Contribution of extracellular vesicles to steatosis-related liver disease and their therapeutic potential.

Extracellular vesicles (EVs) are small particles released by many cell types in different tissues, including the liver, and transfer specific cargo molecules from originating cells to receptor cells. This process generally culminates in activation of distant cells and inflammation and progression of certain diseases. The global chronic liver disease (CLD) epidemic is estimated at 1.5 billion patients worldwide. Cirrhosis and liver cancer are the most common risk factors for CLD. However, hepatitis C and B virus infection and obesity are also highly associated with CLD. Nonetheless, the etiology of many CLD pathophysiological, cellular, and molecular events are unclear. Changes in hepatic lipid metabolism can lead to lipotoxicity events that induce EV release. Here, we aimed to present an overview of EV features, from definition to types and biogenesis, with particular focus on the molecules related to steatosis-related liver disease, diagnosis, and therapy.

Protocolized Regional Citrate Anticoagulation during Continuous Renal Replacement Therapy: A Single Center Experience.

Background: Regional citrate anticoagulation (RCA) has emerged as a treatment modality that reduces bleeding risk and filter clotting. With initial experience of using RCA with continuous renal replacement therapy (CRRT), we have formulated a working protocol based on published literature. Objective: The study aimed to evaluate the protocol for routine use of RCA during CRRT requiring anticoagulation and evaluation of filter life. Methodology: It is a single-center, open-label, prospective, non-randomized, non-interventional, single-arm, observational study conducted at a tertiary care hospital between September 2022 and July 2023. All adult patients with acute kidney injury (AKI) or hyperammonemia requiring CRRT and necessitating the use of anticoagulation were enrolled in the study. The study used Prisma Flex M100 AN 69 dialyzer on Prisma Flex (Baxter) CRRT machines during continuous venovenous hemodiafiltration (CVVHDF). The targeted CRRT dose in all the study patients was 25-30 mL/kg/hour. Based on the published literature, we have developed a working protocol (Appendix 1) for managing patients on CRRT using RCA. Results: A total of 159 patients were analyzed for the study. The median [interquartile range (IQR)] filter life using RCA was 30 (12-55) hours. Filter clotting was observed in 33.3% of patients. Citrate accumulation was present in 52.25% of patients, but no CRRT was discontinued as citrate accumulation resolved after following the corrective steps in the protocol. None of the patients had citrate toxicity. Chronic liver disease (CLD) (p ≤ 0.001) and those who were post-living donor liver transplant recipients (p = 0.004) had a statistically significant increase in citrate accumulation. Also, patients who had higher lactate at baseline (6 hours post-CRRT initiation), had a higher chance of citrate accumulation. Conclusion: Our RCA protocol provides a safe approach to regional anticoagulation during CRRT in critically ill patients. How to cite this article: Pachisia AV, Kumar GP, Harne R, Jagadeesh KN, Patel SJ, Pal D, et al. Protocolized Regional Citrate Anticoagulation during Continuous Renal Replacement Therapy: A Single Center Experience. Indian J Crit Care Med 2024;28(9):859-865.

Sinusoidal communication in chronic liver disease.

The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, specially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.

Hyponatremia Prevalence in Decompensated Chronic Liver Disease: Insights from a Tertiary Care Hospital.

