Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD.

MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid ß-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.

Generalized Periodic Discharges Associated With Catatonia and Delirium: A Case Series.

OBJECTIVE: Generalized periodic discharges are a repeated and generalized electroencephalography (EEG) pattern that can be seen in the context of altered mental status. This article describes a series of five individuals with generalized periodic discharges who demonstrated signs and symptoms of catatonia, a treatable neuropsychiatric condition. METHODS: Inpatients with a clinical diagnosis of catatonia, determined with the Bush-Francis Catatonia Rating Scale (BFCRS), and EEG recordings with generalized periodic discharges were analyzed in a retrospective case series. RESULTS: Five patients with catatonia and generalized periodic discharges on EEG were evaluated from among 106 patients with catatonia and contemporaneous EEG measurements. Four of these patients showed an improvement in catatonia severity when treated with benzodiazepines, with an average reduction of 6.75 points on the BFCRS. CONCLUSIONS: Among patients with generalized periodic discharges, catatonia should be considered, in the appropriate clinical context. Patients with generalized periodic discharges and catatonia may benefit from treatment with empiric trials of benzodiazepines.

Use of ECT for Children With and Without Catatonia: A Single-Site Retrospective Analysis.

OBJECTIVES: The objective study was to investigate the safety and efficacy of electroconvulsive therapy (ECT) in a retrospective cohort of pediatric patients. METHODS: A single-site retrospective analysis was conducted of patients aged younger than 18 years who received ECT in a private university hospital from January 28, 2012 to April 8, 2023. Treatment efficacy and adverse events were determined retrospectively through review of the medical record. RESULTS: A total of 36 pediatric patients met the inclusion criteria. Catatonia was the most common presenting indication for ECT, followed by psychosis and suicidal ideation. For all patients, Clinical Global Impressions-Improvement scale scores indicated that it was very likely for a subject to experience at least "much improvement" with the estimated probability of receiving a Clinical Global Impressions-Improvement scale score better than 3 of 0.852 (t.s. = 16.3; P < 0.001; 95% confidence interval, 0.711-0.931). All patients with catatonia demonstrated a positive clinical response and experienced a statistically significant reduction in total Bush-Francis Catatonia Rating Scale scores observed (t = 11.9; df = 20; SD = 6.3; P < 0.001; 95% confidence interval, 12.6-17.9). No significant adverse events were reported for any patient in the cohort. However, 14 (38.9%) patients experienced prolonged seizures, all of which were terminated with propofol (mean, 49.7 mg). CONCLUSIONS: This study provides further data supporting the safe and effective use of pediatric ECT in the treatment of various psychiatric conditions. However, more research is needed to determine the risk factors associated with prolonged seizures and the optimal seizure parameters in young people.

Coding for Physical Restraint Status Among Hospitalized Patients: a 2019 National Inpatient Sample Analysis.

BACKGROUND: The reduction of physical restraint utilization in the hospital setting is a key goal of high-quality care, but little is known about the rate of restraint use in general hospitals in the USA. OBJECTIVE: This study reports the rate of physical restraint coding among acute care hospital discharges in the USA and explores associated demographic and diagnostic factors. DESIGN: The National Inpatient Sample, a de-identified all-payors database of acute care hospital discharges in the USA, was queried for patients aged 18 and older with a diagnosis code for physical restraint status in 2019. PARTICIPANTS: Hospitalized patients aged 18 and older. MAIN MEASURES: Demographics, discharge diagnoses, in-hospital mortality, length of stay, total hospital charges. KEY RESULTS: In total, 220,470 (95% CI: 208,114 to 232,826) hospitalizations, or 0.7% of overall hospitalizations, included a discharge code for physical restraint status. There was a 700-fold difference in coding for restraint utilization based on diagnosis, with 7.4% of patients with encephalitis receiving restraint diagnosis codes compared to < 0.01% of patients with uncomplicated diabetes. In an adjusted model, male sex was associated with an odds ratio of 1.4 (95% CI: 1.4 to 1.5) for restraint utilization coding, and Black race was associated with an odds ratio of 1.3 (95% CI: 1.2 to 1.4) relative to white race. CONCLUSIONS: In the general hospital setting, there is variability in physical restraint coding by sex, race, and clinical diagnosis. More research is needed into the appropriate utilization of restraints in the hospital setting and possible inequities in restraint utilization.

The occurrence of delirium diagnosis among youth hospitalizations in the United States: A Kids' Inpatient Database analysis.

