Evaluating the Impact of a Pediatric Inpatient Social Care Program in a Community Hospital.

OBJECTIVES: To evaluate the impact of implementing a stakeholder-informed social risk screening and social service referral system in a community hospital setting. METHODS: We implemented a stakeholder-informed social care program at a community hospital in April 2022. The evaluation included patients aged 0 to 17 years admitted to the pediatric unit between April 2021 and March 2022 (1 year preimplementation) and between April 2022 and March 2023 (1 year postimplementation). For a random subset of 232 preimplementation and 218 postimplementation patients, we performed manual data extraction, documenting program process measures and preliminary effectiveness outcomes. We used χ square and Wilcoxon rank tests to compare outcomes between the preimplementation and postimplementation groups. Multivariable logistic regression was used to assess the preliminary effectiveness of the social care program in identifying social risks. RESULTS: Screening rates were higher in the postimplementation group for nearly all social domains. Compared with preimplementation, the postimplementation group had higher rates of social risks identified (17.4% vs 7.8% [P < .01]: adjusted odds ratio 2.9 [95% confidence interval 1.5-5.5]) on multivariate testing. Social work consults were completed more frequently and earlier for the postimplementation group (13.8.% vs 5.6% [P < .01]) and median (19 hours vs 25 hours [P = .03]), respectively. Rates of communication of social risks in discharge summaries were higher in the postimplementation group (46.8% vs 8.2% [P < .001]). CONCLUSIONS: The implementation of a stakeholder-informed social care program within a community hospital setting led to the increased identification of social risks and social work consultations and improved timeliness of social work consultations and written communication of social risks in discharge summaries for primary care providers.

Caregiving Strain Mediates the Relationship Between Terminally Ill Patient's Physical Symptoms and Their Family Caregivers' Wellbeing: A Multicentered Longitudinal Study.

Objectives: Research considered patient outcomes primarily over caregivers in end-of-life care settings. The importance of family caregivers (FCs) in end-of-life care draws growing awareness, evidenced by an increasing number of evaluations of caregiver-targeted interventions. Little is known of FCs' collateral benefits in patient-oriented home-based end-of-life care. The study aims to investigate FC outcomes and change mechanisms in patient-oriented care. Methods: A pre-post-test study. We recruited FCs whose patients with a life expectancy ≤ 6 months enrolled in home-based end-of-life care provided by service organizations in Hong Kong. Patients' symptoms, dimensions of caregiving strain (ie, perception of caregiving, empathetic strain, adjustment demands), and aspects of FCs' wellbeing (ie, perceived health, positive mood, life satisfaction, spiritual well-being) were measured at baseline (T0) and 3 months later (T1). Results: Of the 345 FCs at T0, 113 provided T1 measures. Three months after the service commenced, FCs' caregiving strain significantly reduced, and their positive mood improved. Alleviation of the patient's physical symptoms predicted FC better outcomes, including the perception of caregiving, empathetic strain, and wellbeing. Changes in perception of caregiving mediated the effects of changes in patients' physical symptoms on FCs' changes in life satisfaction and spiritual wellbeing. Changes in empathetic strain mediated the changes between patient's physical symptoms and FCs' positive mood. Conclusions: Collateral benefits of patient-oriented home-based end-of-life care were encouraging for FCs. Patient's physical symptom management matters to FCs' caregiving strain and wellbeing. The active ingredients modifying FCs' perception of caregiving and addressing empathetic strain may amplify their benefits in wellbeing.

Redefining caregiver strain for family caregivers in end-of-life care in Hong Kong.

OBJECTIVES: Caregiving for family members at their end of life is stressful. Caregivers' strain, burden, or stress has been measured in various geographical and sociodemographic contexts. The concept of stress, burden, and strain are sometimes used interchangeably. By analysing the factor structure of the Chinese version of the Modified Caregiver Strain Index (C-M-CSI), this study aimed to examine the caregiving strain concept and its demographic correlates. METHODS: A sample of 453 family caregivers of patients with a terminal illness in Hong Kong was employed. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed. In addition, generalized linear models (GLM) were used to examine the demographic correlates. RESULTS: The EFA yielded a 3-factor model termed "Perception of Caregiving," "Empathetic Strain," and "Adjustment Demand." This 3-factor model explained 50% of the variance and showed good internal consistency. The CFA confirmed the 3-factor construct with satisfactory internal reliability (χ2 [61, N = 226] = 108.86, p < 0.001, CFI = 0.96, TLI = 0.95, SRMR = 0.04, and RMSEA = 0.06). Inspired by this factor structure and concepts of stress and strain from engineering discipline, a new model of caregiver strain is proposed. Additionally, family caregivers of non-cancer patients, who were not living with the patient, or younger were associated negatively with different dimensions of caregiver strain. SIGNIFICANCE OF RESULTS: The results gave insights into the advancement of the conceptualization of caregiver strain, its multidimensional nature, and process of change, which inform directions for future research and practices.

