Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR002345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclaimer: Additionally, the views expressed in this article are those of the author only and should not be construed to represent in any way those of the United States Government, the United States Department of Defense (DoD), or the United States Department of the Army. The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the author, DoD, or any component agency.

<ol>
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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Propensity+scores+for+confounder+adjustment+when+assessing+the+effects+of+medical+interventions+using+nonexperimental+study+designs.">Propensity scores for confounder adjustment when assessing the effects of medical interventions using nonexperimental study designs.</a> Journal of Internal Medicine. 275 (6), 570-580 (2014).</li><li>Schermerhorn, M. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Long-Term+Outcomes+of+Abdominal+Aortic+Aneurysm+in+the+Medicare+Population.">Long-Term Outcomes of Abdominal Aortic Aneurysm in the Medicare Population.</a> New England Journal of Medicine. 373 (4), 328-338 (2015).</li><li>Williams, R. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Propensity-Matched+Analysis+Between+Standard+Versus+Tapered+Oral+Vancomycin+Courses+for+the+Management+of+Recurrent+Clostridium+difficile+Infection.">A Propensity-Matched Analysis Between Standard Versus Tapered Oral Vancomycin Courses for the Management of Recurrent Clostridium difficile Infection.</a> Open Forum Infectious Diseases. 4 (4), (2017).</li><li>Mitchell, J. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Impact+of+Statins+on+Cardiovascular+Outcomes+Following+Coronary+Artery+Calcium+Scoring.">Impact of Statins on Cardiovascular Outcomes Following Coronary Artery Calcium Scoring.</a> Journal of the American College of Cardiology. 72 (25), 3233-3242 (2018).</li><li>Rush, T., McGeary, M., Sicignano, N., Buryk, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+plateau+in+new+onset+type+1+diabetes:+Incidence+of+pediatric+diabetes+in+the+United+States+Military+Health+System.">A plateau in new onset type 1 diabetes: Incidence of pediatric diabetes in the United States Military Health System.</a> Pediatric Diabetes. 19 (5), 917-922 (2018).</li><li>Rhon, D. I., Greenlee, T. A., Marchant, B. G., Sissel, C. D., Cook, C. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comorbidities+in+the+first+2+years+after+arthroscopic+hip+surgery:+substantial+increases+in+mental+health+disorders,+chronic+pain,+substance+abuse+and+cardiometabolic+conditions.">Comorbidities in the first 2 years after arthroscopic hip surgery: substantial increases in mental health disorders, chronic pain, substance abuse and cardiometabolic conditions.</a> British Journal of Sports Medicine. , (2018).</li><li>Mitchell, J., Paisley, R., Moon, P., Novak, E., Villines, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coronary+Artery+Calcium+Score+and+Long-term+Risk+of+Death,+Myocardial+Infarction+and+Stroke:+The+Walter+Reed+Cohort+Study.">Coronary Artery Calcium Score and Long-term Risk of Death, Myocardial Infarction and Stroke: The Walter Reed Cohort Study.</a> Journal of the American College of Cardiology: Cardiovascular Imaging. , (2017).</li><li>McCormick, N., Lacaille, D., Bhole, V., Avina-Zubieta, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Validity+of+myocardial+infarction+diagnoses+in+administrative+databases:+a+systematic+review.">Validity of myocardial infarction diagnoses in administrative databases: a systematic review.</a> PLoS ONE. 9 (3), e92286 (2014).</li><li>Huo, J., Yang, M., Tina Shih, Y. -. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sensitivity+of+Claims-Based+Algorithms+to+Ascertain+Smoking+Status+More+Than+Doubled+with+Meaningful+Use.">Sensitivity of Claims-Based Algorithms to Ascertain Smoking Status More Than Doubled with Meaningful Use.</a> Value in Health. , (2017).</li><li>Nayan, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+value+of+complementing+administrative+data+with+abstracted+information+on+smoking+and+obesity:+A+study+in+kidney+cancer.">The value of complementing administrative data with abstracted information on smoking and obesity: A study in kidney cancer.</a> Canadian Urological Association Journal. 11 (6), 167-171 (2017).</li><li>Birman-Deych, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accuracy+of+ICD-9-CM+codes+for+identifying+cardiovascular+and+stroke+risk+factors.">Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors.</a> Medical Care. 43 (5), 480-485 (2005).</li><li>Preen, D. B., Holman, C. D., Spilsbury, K., Semmens, J. B., Brameld, K. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Length+of+comorbidity+lookback+period+affected+regression+model+performance+of+administrative+health+data.">Length of comorbidity lookback period affected regression model performance of administrative health data.</a> Journal of Clinical Epidemiology. 59 (9), 940-946 (2006).</li><li>Rector, T. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Specificity+and+sensitivity+of+claims-based+algorithms+for+identifying+members+of+Medicare+Choice+health+plans+that+have+chronic+medical+conditions.">Specificity and sensitivity of claims-based algorithms for identifying members of Medicare+Choice health plans that have chronic medical conditions.</a> Health Services Research. 39 (6 Pt 1), 1839-1857 (2004).</li><li>Hern&#225;n, M. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Observational+studies+analyzed+like+randomized+experiments:+an+application+to+postmenopausal+hormone+therapy+and+coronary+heart+disease.">Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.</a> Epidemiology (Cambridge, Mass.). 19 (6), 766-779 (2008).</li><li>Austin, P. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+relative+ability+of+different+propensity+score+methods+to+balance+measured+covariates+between+treated+and+untreated+subjects+in+observational+studies.">The relative ability of different propensity score methods to balance measured covariates between treated and untreated subjects in observational studies.</a> Medical Decision Making. 29 (6), 661-677 (2009).</li><li>Robins, J. M., Hernan, M. A., Brumback, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Marginal+structural+models+and+causal+inference+in+epidemiology.">Marginal structural models and causal inference in epidemiology.</a> Epidemiology. 11 (5), 550-560 (2000).</li><li>Robins, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Marginal+structural+models.">Marginal structural models.</a> 1997 Proceedings of the American Statistical Association, section on Bayesian statistical science. , 1-10 (1998).</li><li>Thoemmes, F., Ong, A. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Primer+on+Inverse+Probability+of+Treatment+Weighting+and+Marginal+Structural+Models.">A Primer on Inverse Probability of Treatment Weighting and Marginal Structural Models.</a> Emerging Adulthood. 4 (1), 40-59 (2016).</li><li>Xu, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Use+of+stabilized+inverse+propensity+scores+as+weights+to+directly+estimate+relative+risk+and+its+confidence+intervals.">Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals.</a> Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research. 13 (2), 273-277 (2010).</li><li>Cowper, D. C., Kubal, J. D., Maynard, C., Hynes, D. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+primer+and+comparative+review+of+major+US+mortality+databases.">A primer and comparative review of major US mortality databases.</a> Annals of Epidemiology. 12 (7), 462-468 (2002).</li><li>Skopp, N. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+a+methodology+to+validate+National+Death+Index+retrieval+results+among+a+cohort+of+U.S.+service+members.">Evaluation of a methodology to validate National Death Index retrieval results among a cohort of U.S. service members.</a> Annals of epidemiology. 27 (6), 397-400 (2017).</li><li>Buck, C. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> 2015 ICD-9-CM for Hospitals, Volumes 1, 2, &#38; 3, Professional Edition. , (2015).</li><li>Buck, C. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> 2018 ICD-10-CM for Hospitals, Professional Edition. , (2018).</li><li>Guo, S., Fraser, W. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Propensity Score Analysis: Statistical Methods and Applications, Second Edition. , (2015).</li><li>Elixhauser, A., Steiner, C., Harris, D. R., Coffey, R. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comorbidity+measures+for+use+with+administrative+data.">Comorbidity measures for use with administrative data.</a> Medical Care. 36 (1), 8-27 (1998).</li><li>Charlson, M. E., Pompei, P., Ales, K. L., MacKenzie, C. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+method+of+classifying+prognostic+comorbidity+in+longitudinal+studies:+development+and+validation.">A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.</a> Journal of Chronic Diseases. 40 (5), 373-383 (1987).</li><li>Deyo, R. A., Cherkin, D. C., Ciol, M. 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The authors have nothing to disclose.

