Predictive Algorithm for Hepatic Steatosis Detection Using Elastography Data in the Veterans Affairs Electronic Health Records.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions. Early detection can identify at-risk patients who can be linked to hepatology care. The vibration-controlled transient elastography (VCTE) controlled attenuation parameter (CAP) is biopsy validated to diagnose hepatic steatosis (HS). We aimed to develop a novel clinical predictive algorithm for HS using the CAP score at a Veterans' Affairs hospital. METHODS: We identified 403 patients in the Greater Los Angeles VA Healthcare System with valid VCTEs during 1/2018-6/2020. Patients with alcohol-associated liver disease, genotype 3 hepatitis C, any malignancies, or liver transplantation were excluded. Linear regression was used to identify predictors of NAFLD. To identify a CAP threshold for HS detection, receiver operating characteristic analysis was applied using liver biopsy, MRI, and ultrasound as the gold standards. RESULTS: The cohort was racially/ethnically diverse (26% Black/African American; 20% Hispanic). Significant positive predictors of elevated CAP score included diabetes, cholesterol, triglycerides, BMI, and self-identifying as Hispanic. Our predictions of CAP scores using this model strongly correlated (r = 0.61, p < 0.001) with actual CAP scores. The NAFLD model was validated in an independent Veteran cohort and yielded a sensitivity of 82% and specificity 83% (p < 0.001, 95% CI 0.46-0.81%). The estimated optimal CAP for our population cut-off was 273.5 dB/m, resulting in AUC = 75.5% (95% CI 70.7-80.3%). CONCLUSION: Our HS predictive algorithm can identify at-risk Veterans for NAFLD to further risk stratify them by non-invasive tests and link them to sub-specialty care. Given the biased referral pattern for VCTEs, future work will need to address its applicability in non-specialty clinics. Proposed clinical algorithm to identify patients at-risk for NAFLD prior to fibrosis staging in Veteran.

Care for Vulnerable Populations with Chronic Liver Disease: A Safety-Net Perspective.

Safety-net hospitals (SNHs) and facilities are the cornerstone of healthcare services for the medically underserved. The burden of chronic liver disease-including end-stage manifestations of cirrhosis and liver cancer-is high and rising among populations living in poverty who primarily seek and receive care in safety-net settings. For many reasons related to social determinants of health, these individuals often present with delayed diagnoses and disease presentations, resulting in higher liver-related mortality. With recent state-based policy changes such as Medicaid expansion that impact access to insurance and critical health services, an overview of the body of literature on SNH care for chronic liver disease is timely and informative for the liver disease community. In this narrative review, we discuss controversies in the definition of a SNH and summarize the known disparities in the cascade of the care and management of common liver-related conditions: (1) steatotic liver disease, (2) liver cancer, (3) chronic viral hepatitis, and (4) cirrhosis and liver transplantation. In addition, we review the specific impact of Medicaid expansion on safety-net systems and liver disease outcomes and highlight effective provider- and system-level interventions. Lastly, we address remaining gaps and challenges to optimizing care for vulnerable populations with chronic liver disease in safety-net settings.

Factors Associated With Liver Transplant Referral Among Patients With Cirrhosis at Multiple Safety-Net Hospitals.

