Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial.

BACKGROUND: New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. METHODS: EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). FINDINGS: From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). INTERPRETATION: In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. FUNDING: Karuna Therapeutics.

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).

Statistical Deconvolution for Inference of Infection Time Series.

Accurate measurement of daily infection incidence is crucial to epidemic response. However, delays in symptom onset, testing, and reporting obscure the dynamics of transmission, necessitating methods to remove the effects of stochastic delays from observed data. Existing estimators can be sensitive to model misspecification and censored observations; many analysts have instead used methods that exhibit strong bias. We develop an estimator with a regularization scheme to cope with stochastic delays, which we term the robust incidence deconvolution estimator. We compare the method to existing estimators in a simulation study, measuring accuracy in a variety of experimental conditions. We then use the method to study COVID-19 records in the United States, highlighting its stability in the face of misspecification and right censoring. To implement the robust incidence deconvolution estimator, we release incidental, a ready-to-use R implementation of our estimator that can aid ongoing efforts to monitor the COVID-19 pandemic.

A comparison of diagnostic algorithms and clinical parameters to diagnose ventilator-associated pneumonia: a prospective observational study.

BACKGROUND: Suspicion and clinical criteria continue to serve as the foundation for ventilator-associated pneumonia (VAP) diagnosis, however the criteria used to diagnose VAP vary widely. Data from head-to-head comparisons of clinical diagnostic algorithms is lacking, thus a prospective observational study was performed to determine the performance characteristics of the Johanson criteria, Clinical Pulmonary Infection Score (CPIS), and Centers for Disease Control and Prevention's National Healthcare Safety Network (CDC/NHSN) criteria as compared to Hospital in Europe Link for Infection Control through Surveillance (HELICS) reference standard. METHODS: A prospective observational cohort study was performed in three mixed medical-surgical ICUs from one academic medical center from 1 October 2016 to 30 April 2018. VAP diagnostic criteria were applied to each patient including CDC/NHSN, CPIS, HELICS and Johanson criteria. Tracheal aspirate cultures (TAC) and serum procalcitonin values were obtained for each patient. RESULTS: Eighty-five patients were enrolled (VAP 45, controls 40). Using HELICS as the reference standard, the sensitivity and specificity for each of the assessed diagnostic algorithms were: CDC/NHSN (Sensitivity 54.2%; Specificity 100%), CPIS (Sensitivity 68.75%; Specificity 95.23%), Johanson (Sensitivity 67.69%; Specificity 95%). The positive TAC rate was 81.2%. The sensitivity for positive TAC with the serum procalcitonin level > 0.5 ng/ml was 51.8%. CONCLUSION: VAP remains a considerable source of morbidity and mortality in modern intensive care units. The optimal diagnostic method remains unclear. Using HELICS criteria as the reference standard, CPIS had the greatest comparative diagnostic accuracy, whereas the sensitivity of the CDC/NHSN was only marginally better than a positive TAC plus serum procalcitonin > 0.5 ng/ml. Algorithm accuracy was improved by adding serum procalcitonin > 0.5 ng/ml, but not positive quantitative TAC. TRIAL REGISTRATION: Not indicated for this study type.

Impact of Religiosity on Delirium Severity Among Critically Ill Shi'a Muslims: A Prospective Multi-Center Observational Study.

This study assesses the impact of religiosity on delirium severity and patient outcomes among Shi'a Muslim intensive care unit (ICU) patients. We conducted a prospective observational cohort study in 21 ICUs from 6 Iranian academic medical centers. Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU) tool. Eligible patients were intubated, receiving mechanical ventilation (MV) for ≥ 48 h. Illness severity was assessed using Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. A total of 4200 patients were enrolled. Patient religiosity was categorized as more (40.6%), moderate (42.3%), or less (17.1%) based on responses to patient and surrogate questionnaires. The findings suggest that lower pre-illness religiosity may be associated with greater delirium severity, MV duration, and ICU and hospital LOS. The lower mortality in the less religiosity group may be related in part to a greater proportion of female patients, but it remains unclear whether and to what extent greater religiosity impacted treatment decisions by patients and families. Further investigation is needed to validate and clarify the mechanism of the mortality findings.