BACKGROUND: Liver cirrhosis is a prominent global contributor to mortality, and hyponatremia is a common complication in patients with decompensated chronic liver disease (DCLD). Hyponatremia is characterized by kidney impairment when eliminating solute-free water. The presence of contradictory findings in existing literature prompted this study. OBJECTIVE: The objective of this study was to determine the prevalence of hyponatremia in patients with DCLDs presenting at a tertiary care hospital. METHODOLOGY:  This six-month cross-sectional study was performed at the Allied Institute of Medical Sciences Teaching Hospital in Gujranwala, Pakistan, from January 2022 to June 2022. A total of 133 patients were selected as subjects. Researchers took blood samples from these patients and sent the samples to the hospital pathology lab for evaluation of serum sodium levels. If sodium levels were ≤130 mmol/L, the patient was considered to have hyponatremia. All information was recorded on proforma. RESULTS:  The mean age of patients was 47.68 ± 12.89 years. Overall, 80 (60.15%) were male, and 53 (39.85%) female. The mean BMI of patients was 23.20 ± 3.11 kg/m2 and the average duration of DCLD was 7.24 ± 4.12 years. Among participants, 48 (36.09%) patients had hyponatremia, whereas 85 (63.91%) did not have hyponatremia. The mean sodium level was 132.39 ± 11.37 mEq/L. Stratified analysis based on patient age revealed that among patients aged 21-45 years, 27 (45.8%) had hyponatremia, whereas, in the group aged 46-70 years, 21 (28.4%) had hyponatremia with a p-value < 0.05. Stratification of the basis of BMI, among underweight patients, all eight (100%) had hyponatremia, whereas of overweight patients, 14 (31.1%) had hyponatremia. This difference was statistically significant (p < 0.05). CONCLUSION: The prevalence of hyponatremia was notably elevated among individuals suffering from DCLD. Age and BMI were the most common risk factors for hyponatremia among subjects with DCLD. This study recommends that patients with DCLD should have their serum sodium levels screened at regular intervals to prevent complications, including encephalopathy, which occurs particularly in younger and underweight DCLD patients.

Trends in the incidence and prevalence of cirrhosis in Manitoba, Canada: A population-based study (2010-2019).

INTRODUCTION AND OBJECTIVES: The burden of chronic liver disease and cirrhosis continues to increase in North America. We sought to estimate the incidence and prevalence of cirrhosis in Manitoba, Canada over time and assess changes in trends between 2010-2019. MATERIAL AND METHODS: We performed a population-based study using Manitoba administrative health care data, and two validated case-finding algorithms. Annual incidence and prevalence rates were estimated using a generalized linear model with generalized estimating equations, adjusting for age and sex. Changes in estimates were tested using linear trend regression models. RESULTS: Two algorithms estimated the number of prevalent cirrhosis to be 16,140 and 29,943 respectively. The age- and sex-adjusted incidence rates increased over the study (from 149 to 264 cases per 100,000 population in 2010, to 177 to 388 cases per 100,000 population in 2019). Cirrhosis incidence increased annually by 2-6%, with the largest increase (6-8% 95% CI 7-9%, p <0.0001) in those aged 18-44 years. Irrespective of the algorithm used, females consistently exhibited higher cirrhosis incidence and prevalence compared to males over time (P <0.0001). Prevalence demonstrated an upward trend among all age groups over time for both algorithms (P < 0.0001). CONCLUSIONS: This population-based study highlights concerning temporal trends in cirrhosis, characterized by rising annual incidence and prevalence estimates, particularly among young adults and females. These findings underscore the urgent need for comprehensive strategies that encompass prevention, early detection, and the delivery of high-quality healthcare and public health initiatives to effectively tackle this escalating health burden.

Reduced muscle mass is an important part of Global Leadership Initiative on Malnutrition criteria in nutritional diagnosis of hepatocellular carcinoma.

BACKGROUND: The Global Leadership Initiative on Malnutrition criteria (GLIM) was established to build a global consensus on the diagnostic criteria for malnutrition. The study aimed to assess the prevalence of the malnutrition diagnosed by GLIM criteria for patients with hepatocellular carcinoma (HCC), and to determine the role of the reduced muscle mass defined by CT scans in the GLIM criteria. METHODS: This cohort research was conducted on adult cirrhotic patients with HCC. The risk of malnutrition was screened by Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. The third lumbar vertebrae (L3-SMI) were used to represent the muscle mass in GLIM criteria. The variables associated with overall mortality were assessed by multivariate Cox regression analyses. RESULTS: The incidence of malnutrition diagnosed by GLIM criteria was 49.7% (179/360) in patients with HCC. If reduced muscle mass was not included in GLIM criteria, the prevalence of malnutrition was 31.7% (114/360). GLIM-defined malnutrition (HR = 1.979, 95%CI 1.019-3.841, P = 0.044) was independently associated with overall mortality in patients with HCC. However, the GLIM-defined malnutrition (without muscle mass) was not associated with overall mortality (HR = 0.863, 95%CI 0.399-1.867, P = 0.709). CONCLUSIONS: Skeletal muscle mass is an integral component of the GLIM criteria for patients with HCC. The malnutrition is common in patients with HCC, and malnourishment is associated with higher overall mortality. GLIM criteria are recommended to assess the nutritional status of hospitalized patients with HCC, which is recommended and can be used as the basis for nutritional interventions.

