Fixed, Dilated, and Cannulated - Medical Management of Elevated Intracranial Pressures due to a Large Intracranial Hemorrhage in a Patient on Veno-Venous Extracorporeal Membrane Oxygenation: Case Report.

A 40-year-old woman presented with mediastinitis, necrotizing pancreatitis, and severe acute respiratory distress syndrome with refractory acidemia (pH 7.14) and hypercapnia (PaCO2 115 mmHg), requiring veno-venous extracorporeal membrane oxygenation (ECMO). Eight hours after cannulation, and rapid correction of PaCO2 to 44 mmHg, she was found to have bilaterally fixed and dilated pupils. Imaging showed a 60 mL left-sided temporoparietal intracranial hemorrhage with surrounding edema, 8 mm midline shift, intraventricular hemorrhage, and impending herniation. Decompressive hemicraniectomy was not offered due to concern for medical instability. After receiving a dose of mannitol, her pupillary and motor exam improved. An intracranial pressure (ICP) monitor was placed to guide hyperosmolar therapy administration, hemodynamic targets, and sweep gas titration. On hospital day (HD) 5, her ICP monitor was removed. Follow-up imaging revealed resolution of mass effect and no brainstem injury. She was subsequently extubated (HD 9) and discharged home (HD 40). One year after hospitalization, she is living at home with minimal residual deficits. This case highlights the utility of targeted, medical ICP management and importance of assessing response to conservative therapies when considering prognosis in patients on ECMO with severe acute brain injury.

Acceptability of a Randomized Trial of Anti-depressant Medication or Interpersonal Therapy for Treatment of Perinatal Depression in Women with HIV.

Postpartum depression (PPD) affects nearly 20% of postpartum women in Sub-Saharan Africa (SSA), where HIV prevalence is high. Depression is associated with worse HIV outcomes in non-pregnant adults and mental health disorders may worsen HIV outcomes for postpartum women and their infants. PPD is effectively treated with psychosocial or pharmacologic interventions; however, few studies have evaluated the acceptability of treatment modalities in SSA. We analyzed interviews with 23 postpartum women with HIV to assess the acceptability of two depression treatments provided in the context of a randomized trial. Most participants expressed acceptability of treatment randomization and study visit procedures. Participants shared perceptions of high treatment efficacy of their assigned intervention. They reported ongoing HIV and mental health stigma in their communities and emphasized the importance of social support from clinic staff. Our findings suggest a full-scale trial of PPD treatment will be acceptable among women with HIV in Zambia.

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1-13 C]pyruvate.

PURPOSE: Pyruvate, produced from either glucose, glycogen, or lactate, is the dominant precursor of cerebral oxidative metabolism. Pyruvate dehydrogenase (PDH) flux is a direct measure of cerebral mitochondrial function and metabolism. Detection of [13 C]bicarbonate in the brain from hyperpolarized [1-13 C]pyruvate using carbon-13 (13 C) MRI provides a unique opportunity for assessing PDH flux in vivo. This study is to assess changes in cerebral PDH flux in response to visual stimuli using in vivo 13 C MRS with hyperpolarized [1-13 C]pyruvate. METHODS: From seven sedentary adults in good general health, time-resolved [13 C]bicarbonate production was measured in the brain using 90° flip angles with minimal perturbation of its precursors, [1-13 C]pyruvate and [1-13 C]lactate, to test the hypothesis that the appearance of [13 C]bicarbonate signals in the brain reflects the metabolic changes associated with neuronal activation. With a separate group of healthy participants (n = 3), the likelihood of the bolus-injected [1-13 C]pyruvate being converted to [1-13 C]lactate prior to decarboxylation was investigated by measuring [13 C]bicarbonate production with and without [1-13 C]lactate saturation. RESULTS: In the course of visual stimulation, the measured [13 C]bicarbonate signal normalized to the total 13 C signal in the visual cortex increased by 17.1% ± 15.9% (p = 0.017), whereas no significant change was detected in [1-13 C]lactate. Proton BOLD fMRI confirmed the regional activation in the visual cortex with the stimuli. Lactate saturation decreased bicarbonate-to-pyruvate ratio by 44.4% ± 9.3% (p < 0.01). CONCLUSION: We demonstrated the utility of 13 C MRS with hyperpolarized [1-13 C]pyruvate for assessing the activation of cerebral PDH flux via the detection of [13 C]bicarbonate production.

