Pertuzumab Plus Trastuzumab in Patients With Biliary Tract Cancer With ERBB2/3 Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with biliary tract cancer (BTC) with ERBB2/3 amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab are reported. METHODS: Eligible patients had advanced BTC, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with ERBB2/3 alterations, and a lack of standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16+ weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Twenty-nine patients were enrolled from February 2017 to January 2022, and all had advanced BTC with an ERBB2/3 alteration. One patient was not evaluable for efficacy. One complete response, eight partial responses, and two SD16+ were observed for DC and OR rates of 40% (90% CI, 27 to 100) and 32% (95% CI, 16 to 52), respectively. The null hypothesis of 15% DC rate was rejected (P = .0015). Four patients had at least one grade 3 adverse event (AE) or serious AE at least possibly related to treatment: anemia, diarrhea, infusion-related reaction, and fatigue. CONCLUSION: Pertuzumab plus trastuzumab met prespecified criteria to declare a signal of activity in patients with BTC and ERBB2/3 amplification, overexpression, or mutation.

Predicting Extubation Readiness in Preterm Infants Utilizing Machine Learning: A Diagnostic Utility Study.

OBJECTIVE: The objective of this study was to predict extubation readiness in preterm infants using machine learning analysis of bedside pulse oximeter and ventilator data. STUDY DESIGN: This is an observational study with prospective recordings of oxygen saturation (SpO2) and ventilator data from infants <30 weeks of gestation age. Research pulse oximeters collected SpO2 (1 Hz sampling rate) to quantify intermittent hypoxemia (IH). Continuous ventilator metrics were collected (4-5-minute sampling) from bedside ventilators. Data modeling was completed using unbiased machine learning algorithms. Three model sets were created using the following data source combinations: (1) IH and ventilator (IH + SIMV), (2) IH, and (3) ventilator (SIMV). Infants were also analyzed separated by postnatal age (infants <2 or ≥2 weeks of age). Models were compared by area under the receiver operating characteristic curve (AUC). RESULTS: A total of 110 extubation events from 110 preterm infants were analyzed. Infants had a median gestation age and birth weight of 26 weeks and 825 g, respectively. Of the 3 models presented, the IH + SIMV model achieved the highest AUC of 0.77 for all infants. Separating infants by postnatal age increased accuracy further achieving AUC of 0.94 for <2 weeks of age group and AUC of 0.83 for ≥2 weeks group. CONCLUSIONS: Machine learning analysis has the potential to enhance prediction accuracy of extubation readiness in preterm infants while utilizing readily available data streams from bedside pulse oximeters and ventilators.

Inequality on the frontline: A multi-country study on gender differences in mental health among healthcare workers during the COVID-19 pandemic.

Healthcare workers (HCWs) were at increased risk for mental health problems during the COVID-19 pandemic, with prior data suggesting women may be particularly vulnerable. Our global mental health study aimed to examine factors associated with gender differences in psychological distress and depressive symptoms among HCWs during COVID-19. Across 22 countries in South America, Europe, Asia and Africa, 32,410 HCWs participated in the COVID-19 HEalth caRe wOrkErS (HEROES) study between March 2020 and February 2021. They completed the General Health Questionnaire-12, the Patient Health Questionnaire-9 and questions about pandemic-relevant exposures. Consistently across countries, women reported elevated mental health problems compared to men. Women also reported increased COVID-19-relevant stressors, including insufficient personal protective equipment and less support from colleagues, while men reported increased contact with COVID-19 patients. At the country level, HCWs in countries with higher gender inequality reported less mental health problems. Higher COVID-19 mortality rates were associated with increased psychological distress merely among women. Our findings suggest that among HCWs, women may have been disproportionately exposed to COVID-19-relevant stressors at the individual and country level. This highlights the importance of considering gender in emergency response efforts to safeguard women's well-being and ensure healthcare system preparedness during future public health crises.

