[Knowledge and practices of the steps prior to the sterilization of heat-resistant medical devices: Study at University Hospital Centre of Sahloul, Sousse-Tunisia - 2022]. / Connaissances et pratiques des étapes préalables à la stérilisation des dispositifs médicaux thermorésistants : étude au centre hospitalo-universitaire Sahloul, Sousse-Tunisie ­ 2022.

OBJECTIVES: The standard process of central sterilization is crucial for the optimal functioning of the operating room. The outcome of this process is closely linked to the steps preceding the steps prior to the sterilization step itself. These steps include pre-disinfection carried out in the operating rooms and other stages, namely washing, drying and packaging, which must be performed in the central sterilization unit. In this context, this study aimed to describe the knowledge of the staff in the operating rooms and the central sterilization unit at Sahloul University Hospital in Sousse (Tunisia) in 2022, regarding the steps prior to the sterilization of reusable thermoresistant medical devices and to describe their practices in terms of compliance with these steps. METHOD: A descriptive study was conducted from January 2022 to June 2022 with the aforementioned staff, using a self-administered questionnaire to assess their knowledge of the pre-sterilization steps and a direct observation audit of their practices with regard to these steps. Both measurement instruments were pre-tested. RESULTS: Out of 102 self-administered questionnaires (knowledge assessment) distributed to the staff concerned, only 80 were returned and correctly filled out, giving a response rate of 78.4%. Participants' responses regarding the order of steps prior to the sterilization were incorrect in 64% of cases. With regard to the evaluation of professional practices, 224 observations were made in the study area (practice audit). In 82% of these observations, the pre-disinfection step was confused with the washing step. The use of Betadine brushes and scrubbing pads for device washing was noted in 89.3%, along with the absence of swabbing of the canals and hollow parts in 9.4% of cases and the absence of drying of the canals with compressed air. CONCLUSION: Mastery of the steps prior to sterilisation of reusable thermoresistant medical devices was insufficient in our institution, suggesting the importance of reinforcing the implementation of the procedure through a continuous training program followed by action plans.

Novel 6-hydroxybenzothiazol-2-carboxamides as potent and selective monoamine oxidase B inhibitors endowed with neuroprotective activity.

In neurodegenerative diseases, using a single molecule that can exert multiple effects to modify the disease may have superior activity over the classical "one molecule-one target" approach. Herein, we describe the discovery of 6-hydroxybenzothiazol-2-carboxamides as highly potent and selective MAO-B inhibitors. Variation of the amide substituent led to several potent compounds having diverse side chains with cyclohexylamide 40 displaying the highest potency towards MAO-B (IC50 = 11 nM). To discover new compounds with extended efficacy against neurotoxic mechanisms in neurodegenerative diseases, MAO-B inhibitors were screened against PHF6, R3 tau, cellular tau and α-synuclein (α-syn) aggregation. We identified the phenethylamide 30 as a multipotent inhibitor of MAO-B (IC50 = 41 nM) and α-syn and tau aggregation. It showed no cytotoxic effects on SH-SY5Y neuroblastoma cells, while also providing neuroprotection against toxicities induced by α-syn and tau. The evaluation of key physicochemical and in vitro-ADME properties revealed a great potential as drug-like small molecules with multitarget neuroprotective activity.

Enhancing proficiency in ascites puncture through procedural simulation: an audit type study investigating medium-term skill retention.

INTRODUCTION: Medical simulation has become an essential teaching method for all health professionals. It not only allows to acquire technical and non-technical knowledge, but also helps the maintenance of acquired knowledge in the medium and long term. Ascites puncture is part of the basic technical procedures learned by medical students during their internship. OBJECTIVES: To evaluate the role of simulation-based learning of ascites puncture on the improvement of theoretical knowledge and maintenance of skills at 3 months. METHODS: We conducted an audit type study with two cycles of data collection at the simulation center at the Faculty of Medicine of Sousse between November 2020 and June 2021. We included learners in their third year of medical studies who had a hospital internship in the gastroenterology department at Sahloul Hospital in Sousse. All learners attended the initial simulation session on ascites fluid puncture. Thereafter, they were free to accept or refuse participation in the evaluation session that was scheduled after 3 months, depending on their availability. RESULTS: Forty learners participated in the procedural simulation of the ascites fluid puncture technique. Thirty-four (85%) were female and six (5%) were male. In our study, we showed that following procedural simulation training of ascites puncture, there was a significant improvement in the theoretical knowledge of the learners (p < 0.000). Objective assessment of technical skills after 3 months showed the benefit of performance maintenance (p < 0.000). CONCLUSION: Our study confirmed the benefit of simulation-based learning on the improvement of theoretical knowledge and the maintenance of technical performance in the medium term.