Importance: A high proportion of underserved patients with cirrhosis receive care at safety-net hospitals (SNHs). While liver transplant (LT) can be a life-saving treatment for cirrhosis, data on referral patterns from SNHs to LT centers are lacking. Objective: To identify factors associated with LT referral within the SNH context. Design, Setting, and Participants: This retrospective cohort study included 521 adult patients with cirrhosis and model for end-stage liver disease-sodium (MELD-Na) scores of 15 or greater. Participants received outpatient hepatology care at 3 SNHs between January 1, 2016, and December 31, 2017, with end of follow-up on May 1, 2022. Exposures: Patient demographic characteristics, socioeconomic status, and liver disease factors. Main Outcomes and Measures: Primary outcome was referral for LT. Descriptive statistics were used to describe patient characteristics. Multivariable logistic regression was performed to evaluate factors associated with LT referral. Multiple chained imputation was used to address missing values. Results: Of 521 patients, 365 (70.1%) were men, the median age was 60 (IQR, 52-66) years, most (311 [59.7%]) were Hispanic or Latinx, 338 (64.9%) had Medicaid insurance, and 427 (82.0%) had a history of alcohol use (127 [24.4%] current vs 300 [57.6%] prior). The most common liver disease etiology was alcohol associated liver disease (280 [53.7%]), followed by hepatitis C virus infection (141 [27.1%]). Median MELD-Na score was 19 (IQR, 16-22). One hundred forty-five patients (27.8%) were referred for LT. Of these, 51 (35.2%) were wait-listed, and 28 (19.3%) underwent LT. In a multivariable model, male sex (adjusted odds ratio [AOR], 0.50 [95% CI, 0.31-0.81]), Black race vs Hispanic or Latinx ethnicity (AOR, 0.19 [95% CI, 0.04-0.89]), uninsured status (AOR, 0.40 [95% CI, 0.18-0.89]), and hospital site (AOR, 0.40 [95% CI, 0.18-0.87]) were associated with lower odds of being referred. Reasons for not being referred (n = 376) included active alcohol use and/or limited sobriety (123 [32.7%]), insurance issues (80 [21.3%]), lack of social support (15 [4.0%]), undocumented status (7 [1.9%]), and unstable housing (6 [1.6%]). Conclusions: In this cohort study of SNHs, less than one-third of patients with cirrhosis and MELD-Na scores of 15 or greater were referred for LT. The identified sociodemographic factors negatively associated with LT referral highlight potential intervention targets and opportunities to standardize LT referral practices to increase access to life-saving transplant among underserved patients.

Case-control study of the association of chronic acid suppression and social determinants of health with COVID-19 infection.

Acid suppressants are widely-used classes of medications linked to increased risks of aerodigestive infections. Prior studies of these medications as potentially reversible risk factors for COVID-19 have been conflicting. We aimed to determine the impact of chronic acid suppression use on COVID-19 infection risk while simultaneously evaluating the influence of social determinants of health to validate known and discover novel risk factors. We assessed the association of chronic acid suppression with incident COVID-19 in a 1:1 case-control study of 900 patients tested across three academic medical centers in California, USA. Medical comorbidities and history of chronic acid suppression use were manually extracted from health records by physicians following a pre-specified protocol. Socio-behavioral factors by geomapping publicly-available data to patient zip codes were incorporated. We identified no evidence to support an association between chronic acid suppression and COVID-19 (adjusted odds ratio 1.04, 95% CI 0.92-1.17, P = 0.515). However, several medical and social features were positive (Latinx ethnicity, BMI ≥ 30, dementia, public transportation use, month of the pandemic) and negative (female sex, concurrent solid tumor, alcohol use disorder) predictors of new infection. These findings demonstrate the value of integrating publicly-available databases with medical data to identify critical features of communicable diseases.

Noninvasive scores for the prediction of esophageal varices and risk stratification in patients with cirrhosis.

The primary purpose of variceal screening in patients with cirrhosis is to detect gastroesophageal varices at high risk of hemorrhage and implement preventative intervention(s). It was previously recommended that all patients with cirrhosis undergo initial and periodic longitudinal variceal screening via upper endoscopy. However, there has been growing interest and methods to identify patients with cirrhosis who may not have clinically significant portal hypertension and therefore be unlikely to have varices requiring intervention or benefit from upper endoscopy. Because the population of patients with compensated advanced chronic liver disease continues to grow, it is neither beneficial nor cost-effective to perform endoscopic variceal screening in all patients. Therefore, there is ongoing research into the development of methods to non-invasively risk stratify patients with cirrhosis for the presence of high-risk esophageal varices and effectively limit the population that undergoes endoscopic variceal screening. This is particularly important and timely in light of increasing healthcare reform and barriers to healthcare. In this review, we discuss and compare, with respect to test characteristics and clinical applicability, the available methods used to non-invasively predict the presence of esophageal varices.

Review article: new therapeutic interventions for advanced hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first-line and second-line treatment options should yield significant improvements in survival. AIM: To summarize the evolving landscape of treatment options for patients with advanced HCC. METHODS: We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences. RESULTS: Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine-kinase inhibitor, was recently shown to have non-inferior survival vs sorafenib and is another first-line treatment option. The tyrosine-kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second-line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population. CONCLUSION: There are several first-line and second-line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.

Survey of Liver Transplantation Practices for Severe Acute Alcoholic Hepatitis.