The impact of intermittent hypoxemia on type 1 retinopathy of prematurity in preterm infants.

BACKGROUND: Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study tests the hypothesis that increased IH is associated with Type 1 ROP; a stage beyond which treatment is indicated. METHODS: IH was quantified by continuously monitoring oxygen saturation (SpO2) using high-resolution pulse oximeters during the first 10 weeks of life. Statistical analyses assessed the relationship and predictive ability of weekly and cumulative IH for Type 1 ROP development. RESULTS: Most analyses showed no association between IH and Type 1 ROP adjusting for gestational age (GA) and birth weight (BW). However, cumulative IH of longer duration during weeks 5-10, 6-10, and 7-10 were significantly associated with Type 1 ROP adjusting for GA and BW, e.g., the adjusted odds ratio of Type 1 ROP was 2.01 (p = 0.03) for every 3.8 seconds increase in IH duration from week 6-10. IH did not provide statistically significant added predictive ability above GA and BW. CONCLUSIONS: For most analyses there was no significant association between IH and Type 1 ROP adjusting for GA and BW. However, infants with longer IH duration during the second month of life had higher risk for Type 1 ROP. IMPACT: The relationship and predictive ability of intermittent hypoxemia (IH) on retinopathy of prematurity (ROP) is controversial. This study shows no significant association between IH events and Type 1 ROP after adjusting for gestational age (GA) and birth weight (BW), except for cumulative IH of longer duration in the second month of life. In this cohort, IH does not provide a statistically significant improvement in ROP prediction over GA and BW. This study is the first to assess the cumulative impact of IH measures on Type 1 ROP. Interventions for reducing IH duration during critical postnatal periods may improve ROP outcomes.

Regorafenib in Patients With Solid Tumors With BRAF Alterations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with BRAF alterations treated with regorafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-1, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as investigator assessment of patients with complete or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low accruing histology-specific cohorts with BRAF alterations treated with regorafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, 0.84; α, .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Twenty-eight patients with 12 tumor types with BRAF alterations were enrolled from June 2016 to June 2021. All patients were evaluable for efficacy. Two patients with PR and four with SD16+ were observed for DC and OR rates of 21% (90% CI, 12 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .24). Eight patients had at least one grade 3 adverse event or serious adverse event at least possibly related to regorafenib. CONCLUSION: Regorafenib did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with BRAF alterations.

Wearable fiber-free optical sensor for continuous monitoring of neonatal cerebral blood flow and oxygenation.

BACKGROUND: Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants. METHODS: DSCFO uses two small laser diodes as focused-point and a tiny CMOS camera as a high-density two-dimensional detector to detect spontaneous spatial fluctuation of diffuse laser speckles for CBF measurement, and light intensity attenuations for cerebral oxygenation measurement. The DSCFO was first validated against the established diffuse correlation spectroscopy (DCS) in neonatal piglets and then utilized for continuous CBF and oxygenation monitoring in preterm infants during intermittent hypoxemia (IH) events. RESULTS: Significant correlations between the DSCFO and DCS measurements of CBF variations in neonatal piglets were observed. IH events induced fluctuations in CBF, cerebral oxygenation, and peripheral cardiorespiratory vitals in preterm infants. However, no consistent correlation patterns were observed among peripheral and cerebral monitoring parameters. CONCLUSIONS: This pilot study demonstrated the feasibility of DSCFO technology to serve as a low-cost wearable sensor for continuous monitoring of multiple cerebral hemodynamic parameters. The results suggested the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations. IMPACT: The innovative DSCFO technology may serve as a low-cost wearable sensor for continuous bedside monitoring of multiple cerebral hemodynamic parameters in neonatal intensive care units. Concurrent DSCFO and DCS measurements of CBF variations in neonatal piglet models generated consistent results. No consistent correlation patterns were observed among peripheral and cerebral monitoring parameters in preterm neonates, suggesting the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations during IH events. Integrating and correlating multiple cerebral functional parameters with clinical outcomes may identify biomarkers for prediction and management of IH associated brain injury.