Intravenous Magnesium Sulfate to Treat Acute Headaches in the Emergency Department: A Systematic Review.

INTRODUCTION: Non-traumatic headaches comprise up to 4% of all emergency department (ED) visits. Current practice is moving toward multimodal analgesia regimens that limit narcotic use. OBJECTIVE: The objective of this systematic review is to address the following research question: In patients with non-traumatic headaches (Population), does administration of intravenous magnesium sulfate (Intervention) compared to placebo, corticosteroids, dopamine antagonists, ergot alkaloids, non-steroidal anti-inflammatory drugs (NSAIDs), triptans, or usual care result in better pain control, lower rate of recurrence at 24 hours, lower requirements for rescue analgesia, and less adverse medication effects (Outcomes)? METHODS: Scholarly databases and relevant bibliographies were searched, as were clinical trial registries and relevant conference proceedings to limit publication bias. Studies were not limited by date, language, or publication status. Inclusion criteria were: (1) randomized clinical trial (RCT), (2) patients age ≥18 years, (3) non-traumatic headache, (4) patients treated in ED or an outpatient acute care treatment center, and (5) magnesium sulfate administered intravenously (IV). Eligible comparison groups included: placebo, conventional therapy, dopamine antagonist, NSAID, corticosteroid, ergot alkaloid, or triptans. RESULTS: Out of 4018 identified references, 7 RCTs (545 participants) that treated migraine headaches (n = 6) and benign non-traumatic headaches (n = 1) met inclusion criteria. Pain intensity was improved with magnesium sulfate vs comparators at 60-120 minutes, but not at earlier time points. Result for the endpoint of pain reduction by 50% were conflicting as 3 studies reported that headache was improved, unchanged, and less with magnesium sulfate. Complete pain relief was improved with magnesium sulfate in 1 study, and in the migraine with aura (MA) subgroup in another. The need for rescue analgesia at any point was improved with magnesium sulfate in 1 study, and in the MA subgroup in another. Twenty-four-hour headache recurrence was improved with magnesium sulfate in 1 study, but unchanged in a second. The intended meta-analysis was not performed due to the clinical heterogeneity among studies. CONCLUSION: While we cannot draw a firm conclusion on the efficacy or benefit of intravenous magnesium sulfate in the treatment of acute non-traumatic headaches, the existing evidence indicates potential benefits in pain control beyond 1 hour, aura duration, and need for rescue analgesia.

Effects of Stress on Critical Care Nurses: A National Cross-Sectional Study.

BACKGROUND:: Health care is a demanding field, with a high level of responsibility and exposure to emotional and physical danger. High levels of stress may result in depression, anxiety, burnout syndrome, and in extreme cases, post-traumatic stress disorder. The aim of this study was to determine which personal, professional, and organizational variables are associated with greater perceived stress among critical care nurses for purposes of developing integrative solutions to decrease stress in the future. METHODS:: We conducted a correlation research survey using a cross-sectional design and an in-person survey method. The questionnaire consisted of 2 parts: (1) socioeconomic, professional, and institutional variables and (2) work stressors. Surveys were conducted between January 1, 2011, and December 1, 2015. Multistage cluster random sampling was utilized for data collection. Inclusion criteria were (1) age ≥18 years, (2) registered nurse, (3) works in the intensive care unit (ICU), and (4) willing and able to complete the survey. RESULTS:: We surveyed 21 767 ICU nurses in Iran and found that male sex, lower levels of peer collaboration, working with a supervisor in the unit, nurse-patient ratios, and working in a surgical ICU were positively associated with greater stress levels. Increasing age and married status were negatively associated with stress. Intensive care unit type (semi-closed vs open), ICU bed number, shift time, working on holidays, education level, and demographic factors including body mass index, and number of children were not significantly associated with stress levels. CONCLUSION:: As the largest study of its kind, these findings support those found in various European, North, and South American studies. Efforts to decrease workplace stress of ICU nurses by focusing on facilitating peer collaboration, improving resource availability, and staffing ratios are likely to show the greatest impact on stress levels.

