatorial circularity and ocular sphericity were used to quantitatively assess the morphological variability of the equatorial and posterior regions, respectively. The association between ocular morphology and ocular parameters and myopic maculopathy was also investigated. Results: The mean (SD) age of 180 participants with pathologic myopia was 55.14 (10.74) years, 127 were female (70.6%), and the mean (SD) axial length of studied eyes was 30.22 (2.25) mm. The predominant equatorial shape was pyriform (66 eyes [36.7%]), followed by round (45 eyes [25.0%]). The predominant posterior shape was bulb-shaped (97 eyes [52.2%]), followed by multidistorted (46 eyes [24.7%]). Equatorial circularity and equatorial shapes were correlated (r = -0.469; 95% CI, -0.584 to -0.346; P < .001) and ocular sphericity was correlated with posterior shapes (r = -0.533; 95% CI, -0.627 to -0.427; P < .001). In eyes with a vertical-elliptical equator, equatorial circularity and ocular sphericity were positively linearly correlated (R2 = 0.246; 95% CI, 0.050-0.496; P = .002) and the prevalence of inferior staphyloma was higher (27.8%; P = .04). Eyes with a horizontal-elliptical equator have the most horizontally oriented axis of corneal flat keratometry (median, 43.55 [interquartile range, 43.84] degrees; P = .01) and tended to present with multidistorted posterior shape (21.7%; P = .04). Conclusions and Relevance: These findings suggest ocular deformation is common in pathologic myopia and can affect the entire eye, including the equatorial and posterior regions. The morphological classification may enhance the understanding of the diverse patterns of ocular shape in pathologic myopia.

Large-Scale CRISPR Screen of LDLR Pathogenic Variants.

Familial hypercholesterolemia (FH) is a frequently occurring genetic disorder that is linked to early-onset cardiovascular disease. If left untreated, patients with this condition can develop severe cardiovascular complications. Unfortunately, many patients remain undiagnosed, and even when diagnosed, the treatment is often not optimal. Although mutations in the LDLR gene are the primary cause of FH, predicting whether novel variants are pathogenic is not a straightforward task. Understanding the functionality of LDLR variants is crucial in uncovering the genetic basis of FH. Our study utilized CRISPR/Cas9 cytosine base editors in pooled screens to establish a novel approach for functionally assessing tens of thousands of LDLR variants on a large scale. A total of more than 100 single guide RNAs (sgRNAs) targeting LDLR pathogenic mutations were successfully screened with relatively high accuracy. Out of these, 5 sgRNAs were further subjected to functional verification studies, including 1 in the promoter, 1 in the antisense RNA, 1 in the exon, and 2 in the intron. Except for the variant caused by the sgRNA located at intron 16, the functionalities of the other LDLR variants were all downregulated. The high similarity of LDLR intron sequences may lead to some false positives. Overall, these results confirm the reliability of the large-scale screening strategy for functional analysis of LDLR variants, and the screened candidate pathogenic mutations could be used as an auxiliary means of clinical gene detection to prevent FH-induced heart disease.