Machine learning and deep learning approaches for enhanced prediction of hERG blockade: a comprehensive QSAR modeling study.

BACKGROUND: Cardiotoxicity is a major cause of drug withdrawal. The hERG channel, regulating ion flow, is pivotal for heart and nervous system function. Its blockade is a concern in drug development. Predicting hERG blockade is essential for identifying cardiac safety issues. Various QSAR models exist, but their performance varies. Ongoing improvements show promise, necessitating continued efforts to enhance accuracy using emerging deep learning algorithms in predicting potential hERG blockade. STUDY DESIGN AND METHOD: Using a large training dataset, six individual QSAR models were developed. Additionally, three ensemble models were constructed. All models were evaluated using 10-fold cross-validations and two external datasets. RESULTS: The 10-fold cross-validations resulted in Mathews correlation coefficient (MCC) values from 0.682 to 0.730, surpassing the best-reported model on the same dataset (0.689). External validations yielded MCC values from 0.520 to 0.715 for the first dataset, exceeding those of previously reported models (0-0.599). For the second dataset, MCC values fell between 0.025 and 0.215, aligning with those of reported models (0.112-0.220). CONCLUSIONS: The developed models can assist the pharmaceutical industry and regulatory agencies in predicting hERG blockage activity, thereby enhancing safety assessments and reducing the risk of adverse cardiac events associated with new drug candidates.

Review of machine learning and deep learning models for toxicity prediction.

The ever-increasing number of chemicals has raised public concerns due to their adverse effects on human health and the environment. To protect public health and the environment, it is critical to assess the toxicity of these chemicals. Traditional in vitro and in vivo toxicity assays are complicated, costly, and time-consuming and may face ethical issues. These constraints raise the need for alternative methods for assessing the toxicity of chemicals. Recently, due to the advancement of machine learning algorithms and the increase in computational power, many toxicity prediction models have been developed using various machine learning and deep learning algorithms such as support vector machine, random forest, k-nearest neighbors, ensemble learning, and deep neural network. This review summarizes the machine learning- and deep learning-based toxicity prediction models developed in recent years. Support vector machine and random forest are the most popular machine learning algorithms, and hepatotoxicity, cardiotoxicity, and carcinogenicity are the frequently modeled toxicity endpoints in predictive toxicology. It is known that datasets impact model performance. The quality of datasets used in the development of toxicity prediction models using machine learning and deep learning is vital to the performance of the developed models. The different toxicity assignments for the same chemicals among different datasets of the same type of toxicity have been observed, indicating benchmarking datasets is needed for developing reliable toxicity prediction models using machine learning and deep learning algorithms. This review provides insights into current machine learning models in predictive toxicology, which are expected to promote the development and application of toxicity prediction models in the future.

Machine learning and deep learning for brain tumor MRI image segmentation.

Brain tumors are often fatal. Therefore, accurate brain tumor image segmentation is critical for the diagnosis, treatment, and monitoring of patients with these tumors. Magnetic resonance imaging (MRI) is a commonly used imaging technique for capturing brain images. Both machine learning and deep learning techniques are popular in analyzing MRI images. This article reviews some commonly used machine learning and deep learning techniques for brain tumor MRI image segmentation. The limitations and advantages of the reviewed machine learning and deep learning methods are discussed. Even though each of these methods has a well-established status in their individual domains, the combination of two or more techniques is currently an emerging trend.

Analyzing 3D structures of the SARS-CoV-2 main protease reveals structural features of ligand binding for COVID-19 drug discovery.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease has an essential role in viral replication and has become a major target for coronavirus 2019 (COVID-19) drug development. Various inhibitors have been discovered or designed to bind to the main protease. The availability of more than 550 3D structures of the main protease provides a wealth of structural details on the main protease in both ligand-free and ligand-bound states. Therefore, we examined these structures to ascertain the structural features for the role of the main protease in the cleavage of polyproteins, the alternative conformations during main protease maturation, and ligand interactions in the main protease. The structural features unearthed could promote the development of COVID-19 drugs targeting the SARS-CoV-2 main protease.