Retrospective analyses using large administrative datasets provide an efficient and cost-effective alternative when randomized controlled trials are not feasible. The appropriate data set will depend on the population and variables of interest, but the MDR is an attractive option that does not have the age restrictions seen with Medicare data. With any data set, it is important to be intimately familiar with its layout and data dictionary. Care should be taken along the way to ensure that complete data are captured, and ...

Randomized, placebo-controlled trials are the strongest study design to quantify efficacy of treatment, but they are not always feasible due to cost and time requirements or a lack of equipoise between treatment groups1. In these instances, a retrospective cohort design using large-scale administrative data (&#34;big data&#34;) often provides an efficient and cost-effective alternative, though the lack of randomization introduces treatment selection bias2. Treatment selection bias occurs in non-randomized studies when the treatment decision is dependent on pre-treatment characteristics that are associated with the outcome of interest. These characteristics are known as confounding factors.
Because propensity scores minimize this bias by balancing the known confounders between treatment groups, they have become increasingly popular3. Propensity scores have been used to compare surgical approaches4 and medical regimens5. Recently, we have used a propensity analysis of data from the United States Military Health System Data Repository (MDR) to assess the effect of statins in primary prevention of cardiovascular outcomes based on the presence and severity of coronary artery calcium6.
The MDR, utilized less frequently than the Medicare and VA data sets for research purposes, contains comprehensive administrative and medical claims information from inpatient and outpatient services provided for active duty military, retirees, and other Department of Defense (DoD) healthcare beneficiaries and their dependents. The database includes services provided worldwide at US military treatment facilities or at civilian facilities billed to the DoD. The database includes complete pharmacy data since October 1, 2001. Laboratory data is available from 2009 but is only limited to military treatment facilities. Within the MDR, cohorts have been defined with methods including use of diagnoses codes (e.g., diabetes mellitus7) or procedure codes (e.g., arthroscopic surgery8). Alternatively, an externally defined cohort of eligible beneficiaries, such as a registry, can be matched to the MDR to obtain baseline and follow-up data9. Unlike Medicare, the MDR includes patients of all ages. It is also less biased towards males than the VA database since it includes dependents. Access to the MDR is limited, however. Generally, only investigators that are members of the Military Health System can request access, analogous to requirements for use of the VA database. Non-government researchers seeking access to Military Health Systems data must do so through a data sharing agreement under the supervision of a government sponsor.
When using any administrative data set, it is important to bear in mind the limitations as well as strengths of administrative coding. The sensitivity and specificity of the code can vary based on the related diagnosis, whether it is a primary or secondary diagnosis, or whether it is an inpatient or outpatient file. Inpatient codes for acute myocardial infarction are generally accurately reported with positive predictive values over 90%10, but tobacco use is often undercoded11. Such undercoding may or may not have a meaningful effect on a study&#39;s results12. Additionally, several codes for a given condition may exist with varying levels of correlation to the disease in question13. An investigative team should perform a comprehensive literature search and review of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) and/or ICD-10-CM coding manuals to ensure that the appropriate codes are included in the study.
Several methods can be employed to improve the sensitivity and accuracy of the diagnostic codes to define comorbid conditions. An appropriate &#34;look-back&#34; period should be included to establish baseline comorbidities. The look-back period includes the inpatient and outpatient services provided prior to study entry. A period of one year may be optimal14. Additionally, requiring two separate claims instead of a single claim can increase specificity, while supplementing coding data with pharmaceutical data can improve sensitivity15. Select manual chart audits on a portion of the data can be used to verify accuracy of the coding strategy.
Once comorbidities have been defined and assessed for the cohort in question, a propensity score may be used to balance differences in covariates between treatment groups. The propensity score is derived from the probability that a patient is assigned to a treatment based on known covariates. Accounting for this propensity treatment reduces the effect that the covariates have on treatment assignment and helps generate a truer estimate of the treatment effect on the outcome. While propensity scores do not necessarily provide superior results to multivariate models, they do allow for assessment of whether the treated and untreated groups are comparable after applying the propensity score3. Study investigators can analyze the absolute standardized differences in covariates before and after propensity matching or inverse probability of treatment weighting (IPTW) to ensure known confounders have been balanced between groups. Importantly, unknown confounders may not be balanced, and one should be aware of the potential for residual confounding.
When executed properly, though, propensity scores are a powerful tool that can predict and replicate results of randomized controlled trials16. Of the available propensity-score techniques, matching and IPTW are generally preferred17. Within IPTW, patients are weighted by their propensity or probability for treatment. Stabilizing weights are generally recommended over raw weights, while trimming of the weights can also be considered18,19,20,21.
Once study groups are balanced, they may be followed until the outcome of interest. Studies utilizing administrative data may be interested in outcomes such as readmission rates and time-to-event analyses. In studies interested in mortality, the Military Health System Data Repository includes a field for vital status that can be further augmented using the national death index (NDI)22,23. The NDI is a centralized database of death record information from state offices that is managed by the Center for Disease Control. Investigators can request basic vital status and/or specific cause of death based on the death certificate.
The following protocol details the process of conducting an administrative database study using the MDR augmented with mortality information from the NDI. It details the use of IPTW to balance baseline differences between two treatment groups including SAS code and example output.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>CD Burner (for NDI Request)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Computer</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Putty.exe</td>
			<td>Putty.org</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SAS 9.4</td>
			<td>SAS Institute Cary, NC</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>WinSCP or other FTP software</td>
			<td><a href="https://winscp.net/eng/index.php" target="_blank">https://winscp.net/eng/index.php</a></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

