Understanding the Role of Past Health Care Discrimination in Help-Seeking and Shared Decision-Making for Depression Treatment Preferences.

As a part of a larger, mixed-methods research study, we conducted semi-structured interviews with 21 adults with depressive symptoms to understand the role that past health care discrimination plays in shaping help-seeking for depression treatment and receiving preferred treatment modalities. We recruited to achieve heterogeneity of racial/ethnic backgrounds and history of health care discrimination in our participant sample. Participants were Hispanic/Latino (n = 4), non-Hispanic/Latino Black (n = 8), or non-Hispanic/Latino White (n = 9). Twelve reported health care discrimination due to race/ethnicity, language, perceived social class, and/or mental health diagnosis. Health care discrimination exacerbated barriers to initiating and continuing depression treatment among patients from diverse backgrounds or with stigmatized mental health conditions. Treatment preferences emerged as fluid and shaped by shared decisions made within a trustworthy patient-provider relationship. However, patients who had experienced health care discrimination faced greater challenges to forming trusting relationships with providers and thus engaging in shared decision-making processes.

Assessing the association between the strength of state policies on school drug prevention and substance use disorders.

BACKGROUND: Adolescent substance use has been linked to numerous adverse health, social, and educational outcomes. While there have been intensive resources placed in school-based prevention programs, the association of these policies on prevention outcomes is still unclear. State variation in policies provides an opportunity to assess the influence of school-based prevention programs. OBJECTIVES: To examine the association between the strength of state high school-based prevention programing and the prevalence of substance use disorders among adolescents ages 14-17 in the United States. METHODS: National Survey on Drug Use and Health (NSDUH) data with state-level identifiers were merged with National Association of State Boards of Education (NASBE) information on school-based prevention policy strength, categorized into "required," "recommended," and "no policy." Unadjusted comparisons and multilevel random intercept linear regression models were estimated to assess the change in rates of substance abuse or dependence from pre- to post- policy implementation, accounting for the nesting of individuals within states. RESULTS: Rates of alcohol and tobacco abuse/dependence were significantly lower in states that required an alcohol prevention curriculum. After covariate adjustment, rates of alcohol abuse/dependence remained significantly lower in those states. CONCLUSIONS: Reinforcing alcohol prevention messaging in school appears to have a modest association with decreased rates of adolescent alcohol use disorders, possibly in part due to a different approach to the curriculum. For other substances, policy requirements appear to be less effective in reducing the prevalence of adolescent substance use disorders, suggesting that more targeted messaging with higher-risk students may be required.

PTS phosphorylation of Mga modulates regulon expression and virulence in the group A streptococcus.

The ability of a bacterial pathogen to monitor available carbon sources in host tissues provides a clear fitness advantage. In the group A streptococcus (GAS), the virulence regulator Mga contains homology to phosphotransferase system (PTS) regulatory domains (PRDs) found in sugar operon regulators. Here we show that Mga was phosphorylated in vitro by the PTS components EI/HPr at conserved PRD histidines. A ΔptsI (EI-deficient) GAS mutant exhibited decreased Mga activity. However, PTS-mediated phosphorylation inhibited Mga-dependent transcription of emm in vitro. Using alanine (unphosphorylated) and aspartate (phosphomimetic) mutations of PRD histidines, we establish that a doubly phosphorylated PRD1 phosphomimetic (D/DMga4) is completely inactive in vivo, shutting down expression of the Mga regulon. Although D/DMga4 is still able to bind DNA in vitro, homo-multimerization of Mga is disrupted and the protein is unable to activate transcription. PTS-mediated regulation of Mga activity appears to be important for pathogenesis, as bacteria expressing either non-phosphorylated (A/A) or phosphomimetic (D/D) PRD1 Mga mutants were attenuated in a model of GAS invasive skin disease. Thus, PTS-mediated phosphorylation of Mga may allow the bacteria to modulate virulence gene expression in response to carbohydrate status. Furthermore, PRD-containing virulence regulators (PCVRs) appear to be widespread in Gram-positive pathogens.

Characterization of the Group A Streptococcus Mga virulence regulator reveals a role for the C-terminal region in oligomerization and transcriptional activation.

