A systematic assessment is crucial to confirm the diagnosis of pulmonary hypertension (PH) and classify it based on its etiological mechanism. This case report describes a young woman with a recent diagnosis of Graves' disease who presented with exertional dyspnea and fatigue. The initial ultrasound heart examination indicated moderate tricuspid regurgitation, an increased estimated systolic pulmonary artery pressure (sPAP), and suggestive alterations of atrial septal communication. For a more detailed characterization of this aspect, a transesophageal echocardiogram (TEE) was performed, which confirmed, through the agitated saline injection method, the presence of a patent foramen ovale (PFO). Further investigation for common causes of pulmonary hypertension yielded negative results. Treatment with methimazole and radioiodine ablation with glucocorticoid coverage was made. One year later, the patient reached a euthyroid state and reported an improvement in the symptoms. Follow-up transthoracic echocardiogram revealed resolution of pulmonary hypertension, with a normal sPAP and normal-sized right chambers. Right heart catheterization confirmed the normal findings. Hyperthyroidism is considered a potential cause of pulmonary hypertension through the effects of high cardiac output and autoimmune-induced pulmonary vascular endothelium injury. As such, it should be included in the etiological investigation of suspected pulmonary hypertension, as its cardiovascular manifestations may be completely reversible without the need for targeted therapy.

Introduction: Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is the most common form of intracranial hemorrhage in preterm infants. We evaluated risk factors for GMH-IVH in preterm infants born before 32 weeks of gestational age. Secondary outcomes included the characterization of neurodevelopmental (ND) prognosis at 24-36 months of corrected age. Methods: We included infants admitted to our Neonatal Intensive Care Unit between May 2011 and January 2017. A total of 161 infants were enrolled, divided into the GMH-IVH group (n = 40) and control group (n = 121). A secondary cohort included the follow-up group (n = 124) at 24-36 months of corrected age. The association of GMH-IVH with risk factors and ND outcomes was investigated. Results: The incidence of GMH-IVH was 24.8%. Significant risk factors for GMH-IVH were exposure to any resuscitation in the Delivery Room (adjusted odds ratio [aOR]: 34.1; 95% confidence interval [CI] 1.8-657.5) and a low Apgar score at 5 minutes of life (aOR: 0.4; 95% CI: 0.2-0.9). The incidence of retinopathy of prematurity was significantly higher in the grade I GMH-IVH (p < 0.001) group. Gross motor and locomotion dysfunction were significantly more frequent in the GMH-IVH group (24.1% vs. 4.4%; p = 0.004) as was auditory and language dysfunction (24.1% vs. 7.8%; p = 0.040). GMH-IVH was independently associated with visual impairment (aOR: 21.6; 95% CI: 3.2-145.0). Conclusions: Lower Apgar score at 5 minutes of life and any resuscitation were independent risk factors for GMH-IVH. GMH-IVH was associated with higher ND morbidity. ND prognosis of grade II GMH-IVH was comparable to grade III GMH-IVH.

Background: The concept that significant left ventricular (LV) reverse remodelling is needed to define “responders” to cardiac resynchronisation therapy (CRT) has been increasingly questioned. Since heart failure (HF) is a progressive disease, patients with minimal changes in LV geometry, recently defined as “Non-Progressors”, may also derive some benefit from CRT. The main purpose of this study was to evaluate long-term prognosis according to LV end-systolic volume (LVESV) change after CRT. Methods and Results: We included 207 consecutive patients submitted to CRT, divided into 3 groups based on LVESV variation at 6-month follow-up: “Responders” (R): ≥15% LVESV reduction; “Non-Progressors” (NPr): 0-15% and “Progressors” (Pr): increase in LVESV. During a follow-up of 54.2±33.1 months, all-cause and cardiovascular mortality, HF hospitalisations, functional class and cardiac transplantation need were evaluated. Independent predictors of HF progression were also assessed. At 6-month after CRT, there were 117 (56.5%) R, 32 (15.5%) NPr, and 58 (28.0%) Pr. NPr demonstrated a non-significant improvement of all predefined outcomes compared to the Pr. Nevertheless, the hazard ratio for time-to-event risk analysis of all-cause mortality and HF hospitalisations, showed R to have a two-fold lower risk compared to the Pr and, to a lesser extent yet still approximated, to the NPr. Ischemic cardiomyopathy, chronic kidney disease and NYHA class IV at baseline were identified as independent predictors of HF progression. Conclusion: Non-Progressors demonstrated better outcomes than Progressors. However, regarding survival and HF hospitalisations, positive reverse remodelling, and not only stabilisation, seems to confer better long-term prognosis with fewer time-to-event risks associated.

