Longitudinal myelin content measures of slowly expanding lesions using 7T MRI in multiple sclerosis.

BACKGROUND AND PURPOSE: Slowly expanding lesions (SELs) are thought to represent a subset of chronic active lesions and have been associated with clinical disability, severity, and disease progression. The purpose of this study was to characterize SELs using advanced magnetic resonance imaging (MRI) measures related to myelin and neurite density on 7 Tesla (T) MRI. METHODS: The study design was retrospective, longitudinal, observational cohort with multiple sclerosis (n = 15). Magnetom 7T scanner was used to acquire magnetization-prepared 2 rapid acquisition gradient echo and advanced MRI including visualization of short transverse relaxation time component (ViSTa) for myelin, quantitative magnetization transfer (qMT) for myelin, and neurite orientation dispersion density imaging (NODDI). SELs were defined as lesions showing ≥12% of growth over 12 months on serial MRI. Comparisons of quantitative measures in SELs and non-SELs were performed at baseline and over time. Statistical analyses included two-sample t-test, analysis of variance, and mixed-effects linear model for MRI metrics between lesion types. RESULTS: A total of 1075 lesions were evaluated. Two hundred twenty-four lesions (21%) were SELs, and 216 (96%) of the SELs were black holes. At baseline, compared to non-SELs, SELs showed significantly lower ViSTa (1.38 vs. 1.53, p < .001) and qMT (2.47 vs. 2.97, p < .001) but not in NODDI measures (p > .27). Longitudinally, only ViSTa showed a greater loss when comparing SEL and non-SEL (p = .03). CONCLUSIONS: SELs have a lower myelin content relative to non-SELs without a difference in neurite measures. SELs showed a longitudinal decrease in apparent myelin water fraction reflecting greater tissue injury.

Streptococcus alactolyticus Infective Endocarditis and Stroke in a Healthy Young Female.

Streptococcus bovis/Streptococcus equinus complex includes the subspecies Streptococcus alactolyticus. The prevalence of systemic infection in humans with S alactolyticus is scarce. We present a case of infective endocarditis complicated with hemorrhagic and ischemic stroke in a healthy 31-year-old woman.

Artificial Intelligence in Transcatheter Aortic Valve Replacement: Its Current Role and Ongoing Challenges.

Transcatheter aortic valve replacement (TAVR) has emerged as a viable alternative to surgical aortic valve replacement, as accumulating clinical evidence has demonstrated its safety and efficacy. TAVR indications have expanded beyond high-risk or inoperable patients to include intermediate and low-risk patients with severe aortic stenosis. Artificial intelligence (AI) is revolutionizing the field of cardiology, aiding in the interpretation of medical imaging and developing risk models for at-risk individuals and those with cardiac disease. This article explores the growing role of AI in TAVR procedures and assesses its potential impact, with particular focus on its ability to improve patient selection, procedural planning, post-implantation monitoring and contribute to optimized patient outcomes. In addition, current challenges and future directions in AI implementation are highlighted.

Use of a Percutaneous Right Ventricular Assist Device to Manage Right Ventricular Failure in Inferior STEMIs.

Acute right heart failure is a complication of inferior ST-elevation myocardial infarctions. Given the further hemodynamic instability that results from right-sided failure, a treatment option is needed to help bridge toward cardiac recovery. We present a case of using a right ventricular assist device in a patient who had marked improvement in cardiac function after an instance of acute right heart failure.

Perceptions of Obstetrics/Gynecology Surgeons on Non-medically Indicated Cesarean Sections: A Cross-Sectional Study.

