Oxygen Extraction Fraction Mapping on Admission Magnetic Resonance Imaging May Predict Recovery of Hyperacute Ischemic Brain Lesions After Successful Thrombectomy: A Retrospective Observational Study.

BACKGROUND: In acute stroke, diffusion-weighted imaging (DWI) is used to assess the ischemic core. Dynamic-susceptibility contrast perfusion magnetic resonance imaging allows an estimation of the oxygen extraction fraction (OEF), but the outcome of DWI lesions with increased OEF postrecanalization is unclear. This study investigated the impact of OEF on the fate of DWI lesions in patients achieving recanalization after thrombectomy. METHODS: This was a retrospective analysis of the HIBISCUS-STROKE cohort (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke; NCT: 03149705), a single-center observational study that prospectively enrolled patients who underwent magnetic resonance imaging triage for thrombectomy and a day-6 T2-fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging. Automated postprocessing of admission dynamic-susceptibility contrast perfusion magnetic resonance imaging generated OEF maps. At visual analysis, the OEF status within DWI lesions was assessed in comparison to the contralateral side and correlated with volume changes (difference of ischemic lesion between admission DWI and registered day-6 T2-FLAIR). At voxel-based analysis, recovered DWI regions (lesions present on the admission DWI but absent on the registered day-6 T2-FLAIR) and nonrecovered regions were segmented to extract semiquantitative OEF values. RESULTS: Of the participants enrolled from 2016 to 2022, 134 of 321 (41.7%) were included (median age, 71.0 years; 58.2% male; median baseline National Institutes of Health Scale score, 15.0). At visual analysis, 46 of 134 (34.3%) patients had increased OEF within DWI lesions. These patients were more likely to show a reduction in ischemic lesion volumes compared with those without increased OEF (median change, -4.0 versus 4.8 mL; P<0.0001). Multivariable analysis indicated that increased OEF within DWI lesions was associated with a reduction in ischemic lesion volumes from admission DWI to day-6 T2-FLAIR (odds ratio, 0.68 [95% CI, 0.49-0.87]; P=0.008). At voxel-based analysis, recovered DWI regions had increased OEF, while nonrecovered regions had decreased OEF (median, 126.9% versus -27.0%; P<0.0001). CONCLUSIONS: Increased OEF within hyperacute DWI lesions was associated with ischemic lesion recovery between admission DWI and day-6 T2-FLAIR in patients achieving recanalization after thrombectomy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03149705.

Adaptation and validation of the Spanish version of the Being a Mother scale.

Background: Becoming a mother is a very important process because of the impact it can have on women and their families. Currently, there is no validated questionnaire that evaluates the process of becoming a mother in the Spanish population. Moreover, no consistent results have been obtained to identify significant differences between primiparous and multiparous mothers. Aim: (1) Linguistic and metric validation of the Being a Mother scale (BaM-13) in the Spanish population, (2) analysis of possible differences between primiparous and multiparous mothers' experience of motherhood. Methods: Instrumental design. In 2016-2017, a sample of 579 mothers with children between 6 and 11 months of age completed the Spanish version of BaM-13. The instrument was translated using forward and back translation. Construct validity, internal consistency, and criterion validity were empirically analyzed. Results: Factorial analyses showed that the scale presented two adequate factors. Internal consistency of the global scale (α = 0.818, ω = 0.861), the Postnatal bonding factor (α = 0.773, ω = 0.784), and the Adult's experience factor (α = 0.710, ω = 0.721) was adequate. Significant associations were found with postpartum depression (r = 0.560), parental competence (r =  - 0.584) and postnatal bonding (r =  - 0.327). In terms of parity, primiparous mothers have greater difficulty in postnatal bonding, compared to multiparous mothers (p = 0.006). Conclusions: The Spanish version of the BaM-13 scale is valid for measuring mothers' experience of motherhood in a wide range of domains. The findings of the study show the importance of considering parity in the experience of becoming a mother, highlighting the approach to postnatal bonding in primiparous mothers. Additionally, we underline that it should not be assumed that multiparous mothers experience fewer difficulties in their motherhood process.

Investigating the relationship between impairment and performance in goalball: A level playing field?