Aetiology-specific inflammation patterns in patients and rat models of compensated cirrhosis.

BACKGROUND: Cirrhosis is associated with a proinflammatory environment. AIMS: To analyse aetiology-specific inflammation patterns in compensated cirrhosis in animal models and patients. METHODS: Portal pressure (PP), fibrosis (collagen proportionate area [CPA]) and hepatic inflammation were measured in cirrhotic rat models (thioacetamide [TAA;n = 12]; choline-deficient high-fat diet [CDHFD;n = 12]; bile duct ligation [BDL;n = 16]). Compensated cirrhotic patients (alcohol-related liver disease [ALD;n = 67]; metabolic dysfunction-associated steatohepatitis [MASH;n = 50]; cholestatic liver disease [primary biliary cholangitis [PBC]/primary sclerosing cholangitis [PSC];n = 22]) undergoing hepatic venous pressure gradient (HVPG) measurement were included. RESULTS: In rats, hepatic proinflammatory gene expression was highest in CDHFD and lowest in TAA, despite comparable PP levels. Across all animal models, Tnfa/Il6 correlated positively with CPA, and Mcp1 with elevated PP. Mcp1 was also associated with increased CPA in TAA/CDHFD. Mcp1/Cxcl1 showed a model-independent positive correlation to transaminases. Il1b correlated positively with CPA/PP in BDL and with transaminases in CDHFD. In patients, CRP/IL-6 were lower in MASH compared to ALD or PBC/PSC, regardless of hepatic function. IgA/IgG were highest and complement factors lowest in ALD. More pronounced systemic inflammation was linked to higher HVPG primarily in ALD/MASH. CONCLUSION: Proinflammatory pathways are upregulated across all liver disease aetiologies, yet their association with fibrosis and portal hypertension can vary.

Follow-up post-HCV virological response to DAA in advanced chronic liver disease.

Direct-acting antivirals (DAA) achieve high virological response rates with minimal side effects for many patients. Despite their significant impact on the progression and epidemiology of hepatitis C virus (HCV) associated liver disease, the global annual incidence of chronic infections is expected to remain relatively constant, averaging 1.42 million new cases each year until 2030. Furthermore, by 2030, there will be a 14-17% increase in end-stage liver disease outcomes such as liver-related deaths, hepatocellular carcinoma (HCC), and decompensated cirrhosis in adults aged 18 years and over. Although reductions in liver decompensation, HCC occurrence, and mortality have been shown in patients with advanced liver disease who achieved sustained virological response (SVR) with DAA, these benefits may be less significant in those with decompensated liver cirrhosis. This review aims to summarise the impact of the virological response to DAA on liver disease progression and outcomes in patients with advanced chronic liver disease, which appears to be crucial for defining patient-specific follow-up.

Extracellular vesicles: A potential new way to assess cholestasis.

Extracellular vesicles (EVs) are small, nonreplicating, lipid-encapsulated nanoparticles that carry protein and nucleic acid cargo derived from their tissue of origin. Due to their capacity to provide comparable insights to solid organ biopsy through a minimally invasive collection procedure, EVs provide an attractive biomarker source. This review will provide an insight, how EVs in circulation may provide a novel way to assess cholestasis and will address the possibility of getting a better understanding of the mechanisms of cholestasis of pregnancy through the use of serial hepatic-specific EVs as a window.