The Group A Streptococcus (GAS) is a strict human pathogen that causes a broad spectrum of illnesses. One of the key regulators of virulence in GAS is the transcriptional activator Mga, which co-ordinates the early stages of infection. Although the targets of Mga have been well characterized, basic biochemical analyses have been limited due to difficulties in obtaining purified protein. In this study, high-level purification of soluble Mga was achieved, enabling the first detailed characterization of the protein. Fluorescence titrations coupled with filter-binding assays indicate that Mga binds cognate DNA with nanomolar affinity. Gel filtration analyses, analytical ultracentrifugation and co-immunoprecipitation experiments demonstrate that Mga forms oligomers in solution.Moreover, the ability of the protein to oligomerize in solution was found to correlate with transcriptional activation; DNA binding appears to be necessary but insufficient for full activity. Truncation analyses reveal that the uncharacterized C-terminal region of Mga, possessing similarity to phosphotransferase system EIIB proteins, plays a critical role in oligomerization and in vivo activity. Mga from a divergent serotype was found to behave similarly, suggesting that this study describes a general mechanism for Mga regulation of target virulence genes within GAS and provides insight into related regulators in other Gram-positive pathogens.

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.

On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.

The Association between a Novel Baby-Friendly Hospital Program and Equitable Support for Breastfeeding in Vietnam.

Background: Rates of early initiation of breastfeeding are low in Southeast Asia, despite evidence that increased initiation of early breastfeeding would lead to better long-term infant and child health and decrease inequities in long-term health and well-being. In response, a novel performance-based, baby-friendly hospital program designates hospitals that adhere to evidence-based early essential newborn care (EENC) and breastfeeding interventions as Centers of Excellence for Breastfeeding (COE). This study examined whether hospital participation in the program was associated with better breastfeeding outcomes. Methods: Hospitals (n = 28) were invited into the program in December 2018. Hospitals developed an improvement plan for promoting a breastfeeding-friendly environment and meeting the standards of the COE accreditation process and were enrolled on a rolling basis over the course of a year. Post-partum surveys were conducted with parents (n = 9585) from January 2019 through April 2020 to assess their breastfeeding and post-partum experience. Segmented regression models were used to assess how breastfeeding outcomes evolved before and after hospital enrollment in the COE program. Results: Enrollment was associated with a 6 percentage-point (95% CI: 3, 9) increase in the level of early initiation of breastfeeding, which continued to increase in the post-enrollment period, and a 5 percentage-point (95% CI: 2, 9) increase in the level of exclusive breastfeeding during hospital stay. We did not observe evidence that enrollment was immediately associated with receipt of lactation counseling or exclusive breastfeeding at survey time. Conclusion: The prevalence of early and exclusive breastfeeding increased after enrollment in the COE program, suggesting that the program has the potential to improve breastfeeding initiation rates and longer-term child health and well-being. Further research should be conducted to examine whether the program has an impact on the overall duration of breastfeeding.

Patient and provider perception of appropriateness, acceptability, and feasibility of behavioral health home (BHH) core components based on program implementation in an urban, safety-net health system.

Background: This manuscript evaluates patient and provider perspectives on the core components of a Behavioral Health Home (BHH) implemented in an urban, safety-net health system. The BHH integrated primary care and wellness services (e.g., on-site Nurse Practitioner and Care Manager, wellness groups and tools, population health management) into an existing outpatient clinic for people with serious mental illness (SMI). Methods: As the qualitative component of a Hybrid Type I effectiveness-implementation study, semi-structured interviews were conducted with providers and patients 6 months after program implementation, and responses were analyzed using thematic analysis. Valence coding (i.e., positive vs. negative acceptability) was also used to rate interviewees' transcriptions with respect to their feedback of the appropriateness, acceptability, and feasibility/sustainability of 9 well-described and desirable Integrated Behavioral Health Core components (seven from prior literature and two additional components developed for this intervention). Themes from the thematic analysis were then mapped and organized by each of the 9 components and the degree to which these themes explain valence ratings by component. Results: Responses about the team-based approach and universal screening for health conditions had the most positive valence across appropriateness, acceptability, and feasibility/sustainability by both providers and patients. Areas of especially high mismatch between perceived provider appropriateness and measures of acceptability and feasibility/sustainability included population health management and use of evidence-based clinical models to improve physical wellness where patient engagement in specific activities and tools varied. Social and peer support was highly valued by patients while incorporating patient voice was also found to be challenging. Conclusions: Findings reveal component-specific challenges regarding the acceptability, feasibility, and sustainability of specific components. These findings may partly explain mixed results from BHH models studied thus far in the peer-reviewed literature and may help provide concrete data for providers to improve BHH program implementation in clinical settings. Plain language abstract: Many people with serious mental illness also have medical problems, which are made worse by lack of access to primary care. The Behavioral Health Home (BHH) model seeks to address this by adding primary care access into existing interdisciplinary mental health clinics. As these models are implemented with increasing frequency nationwide and a growing body of research continues to assess their health impacts, it is crucial to examine patient and provider experiences of BHH implementation to understand how implementation factors may contribute to clinical effectiveness. This study examines provider and patient perspectives of acceptability, appropriateness, and feasibility/sustainability of BHH model components at 6-7 months after program implementation at an urban, safety-net health system. The team-based approach of the BHH was perceived to be highly acceptable and appropriate. Although providers found certain BHH components to be highly appropriate in theory (e.g., population-level health management), their acceptability of these approaches as implemented in practice was not as high, and their feedback provides suggestions for model improvements at this and other health systems. Similarly, social and peer support was found to be highly appropriate by both providers and patients, but in practice, at months 6-7, the BHH studied had not yet developed a process of engaging patients in ongoing program operations that was highly acceptable by providers and patients alike. We provide these data on each specific BHH model component, which will be useful to improving implementation in clinical settings of BHH programs that share some or all of these program components.

FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer.

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer.

On December 20, 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki [DS-8201a; T-DXd; tradename ENHERTU (Daiichi Sankyo)] for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Approval was based on data from study DS8201-A-U201 (DESTINY-Breast01) with supportive safety data from study DS8201-A-J101. The primary efficacy endpoint in DESTINY-Breast01 was overall response rate (ORR) based on confirmed responses by blinded independent central review (ICR) using RECIST v1.1 in all participants who were assigned to receive the recommended dose of 5.4 mg/kg while secondary endpoints included duration of response (DoR). The confirmed ORR based on ICR in these 184 patients was 60.3% [95% confidence interval (CI): 52.9-67.4] and the median DoR was 14.8 months (95% CI: 13.8-16.9). Interstitial lung disease, including pneumonitis, was experienced in patients treated with T-DXd and can be severe, life threatening, or fatal. In addition, neutropenia and left ventricular dysfunction were included as Warnings and Precautions in labeling. Other important common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, diarrhea, and thrombocytopenia. Overall, the totality of efficacy and safety data supported the accelerated approval of T-DXd for the intended indication.

FDA Approval Summary: Atezolizumab Plus Paclitaxel Protein-bound for the Treatment of Patients with Advanced or Metastatic TNBC Whose Tumors Express PD-L1.

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR = 0.60; 95% confidence interval (CI), 0.48-0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1-expressing population to predict clinical benefit.

A Review of Mental Health and Mental Health Care Disparities Research: 2011-2014.

Racial/ethnic minorities in the United States are more likely than Whites to have severe and persistent mental disorders and less likely to access mental health care. This comprehensive review evaluates studies of mental health and mental health care disparities funded by the National Institute of Mental Health (NIMH) to provide a benchmark for the 2015 NIMH revised strategic plan. A total of 615 articles were categorized into five pathways underlying mental health care and three pathways underlying mental health disparities. Identified studies demonstrate that socioeconomic mechanisms and demographic moderators of disparities in mental health status and treatment are well described, as are treatment options that support diverse patient needs. In contrast, there is a need for studies that focus on community- and policy-level predictors of mental health care disparities, link discrimination- and trauma-induced neurobiological pathways to disparities in mental illness, assess the cost effectiveness of disparities reduction programs, and scale up culturally adapted interventions.

Long-Run Trends in Antidepressant Use Among Youths After the FDA Black Box Warning.

OBJECTIVE: In October 2004, the Food and Drug Administration directed pharmaceutical companies to issue a black box warning about the potential link between the use of antidepressants and suicidal ideation among children. This study analyzed long-run trends in antidepressant use among children before and after the black box warning for those with and without severe psychological impairment. METHODS: The analysis used data from the Medical Expenditure Panel Survey for children ages five to 17, covering years 2000-2011 (N=75,819). The study used multivariate probit models to compare the changes in the rate of any antidepressant use in the early (2004-2007) and late (2008-2011) postwarning years with the rate in the prewarning years (2002-2003). Recycled predictions methods were used to estimate yearly predicted probabilities of use. RESULTS: After adjustment for all covariates, there was a .5% statistically significant decline in the probability of using any antidepressants during the early postwarning years (2004-2007) compared with prewarning years. In the long run (2008-2011), however, there was no statistically significant difference. Five years after the black box warning, the adjusted rates of use increased to their prewarning levels (2.29% in 2003 and 2.26% in 2009). The initial impact of the warning differed between the severe and nonsevere populations, with a significant effect on those with nonsevere psychological impairment. CONCLUSIONS: The return to the rates before the black box warning raises concern that the impact of the warning may have dissipated over time. More frequent updates of the warning might be necessary.