Factors associated with satisfaction and perceived helpfulness of mental healthcare: a World Mental Health Surveys report.

BACKGROUND: Mental health service providers are increasingly interested in patient perspectives. We examined rates and predictors of patient-reported satisfaction and perceived helpfulness in a cross-national general population survey of adults with 12-month DSM-IV disorders who saw a provider for help with their mental health. METHODS: Data were obtained from epidemiological surveys in the World Mental Health Survey Initiative. Respondents were asked about satisfaction with treatments received from up to 11 different types of providers (very satisfied, satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, very dissatisfied) and helpfulness of the provider (a lot, some, a little, not at all). We modelled predictors of satisfaction and helpfulness using a dataset of patient-provider observations (n = 5,248). RESULTS: Most treatment was provided by general medical providers (37.4%), psychiatrists (18.4%) and psychologists (12.7%). Most patients were satisfied or very satisfied (65.9-87.5%, across provider) and helped a lot or some (64.4-90.3%). Spiritual advisors and healers were most often rated satisfactory and helpful. Social workers in human services settings were rated lowest on both dimensions. Patients also reported comparatively low satisfaction with general medical doctors and psychiatrists/psychologists and found general medical doctors less helpful than other providers. Men and students reported lower levels of satisfaction than women and nonstudents. Respondents with high education reported higher satisfaction and helpfulness than those with lower education. Type of mental disorder was unrelated to satisfaction but in some cases (depression, bipolar spectrum disorder, social phobia) was associated with low perceived helpfulness. Insurance was unrelated to either satisfaction or perceived helpfulness but in some cases was associated with elevated perceived helpfulness for a given level of satisfaction. CONCLUSIONS: Satisfaction with and perceived helpfulness of treatment varied as a function of type of provider, service setting, mental status, and socio-demographic variables. Invariably, caution is needed in combining data from multiple countries where there are cultural and service delivery variations. Even so, our findings underscore the utility of patient perspectives in treatment evaluation and may also be relevant in efforts to match patients to treatments.

The role of environmental sensitivity in post-traumatic stress symptoms in Lebanese children and adolescents.

Children differ substantially in their sensitivity to the quality of their environment. Some are more sensitive and more likely to develop Post-Traumatic Stress Disorder (PTSD) in response to Childhood Adversities (CAs), but might also benefit more from Positive Home Experiences (PHE). The aim of this study is to investigate the role of Environmental Sensitivity (ES), CAs and PHEs in PTSD development in children and adolescents. Data was collected from N = 2,569 children/adolescents. PTSD symptoms, CAs, PHEs and ES were assessed with self-report measures. We found that higher ES and CAs emerged as risk factors for PTSD development whereas higher levels of PHEs protected against PTSD. ES moderated the effects of CAs (ß = 1.08, p < .001) on PTSD symptoms in the total sample. This moderating effect was more pronounced in girls, suggesting that highly sensitive girls with high childhood adversities were more likely to have higher PTSD symptoms than girls with low levels of sensitivity (ß = 1.09, p < .001). In conclusion, Environmental Sensitivity played an important role as a risk factor for PTSD and as a moderating factor that accentuated the main effects of childhood adversities, particularly in girls.

Patterns, predictors, and patient-reported reasons for antidepressant discontinuation in the WHO World Mental Health Surveys.