Currently, all eligible goalball players compete together irrespective of their level of vision impairment, yet it remains unclear whether those with more impairment are disadvantaged during competition. Following the International Paralympic Committee's requirement for evidence-based, sport-specific classification, this study assessed whether individual goalball performance relates to the level of visual impairment. Using results from the 2016 and 2020 Paralympic Games, players' sport classes and in-competition key performance statistics (minutes played, throws per minute, goals per minute, penalties conceded per minute, blocks per minute, and goals per throw) were extracted. Players' visual acuity and visual field results were obtained through the IBSA Sport Administration System. Results showed no statistically significant differences in performance between classes. Further, there were no significant relationships between vision and performance for all six variables for female players. A small but significant positive correlation was found between visual acuity and the number of penalties conceded for male players. Collectively, the results suggest that currently eligible players compete fairly against one another during competitive goalball matches. Results provide support for the existing system of classification whereby all eligible athletes compete against each other irrespective of their level of impairment.

Mechanisms governing lineage plasticity and metabolic reprogramming in cancer.

Dynamic alterations in cellular phenotypes during cancer progression are attributed to a phenomenon known as 'lineage plasticity'. This process is associated with therapeutic resistance and involves concurrent shifts in metabolic states that facilitate adaptation to various stressors inherent in malignant growth. Certain metabolites also serve as synthetic reservoirs for chromatin modification, thus linking metabolic states with epigenetic regulation. There remains a critical need to understand the mechanisms that converge on lineage plasticity and metabolic reprogramming to prevent the emergence of lethal disease. This review attempts to offer an overview of our current understanding of the interplay between metabolic reprogramming and lineage plasticity in the context of cancer, highlighting the intersecting drivers of cancer hallmarks, with an emphasis on solid tumors.

High incidence of dural tears with 3-column osteotomies: a systematic review of adult spinal deformity surgery literature for the past decade.

PURPOSE: Dural tear (DT) is a well-known complication of spinal surgery. We aimed to systematically review the literature from the past decade and determine the incidence and risk factors for DT in the adult spinal deformity (ASD) population to improve both the surgical strategy and counseling of patients undergoing ASD correction. METHODS: A systematic review from 2013 to 2023 utilizing PRISMA guidelines was performed. The MEDLINE database was used to collect primary English language articles. The inclusion criterion for patients was degenerative ASD. Pediatric studies, animal studies, review articles, case reports, studies investigating minimally invasive surgery (MIS), studies lacking data on DT incidence, and articles pertaining to infectious, metastatic or neoplastic, traumatic, or posttraumatic etiologies of ASD were excluded. RESULTS: Our results demonstrate that the incidence of DT in ASD surgery ranges from 2.0% to 35.7%, which is a much broader range than the reported incidence for non deformity surgery. Moreover, the average rate of DT during ASD surgery stratified by surgical technique was greater for osteotomy overall (19.5% +/- 7.9%), especially for 3-column osteotomy (3CO), and lower for interbody fusion (14.3% +/- 9.9%). Risk factors for DT in the ASD surgery cohort included older age, revision surgery, chronic severe compression, higher-grade osteotomy, complexity of surgery, rheumatoid arthritis (RA), and higher Anesthesiology Society of America (ASA) grade. CONCLUSION: To our knowledge, this is the first systematic review discussing the incidence of and risk factors for DT in the ASD population. We found that the risk factors for DT in ASD patients were older age, revision surgery, chronic severe compression, a greater degree of osteotomy, complexity of surgery, RA, and a higher ASA grade. These findings will help guide spine surgeons in patient counseling as well as surgical planning.

Cerebral collaterals are associated with pre-treatment brain-blood barrier permeability in acute ischemic stroke patients.