OBJECTIVES: Delirium is an acute neuropsychiatric condition associated with increased morbidity and mortality. There is increasing recognition of delirium as a substantial health burden in younger patients, although few studies have characterized its occurrence. This study analyzes the occurrence of delirium diagnosis, its comorbidities, and cost among youth hospitalized in the United States. METHODS: The Kids' Inpatient Database, a national all-payers sample of pediatric hospitalizations in general hospitals, was examined for the year 2019. Hospitalizations with a discharge diagnosis of delirium among patients aged 1-20 years were included in the analysis. RESULTS: Delirium was diagnosed in 43,138 hospitalizations (95% CI: 41,170-45,106), or 2.3% of studied hospitalizations. Delirium was diagnosed in a broad range of illnesses, with suicide and self-inflicted injury as the most common primary discharge diagnosis among patients with delirium. In-hospital mortality was seven times greater in hospitalizations caring a delirium diagnosis. The diagnosis of delirium was associated with an adjusted increased hospital cost of $8648 per hospitalization, or $373 million in aggregate cost. CONCLUSIONS: Based on a large national claims database, delirium was diagnosed in youth at a lower rate than expected based on prospective studies. The relative absence of delirium diagnosis in claims data may reflect underdiagnosis, a failure to code, and/or a lower rate of delirium in general hospitals compared with other settings. Further research is needed to better characterize the incidence and prevalence of delirium in young people in the hospital setting.

Factors associated with early and late response to electroconvulsive therapy.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment for severe depressive symptoms, yet more research is needed to examine predictors of treatment response, and factors associated with response in patients not initially improving with treatment. This study reports factors associated with time to response (early vs. late) to ECT in a real-world setting. METHODS: This was a retrospective, single-center cohort study of patients endorsing moderate to severe depressive symptoms using the Quick Inventory of Depressive Symptomatology (QIDS; QIDS>10). Response was defined as 50% or greater decrease in QIDS score from baseline. We used logistic regression to predict response at treatment #5 (early response) as well as after treatment #5 (late response) and followed patients through ECT discontinuation or through treatment #20. RESULTS: Of the 1699 patients included in this study, 555 patients (32.7%) responded to ECT treatment at treatment #5 and 397 (23.4%) responded after treatment #5. Among patients who did not respond by treatment #5, those who switched to brief pulse width ECT from ultrabrief pulse ECT had increased odds of response after treatment #5 compared with patients only receiving ultrabrief pulse (aOR = 1.55, 95% CI: 1.16-2.07). Additionally, patients with less improvement in QIDS from baseline to treatment #5 had decreased odds of response after treatment #5 (aOR = 0.97, 95% CI = 0.97-0.98). CONCLUSION: Among depressed patients treated with ECT, response occurred in 56.0% of patients by treatment #20. Patient receiving ultrabrief pulse ECT at baseline and who did not respond by treatment #5 had greater odds of subsequent response if switched to brief pulse ECT than if continued with ultrabrief pulse.

Changes in self-reported suicidal ideation during treatment with electroconvulsive therapy: A retrospective cohort study.

OBJECTIVE: Suicidal ideation (SI) is common in patients with depressive symptoms, who are the most common recipients of electroconvulsive therapy (ECT). We sought to quantify changes in self-reported SI occurring during treatment with ECT, and to identify factors associated with persistence of SI in patients beginning treatment with SI. METHOD: Retrospective, single-center cohort study of patients receiving ECT and who self-reported symptoms using Quick Inventory of Depressive Symptomatology (QIDS) prior to ECT and after treatment #5 or #10. Changes in QIDS-reported SI over the course of ECT were calculated, and logistic regression models were performed to assess factors associated with reporting SI at the end of treatment. RESULTS: 2554 provided baseline and follow-up SI scores, of whom, 1931 (75.6%) endorsed SI at baseline. There was a reduction in SI with ECT treatment (McNemar's test; df = 1, Χ2 = 803.7; p < 0.001), and in adjusted models 64.0% of individuals with baseline SI reported resolution of SI with ECT treatment, while 3.3% without baseline SI reported SI at the end of treatment. Higher baseline SI severity and outpatient treatment were associated with a higher odds of persistent SI among individuals beginning treatment with SI. CONCLUSION: Electroconvulsive therapy treatment was associated with reductions in self-reported SI. These results support the use of ECT in the treatment of patients with SI, but further research is needed to determine the effects of ECT on suicidal behavior.

