United States

Background and Purpose: Deep burns and wounds remain difficult to treat effectively. Recent advances in tissue engineering and biotechnology have led to the advent of several skin substitutes (SS) including xenografts, bioscaffolds, and tissue-engineered dermal templates, though no product has been proven superior to current standards of care (SOC) for burns or wounds. We aim provide a systematic review and meta-analysis on clinical trials (CT) and randomized controlled trials (RCT) investigating the available skin substitute options for burn and wound treatment.

Methods: A systematic review of the PubMed, Scopus, and CINAHL databases was performed using PRISMA guidelines for CTs and RCTs published between 2017 and 2022. Articles were screened for relevance using Covidence®. Studies were then grouped by indication for use in burn or wound treatment. Meta-analysis was performed using RevMan v.5® on burn studies that assessed mean time to complete re-epithelialization and wound studies that assessed the proportion of wounds completely closed at 12 months. 

Results: 48 studies (39 RCT; 9 CT) were included and stratified by indication: burns (20 studies) or wounds (28 studies). For burns, 4 studies compared SS to SOC silver sulfadiazine cream as assessed by mean time to complete re-epithelialization (190 burns) and were included in meta-analyses. Fish skin xenografts (FSX) significantly outperformed SOC (p=0.0003) with burn depths ranging from superficial partial thickness to deep 2nd degree. For wounds, 13 studies compared SS to SOC alginate dressings assessed by the proportion of wounds completely healed at 12 weeks (2529 wounds) and were included in meta-analysis. Dehydrated human amnion and chorion allografts (dHACA; p=0.01) and human reticular acellular dermal matrices (HR-ADM, p&lt;0.00001) all significantly outperformed SOC.

Conclusions: FSXs were superior to SOC in the treatment of burns and both dHACAs and HR-ADMs were superior to SOC for wound treatment.


2022 AMA Research Challenge

State-of-the-art Skin Substitute and Scaffold Designs for Burns and Wounds: A Systematic Review and Meta-Analysis

Welcome to the largest national, multi-specialty research event **featuring research from 750 medical students, residents and fellows, and international medical graduates.**


#### Event Details
The 2022 American Medical Association Research Challenge includes a poster symposium hall and a semifinals hall with the top scored research. Log in at any time throughout the event to:
* **View posters and presentations** on a variety of topics and specialties
* **Score posters in the semifinals** to help decide the top five finalists (AMA member exclusive opportunity)
* **Connect with participants** and provide feedback to help advance their research

At the conclusion of this event, the AMA will announce the top five finalists who will advance to the AMA Research Challenge finals, present their research to an elite panel of judges and compete to win a $10,000 grand prize sponsored by Laurel Road.
 

#### Attend Live Forums
**Oct. 20, 6 — 7 p.m. Central**
 **How to plan a career in academic medicine** 
 Learn how to plan a career in academic medicine and get your questions answered. [Access Here](https://underline.io/events/363/lounge)
 
 **Speakers**
![](https://assets.underline.io/uploads/markdown_image/1/image/d5adb133dfc58eb0a6d469e9cedcd5d4.jpg)
Ricardo Correa, MD, EdD
![](https://assets.underline.io/uploads/markdown_image/1/image/5f9437ab87861538bf02b9ca7c0d926e.jpg)
Stuart M. Greenstein, MD
![](https://assets.underline.io/uploads/markdown_image/1/image/05b1b637c99286d558c371f8e8b185ce.jpg)
Stephanie Strohbeen, MD
 
 **Oct. 22, 11 a.m. — Noon Central**
 **How to get published**
 Learn tips to get your research published and get your questions answered. [Access Here](https://underline.io/events/363/lounge)
 
 **Speakers**
![](https://assets.underline.io/uploads/markdown_image/1/image/8ce6235e957d31cb5e6f9097cc6f6972.jpg)
Jessica Li, MD/PhD Candidate
![](https://assets.underline.io/uploads/markdown_image/1/image/9950ef2e0237f54cb3d8280334d42491.jpg)
Charles Lopresto, DO

### Sponsor
AMA would like to thank Laurel Road for sponsoring a $10,000 grand prize for the winner of the AMA Research Challenge. Laurel Road is not involved in the judging or scoring process to select the winner. The winner will be announced on Dec. 7 during the AMA Research Challenge finals. Payment of the grand prize will be directly from Laurel Road. See the AMA Research Challenge Official Rules for terms and conditions.