BACKGROUND: Despite their documented efficacy, substantial proportions of patients discontinue antidepressant medication (ADM) without a doctor's recommendation. The current report integrates data on patient-reported reasons into an investigation of patterns and predictors of ADM discontinuation. METHODS: Face-to-face interviews with community samples from 13 countries (n = 30 697) in the World Mental Health (WMH) Surveys included n = 1890 respondents who used ADMs within the past 12 months. RESULTS: 10.9% of 12-month ADM users reported discontinuation-based on recommendation of the prescriber while 15.7% discontinued in the absence of prescriber recommendation. The main patient-reported reason for discontinuation was feeling better (46.6%), which was reported by a higher proportion of patients who discontinued within the first 2 weeks of treatment than later. Perceived ineffectiveness (18.5%), predisposing factors (e.g. fear of dependence) (20.0%), and enabling factors (e.g. inability to afford treatment cost) (5.0%) were much less commonly reported reasons. Discontinuation in the absence of prescriber recommendation was associated with low country income level, being employed, and having above average personal income. Age, prior history of psychotropic medication use, and being prescribed treatment from a psychiatrist rather than from a general medical practitioner, in comparison, were associated with a lower probability of this type of discontinuation. However, these predictors varied substantially depending on patient-reported reasons for discontinuation. CONCLUSION: Dropping out early is not necessarily negative with almost half of individuals noting they felt better. The study underscores the diverse reasons given for dropping out and the need to evaluate how and whether dropping out influences short- or long-term functioning.

Risk and resilience in Syrian refugee children: A multisystem analysis.

Refugee children are often exposed to substantial trauma, placing them at increased risk for mental illness. However, this risk can be mitigated by a capacity for resilience, conferred from multiple ecological systems (e.g., family, community), including at an individual biological level. We examined the ability of hair cortisol concentrations and polygenic scores for mental health to predict risk and resilience in a sample of Syrian refugee children (n = 1359). Children were categorized as either at-risk or resilient depending on clinical thresholds for posttraumatic stress disorder, depression, and externalizing behavior problems. Logistic regression was used to examine main and interacting effects while controlling for covariates. Elevated hair cortisol concentrations were significantly associated with reduced resilience (odds ratio (OR)=0.58, 95%CI [0.40, 0.83]) while controlling for levels of war exposure. Polygenic scores for depression, self-harm, and neuroticism were not found to have any significant main effects. However, a significant interaction emerged between hair cortisol and polygenic scores for depression (OR=0.04, 95%CI [0.003 0.47]), suggesting that children predisposed to depression were more at risk for mental health problems when hair cortisol concentrations were high. Our results suggest that biomarkers (separately and in combination) might support early identification of refugee children at risk for mental health problems.

A Wearable Fiber-Free Optical Sensor for Continuous Monitoring of Neonatal Cerebral Blood Flow and Oxygenation.

Impact: The innovative DSCFO technology may serve as a low-cost wearable sensor for continuous bedside monitoring of multiple cerebral hemodynamic parameters in neonatal intensive care units.Concurrent DSCFO and DCS measurements of CBF variations in neonatal piglet models generated consistent results.No consistent correlation patterns were observed among peripheral and cerebral monitoring parameters in preterm neonates, suggesting the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations during IH events.Integrating and correlating multiple cerebral functional parameters with clinical outcomes may identify biomarkers for prediction and management of IH associated brain injury. Background: Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants. Methods: DSCFO uses two small laser diodes as focused-point and a tiny CMOS camera as a high-density two-dimensional detector to detect spontaneous spatial fluctuation of diffuse laser speckles for CBF measurement, and light intensity attenuations for cerebral oxygenation measurement. The DSCFO was first validated against the established diffuse correlation spectroscopy (DCS) in neonatal piglets and then utilized for continuous CBF and oxygenation monitoring in preterm infants during intermittent hypoxemia (IH) events. Results: Consistent results between the DSCFO and DCS measurements of CBF variations in neonatal piglets were observed. IH events induced fluctuations in CBF, cerebral oxygenation, and peripheral cardiorespiratory vitals in preterm infants. However, no consistent correlation patterns were observed among peripheral and cerebral monitoring parameters. Conclusions: This pilot study demonstrated the feasibility of DSCFO technology to serve as a low-cost wearable sensor for continuous monitoring of multiple cerebral hemodynamic parameters. The results suggested the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations.

The Impact of Intermittent Hypoxemia on Type 1 Retinopathy of Prematurity in Preterm Infants.