Discriminatory Healthcare Experiences and Medical Mistrust in Patients With Serious Illness.

CONTEXT: Though discrimination in healthcare settings is increasingly recognized, the discriminatory experiences of patients with serious illness has not been well studied. OBJECTIVES: Describe racial differences in patient-reported experiences with discrimination in the healthcare setting and examine its association with mistrust. METHODS: We used surveys containing patient-reported frequency of discrimination using the Discrimination in Medical Setting (DMS) and Microaggressions in Health Care Settings (MHCS) scales, mistrust using the Group Based Medical Mistrust (GBMM) scale, and patient characteristics including patient-reported race, income, wealth, insurance status, and educational attainment. Univariable and multivariable linear regression models as well as risk ratios were used to examine associations between patient characteristics including self-reported race, and DMS, MHCS, and GBMM scores. RESULTS: In 174 participants with serious illness, racially minoritized patients were more likely to report experiencing discrimination and microaggressions. In adjusted analyses, DMS scores were associated with elements of class and not with race. Black, Native American/Alaskan Native (NA/AN), and multiracial participants had higher MHCS scores compared to White participants with similar levels of income and education. Higher income was associated with lower GBMM scores in participants with similar DMS or MHCS scores, but Black and NA/AN participants still reported higher levels of mistrust. CONCLUSION: In this cross-sectional study of patients with serious illness, discriminatory experiences were associated with worse mistrust in the medical system, particularly for Black and NA/AN participants. These findings suggest that race-conscious approaches are needed to address discrimination and mistrust in marginalized patients with serious illness and their families.

Physician Perspectives on Addressing Anti-Black Racism.

Importance: Uncertainty remains among clinicians regarding processes to address and resolve conflict around anti-Black racism. Objective: To elicit clinicians' perceptions of their role in addressing concerns about anti-Black racism among Black patients with serious illness as well as their families. Design, Setting, and Participants: In this qualitative study, one-on-one semistructured interviews were conducted with 21 physicians at an academic county hospital between August 1 and October 31, 2022. Participants were provided clinical scenarios where anti-Black racism was a concern of a patient with serious illness. Participants were asked open-ended questions about initial impressions, prior similar experiences, potential strategies to address patients' concerns, and additional resources to support these conversations. A framework based on restorative justice was used to guide qualitative analyses. Main Outcomes and Measures: Perspectives on addressing anti-Black racism as described by physicians. Results: A total of 21 medical subspecialists (mean [SD] age, 44.2 [7.8] years) participated in the study. Most physicians were women (14 [66.7%]), 4 were Asian (19.0%), 3 were Black (14.3%), and 14 were White (66.7%). Participants identified practices that are normalized in clinical settings that may perpetuate and exacerbate perceptions of anti-Black racism. Using provided scenarios and personal experiences, participants were able to describe how Black patients are harmed as a result of these practices. Last, participants identified strategies and resources for addressing Black patients' concerns and facilitating conflict resolution, but they stopped short of promoting personal or team accountability for anti-Black racism. Conclusions and Relevance: In this qualitative study, physicians identified resources, skills, and processes that partially aligned with a restorative justice framework to address anti-Black racism and facilitate conflict resolution, but did not provide steps for actualizing accountability. Restorative justice and similar processes may provide space within a mediated setting for clinicians to repair harm, provide accountability, and facilitate racial healing.

Temporal dynamics of neurobehavioral hormone sensitivity in a scaled-down experimental model of early pregnancy and parturition.

The hormonal changes of pregnancy and parturition can trigger robust changes in affective state, particularly among patients with a history of postpartum depression. However, more work is needed to elucidate the temporal dynamics of symptom emergence. The current study explored how quickly hormone-sensitive (HS+) individuals can be differentiated from hormone-insensitive (HS-) controls in the context of a tightly controlled experimental hormone manipulation, and which symptoms demonstrate the most rapid, consistent, and largest response during this protocol. Participants were female, non-pregnant, and euthymic, with a history of DSM-5 major depressive episode with peripartum onset (n = 15) or parous healthy controls with no psychiatric history (n = 15). Perinatal hormonal changes were simulated by inducing hypogonadism, adding back estradiol (E2) and progesterone (P4) to reach first-trimester levels for 8 weeks, and then subsequently withdrawing both hormones. Those reporting a 30% or greater increase during addback or withdrawal on select subscales of the Inventory of Depression and Anxiety Symptoms (IDAS) were identified as HS+. Participants provided daily ratings of symptoms throughout the study via the Daily Record of Severity of Problems. Results indicated that HS+ participants could be differentiated from HS- participants early in the hormone protocol, with many symptoms showing significantly greater change from baseline within the first week of addback. Notably, the most rapid symptom increases were observed for Anger/Irritability, Mood Swings, Overwhelm, Lethargy, Increased Appetite, Joint and Muscle Pain, and Breast Tenderness, reaching 50% of peak group contrast within the first week of hormone addback. The largest group effects were observed for Anger/Irritability, followed by Fatigue and Anxiety, and the most consistent group effects were observed for Anger/Irritability, Interpersonal Conflict, Overwhelm, and Hopelessness. Findings support the role of reproductive hormones in the onset of perinatal affective disorders. The rapid emergence of anger and irritability in HS+ participants suggests that these symptoms may be early indicators of perinatal hormone sensitivity.