![](https://assets.underline.io/uploads/markdown_image/1/image/611e331d4a0eba0920f240cfc04b4d77.png)

**There is no registration fee for this event! **

Register to explore research in a variety of topics. AMA members get exclusive access to score posters in the semifinals.

**Please use the link below to register for free if you have not already done so:**

https://www.ama-assn.org/about/events/ama-research-challenge

Registration Is Required

Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


Background and Purpose: Deep burns and wounds remain difficult to treat effectively. Recent advances in tissue engineering and biotechnology have led to the advent of several skin substitutes (SS) including xenografts, bioscaffolds, and tissue-engineered dermal templates, though no product has been proven superior to current standards of care (SOC) for burns or wounds. We aim provide a systematic review and meta-analysis on clinical trials (CT) and randomized controlled trials (RCT) investigating the available skin substitute options for burn and wound treatment.

Methods: A systematic review of the PubMed, Scopus, and CINAHL databases was performed using PRISMA guidelines for CTs and RCTs published between 2017 and 2022. Articles were screened for relevance using Covidence®. Studies were then grouped by indication for use in burn or wound treatment. Meta-analysis was performed using RevMan v.5® on burn studies that assessed mean time to complete re-epithelialization and wound studies that assessed the proportion of wounds completely closed at 12 months. 

Results: 48 studies (39 RCT; 9 CT) were included and stratified by indication: burns (20 studies) or wounds (28 studies). For burns, 4 studies compared SS to SOC silver sulfadiazine cream as assessed by mean time to complete re-epithelialization (190 burns) and were included in meta-analyses. Fish skin xenografts (FSX) significantly outperformed SOC (p=0.0003) with burn depths ranging from superficial partial thickness to deep 2nd degree. For wounds, 13 studies compared SS to SOC alginate dressings assessed by the proportion of wounds completely healed at 12 weeks (2529 wounds) and were included in meta-analysis. Dehydrated human amnion and chorion allografts (dHACA; p=0.01) and human reticular acellular dermal matrices (HR-ADM, p<0.00001) all significantly outperformed SOC.

Conclusions: FSXs were superior to SOC in the treatment of burns and both dHACAs and HR-ADMs were superior to SOC for wound treatment.

technical paper

Background: Despite the significant advances in detecting pulmonary nodules, the management plan of small tumors with malignant potential remains controversial. The objective of this study was to evaluate the overall survival of patients with ≤8 mm non-small cell lung cancer (NSCLC) who undergo stereotactic body radiation therapy (SBRT) versus wedge resection.

Methods: Kaplan-Meier analysis, multivariable Cox proportional hazards modeling, and propensity score-matched analysis were performed to evaluate the overall survival of patients with ≤8 mm NSCLC in the National Cancer Database (NCDB) from 2004-2017 who underwent SBRT versus patients who underwent wedge resection. The above-mentioned matched analyses were repeated for patients with no comorbidities. Patients who were coded in the NCDB as having undergone radiation because surgery was contraindicated due to patient risk factors (e.g., comorbid conditions, advance age, etc.) and those with a history of prior malignancy were excluded from analysis.

Results: Of the 1,505 patients who had NSCLC ≤8 mm during the study period, 1,339 (89%) patients underwent wedge resection, and 166 (11%) patients underwent SBRT. In both unadjusted analysis and in multivariable Cox modeling and propensity score-matched analysis, wedge resection was associated with improved survival when compared to SBRT. These results were consistent in a sensitivity analysis limited to patients with no comorbidities.

Conclusion: In this national analysis, patients with NSCLC ≤8 mm undergoing wedge resection experienced improved survival when compared to SBRT. This finding can be used to help inform the treatment decision-making process for tumors that are being discovered incidentally or through lung cancer screening. 