inverse probability of treatment weighting (propensity score) using the military health system data repository and national death index

When randomized controlled trials are not feasible, retrospective studies using big data provide an efficient and cost-effective alternative, though they are at risk for treatment selection bias. Treatment selection bias occurs in a non-randomized study when treatment selection is based on pre-treatment characteristics that are also associated with the outcome. These pre-treatment characteristics, or confounders, can influence evaluation of a treatment&#39;s effect on the outcome. Propensity scores minimize this bias by balancing the known confounders between treatment groups. There are a few approaches to performing propensity score analyses, including stratifying by the propensity score, propensity matching, and inverse probability of treatment weighting (IPTW). Described here is the use of IPTW to balance baseline comorbidities in a cohort of patients within the US Military Health System Data Repository (MDR). The MDR is a relatively optimal data source, as it provides a contained cohort in which nearly complete information on inpatient and outpatient services is available for eligible beneficiaries. Outlined below is the use of the MDR supplemented with information from the national death index to provide robust mortality data. Also provided are suggestions for using administrative data. Finally, the protocol shares an SAS code for using IPTW to balance known confounders and plot the cumulative incidence function for the outcome of interest.

Upon completion of IPTW, tables or plots of the absolute standardized differences can be generated using the stddiff macro code or the asdplot macro code, respectively. Figure 1 shows an example of appropriate balancing in a large cohort of 10,000 participants using the asdplot macro. After application of the propensity score, the absolute standardized differences were reduced significantly. The cutoff used for the absolute standardized difference is somewhat...

Watch this Scientific Journal Video about Inverse Probability of Treatment Weighting Propensity Score using the Military Health System Data Repository and National Death Index at JoVE.com

Inverse Probability of Treatment Weighting Propensity Score using the Military Health System Data Repository and National Death Index

When randomized controlled trials are not feasible, a comprehensive health care data source like the Military Health System Data Repository provides an attractive alternative for retrospective analyses. Incorporating mortality data from the national death index and balancing differences between groups using propensity weighting helps reduce biases inherent in retrospective designs.

Inverse Probability of Treatment Weighting (Propensity Score) using the Military Health System Data Repository and National Death Index

When randomized controlled trials are not feasible, retrospective studies using big data provide an efficient and cost-effective alternative, though they ...