Changes in Inpatient Electroconvulsive Therapy Utilization Between 2019 and 2020: A National Inpatient Sample Analysis.

OBJECTIVES: Electroconvulsive therapy (ECT) is an essential procedure for a range of psychiatric conditions. Multiple single-center studies have documented reduction in ECT administration in 2020 because of the coronavirus disease 2019 pandemic, but there have been little nationally representative data from the United States. The aim of this study was to examine the demographics of patients receiving ECT in 2019 and 2020 and to characterize temporal and regional variations in ECT utilization. METHODS: The 2019 and 2020 National Inpatient Sample, an administrative database of inpatient hospitalizations in the United States, was queried for hospitalizations involving the delivery of ECT based on procedural codes. Overall number of ECT procedures was calculated based on the overall number of ECT procedural claims. RESULTS: In the 2019 NIS, 14,230 inpatient hospitalizations (95% confidence interval, 12,936-15,524) involved the use of ECT, with a cumulative 52,450 inpatient ECT procedures administered. In 2020, the number of inpatient hospitalizations with ECT decreased to 12,055 (95% confidence interval, 10,878-13,232), with a 10.0% reduction in overall procedures to 47,180. Whereas January and February ECT hospitalizations were comparable in both years, ECT hospitalizations decreased by more than 25% in March through May 2020 relative to 2019 volume. There was regional variability in the change in ECT utilization between 2019 and 2020. CONCLUSIONS: Electroconvulsive therapy use among general hospital inpatients declined between 2019 and 2020, with regional variability in the magnitude of change. Further study is warranted into the root causes and optimal responses to these changes.

Demographics and medical comorbidities among hospitalized patients with Prader-Willi Syndrome: A National Inpatient Sample analysis.

Prader-Willi Syndrome (PWS) is a multi-system genetic disorder characterized by hyperphagia and a range of medical complications. While register and cohort studies have explored the natural course of the syndrome, there is little nationally-representative data. In this study the National Inpatient Sample, a de-identified all-payors database of acute care hospital discharges in the United States, was queried for patients discharged with a diagnosis of PWS in 2019. Hospitalizations involving PWS were compared to hospitalizations without a PWS diagnosis matched based on demographic and hospital factors. In total, 540 hospitalizations (95% CI: 513-567) included a diagnosis of PWS. Median age at time of admission was 22 years, with an interquartile range of 6.3-37.8 years. Respiratory conditions accounted for 110 (20.4%) of primary discharge diagnoses, with infectious conditions for 70 (13.0%) and digestive conditions for 65 (12.0%). Hospitalizations involving PWS were significantly more likely to involve respiratory failure (OR 5.49; 95% CI 3.86-7.80), septicemia (OR 2.80, 95% CI 1.97-3.96), or intestinal obstruction and ileus (OR 6.29; 95% CI 3.70-10.7) compared to matched hospitalizations without PWS. Obesity was diagnosed in 230 PWS hospitalizations (42.6%; OR 3.86, 95% CI 3.17-4.72 relative to non-PWS hospitalizations). These results point to an ongoing need for the improved diagnosis and treatment of PWS complications, and highlight the importance of specific billing codes for rare diseases to enhance the collection of real world evidence.

The Effects of Baseline Impaired Global Cognitive Function on the Efficacy and Cognitive Effects of Electroconvulsive Therapy in Geriatric Patients: A Retrospective Cohort Study.

OBJECTIVES: This study explores the association between baseline impaired global cognitive function and changes in global cognitive function and depression among geriatric patients undergoing acute course electroconvulsive therapy (ECT). DESIGN: Retrospective cohort study. SETTING: Single freestanding psychiatric hospital. PARTICIPANTS: Patients aged 50 and older receiving ECT. INTERVENTIONS: 10 ECT treatments. MEASUREMENTS: Cognitive assessments with the Montreal Cognitive Assessment (MoCA). Depression assessment with the Quick Inventory of Depressive Symptomatology Self Report 16 item scale (QIDS). RESULTS: Baseline and follow-up data were available for 684 patients. On average, patients with baseline normal cognition (MoCA ≥26; N = 371) had a decrease in MoCA of -1.44±0.26 points over the course of treatment, while those with baseline impaired global cognitive function (MoCA <26; N = 313) had an increase in MoCA of 1.72±0.25 points. Baseline cognitive status was not associated with a differential response on the QIDS. CONCLUSIONS: Patients with baseline impaired global cognitive function did not demonstrate a worsening in cognition following ECT, and baseline global cognitive function was not associated with a differential change in depression with ECT. These results suggest that impaired global cognitive function should not be viewed as a contraindication to ECT in geriatric patients.