Motor Strength Measurements Obtained Using an Inexpensive Spring Tensiometer and a Clinical Dynamometer Correlated Well: A Prospective Cohort Study.

OBJECTIVE: Manual muscle strength testing is the primary method for testing muscle strength in clinical settings but is highly subjective. An objective measure of muscle strength can be obtained using a handheld dynamometer, but its cost inhibits its widespread usage. We hypothesized that a spring tensiometer (ST) could be an objective tool that can be used as a viable alternative to a dynamometer. METHODS: Twenty-six outpatients were included, and the strengths of several muscle groups were measured using tensiometers and dynamometers. A paired t-test and Pearson's correlation coefficient and Bland-Altman plot analyses were used to estimate the reliability and measurement accuracy of both tools. Multiple regression analysis was performed to identify the factors contributing to the measurement gap between the two instruments. RESULTS: A total of 260 muscle force values were evaluated. Pearson's correlation coefficient and Bland-Altman analyses indicated that the measurements of the two instruments were strongly correlated and highly accurate. In the multiple regression analysis, the gap between the two instruments was significantly related to the original muscle strength and muscle part but was not significantly related to sex, age, body mass index, or laterality. For biceps and triceps muscle groups, the correlations were particularly strong and accurate, indicating that a tensiometer could be well substituted for a dynamometer. CONCLUSIONS: Our data show that a ST is similar to a dynamometer in terms of precision. A ST is an inexpensive alternative to a dynamometer and more accessible for clinical use than a dynamometer.

Beyond Physical Well-being: Exploring Demographic Variances in Psychosocial Well-being before Breast Reconstruction.

A patient's preoperative satisfaction with their breasts and baseline psychosocial, sexual, and physical well-being are important considerations when planning breast reconstruction. We sought to elucidate variances in preoperative responses among patients undergoing postmastectomy breast reconstruction. Methods: Preoperative BREAST-Q responses and demographic data, including race, generation, median household incomeinstitutional review board and body mass index (BMI) were collected from breast cancer patients scheduled for mastectomy. Associations between demographic group and survey response were analyzed by chi-square or independent t-tests. Results: In total, 646 of 826 patients identified had complete data and were included in the final analysis. Patients in BMI group 1 (16-24.9) were more likely to report feeling "very satisfied" with how they looked unclothed compared with patients in other BMI groups (P = 0.031). Conversely, patients in groups 3 and 4 (35+), reported lower satisfaction (P = 0.037) and felt less attractive without clothes (P = 0.034). Asian women were less likely to feel attractive (P = 0.007), and Black patients were less likely to feel of equal worth to other women (P < 0.001). Finally, patients were less likely to report confidence in social settings if they were Black (P < 0.001), Asian (P < 0.001), from the millennial generation (P = 0.017), or living in zip codes with median household income less than $55,000 (P = 0.042). Conclusions: Breast cancer patients' feelings toward their natural breasts vary widely between demographic groups. Understanding baseline psychosocial factors in this population is key to informing preoperative discussions and interpreting postoperative satisfaction.

Short-term Satisfaction, Psychosocial Impact, and Complication Profile of Reduction Mammaplasty During Adolescence.