BACKGROUND: Numerous factors can influence decisions regarding the type of delivery of human babies. There is an increasing demand for non-medically indicated cesarean sections (CS) (non-miCS) or CS on request (CSor). Therefore, this survey study aimed to identify the factors that may foster the decision of CS among obstetricians. METHODS: After the sample size calculation returned with 132 needed participants, confidence surveys were sent electronically or disseminated in paper form to nearly all obstetricians (around 200) in the province between mid-August 2021 and mid-February 2022. After signing the consent form, obstetricians were able to provide responses to the four sections of the questionnaire. Data from the copies of the paper were entered into Excel by a local data collector. The data analysis was done using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Armonk, NY) and followed the following sequence: summary statistics were done first; then the groups (for and against non-miCS) were compared using analysis of variance (ANOVA); and, finally, regression models were conducted to determine the factors that may affect the favorability of doing non-miCS. RESULTS: A total of 104 obstetricians responded to the survey. Approximately 62.5% of them performed CSor for women who requested it. In addition, more than half (57.7%) agreed that all women had the right and autonomy to choose their mode of delivery. Most providers (65.4) agreed that fear of vaginal delivery (VD) and a bad experience with it are rational reasons for performing a CSor. Unfortunately, some obstetricians (18.3%) faced lawsuits when they refused to perform CSor. As for the factors that may influence the acceptance of obstetricians to non-miCS, it was found that obstetricians who are unsure or refuse to answer (OR=4.30, 95%-CI 1.25-16.29, p=0.025), along with people who do not always perform CSor (OR=4.33, 95%-CI 1.59-12.50, p=0.005) or even refuse it (3.54, 95%-CI 1.05-12.96, p=0.046), are more likely to agree that women have the right to request CSor. CONCLUSION: The surge in CSor rates was mostly correlated with an attempt to escape the fear of VD. However, given the wide discrepancies in obstetricians' opinions in this survey, we cannot draw firm conclusions about the reasons behind this phenomenon. It is also important to explore possible ways to address the problem, such as through litigation with providers who refuse to perform a CSor and through economic reform to protect women from money-grubbing obstetricians.

A Multisite Electronic Health Record Integrated Remote Monitoring Intervention for Hypertension Improvement: Protocol for a Randomized Pragmatic Comparative Effectiveness Trial.

BACKGROUND: Hypertension is a major contributor to various adverse health outcomes. Although previous studies have shown the benefits of home blood pressure (BP) monitoring over office-based measurements, there is limited evidence comparing the effectiveness of whether a BP monitor integrated into the electronic health record is superior to a nonintegrated BP monitor. OBJECTIVE: In this paper, we describe the protocol for a pragmatic multisite implementation of a quality improvement initiative directly comparing integrated to nonintegrated BP monitors for hypertension improvement. METHODS: We will conduct a randomized, comparative effectiveness trial at 3 large academic health centers across California. The 3 sites will enroll a total of 660 participants (approximately n=220 per site), with 330 in the integrated BP monitor arm and 330 in the nonintegrated BP control arm. The primary outcome of this study will be the absolute difference in systolic BP in mm Hg from enrollment to 6 months. Secondary outcome measures include binary measures of hypertension (controlled vs uncontrolled), hypertension-related health complications, hospitalizations, and death. The list of possible participants will be generated from a central data warehouse. Randomization will occur after enrollment in the study. Participants will use their assigned BP monitor and join site-specific hypertension interventions. Cross-site learning will occur at regular all-site meetings facilitated by the University of California, Los Angeles Value-Based Care Research Consortium. A pre- and poststudy questionnaire will be conducted to further evaluate participants' perspectives regarding their BP monitor. Linear mixed effects models will be used to compare the primary outcome measure between study arms. Mixed effects logistic regression models will be used to compare secondary outcome measures between study arms. RESULTS: The study will start enrolling participants in the second quarter of 2023 and will be completed by the first half of 2024. Results will be published by the end of 2024. CONCLUSIONS: This pragmatic trial will contribute to the growing field of chronic care management using remote monitoring by answering whether a hypertension intervention coupled with an electronic health record integrated home BP monitor improves patients' hypertension better than a hypertension intervention with a nonintegrated BP monitor. The outcomes of this study may help health system decision makers determine whether to invest in integrated BP monitors for vulnerable patient populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT05390502; clinicaltrials.gov/study/NCT05390502. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45915.

Experimental and theoretical study of the cytosine tautomerism through excited states.