Trends in Racial-Ethnic Disparities in Access to Mental Health Care, 2004-2012.

OBJECTIVE: This study compared trends in racial-ethnic disparities in mental health care access among whites, blacks, Hispanics, and Asians by using the Institute of Medicine definition of disparities as all differences except those due to clinical appropriateness, clinical need, and patient preferences. METHODS: Racial-ethnic disparities in mental health care access were examined by using data from a nationally representative sample of 214,597 adults from the 2004-2012 Medical Expenditure Panel Surveys. The main outcome measures included three mental health care access measures (use of any mental health care, any outpatient care, and any psychotropic medication in the past year). RESULTS: Significant disparities were found in 2004-2005 and in 2011-2012 for all three racial-ethnic minority groups compared with whites in all three measures of access. Between 2004 and 2012, black-white disparities in any mental health care and any psychotropic medication use increased, respectively, from 8.2% to 10.8% and from 7.6% to 10.0%. Similarly, Hispanic-white disparities in any mental health care and any psychotropic medication use increased, respectively, from 8.4% to 10.9% and 7.3% to 10.3%. CONCLUSIONS: No reductions in racial-ethnic disparities in access to mental health care were identified between 2004 and 2012. For blacks and Hispanics, disparities were exacerbated over this period. Clinical interventions that improve identification of symptoms of mental illness, expansion of health insurance, and other policy interventions that remove financial barriers to access may help to reduce these disparities.

Association Between Substance Use Diagnoses and Psychiatric Disorders in an Adolescent and Young Adult Clinic-Based Population.

PURPOSE: Adolescents with substance use disorders are more likely to have a current psychiatric disorder. However, when compared with the adult literature, there is relatively limited information regarding the specific co-occurrence of certain mental health diagnoses and substance use disorders in adolescents. The objectives of this study were to build on the previous literature regarding mental health diagnoses and different types of substance use disorders in adolescents, as well as explore the differences, if any, between groupings of mental health diagnosis and type of substance used. METHODS: Data were extracted from the clinical records of 483 individuals aged 11-24 years referred for an evaluation at the Adolescent Substance Abuse Program at Boston Children's Hospital. According to DSM-IV-Text Revision criteria, individuals received diagnoses of substance abuse or dependence and any additional psychiatric disorders. Problematic use was included within the sample for greater power analysis. A multivariable logistic regression model estimated the association between psychiatric diagnosis and substance use while adjusting for covariates including age and gender. RESULTS: Multiple significant associations were found, including having any anxiety-related diagnosis and opioid use (odds ratio [OR] = 2.23, p < .001), generalized anxiety disorder and opioids (OR = 3.42, p = .008), cocaine and post-traumatic stress disorder (OR = 3.61, p = .01), and marijuana and externalizing behavior disorders (OR = 2.10, p = .024). CONCLUSIONS: Our study found multiple significant associations between specific substances and certain co-occurring psychiatric disorders. The use of office screening systems to efficiently identify these youths should be a part of routine medical and psychiatric care.

Novel Use of Natural Language Processing (NLP) to Predict Suicidal Ideation and Psychiatric Symptoms in a Text-Based Mental Health Intervention in Madrid.

Natural language processing (NLP) and machine learning were used to predict suicidal ideation and heightened psychiatric symptoms among adults recently discharged from psychiatric inpatient or emergency room settings in Madrid, Spain. Participants responded to structured mental and physical health instruments at multiple follow-up points. Outcome variables of interest were suicidal ideation and psychiatric symptoms (GHQ-12). Predictor variables included structured items (e.g., relating to sleep and well-being) and responses to one unstructured question, "how do you feel today?" We compared NLP-based models using the unstructured question with logistic regression prediction models using structured data. The PPV, sensitivity, and specificity for NLP-based models of suicidal ideation were 0.61, 0.56, and 0.57, respectively, compared to 0.73, 0.76, and 0.62 of structured data-based models. The PPV, sensitivity, and specificity for NLP-based models of heightened psychiatric symptoms (GHQ-12 ≥ 4) were 0.56, 0.59, and 0.60, respectively, compared to 0.79, 0.79, and 0.85 in structured models. NLP-based models were able to generate relatively high predictive values based solely on responses to a simple general mood question. These models have promise for rapidly identifying persons at risk of suicide or psychological distress and could provide a low-cost screening alternative in settings where lengthy structured item surveys are not feasible.