Stereotactic Body Radiation Therapy Versus Wedge Resection for Early-Stage Node-Negative Non-Small Cell Lung Cancer Tumors ≤8 mm: A National Analysis

Hannah Kelly, Grant Fabrizio, Lauren Yap, Isela Melendez-Carpio, Susan M. Cheng, H. Carrie Chen

Diversity in medical education is imperative for future physicians as they prepare to treat heterogeneous patient populations. For aspiring physicians, mentorship plays an important role in navigating the pre-medical journey. Currently, gaps in medical mentorship are monopolized by costly, third-party “admission consulting” agencies. Inaccessibility to these services disproportionately impacts underrepresented minority and first-generation students. We addressed this gap by implementing and evaluating an extension of Georgetown’s Students Helping Aspiring Physicians Excel (SHAPE) initiative, housed within the Office of Diversity, Equity and Inclusion, called SHAPE Summer Mentors program. This free, 7-week mentorship experience includes an individualized mentor/mentee matching process, an interactive weekly curriculum addressing common secondary application essay themes, and consistent quality time and support from trained first-year medical student mentors.

Program participants from the 2021-2022 AMCAS application cycle answered pre- and post- program surveys about their background and experiences regarding stress, confidence, and support.  Sixteen questions used a 5-point likert scale. Data analysis included descriptive statistics and two-tailed t-test for independent means.

One hundred twenty-one pre-medical mentees participated in the program; 79 (65.3%) completed the pre-program survey and 76 (62.8%) completed the post-program survey. Of those participating, 30 (24.8%) identified as underrepresented in medicine, 62 (51.2%) as first- or second-generation immigrants, and 38 (31.4%) as first-generation college students in the United States. Responses from the pre- to post-program surveys indicated that after going through the SHAPE Summer Mentors program, participants felt more supported in their medical school application process (4.08 to 4.33, p=0.0383) and less stressed about applying (4.46 to 4.08, p=0.0098). Participants also reported improved confidence in their ability to write secondary essays (3.28 to 3.92, p<0.0001) and improved comfort with interviews (3.23 to 4.04, p=0.0027). Additionally, there was a notable trend in which participants had increased confidence that they will be accepted to medical school (2.99 to 3.29, p=0.0639). Upon program completion, 100% of participants felt more prepared for the application cycle.

Preliminary evaluation results of the SHAPE Summer Mentors program indicate that the program is successful in supporting participants and improving their confidence through the medical school application process. The SHAPE Summer Mentors program’s student-led curriculum offers an innovative solution to reduce barriers and increase access for pre-medical students from a variety of backgrounds, including underrepresented minority and first-generation students in medicine.

Students Helping Aspiring Physicians Excel (SHAPE) Summer Mentors: A Novel Peer-to-Peer Mentorship Program for Medical School Admissions

Background
Patients diagnosed with breast cancer at our safety-net hospital (SNH) are significantly more likely to be diagnosed at later stages, and this late-stage-at-diagnosis is most highly associated with lack of screening mammogram. We showed that a two-part intervention - phone call and assistance with scheduling - significantly increased mammography uptake by 12% among our safety-net population. Implementing this finding system-wide proved challenging and resource heavy. Prior studies show success with text message reminders in low-income populations, but none evaluate the utility of scheduling by text. Here, we seek to determine whether a text-based intervention with reminder and scheduling could increase mammography uptake.
Methods
A randomized controlled study included 843 women aged 50-65 who had not had a screening or diagnostic mammogram in the past two years, but had established care at a primary care clinic (PCC) within our SNH. One-third of the participants were assigned to each of the following groups: Intervention 1 (text reminder with specific scheduling options), Intervention 2 (text reminder with open-ended scheduling options) and usual-care control. Participants in both intervention groups could engage in two-way texting, and up to three texts were sent to each patient. Differences in percent mammography uptake at 3 months were compared between intervention and control groups using a two-tailed chi-square.
Results
Patients receiving a text-based reminder and scheduling opportunity were significantly more likely to get mammograms within 3 months than those in the usual care control group (10.2% and 6.2%, respectively; chi2 = 5.6279, p < 0.017). 14.8% of participants responded to text message. 9% of participants scheduled an appointment for mammogram via text, of which 63% received mammogram. Mammography compliance did not differ by type of scheduling offered (specific vs. general) or by PCC.
Conclusion
Reminders and scheduling through two-way text-messaging is effective in increasing mammography uptake among primary care clinic patients in an urban safety-net setting. Scheduling component was a key feature in the success of the intervention. The safety-net is a diverse and hard-to-reach population. Future studies should combine different types of interventions to design a multi-pronged approach that is tailored to this population with unique needs.