Enterocolitis in a Child With Hirschsprung Disease.

Hirschsprung disease is a congenital abnormality that can be surgically corrected. However, Hirschsprung-associated enterocolitis can be a life-threatening sequela. Very little has been published in the emergency medicine literature about the risk of enterocolitis and shock in patients with a history of Hirschsprung disease. We describe the case of a 6-month-old male infant with a history of multiple surgeries for Hirschsprung disease who presented to the emergency department with a seemingly benign viral gastrointestinal illness. His stable condition led him to be discharged. However, 4 days later, he returned to the emergency department with severe diarrhea and was subsequently admitted to the pediatric intensive care unit for the management of enterocolitis and shock. With this case report, we aim to raise emergency physicians' awareness of the serious and possibly fatal complications of Hirschsprung disease. We argue that this single element of a patient's medical history can alter the management of seemingly simple viral gastrointestinal illnesses; rather than be discharged, such a patient requires surgical consultation and possibly admission for close monitoring and treatment.

High-Frequency Ventilation Modalities as Salvage Therapy for Smoke Inhalation-Associated Acute Lung Injury: A Systematic Review.

BACKGROUND: Smoke inhalation-associated acute lung injury (SI-ALI) is a major cause of morbidity and mortality in victims of fire tragedies. To date, there are no evidence-based guidelines on ventilation strategies in acute respiratory distress syndrome (ARDS) after smoke inhalation. We reviewed the existing literature for clinical studies of salvage mechanical ventilation (MV) strategies in patients with SI-ALI, focusing on mortality and pneumonia as outcomes. METHODS: A systematic search was designed in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Risk of bias assessment was performed using the Newcastle-Ottawa Quality Assessment Scale (NOS; 0 to 9 stars), with a score ≥7 being the threshold for inclusion in the meta-analysis. A systematic search strategy was used to search 10 databases. Clinical studies were included in which patients: (1) experienced smoke inhalation, (2) treated with MV, and (3) described a concurrent or historical control group. RESULTS: A total of 226 potentially relevant studies were identified, of which 7 studies on high-frequency percussive ventilation (HFPV) met inclusion criteria. No studies met inclusion for meta-analysis (NOS ≥ 7). In studies comparing HFPV to conventional mechanical ventilation (CMV), mortality and pneumonia incidence improved in 3 studies and remained unchanged in 3 others. No change in ventilator days or ICU length of stay was observed; however, oxygenation and work of breathing improved with HFPV. CONCLUSIONS: Mechanical ventilation in patients with SI-ALI has not been well studied. High-frequency percussive ventilation may decrease in-hospital mortality and pneumonia incidence when compared to CMV. The absence of "good" quality evidence precluded meta-analysis. Based upon low-quality evidence, there was a very weak recommendation that HFPV use may be associated with lower mortality and pneumonia rates in patients with SI-ALI. Given SI-ALI's unique underlying pathophysiology, and its potential implications on therapy, randomized controlled studies are required to ensure that patients receive the safest and most effective care. TRIAL REGISTRATION: The study was registered with PROSPERO International prospective register of systematic reviews (#47015).

Spiritual Health and Outcomes in Muslim ICU Patients: A Nationwide Cross-Sectional Study.