BACKGROUND: Reduction mammaplasty is an effective and safe treatment option for adults with symptomatic macromastia, but there are few data regarding outcomes in adolescents. OBJECTIVES: The purpose of this study was to determine the short-term psychosocial impact, satisfaction, and safety of reduction mammaplasty when performed during adolescence. METHODS: A retrospective review was performed of a single pediatric plastic surgeon's experience with reduction mammaplasty from 2018 to 2021 in patients aged ≤18 years. Patients completed the preoperative and postoperative "Satisfaction with Breasts" and "Psychosocial Well-being" sections of the BREAST-Q survey. Clinical variables gathered included age, weight, BMI, complication profile, specimen resection weight, and follow-up duration. RESULTS: In total, 41 patients met inclusion criteria. The mean converted Rasch scores for BREAST-Q "Satisfaction with Breasts" and "Psychosocial Well-being" increased significantly following reduction mammaplasty ("Satisfaction with Breasts": preoperative, 24.1 vs postoperative, 92.6; "Psychosocial Well-being": preoperative, 37.7 vs postoperative, 90.4; P < .001). Obesity (BMI ≥ 30 kg/m2) was associated with lower preoperative "Psychosocial Well-being" scores (obese, 29.7 vs nonobese, 43.3; P < .001) but a greater improvement in score following surgery (obese, +63.9 vs nonobese, +44.9; P < .001). Specimen weight ≥1000 grams was also associated with greater improvement in score on the "Psychosocial Well-being" section (≥1000 grams, +58 vs <1000 grams, +49.7; P = .046). Overall complication rate was 31.7% while the major complication rate was 2.4%. Mean specimen resection weight was higher in patients who experienced complications (1141.3 grams vs 836.8 grams, P = .008). CONCLUSIONS: Reduction mammaplasty during adolescence predictably improves both short-term satisfaction with breasts and psychosocial well-being while demonstrating a favorable short-term complication profile.

High-Fidelity Permeability and Porosity Prediction Using Deep Learning With the Self-Attention Mechanism.

Accurate estimation of reservoir parameters (e.g., permeability and porosity) helps to understand the movement of underground fluids. However, reservoir parameters are usually expensive and time-consuming to obtain through petrophysical experiments of core samples, which makes a fast and reliable prediction method highly demanded. In this article, we propose a deep learning model that combines the 1-D convo- lutional layer and the bidirectional long short-term memory network to predict reservoir permeability and porosity. The mapping relationship between logging data and reservoir parameters is established by training a network with a combination of nonlinear and linear modules. Optimization algorithms, such as layer normalization, recurrent dropout, and early stopping, can help obtain a more accurate training model. Besides, the self-attention mechanism enables the network to better allocate weights to improve the prediction accuracy. The testing results of the well-trained network in blind wells of three different regions show that our proposed method is accurate and robust in the reservoir parameters prediction task.

Self-Attention Fully Convolutional DenseNets for Automatic Salt Segmentation.

3-D salt segmentation is important for many research topics spanning from exploration geophysics to structural geology. In seismic exploration, 3-D salt segmentation is directly related to the velocity modeling building that affects many processing steps, such as seismic migration and full waveform inversion. Manually picking the salt boundary becomes prohibitively time-consuming when the data size is too large. Here, we develop a highly generalized fully convolutional DenseNet for automatic salt segmentation. A squeeze-and-excitation network is used as a self-attention mechanism for guiding the proposed network to extract the most significant information related to the salt signals and discard the others. The proposed framework is a supervised technique and shows robust performance when applied to a new dataset using transfer learning and a small amount of training data. We test the robustness of the proposed framework on the Kaggle TGS salt segmentation dataset. To demonstrate the generalization ability of the framework, we further apply the trained model to an independent dataset synthesized from the 3-D SEAM model. We apply transfer learning to finely tune the trained model from the TGS dataset using only a small percentage of data from the 3-D SEAM dataset and obtain satisfactory results.

Impact of Socioeconomic Status on Breast Reconstruction Outcomes.