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14.3K Views.  Washington University School of Medicine. When randomized controlled trials are not feasible, a comprehensive health care data source like the Military Health System Data Repository provides an attractive alternative for retrospective analyses. Incorporating mortality data from the national death index and balancing differences between groups using propensity weighting helps reduce biases inherent in retrospective designs.

Video: Inverse Probability of Treatment Weighting Propensity Score using the Military Health System Data Repository and National Death Index

Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several techniques, including infusion of exogenous bacterial toxin (endotoxemia) or bacteria (bacteremia), as well as surgical perforation of the cecum by cecal ligation and puncture (CLP)1-3. CLP allows bacteria spillage and fecal contamination of the peritoneal cavity, mimicking the human clinical disease of perforated appendicitis or diverticulitis. The severity of sepsis, as reflected by the eventual mortality rates, can be controlled surgically by varying the size of the needle used for cecal puncture2. In animals, CLP induces similar, biphasic hemodynamic cardiovascular, metabolic, and immunological responses as observed during the clinical course of human sepsis3. Thus, the CLP model is considered as one of the most clinically relevant models for experimental sepsis1-3.
Various animal models have been used to elucidate the intricate mechanisms underlying the pathogenesis of experimental sepsis. The lethal consequence of sepsis is attributable partly to an excessive accumulation of early cytokines (such as TNF, IL-1 and IFN-&gamma;)4-6 and late proinflammatory mediators (e.g., HMGB1)7. Compared with early proinflammatory cytokines, late-acting mediators have a wider therapeutic window for clinical applications. For instance, delayed administration of HMGB1-neutralizing antibodies beginning 24 hours after CLP, still rescued mice from lethality8,9, establishing HMGB1 as a late mediator of lethal sepsis. The discovery of HMGB1 as a late-acting mediator has initiated a new field of investigation for the development of sepsis therapies using Traditional Chinese Herbal Medicine. In this paper, we describe a procedure of CLP-induced sepsis, and its usage in screening herbal medicine for HMGB1-targeting therapies.

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection, and can be simulated by a surgical technique termed cecal ligation and puncture (CLP). Here we describe a method to use CLP-induced animal model to screen medicinal herbs for therapeutic agents.

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several ...

Intraoperative Detection of Subtle Endometriosis: A Novel Paradigm for Detection and Treatment of Pelvic Pain Associated with the Loss of Peritoneal Integrity

Endometriosis is a common disease affecting 40 to 70% of reproductive-aged women with chronic pelvic pain (CPP) and/or infertility. The purpose of this study was to demonstrate the use of a blue dye (methylene blue) to stain peritoneal surfaces during laparoscopy (L/S) to detect the loss of peritoneal integrity in patients with pelvic pain and suspected endometriosis. Forty women with CPP and 5 women without pain were evaluated in this pilot study. During L/S, concentrated dye was sprayed onto peritoneal surfaces, then aspirated and rinsed with Lactated Ringers solution. Areas of localized dye uptake were evaluated for the presence of visible endometriotic lesions. Areas of intense peritoneal staining were resected and some fixed in 2.5% buffered gluteraldehyde and examined by scanning (SEM) electron microscopy. Blue dye uptake was more common in women with endometriosis and chronic pelvic pain than controls (85% vs. 40%). Resection of the blue stained areas revealed endometriosis by SEM and loss of peritoneal cell-cell contact compared to normal, non-staining peritoneum. Affected peritoneum was associated with visible endometriotic implants in most but not all patients. Subjective pain relief was reported in 80% of subjects. Based on scanning electron microscopy, we conclude that endometrial cells extend well beyond visible implants of endometriosis and appear to disrupt the underlying mesothelium. Subtle lesions of endometriosis could therefore cause pelvic pain by disruption of peritoneal integrity, allowing menstrual or ovulatory blood and associated pain factors access to underlying sensory nerves. Complete resection of affected peritoneum may provide a better long-term treatment for endometriosis and CPP. This simple technique appears to improve detection of subtle or near invisible endometriosis in women with CPP and minimal visual findings at L/S and may serve to elevate diagnostic accuracy for endometriosis at laparoscopy.