Development of a primate model to evaluate the effects of ketamine and surgical stress on the neonatal brain.

With advances in pediatric and obstetric surgery, pediatric patients are subject to complex procedures under general anesthesia. The effects of anesthetic exposure on the developing brain may be confounded by several factors including pre-existing disorders and surgery-induced stress. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is routinely used as a pediatric general anesthetic. However, controversy remains about whether ketamine exposure may be neuroprotective or induce neuronal degeneration in the developing brain. Here, we report the effects of ketamine exposure on the neonatal nonhuman primate brain under surgical stress. Eight neonatal rhesus monkeys (postnatal days 5-7) were randomly assigned to each of two groups: Group A (n = 4) received 2 mg/kg ketamine via intravenous bolus prior to surgery and a 0.5 mg/kg/h ketamine infusion during surgery in the presence of a standardized pediatric anesthetic regimen; Group B (n = 4) received volumes of normal saline equivalent to those of ketamine given to Group A animals prior to and during surgery, also in the presence of a standardized pediatric anesthetic regimen. Under anesthesia, the surgery consisted of a thoracotomy followed by closing the pleural space and tissue in layers using standard surgical techniques. Vital signs were monitored to be within normal ranges throughout anesthesia. Elevated levels of cytokines interleukin (IL)-8, IL-15, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1ß at 6 and 24 h after surgery were detected in ketamine-exposed animals. Fluoro-Jade C staining revealed significantly higher neuronal degeneration in the frontal cortex of ketamine-exposed animals, compared with control animals. Intravenous ketamine administration prior to and throughout surgery in a clinically relevant neonatal primate model appears to elevate cytokine levels and increase neuronal degeneration. Consistent with previous data on the effects of ketamine on the developing brain, the results from the current randomized controlled study in neonatal monkeys undergoing simulated surgery show that ketamine does not provide neuroprotective or anti-inflammatory effects.

Transdiscal instrumentation in single-level lumbosacral fusion for high-grade isthmic pediatric spondylolisthesis: Technical note and review of the literature.

Pediatric spondylolisthesis is a common cause of back pain in children, typically managed conservatively with bracing and non-steroidal anti-inflammatory drugs. When posterolateral fusion is performed for refractory pain, pseudarthrosis and implant failure may occur, necessitating reoperation. To improve patient outcomes, there is a need for alternative surgical techniques to effectively manage high-grade isthmic slips. Here, the authors report the case of a child with Meyerding grade III anterolisthesis of L5 on S1 who was treated with a single-level, instrumented fusion using bilateral S1-L5 transdiscal screws, supported with L5-S1 posterolateral instrumentation and arthrodesis. Postoperatively, there was improvement in the patient's symptoms with good clinical and radiographic outcomes. The patient continues to be symptom free with radiographic evidence of hardware stability and bony fusion across the segment. The authors detail a novel surgical technique in children as well as a review of lumbosacral transdiscal screw fixation. Further evidence is required to definitively establish the safety, outcomes, and biomechanical strength of this technique.

Plastic Surgery Away Rotations During the Coronavirus Disease Pandemic: A Virtual Experience.

BACKGROUND: Plastic surgery has traditionally been a specialty that places a strong emphasis on away rotations during the final year of medical school. These rotations allow the program and residency candidates to become better acquainted and are often crucial, as a large portion of applicants match at programs where they rotated. The coronavirus disease 2019 (COVID-19) pandemic forced many institutions to modify their educational curriculums when away rotations were canceled. We present our experience creating and implementing a virtual plastic surgery rotation. METHODS: Our virtual program was designed to mirror the in-person away rotations as much as possible. Prerotation and postrotation surveys from the students as well as feedback interviews with the students, residents, and faculty were used to gather information on the experience. RESULTS: We created a 2-week curriculum including approximately 20 hours of lecture time, 28 hours of operating room time, 2.5 hours of one-on-one mentorship, and 3 hours of social opportunities. Students reported that they learned more about plastic surgery and the residency program, but in contrast to this, some found it difficult to make an impression. CONCLUSIONS: We developed a novel 2-week virtual curriculum that provided visiting medical students from across the country an opportunity to learn more about plastic surgery and our residency program. Virtual learning is becoming a vital part of education, and our study provides pearls and pitfalls when structuring these experiences.

Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations.

Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17ß-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses.

Lymphovenous shunts: from development to clinical applications.

The lymphatic system is a vast network of vessels that functions to return excess fluid from the interstitial space to the blood stream. Lymphovenous shunts are anastomoses, either natural or surgical, that connect the lymphatic and venous systems. Connections between the thoracic duct and venous system or between the right lymphatic duct and venous system are prime examples of anatomic lymphovenous shunts. Lymphovenous shunts are also present peripherally in tissues such as lymph nodes. Furthermore, pathologic lymphovenous shunts are observed in conditions such as lymphedema, malignancy, and lymphovenous malformations. Surgically, lymphovenous shunts may be constructed as an approach to treat lymphedema. Here, we discuss anatomic and surgical lymphovenous shunts in the context of normal development and disease. This perspective is intended to give an understanding of the role of lymphovenous shunts in health and disease and to show how they can be leveraged to treat disease surgically.

Medical Student Research in Surgery: From Abstract Presentation to Publication.

OBJECTIVE: Early career mentorship in surgical research often begins in medical school, and scholarly activity in the forms of abstract presentations and publications is seen as a critical criterion in residency applications. The goal of this study was to examine how often medical student abstract presentations at the American College of Surgeons (ACS) Clinical Congress are eventually published as peer-reviewed publications. DESIGN: Medical student abstract presentations from ACS Clinical Congress 2014 to 2018 were reviewed. Abstract information was cross-referenced for companion peer-reviewed publication in the PubMed and Google Scholar databases. RESULTS: In total, 219 students presented abstracts at the ACS Clinical Congress between 2014 and 2018. Of these, 101 (46%) led to publications in 61 different journals. The percentage of presentations that were published was 63% from 2014, 51% from 2015, 56% from 2016, 39% from 2017, and 25% from 2018. Medical students were named as first authors on 54%, second authors on 19%, and third authors on 13% of publications. The basic science presentation category had the greatest conversion to publications (54%), followed by clinical research (48%) and outcomes (45%). CONCLUSIONS: Forty-six percent of medical student abstract presentations at the ACS Clinical Congress were converted to peer-reviewed publications. While it is encouraging that the ACS Clinical Congress is a productive forum to showcase medical student scholarly activity, more can be done to encourage full translation of research activity to peer-reviewed work. Further studies should be performed to look at influential factors amongst medical students, faculty mentors, and medical schools.

Effects of Xenon-Based Anesthetic Exposure on the Expression Levels of Polysialic Acid Neural Cell Adhesion Molecule (PSA-NCAM) on Human Neural Stem Cell-Derived Neurons.

Numerous studies suggest a long duration of anesthesia during the late gestation period and infancy is associated with an increased risk of neuronal damage and neurocognitive impairment. The noble gas xenon is an anesthetic that is reported to have neuroprotective effects in some circumstances at certain concentrations. Currently, the effects of xenon on the brain and its potential neuroprotective properties, and/or the effects of xenon used in combination with other anesthetics, are not clearly understood and some reported data appear contradictory. In the present study, human neural stem cells were employed as a human-relevant model to evaluate the effects of xenon when it was co-administered with propofol, a frequently used anesthetic in pediatric anesthesia, and to understand the mechanism(s). The expression of polysialic acid (PSA) neural cell adhesion molecule (NCAM) on human neural stem cell-differentiated neurons was investigated as a key target molecule. PSA is a specific marker of developing neurons. It is essential for neuronal viability and plasticity. Human neural stem cells were maintained in neural differentiation medium and directed to differentiate into neuronal and glial lineages, and were exposed to propofol (50 µM) for 16 h in the presence or absence of xenon (33%). The neural stem cell-derived neurons were characterized by labelling cells with PSA-NCAM, after 5 days of differentiation. Propofol- and/or xenon-induced neurotoxicities were determined by measuring PSA immunoreactivity. A time course study showed that neuronal cell surface PSA was clearly cleaved off from NCAM by endoneuraminidase N (Endo-N), and eliminated PSA immunostaining was not re-expressed 4, 8, or 16 h after Endo-N washout. However, in the presence of 33% xenon, intense PSA staining on neuronal cell surface and processes was evident 16 h after Endo-N washout. In addition, prolonged (16 h) propofol exposure significantly decreased the positive rate of PSA-labeled neurons. When combined with xenon, propofol's adverse effects on neurons were attenuated. This work, conducted on the human neural stem cell-derived models, has provided evidence of the beneficiary effects of xenon on neurons and helps develop xenon-based anesthesia regimens in the pediatric population.