A true challenge: Disseminated tuberculosis with tuberculous meningitis in a patient with underlying chronic liver disease.

Tuberculous meningitis (TBM) is a potentially life-threatening form of tuberculosis (TB) that affects the central nervous system. Its management in patients with concomitant chronic liver disease (CLD) presents unique challenges due to altered drug metabolism with potentially impaired spinal fluid drug penetration and hepatotoxicity. The standard regimen for TBM includes isoniazid (INH) and rifampin (RIF), and Pyrazinamide (PZA) which are metabolized by the liver and may cause hepatotoxicity, which can exacerbate preexisting liver disease. Thus, careful consideration is required to balance therapeutic efficacy with potential drug-induced hepatotoxicity. Regular monitoring of liver function tests and clinical response is essential to minimize adverse effects and optimize treatment outcomes. Further research is needed to establish evidence-based guidelines for the tailored management of TBM in this vulnerable patient subset. Overall, the treatment of TBM in patients with severe liver disease should be individualized and closely monitored.

Progressive familial intrahepatic cholestasis 3 Camouflaging as Wilson disease in a 12-year-old: a diagnostic Odyssey.

Primary Familial Intrahepatic Cholestasis type 3 is an exceedingly rare genetic cholestatic disorder characterized by the defective hepatocanaliculr bile acid transport leading to progressive liver disease. In this case report, we describe the course of treatment for a 12-year-old kid diagnosed with Wilson disease based on Leipzig score and copper investigations. The child did not improve with chelation therapy and was subsequently genetically classified as PFIC-3. This case highlighted the caveats in Wilson disease diagnostic scoring system. The diagnostic odyssey, therapeutic interventions, and outcome of this case underscore the intricate interplay between clinical suspicion, investigative strategies, and the pivotal role of genetic testing to elucidate rare liver disorders in children.

Efficacy and Safety of Terlipressin Infusion in Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Retrospective Observational Study.

Background Hepatorenal syndrome-acute kidney injury (HRS-AKI) is an event that occurs in chronic liver disease (CLD) and is associated with high morbidity and mortality. Terlipressin, a vasopressin analog, is used for the treatment of portal hypertension-related gastrointestinal (GI) bleeding and is found to be effective in the management of HRS-AKI. Continuous infusion of terlipressin maintains a high mean arterial pressure while reducing adverse events. It is better tolerated and equally effective at lower doses than intravenous boluses in patients with HRS-AKI. Aim of the study This study aimed to evaluate the safety and efficacy of terlipressin infusion at the rate of 4 mg/day in the treatment of HRS-AKI. Methods This retrospective study included patients who had HRS-AKI according to the modified International Club of Ascites (ICA) definition. Patients were started on a continuous intravenous infusion. The included patients received terlipressin 1 mg stat followed by a 4 mg infusion over 24 hours, and the infusion was continued until specific response criteria were met or for a maximum of seven days. Results In total, 136 patients were included in this study. The mean age of the study group was 45 years, the mean Child-Turcotte-Pugh (CTP) score was 11, the mean model for end-stage liver disease (MELD) score was 30, and the mean serum creatinine was 2.46 mg/dl. A response to treatment in the form of reduction of serum creatinine was observed in 94 (69.1%) patients, 30 (22%) patients showed no response, and worsening of creatinine was seen in 12 (8.8%) patients. The mean duration of hospital stay was 7.6 days, the mean serum creatinine was 1.17 mg/dl at the end of treatment, and the mean CTP and MELD scores in treatment responders were nine and 27, respectively. A total of 29 (21.3%) of 136 patients had adverse events during the terlipressin infusion therapy.  Conclusion Terlipressin infusion has sustained effects on splanchnic hemodynamics with fewer and less severe adverse events than intravenous bolus doses. Terlipressin infusion at a dose of 4 mg/day appeared to be well tolerated, with similar outcomes to that of 2 mg/day with a significantly lower albumin dose. These findings emphasize the importance of optimizing treatment protocols, particularly those favoring infusion methods, to enhance efficacy and minimize adverse effects.

