Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.

Publisher Correction: Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.

Monolithic 3D integration of 2D materials-based electronics towards ultimate edge computing solutions.

Three-dimensional (3D) hetero-integration technology is poised to revolutionize the field of electronics by stacking functional layers vertically, thereby creating novel 3D circuity architectures with high integration density and unparalleled multifunctionality. However, the conventional 3D integration technique involves complex wafer processing and intricate interlayer wiring. Here we demonstrate monolithic 3D integration of two-dimensional, material-based artificial intelligence (AI)-processing hardware with ultimate integrability and multifunctionality. A total of six layers of transistor and memristor arrays were vertically integrated into a 3D nanosystem to perform AI tasks, by peeling and stacking of AI processing layers made from bottom-up synthesized two-dimensional materials. This fully monolithic-3D-integrated AI system substantially reduces processing time, voltage drops, latency and footprint due to its densely packed AI processing layers with dense interlayer connectivity. The successful demonstration of this monolithic-3D-integrated AI system will not only provide a material-level solution for hetero-integration of electronics, but also pave the way for unprecedented multifunctional computing hardware with ultimate parallelism.

Tranexamic Acid Can Reduce Early Tendon Adhesions After Rotator Cuff Repair and Is Not Detrimental to Tendon-Bone Healing: A Comparative Animal Model Study.

PURPOSE: To determine the effects of topical tranexamic acid (TXA) administration on tendon adhesions, shoulder range of motion (ROM), and tendon healing in an acute rotator cuff repair rat model. METHODS: A total of 20 Sprague Dawley rats were used. Tendon adhesion, ROM, and biomechanical and histological analysis of tendon-bone healing was conducted at 3 and 6 weeks after surgery. The rats underwent rotator cuff repair surgery on both shoulders and were administered TXA via subacromial injections. The tendon adhesion was evaluated macroscopically and histologically. Biomechanical tendon healing was measured using a universal testing machine, and histological analysis was quantified by H&E, Masson's trichrome, and picrosirius red staining. RESULTS: At 3 weeks after surgery, the adhesion score was significantly lower in the TXA group (2.10 ± 0.32) than in the control group (2.70 ± 0.48) (P = .005), but there was no significant difference between the 2 groups at 6 weeks. Regarding ROM, compared with the control group, the TXA group showed significantly higher external rotation (36.35° ± 4.52° vs 28.42° ± 4.66°, P < .001) and internal rotation (45.35° ± 9.36° vs 38.94° ± 5.23°, P = .013) 3 weeks after surgery. However, at 6 weeks, there were no significant differences in external and internal rotation between the 2 groups. In the biomechanical analysis, no significant differences in gross examination (3 weeks, P = .175, 6 weeks, P = .295), load to failure (3 weeks, P = .117, 6 weeks, P = .295), or ultimate stress (3 weeks, P = .602, 6 weeks, P = .917) were noted between the 2 groups 3 and 6 weeks after surgery. In the histological analysis of tendon healing, no significant differences in the total score (3 weeks, P = .323, 6 weeks, P = .572) were found between the 2 groups 3 and 6 weeks after surgery. CONCLUSIONS: Topical TXA administration showed a beneficial effect in reducing tendon adhesions and improving ROM 3 weeks postoperatively and had no effect at 6 weeks. This suggests that additional intervention with TXA may be useful in achieving long-term improvement in shoulder stiffness. Additionally, TXA may increase tissue ground substance accumulation in the late postoperative period but does not adversely affect tendon-bone interface healing. CLINICAL RELEVANCE: The use of TXA after rotator cuff repair has no effect on tendon-bone interface healing in clinical practice and can improve shoulder stiffness in the early postoperative period. Additional research on the long-term effects is needed.

Direct Visualization of Subnanometer Variations in the Excitonic Spectra of 2D/3D Semiconductor/Metal Heterostructures.