The aim of the present study is to describe how religiosity and spirituality affect the psychiatric morbidity of Muslim intensive care unit (ICU) patients. We conducted a prospective nationwide cross-sectional study of ICU patients discharged from 45 medical centers spanning 31 proivinces in Iran. Adults (age ≥ 18 years) admitted to the ICU and treated with invasive mechanical ventilation were eligible. Nine validated survey tools were administered to detect direct and indirect associations between spiritual health (SH) and depression, anxiety, and post-traumatic disorder. The Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale-Revised (IES-R), Post-Traumatic Stress Syndrome 14 question (PTSS-14) quality-of-life (QoL), and quality of patient to physician or nurse communication (PP-QoC and PN-QoC) scales were modeled through two mediators by structural equation modeling (SEM). Sex, ICU type, LOS, and APACHE II score were added in the independent variable list. 338 eligible patients were discharged from the ICUs during the study period. 56 were excluded (clinical status), and 282 were administered the survey. 278 returned it, with 272 complete and 6 partial responses. SH displayed no direct or indirect association to QoL. SH was indirectly associated with decreased depression and anxiety (B = - 0.081, p < 0.05) via PP-QoC mediator. Both direct and indirect positive associations were observed between SH and IES-R (B = 0.293, p < 0.05; via PP-QoC) and PTSS-14 scores (B = 0.267, p < 0.001; via PP-QoC). Medical ICU location was associated with decreased PTSS-14 scores via the same mediator. In this survey of Muslim ICU patients treated with invasive mechanical ventilation, SH correlated with decreased depression and anxiety, but paradoxically increased post-traumatic stress. The most influential mediator was patient-physician quality-of-communication.

Impact of the Affordable Care Act Medicaid expansion on emergency department high utilizers with ambulatory care sensitive conditions: A cross-sectional study.

OBJECTIVES: The effect of the Affordable Care Act on emergency department (ED) high utilizers has not yet been thoroughly studied. We sought to determine the impact of changes in insurance eligibility following the 2014 Medicaid expansion on ED utilization for ambulatory care sensitive conditions (ACSC) by high ED utilizers in an urban safety net hospital. METHODS: High utilizers were defined as patients with ≥4 visits in the 6months before their most recent visit in the study period (July-December before and after Maryland's Medicaid expansion in January 2014). A differences-in-differences approach using logistic regression was used to investigate if differences between high and low utilizer cohorts changed from before and after the expansion. RESULTS: During the study period, 726 (4.1%) out of 17,795 unique patients in 2013 and 380 (2.4%) of 16,458 during the same period in 2014 were high utilizers (p-value <0.001). ACSC-associated visit predicted being a high utilizer in 2013 (OR 1.66 (95% CI [1.37, 2.01])) and 2014 (OR 1.65 (95% CI [1.27, 2.15])) but this was not different between years (OR ratio 0.99, 95% CI [0.72, 1.38], p-value 0.97). CONCLUSION: Although the proportion of high utilizers decreased significantly after Maryland's Medicaid expansion, ACSC-associated ED visits by high ED utilizers were unaffected.

Effect of the Cardio First Angel™ device on CPR indices: a randomized controlled clinical trial.

BACKGROUND: A number of cardiopulmonary resuscitation (CPR) adjunct devices have been developed to improve the consistency and quality of manual chest compressions. We investigated whether a CPR feedback device would improve CPR quality and consistency, as well as patient survival. METHODS: We conducted a randomized controlled study of patients undergoing CPR for cardiac arrest in the mixed medical-surgical intensive care units of four academic teaching hospitals. Patients were randomized to receive either standard manual CPR or CPR using the Cardio First Angel™ CPR feedback device. Recorded variables included guideline adherence, CPR quality, return of spontaneous circulation (ROSC) rates, and CPR-associated morbidity. RESULTS: A total of 229 subjects were randomized; 149 were excluded; and 80 were included. Patient demographics were similar. Adherence to published CPR guidelines and CPR quality was significantly improved in the intervention group (p < 0.0001), as were ROSC rates (72 % vs. 35 %; p = 0.001). A significant decrease was observed in rib fractures (57 % vs. 85 %; p = 0.02), but not sternum fractures (5 % vs. 17 %; p = 0.15). CONCLUSIONS: Use of the Cardio First Angel™ CPR feedback device improved adherence to published CPR guidelines and CPR quality, and it was associated with increased rates of ROSC. A decrease in rib but not sternum fractures was observed with device use. Further independent prospective validation is warranted to determine if these results are reproducible in other acute care settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02394977 . Registered on 5 Mar 2015.

Opinions on the Legitimacy of Brain Death Among Sunni and Shi'a Scholars.