Derivation of Splenic Stiffness in Subjects with Normal Liver Stiffness and No Vascular Liver Disease Using Transient Elastography with a Spleen-Dedicated Module: A Large Cross Sectional Study.

BACKGROUND: Liver and splenic stiffness measurements (LSM and SSM) are useful to predict varices and clinical decompensation in cirrhosis. SSM values are highly variable and overlapping and no guidelines exists on what constitutes normal SSM, that might limit interpretation of results. METHODS: Consecutive subjects with LSM < 6 kPa and reliable SSM (FibroScan630 Expert device with spleen-dedicated module) and no vascular liver disease were analysed for significant correlations of SSM values with age, sex, BMI, portal and splenic vein diameter, splenic diameter, liver fat and diabetes. Based on timeline of SSM, subjects were randomly assigned in 70:30 ratio into derivation [n = 502] and validation subset [n = 214]. RESULTS: Of 7200 subjects with simultaneous reliable LSM and SSM, 715 fulfilled the selection criteria (mean age: 43.8 ± 12.8 years, 67.2% male, mean BMI-26.4 ± 4.5 kg/m2). The mean SSM was 22.6 ± 5.8 kPa (c10-c90 percentile range: 15.2-31.3 kPa) and followed the normal distribution curve. In the derivation subset, mean SSM for males was higher than female (23.06 ± 6.2 vs. 21.78 ± 5.93 kPa; p = 0.028). SSM value correlated with LSM (r = 0.454, p = 0.001). Mean SSM in subjects with LSM 3-4, 4.1-5 and 5.1-6 kPa were 21.7 ± 5.8, 22.27 ± 5.67 and 23.76 ± 5.88 kPa (p value = 0.001). There was no difference in SSM based on age, BMI, diabetes and liver fat on ultrasound. Above results hold true for subjects in validation subset. CONCLUSION: SSM range in subjects with normal LSM and no vascular liver disease using spleen-dedicated module varies from 15.2 to 31.3 kPa, values being higher in male and not affected by Age, BMI, spleen size, liver fat and diabetes. Our results may serve as reference point in evaluation of SSM in compensated advanced liver disease patients.

RANK-RANKL-OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives.

Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.

Missed and Delayed Diagnoses of Chronic Liver Disease in Primary Care Patients with Cirrhosis.

BACKGROUND: Chronic liver diseases (CLD), cirrhosis, and hepatocellular carcinoma (HCC) cause significant morbidity and mortality. Unfortunately, patients with CLD often go undiagnosed until progression to cirrhosis and HCC. We aimed to determine the proportion of primary care patients with severe liver disease outcomes that had missed or delayed CLD diagnoses. METHODS: This retrospective cohort study evaluated primary care patients with a diagnosis of cirrhosis, HCC, or other severe liver disease outcome between 2012 and 2021. The outcomes of interest were missed and delayed diagnoses of CLD, defined as the absence of a CLD diagnosis (missed) or first appearance of CLD on the same day as the cirrhosis diagnosis (delayed). Univariate analyses were performed to describe the cohort. Multivariable logistic regression models analyzed the association of aminotransferase elevations with the outcomes of interest. RESULTS: Of 667 patients with cirrhosis or HCC, 133 (20%) had a missed CLD diagnosis, and 243 (36%) had a delayed CLD diagnosis. Alcohol-related liver disease was the most common etiology among patients with missed/delayed diagnoses. A lower proportion of patients with missed/delayed diagnoses had an elevation in ALT or AST compared to patients with timely diagnoses (61% vs. 77%, p < 0.001). Elevated aminotransferase values were associated with lower odds of a missed/delayed diagnosis (OR 0.47; 95%CI 0.34-0.66). CONCLUSIONS: Most patients with cirrhosis or HCC had missed or delayed diagnoses of CLD in the context of probable overreliance on aminotransferase elevation for CLD detection. Enhanced screening for high prevalence CLD, especially alcohol, in primary care is needed.