The integration of metallic contacts with two-dimensional (2D) semiconductors is routinely required for the fabrication of nanoscale devices. However, nanometer-scale variations in the 2D/metal interface can drastically alter the local optoelectronic properties. Here, we map local excitonic changes of the 2D semiconductor MoS2 in contact with Au. We utilize a suspended and epitaxially grown 2D/metal platform that allows correlated electron energy-loss spectroscopy (EELS) and angle resolved photoelectron spectroscopy (nanoARPES) mapping. Spatial localization of MoS2 excitons uncovers an additional EELS peak related to the MoS2/Au interface. NanoARPES measurements indicate that Au-S hybridization decreases substantially with distance from the 2D/metal interface, suggesting that the observed EELS peak arises due to dielectric screening of the excitonic Coulomb interaction. Our results suggest that increasing the van der Waals distance could optimize excitonic spectra of mixed-dimensional 2D/3D interfaces and highlight opportunities for Coulomb engineering of exciton energies by the local dielectric environment or moiré engineering.

Current research trends on the effect of diabetes mellitus on rotator cuff tendon healing/tendinopathy.

Rotator cuff tendon tears are a leading cause of shoulder pain. They are challenging to treat, and tendon-bone healing has a high failure rate despite successful surgery. Tendons connect the muscles and bones, which make them important for the body's overall mobility and stability. Metabolic diseases, including diabetes or high blood pressure, can affect the healing process after repair of a damaged tendon. With a global incidence of 9.3%, diabetes is considered as a significant risk factor for rotator cuff tendon healing because it causes structural, inflammatory, and vascular changes in the tendon. However, the mechanisms of how diabetes affects tendon healing remain unknown. Several factors have been suggested, including glycation product accumulation, adipokine dysregulation, increased levels of reactive oxygen species, apoptosis, inflammatory cytokines, imbalanced matrix-metalloproteinase-to-tissue-inhibitor ratio, and impaired angiogenesis and differentiation of the tendon sheath. Despite the effects of diabetes on tendon function and healing, few treatments are available to improve recovery in these patients. This review summarizes the current literature on the pathophysiological changes of the tendon in diabetes and hyperlipidemia. Preclinical and clinical evidence regarding the association between diabetes and tendon healing is presented. Moreover, current approaches to improve tendon healing in patients with diabetes are reviewed.

Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia.

Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

COMPARISON OF SURGEON MUSCULAR PROPERTIES BETWEEN STANDARD OPERATING MICROSCOPE AND DIGITALLY ASSISTED VITREORETINAL SURGERY SYSTEMS.

PURPOSE: To quantitatively analyze surgical ergonomics between standard operating microscope (SOM) and digitally assisted vitreoretinal surgery (DAVS) systems. METHODS: The surgeon conducted procedures on 110 patients; 52 patients underwent a combined phacoemulsification and pars plana vitrectomy (Phaco-PPV group, 24 using SOM and 28 using DAVS), and 58 patients underwent phacoemulsification (Phaco group, 30 using SOM and 28 using DAVS). The surgeon's muscle tone and stiffness in the sternocleidomastoid and the two positions of the upper trapezius (UT), which are 2-cm intervals along the UT muscle fibers, UT1 and UT2, were measured at preoperative, intraoperative, and postoperative time points. RESULTS: In the Phaco-PPV group using the SOM, intraoperative muscle tone and stiffness were higher than preoperative and postoperative values in the sternocleidomastoid ( P < 0.001, respectively), UT1 ( P < 0.001, respectively), and UT2 ( P < 0.001 and P < 0.01, respectively). In the Phaco group using the SOM, intraoperative muscle tone and stiffness were higher than pre- and postoperative values in the sternocleidomastoid ( P < 0.001, respectively) and UT1 ( P < 0.001 and P < 0.01, respectively). By contrast, when the surgeon used the DAVS, there were no differences in muscle properties at any measurement site or during any time point in the Phaco-PPV and Phaco groups ( P > 0.05). CONCLUSION: This study provides quantitative measurement of retina surgeon ergonomics, suggesting that compared with a SOM, the DAVS can reduce intraoperative muscle fatigue.

Toxoplasma gondii effector TgIST blocks type I interferon signaling to promote infection.

In contrast to the importance of type II interferon-γ (IFN-γ) in control of toxoplasmosis, the role of type I IFN is less clear. We demonstrate here that TgIST, a secreted effector previously implicated in blocking type II IFN-γ signaling, also blocked IFN-ß responses by inhibiting STAT1/STAT2-mediated transcription in infected cells. Consistent with a role for type I IFN in cell intrinsic control, ∆Tgist mutants were more susceptible to growth inhibition by murine and human macrophages activated with IFN-ß. Additionally, type I IFN was important for production of IFN-γ by natural killer (NK) cells and recruitment of inflammatory monocytes at the site of infection. Mice lacking type I IFN receptors (Ifnar1-/-) showed increased mortality following infection with wild-type parasites and decreased virulence of ∆Tgist parasites was restored in Ifnar1-/- mice. The findings highlight the importance of type I IFN in control of toxoplasmosis and illuminate a parasite mechanism to counteract the effects of both type I and II IFN-mediated host defenses.