CONTEXT: The irradiation of water solution of cytosine with UV light (λmax = 254 nm) shows oxo-hydroxy tautomerism with a rate constant of 6.297 × 10-3 min-1. The order of the reaction implies a tautomeric conversion. After removing the UV light source, we observed a dark reaction with a rate constant of 1.473 × 10-3 min-1 which leads to a restoration of the initial tautomer as before the irradiation. The mechanism of oxo-hydroxy tautomerism of cytosine in water solution was studied in the excited state. It was found that the transformations occur along the 1πσ* excited-state reaction paths which link the Franck-Condon geometries of the tautomers and the conical intersections S0/S1 connected with the H-detachment processes of the corresponding bonds. Furthermore, we established that the conical intersections S0/S1 are also mutually accessible along the 1πσ* excited-state reaction paths. METHODS: The ground-state equilibrium geometries were optimized at the B3LYP/aug-cc-pVDZ level of theory in water environment according to PCM as well as at the CC2/aug-cc-pVDZ level in the gas phase. The TD B3LYP and CC2 methods were applied for the study of the excited states. The tautomerization mechanisms were studied with the use of the linear interpolation in internal coordinates approach using the optimized geometries of tautomers minima and conical intersections S0/S1 at the CASSCF(6,6)/6-31G* level. All calculations were performed with the GAUSSIAN 16 commercial software.

Detection of vitrector shavings on OCT.

PURPOSE: To describe multiple retained intraocular foreign bodies felt to be from a vitrectomy instrument. METHODS: Observational case report. PATIENT: A 66-year-old male with history of rhegmatogenous retinal detachment repaired with PPV, scleral buckle, endolaser, and fluid-air exchange presented with dyschromatopsia OD. RESULTS: OCT demonstrated metallic vitrector shavings detected on OCT above the optic nerve head and macula. Repeat OCT 9 months later demonstrated movement of the vitrector shavings throughout the vitreous. CONCLUSION: We demonstrate retained intraocular foreign body shavings which are rarely seen following vitrectomy. These can be confirmed using OCT.

Pregnancy Outcomes in Patients with Obstructed Hemivagina Ipsilateral Renal Agenesis.

STUDY OBJECTIVE: Obstructed hemivagina with ipsilateral renal agenesis (OHVIRA) is a rare congenital Müllerian anomaly. We sought to explore the impact of OHVIRA on pregnancy outcomes. METHODS: A retrospective chart review identified 8 patients with an OHVIRA diagnosis and at least 1 documented pregnancy. Data collected included demographic characteristics, age at diagnosis and repair, gynecologic history, and pregnancy outcomes. Descriptive analysis was performed. RESULTS: Twenty-three pregnancies were identified among the 8 patients (range 1-5 pregnancies per patient), resulting in 9 term births, 6 preterm births, and 8 first-trimester spontaneous abortions. The most common pregnancy complications were fetal growth restriction (2/15) and preeclampsia with severe features (2/15). The average gestational age at delivery was 37 2/7 weeks; however, 60% (9/15) of live births were at term. Two patients delivered after going into preterm labor, one of whom also had preterm premature rupture of membranes. Of the 15 live births, there were 10 cesarean deliveries, 4 vaginal deliveries, and 1 forceps-assisted vaginal delivery. Three patients (30%) underwent primary cesarean deliveries due to fetal malpresentation. Five live births were repeat cesarean deliveries, and 2 were unscheduled cesareans, at 34 and 36 weeks, due to preeclampsia with severe features. CONCLUSION: This study is among the first to examine pregnancy outcomes in patients with OHVIRA. Among these patients, there were 23 total pregnancies, with higher incidences of spontaneous abortion, preterm birth, breech presentation, and cesarean delivery compared with the general population. This descriptive data set addresses a knowledge gap to help clinicians more effectively advise patients with OHVIRA about pregnancy outcomes.

The Tyr Phenomenon: A Hypocalcemic Response in High-Volume Treatment Responders to 177Lu-Prostate-Specific Membrane Antigen Therapy.

177Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer. Rarer treatment-related adverse events have not yet been described. Methods: We present case reviews of 2 men with a marked hypocalcemic osteosclerotic response to 177Lu-PSMA-I&T therapy. A clinical dataset of 177Lu-PSMA-I&T therapy was evaluated to estimate the incidence and clinical association with hypocalcemia. Results: Forty-one of the 127 men (32%) had a serum calcium drop, and 6 (5%) developed clinical hypocalcemia during 177Lu-PSMA therapy. The baseline total tumor volume was significantly higher in those who developed hypocalcemia (median, 3,249 cm3 [interquartile range, 1,856-3,852] vs. 465 [interquartile range 135-1,172]; P = 0.002). The mean prostate-specific antigen response in those with hypocalcemia was 78% (SD, 24%). Conclusion: Hypocalcemia may occur in response to 177Lu-PSMA-I&T, particularly with both high-volume bone metastases and a significant prostate-specific antigen response, and may be severe, requiring corticosteroids. Further evaluation of 177Lu-PSMA-induced hypocalcemia is required to better understand mechanisms, optimal treatments, and repercussions from any subsequent osteosclerotic response.