Liver transplantation (LT) has a demonstrated survival benefit in select patients with severe acute alcoholic hepatitis (SAH) who do not respond to steroids, but prior studies suggest low adoption among US LT centers. Our study explored current perceptions and practice patterns of LT for SAH in the United States. We administered a Web-based survey to medical directors of US LT centers between May and October of 2017 to characterize practice patterns and perceptions of LT for SAH. We obtained responses from 45 (41.3%) of 109 surveyed centers, representing all 11 (100%) United Network for Organ Sharing regions. Half (n = 23; 51.1%) reported performing at least 1 LT for SAH, although most (n = 19; 82.6%) of those had performed ≤5 LTs for that indication. Centers expressed near consensus for selection criteria, requiring strong social support (100%), no prior presentations with SAH (91.3%), absence of a severe coexisting psychiatric disorder (91.3%), and official psychosocial evaluation (87.0%). Reported posttransplant survival of SAH patients was excellent, with 17 (73.9%) centers reporting 1-year posttransplant survival exceeding 90%. Among centers that had not performed LT for SAH, the most commonly cited reason was perceived high risk of alcohol relapse. In conclusion, our data demonstrate that LT is increasingly adopted as a therapeutic intervention for patients with SAH and that careful selection allows for excellent 1-year posttransplant survival. Despite this, nearly half of US centers do not perform LT for this indication due to perceived high risk of alcohol relapse. Our data support the use of LT for well-selected patients with SAH.

HHV-8-associated haemophagocytic lymphohistiocytosis in a patient with advanced AIDS.

We present a patient with advanced AIDS admitted with recurrent shock of unclear aetiology, fevers, altered mental status and refractory cytopenias. His case posed a diagnostic challenge because evaluation of septic shock in the setting of advanced AIDS requires a time-consuming work-up for broad infectious aetiologies that can delay consideration of other diagnoses, including primary or secondary haemophagocytic lymphohistiocytosis (HLH). After this patient did not improve with supportive care and empiric antimicrobials, there was concern for HLH given that he met ≥5 of the HLH consortium criteria. He underwent bone marrow biopsy, which was non-diagnostic. Empiric therapy for HLH was initiated, but unfortunately, the patient died. Autopsy revealed extensive haemophagocytosis in the spleen, bone marrow and liver, confirming the diagnosis of HLH. Postmortem, his soluble CD-25 returned 18 890 pg/mL (<1033 pg/mL), and his serum HHV-8 PCR resulted positive. The diagnosis was HLH secondary to Human Herpes Virus 8 (HHV-8) in a patient with advanced AIDS.

Severe Elevation of Liver Tests in Choledocholithiasis: An Uncommon Occurrence With Important Clinical Implications.

BACKGROUND AND AIMS: Choledocholithiasis is not commonly associated with dramatic elevations in aminotransferase or total serum bilirubin. Ours is the largest case series thus far studying the prevalence of dramatic elevations in liver tests associated with choledocholithiasis. MATERIALS AND METHODS: We performed a retrospective chart review of all patients with choledocholithiasis diagnosed on endoscopic retrograde pancreatocholangiogram at a tertiary referral hospital over 7 years. We identified 740 patients with available liver tests and determined the prevalence of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >1000 IU/L and of total serum bilirubin >10 mg/dL. We compared clinical characteristics of these 2 nonoverlapping groups. RESULTS: Of 740 patients, AST and/or ALT values >1000 IU/L were present in 45 (6.1%) patients. On average AST and ALT decreased 79% and 56%, respectively, at discharge 1 to 8 days later. Total serum bilirubin levels >10 mg/dL were present in 35 (4.7%) patients and decreased by an average of 64% at discharge 1 to 8 days later. When compared with the group with total serum bilirubin >10 mg/dL, the group with elevated aminotransferases had significantly more females (93% vs. 43%, P<0.001), had smaller common bile duct diameter (8.5 vs. 10.6 mm, P=0.04), and were more likely to have had a prior cholecystectomy (40% vs. 14%, P=0.01). These 80 patients had higher utilization of health resources: half had additional laboratory studies and one fourth had additional imaging studies performed. CONCLUSIONS: In patients with high AST and/or ALT and serum total bilirubin levels with known choledocholithiasis, elaborate work up to look for another etiology is not required. As long as the values decrease significantly, they do not need to be followed until they normalize in the same hospitalization.

A Bystander Effect of Lung Cancer Chemotherapy on Chronic Echinococcal Disease.