The Feasibility of Cross-Linguistic Speech Evaluation in the Care of International Cleft Palate Patients.

ABSTRACT: Many patients with cleft palate in developing countries never receive postoperative speech assessment or therapy. The use of audiovisual recordings could improve access to post-repair speech care. The present study evaluated whether English-speaking speech-language pathologists (SLPs) could assess cleft palate patients speaking an unfamiliar language (Tamil) using recorded media. Recordings obtained from Tamil-speaking participants were rated by 1 Tamil-speaking SLP and 3 English-speaking SLPs. Ratings were analyzed for inter-rater reliability and scored for percent correct. Accuracy of the English SLPs was compared with independent t tests and Analysis of Variance. Sixteen participants (mean age 14.5 years, standard deviation [SD] 7.4 years; mean age of surgery of 2.7 years, SD 3.7 years; time since surgery: 10.8 years, SD 5.7 years) were evaluated. Across the 4 SLPs, 5 speech elements were found to have moderate agreement, and the mean kappa was 0.145 (slight agreement). Amongst the English-speaking SLPs, 10 speech elements were found to have substantial or moderate agreement, and the mean kappa was 0.333 (fair agreement). Speech measures with the highest inter-rater reliability were hypernasality and consonant production errors. The average percent correct of the English SLPs was 60.7% (SD 20.2%). English SLPs were more accurate if the participant was female, under eighteen, bilingual, or had speech therapy. The results demonstrate that English SLPs without training in a specific language (Tamil) have limited potential to assess speech elements accurately. This research could guide training interventions to augment the ability of SLPs to conduct cross-linguistic evaluations and improve international cleft care by global health teams.

A novel DENND1B-localized structure found at the basal side of adherent cells.

Rab35 is a small G protein involved in various cellular events including clathrin-dependent endocytosis, phagocytosis, and autophagy. DENND1B, a DENN family member, acts as a guanine nucleotide exchange factor (GEF) for Rab35 to convert it to the GTP-bound active form from the GDP-bound inactive form. DENND1B contains the DENN domain which harbors GEF activity for Rab35 in the N-terminus, while the clathrin binding motif and adaptor protein-2-interaction motif are at the C-terminus. In this study, we investigated the intracellular localization of DENN1B in various cell types and found novel DENND1B-localized gathered line structures in BS-C-1 cells and in some other cell types. The localization of DENND1B to gathered line structures was dependent on a specific region located in the C-terminus of DENND1B protein. DENND1B-localized gathered lines were partially associated with microtubules but not with F-actin; instead, F-actin bundles surrounded the assembly of gathered lines. We also show that the gathered line structures appeared at the bottom of spreading lamellipodia and disappeared at the retracting site during cell motility in EGF-stimulated BS-C-1 cells. These results shed light on a new role for DENND1B in the regulation of cell migration.

Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.

B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

Ultrasound Diagnosis of Prenatal Cleft Lip: How Does Its Accuracy Affect the Family?

ABSTRACT: Factors impacting the accuracy of ultrasound (US) diagnosis of cleft lip (CL) and its subsequent effect on parents are not well understood. Our objectives were to evaluate how the type of CL (complete versus incomplete) and associated cleft palate affect the accuracy of CL's prenatal diagnosis and to evaluate differences between parents' perception of prenatal US in cases of true-positive versus false-negative results. The authors performed a retrospective review of all patients who underwent repair for nonsyndromic CL following prenatal US. Patients were stratified by type of CL and associated cleft palate. Parents were called to determine if their child's CL was diagnosed via US and their perception of the results. Forty-seven children with complete and 40 with incomplete CL responded to phone calls. The presence of a complete CL (P = 0.001) and an associated cleft palate (P = 0.014) were independently associated with an increased likelihood of prenatal diagnosis. Parents who received a true-positive prenatal diagnosis of CL were more satisfied than those who received a false-negative diagnosis (P = 0.0063). True-positives perceived knowing of their child's diagnosis in advance to be more helpful than false-negatives believed it would have been. These results afford an improved context to interpret US studies and help physicians provide more informed prenatal counseling.