INTRODUCTION: To investigate the relationship between collaterals and blood-brain barrier (BBB) permeability on pre-treatment MRI in a cohort of acute ischemic stroke (AIS) patients treated with thrombectomy. METHODS: We conducted a retrospective analysis of the HIBISCUS-STROKE cohort, a single-center observational study that enrolled patients treated with thrombectomy from 2016 to 2022. Dynamic-susceptibility MRIs were post-processed to generate K2 maps with arrival-time correction, which were co-registered with apparent diffusion coefficient (ADC) maps. The 90th percentile of K2 was extracted from the infarct core-defined by an ADC ≤ 620 × 10-6 mm2/s with manual adjustments-and expressed as a percentage change compared to the contralateral white matter. Collaterals were assessed using pre-thrombectomy digital subtraction arteriography with an ASITN/SIR score < 3 defining poor collaterals. RESULTS: Out of 249 enrolled, 101 (40.6%) were included (median age: 72.0 years, 52.5% of males, median NIHSS score at admission: 15.0). Patients with poor collaterals (n = 44) had worse NIHSS scores (median: 16.0 vs 13.0, p = 0.04), larger infarct core volumes (median: 43.7 mL vs 9.5 mL, p < 0.0001), and higher increases in K2 (median: 346.3% vs 152.7%, p = 0.003). They were less likely to achieve successful recanalization (21/44 vs 51/57, p < 0.0001) and experienced more frequent hemorrhagic transformation (16/44 vs 9/57, p = 0.03). On multiple variable analysis, poor collaterals were associated with larger infarct cores (odds ratio (OR) = 1.12, 95% confidence interval (CI): [1.07, 1.17], p < 0.0001) and higher increases in K2 (OR = 6.63, 95% CI: [2.19, 20.08], p = 0.001). CONCLUSION: Poor collaterals are associated with larger infarct cores and increased BBB permeability at admission MRI. CLINICAL RELEVANCE STATEMENT: Poor collaterals are associated with a larger infarct core and increased BBB permeability at admission MRI of AIS patients treated with thrombectomy. These findings may have translational interests for extending thrombolytic treatment eligibility and developing neuroprotective strategies. KEY POINTS: In AIS, collaterals and BBB disruption have been both linked to hemorrhagic transformation. Poor collaterals were associated with larger ischemic cores and increased BBB permeability on pre-treatment MRI. These findings could contribute to hemorrhagic transformation risk stratification, thereby refining clinical decision-making for reperfusion therapies.

Learning curve of achieving competency in emergency endoscopy in upper gastrointestinal bleeding: how much experience is necessary?

OBJECTIVES: The management of upper gastrointestinal bleeding (UGIB) has seen rapid advancements with revolutionising innovations. However, insufficient data exist on the necessary number of emergency endoscopies needed to achieve competency in haemostatic interventions. DESIGN: We retrospectively analysed all oesophagogastroduodenoscopies with signs of recent haemorrhage performed between 2015 and 2022 at our university hospital. A learning curve was created by plotting the number of previously performed oesophagogastroduodenoscopies with signs of recent haemorrhage against the treatment failure rate, defined as failed haemostasis, rebleeding and necessary surgical or radiological intervention. RESULTS: The study population included 787 cases with a median age of 66 years. Active bleeding was detected in 576 cases (73.2%). Treatment failure occurred in 225 (28.6%) cases. The learning curve showed a marked decline in treatment failure rates after nine oesophagogastroduodenoscopies had been performed by the respective endoscopists followed by a first plateau between 20 and 50 procedures. A second decline was observed after 51 emergency procedures followed by a second plateau. Endoscopists with experience of <10 emergency procedures had higher treatment failure rates compared with endoscopists with >51 emergency oesophagogastroduodenoscopies performed (p=0.039) or consultants (p=0.041). CONCLUSIONS: Our data suggest that a minimum number of 20 oesophagogastroduodenoscopies with signs of recent haemorrhage is necessary before endoscopists should be considered proficient to perform emergency procedures independently. Endoscopists might be considered as advanced-qualified experts in managing UGIB after a minimum of 50 haemostatic procedure performed. Implementing recommendations on minimum numbers of emergency endoscopies in education programmes of endoscopy trainees could improve their confidence and competency in managing acute UGIB.

It Looks Like a Spinal Cord Tumor but It Is Not.

Differentiating neoplastic from non-neoplastic spinal cord pathologies may be challenging due to overlapping clinical and radiological features. Spinal cord tumors, which comprise only 2-4% of central nervous system tumors, are rarer than non-tumoral myelopathies of inflammatory, vascular, or infectious origins. The risk of neurological deterioration and the high rate of false negatives or misdiagnoses associated with spinal cord biopsies require a cautious approach. Facing a spinal cord lesion, prioritizing more common non-surgical myelopathies in differential diagnoses is essential. A comprehensive radiological diagnostic approach is mandatory to identify spinal cord tumor mimics. The diagnostic process involves a multi-step approach: detecting lesions primarily using MRI techniques, precise localization of lesions, assessing lesion signal intensity characteristics, and searching for potentially associated anomalies at spinal cord and cerebral MRI. This review aims to delineate the radiological diagnostic approach for spinal cord lesions that may mimic tumors and briefly highlight the primary pathologies behind these lesions.