Molar Bud-to-Cap Transition Is Proliferation Independent.

Tooth germs undergo a series of dynamic morphologic changes through bud, cap, and bell stages, in which odontogenic epithelium continuously extends into the underlying mesenchyme. During the transition from the bud stage to the cap stage, the base of the bud flattens and then bends into a cap shape whose edges are referred to as "cervical loops." Although genetic mechanisms for cap formation have been well described, little is understood about the morphogenetic mechanisms. Computer modeling and cell trajectory tracking have suggested that the epithelial bending is driven purely by differential cell proliferation and adhesion in different parts of the tooth germ. Here, we show that, unexpectedly, inhibition of cell proliferation did not prevent bud-to-cap morphogenesis. We quantified cell shapes and actin and myosin distributions in different parts of the tooth epithelium at the critical stages and found that these are consistent with basal relaxation in the forming cervical loops and basal constriction around enamel knot at the center of the cap. Inhibition of focal adhesion kinase, which is required for basal constriction in other systems, arrested the molar explant morphogenesis at the bud stage. Together, these results show that the bud-to-cap transition is largely proliferation independent, and we propose that it is driven by classic actomyosin-driven cell shape-dependent mechanisms. We discuss how these results can be reconciled with the previous models and data.

Screening for carbapenemase-producing Enterobacteriaceae in previous carriers readmitted to hospital: evaluation of a change in screening policy.

Carbapenemase-producing Enterobacteriaceae (CPE) are a growing problem in UK hospitals. Preventing transmission requires early detection. This study evaluates a new screening policy for patients with a history of blaKPC-associated CPE (KPC-CPE) in a higher incidence hospital. Previous policy assumed 'once positive always positive'. New policy uses rapid screening and risk assessment. Results show that most (76.5%) patients with a history of KPC-CPE do not have detectable KPC-CPE on readmission or during their subsequent hospital stay but that repeat screening after an initial negative result is required. The new policy takes a risk-based approach while prioritizing isolation facilities in a higher incidence trust.

Neurenteric cyst of the conus medullaris.

BACKGROUND: Neurenteric cysts (NECs) are rare developmental malformations of the central nervous system (CNS) which originate as benign congenital lesions. They originate from developmental foregut precursors, and are presumed to be the result of abnormal partitioning of the embryonic notochord plate. Such NECs predominantly arise in the cervical region in patients around 6 years of age or in their twenties or thirties. Notably, NECs of the conus medullaris are exceedingly rare, especially in patients of advanced age. CASE DESCRIPTION: A 70-year-old male presented with bilateral upper thigh and leg pain of over 20 years duration. His pain worsened over the past 3 years, and he sought surgical management. Although his neurological exam was normal, the lumbar magnetic resonance imaging revealed an intradural, nonenhancing, thin-walled, cystic lesion at L1/conus medullaris. The lesion was successfully resected without any adverse sequelae. CONCLUSIONS: NECs are rare congenital legions that involve the spine. Here, an L1 intradural extramedullay neuroenteric cyst of the conus medullaris was resected without complications.