Immune-related biomarkers and suicidal behaviors: A meta-analysis.

Biomarkers that can differentiate between psychiatric disorders with and without suicidal behavior history from each other and from healthy volunteers may explain part of the pathogenesis of suicidal behavior. We conducted the hitherto largest meta-analysis comparing immune biomarkers between subjects with and without suicide attempt history or death by suicide. The study protocol was registered with PROSPERO, CRD42020212841. Standardized mean differences (SMD) were pooled with random-effects models. Heterogeneity between studies was assessed with the I2-statistic and publication bias was evaluated by the Egger test and funnel plots. Data were based on 36 studies including 2679 persons with suicidal behaviors and 6839 comparison subjects, and four immune-related biomarkers (CRP, IL-6, TNF-α and IL-1ß). Suicidal behavior was associated with higher CRP blood levels compared with: healthy controls (SMD [95%CI] = 1.42[0.85-1.98]); patients with depression alone (SMD [95%CI] = 1.23[0.20-2.26]); and patients with any psychiatric disorders (SMD [95%CI] = 0.39[0.22-0.55]). IL-6 blood level was higher in patients with suicidal behaviors compared with healthy controls (SMD [95%CI] = 1.13[0.45-1.82]) and when compared with psychiatric patients without suicidal behaviors (SMD [95%CI] = 0.22 [0.11-0.33]). Meta-regression and subgroup analyses revealed that increased CRP in suicidal behavior is primarily driven by recent suicidal behavior. These results implicate the immune system and inflammatory response in suicidal behavior independent of a relationship to major psychiatric disorders, and that these biological measures are predominantly state-dependent markers. Future studies are needed to determine the cause-and-effect relationship of these immune system biomarkers with suicidal behavior, and their potential predictive properties.

The impact of the COVID-19 lockdown on retinopathy of prematurity screening and management in the United States: a multicenter study.

PURPOSE: To study the effect of the pandemic-related lockdown (physical distance measures and movement restrictions) on the characteristics and management of retinopathy of prematurity (ROP). METHODS: In this controlled, multicenter cohort study, the medical records of patients born prematurely and screened for ROP in the neonatal intensive care unit during four time periods were reviewed retrospectively: (1) November 1, 2018, to March 15, 2019; (2) March 16, 2019, to August 2, 2019 (lockdown control period); (3) November 1, 2019, to March 15, 2020; and (4) March 16, 2020-August 2, 2020. RESULTS: A total of 1,645 patients met inclusion criteria. Among the 1,633 patients with complete data, mean gestational age (GA) at birth was 28.2, 28.4, 28.0, and 28.3 weeks across time periods 1 to 4, respectively (P = 0.16). The mean birth weight of all patients was 1079.1 ± 378.60 g, with no significant variation across time periods (P = 0.08). There were fewer patients screened during the lockdown period (n = 411) compared with the period immediately before (n = 491) and the same period in the prior year (n = 533). Significantly more patients were screened using indirect ophthalmoscopy, compared to digital imaging (telemedicine), during the lockdown (P < 0.01). There were 11.7%, 7.7%, 9.0%, and 8.8% of patients requiring treatment in each time period, respectively (P = 0.42), with a median postmenstrual age at initial treatment of 37.2, 36.45, 37.1, and 36.3 weeks, respectively (P = 0.32). CONCLUSIONS: We recorded a decrease in the number of infants meeting criteria for ROP screening during the lockdown. The GA at birth and birth weight did not differ. Significantly more infants were screened with indirect ophthalmoscopy, compared to digital imaging, during the lockdown.

Benefit of icosapent ethyl on coronary physiology assessed by computed tomography angiography fractional flow reserve: EVAPORATE-FFRCT.