Background: Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study aims to assess the influence and evaluate the predictive ability of IH measures on Type 1 ROP, a stage beyond which ROP treatment is indicated. Methods: IH was quantified by continuously monitoring oxygen saturation (SpO2) using high-resolution pulse oximeters during the first 10 weeks of life. Statistical analyses assessed the relationship and predictive ability of weekly and cumulative IH variables for Type 1 ROP development. Results: Univariate analyses suggested that IH measures are greater in infants with Type 1 ROP and are predictive of Type 1 ROP development. Multivariable logistic regression analyses revealed that cumulative IH of longer duration during certain postnatal periods are associated with Type 1 ROP development after adjusting for gestational age (GA) or birth weight (BW). Although area under the curve (AUC) analyses revealed added predictivity of cumulative IH variables above GA or BW, these increments in AUC were not statistically significant. Conclusions: The duration of IH events was associated with Type 1 ROP development. Interventions for reducing the duration of IH events may potentially improve ROP outcomes.

Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries.

BACKGROUND: Information on the frequency and timing of mental disorder onsets across the lifespan is of fundamental importance for public health planning. Broad, cross-national estimates of this information from coordinated general population surveys were last updated in 2007. We aimed to provide updated and improved estimates of age-of-onset distributions, lifetime prevalence, and morbid risk. METHODS: In this cross-national analysis, we analysed data from respondents aged 18 years or older to the World Mental Health surveys, a coordinated series of cross-sectional, face-to-face community epidemiological surveys administered between 2001 and 2022. In the surveys, the WHO Composite International Diagnostic Interview, a fully structured psychiatric diagnostic interview, was used to assess age of onset, lifetime prevalence, and morbid risk of 13 DSM-IV mental disorders until age 75 years across surveys by sex. We did not assess ethnicity. The surveys were geographically clustered and weighted to adjust for selection probability, and standard errors of incidence rates and cumulative incidence curves were calculated using the jackknife repeated replications simulation method, taking weighting and geographical clustering of data into account. FINDINGS: We included 156 331 respondents from 32 surveys in 29 countries, including 12 low-income and middle-income countries and 17 high-income countries, and including 85 308 (54·5%) female respondents and 71 023 (45·4%) male respondents. The lifetime prevalence of any mental disorder was 28·6% (95% CI 27·9-29·2) for male respondents and 29·8% (29·2-30·3) for female respondents. Morbid risk of any mental disorder by age 75 years was 46·4% (44·9-47·8) for male respondents and 53·1% (51·9-54·3) for female respondents. Conditional probabilities of first onset peaked at approximately age 15 years, with a median age of onset of 19 years (IQR 14-32) for male respondents and 20 years (12-36) for female respondents. The two most prevalent disorders were alcohol use disorder and major depressive disorder for male respondents and major depressive disorder and specific phobia for female respondents. INTERPRETATION: By age 75 years, approximately half the population can expect to develop one or more of the 13 mental disorders considered in this Article. These disorders typically first emerge in childhood, adolescence, or young adulthood. Services should have the capacity to detect and treat common mental disorders promptly and to optimise care that suits people at these crucial parts of the life course. FUNDING: None.

Findings From the World Mental Health Surveys of Civil Violence Exposure and Its Association With Subsequent Onset and Persistence of Mental Disorders.