A review of atypical subtrochanteric femoral fractures in Northern Ireland between 2010 and 2014.

The term atypical femoral fractures most commonly occur in the subtrochanteric area. Concerns exist regarding the role of bisphosphonate treatment in their aetiology. Which surgical intervention provides the best outcome remains contentious. We reviewed all atypical subtrochanteric femoral fractures treated in Northern Ireland over 5 years, specifically investigating incidence, prodromal symptoms, association with bisphosphonates and optimal fixation methods. All subtrochanteric fractures treated in the region were identified and reviewed for atypical features. Case notes and imaging were then reviewed for each patient. A total of 364 subtrochanteric femoral fractures were identified during the 5-year study period. Twenty-six of these met the criteria for an atypical fracture (7%). Thirteen patients (50%) had presented with prodromal symptoms prior to complete fracture, six of which had radiological evidence of an incomplete fracture of the lateral cortex. Thirteen patients had a history of bisphosphonate treatment. All were treated operatively, with twenty-five cephalomedullary nails and one dynamic hip screw. Twenty-one patients had follow-up for greater than 2 months, nine of which (42.9%) achieved radiological union with a mean time to union of 297 days. Dynamically locked nails had a higher union rate than statically locked (80% versus 33.3%). Four patients required major revision surgery (15.4%). The quality of reduction was statistically significant in predicting need for revision. Atypical fractures often present with prodromal symptoms. Complete fractures are difficult to successfully manage with longer than expected times to union. Treatment with a dynamically locked, cephalomedullary with a good reduction provided the best results.

The Impact of the Eda Pathway on Tooth Root Development.

The Eda pathway ( Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig's epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes.

Predictors for 1-year mortality following hip fracture: a retrospective review of 465 consecutive patients.

INTRODUCTION: In Europe, trauma admissions and in particular hip fractures are on the rise. In recent years, health care systems have placed particular emphasis, including financial incentives, on delivering patients quickly and safely to surgery. At our unit, we have observed that hip fracture patients appear to be at significant risk of mortality even up to a year following injury. This study reviews a consecutive population of hip fracture patients to identify predictors of excess risk. MATERIALS AND METHODS: Four hundred and sixty-five consecutive patients were treated over a 2-year period at our district general hospital with no ward-based orthogeriatricians. Follow-up was for 1 year following hip fracture admission. Statistical analysis of variables and their influence on 1-year mortality were performed by calculating odd's ratio (OR) using a logistic regression model and a p value <0.05 was considered statistically significant. RESULTS: Four patients were lost to follow-up, 18 patients (4.1 %) were managed conservatively, 16 were too unwell for surgery and their mortality rate at 1 year was 50 %. Following hip fracture, we found an overall 1-year mortality rate of 15.1 %. Patients with a time to surgery ≥36 h were at significantly increased risk of mortality even up to 1 year. We did not identify a further reduction in mortality in those operated on within 24 h. Raised ORs (p > 0.05) were found with increasing comorbidity, surgery type, independence on discharge, alcohol ingestion, history of smoking, readmission and several biochemical markers. CONCLUSION: Minimising mortality risk, even over the longer term, should begin on admission with prompt optimisation of any acute medical or biochemical abnormalities, followed by early surgery and intensive rehabilitation to maintain patients' functional independence.

Is there any place for the variable angle proximal femoral plate? A case matched cohort study against the Dynamic Hip Screw system.