AIMS: Icosapent ethyl (IPE) significantly reduced ischaemic events in statin-treated patients with atherosclerosis or diabetes and elevated triglycerides in REDUCE-IT, including large reductions in myocardial infarction and elective, urgent, and emergent coronary revascularization. However, the mechanisms driving this clinical benefit are not fully known. The EVAPORATE trial demonstrated that IPE significantly reduced plaque burden. No study to date has assessed the impact of IPE on coronary physiology. Fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) data sets (FFRCT) applies computational fluid dynamics to calculate FFR values in epicardial coronary arteries. Our objective was to assess the impact of IPE on coronary physiology assessed by FFRCT using imaging data from EVAPORATE. METHODS AND RESULTS: A total of 47 patients and of 507 coronary lesions at baseline, 9 months, and 18 months with coronary CTA and FFRCT were studied in a blinded core lab. The pre-specified primary endpoint was the FFRCT value in the distal coronary segment from baseline to follow-up in the most diseased vessel per patient using IPE compared with placebo. The pre-specified secondary endpoint was the change in translesional FFRCT (ΔFFRCT) across the most severe (minimum 30% diameter stenosis) coronary lesion per vessel. Baseline FFRCT was similar for IPE compared with placebo (0.83 ± 0.08 vs. 0.84 ± 0.08, P = 0.55). There was significant improvement in the primary endpoint, as IPE improved mean distal segment FFRCT at 9- and 18-month follow-up compared with placebo (0.01 ± 0.05 vs. -0.05 ± 0.09, P = 0.02, and -0.01 ± 0.09 vs. -0.09 ± 0.12, P = 0.03, respectively). ΔFFRCT in 140 coronary lesions was improved, although not statistically significant, with IPE compared with placebo (-0.06 ± 0.08 vs. -0.09 ± 0.1, P = 0.054). CONCLUSION: Icosapent ethyl demonstrated significant benefits in coronary physiology compared with placebo. This early and sustained improvement in FFRCT at 9- and 18-month follow-up provides mechanistic insight into the clinical benefit observed in the REDUCE-IT trial. Furthermore, this is the first assessment of FFRCT to determine drug effect.

Low Contrast and Low kV CTA Before Transcatheter Aortic Valve Replacement: A Systematic Review.

BACKGROUND: Minimizing contrast dose and radiation exposure while maintaining image quality during computed tomography angiography (CTA) for transcatheter aortic valve replacement (TAVR) is desirable, but not well established. This systematic review compares image quality for low contrast and low kV CTA versus conventional CTA in patients with aortic stenosis undergoing TAVR planning. METHODS: We performed a systematic literature review to identify clinical studies comparing imaging strategies for patients with aortic stenosis undergoing TAVR planning. The primary outcomes of image quality as assessed by the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were reported as random effects mean difference with 95% confidence interval (CI). RESULTS: We included 6 studies reporting on 353 patients. There was no difference in cardiac SNR (mean difference, -1.42; 95% CI, -5.71 to 2.88; p = 0.52), cardiac CNR (mean difference, -3.83; 95% CI, -9.98 to 2.32; p = 0.22), aortic SNR (mean difference, -0.23; 95% CI, -7.83 to 7.37; p = 0.95), aortic CNR (mean difference, -3.95; 95% CI, -12.03 to 4.13; p = 0.34), and ileofemoral SNR (mean difference, -6.09; 95% CI, -13.80 to 1.62; p = 0.12) between the low dose and conventional protocols. There was a difference in ileofemoral CNR between the low dose and conventional protocols with a mean difference of -9.26 (95% CI, -15.06 to -3.46; p = 0.002). Overall, subjective image quality was similar between the 2 protocols. CONCLUSIONS: This systematic review suggests that low contrast and low kV CTA for TAVR planning provides similar image quality to conventional CTA.

Chilaiditi Sign in a Patient With Acute Coronary Syndrome: A Case Report.

Chilaiditi sign is a radiographic finding where part of the colon is found to be between the diaphragm and liver. Chilaiditi syndrome is characterized by symptoms such as chest or abdominal pain and shortness of breath once Chilaiditi sign is found on imaging. Chilaiditi sign is typically diagnosed by CT angiography (CTA) scan although it can also be seen on X-ray imaging at times. In most cases, Chilaiditi sign does not require acute intervention, as will be seen in our patient; however, it is important to include it in the differential diagnosis when a patient presents with characteristic symptoms. We present a case of a 71-year-old female who presented with chest pressure and shortness of breath due to acute coronary syndrome; however, she was found to have Chilaiditi sign, which was diagnosed by CTA chest.