We assess the impact of adopting a transnational supervisor on the distance-to-distress and credit risk of large and complex banks, exploring the establishment of the Single Supervisory Mechanism (SSM) in 2014 as a quasi-natural experiment. Using a differences-in-differences approach, we compare SSM banks vis-à-vis banks with a similar size and complexity operating in European countries outside the SSM. Our results suggest that adopting a transnational supervisor increases the distance-to-distress, particularly for banks operating in countries with larger banking sectors, higher market concentration and greater supervisory discretion. We also show that SSM banks reduced loan loss reserves and NPLs significantly more than non-SSM banks, but only among the most capitalized banks – which is consistent with the notion that well-capitalized banks are better able to weather haircuts induced by credit risk reduction initiatives. Interestingly, we find that SSM banks from countries with greater supervisory discretion saw their NPLs increase in the first years of the SSM, which could reflect the elimination of national idiosyncrasies in credit risk accounting. In general, the evidence presented in our paper suggests that transnational supervision bears a superior ability to increase the distance-to-distress, reduce credit risk, and harmonize supervisory practices among large and complex banks.

Background: The concept that significant left ventricular (LV) reverse remodelling is needed to define “responders” to cardiac resynchronisation therapy (CRT) has been increasingly questioned. Since heart failure (HF) is a progressive disease, patients with minimal changes in LV geometry, recently defined as “Non-Progressors”, may also derive some benefit from CRT. The main purpose of this study was to evaluate long-term prognosis according to LV end-systolic volume (LVESV) change after CRT. Methods and Results: We included 207 consecutive patients submitted to CRT, divided into 3 groups based on LVESV variation at 6-month follow-up: “Responders” (R): ≥15% LVESV reduction; “Non-Progressors” (NPr): 0-15% and “Progressors” (Pr): increase in LVESV. During a follow-up of 54.2±33.1 months, all-cause and cardiovascular mortality, HF hospitalisations, functional class and cardiac transplantation need were evaluated. Independent predictors of HF progression were also assessed. At 6-month after CRT, there were 117 (56.5%) R, 32 (15.5%) NPr, and 58 (28.0%) Pr. NPr demonstrated a non-significant improvement of all predefined outcomes compared to the Pr. Nevertheless, the hazard ratio for time-to-event risk analysis of all-cause mortality and HF hospitalisations, showed R to have a two-fold lower risk compared to the Pr and, to a lesser extent yet still approximated, to the NPr. Ischemic cardiomyopathy, chronic kidney disease and NYHA class IV at baseline were identified as independent predictors of HF progression. Conclusion: Non-Progressors demonstrated better outcomes than Progressors. However, regarding survival and HF hospitalisations, positive reverse remodelling, and not only stabilisation, seems to confer better long-term prognosis with fewer time-to-event risks associated.

Herpetic esophagitis (HE) is an esophageal infection caused by herpes simplex virus (HSV). Although less common, it can occasionally affect immunocompetent hosts. It can manifest as odynophagia and/or dysphagia and should lead to an investigation by upper digestive endoscopy with a biopsy. The authors report a case of a 65-year-old man with a past medical history relevant for schizophrenia, oligophrenia, and malnutrition, and no other history or evidence of immunosuppression, who presented with severe dysphagia over weeks and recent episodes of food aspiration with consequent pneumonia. An upper gastrointestinal endoscopy was performed, revealing severe stenosis at the level of the gastroesophageal junction with scar tissue, not transposable with the endoscope. The biopsy led to the diagnosis of hepatic esophagitis. Despite the immunocompetent status (excepting only the risk factor malnutrition) and treatment with acyclovir, with initial clinical improvement, the patient died a few weeks after diagnosis after multiple respiratory complications such as nosocomial infection. This case highlights that herpetic esophagitis is sometimes observed in immunocompetent hosts. HE has a self-limited course, with severe complications more frequent in immunosuppressed patients. However, it is also important to suspect this condition in immunocompetent patients and look for risk factors, given the potential morbidity this disease entails. In this group of patients, the presence of predisposing factors and associated comorbidities, such as malnutrition, alcohol consumption, or use of corticosteroids, have been associated with the development of viral esophagitis (including HE). HE remains a clinical challenge, especially in patients with risk factors for immunosuppression, such as malnutrition, as in the reported case.