Evaluation of a flexible assertive community treatment (FACT) program for patients with severe mental illness: an observational study in Salzburg, Austria.

BACKGROUND: Inpatient treatment of severe mentally ill patients binds substantial resources and creates the dilemma of "revolving-door hospitalizations". Evidence suggests that these patients benefit more from an assertive outreach community psychiatric treatment. This descriptive study evaluates the implementation of a new treatment program for severe mentally ill patients provided by a flexible assertive community treatment (FACT) team. METHODS: An uncontrolled design with routine data was used to measure the total length of stays, readmission rates and number of contacts one year prior to the implementation of the FACT program and the following first three years of treatment. RESULTS: A continuous decrease of hospitalization among patients with severe mental illness was observed with the implementation of the FACT program with declines in total length of stays and readmission rates and accompanied with a decreasing number of contacts per year. CONCLUSION: Our findings indicate that this program may create effects in stabilizing patients with severe mental illness and may be highly relevant also for other patient groups.

Mobile treatment for opioid use disorder: Implementation of community-based, same-day medication access interventions.

BACKGROUND: Medications for Opioid Use Disorder (MOUD) are lifesaving, but <20 % of individuals in the US who could benefit receive them. As part of the NIH-supported HEALing Communities Study (HCS), coalitions in several communities in Massachusetts and Ohio implemented mobile MOUD programs to overcome barriers to MOUD receipt. We defined mobile MOUD programs as units that provide same-day access to MOUD at remote sites. We aimed to (1) document the design and organizational structure of mobile programs providing same-day or next-day MOUD, and (2) explore the barriers and facilitators to implementation as well as the successes and challenges of ongoing operation. METHODS: Program staff from five programs in two states (n = 11) participated in semi-structured interviews. Two authors conducted thematic analysis of the transcripts based on the domains of the social-ecological model and the semi-structured interview guide. RESULTS: Mobile MOUD units sought to improve immediate access to MOUD ("Our answer is pretty much always, 'Yes, we'll get you started right here, right now,'"), advance equity ("making sure that we have staff who speak other languages, who are on the unit and have some resources that are in different languages,"), and decrease opioid overdose deaths. Salient program characteristics included diverse staff, including staff with lived experience of substance use ("She just had that personal knowledge of where we should be going"). Mobile units offered harm reduction services, broad medical services (in particular, wound care), and connection to transportation programs and incorporated consistency in service provision and telemedicine access. Implementation facilitators included trusting relationships with partner organizations (particularly pharmacies and correctional facilities), nuanced understanding of local politics, advertising, protocol flexibility, and on-unit prescriber hours. Barriers included unclear licensing requirements, staffing shortages and competing priorities for staff, funding challenges due to inconsistency in grant funding and low reimbursement ("It's not really possible that billing in and of itself is going to be able to sustain it"), and community stigma toward addiction services generally. CONCLUSIONS: Despite organizational, community, and policy barriers, participants described mobile MOUD units as an innovative way to expand access to life-saving medications, promote equity in MOUD treatment, and overcome stigma.

Research Compensation and Enhanced Contacts in Studies With Persons Who Use Drugs: Lessons From the COVID-19 Pandemic Demand a Reset.

Policy changes resulting from the coronavirus 2019 (COVID-19) pandemic have had a substantial and positive impact on the clinical care of persons with opioid use disorder. These innovative paradigm shifts created a ripe environment for re-evaluating traditional approaches to recruiting and retaining persons who use drugs into research studies. For example, changes to methadone prescribing requirements and authorization of buprenorphine prescriptions via telehealth have both increased access to medications. In this commentary, we contribute to ongoing conversations about the ethics of compensation for participants in addiction-related clinical research and share methods of payment that proved successful in research performed during the pandemic. We also discuss approaches to enrollment and follow-up that were implemented during the height of COVID restrictions. These approaches may mutually benefit both participants and researchers in a post-pandemic era.