Loss of peritoneal integrity provides a new paradigm to understand and treat chronic pelvic pain in women with mild forms of endometriosis and can be easily detected using intraoperative instillation of dye at the time of laparoscopy.

Endometriosis is a  common disease affecting 40 to 70% of reproductive-aged women with chronic  pelvic pain (CPP) and/or infertility. The purpose of this ...

Probe-based Confocal Laser Endomicroscopy of the Urinary Tract: The Technique

Probe-based confocal laser endomicroscopy (CLE) is an emerging optical imaging technology that enables real-time in vivo microscopy of mucosal surfaces during standard endoscopy. With applications currently in the respiratory1 and gastrointestinal tracts,2-6 CLE has also been explored in the urinary tract for bladder cancer diagnosis.7-10 Cellular morphology and tissue microarchitecture can be resolved with micron scale resolution in real time, in addition to dynamic imaging of the normal and pathological vasculature.7
The probe-based CLE system (Cellvizio, Mauna Kea Technologies, France) consists of a reusable fiberoptic imaging probe coupled to a 488 nm laser scanning unit. The imaging probe is inserted in the working channels of standard flexible and rigid endoscopes. An endoscope-based CLE system (Optiscan, Australia), in which the confocal endomicroscopy functionality is integrated onto the endoscope, is also used in the gastrointestinal tract. Given the larger scope diameter, however, application in the urinary tract is currently limited to ex vivo use.11 Confocal image acquisition is done through direct contact of the imaging probe with the target tissue and recorded as video sequences. As in the gastrointestinal tract, endomicroscopy of the urinary tract requires an exogenenous contrast agent&mdash;most commonly fluorescein, which can be administered intravenously or intravesically. Intravesical administration is a well-established method to introduce pharmacological agents locally with minimal systemic toxicity that is unique to the urinary tract. Fluorescein rapidly stains the extracellular matrix and has an established safety profile.12 Imaging probes of various diameters enable compatibility with different caliber endoscopes. To date, 1.4 and 2.6 mm probes have been evaluated with flexible and rigid cystoscopy.10 Recent availability of a &lt; 1 mm imaging probe13 opens up the possibility of CLE in the upper urinary tract during ureteroscopy. Fluorescence cystoscopy (i.e. photodynamic diagnosis) and narrow band imaging are additional endoscope-based optical imaging modalities14 that can be combined with CLE to achieve multimodal imaging of the urinary tract. In the future, CLE may be coupled with molecular contrast agents such as fluorescently labeled peptides15 and antibodies for endoscopic imaging of disease processes with molecular specificity.

Probe-based confocal laser endomicroscopy enables real-time microscopy of the human urinary tract during cystoscopy, providing dynamic, intravital imaging of pathological states such as bladder cancer with cellular resolution. Endomicroscopy may augment the diagnostic accuracy of standard white light endoscopy and provide intraoperative image guidance to improve surgical resection.

Probe-based  confocal laser endomicroscopy (CLE) is an emerging optical imaging technology  that enables real-time in vivo microscopy of mucosal surfaces ...

Human Vastus Lateralis Skeletal Muscle Biopsy Using the Weil-Blakesley Conchotome

Percutaneous muscle biopsy using the Weil-Blakesley conchotome is well established in both clinical and research practice. It is a safe, effective and well tolerated technique. The Weil-Blakesley conchotome has a sharp biting tip with a 4 - 6 mm wide hollow. It is inserted through a 5 - 10 mm skin incision and can be maneuvered for controlled tissue penetration. The tip is opened and closed within the tissue and then rotated through 90 -180&#176; to cut the muscle. The amount of muscle obtained following repeated sampling can vary from 20 mg to 290 mg which can be processed for both histology and molecular studies. The wound needs to be kept dry and vigorous physical activity kept to a minimum for approximately 72 hr although normal levels of activity can restart immediately following the procedure. This procedure is safe and effective when close attention is paid to the selection of subjects, full asepsis and post procedure care. &#160;Both right and left vastus lateralis are suitable for biopsy dependent on participant preference.