Malignant peritoneal mesothelioma (MPM) is a rare tumor of the serous membranes of the peritoneum and has been linked to exposure to asbestos and other risk factors.The clinical manifestations are vague, with a wide clinical spectrum, predominantly related to the abdominal involvement of the disease.Localized mesothelioma is an uncommon manifestation of the disease.Common symptoms include abdominal pain or abdominal distention, nausea, anorexia, and weight loss.Rarely, patients present with paraneoplastic syndrome.Due to the nonspecific symptoms, many patients already have advanced disease at the time of diagnosis.The authors report a case of a 75-year-old female patient who presented with symptoms of asthenia, anorexia, progressive paleness, and weight loss lasting five months.She reports later new-onset symptoms of diffuse abdominal pain and diarrhea associated with nausea.Laboratory tests showed anemia, mild leukocytosis, thrombocytosis, elevated C-reactive protein (CRP), and elevated liver enzymes.An abdominal and pelvic computed tomography (CT) scan revealed marked tissue thickening of an irregular and striated configuration of the leaflets and peritoneal reflections in an omental cake pattern, and a chest CT scan showed multiple bilateral pulmonary nodules, suggesting diffuse malignant disease.A CT-guided biopsy of a peritoneal implant was performed, establishing the diagnosis of malignant peritoneal mesothelioma.Due to rapid clinical deterioration, the patient did not receive any systemic treatment, surgery, or radiotherapy and was transitioned to comfort care.As in the presented case, most cases of MPM have diffuse peritoneal involvement at the time of diagnosis, although extra-abdominal involvement is very rare.This disease presentation is associated with high morbidity and mortality compared to cases of localized disease.There is no specific imaging diagnostic modality or valuable tumor markers for MPM.Although a CT scan remains important in the diagnostic approach, the changes found are not specific.Radiographically, MPM may present as mesenteric or parietal peritoneal nodules, visceral peritoneal thickening, ascites, or omental masses.Although these features may raise suspicion of MPM, a biopsy is necessary to confirm the diagnosis.Therefore, due to the rarity of this disease and its nonspecific signs or symptoms, MPM is difficult to diagnose, and the prognosis remains poor.

Chest radiography is one of the most ubiquitous medical imaging modalities. Nevertheless, the interpretation of chest radiography images is time-consuming, complex and subject to observer variability. As such, automated diagnosis systems for pathology detection have been proposed, aiming to reduce the burden on radiologists. The advent of deep learning has fostered the development of solutions for both abnormality detection with promising results. However, these tools suffer from poor explainability as the reasons that led to a decision cannot be easily understood, representing a major hurdle for their adoption in clinical practice. In order to overcome this issue, a method for chest radiography abnormality detection is presented which relies on an object detection framework to detect individual findings and thus separate normal and abnormal CXRs. It is shown that this framework is capable of an excellent performance in abnormality detection (AUC: 0.993), outperforming other state-of-the-art classification methodologies (AUC: 0.976 using the same classes). Furthermore, validation on external datasets shows that the proposed framework has a smaller drop in performance when applied to previously unseen data (21.9% vs 23.4% on average). Several approaches for object detection are compared and it is shown that merging pathology classes to minimize radiologist variability improves the localization of abnormal regions (0.529 vs 0.491 APF when using all pathology classes), resulting in a network which is more explainable and thus more suitable for integration in clinical practice.