Peer recovery coaching for comprehensive HIV, hepatitis C, and opioid use disorder management: The CHORUS pilot study.

Introduction: Amidst a surge in HIV and hepatitis C virus (HCV) infections in persons who use drugs, medications that effectively prevent HIV and treat opioid use disorder and HCV remain underutilized. Methods: We developed a 6-month peer recovery coaching intervention (brief motivational interviewing followed by weekly virtual or in-person coaching) and collected data on uptake of medications for opioid use disorder (MOUD), HIV pre-exposure prophylaxis (PrEP), and HCV treatment. The primary outcomes were intervention acceptability and feasibility. Results: At a Boston substance use disorder bridge clinic, we enrolled 31 HIV-negative patients who used opioids. Participants reported high intervention satisfaction at 6 months (95% "satisfied" or "very satisfied"). At study completion, 48% of the participants were on MOUD, 43% who met CDC guidelines were on PrEP, and 22% with HCV were engaged with treatment. Conclusions: A peer recovery coaching intervention is feasible and acceptable, with positive preliminary findings regarding MOUD, PrEP and HCV treatment uptake.

Accurate Diagnosis of Cortical and Infratentorial Lesions in Multiple Sclerosis Using Accelerated Fluid and White Matter Suppression Imaging.

OBJECTIVES: The precise location of multiple sclerosis (MS) cortical lesions can be very challenging at 3 T, yet distinguishing them from subcortical lesions is essential for the diagnosis and prognosis of the disease. Compressed sensing-accelerated fluid and white matter suppression imaging (CS-FLAWS) is a new magnetic resonance imaging sequence derived from magnetization-prepared 2 rapid acquisition gradient echo with promising features for the detection and classification of MS lesions. The objective of this study was to compare the diagnostic performances of CS-FLAWS (evaluated imaging) and phase sensitive inversion recovery (PSIR; reference imaging) for classification of cortical lesions (primary objective) and infratentorial lesions (secondary objective) in MS, in combination with 3-dimensional (3D) double inversion recovery (DIR). MATERIALS AND METHODS: Prospective 3 T scans (MS first diagnosis or follow-up) acquired between March and August 2021 were retrospectively analyzed. All underwent 3D CS-FLAWS, axial 2D PSIR, and 3D DIR. Double-blinded reading sessions exclusively in axial plane and final consensual reading were performed to assess the number of cortical and infratentorial lesions. Wilcoxon test was used to compare the 2 imaging datasets (FLAWS + DIR and PSIR + DIR), and intraobserver and interobserver agreement was assessed using the intraclass correlation coefficient. RESULTS: Forty-two patients were analyzed (38 with relapsing-remitting MS, 29 women, 42.7 ± 12.6 years old). Compressed sensing-accelerated FLAWS allowed the identification of 263 cortical lesions versus 251 with PSIR ( P = 0.74) and 123 infratentorial lesions versus 109 with PSIR ( P = 0.63), corresponding to a nonsignificant difference between the 2 sequences. Compressed sensing-accelerated FLAWS exhibited fewer false-negative findings than PSIR either for cortical lesions (1 vs 13; P < 0.01) or infratentorial lesions (1 vs 15; P < 0.01). No false-positive findings were found with any of the 2 sequences. Diagnostic confidence was high for each contrast. CONCLUSION: Three-dimensional CS-FLAWS is as accurate as 2D PSIR imaging for classification of cortical and infratentorial MS lesions, with fewer false-negative findings, opening the way to a reliable full brain MS exploration in a clinically acceptable duration (5 minutes 15 seconds).

Expert Views on Evidence-Based Classification for Goalball: A Delphi Study.

Para sport classification aims to minimize the impact of impairments on the outcome of competition. The International Paralympic Committee requires classification systems to be evidence based and sport specific, yet the sport of goalball uses a structure that is not supported by evidence demonstrating its legitimacy for competition. This study aimed to establish expert opinions on how a sport-specific system of classification should be structured in the sport of goalball. Using a three-round Delphi survey, 30 international experts expressed their views across topics linked to goalball classification. Participants were divided as to whether the current system fulfills the aim to minimize the impact of impairment on competition. Most felt that less impairment should be required to compete but that the one-class structure should remain. Experts identified measures of visual function that should be considered and 15 core components of individual goalball performance. Findings constitute a crucial first step toward evidence-based classification in goalball.