Hydatid cystic disease is a parasitic infestation caused by Echinococcus granulosus and commonly manifests as hepatic and pulmonary cysts. When feasible, based on cyst size and location, surgical resection is potentially curative. Post-surgical recurrence of disease is encountered in up to 25% of patients. Secondary peritoneal contamination is a recognized complication in 5-10% of cases. Disseminated disease is usually palliated using systemic anti-parasitic agents such as benzimidazoles, albendazole and mebendazole but worsening of disease post-systemic treatment is frequent in 14-25% of patients. In this report, we share our experience of a patient with long-standing, chronic disseminated hydatidosis and subsequent diagnosis of non-small cell lung cancer who manifested evidence of reduced activity of the echinococcal disease following institution of chemotherapy for his new diagnosis of lung cancer. There was significant reduction in the serum level of anti-echinococcal antibody titers in tandem with chemotherapy administration. There was also minimal but notable decrease in the size of the cysts on serial cross-sectional imaging obtained for monitoring cancer response to chemotherapy. This intriguing observation of a possible benefit of anticancer chemotherapy against echinococcal disease in this index case may provide new insights for therapeutic exploration in disseminated echinococcal disease.

Striatum-based circuitry of adolescent depression and anhedonia.

OBJECTIVE: Striatum-based circuits have been implicated in both major depressive disorder (MDD) and anhedonia, a symptom that reflects deficits of reward processing. Yet adolescents with MDD often exhibit a wide range of anhedonia severity. Addressing this clinical phenomenon, we aimed to use intrinsic functional connectivity (iFC) to study striatum-based circuitry in relation to categorical diagnosis of MDD and anhedonia severity. METHOD: A total of 21 psychotropic medication-free adolescents with MDD and 21 healthy controls (HC), group-matched for age and sex, underwent resting-state functional magnetic resonance imagining (fMRI) scans. Voxelwise maps indicating correlation strengths of spontaneous blood-oxygenation-level-dependent (BOLD) signals among 6 bilateral striatal seeds (dorsal caudate, ventral caudate, nucleus accumbens, dorsal-rostral putamen, dorsal-caudal putamen, ventral-rostral putamen) and the remaining brain regions were compared between groups. Relationships between striatal iFC and severity of MDD and anhedonia were examined in the MDD group. Analyses were corrected for multiple comparisons. RESULTS: Adolescents with MDD manifested increased iFC between all striatal regions bilaterally and the dorsomedial prefrontal cortex (dmPFC), as well as between the right ventral caudate and the anterior cingulate cortex (ACC). MDD severity was associated with iFC between the striatum and midline structures including the precuneus, posterior cingulate cortex, and dmPFC. However, distinct striatal iFC patterns involving the pregenual ACC, subgenual ACC, supplementary motor area, and supramarginal gyrus were associated with anhedonia severity. CONCLUSIONS: Although MDD diagnosis and severity were related to striatal networks involving midline cortical structures, distinct circuits within the reward system were associated with anhedonia. Findings support the incorporation of both categorical and dimensional approaches in neuropsychiatric research.

The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry.

The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6-85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data.

In recent years, there has been growing enthusiasm that functional magnetic resonance imaging (MRI) could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement-related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to (1) examine the impact of emerging techniques for controlling for "micro-movements," and (2) provide novel insights into the neural correlates of ADHD subtypes. Using support vector machine (SVM)-based multivariate pattern analysis (MVPA) we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C) and Inattentive (ADHD-I) subtypes demonstrated some overlapping (particularly sensorimotor systems), but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that resting-state functional connectivity MRI (rs-fcMRI) data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical heterogeneity of ADHD.

Growing together and growing apart: regional and sex differences in the lifespan developmental trajectories of functional homotopy.

Functional homotopy, the high degree of synchrony in spontaneous activity between geometrically corresponding interhemispheric (i.e., homotopic) regions, is a fundamental characteristic of the intrinsic functional architecture of the brain. However, despite its prominence, the lifespan development of the homotopic resting-state functional connectivity (RSFC) of the human brain is rarely directly examined in functional magnetic resonance imaging studies. Here, we systematically investigated age-related changes in homotopic RSFC in 214 healthy individuals ranging in age from 7 to 85 years. We observed marked age-related changes in homotopic RSFC with regionally specific developmental trajectories of varying levels of complexity. Sensorimotor regions tended to show increasing homotopic RSFC, whereas higher-order processing regions showed decreasing connectivity (i.e., increasing segregation) with age. More complex maturational curves were also detected, with regions such as the insula and lingual gyrus exhibiting quadratic trajectories and the superior frontal gyrus and putamen exhibiting cubic trajectories. Sex-related differences in the developmental trajectory of functional homotopy were detected within dorsolateral prefrontal cortex (Brodmann areas 9 and 46) and amygdala. Evidence of robust developmental effects in homotopic RSFC across the lifespan should serve to motivate studies of the physiological mechanisms underlying functional homotopy in neurodegenerative and psychiatric disorders.