Background and Aim:Aeromonas are Gram-negative rods known to cause a spectrum of diseases. Inflammatory bowel disease (IBD) is an idiopathic complex condition resulting from interaction of multiple factors. Aeromonas infection in association with IBD is still largely unknown. We aim to look for the significance of Aeromonas infection and for significant differences between IBD and non-IBD patients.Methods:A retrospective observational analysis was performed of all patients positive for Aeromonas in stool cultures, during a 10-year period, from a tertiary and university hospital.Results:Fifty patients were included, 56% male with a mean age of 42.1 years. Thirty-eight (76%) were non-IBD and 12 (24%) IBD patients. IBD patients were more frequently under immunosuppressors. Two patients were asymptomatic and 44% developed mild, 44% moderate, and 16.7% severe infection. The main strains isolated were Aeromonas hydrophila/caviae. Bacterial co-isolation was found in 4 non-IBD and histological findings of cytomegalovirus in 2 IBD patients. Non-IBD patients presented more frequently with fever and IBD patients with bloody diarrhea and abdominal pain. There was higher tendency for severe infection rate in IBD patients with higher antimicrobial therapy use. Steroids were exclusively used in the IBD group. From IBD, 4 patients had the diagnosis of ulcerative colitis and 9 of Crohn's disease with colonic involvement. Of these patients, 5 received IBD diagnosis after the acute episode of Aeromonas infection.Conclusions:Clinical presentation of Aeromonas infection differs between IBD and non-IBD patients. Non-IBD patients had milder severity of infection with less use of antibiotics. Aeromonas infection seems to greatly contribute to IBD manifestation.

Parkinson's disease (PD) is a neurodegenerative disorder that impairs people's mobility. Due to its erratic nature and complexity, the progression of the disease differs from person to person, making it difficult to keep track of the patient's progress. These factors, together with the limited number of annual clinical appointments, create the need to have a tool that can help patients and healthcare professionals better manage Parkinson's outside of the clinical environment. PDapp strives to address this need combining mHealth features with the capabilities of the iHandU appcessory, a novel and seamless wearable device designed to measure wrist rigidity, bradykinesia (slow movement), and tremor, thus enabling continuous effective follow-up, while connecting patients and clinicians remotely. The PDapp system is comprised of a mobile application where patients can manage their medication, self-perform various symptom tests, and maintain clinicians informed of relevant events; a specialized web dashboard for clinicians to monitor all their patient's history and recent events; and a cloud database that exhibits existing data in real-time. The first prototype integrates all these components and provides a promising proof-of-concept that, with a few additions, can be a system that brings value to Parkinson's management. This application design and functionalities were developed jointly with clinicians, addressing their problems and needs. The collected feedback was very positive stating that its usability and simplicity is completely suitable for patients to use. PDapp will introduce a complete and innovative methodology to follow-up PD patient's disease progression and support clinicians during appointments and patients at home, guiding medication adjustment for better disease management. This system is intended as one more step to the PD mHealth ecosystem, improving follow-up and disease therapy yet reducing clinicians' workload.

This paper presents the optimization process for the development of an innovative double chamber syringe. Several aspects are involved such as design, functionality, fluid-structure interaction and friction between solids. To assist in the development of this medical device, a numerical based methodology was developed and validated in order to predict the syringe´s functionality, as well as its production by injection molding. The mechanical and flow behavior, during the filling and administration of medicine and washing solutions, were numerically modelled using the commercial software ABAQUS and FLUENT, respectively. The injection molding process was analyzed using the software MOLDFLOW. The aim was to evaluate the feasibility of the proposed concept in terms of mechanical design, fluid flow and production process behavior. By highlighting critical design issues in this way, it was possible to identify promising geometric changes and, consequently, optimize iteratively the syringe's design, until all the defined requirements are fulfilled. This iterative process based on numerical simulations proved to be a powerful tool for product development that generated fast and accurate results without the need to produce multiple prototypes.