The Physical and Psychosocial Outcomes of a Psychosocial Home-Based end-of-Life Care Intervention in Hong Kong.

OBJECTIVE: Living the final days of life being cared for at home is a preference expressed by many. The data on the effectiveness of home-based end-of-life care (EoLC) intervention to improve the holistic conditions of terminally ill patients are scanty. This study sought to evaluate a psychosocial home-based EoLC intervention for terminally ill patients in Hong Kong. METHODS: A prospective cohort study was conducted, applying the Integrated Palliative Care Outcome Scale (IPOS) at 3 timepoints (service intake, 1-month, and 3-months after enrollment). A total of 485 eligible, consenting terminally ill people (mean age = 75.48, SD = 11.39) were enrolled, with 40.21% (n = 195) providing data at all 3 timepoints for this study. RESULTS: Decreasing symptom severity scores were observed for all IPOS psychosocial symptoms, and most physical symptoms, over the 3 timepoints. Improvements in depression and practical concerns had the highest omnibus time effects (F > 31.92, P < .01) and T0 to T2 paired comparison effects (Cohen's d > 0.54, P < .01). Physical symptoms of weakness/lack of energy, poor mobility, and poor appetite also showed significant improvements at T1 and T2 (Cohen's d: 0.22-0.46, P < .05). Bivariate regression analyses showed that improvements in anxiety, depression, and family anxiety were associated with improvements in physical symptoms of pain, shortness of breath, weakness/lack of energy, nausea, poor appetite, and poor mobility. Patients' demographic and clinical characteristics were not associated with changes in symptoms. CONCLUSIONS: The psychosocial home-based EoLC intervention effectively improved the psychosocial and physical status of terminally ill patients, irrespective of their clinical characteristics or demographics.

Factors associated with reduced function and quality of life among adult people with HIV with depression and substance use in the Asia-Pacific region.

BACKGROUND: Depression and substance use (SU) disorders are prevalent among people with HIV (PWH) and impact health outcomes despite successful antiretroviral therapy (ART). We explored quality of life, functional ability and associated factors among PWH screened positive for depression and/or SU. METHODS: This cross-sectional study recruited adult PWH during routine follow-up at five HIV clinical sites in the Asia-Pacific region. Participants were screened for depression using Patient Health Questionnaire-9 and SU using Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Quality of life (QoL) was assessed with WHOQOL-HIV BREF and functional ability with World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with mean QoL and disability scores were analysed using linear regression. RESULTS: Of 864 PWH enrolled, 753 screened positive for depression or SU. The median (interquartile range, IQR) age was 38 (31-47) years and 97% were on ART. Overall mean WHOQOL-HIV BREF and WHODAS scores indicated greater impairment with increasing depressive symptom severity and SU risk. In multivariate analysis, PWH reporting previous trauma/stress (difference = 2.7, 95% confidence interval [CI] 1.5-3.9, P  < 0.001) and past mental health diagnosis (difference = 5.0, 95% CI 2.9-7.1, P  < 0.001) were associated with greater disability and poorer QoL scores across multiple domains ( P < 0.01 for all). Higher CD4 T-cell counts was also associated with better QoL scores and functional ability. CONCLUSION: PWH with depression/SU experienced poorer QoL and function despite routine engagement in HIV care. Efforts to integrate mental health services and interventions addressing disability into HIV management should be prioritized in the region.

The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 -) advanced/metastatic breast cancer.

PURPOSE: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. METHODS: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 -) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. RESULTS: Patients (N = 152) received GDC-0810 100-800 mg once daily (QD) or 300-400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). CONCLUSION: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 .

Prevalence and Risks of Depression and Substance Use Among Adults Living with HIV in the Asia-Pacific Region.