The beta subunit of voltage-gated Ca2+ channels interacts with and regulates the activity of a novel isoform of Pax6.

Ca(2+) channel beta subunits (Ca(v)betas) are essential for regulating the surface expression and gating of high voltage-activated Ca(2+) channels through their interaction with Ca(2+) channel alpha(1) subunits. In efforts to uncover new interacting partners and new functions for Ca(v)beta, we identified a new splicing isoform of Pax6, a transcription factor crucial for the development of the eye, nose, brain, and pancreas. Pax6 contains two DNA binding domains (paired domain and homeodomain), a glycine-rich linker connecting these two domains and a C-terminal proline-, serine-, and threonine-rich transactivation domain. The protein sequence and function of Pax6 are highly conserved from invertebrate to human. The newly isolated isoform, named Pax6(S), retains the paired domain, linker, and homeodomain of Pax6, but its C terminus is composed of a truncated classic proline, serine, and threonine domain and a unique S tail. Pax6(S) shows a similar level of transcriptional activity in vitro as does Pax6, but only in primates is the protein sequence highly conserved. Its spatial-temporal expression profiles are also different from those of Pax6. These divergences suggest a noncanonical role of Pax6(S) during development. The interaction between Pax6(S) and Ca(v)beta is mainly endowed by the S tail. Co-expression of Pax6(S) with a Ca(2+) channel complex containing the beta(3) subunit in Xenopus oocytes does not affect channel properties. Conversely, however, beta(3) is able to suppress the transcriptional activity of Pax6(S). Furthermore, in the presence of Pax6(S), beta(3) is translocated from the cytoplasm to the nucleus. These results suggest that full-length Ca(v)beta may act directly as a transcription regulator independent of its role in regulating Ca(2+) channel activity.

Origin of the voltage dependence of G-protein regulation of P/Q-type Ca2+ channels.

G-protein (Gbetagamma)-mediated voltage-dependent inhibition of N- and P/Q-type Ca(2+) channels contributes to presynaptic inhibition and short-term synaptic plasticity. The voltage dependence derives from the dissociation of Gbetagamma from the inhibited channels, but the underlying molecular and biophysical mechanisms remain largely unclear. In this study we investigated the role in this process of Ca(2+) channel beta subunit (Ca(v)beta) and a rigid alpha-helical structure between the alpha-interacting domain (AID), the primary Ca(v)beta docking site on the channel alpha(1) subunit, and the pore-lining IS6 segment. Gbetagamma inhibition of P/Q-type channels was reconstituted in giant inside-out membrane patches from Xenopus oocytes. Large populations of channels devoid of Ca(v)beta were produced by washing out a mutant Ca(v)beta with a reduced affinity for the AID. These beta-less channels were still inhibited by Gbetagamma, but without any voltage dependence, indicating that Ca(v)beta is indispensable for voltage-dependent Gbetagamma inhibition. A truncated Ca(v)beta containing only the AID-binding guanylate kinase (GK) domain could fully confer voltage dependence to Gbetagamma inhibition. Gbetagamma did not alter inactivation properties, and channels recovered from Gbetagamma inhibition exhibited the same activation property as un-inhibited channels, indicating that Gbetagamma does not dislodge Ca(v)beta from the inhibited channel. Furthermore, voltage-dependent Gbetagamma inhibition was abolished when the rigid alpha-helix between the AID and IS6 was disrupted by insertion of multiple glycines, which also eliminated Ca(v)beta regulation of channel gating, revealing a pivotal role of this rigid alpha-helix in both processes. These results suggest that depolarization-triggered movement of IS6, coupled to the subsequent conformational change of the Gbetagamma-binding pocket through a rigid alpha-helix induced partly by the Ca(v)beta GK domain, causes the dissociation of Gbetagamma and is fundamental to voltage-dependent Gbetagamma inhibition.