Toddler negative affectivity and effortful control: Relations with parent-toddler conversation engagement and indirect effects on language.

Evidence that early parent-child conversation supports early language development suggests a need to understand factors that account for individual differences in parent-child conversation engagement. Whereas most studies focus on demographic factors, we investigated the role of toddler temperament in a longitudinal study of 120 economically strained families. Specifically, we investigated the degree to which toddlers' negative affectivity and effortful control, considered together as a composite reflecting challenging temperament, accounted for variability in parent-toddler conversation engagement, and whether the frequency of that engagement mediated associations between toddler temperament and toddler expressive language skills. Toddler challenging temperament (i.e., high negative affectivity and low effortful control) and parent-toddler conversation engagement were measured at 18 and 30 months. Toddler expressive language skills were measured at 18, 24, and 36 months. As expected, a path model indicated inverse relations between toddler challenging temperament and concurrent parent-toddler conversation engagement at both 18 and 30 months. Unexpectedly, there were no direct associations between toddler challenging temperament and toddler expressive language skills either concurrently or longitudinally. However, we found indirect effects of toddler challenging temperament on later toddler expressive language skills via parent-toddler conversation engagement. Findings highlight the importance of considering toddler temperamental characteristics in addition to family demographics as important factors that account for variability in parent-toddler conversation engagement.

Physician Perspectives on Responding to Clinician-Perpetuated Interpersonal Racism Against Black Patients with Serious Illness.

BACKGROUND: Racism negatively affects clinical outcomes in Black patients, but uncertainty remains among physicians regarding how to address interpersonal anti-Black racism incidences involving them to facilitate racial healing and promote accountability. OBJECTIVE: Elicit physician perspectives on addressing concerns from Black patients about interpersonal racism involving them or their team. PARTICIPANTS: Twenty-one physician subspecialists at an urban academic medical center. APPROACH: We conducted one-on-one semi-structured interviews to help inform the development of a clinician-facing component of a program to address the distress of racism experienced by Black patients with serious illness. We asked clinicians to describe experiences discussing racism with patients and identify additional resources to support these conversations. MAIN MEASURES: Physician perspectives, including barriers and facilitators, to promote racial healing and clinician accountability when discussing clinician-perpetuated interpersonal racism with Black patients. KEY RESULTS: Of the 21 participating physicians, 67% were women with a mean age of 44.2 years and mean of 10.8 years of experience as an attending physician. Four identified as Asian, three identified as Black, and 14 identified as White. Participants largely felt unprepared to discuss racism with their patients, especially if the harm was caused by them or their team. Participants felt patients should be given tools to discuss concerns about racism with their clinicians, but worried about adding additional burdens to Black patients to call out racism. Participants believed programs and processes with both patient- and clinicians-facing components had the potential to empower patients while providing resources and tools for clinicians to engage in these highly sensitive discussions without perpetuating more harm. CONCLUSIONS: Addressing and improving communication about interpersonal racism in clinical settings are challenging. Dual-facing programs involving patients and clinicians may help provide additional resources to address experiences of interpersonal racism and hold clinicians accountable.

Simultaneous Symmetry Procedure in Patients Undergoing Oncoplastic Breast-Conserving Surgery: An Evaluation of Patient Desire and Revision Rates.