Human Vastus Lateralis Skeletal Muscle Biopsy Using the Weil-Blakesley Conchotome

This video demonstrates the technique of percutaneous muscle biopsy of the human vastus lateralis using the Weil-Blakesley conchotome.

Percutaneous muscle biopsy using the Weil-Blakesley conchotome is well established in both clinical and research practice. It is a safe, effective and ...

A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data

This report describes a novel Stata-based application of trigonometric regression modelling to 55 years of multiple sclerosis relapse data from 46 clinical centers across 20 countries located in both hemispheres. Central to the success of this method was the strategic use of plot analysis to guide and corroborate the statistical regression modelling. Initial plot analysis was necessary for establishing realistic hypotheses regarding the presence and structural form of seasonal and latitudinal influences on relapse probability and then testing the performance of the resultant models. Trigonometric regression was then necessary to quantify these relationships, adjust for important confounders and provide a measure of certainty as to how plausible these associations were. Synchronization of graphing techniques with regression modelling permitted a systematic refinement of models until best-fit convergence was achieved, enabling novel inferences to be made regarding the independent influence of both season and latitude in predicting relapse onset timing in MS. These methods have the potential for application across other complex disease and epidemiological phenomena suspected or known to vary systematically with season and/or geographic location.

Combining plot analysis with trigonometric regression is a robust method for exploring complex, cyclical phenomena such as relapse onset timing in multiple sclerosis (MS). This method enabled unbiased characterisation of seasonal trends in relapse onset permitting novel inferences around the influence of seasonal variation, ultraviolet radiation (UVR) and latitude.

This report describes a novel Stata-based application of trigonometric regression modelling to  55 years of multiple sclerosis relapse data from 46 ...

Network Analysis of Foramen Ovale Electrode Recordings in Drug-resistant Temporal Lobe Epilepsy Patients

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control seizures. However, a significant minority of patients continues to exhibit post-operative seizures, even in those cases in which the suspected source of seizures has been correctly localized and resected. The protocol presented here combines a clinical procedure routinely employed during the pre-operative evaluation of temporal lobe epilepsy (TLE) patients with a novel technique for network analysis. The method allows for the evaluation of the temporal evolution of mesial network parameters. The bilateral insertion of foramen ovale electrodes (FOE) into the ambient cistern simultaneously records electrocortical activity at several mesial areas in the temporal lobe. Furthermore, network methodology applied to the recorded time series tracks the temporal evolution of the mesial networks both interictally and during the seizures. In this way, the presented protocol offers a unique way to visualize and quantify measures that considers the relationships between several mesial areas instead of a single area.

This protocol describes a procedure to track the evolution of mesial network measures in temporal lobe epilepsy (TLE) patients. It is based on the combination of intracranial recordings with a novel numerical technique for data analysis. Specifically, we present a protocol for network analyses of foramen ovale recordings.

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control ...

Using Retinal Imaging to Study Dementia

The retina offers a unique &#8220;window&#8221; to study pathophysiological processes of dementia in the brain, as it is an extension of the central nervous system (CNS) and shares prominent similarities with the brain in terms of embryological origin, anatomical features and physiological properties.&#160; The vascular and neuronal structure in the retina can now be visualized easily and non-invasively using retinal imaging techniques, including fundus photography and optical coherence tomography (OCT), and quantified semi-automatically using computer-assisted analysis programs. Studying the associations between vascular and neuronal changes in the retina and dementia could improve our understanding of dementia and, potentially, aid in diagnosis and risk assessment.&#160; This protocol aims to describe a method of quantifying and analyzing retinal vasculature and neuronal structure, which are potentially associated with dementia. This protocol also provides examples of retinal changes in subjects with dementia, and discusses technical issues and current limitations of retinal imaging.

The retina shares prominent similarities with the brain and thus represents a unique window to study vasculature and neuronal structure in the brain non-invasively. This protocol describes a method to study dementia using retinal imaging techniques. This method can potentially aid in diagnosis and risk assessment of dementia.

The retina offers a unique &#8220;window&#8221; to study pathophysiological processes of dementia in the brain, as it is an extension of the central ...

Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the safety of stem cell transplantation. Although the transplantation of differentiated rather than undifferentiated cells is common practice, teratomas can still arise from the presence of residual undifferentiated stem cells at the time of transplant or from spontaneous mutations in differentiated cells. Because stem cell therapies are often delivered into anatomically sensitive sites, even small tumors can be clinically devastating, resulting in blindness, paralysis, cognitive abnormalities, and cardiovascular dysfunction. Surgical access to these sites may also be limited, leaving patients with few therapeutic options. Controlling stem cell misbehavior is, therefore, critical for the clinical translation of stem cell therapy.
External beam radiation offers an effective means of delivering targeted therapy to decrease the teratoma burden while minimizing injury to surrounding organs. Additionally, this method avoids genetic manipulation or viral transduction of stem cells-which are associated with additional clinical safety and efficacy concerns. Here, we describe a protocol to create pluripotent stem cell-derived teratomas in mice and to apply external beam radiation therapy to selectively ablate these tumors in vivo.

Research on treatment strategies for pluripotent stem cell-derived teratomas is important for the clinical translation of stem cell therapy. Here, we describe a protocol to, first, generate stem cell-derived teratomas in mice and, then, to selectively target and treat these tumors in vivo using a small-animal irradiator.

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the ...

Enucleation of the Prostate for the Treatment of Benign Prostatic Hyperplasia Using a 980 nm Diode Laser

In the aging male population, the occurrence of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) is a common problem. Here, we introduce a new technique called 980 nm diode laser enucleation (DiLEP) to treat BPH1. Diode lasers can absorb both water and hemoglobin at the same time, so they are good for cutting and hemostasis2. The diode laser was approved by the FDA in 2007, and has been used in the treatment of BPH because of its effective cutting and hemostasis effect3. DiLEP presents several advantages over other techniques, such as TURP, HoLEP, and PVP. During the procedure, we define the boundary of a high-volume prostate and separate it into three lobes with a diode laser by burning two rings and one groove (like a Cupid&#39;s arrow). Compared to other procedures, mDiLEP has fewer intraoperative complications, a shorter learning curve, and achieves more tissue resection.

Here, we present a protocol for modified 980 nm diode laser enucleation to treat large volume benign prostatic hyperplasia.

In the aging male population, the occurrence of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) is a common problem. ...

Comparing Objective Conjunctival Hyperemia Grading and the Ocular Surface Disease Index Score in Dry Eye Syndrome During COVID-19

The incidence of dry eye syndrome (DES) has increased due to wearing masks, utilizing digital devices, and working remotely during the pandemic. A survey was conducted during the COVID-19 pandemic to determine the prevalence of dry eye syndrome. A cross-sectional study investigated how prevalent DES is during COVID-19 in healthy patients aged 20-45 in the United States. An Ocular Surface Disease Index (OSDI) questionnaire was given to 40 individuals remotely from October 31, 2021, to December 1, 2021. The AOS and the OSDI survey were used to evaluate DES. The subjects were 29 years old on average (SD 14.14), with 23 males (57.5%) and 17 females (42.5%). According to the OSDI survey, low DES, moderate DES, and severe DES had prevalence rates of 15%, 77.5%, and 7.5%, respectively. White (W) people represent 50% of the population, while African Americans (AA) represent 35%, Asians represent 7.5%, and Hispanics represent 7.5%. Mild DES affected 77.5% of subjects, with 64.50% males and 35.50% females. According to the AOS objective grading system, mild (M) DES, moderate (MO) DES, and severe (S) DES had prevalence rates of 40%, 12.5%, and 15%, respectively. Linear regression was used to compare the two grading systems, and it demonstrated a strong relationship between the two grading systems.

The present protocol describes the cross-sectional research performed on 40 healthy subjects between the ages of 20 and 45 to assess the prevalence of dry eye syndrome (DES) during COVID-19. The OSDI survey evaluated DES, and the advanced ophthalmic systems (AOS) software was used to assess limbal redness.

The incidence of dry eye syndrome (DES) has increased due to wearing masks, utilizing digital devices, and working remotely during the pandemic. A survey ...