BACKGROUND: Minority patients and those from low socioeconomic backgrounds are faced with barriers to care regarding breast reconstruction. With this study, we seek to elucidate variances in demographics to determine predictors of complications in implant-based breast reconstruction. METHODS: Patients who underwent breast reconstruction with either direct to implant or immediate expander reconstruction by 1 surgeon were identified using the preoperative Breast-Q.Current income statistics available from the US Census Bureau by self-reported zip code were used to determine the median household income (MHI) to stratify differing socioeconomic backgrounds. Demographics were compared with body mass index, comorbidities, overall rate of postoperative complications, rate of implant infection, and type of reconstruction. RESULTS: Two hundred ninety-five patients met inclusion criteria. Overall rate of complications and rate of breast implant infection was higher for MHI of less than $50,000 compared with greater than $50,000 (P = 0.043 overall complications 40.20% vs 28.8%) (P = 0.04 implant infection 14.4% vs 7.1%). African American patients had higher body mass index (P = <0.001), rates of HTN (P = <0.001), and diabetes (P = 0.001), and were more likely to have a lower income (P = <0.001). There was, however, no difference in overall complications (P = 0.26), implant infection rate (P = 0.994), or capsular contracture (0.367) based on race. There was no difference in rate of comorbidities between low and high socioeconomic areas. CONCLUSION: This cohort demonstrates a higher rate of overall complications and infection in patients with a lower MHI and no difference based on race despite having higher risk factors for complications.Socioeconomic status is a multifaceted barrier to care that must be addressed in the perioperative period to decrease breast implant associated complications.

The renal clear cell carcinoma immune landscape.

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.

Tobacco Smoke and Electronic Cigarette Vapor Alter Enhancer RNA Expression That Can Regulate the Pathogenesis of Lung Squamous Cell Carcinoma.

Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA expression in relation to LUSC outcomes. We extracted eRNA counts from RNA-sequencing data of tumor/adjacent normal tissue and before/after e-cigarette tissue from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. Tobacco-mediated LUSC eRNAs were correlated to patient survival, clinical variables, and immune-associated elements. eRNA expression was also correlated to mutation rates through the Repeated Evaluation of Variables Conditional Entropy and Redundance (REVEALER) algorithm and methylated sites through methylationArrayAnalysis. Differential expression analysis was then completed for the e-cigarette data to compare with key tobacco-mediated eRNAs. We identified 684 downregulated eRNAs and 819 upregulated eRNAs associated with tobacco-mediated LUSC, specifically, with the cancer pathological stage. We also observed a decrease in immune cell abundance in tobacco-mediated LUSC. Yet, we found an increased association of eRNA expression with immune cell abundance in tobacco-mediated LUSC. We identified 16 key eRNAs with significant correlations to 8 clinical variables, implicating these eRNAs in LUSC malignancy. Furthermore, we observed that these 16 eRNAs were highly associated with chromosomal alterations and reduced CpG site methylation. Finally, we observed large eRNA expression upregulation with e-cigarette use, which corresponded to the upregulation of the 16 key eRNAs. Our findings provide a novel mechanism by which tobacco and e-cigarette smoke influences eRNA interactions to promote LUSC pathogenesis and provide insight regarding disease progression at a molecular level.

No association between the SARS-CoV-2 variants and mortality rates in the Eastern Mediterranean Region

As the novel coronavirus SARS-CoV-2 continues to spread in all countries, there is a growing interest in monitoring and understanding the impact of emerging strains on virus transmission and disease severity. Here, we analyzed SARS-CoV-2 genomic sequences reported in the Eastern Mediterranean Region (EMR) countries, as of 1 January 2021. The majority ([~]75%) of these sequences originated from three out of 22 EMR countries, and 65.8% of all sequences belonged to GISAID clades GR, GH, G and GV. A delay ranging between 30-150 days from sample collection to sequence submission was observed across all countries, limiting the utility of such data in informing public health policies. We identified ten common non-synonymous mutations represented among SARS-CoV-2 in the EMR and several country-specific ones. Two substitutions, spike_D614G and NSP12_P323L, were predominantly concurrent in most countries. While the single incidence of NSP12_P323L was positively correlated with higher case fatality rates in EMR, no such association was established for the double (spike_D614G and NSP12_P323L) concurrent variant across the region. Our study identified critical data gaps in EMR highlighting the importance of enhancing surveillance and sequencing capacities in the region.

Towards hepatitis C virus elimination: Egyptian experience, achievements and limitations.