Real-world evidence of age-independent electroconvulsive therapy efficacy: A retrospective cohort study.

OBJECTIVES: Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders and approved for use in adolescents and adults, but it is unclear whether efficacy or cognitive side effect burden differs with age or if effectiveness in usual clinical practice matches that in prospective studies. We examined the effects of ECT on depression and cognition in a large clinical cohort. METHODS: A retrospective cohort study of patients ages 16 and older receiving ECT between 2011 and 2020 and who were evaluated with the Quick Inventory of Depressive Symptomatology (QIDS), the Behavior and Symptom Identification Scale-24 (BASIS-24), and the Montreal Cognitive Assessment (MoCA) at baseline and after treatment #10. RESULTS: Among 1698 patients, ECT was associated with a decrease in depression symptoms (QIDS reduction from 17.1 ± 4.9 to 10.1 ± 5.2) and improvement in self-reported mental health (BASIS-24 scores improved from 1.92 ± 0.55 to 1.17 ± 0.60). There was a reduction in MoCA scores from 25.8 ± 3.1 to 25.4 ± 3.1. In multivariate models, age was not associated with a differential QIDS or BASIS-24 response, but older age was associated with a lesser reduction in MoCA. CONCLUSION: Among 1698 patients aged 16 and older, ECT was associated with improvement in depression and overall self-reported mental health, with a slight decrease in cognition. Age was not associated with changes in efficacy, but older age was associated with a lesser cognitive change as measured by the MoCA. These results provide normative data of real-world effectiveness of ECT, and add further support to its utility in patients with severe psychiatric illness.

The Duration in Treatment With Electroconvulsive Therapy Among Patients Screening Positive or Negative for Borderline Personality Disorder Traits: A Retrospective Cohort Study.

OBJECTIVE: While emerging evidence suggests that electroconvulsive therapy (ECT) is an effective treatment for depressive symptoms in patients with co-occurring borderline personality disorder (BPD) traits, it is unclear whether the presence of BPD traits modulates the tolerability of ECT. This study estimates the association between BPD traits and retention in acute course ECT treatment. METHODS: This study used a retrospective cohort of patients receiving ECT between 2015 and 2020 and who were assessed using the McLean Screening Instrument for BPD, the Quick Inventory of Depressive Symptomatology Self-Report 16-item scale, and the Montreal Cognitive Assessment before initiating treatment. RESULTS: One thousand five hundred eight patients received ECT during the study period, of whom 277 (18.4%) screened positive for BPD traits. Borderline personality disorder traits were associated with a higher odds of remaining in ECT for at least 10 treatments (adjusted odds ratio, 1.502; 95% confidence interval, 1.11-2.02; P = 0.007). Among individual symptom domains, only endorsing chronically feeling empty was associated with duration in ECT treatment. CONCLUSIONS: Among patients receiving ECT, screening positive for BPD traits was associated with a higher odds of receiving at least 10 ECT treatments. These results support the overall tolerability of ECT in patients with BPD traits.

Rate of continuing acute course treatment using right unilateral ultrabrief pulse electroconvulsive therapy at a large academic medical center.

Right unilateral ultrabrief pulse (RUL-UBP) ECT has emerged as a promising technique for minimizing cognitive side effects of ECT while retaining clinical efficacy, but it is unknown how often patients will require alternative treatment parameters and at what point in the treatment course this occurs. To better define this problem, this study analyzes continuation in RUL-UBP ECT in a retrospective cohort of patients beginning acute course treatment. A single-center retrospective chart review was conducted of adult patients receiving a first lifetime course of ECT from 2010 to 2017 starting with RUL-UBP treatment parameters. 1793 patients met study criteria. Patients received a mean of 10.0 ± 3.2 ECT treatments, of which a mean of 8.4 ± 3.4 were RUL-UBP treatments; proportion using RUL-UBP through 12 treatments was 57.8%. In total, 65.6% of patients were treated with RUL-UPB ECT exclusively. Mean dose increased from 7.6 × seizure threshold at the second RUL-UBP treatment to 14.3 × seizure threshold at the twelfth RUL-UBP treatment. Rates of continuation in RUL-UBP ECT did not differ based on age or on primary diagnosis of major depression vs. bipolar disorder. Among patients beginning acute-course treatment using RUL-UPB ECT, two thirds were treated with these parameters exclusively. Among patients who received twelve RUL-UBP treatments, mean final dose was 14.3 × seizure threshold. Further studies regarding optimal dosing of RUL-UBP ECT are indicated.