Machine-Learning Model Identifies Patients With Alpha-1 Antitrypsin Deficiency Using Claims Records.

Identifying patients with rare diseases like alpha-1 antitrypsin deficiency (AATD) is challenging. Machine-learning models may be trained to identify patients with rare diseases using large-scale, real-world databases, whereas electronic medical records have low numbers of confirmed cases and have limited use in training such models. We applied a machine-learning model to a large US claims database to identify undiagnosed symptomatic patients with AATD. Using deidentified data from the Komodo US claims database (April 26, 2016-January 31, 2023), a model was trained to identify symptomatic patients with high probability of AATD. Eighty claims records for high-probability candidates identified by the model were independently reviewed and validated by 2 clinical experts. The experts independently indicated that of the 80 high-probability candidate patients, 65 (81%) and 62 (78%) patients, respectively, should be tested for AATD. Feedback from this validation step informed model optimization. The optimized model was applied to claims data to identify symptomatic patients with probable AATD. Eleven and 14 "features" of the claims data were informative in distinguishing patients with AATD from patients with COPD without AATD and from unspecified chronic liver diseases. Moreover, patients with diagnosed AATD and COPD without AATD had unique cadences of similar medical events in their diagnostic journeys. Our work shows that a machine-learning model trained on a large US claims database can accurately identify symptomatic patients with AATD and provides useful insights into the diagnostic journey of patients with AATD.

A comprehensive 26-color immunophenotyping panel to study the role of the gut-liver axis in chronic liver diseases.

The gut-liver axis includes the bidirectional communication between the gut and the liver, and thus covers signals from liver-to-gut and from gut-to-liver. Disruptions of the gut-liver axis have been associated with the progression of chronic liver diseases, including alcohol-related and metabolic dysfunction-associated steatotic liver disease and cholangiopathies. Immune cells and their expression of pattern recognition receptors, activation markers or immune checkpoints might play an active role in the communication between gut and liver. Here, we present a 26-color full spectrum flow cytometry panel for human cells to decipher the role of circulating immune cells in gut-liver communication during the progression of chronic liver diseases in a non-invasive manner, which has been optimized to be used on patient-derived whole blood samples, the most abundantly available clinical material. Our panel focuses on changes in pattern recognition receptors, including toll-like receptors (TLRs) or Dectin-1, and also includes other immunomodulatory molecules such as bile acid receptors and checkpoint molecules. Moreover, this panel can be utilized to follow the progression of chronic liver diseases and could be used as a tool to evaluate the efficiency of therapeutic targets directed against microbial mediators or modulating immune cell activation.

Palliative care in terminally ill advanced chronic liver disease patients.

While mortality rates from advanced chronic liver disease (ACLD) are rapidly increasing, patients with an advanced disease stage have a comparable or even higher symptom burden than those with other life-limiting diseases. Although evidence is limited there is increasing recognition of the need to improve care for patients with ACLD; however, there are many limiting factors to providing good palliative care for these patients, including unpredictable disease progression, the misconception of palliative care and end of life care as being equivalent, a lack of confidence in prescribing medication and a lack of time and resources. Health professionals working with these patients need to develop the skills to ensure effective palliative care, while referral to specialized palliative care centers should be reserved for patients with complex needs. Basic palliative care, along with active disease management, is best delivered by the treating hepatologists. This includes discussions about disease progression and advance care planning, alongside the active management of disease complications. Liver disease is closely associated with significant social, psychological, and financial burdens for patients and their caregivers. Strategies to engage the discussion in multidisciplinary teams early in disease progression help to ensure addressing these issues proactively. This review summarizes the evidence on palliative care for patients with ACLD, provides examples of current best practice and offers suggestions on how disease-modifying and palliative care can coexist, to ensure that patients do not miss opportunities for quality of life improving interventions.