INTRODUCTION: In the era of oncoplastic breast conserving-surgery (OBCS), cosmetic outcomes and the desire for symmetry have become essential elements of the surgical management of breast cancer (BC). The timing of contralateral symmetry procedures remains a controversial topic. Simultaneous symmetry procedures (SSP) in OBCS have not been routinely offered due to the perceived risk of delayed asymmetry, potentially increasing the need for delayed cosmetic revision. This study evaluates the rate of revision after SSP in patients undergoing OBCS. METHODS: We reviewed our institutional prospectively maintained database identifying all BC patients treated surgically since our introduction of oncoplastic surgery in 2018. We routinely offer SSP when appropriate. Descriptive statistics evaluated oncoplastic surgical techniques, SSP offerings and procedures, perioperative complications, and revision rates after treatment completion. RESULTS: Between 2018 and 2022, 485 breast cancer patients underwent partial mastectomy, and 396 (82%) underwent OBCS. Of the 313 patients offered SSP, 272 (87%) accepted. The margin reexcision rate of this cohort was 20%. Of the 272 patients with SSP, 152 (56%) underwent intraoperative radiation therapy (IORT), and 105 (39%) had adjuvant external beam radiation therapy. Three patients (1%) experienced complications involving the symmetry side. No patients with complications experienced a delay in adjuvant therapies or requested cosmetic revisions. Three patients (1%) desired surgical revisions due to asymmetry. CONCLUSIONS: Symmetry procedures at the time of OBCS are widely accepted by patients and rarely require delayed cosmetic revision. Simultaneous symmetry procedures should be routinely discussed with patients during the surgical planning of OBCS.

A Look at the Other Side: High-Risk Lesions and Occult Contralateral Malignancy in Symmetry Procedures for Patients Undergoing Oncoplastic Breast-Conserving Surgery.

BACKGROUND: The incidence of occult breast cancer among patients undergoing reduction mammoplasty or risk-reducing mastectomies ranges from 1% to approximately 10%, respectively. Identification of incidental cancer often mandates subsequent mastectomy due to ambiguous margins. This study aimed to determine the incidence of contralateral malignancy among patients undergoing oncoplastic breast-conserving surgery (OBCS) with concurrent symmetry procedures. METHODS: The authors reviewed their prospectively maintained institutional database of patients with unilateral breast cancer who underwent OBCS. Patients who underwent excisional biopsy on the contralateral breast were analyzed separately. Patient demographics, pathologic features, and subsequent disease management were evaluated. RESULTS: Between March 2018 and July 2022, 289 patients underwent OBCS with a symmetry procedure, and 100 patients yielded contralateral breast tissue specimens. For 14 patients, a planned excisional biopsy was performed with their symmetry procedure, and five lesions (36%) were found to be malignant. Of the remaining 86 patients, 92% underwent preoperative breast magnetic resonance imaging (MRI). Four patients (4.7%) had occult malignancies identified on the contralateral breast pathology; three patients with ductal carcinoma in situ and one patient with invasive lobular carcinoma. Three patients had undergone preoperative MRI without suspicious findings. No patients required mastectomy for treatment of the contralateral breast cancer. CONCLUSION: The incidence of occult malignancy among OBCS symmetry procedures approaches 5%. The final pathology of excisional biopsies had a higher upgrade rate than previously reported. All identified malignancies were early-stage disease. The higher incidence of occult breast cancer in this population warrants the routine orientation of all specimens, which allows patients with incidental early-stage cancer the option of breast preservation.

Perspectives About Racism and Patient-Clinician Communication Among Black Adults With Serious Illness.