Total Charge Required to Induce a Seizure in a Retrospective Cohort of Patients Undergoing Dose Titration of Right Unilateral Ultrabrief Pulse Electroconvulsive Therapy.

OBJECTIVES: The use of ultrabrief pulse (UBP) stimuli and individual seizure threshold determination have been proposed as ways of minimizing the cognitive side effects of electroconvulsive therapy (ECT), but large samples of patients receiving UBP ECT are lacking. This study reports a retrospective cohort of patients receiving an index course of right unilateral UBP ECT and characterizes the amount of charge required to induce a seizure. METHODS: A single-center retrospective chart review was conducted of adult patients receiving a first lifetime course of ECT using an UBP titration from 2005 to 2017. RESULTS: There were 2328 patients that received a dose titration during the study period, with a mean dose of 21.82 ± 21.61 mC applied to induce a seizure. During the early part of the study period, a mean dose of 18.73 ± 8.99 mC was used, with 28% of patients seizing at a dose of less than 19.2 mC. In the later period, the initial step of dose titration was standardized at 19.2 mC, yielding a mean initial dose to induce a seizure of 22.72 ± 24.00 mC. CONCLUSIONS: Mean seizure thresholds may be lower than reported in previous studies, and a significant proportion of patients may have a seizure threshold lower than the first step of many existing dose titration protocols.

Duration of Treatment in Electroconvulsive Therapy Among Patients Beginning With Acute Course Right Unilateral Brief Pulse Stimuli.

OBJECTIVES: Right unilateral brief pulse (RUL-BP) electroconvulsive therapy (ECT) has been adopted as a technique for reducing the cognitive side effects of ECT relative to sine wave or bilateral treatments, but it is unknown how often patients are transitioned to alternative electrode placements. This study analyzes time in first lifetime acute course RUL-BP ECT. METHODS: A single-center retrospective chart review was conducted of adult patients receiving a first lifetime course of ECT from 2000 to 2017 beginning with individualized seizure threshold determination using RUL-BP treatment parameters. RESULTS: A total of 1383 patients met study criteria and received a mean number of 9.4 ± 3.1 treatments, of which 7.6 ± 3.3 were using RUL-BP stimuli. Only 37.5% of patients were transitioned from RUL to bilateral treatments. Younger patients and those diagnosed with bipolar disorder were more likely to transition from RUL-BP to bilateral treatments, but the overall number of treatments did not differ based on age or primary diagnosis. CONCLUSIONS: Among patients who begin treatment with RUL-BP ECT, more than 60% use exclusively those parameters throughout their acute course.

Modified Anesthesia Protocol for Electroconvulsive Therapy Permits Reduction in Aerosol-Generating Bag-Mask Ventilation during the COVID-19 Pandemic.

INTRODUCTION: Electroconvulsive therapy (ECT) is a critical procedure in psychiatric treatment, but as typically delivered involves the use of bag-mask ventilation (BMV), which during the COVID-19 pandemic exposes patients and treatment staff to potentially infectious aerosols. OBJECTIVE: To demonstrate the utility of a modified anesthesia protocol for ECT utilizing preoxygenation by facemask and withholding the use of BMV for only those patients who desaturate during the apneic period. METHODS: This chart review study analyzes patients who were treated with ECT using both the traditional and modified anesthesia protocols. RESULTS: A total of 106 patients were analyzed, of whom 51 (48.1%) required BMV using the new protocol. Of clinical factors, only patient BMI was significantly associated with the requirement for BMV. Mean seizure duration reduced from 52.0 ± 22.4 to 46.6 ± 17.1 s, but seizure duration was adequate in all cases. No acute physical, respiratory, or psychiatric complications occurred during treatment. CONCLUSIONS: A modified anesthesia protocol reduces the use of BMV by more than 50%, while retaining adequate seizure duration.

Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the biggest health threats of our generation. A significant portion of patients are presenting with delirium and neuropsychiatric sequelae of the disease. Unique examination findings and responses to treatment have been identified. OBJECTIVE: In this article, we seek to provide pharmacologic and treatment recommendations specific to delirium in patients with COVID-19. METHODS: We performed a literature search reviewing the neuropsychiatric complications and treatments in prior coronavirus epidemics including Middle Eastern respiratory syndrome and severe acute respiratory syndrome coronaviruses, as well as the emerging literature regarding COVID-19. We also convened a work group of consultation-liaison psychiatrists actively managing patients with COVID-19 in our hospital. Finally, we synthesized these findings to provide preliminary pharmacologic recommendations for treating delirium in these patients. RESULTS: Delirium is frequently found in patients who test positive for COVID-19, even in the absence of respiratory symptoms. There appears to be a higher rate of agitation, myoclonus, abulia, and alogia. No data are currently available on the treatment of delirium in patients with COVID-19. Extrapolating from general delirium treatment, Middle Eastern respiratory syndrome/severe acute respiratory syndrome case reports, and our experience, preliminary recommendations for pharmacologic management have been assembled. CONCLUSIONS: COVID-19 is associated with neuropsychiatric symptoms. Low-potency neuroleptics and alpha-2 adrenergic agents may be especially useful in this setting. Further research into the pathophysiology of COVID-19 will be key in developing more targeted treatment guidelines.

Demographics of Patients Receiving Electroconvulsive Therapy Based on State-Mandated Reporting Data.

OBJECTIVES: Electroconvulsive therapy (ECT) is an effective treatment of depression and other psychiatric conditions. There are few comprehensive data on how many patients receive ECT in the United States or about the demographics of ECT recipients. This study characterizes the demographics of those receiving ECT and how these demographics may have changed with time. METHODS: Freedom of information requests for all data from record keeping inception to January 2019 were sent to the Department of Health or equivalent agency of states that mandate reporting of ECT. Information on demographics and the number of treating facilities was extracted. RESULTS: Data on 62,602 patients receiving treatment in 3 states (California, Illinois, Vermont) were obtained. Overall, 62.3% were women. Fewer than 1% of patients treated were younger than 18 years, whereas 30.3% were 65 years or older. White patients received a disproportionate proportion of treatments, with all other races underrepresented. The total number of facilities offering ECT in the 3 states declined over the study period. CONCLUSIONS: Recipients of ECT are more likely to be female, more likely to be elderly, and more likely to be white than the average person in their state.

Allosteric sensitization of proapoptotic BAX.

BCL-2-associated X protein (BAX) is a critical apoptotic regulator that can be transformed from a cytosolic monomer into a lethal mitochondrial oligomer, yet drug strategies to modulate it are underdeveloped due to longstanding difficulties in conducting screens on this aggregation-prone protein. Here, we overcame prior challenges and performed an NMR-based fragment screen of full-length human BAX. We identified a compound that sensitizes BAX activation by binding to a pocket formed by the junction of the α3-α4 and α5-α6 hairpins. Biochemical and structural analyses revealed that the molecule sensitizes BAX by allosterically mobilizing the α1-α2 loop and BAX BH3 helix, two motifs implicated in the activation and oligomerization of BAX, respectively. By engaging a region of core hydrophobic interactions that otherwise preserve the BAX inactive state, the identified compound reveals fundamental mechanisms for conformational regulation of BAX and provides a new opportunity to reduce the apoptotic threshold for potential therapeutic benefit.

Hydrogen-Bond-Dependent Conformational Switching: A Computational Challenge from Experimental Thermochemistry.

We have compiled an experimental data set (SWITCH10) of equilibrium constants for a series of hydrogen-bond-dependent conformational switches. These organic molecules possess common functionalities and are representative in terms of size and composition of systems routinely studied computationally. They exist as two well-defined conformations which serve as a useful tool to benchmark computational estimates of experimental Gibbs energy differences. We examine the performance of HF theory and a variety of density functionals (B3LYP, B3LYP-D3, CAM-B3LYP, ωB97X-D, M06-2X) against these experimental benchmarks. Surprisingly, despite a strong similarity between the two switch conformations, the average errors (0.4-1.7 kcal·mol-1) obtained across the data set for all methods are larger than obtained with HF calculations. B3LYP was found to outperform implicitly and explicitly dispersion-corrected functionals, with an average error smaller by 1 kcal·mol-1. Unsystematic errors in the optimized structures were found to contribute to the relatively poor performance obtained, while quasi-rigid rotor harmonic oscillator thermal contributions are important in improving the accuracy of computed Gibbs energy differences. These results emphasize the challenge of quantitative accuracy in computing solution-phase thermochemistry for flexible systems and caution against the often used (but unstated) assumption of favorable error cancellation in comparing conformers or stereoisomers.