Large Solitary Fibrous Tumor of the Kidney.

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that can affect any soft tissue in the body. Given their infrequency, no definitive risk factors have been identified. Typically, surgical extrication en bloc is the only known curative treatment option for SFTs; however, systemic therapy can be used for metastatic or unresectable disease. Only 10 perent to 15 perent of SFTs are aggressive in behavior and termed malignant, leading to a high survival rate for affected patients. Surveillance is required post-operatively to detect recurrence.

Zebrafish model of posttraumatic epilepsy.

OBJECTIVE: Posttraumatic epilepsy (PTE) is defined as recurrent and unprovoked seizures occurring >1 week after traumatic brain injury (TBI). Animal studies of PTE are lengthy and expensive. In this study, we developed a cost-effective PTE animal model using zebrafish to bridge the gap between in vitro studies and low-throughput animal studies. METHODS: We used two different sets of parameters (G1 and G2) to induce closed-head TBI in adult zebrafish using pulsed high-intensity focused ultrasound. Injured fish and naive controls were evaluated for behavioral deficits and spontaneous behavioral seizure activity up to 21 days postinjury (DPI). We also assessed behavioral seizure susceptibility to a subconvulsive dose of pentylenetetrazole (PTZ; 2.5 mmol·L-1 ) and recorded electrophysiological signals to confirm seizure activity up to 40 DPI. In addition, we investigated injury-related changes in the blood-brain barrier and expression levels of various proteins altered in rodent and human TBI. RESULTS: The G2 parameters resulted in a more severe TBI, with a mortality rate of 25%, as well as motor dysfunction and heightened anxiety persisting at 21 DPI. One hundred percent of the G2 group showed spontaneous myocloniclike behavior, and 80% demonstrated tonic-clonic-like behavioral seizures by 21 DPI. Such activities were not detected in the naive group. After the application of 2.5 mmol·L-1 PTZ, 100% of injured zebrafish had cloniclike seizures at 21 DPI, versus 30% of the naive group. We also demonstrated electrographic seizure activity at 40 DPI, which was not detected in the naive controls. Lastly, we observed acute blood-brain barrier dysfunction and increased levels of HMGB1 and ratios of phosphorylated/total Akt and tau through 21 DPI. SIGNIFICANCE: Together, the results indicate that severe TBI in the adult zebrafish leads to similar behavioral and physiological changes to those of more traditional models, including the development of PTE, and suggest this may be a useful model that can accelerate research in TBI/PTE.

Clinical and radiological outcomes between biportal endoscopic decompression and microscopic decompression in lumbar spinal stenosis.

BACKGROUND CONTEXT: Numerous minimal invasive techniques treating lumbar spinal stenosis have been introduced. Clinical results using biportal endoscopic spinal surgery has recently been introduced as a treatment option for lumbar spinal stenosis. The purpose of this study was to compare the clinical and radiologic outcome between microscopic unilateral laminotomy bilateral decompression and biportal endoscopic unilateral laminotomy bilateral decompression in patients with degenerative lumbar spinal stenosis. METHOD: A total of 89 patients were evaluated for this study. Only single-level patients were enrolled for accurate comparison. Patients that underwent biportal endoscopic surgery were assigned to Group A, and patients that underwent microscopic surgery were designated Group B. Clinical outcomes were evaluated using modified Macnab criteria, Oswestry Disability Index, and Visual Analog Scale. Postoperative complications were checked until final follow up. Plain radiographs before and after surgery were compared to analyze the change of alignment. RESULT: There was a significant difference between Group A and B in VAS of back on postoperative 2 months. Other clinical measurements except for postoperative 2 months VAS of back showed no significant difference. There were no significant differences between Group A and Group B regarding preoperative and postoperative radiological findings. CONCLUSION: Two different decompression techniques preserve the spinal structure and exhibit a favorable clinical outcome and have the advantage of not causing postoperative instability in the short term follow up. Biportal endoscopic surgery may leads to less postoperative back pain than microscopic surgery, which may allow early ambulation and shorter hospitalization period.