Importance: Black patients with serious illness experience higher-intensity care at the end of life. Little research has used critical, race-conscious approaches to examine factors associated with these outcomes. Objective: To investigate the lived experiences of Black patients with serious illness and how various factors may be associated with patient-clinician communication and medical decision-making. Design, Setting, and Participants: In this qualitative study, one-on-one, semistructured interviews were conducted with 25 Black patients with serious illness hospitalized at an urban academic medical center in Washington State between January 2021 and February 2023. Patients were asked to discuss experiences with racism, how those experiences affected the way they communicated with clinicians, and how racism impacted medical decision-making. Public Health Critical Race Praxis was used as framework and process. Main Outcomes and Measures: The experience and of racism and its association, as described by Black patients who had serious illness, with patient-clinician communication and medical decision-making within a racialized health care setting. Results: A total of 25 Black patients (mean [SD] age, 62.0 [10.3] years; 20 males [80.0%]) with serious illness were interviewed. Participants had substantial socioeconomic disadvantage, with low levels of wealth (10 patients with 0 assets [40.0%]), income (annual income <$25 000 among 19 of 24 patients with income data [79.2%]), educational attainment (mean [SD] 13.4 [2.7] years of schooling), and health literacy (mean [SD] score in the Rapid Estimate of Adult Literacy in Medicine-Short Form, 5.8 [2.0]). Participants reported high levels of medical mistrust and high frequency of discrimination and microaggressions experienced in health care settings. Participants reported epistemic injustice as the most common manifestation of racism: silencing of their own knowledge and lived experiences about their bodies and illness by health care workers. Participants reported that these experiences made them feel isolated and devalued, especially if they had intersecting, marginalized identities, such as being underinsured or unhoused. These experiences were associated with exacerbation of existing medical mistrust and poor patient-clinician communication. Participants described various mechanisms of self-advocacy and medical decision-making based on prior experiences with mistreatment from health care workers and medical trauma. Conclusions and Relevance: This study found that Black patients' experiences with racism, specifically epistemic injustice, were associated with their perspectives on medical care and decision-making during serious illness and end of life. These findings suggest that race-conscious, intersectional approaches may be needed to improve patient-clinician communication and support Black patients with serious illness to alleviate the distress and trauma of racism as these patients near the end of life.

Scaling up quality-assured psychotherapy: The role of therapist competence on perinatal depression and anxiety outcomes.

OBJECTIVES: To examine: (1) the psychometric properties of two therapist competence measures-multiple choice questionnaire (MCQ) and standardized role-plays; (2) whether therapist competence differed between non-specialist (NSPs) and specialist (SPs) providers; and (3) the relations between therapist competence and patient outcomes among perinatal patients receiving brief psychotherapy. METHODS: This study is embedded within the SUMMIT Trial-a large, ongoing psychotherapy trial for perinatal women with depressive and anxiety symptoms. We assessed the: (1) psychometric properties of therapist competence measures using Cronbach's alpha and inter-class correlation; (2) differences in therapist competence scores between n = 23 NSPs and n = 22 SPs using a two-sample t-test; and (3) relations between therapist competence measures and perinatal patient outcomes through a linear regression model. RESULTS: Internal consistency for role-play was acceptable (α = 0.71), whereas MCQ was excellent (α = 0.97). Role-play showed good inter-rater reliability (ICC = 0.80) and scores were higher for SPs compared with NSPs (t(2,38) = -2.86, p = 0.0069) and associated with outcomes of anxiety (B = 1.52, SE = 0.60, p = 0.01) and depressive (B = 0.96, SE = 0.55, p = 0.08) symptom scores. CONCLUSIONS: Our study highlights the importance of demonstrating psychological treatment skills through standardized role-plays over knowledge-based competence to predict perinatal patient outcomes. Using well-defined evidence-based tools is critical for deploying NSPs to provide high-quality psychotherapy and increase accessibility to psychological treatments for perinatal populations worldwide.

Intervention to Promote Communication About Goals of Care for Hospitalized Patients With Serious Illness: A Randomized Clinical Trial.