Importance: Understanding the association of civil violence with mental disorders is important for developing effective postconflict recovery policies. Objective: To estimate the association between exposure to civil violence and the subsequent onset and persistence of common mental disorders (in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) in representative surveys of civilians from countries that have experienced civil violence since World War II. Design, Setting, and Participants: This study used data from cross-sectional World Health Organization World Mental Health (WMH) surveys administered to households between February 5, 2001, and January 5, 2022, in 7 countries that experienced periods of civil violence after World War II (Argentina, Colombia, Lebanon, Nigeria, Northern Ireland, Peru, and South Africa). Data from respondents in other WMH surveys who immigrated from countries with civil violence in Africa and Latin America were also included. Representative samples comprised adults (aged ≥18 years) from eligible countries. Data analysis was performed from February 10 to 13, 2023. Exposures: Exposure was defined as a self-report of having been a civilian in a war zone or region of terror. Related stressors (being displaced, witnessing atrocities, or being a combatant) were also assessed. Exposures occurred a median of 21 (IQR, 12-30) years before the interview. Main Outcomes and Measures: The main outcome was the retrospectively reported lifetime prevalence and 12-month persistence (estimated by calculating 12-month prevalence among lifetime cases) of DSM-IV anxiety, mood, and externalizing (alcohol use, illicit drug use, or intermittent explosive) disorders. Results: This study included 18 212 respondents from 7 countries. Of these individuals, 2096 reported that they were exposed to civil violence (56.5% were men; median age, 40 [IQR, 30-52] years) and 16 116 were not exposed (45.2% were men; median age, 35 [IQR, 26-48] years). Respondents who reported being exposed to civil violence had a significantly elevated onset risk of anxiety (risk ratio [RR], 1.8 [95% CI, 1.5-2.1]), mood (RR, 1.5 [95% CI, 1.3-1.7]), and externalizing (RR, 1.6 [95% CI, 1.3-1.9]) disorders. Combatants additionally had a significantly elevated onset risk of anxiety disorders (RR, 2.0 [95% CI, 1.3-3.1]) and refugees had an increased onset risk of mood (RR, 1.5 [95% CI, 1.1-2.0]) and externalizing (RR, 1.6 [95% CI, 1.0-2.4]) disorders. Elevated disorder onset risks persisted for more than 2 decades if conflicts persisted but not after either termination of hostilities or emigration. Persistence (ie, 12-month prevalence among respondents with lifetime prevalence of the disorder), in comparison, was generally not associated with exposure. Conclusions: In this survey study of exposure to civil violence, exposure was associated with an elevated risk of mental disorders among civilians for many years after initial exposure. These findings suggest that policy makers should recognize these associations when projecting future mental disorder treatment needs in countries experiencing civil violence and among affected migrants.

Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival. RESULTS: Twenty-eight patients with lung cancer (27 non-small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P = .005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T. CONCLUSION: Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.

Mifepristone as a pharmacological intervention for stress-induced alcohol craving: A human laboratory study.

Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N = 32). We assessed safety, alcohol craving and consumption, after 1-week mifepristone 600 mg/day administration, in a human laboratory study comprised of a single oral yohimbine administration (32.4 mg), a cue-reactivity procedure and alcohol self-administration. Safety was monitored by adverse events and hemodynamic parameters, alcohol craving by alcohol craving questionnaire and cue-induced saliva output. During the alcohol self-administration, we assessed alcohol pharmacokinetics, subjective effects and consumption. Outcomes were assessed using Generalized Estimating Equations and mediation analysis. Mild-moderate adverse events were reported in both conditions. There was no statistically significant difference between mifepristone and placebo in alcohol pharmacokinetics and subjective effects. Furthermore, blood pressure increased only in the placebo condition after the stress-induced laboratory procedures. Mifepristone, compared to placebo, significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a developed preclinical procedure to a human laboratory study, confirming the safety of mifepristone in people with AUD and providing evidence to its role in reducing alcohol craving under stress procedures. The lack of effects on alcohol drinking may be related to the selection of non-treatment seekers and suggests future treatment-oriented trials should investigate mifepristone in people with AUD.

The role of affective temperaments in bipolar disorder: The solid role of the cyclothymic, the contentious role of the hyperthymic, and the neglected role of the irritable temperaments.