Worldwide, more than one million people die each year from hepatitis C virus (HCV) related diseases, and over 300 million people are chronically infected with hepatitis B or C. Egypt used to be on the top of the countries with heavy HCV burden. Some countries are making advances in elimination of HCV, yet multiple factors preventing progress; remain for the majority. These factors include lack of global funding sources for treatment, late diagnosis, poor data, and inadequate screening. Treatment of HCV in Egypt has become one of the top national priorities since 2007. Egypt started a national treatment program intending to provide cure for Egyptian HCV-infected patients. Mass HCV treatment program had started using Pegylated interferon and ribavirin between 2007 and 2014. Yet, with the development of highly-effective direct acting antivirals (DAAs) for HCV, elimination of viral hepatitis has become a real possibility. The Egyptian National Committee for the Control of Viral Hepatitis did its best to provide Egyptian HCV patients with DAAs. Egypt adopted a strategy that represents a model of care that could help other countries with high HCV prevalence rate in their battle against HCV. This review covers the effects of HCV management in Egyptian real life settings and the outcome of different treatment protocols. Also, it deals with the current and future strategies for HCV prevention and screening as well as the challenges facing HCV elimination and the prospect of future eradication of HCV.

Evaluating Diagnostic Accuracy of Noninvasive Tests in Assessment of Significant Liver Fibrosis in Chronic Hepatitis C Egyptian Patients.

Stage of liver fibrosis is critical for treatment decision and prediction of outcomes in chronic hepatitis C (CHC) patients. We evaluated the diagnostic accuracy of transient elastography (TE)-FibroScan and noninvasive serum markers tests in the assessment of liver fibrosis in CHC patients, in reference to liver biopsy. One-hundred treatment-naive CHC patients were subjected to liver biopsy, TE-FibroScan, and eight serum biomarkers tests; AST/ALT ratio (AAR), AST to platelet ratio index (APRI), age-platelet index (AP index), fibrosis quotient (FibroQ), fibrosis 4 index (FIB-4), cirrhosis discriminant score (CDS), King score, and Goteborg University Cirrhosis Index (GUCI). Receiver operating characteristic curves were constructed to compare the diagnostic accuracy of these noninvasive methods in predicting significant fibrosis in CHC patients. TE-FibroScan predicted significant fibrosis at cutoff value 8.5 kPa with area under the receiver operating characteristic (AUROC) 0.90, sensitivity 83%, specificity 91.5%, positive predictive value (PPV) 91.2%, and negative predictive value (NPV) 84.4%. Serum biomarkers tests showed that AP index and FibroQ had the highest diagnostic accuracy in predicting significant liver fibrosis at cutoff 4.5 and 2.7, AUROC was 0.8 and 0.8 with sensitivity 73.6% and 73.6%, specificity 70.2% and 68.1%, PPV 71.1% and 69.8%, and NPV 72.9% and 72.3%, respectively. Combined AP index and FibroQ had AUROC 0.83 with sensitivity 73.6%, specificity 80.9%, PPV 79.6%, and NPV 75.7% for predicting significant liver fibrosis. APRI, FIB-4, CDS, King score, and GUCI had intermediate accuracy in predicting significant liver fibrosis with AUROC 0.68, 0.78, 0.74, 0.74, and 0.67, respectively, while AAR had low accuracy in predicting significant liver fibrosis. TE-FibroScan is the most accurate noninvasive alternative to liver biopsy. AP index and FibroQ, either as individual tests or combined, have good accuracy in predicting significant liver fibrosis, and are better combined for higher specificity.

The Effect of Endothelin Receptor Antagonists in Patients with Eisenmenger Syndrome: A Systematic Review.