Importance: Discussions about goals of care are important for high-quality palliative care yet are often lacking for hospitalized older patients with serious illness. Objective: To evaluate a communication-priming intervention to promote goals-of-care discussions between clinicians and hospitalized older patients with serious illness. Design, Setting, and Participants: A pragmatic, randomized clinical trial of a clinician-facing communication-priming intervention vs usual care was conducted at 3 US hospitals within 1 health care system, including a university, county, and community hospital. Eligible hospitalized patients were aged 55 years or older with any of the chronic illnesses used by the Dartmouth Atlas project to study end-of-life care or were aged 80 years or older. Patients with documented goals-of-care discussions or a palliative care consultation between hospital admission and eligibility screening were excluded. Randomization occurred between April 2020 and March 2021 and was stratified by study site and history of dementia. Intervention: Physicians and advance practice clinicians who were treating the patients randomized to the intervention received a 1-page, patient-specific intervention (Jumpstart Guide) to prompt and guide goals-of-care discussions. Main Outcomes and Measures: The primary outcome was the proportion of patients with electronic health record-documented goals-of-care discussions within 30 days. There was also an evaluation of whether the effect of the intervention varied by age, sex, history of dementia, minoritized race or ethnicity, or study site. Results: Of 3918 patients screened, 2512 were enrolled (mean age, 71.7 [SD, 10.8] years and 42% were women) and randomized (1255 to the intervention group and 1257 to the usual care group). The patients were American Indian or Alaska Native (1.8%), Asian (12%), Black (13%), Hispanic (6%), Native Hawaiian or Pacific Islander (0.5%), non-Hispanic (93%), and White (70%). The proportion of patients with electronic health record-documented goals-of-care discussions within 30 days was 34.5% (433 of 1255 patients) in the intervention group vs 30.4% (382 of 1257 patients) in the usual care group (hospital- and dementia-adjusted difference, 4.1% [95% CI, 0.4% to 7.8%]). The analyses of the treatment effect modifiers suggested that the intervention had a larger effect size among patients with minoritized race or ethnicity. Among 803 patients with minoritized race or ethnicity, the hospital- and dementia-adjusted proportion with goals-of-care discussions was 10.2% (95% CI, 4.0% to 16.5%) higher in the intervention group than in the usual care group. Among 1641 non-Hispanic White patients, the adjusted proportion with goals-of-care discussions was 1.6% (95% CI, -3.0% to 6.2%) higher in the intervention group than in the usual care group. There was no evidence of differential treatment effects of the intervention on the primary outcome by age, sex, history of dementia, or study site. Conclusions and Relevance: Among hospitalized older adults with serious illness, a pragmatic clinician-facing communication-priming intervention significantly improved documentation of goals-of-care discussions in the electronic health record, with a greater effect size in racially or ethnically minoritized patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04281784.

Race-conscious serious illness communication: An interpersonal tool to dismantle racism in practice and research.

BACKGROUND: Racism significantly contributes to inequitable care quality and outcomes for people of color with serious illness, their families, and their communities. Clinicians use serious illness communication (SIC) to foster trust, elicit patients' needs and values, and deliver goal-concordant services. Current SIC tools do not actively guide users to incorporate patients' experiences with racism into care. OBJECTIVES: 1) To explicitly address racism during SIC in the context of the patient's lived experience and 2) to provide race-conscious SIC recommendations for clinicians and researchers. METHODS: Applying the conceptual elements of Public Health Critical Race Praxis to SIC practice and research through reflection on inclusive SIC approaches and a composite case. RESULTS: Patients' historical and ongoing narratives of racism must be intentionally welcomed in physically and psychologically safe environments by leveraging empathic communication opportunities, forging antiracist palliative care practices, removing interpersonal barriers to promote transparent patient-clinician relationships, and strengthening organizational commitments to strategically dismantle racism. Race-conscious SIC communication strategies, skills, and examples of talking points are provided. DISCUSSION: Race-conscious SIC practices may assist to acknowledge racial dynamics within the patient-clinician encounter. Furthermore, race-conscious SIC may help to mitigate implicit and explicit bias in clinical practices and the exclusionary research cultures that guide them.

3D Printability of Silk/Hydroxyapatite Composites for Microprosthetic Applications.

Micro-prosthetics requires the fabrication of mechanically robust and personalized components with sub-millimetric feature accuracy. Three-dimensional (3D) printing technologies have had a major impact on manufacturing such miniaturized devices for biomedical applications; however, biocompatibility requirements greatly constrain the choice of usable materials. Hydroxyapatite (HA) and its composites have been widely employed to fabricate bone-like structures, especially at the macroscale. In this work, we investigate the rheology, printability, and prosthetic mechanical properties of HA and HA-silk protein composites, focusing on the roles of composition and water content. We correlate key linear and nonlinear shear rheological parameters to geometric outcomes of printing and explain how silk compensates for the inherent brittleness of printed HA components. By increasing ink ductility, the inclusion of silk improves the quality of printed items through two mechanisms: (1) reducing underextrusion by lowering the required elastic modulus and, (2) reducing slumping by increasing the ink yield stress proportional to the modulus. We demonstrate that the elastic modulus and compressive strength of parts fabricated from silk-HA inks are higher than those for rheologically comparable pure-HA inks. We construct a printing map to guide the manufacturing of HA-based inks with excellent final properties, especially for use in biomedical applications for which sub-millimetric features are required.

Structural basis for reduced ribosomal A-site fidelity in response to P-site codon-anticodon mismatches.