Background and Aims: Colonoscopy is effective to detect and remove colorectal lesions. However, after a negative colonoscopy, cancers could be detected during the interval follow-up. This study was designed to identify characteristics and risk factors for postcolonoscopy colorectal cancer – interval type. Methods: Medical records of individuals who were newly diagnosed with colorectal cancer between January 2018 and December 2019 were reviewed. Clinical, demographic, and endoscopic variables were analyzed. Those with the diagnosis of colorectal cancer between two consecutive colonoscopies performed within the appropriated surveillance range were considered to have postcolonoscopy colorectal cancer – interval type. A comparison between the group of patients with non-postcolonoscopy colorectal cancer – interval type and the group of patients with postcolonoscopy colorectal cancer – interval type was then performed. Results: During the study period, 491 patients were newly diagnosed with colorectal cancer. Among them, 61 (12.4%) had postcolonoscopy colorectal cancer – interval subtype. Postcolonoscopy colorectal cancer – interval type was three times more prevalent on the proximal colon (p = 0.014) and was associated with the presence of two or more cardiovascular risk factors (aOR = 4.25; p = 0.016), cholecystectomy in the past (aOR = 10.09; p = 0.019), and family history of colorectal cancer on a first-degree relative (aOR = 4.25; p = 0.006). Moreover, isolated cardiovascular risk factors revealed a protective effect for the absence of all cardiovascular risk factors (aOR = 20; p = 0.034). The ROC curve associated with the multivariate model revealed a predictive power of 77.8% (p < 0.001). Conclusions: Postcolonoscopy colorectal cancer – interval type is more common in the proximal colon and in patients with a family history (first-degree relative) of colorectal cancer, two or more cardiovascular risk factors, and a history of cholecystectomy. All of these are easily detectable in clinical practice and may be of extreme importance in the control of postcolonoscopy colorectal cancer in the near future.

This study aimed to evaluate the effects of short-term supplementation, with 2% Chlorella vulgaris (C. vulgaris) biomass and two 0.1% C. vulgaris extracts, on the health status (experiment one) and on the inflammatory response (experiment two) of gilthead seabream (Sparus aurata). The trial comprised four isoproteic (50% crude protein) and isolipidic (17% crude fat) diets. A fishmeal-based (FM), practical diet was used as a control (CTR), whereas three experimental diets based on CTR were further supplemented with a 2% inclusion of C. vulgaris biomass (Diet D1); 0.1% inclusion of C. vulgaris peptide-enriched extract (Diet D2) and finally a 0.1% inclusion of C. vulgaris insoluble fraction (Diet D3). Diets were randomly assigned to quadruplicate groups of 97 fish/tank (IBW: 33.4 ± 4.1 g), fed to satiation three times a day in a recirculation seawater system. In experiment one, seabream juveniles were fed for 2 weeks and sampled for tissues at 1 week and at the end of the feeding period. Afterwards, randomly selected fish from each group were subjected to an inflammatory insult (experiment two) by intraperitoneal injection of inactivated gram-negative bacteria, following 24 and 48 h fish were sampled for tissues. Blood was withdrawn for haematological procedures, whereas plasma and gut tissue were sampled for immune and oxidative stress parameters. The anterior gut was also collected for gene expression measurements. After 1 and 2 weeks of feeding, fish fed D2 showed higher circulating neutrophils than seabream fed CTR. In contrast, dietary treatments induced mild effects on the innate immune and antioxidant functions of gilthead seabream juveniles fed for 2 weeks. In the inflammatory response following the inflammatory insult, mild effects could be attributed to C. vulgaris supplementation either in biomass form or extract. However, the C. vulgaris soluble peptide-enriched extract seems to confer a protective, anti-stress effect in the gut at the molecular level, which should be further explored in future studies.

Microalgae are known as a producer of proteins and lipids, but also of valuable compounds for human health benefits (e.g., polyunsaturated fatty acids (PUFAs); minerals, vitamins, or other compounds). The overall objective of this research was to prospect novel products, such as nutraceuticals from microalgae, for application in human health, particularly for metabolic diseases. Chlorella vulgaris and Chlorococcum amblystomatis were grown autotrophically, and C. vulgaris was additionally grown heterotrophically. Microalgae biomass was extracted using organic solvents (dichloromethane, ethanol, ethanol with ultrasound-assisted extraction). Those extracts were evaluated for their bioactivities, toxicity, and metabolite profile. Some of the extracts reduced the neutral lipid content using the zebrafish larvae fat metabolism assay, reduced lipid accumulation in fatty-acid-overloaded HepG2 liver cells, or decreased the LPS-induced inflammation reaction in RAW264.7 macrophages. Toxicity was not observed in the MTT assay in vitro or by the appearance of lethality or malformations in zebrafish larvae in vivo. Differences in metabolite profiles of microalgae extracts obtained by UPLC-LC-MS/MS and GNPS analyses revealed unique compounds in the active extracts, whose majority did not have a match in mass spectrometry databases and could be potentially novel compounds. In conclusion, microalgae extracts demonstrated anti-obesity, anti-steatosis, and anti-inflammatory activities and could be valuable resources for developing future nutraceuticals. In particular, the ultrasound-assisted ethanolic extract of the heterotrophic C. vulgaris significantly enhanced the anti-obesity activity and demonstrated that the alteration of culture conditions is a valuable approach to increase the production of high-value compounds.