The concept of brain death poses a great challenge to clinicians who may be required to bridge the interface of culture, religion, law, and medicine. This review discusses and applies Islamic jurisprudence to the question of whether brain death is accepted as true death under Islamic law. Among the five sources of Islamic law, the Qur'an and Sunnah do not directly address brain death. Scholarly consensus (Ijma') does not exist, and Qiya does not apply. When applying Ijtihad, the identified collection of non-binding fatwa offer conflicting results. Debate continues as to the validity of brain-death criteria within Islamic circles.

Inhaled anticoagulation regimens for the treatment of smoke inhalation-associated acute lung injury: a systematic review.

OBJECTIVE: Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival. DATA SOURCES: PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Relevant unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, MINDCULL.com, Current Controlled Trials, and Google. STUDY SELECTION: Inclusion criteria were any preclinical or clinical study in which 1) animals or subjects experienced smoke inhalation exposure, 2) they were treated with nebulized or aerosolized anticoagulation regimens, including heparin, heparinoids, antithrombins, or fibrinolytics (e.g., tissue plasminogen activator), 3) a control and/or sham group was described for preclinical studies, and 4) a concurrent or historical control group described for clinical studies. Exclusion criteria were 1) the absence of a group treated with a nebulized or aerosolized anticoagulation regimen, 2) the absence of a control or sham group, and 3) case reports. DATA EXTRACTION: Ninety-nine potentially relevant references were identified. Twenty-seven references met inclusion criteria including 19 preclinical references reporting 18 studies and eight clinical references reporting five clinical studies. DATA SYNTHESIS: A systematic review of the literature is provided. Both clinical and methodological diversity precluded combining these studies in a meta-analysis. CONCLUSIONS: The high mortality associated with smoke inhalation-associated acute lung injury results from airway damage, mucosal dysfunction, neutrophil infiltration, airway coagulopathy with cast formation, ventilation-perfusion mismatching with shunt, and barotrauma. Inhaled anticoagulation regimens in both preclinical and clinical studies improve survival and decrease morbidity without altering systemic markers of clotting and anticoagulation. In some preclinical and clinical studies, inhaled anticoagulants were associated with a favorable effect on survival. This approach appears sufficiently promising to merit a well-designed prospective study to validate its use in patients with severe smoke inhalation-associated acute lung injury requiring mechanical ventilation.

Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials.

BACKGROUND: Currently approved antipsychotics do not adequately treat negative symptoms (NS), which are a major determinant of functional disability in schizophrenia. KarXT, an M1 /M4 preferring muscarinic receptor agonist, has shown efficacy as a broad-spectrum monotherapy for the treatment of schizophrenia in participants with acute psychosis. Post hoc analyses evaluated the possibility that NS improve independently of positive symptoms with KarXT in a subgroup of participants with moderate-to-severe NS and no predominance of positive symptoms. METHODS: Data were pooled from the three pivotal trials of KarXT monotherapy in people with schizophrenia with an acute exacerbation of psychosis. All 3 studies used similar 5-week randomized, double-blind, placebo-controlled designs (modified intention-to-treat sample N = 640). PANSS criteria proposed in the literature identified a subset of study participants (n = 64) with prominent NS. RESULTS: KarXT was significantly better than placebo on PANSS Marder Negative Factor Scores in the full sample (p < .001; Cohen's d = 0.42) and more so in the prominent NS subgroup (p < .001; Cohen's d = 1.18). Further, the KarXT effect in the NS subgroup remained significant after accounting for changes in positive symptoms, depression/anxiety, disorganization, and hostility. CONCLUSIONS: Participants with prominent NS revealed greater improvement of NS following KarXT therapy than the full sample that persisted after accounting for positive and other symptoms. While these findings must be interpreted with caution, they are consistent with the possibility that NS improvements associated with KarXT are not secondary to improvements in other symptom domains and support further investigation in larger, stable outpatient studies.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial.

Importance: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. Objective: To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. Design, Setting, and Participants: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Interventions: Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. Main Outcomes and Measures: The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. Results: A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Conclusions and Relevance: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. Trial Registration: ClinicalTrials.gov Identifier: NCT04738123.