Aroma-active volatiles and rheological characteristics of the plastic mass during conching of dark chocolate.

Chocolate conching is a highly complex, thermomechanical process that transforms the aroma and flow properties of a dry starting material. Different conched plastic masses of dark chocolate were characterized. Rheological characterization of plastic masses was performed for the first time using a closed cavity rheometer (CCR1). In free cocoa butter derived from the plastic masses, acetic acid, benzaldehyde, (R,S)-(±)-linalool, 2,3,5,6-tetramethylpyrazine, and 2-phenylethanol were quantified by stable isotope dilution analysis (SIDA2) and gas chromatography-mass spectrometry. During the conching process, the amount of free cocoa butter increased possibly due to de-agglomeration. The complex viscosity of the plastic mass decreased as a function of conching time. Regarding aroma refinement, the concentrations of all five aroma-active volatiles decreased with increasing conching duration, albeit to varying degrees. The level of acetic acid showed the most pronounced decrease of about 60%, whereas linalool exhibited the lowest decrease in concentration, up to 26%. Overall, a lower polarity or boiling point of the aroma-active volatiles was linked to a stronger decrease in concentration during conching. These data illustrate the influence of conching on texture and the respective aroma changes, which deepens understanding of the conching effect on the sensory quality of dark chocolate.

Dietary omega-6/omega-3 ratio is not associated with gut microbiota composition and disease severity in patients with nonalcoholic fatty liver disease.

In this cross-sectional study, we hypothesized that a high dietary ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids could be associated with an altered gut bacterial composition and with the disease severity in patients with nonalcoholic fatty liver disease (NAFLD). A total of 101 NAFLD patients were included in the study, of which 63 underwent a liver biopsy. All 101 patients completed a 14-day food and activity record. Ebispro 2016 professional software was used to calculate individual macronutrients and micronutrients consumed. Patients were grouped into 3 quantiles (Q) according to a low (Q1: <6.1, n = 34), moderate (Q2: 6.1-7.8, n = 33), or high (Q3: >7.8, n = 34) dietary n-6/n-3 ratio. Stool samples were analyzed using 16S rRNA gene sequencing. Spearman correlation coefficients and principal coordinate analysis were used to detect differences in the bacterial composition of the gut microbiota. The median dietary n-6/n-3 ratio of all patients was 6.7 (range, 3.1-14.9). No significant associations between the dietary n-6/n-3 ratio and the gut microbiota composition or disease severity were observed. However, the abundance of specific bacteria such as Catenibacterium or Lactobacillus ruminis were found to be positively correlated and the abundance of Clostridium were negatively correlated with dietary n-6 fatty acid intake. The results indicate that a high dietary n-6/n-3 ratio is probably not a highly relevant factor in the pathogenesis of human NAFLD. Further studies are needed to clarify the importance of interactions between gut bacterial taxa and n-6 fatty acids in the pathophysiology of NAFLD.

Management of Dyslipidemia in Patients with Non-Alcoholic Fatty Liver Disease.

PURPOSE OF REVIEW: Patients with non-alcoholic fatty liver disease (NAFLD), often considered as the hepatic manifestation of the metabolic syndrome, represent a population at high cardiovascular risk and frequently suffer from atherogenic dyslipidemia. This article reviews the pathogenic interrelationship between NAFLD and dyslipidemia, elucidates underlying pathophysiological mechanisms and focuses on management approaches for dyslipidemic patients with NAFLD. RECENT FINDINGS: Atherogenic dyslipidemia in patients with NAFLD results from hepatic and peripheral insulin resistance along with associated alterations of hepatic glucose and lipoprotein metabolism, gut dysbiosis, and genetic factors. Since atherogenic dyslipidemia and NAFLD share a bi-directional relationship and are both major driving forces of atherosclerotic cardiovascular disease (ASCVD) development, early detection and adequate treatment are warranted. Thus, integrative screening and management programs are urgently needed. A stepwise approach for dyslipidemic patients with NAFLD includes (i) characterization of dyslipidemia phenotype, (ii) individual risk stratification, (iii) definition of treatment targets, (iv) lifestyle modification, and (v) pharmacotherapy if indicated.