Text-based Intervention Increases Mammography Uptake among Overdue Patients at an Urban, Safety-Net Hospital: A Randomized Controlled Study

Background
Neuroblastoma is the most common extracranial childhood tumor. Despite intensive multi-modality therapies, approximately 50% of high-risk patients die from progressive disease. Although retinoic acid-based therapies provide clinical benefit, patients eventually relapse due to resistance, underscoring the critical need for novel treatments. Amplification of MYCN, an oncogene present in 40-50% of high-risk neuroblastoma cases, is associated with poor patient prognosis and poor response to retinoid therapies. However, MycN is “undruggable,” prompting efforts to indirectly impair its expression or function. The aryl hydrocarbon receptor (AhR) is a transcription factor whose role in neuroblastoma remains incompletely characterized. Here, we investigate AhR as a novel tumor promoter that regulates MycN and retinoic acid pathways in neuroblastoma. 

Methods
Human neuroblastoma cells were modified to over- or under-express AhR, or were treated pharmacologically with the AhR antagonist, clofazimine (CLF). To assess tumorigenicity, invasion, clonogenicity, and tumor growth were measured. For MycN regulation studies, AhR and MycN protein expression were detected by immunoblotting. Cells were treated with retinoic acid after AhR depletion or inhibition and examined by microscopy. 

Results
We found AhR depletion decreases clonogenicity and tumor growth in vivo. Notably, treatment with clofazimine (CLF), an FDA-approved anti-leprosy drug we previously identified to be a novel AhR antagonist, has the same effect. CLF is orally bioavailable, safe, cost-effective, and approved for use in children, representing a promising new therapy for neuroblastoma patients. Our work further reveals that AhR depletion and inhibition reduces MycN expression and induces differentiation. Finally, we found AhR depletion and inhibition potentiates retinoid-induced neuroblastoma differentiation. 

Conclusion
Our work uncovers a novel role for AhR as a tumor promoter in neuroblastoma and could lead to an already FDA-approved drug, CLF, as a promising new therapy for neuroblastoma patients that improves efficacy of retinoic acid-based treatments. 


The Aryl Hydrocarbon Receptor (AhR) as a Novel Therapeutic Target in Neuroblastoma

Immigrant Haitian women in New York City (NYC) have the highest rate of Severe Maternal Morbidity of 494.0 per 10,000 deliveries, compared to 229.8 for U.S.-born women. There is little study into the needs and barriers of the Haitian immigrant community, which is one of the largest growing immigrant populations in the United States today. We sought to understand pregnant and postpartum Haitian women’s barriers to healthcare services in NYC and explore ways to improve their overall health outcomes.

The Barriers to Healthcare Pregnant and Postpartum Haitian Women Experience in New York City

Background 
Patients with severe aplastic anemia (SAA) develop high-risk infections. Prior data suggest efficacy and safety of granulocyte transfusion (GT) as an infection management tool in this population. A multicenter randomized control trial of GT in patients with severe neutropenia of varying etiologies did not reveal a significant difference in overall survival (OS) or microbial response but was limited by low enrollment and variable granulocyte dose. In this study of SAA patients who received GTs at our institution, we characterize patients’ clinical and survival outcomes and the role of GTs as a bridge to curative therapy. 

Methods 
SAA patients treated with immunosuppressive therapy who received GTs between 2011 and 2020 are included in our analysis. The primary outcomes are survival from first GT, including OS, and number of patients surviving to discharge and HSCT in patients awaiting HSCT. Secondary outcomes include evaluation of response at 30 days after initiation of GTs based on clinical, microbiological, and radiographical criteria. Cox proportional-hazards model was utilized to determine impact of neutrophil response and infection type on survival. Kaplan-Meier was used to assess OS. 

Results 
Twenty-eight SAA patients of median age 20 years (range 6-65 years) underwent 30 GT courses of median 8 products per course (range 1-39 products), over median 23.5 days (range 3-103 days), with a per-dose median 1.28 x 10^9 granulocyte cells/kg (range 0.45-4.52 x 10^9). Infection type included bacterial (n=15), fungal (n=12), and mixed (n=3). OS from initial GT was 50% with a median length of follow up at 550.5 days (range 2-4213 days). 18 of 28 (64.3%) patients survived to hospital discharge. Of the 21 patients awaiting HSCT during granulocyte therapy, 18 (85.7%) received HSCT. Patients achieving complete, partial or stable response at 30 days had significantly improved OS compared to non-responders (p=0.00004). Sex, type of infection, or % of days with ANC >200 cells/mcL during the granulocyte course, were not predictive of survival (p=0.52, p=0.7, p=0.28 respectively). 