BACKGROUND: The aim of the present study is to evaluate the role of individual affective temperaments as clinical predictors of bipolarity in the clinical setting. METHODS: The affective temperaments of 1723 consecutive adult outpatients presenting for various symptoms to a university-based mental health clinical setting were assessed. Patients were administered the Hypomania Checklist-32 and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego - Auto-questionnaire (TEMPS-A) and were diagnosed by psychiatrists according to the DSM-5 criteria. TEMPS-A scores were studied as both continuous and normalized categorical z-scores from a previously established nationwide study on the general population of Lebanon. Simple and multiple binary logistic regressions were done on patients who have any of the DSM-5 defined bipolar types, as a combined group or separately, versus patients without any bipolar diagnosis. RESULTS: At the multivariable level and taking into account all temperaments, the irritable temperament is a consistent predictor of bipolar I and bipolar II disorders. Cyclothymic temperament also played a strong role in bipolarity but more decisively so in bipolar II and substance-induced bipolarity. The hyperthymic temperament had no role in bipolar I or bipolar II disorder.

Antidepressant use in low- middle- and high-income countries: a World Mental Health Surveys report.

BACKGROUND: The most common treatment for major depressive disorder (MDD) is antidepressant medication (ADM). Results are reported on frequency of ADM use, reasons for use, and perceived effectiveness of use in general population surveys across 20 countries. METHODS: Face-to-face interviews with community samples totaling n = 49 919 respondents in the World Health Organization (WHO) World Mental Health (WMH) Surveys asked about ADM use anytime in the prior 12 months in conjunction with validated fully structured diagnostic interviews. Treatment questions were administered independently of diagnoses and asked of all respondents. RESULTS: 3.1% of respondents reported ADM use within the past 12 months. In high-income countries (HICs), depression (49.2%) and anxiety (36.4%) were the most common reasons for use. In low- and middle-income countries (LMICs), depression (38.4%) and sleep problems (31.9%) were the most common reasons for use. Prevalence of use was 2-4 times as high in HICs as LMICs across all examined diagnoses. Newer ADMs were proportionally used more often in HICs than LMICs. Across all conditions, ADMs were reported as very effective by 58.8% of users and somewhat effective by an additional 28.3% of users, with both proportions higher in LMICs than HICs. Neither ADM class nor reason for use was a significant predictor of perceived effectiveness. CONCLUSION: ADMs are in widespread use and for a variety of conditions including but going beyond depression and anxiety. In a general population sample from multiple LMICs and HICs, ADMs were widely perceived to be either very or somewhat effective by the people who use them.

Determinants of effective treatment coverage for posttraumatic stress disorder: findings from the World Mental Health Surveys.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with significant morbidity, but efficacious pharmacotherapy and psychotherapy are available. Data from the World Mental Health Surveys were used to investigate extent and predictors of treatment coverage for PTSD in high-income countries (HICs) as well as in low- and middle-income countries (LMICs). METHODS: Seventeen surveys were conducted across 15 countries (9 HICs, 6 LMICs) by the World Health Organization (WHO) World Mental Health Surveys. Of 35,012 respondents, 914 met DSM-IV criteria for 12-month PTSD. Components of treatment coverage analyzed were: (a) any mental health service utilization; (b) adequate pharmacotherapy; (c) adequate psychotherapy; and (d) effective treatment coverage. Regression models investigated predictors of treatment coverage. RESULTS: 12-month PTSD prevalence in trauma exposed individuals was 1.49 (S.E., 0.08). A total of 43.0% (S.E., 2.2) received any mental health services, with fewer receiving adequate pharmacotherapy (13.5%), adequate psychotherapy (17.2%), or effective treatment coverage (14.4%), and with all components of treatment coverage lower in LMICs than HICs. In a multivariable model having insurance (OR = 2.31, 95 CI 1.17, 4.57) and severity of symptoms (OR = .35, 95% CI 0.18, 0.70) were predictive of effective treatment coverage. CONCLUSION: There is a clear need to improve pharmacotherapy and psychotherapy coverage for PTSD, particularly in those with mild symptoms, and especially in LMICs. Universal health care insurance can be expected to increase effective treatment coverage and therefore improve outcomes.