WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis.

The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non-transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.

Factors Associated With Dysphagia in Patients Undergoing Tracheal Resection.

Importance: Patients undergoing tracheal resection commonly experience dysphagia postoperatively, and the patient factors that predict severity and duration of symptoms are currently unclear. Objective: To determine the association of patient and surgical factors on postoperative dysphagia in adult patients undergoing tracheal resection. Design, Setting, and Participants: This was a retrospective cohort study of patients undergoing tracheal resection at 2 tertiary academic centers from February 2014 to May 2021. The centers included LAC+USC (Los Angeles County + University of Southern California) Medical Center and Keck Hospital of USC, both tertiary care academic institutions. Patients involved in the study underwent a tracheal or cricotracheal resection. Exposures: Tracheal or cricotracheal resection. Main Outcomes and Measures: The main outcome was dysphagia symptoms as measured by the functional oral intake scale (FOIS) on postoperative days (PODs) 3, 5, and 7, on the day of discharge, and at the 1-month follow-up visit. Demographics, medical comorbidities, and surgical factors were evaluated for association with FOIS scores at each time period using Kendall rank correlation and Cliff delta. Results: The study cohort consisted of 54 patients, with a mean (SD) age of 47 (15.7) years old, of whom 34 (63%) were male. Length of resection segment ranged from 2 to 6 cm, with a mean (SD) length of 3.8 (1.2) cm. The median (range) FOIS score was 4 (1-7) on PODs 3, 5, 7. On the day of discharge and at 1-month postoperative follow-up, the median (range) FOIS score was 5 (1-7) and 7 (1-7), respectively. Increasing patient age was moderately associated with decreasing FOIS scores at all measured time points (τ = -0.33; 95% CI, -0.51 to -0.15 on POD 3; τ = -0.38; 95% CI, -0.55 to -0.21 on POD 5; τ = -0.33; 95% CI, -0.58 to -0.08 on POD 7; τ = -0.22; 95% CI, -0.42 to -0.01 on day of discharge; and τ = -0.31; 95% CI, -0.53 to -0.09 at 1-month follow-up visit). History of neurological disease, including traumatic brain injury and intraoperative hyoid release, was not associated with FOIS score at any of the measured time points (δ = 0.03; 95% CI, -0.31 to 0.36 on POD 3; δ = 0.11; 95% CI, -0.28 to 0.47 on POD 5, δ = 0.3; 95% CI, -0.25 to 0.70 on POD 7; δ = 0.15; 95% CI, -0.24 to 0.51 on the day of discharge, and δ = 0.27; 95% CI, -0.05 to 0.53 at follow-up). Resection length was also not correlated with FOIS score with τ ranging from -0.04 to -0.23. Conclusions and Relevance: In this retrospective cohort study, most patients undergoing tracheal or cricotracheal resection experienced full resolution of dysphagia symptoms within the initial follow-up period. During preoperative patient selection and counseling, physicians should consider that older adult patients will experience greater severity of dysphagia throughout their postoperative course and delayed resolution of symptoms.

Review of blast noise and the auditory system.

The auditory system is particularly vulnerable to blast injury due to the ear's role as a highly sensitive pressure transducer. Over the past several decades, studies have used a variety of animal models and experimental procedures to recreate blast-induced acoustic trauma. Given the developing nature of this field and our incomplete understanding of molecular mechanisms underlying blast-related auditory disturbances, an updated discussion about these studies is warranted. Here, we comprehensively review well-established blast-related auditory pathology including tympanic membrane perforation and hair cell loss. In addition, we discuss important mechanistic studies that aim to bridge gaps in our current understanding of the molecular and microstructural events underlying blast-induced cochlear, auditory nerve, brainstem, and central auditory system damage. Key findings from the recent literature include the association between endolymphatic hydrops and cochlear synaptic loss, blast-induced neuroinflammatory markers in the peripheral and central auditory system, and therapeutic approaches targeting biochemical markers of blast injury. We conclude that blast is an extreme form of noise exposure. Blast waves produce cochlear damage that appears similar to, but more extreme than, the standard noise exposure protocols used in auditory research. However, experimental variations in studies of blast-induced acoustic trauma make it challenging to compare and interpret data across studies.

Contemporary Review of Submandibular Gland Sialolithiasis and Surgical Management Options.

One of the most common disorders of the salivary glands is obstructive sialolithiasis. Salivary gland obstruction is important to address, as it can significantly impact patient quality of life and can progress to extensive cellulitis and abscess formation if left untreated. For small and accessible stones, conservative therapies often produce satisfactory outcomes. Operative management should be considered when stones are inaccessible or larger in size, and options include sialendoscopy, laser lithotripsy, extracorporeal shockwave lithotripsy, transoral surgery, and submandibular gland adenectomy. Robotic approaches are also becoming increasingly used for submandibular stone management. The purpose of this review is to summarize the modern-day management of submandibular gland obstructive sialolithiasis with an emphasis on operative treatment modalities. A total of 77 articles were reviewed from PubMed and Embase databases, specifically looking at the pathophysiology, clinical presentation, diagnosis, and management of submandibular sialolithiasis.

Deep-learning models for the detection and incidence prediction of chronic kidney disease and type 2 diabetes from retinal fundus images.

Regular screening for the early detection of common chronic diseases might benefit from the use of deep-learning approaches, particularly in resource-poor or remote settings. Here we show that deep-learning models can be used to identify chronic kidney disease and type 2 diabetes solely from fundus images or in combination with clinical metadata (age, sex, height, weight, body-mass index and blood pressure) with areas under the receiver operating characteristic curve of 0.85-0.93. The models were trained and validated with a total of 115,344 retinal fundus photographs from 57,672 patients and can also be used to predict estimated glomerulal filtration rates and blood-glucose levels, with mean absolute errors of 11.1-13.4 ml min-1 per 1.73 m2 and 0.65-1.1 mmol l-1, and to stratify patients according to disease-progression risk. We evaluated the generalizability of the models for the identification of chronic kidney disease and type 2 diabetes with population-based external validation cohorts and via a prospective study with fundus images captured with smartphones, and assessed the feasibility of predicting disease progression in a longitudinal cohort.

A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.

Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.