Quantitative Imaging of Organic Ligand Density on Anisotropic Inorganic Nanocrystals.

A longstanding challenge in nanoparticle characterization is to understand anisotropic distributions of organic ligands at the surface of inorganic nanoparticles. Here, we show that using electron energy loss spectroscopy in an aberration-corrected scanning transmission electron microscope we can directly visualize and quantify ligand distributions on gold nanorods (AuNRs). These experiments analyze dozens of particles on graphene substrates, providing insight into how ligand binding densities vary within and between individual nanoparticles. We demonstrate that the distribution of cetyltrimethylammonium bromide (CTAB) on AuNRs is anisotropic, with a 30% decrease in ligand density at the poles of the nanoparticles. In contrast, the distribution of (16-mercaptohexadecyl)trimethylammonium bromide (MTAB) is more uniform. These results are consistent with literature reported higher reactivity at the ends of CTAB-coated AuNRs. Our results demonstrate the impact of electron spectroscopy to probe molecular distributions at soft-hard interfaces and how they produce spatially heterogeneous properties in colloidal nanoparticles.

An Innovative Pain Control Method Using Peripheral Nerve Block and Patient-Controlled Analgesia With Ketorolac After Bone Surgery in the Ankle Area: A Prospective Study.

Although postoperative pain is inevitable after bone surgery, there is no general consensus regarding its ideal management. We hypothesized that the combination of ultrasound-guided peripheral nerve block (PNB) and patient-controlled analgesia (PCA) with ketorolac would be useful for pain control and reducing opioid usage. This prospective study aimed to evaluate the effectiveness of this method. This study included 95 patients aged >18 years who underwent bone surgery in the ankle area from June to December 2018. All operations were performed under anesthetic PNB, and additional PNB was given for pain control ∼11 hours after preoperative PNB. An additional PCA with ketorolac, started before rebound pain was experienced, was used for pain control in group A (49 patients) but not group B (46 patients). We used intramuscular injection with pethidine or ketorolac as rescue analgesics if pain persisted. A visual analogue scale (VAS) for pain was used to quantify pain at 6, 12, 18, 24, 36, 48, and 72 hours postoperatively. Patient satisfaction was assessed, along with side effects in both groups. VAS pain scores differed significantly between the groups at 24 hours after the operation (p = .013). All patients in group A were satisfied with the pain control method; however, 5 patients in group B were dissatisfied (p = .001), 3 owing to severe postoperative pain and 2 owing to postoperative nausea and vomiting. An average of 0.75 and 11.40 mg pethidine per patient was used in groups A and B, respectively, for 3 days. We concluded that the combined use of ultrasound-guided PNB and PCA with ketorolac can be an effective postoperative method of pain control that can reduce opioid usage.

Identifying Aesthetically Appealing Upper Eyelid Topographic Proportions.

BACKGROUND: The goal of upper eyelid procedures is to restore or create the ideal proportions between the pretarsal space and the upper lid fold. OBJECTIVES: The aim of this study was to define the topographic features of the attractive upper lid. METHODS: Caucasian female frontal facial photographs were obtained from public media and periorbital areas were cropped. A total of 294 photographs of eyes were rated by 6 evaluators using a 4-point Likert scale. Eyes rating an average ≥3.5 were defined as "attractive," whereas those rated ≤2.0 were defined as "unattractive" and analyzed using Adobe Illustrator. RESULTS: Fifty-one and 19 eyes were included in the attractive and unattractive cohorts, respectively. (Upper lid foldPretarsal) shows ratios averaged between 1.8 and 3.0 among attractive eyes, and larger ratios were observed laterally. These ratios were significantly larger laterally among attractive vs unattractive eyes (P ≤ 0.003). The lash line peak (P < 10-4), lid crease peak (P < 10-3), and brow peak (P < 0.05) were significantly more lateralized in attractive eyes. CONCLUSIONS: Attractive eyes tend to exhibit decreased pretarsal show. However, there is pronounced variability in these ratios among attractive eyes, suggesting the importance of other features. Interestingly, progressive lateralization of the lash line, lid crease, and brow peaks appears to be an undescribed feature common to attractive eyes. Knowledge of attractive eyelid features may be an important consideration for planning and optimization of upper lid rejuvenation procedures.