INTRODUCTION: The Variable angle Martin Plate (MP) is designed to offer patient-specific adaption for the treatment of intertrochanteric hip fractures. Its proposed benefits include optimization of lag screw placement, plate shaft congruence and reduced risk of failure. Often its use has been criticized as representing a poor reduction of the fracture. The purpose of this study was to assess for a poorer quality of reduction, and compare functional outcomes and mortality, using a MP to that of a fixed angle Dynamic Hip Screw (DHS) in a matched cohort of patients. METHODS: A retrospective review of a prospective fracture database system was undertaken between 1st January 2004 to 31st December 2013. MP patients were matched to a cohort of DHS patients. Outcomes measure were a quality of procedure score(QPS), 1-year mortality rates, reoperation rates, and Barthel Index functional outcome. Minimum follow up was 12 months. RESULTS: A total of 77 Martin Plate patients were identified and case matched. The mean pre- and post-op Neck Shaft Angle (NSA) in the MPs was significantly different (132.97±7.78 Vs 126±8.62; p<0.0001). Conversely, the mean pre op DHS NSA and the mean post op NSA was not (p=0.397). Mean Tip-Apex Distance (TAD) was significantly different between groups; MP mean 26.51±9.09mm vs DHS 23.50±8.14mm (p=0.023). The QPS consisted of 4 variables. A significant inverse relationship between QPS and the incidence of construct related complications exists. TAD>25mm, and a change in AP NSA of >5°conveyed the greatest risk of complications. No difference occurred in complications, nor 12-month mortality. CONCLUSIONS: No statistical difference was found in the quality of reduction between MP and DHS in this group of matched patients. QPS demonstrated a significant inverse correlation with implant-related complications. No significant difference was noted in the incidence of complications, Barthel Index functional scores, or 12-month mortality between implants. A rationale exists regarding the use of MPs, particularly in patients with varus NSA. However, planning and adequate reduction are essential regardless of implant choice.

Root and Eruption Defects in c-Fos Mice Are Driven by Loss of Osteoclasts.

c-Fos homozygous mice lack osteoclasts with a failure of the teeth to erupt and with an arrest of root development. Here, we characterize the defects associated with the failure in root development and the loss of the tooth-bone interface, and we investigate the underlying causes. We show that, while homozygous c-Fos mice have no multinucleated osteoclasts, heterozygous mice have a reduction in the number of osteoclasts with a reduction in the tooth-bone interface during development and subtle skeletal defects postnatally. In the homozygous mutants bone is found to penetrate the tooth, particularly at the apical end, physically disrupting the root forming HERS (Hertwig's epithelial root sheath) cells. The cells of the HERS continue to proliferate but cannot extend downward due to the presence of bone, leading to a loss of root formation. Tooth germ culture showed that the developing tooth invaded the static bone in mutant tissue, rather than the bone encroaching on the tooth. Although c-Fos has been shown to be expressed in developing teeth, the defect in maintenance of the tooth-bone interface appears to be driven solely by the lack of osteoclasts, as this defect can be rescued in the presence of donor osteoclasts. The rescue suggests that signals from the tooth recruit osteoclasts to clear the bone from around the tooth, allowing the tooth to grow, form roots, and later erupt.

Salivary Gland Dysplasia in Fgf10 Heterozygous Mice: A New Mouse Model of Xerostomia.

Xerostomia, or chronic dry mouth, is a common syndrome caused by a lack of saliva that can lead to severe eating difficulties, dental caries and oral candida infections. The prevalence of xerostomia increases with age and affects approximately 30% of people aged 65 or older. Given the large numbers of sufferers, and the potential increase in incidence given our aging population, it is important to understand the complex mechanisms that drive hyposalivation and the consequences for the dentition and oral mucosa. From this study we propose the Fgf10 +/- mouse as a model to investigate xerostomia. By following embryonic salivary gland development, in vivo and in vitro, we show that a reduction in Fgf10 causes a delay in branching of salivary glands. This leads to hypoplasia of the glands, a phenotype that is not rescued postnatally or by adulthood in both male and female Fgf10 +/- mice. Histological analysis of the glands showed no obvious defect in cellular differentiation or acini/ductal arrangements, however there was a significant reduction in their size and weight. Analysis of saliva secretion showed that hypoplasia of the glands led to a significant reduction in saliva production in Fgf10 +/- adults, giving rise to a reduced saliva pellicle in the oral cavity of these mice. Mature mice were shown to drink more and in many cases had severe tooth wear. The Fgf10 +/- mouse is therefore a useful model to explore the causes and effects of xerostomia.