INTRODUCTION: The efficacy of endothelin receptor antagonists (ERAs) in the management of Eisenmenger syndrome (ES) remains controversial. The aim of this study is to systemically review the safety and effects of ERAs in improving the quality of life and basic cardiac functions of these patients. METHODS: Twelve databases were searched, including PubMed, Web of Science, Scopus, Virtual Health Library, World Health Organization (WHO) Global Health Library, Google Scholar, POPLINE, Systems for Information of Grey Literature in Europe, New York Academy of Medicine, ClinicalTrials.gov, metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform, through August 2016. We included randomized clinical trials addressing the effect of ERAs on cardiac functions in patients with ES. The quality of studies was assessed using the Cochrane Collaboration tool. RESULTS: We included two trials represented by four papers, of which three papers reported the efficacy of bosentan against placebo and one paper reported the results of a combination of bosentan and sildenafil versus placebo and bosentan. One trial showed a significant effect of bosentan treatment over placebo on indexed pulmonary vascular resistance and mean pulmonary artery pressure, but a non-significant increase in 6-min walk distance and a non-significant effect on systemic pulse oximetry. The other trial reported the safe but non-significant effect of combination therapy of bosentan and sildenafil compared with bosentan and placebo. CONCLUSIONS: This study demonstrated safety and improved hemodynamic effects of bosentan in ES, with a controversial effect on exercise capacity. Further randomized controlled trials with longer follow-up duration are needed to confirm these results.

Synthesis, PASS-Predication and in Vitro Antimicrobial Activity of Benzyl 4-O-benzoyl-α-l-rhamnopyranoside Derivatives.

Benzyl α-l-rhamnopyranoside 4, obtained by both conventional and microwave assisted glycosidation techniques, was subjected to 2,3-O-isopropylidene protection to yield compound 5 which on benzoylation and subsequent deprotection of isopropylidene group gave the desired 4-O-benzoylrhamnopyranoside 7 in reasonable yield. Di-O-acetyl derivative of benzoate 7 was prepared to get newer rhamnopyranoside. The structure activity relationship (SAR) of the designed compounds was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antimicrobial activities verified the predictions obtained by the PASS software. Protected rhamnopyranosides 5 and 6 exhibited slight distortion from regular ¹C4 conformation, probably due to the fusion of pyranose and isopropylidene ring. Synthesized rhamnopyranosides 4-8 were employed as test chemicals for in vitro antimicrobial evaluation against eight human pathogenic bacteria and two fungi. Antimicrobial and SAR study showed that the rhamnopyranosides were prone against fungal organisms as compared to that of the bacterial pathogens. Interestingly, PASS prediction of the rhamnopyranoside derivatives 4-8 were 0.49 < Pa < 0.60 (where Pa is probability 'to be active') as antibacterial and 0.65 < Pa < 0.73 as antifungal activities, which showed significant agreement with experimental data, suggesting rhamnopyranoside derivatives 4-8 were more active against pathogenic fungi as compared to human pathogenic bacteria thus, there is a more than 50% chance that the rhamnopyranoside derivative structures 4-8 have not been reported with antimicrobial activity, making it a possible valuable lead compound.

Rational Design and Synthesis of New, High Efficiency, Multipotent Schiff Base-1,2,4-triazole Antioxidants Bearing Butylated Hydroxytoluene Moieties.

A new series of multipotent antioxidants (MPAOs), namely Schiff base-1,2,4-triazoles attached to the oxygen-derived free radical scavenging moiety butylated hydroxytoluene (BHT) were designed and subsequently synthesized. The structure-activity relationship (SAR) of the designed antioxidants was established alongside the prediction of activity spectra for substances (PASS). The antioxidant activities of the synthesized compounds 4-10 were tested by the DPPH bioassay. The synthesized compounds 4-10 inhibited stable DPPH free radicals at a level that is 10(-4) M more than the well-known standard antioxidant BHT. Compounds 8-10 with para-substituents were less active than compounds 4 and 5 with trimethoxy substituents compared to those with a second BHT moiety (compounds 6 and 7). With an IC50 of 46.13 ± 0.31 µM, compound 6 exhibited the most promising in vitro inhibition at 89%. Therefore, novel MPAOs containing active triazole rings, thioethers, Schiff bases, and BHT moieties are suggested as potential antioxidants for inhibiting oxidative stress processes and scavenging free radicals, hence, this combination of functions is anticipated to play a vital role in repairing cellular damage, preventing various human diseases and in medical therapeutic applications.