Conclusion 
GTs of adequate dose and course duration are a valuable adjunctive therapy to manage severe infections in SAA patients and may be particularly valuable as a bridge to undergoing curative treatment with HSCT.

The Clinical Role of Granulocyte Transfusions in Severe Aplastic Anemia

Strabismus is a visible disability that impacts one's ability to make eye contact. In this study, we evaluate the impact that strabismus has on quality of life in adults and explore how strabismus surgery can be effective in improving quality of life.

The impact of strabismus on quality of life in adults

Introduction: The Rotterdam CT (RCT) score is a prognostic metric used to predict mortality in patients with traumatic brain injury (TBI) using injury characteristics observed on initial CT. Withdrawal of life-sustaining therapies (WLST) following trauma may be related to certain patient factors such as age and injury severity, but its relationship to RCT remains unknown. 

Objectives: The present study aims to determine whether the RCT score can be used as a reliable predictor of WLST in patients with TBI and to validate previous studies demonstrating that the RCT score can reliably predict mortality in patients with TBI. 

Methods: All patients ≥ 18 years old with TBI were identified from the MetroHealth TBI Database, a registry of patients admitted to MetroHealth Medical Center (Cleveland, OH) with TBI between 2018-2021. We collected factors related to RCT score, baseline demographic data, clinical presentation, neurosurgical intervention, and do not attempt resuscitation (DNAR) orders. The primary outcome measure was WLST, and the secondary outcome measure was mortality. Binary logistic regression models were created to determine factors independently associated with WLST and mortality. 

Results: A total of 1110 patients were identified. The median age was 61 years old and 69.3% (770/1110) were male. In this cohort, 11.3% (n = 125) of patients underwent WLST. A bivariate logistic regression model revealed that RCT score (continuous) (odds-ratio (OR) 1.6 [95% confidence-interval (95%-CI) 1.2-2.2]), Glasgow Coma Scale (continuous; GCS) (OR 0.84 [95%-CI 0.78-0.91]), Injury Severity Scale score (continuous; ISS) (OR 1.04 [95%-CI 1.01-1.07]), ventricular drain (OR 4.7 [95%-CI 1.1-19.6]), and DNAR (OR 47.8 [23.8-95.6]) were all independently associated with WLST. An additional bivariate logistic regression model revealed that RCT score (OR 2.08 [95%-CI 1.49-2.91]), ISS (OR 1.06 [95%-CI 1.03-1.10]), GCS (OR 0.81 [95%-CI 0.74-0.88]), undergoing a craniectomy (OR 0.28 [95%-CI 0.09-0.83]), and DNAR (OR 73.3 [95%-CI 34.8-145.7]) were all independently associated with mortality. These models demonstrated excellent accuracy and discrimination ability for both WLST and mortality as endpoints, as demonstrated by concordance statistics of 0.97.

Conclusion: In adult TBI patients, the RCT score can be accurately used to independently predict both WLST and mortality with high predictive validity.

The Predictive Validity of the Rotterdam Computed Tomography Score on Withdrawal of Life-Sustaining Therapies in Patients with Traumatic Brain Injury