Development of ALOHa-G Risk Score for Detecting Postpartum Dyslipidemia Among Normoglycemic Women with Previous Gestational Diabetes: Observational Cohort Study.

INTRODUCTION: Previous gestational diabetes (pGD) is associated with a high risk of postpartum dyslipidemia (pD). Our study was aimed at investigating the prevalence of pD and estimating the risk for pD based on metabolic pregnancy parameters in normoglycemic women with pGD. METHODS: 147 women with pGD and normoglycemia after delivery were divided into groups: A (n = 63) with pD and B (n = 84) with normal lipids, defined by the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report (NCEP ATP III). We recorded age, body mass index (BMI) at conception, fasting glucose (FG), HbA1c, total cholesterol (TC), triglycerides (Tg), low-density lipoprotein (LDL-c), and high-density lipoprotein cholesterol (HDL-c) measured mid-pregnancy and 1-6 months after delivery. GD was diagnosed by 2 h oral glucose tolerance test (OGTT) between the 24th and the 28th week of gestation, which was repeated after delivery to confirm normoglycemia. RESULTS: 42.8% had pD (group A) while 57.2% had normal lipids (group B). Group A was older (36.8 ± 2.7) than B (33.0 ± 4.2 years, p < 0.001) and had a higher BMI (A 31.2 ± 6.4 vs. B 25.5 ± 2.4 kg/m2, p < 0.001). Simultaneously, HbA1c and FG were higher in group A (5.4 ± 0.3, 5.1 ± 0.4) than B (5.2 ± 0.0%, p = 0.001; 4.8 ± 0.0 mmol/L, p < 0.001). Also, group A had higher TC, LDL-c, and Tg [6.6 (6.1-6.9); 4.2 ± 0.4; 2.9 ± 0.8] compared to B [6.2 (5.4-6.9), p < 0.001; 3.4 ± 0.9, p = 0.001; 2.5 ± 0.6, p < 0.001], while the two groups had comparable HDL-c (A: 1.2 ± 0.3 vs. B: 1.2 ± 0.2 mmol/L, p = 0.998). Calculating the cutoff for age, BMI, HbA1c, FG, LDL-c, and Tg (> 35 years, 26.4 kg/m2, 5.2%, 4.8, 3.9 and 2.7 mmol/L, respectively), univariate regression analysis showed a difference for each (p < 0.001). Allocating 1 point to each predictor, we developed ALOHa G score, which showed high accuracy (AUC 0.931, p < 0.001) for risk of pD in normoglycemic women with pGD. According to the ALOHa-G score, more women in group A were at high risk (≥ 4) and medium risk (= 3) (61.9; 34.9) for pD than in group B (4.8; 14.3), with a lower percentage at low risk for PD (≤ 2) in group A than in group B (3.2 vs. 81.0%). CONCLUSION: Our results implied a remarkable occurrence of pD in normoglycemic women with pGD. Also, the ALOHa-G score was developed based on pregnancy metabolic predictors and could be used to identify normoglycemic women with pGD who are at high risk for pD.

Rethinking the medication management of major depression.

INTRODUCTION: Current treatment of major depressive disorder (MDD) warrants critical reexamination. Initial treatment response rates are modest and drop dramatically after 3 months. Meanwhile, MDD is emerging as the leading cause of disease burden worldwide. AREAS COVERED: We searched PubMed (up to June 2021) for randomized controlled trials comparing antidepressant combinations versus monotherapy. We discuss findings from these studies in light of current treatment guidelines for MDD. These recommend a sequence of single, six-week-long, medication trials, before trying antidepressant combinations. The result leaves one third of patients still depressed after six months of treatment. EXPERT OPINION: Optimizing the first three months of MDD treatment is crucial because response rates during this period are five times better than in the second three months. We propose a new, evidence-based algorithm of sequential antidepressant treatment steps, termed Accelerated Sequential Antidepressant Protocol (ASAP), that may offer better response rates than current guidelines. ASAP involves shorter duration medication trials (2-4 weeks) and earlier use of antidepressant combinations, seeking additive antidepressant effects without worsening side effects. Future research should compare ASAP to current treatment guidelines. Research is also needed on the role of rapidly acting antidepressants like ketamine for acutely ill and suicidal depressed patients.