The usage of reclaimed wastewater (RWW) for irrigation of agricultural soils is increasingly being acknowledged for reducing water consumption by promoting reuse of treated wastewater, and for the delivery of extant nutrients in the soil. The downside is that RWW may be a vector for contamination of soils with contaminants of emerging concern (CECs), if left uncontrolled. Its usage is anticipated to alter the soil properties, consequently also the soil microbial community. In the present study, soil microcosms were set to monitor how short periods (up to fourteen days) of RWW irrigation influence the soil ecosystem, namely its physicochemical properties, functioning, and colonising microbiota (differentiating fungi from bacteria). Two scenarios were studied: clean soil and soil contaminated (spiked) with 9 CECs, at conditions that limit any abiotic decay processes, monitoring along time fluctuations in the taxonomic and functional microbiota diversity. As shortly as fourteen days, the irrigation of either soil with RWW did not significantly (p > 0.05) alter its physicochemical properties and scarcely impacted the bioremediation processes of the CECs that showed decay levels ranging from 24% to 100%. Bacillus spp. dominance was enhanced along time in all the soil microcosms (reaching over 70% of the total abundance on the 7th day) but the RWW help to preserve, to some extent, high bacterial diversity. Besides, irrigation with RWW acted as a buffer of the soil mycobiota, limiting alterations in its composition caused either along time (to a minor degree) or due to contamination with CECs (to a great degree). This includes limiting the rise of Rhizopus sp. relative abundance. Collectively, our data support the utility of short-term periods of RWW irrigation for preserving the soil microbial diversity and functioning, especially when fungi are considered.

Volatile methylsiloxanes are wastewater organic pollutants originating from industrial and personal care products. They accumulate in sewage sludge and hamper biogas production through the formation of silicon dioxide on the surfaces of gas engines and turbines, yet there is few knowledge on their fate in sludge treatment systems. Here we studied the occurrence and removal of seven volatile methylsiloxanes along the solid treatment line of an urban wastewater treatment plant. We analyzed 75 sludge samples from seven locations using ultrasound-assisted solid–liquid extraction followed by gas chromatography-mass spectrometry. Results show that volatile methylsiloxanes occur in all samples with a predominance of cyclic homologues, particularly decamethylcyclopentasiloxane. Total siloxane levels reach 6087 ng/g dry weight in the secondary sludge, average at 3575 ng/g in digested sludge, and 5703 ng/g in the dewatered sludge, the latter being likely due to the addition of a polyelectrolyte. Overall, these levels call for measures to reduce methylsiloxane levels before the biogas production step.

This paper is to assess the efficacy of different biologic DMARDs (bDMARDs) on several patient-reported outcomes (PROs) in randomized controlled trials (RCT) in axial spondyloarthritis (axSpA). A systematic literature review (SLR) was performed. MEDLINE (May 1, 2018) was used with the filters “published in the last 10 years” and “humans.” The PICO criteria used were Patients: adults with radiographic axSpA (r-axSpA) or non-radiographic axSpA (nr-axSpA); Intervention: any bDMARD; Compararator: placebo (PBO)/any different drug; Outcome: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL), the EuroQol-5D (EQ-5D), the Short Form 36 Health Survey physical component summary (SF36-PCS), the Short Form 36 Health Survey mental component summary (SF36-MCS), and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F). After screening 84 initial references and manually selecting other 9, 24 publications, assessing TNF inhibitors (TNFi) or IL17A inhibitors (IL17Ai) were selected. Four RCTs quantified the minimal clinical important difference (MCID) between treatment arms. Most of the RCTs compared the mean difference of PROs between different timepoints. Overall, the treatment arm was superior to the comparator. PROs were often underreported or highly heterogeneously presented. MCID was seldom mentioned. There is a need to raise the standard of care on SpA by aiming at remission and PRO associated improvements. In order to achieve this goal, the target must be clearly defined, reported, and tested.