Objective: 
The primary purpose of this study was to determine if treating endometriosis with optimal excision surgery leads to lower rates of repeat surgery as compared to historical rates of repeat surgery by ablation. A secondary outcome was to examine whether the use of hormonal suppression differed before surgery, depending on the stage of endometriosis found at surgery.
Study design: 
We performed a prospective cohort study (Canadian Task Force class II-3).
Materials and methods: 
Preoperative data, operative data, and follow-up postoperative data were collected prospectively (IRB 20900) at the Saint Louis University Center for Endometriosis, a referral center for the surgical management of endometriosis specializing in the optimal excision of endometriosis, from time frame 2012-2019. Optimal excision was defined as completely excising all areas of abnormal peritoneum, wherever found in the pelvis, having looked systematically with near contact laparoscopy. All surgeries were performed by a single surgeon specializing in optimal excision. Follow-up data was collected from annual questionnaires sent postoperatively to patients.
Results: 
Of the 756 patients in the database who underwent surgery for endometriosis, 620 patients had histological confirmation of endometriosis in any location excised, yielding a rate of finding tissue-proven endometriosis to be 82%. The mean follow-up time period in months was 32 months (range 5-136 months). Of the 620 patients with tissue-proven endometriosis, 570 women had optimal excision (OE) surgery for endometriosis (91.9%) of which 14 patients underwent repeat surgery (2.5%). Of the 620 patients, 366 women (60%) were on hormonal suppression specifically: 96.4% of the 366 women on hormonal contraceptives, 29.5% on GnRH agonists/antagonists/chemical menopause, and 14.6% on progesterone-secreting IUDs with a median length of suppression of 36 months. At surgery, 62.9% of patients were categorized as endometriosis stage 1 or 2, 11.8% for stage 3, and 25.3% for stage 4. There was also no significant association between hormonal suppression before endometriosis excision surgery with the stage of endometriosis found at surgery. 
Conclusion: 
The rate of repeat surgery is an important clinical factor when looking at surgical outcomes. The rate of repeat surgery after optimal excision surgery for endometriosis was remarkably low (2.5%) as compared to historical rates of repeat surgery by ablation (40-60% in 1-2 years following initial procedure ). Additionally, the lack of significant evidence between hormonal suppression use and progression of stage of endometriosis provides implicit evidence that hormonal suppression does not prevent progression of the disease. Further controlled studies are needed to verify these findings.


The Rate of Repeat Surgery After Optimal Excision Surgery of Endometriosis at a Single Tertiary Referral Center

BACKGROUND: Otitis Media (OM) is one of the most prevalent pediatric infectious diseases often comprising two common diagnoses: acute otitis media (AOM) and otitis media with effusion (OME). The current guidelines on managing OM have emphasized the need to accurately diagnose fluid presence in the ear, and the latest methods for OM diagnosis are often inaccurate or under-utilized. This frequently results in over-usage of antibiotics for AOM or misdiagnosis of middle ear effusion in OME. Emerging technologies including leveraging artificial intelligence (AI) and automation to improve OM diagnosis are likely to play a significant role for clinicians into the future. As a specific example, optical coherence tomography (OCT), capable of imaging body cavities and tissue, has recently been introduced as a promising technology for the accurate diagnosis of OM. This study was conducted to capture the current state of advances in automation and technological innovations in OM diagnosis.
METHODS: A qualitative systematic review of PubMed, Scopus, and Google Scholar was conducted to analyze the role of AI and automation in the diagnosis and management of OM. Articles were reviewed for eligibility and 41 studies met inclusion criteria.
RESULTS: Across studies, use of AI has shown promising progress toward more accurate diagnosis of AOM. Clinicians can use AI and obtain reliable imaging focused on AOM and OME, aiding in both management and diagnosis. Applications of OCT have provided for high- quality detection, diagnostics, and monitoring prognosis of OM. Smartphone attachments employing acoustic reflectance have recently demonstrated great potential for cost-effective and remote OM diagnosis. Although smartphone otoscopes are available for remote use by parents, there remains risk for discrepancies when compared to data acquired by physicians.
CONCLUSION: Through the development of an automated diagnostic algorithm for OM, AI and automation technologies would provide several benefits to OM patients worldwide. This cost-effective approach can account for early detection of OM in pediatric patients, assist parents in deciding whether their children need professional help, and aid clinicians in managing OM with potentially more reliability than current technologies.

Premium content

State-of-the-art Skin Substitute and Scaffold Designs for Burns and Wounds: A Systematic Review and Meta-Analysis

Downloads

Next from 2022 AMA Research Challenge

Stereotactic Body Radiation Therapy Versus Wedge Resection for Early-Stage Node-Negative Non-Small Cell Lung Cancer Tumors ≤8 mm: A National Analysis

Similar lecture

Patient Shared Decision-Making in Deep Inferior Epigastric Perforator (DIEP) Flap Donor Site Complications: A Patient Centric Classification Validated by BREAST-Q Improves Satisfaction

Stay up to date with the latest Underline news!

PRESENTATIONS

CONFERENCES

COMPANY

RESOURCES