Rapid and accurate translation is essential in all organisms to produce properly folded and functional proteins. mRNA codons that define the protein-coding sequences are decoded by tRNAs on the ribosome in the aminoacyl (A) binding site. The mRNA codon and the tRNA anticodon interaction is extensively monitored by the ribosome to ensure accuracy in tRNA selection. While other polymerases that synthesize DNA and RNA can correct for misincorporations, the ribosome is unable to correct mistakes. Instead, when a misincorporation occurs, the mismatched tRNA-mRNA pair moves to the peptidyl (P) site and, from this location, causes a reduction in the fidelity at the A site, triggering post-peptidyl transfer quality control. This reduced fidelity allows for additional incorrect tRNAs to be accepted and for release factor 2 (RF2) to recognize sense codons, leading to hydrolysis of the aberrant peptide. Here, we present crystal structures of the ribosome containing a tRNALys in the P site with a U•U mismatch with the mRNA codon. We find that when the mismatch occurs in the second position of the P-site codon-anticodon interaction, the first nucleotide of the A-site codon flips from the mRNA path to engage highly conserved 16S rRNA nucleotide A1493 in the decoding center. We propose that this mRNA nucleotide mispositioning leads to reduced fidelity at the A site. Further, this state may provide an opportunity for RF2 to initiate premature termination before erroneous nascent chains disrupt the cellular proteome.

Perimenopausal Effects of Estradiol on Anhedonia and Psychosis Study (PEEPs): study protocol for a neural and molecular mechanistic clinical trial.

BACKGROUND: The perimenopausal transition is accompanied by psychiatric symptoms in over 10% of women. Symptoms commonly include depressed mood and anhedonia and less commonly include psychosis. Psychiatric symptoms have been linked to the depletion and/or variability of circulating estradiol, and estradiol treatment reduces perimenopausal anhedonia and psychosis in some women. Estrogen fluctuations may disrupt function in the mesolimbic reward system in some women, leading to psychiatric symptoms like anhedonia or psychosis. The Perimenopausal Effects of Estradiol on Anhedonia and Psychosis Study (PEEPs) is a mechanistic clinical trial that aims to (1) identify relationships between perimenopausal-onset anhedonia and psychosis and neuromolecular markers of mesolimbic reward responses and (2) determine the extent to which estradiol treatment-induced changes in mesolimbic reward responses are associated with alleviation of perimenopausal onset anhedonia or psychosis. METHODS: This study will recruit 100 unmedicated women ages 44-55 in the late-stage perimenopausal transition, sampling across the range of mild-to-high anhedonia and absent-to-moderate psychosis symptoms. Patients will be randomized to receive either estradiol or placebo treatment for 3 weeks. Clinical outcome measures will include symptoms of anhedonia (measured with Snaith-Hamilton Pleasure Scale; SHAPS) and psychosis (measured with Brief Psychiatric Rating Scale; BPRS psychosis subscale) as well as neural markers of mesolimbic reward system functioning, including reward-related fMRI activation and PET-derived measure of striatal dopamine binding. Pre-treatment associations between (1) SHAPS/BPRS scores and (2) reward-related striatal dopamine binding/BOLD activation will be examined. Furthermore, longitudinal mixed models will be used to estimate (1) symptom and neuromolecular trajectories as a function of estradiol vs. placebo treatment and (2) how changes in reward-related striatal dopamine binding and BOLD activation predict variability in symptom trajectories in response to estradiol treatment. DISCUSSION: This clinical trial will be the first to characterize neural and molecular mechanisms by which estradiol treatment ameliorates anhedonia and psychosis symptoms during the perimenopausal transition, thus laying the groundwork for future biomarker research to predict susceptibility and prognosis and develop targeted treatments for perimenopausal psychiatric symptoms. Furthermore, in alignment with the National Institute for Mental Health Research Domain Criteria initiative, this trial will improve our understanding of a range of disorders characterized by anhedonia, psychosis, and reward system dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT05282277.

Psychological distress and treatment preferences among parents amidst the COVID-19 pandemic.

The COVID-19 pandemic has presented many stressors for parents. This study was conducted to examine treatment preferences and barriers to care amidst COVID-19. Parents (N â€‹= â€‹95) completed self-report measures. Education was provided on interventions (e.g., individual therapy, medication), and acceptability assessed. Elevated stress and distress were observed. Parents indicated interest in services for parenting concerns, stress, anxiety, and depression. Individual therapy and telehealth were highly acceptable, while medication and group therapy were less accepted. Findings highlight the need for specific supports among parents amidst the pandemic. Factors that influence treatment preference warrant further attention. Implications for healthcare service delivery are discussed.