Despite the mental health and substance use burden among people living with HIV (PLHIV) in the Asia-Pacific, data on their associations with HIV clinical outcomes are limited. This cross-sectional study of PLHIV at five sites assessed depression and substance use using PHQ-9 and ASSIST. Among 864 participants, 88% were male, median age was 39 years, 97% were on ART, 67% had an HIV viral load available and < 1000 copies/mL, 19% had moderate-to-severe depressive symptoms, and 80% had ever used at least one substance. Younger age, lower income, and suboptimal ART adherence were associated with moderate-to-severe depressive symptoms. Moderate-to-high risk substance use, found in 62% of users, was associated with younger age, being male, previous stressors, and suboptimal adherence. Our findings highlight the need for improved access to mental health and substance use services in HIV clinical settings.

The 'sustainability gap' of US broiler chicken production: trade-offs between welfare, land use and consumption.

In 2018, over nine billion chickens were slaughtered in the United States. As the demand for chickens increases, so too have concerns regarding the welfare of the chickens in these systems and the damage such practices cause to the surrounding ecosystems. To address welfare concerns, there is large-scale interest in raising chickens on pasture and switching to slower-growing, higher-welfare breeds as soon as 2024. We created a box model of US chicken demographics to characterize aggregate broiler chicken welfare and land-use consequences at the country scale for US shifts to slower-growing chickens, housing with outdoor access, and pasture management. The US produces roughly 20 million metric tons of chicken meat annually. Maintaining this level of consumption entirely with a slower-growing breed would require a 44.6%-86.8% larger population of chickens and a 19.2%-27.2% higher annual slaughter rate, relative to the current demographics of primarily 'Ross 308' chickens that are slaughtered at a rate of 9.25 billion per year. Generating this quantity of slower-growing breeds in conventional concentrated animal feeding operations (CAFO) would require 90 582-98 687 km2, an increase of 19.9-30.6% over the 75 577 km2 of land used for current production of Ross 308. Housing slower-growing breeds on pasture, the more individually welfare-friendly option, would require 108 642-121 019 km2, a 43.8-60.1% increase over current land use. Allowing slower-growing breeds occasional outdoor access is an intermediate approach that would require 90 691-98 811 km2, an increase of 20-30.7% of the current land use, a very minor increase of land relative to managing slower-growing breeds in CAFOs. In sum, without a drastic reduction in consumption, switching to alternative breeds will lead to a substantial increase in the number of individuals killed each year, an untenable increase in land use, and a possible decrease in aggregate chicken welfare at the country-level scale. Pasture-based management requires substantial additional land use. These results demonstrate constraints and trade-offs in animal welfare, environmental conservation and food animal consumption, while highlighting opportunities for policies to mitigate impacts in an integrated manner using a One Health approach.

Circulating hyaluronan as a marker of endothelial glycocalyx damage in dogs with myxomatous mitral valve disease and dogs in a hypercoagulable state.

The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells, maintaining vascular health. Glycocalyx damage is pathophysiologically important in many diseases across species however few studies have investigated its breakdown in naturally occurring disease in dogs. The aims of the study were to investigate eGlx damage in dogs with myxomatous mitral valve disease (MMVD) diagnosed on echocardiography, and dogs in a hypercoagulable state diagnosed using thromboelastography (TEG), by measuring serum hyaluronan concentrations. Serum hyaluronan was quantified in dogs with MMVD (n = 27), hypercoagulability (n = 21), and in healthy controls dogs (n = 18). Serum hyaluronan concentrations were measured using a commercially-available ELISA validated for use in dogs. Hyaluronan concentrations were compared among groups using Kruskal-Wallis tests, and post-hoc with Dunn's tests. Serum hyaluronan concentrations (median [range]) were significantly increased in dogs with MMVD (62.4 [22.8-201] ng/mL; P = 0.031) and hypercoagulability (92.40 [16.9-247.6] ng/mL; P < 0.001) compared to controls (45.7 [8.7-80.2] ng/mL). Measurement of serum hyaluronan concentration offers a clinically applicable marker of eGlx health and suggests the presence of eGlx damage in dogs with MMVD and dogs in a hypercoagulable state.

Effectiveness of Educational Programs on Palliative and End-of-life Care in Promoting Perceived Competence Among Health and Social Care Professionals.

BACKGROUND: There is a growing need for palliative care for patients near the end of life and their caregivers. Palliative and end-of-life care (EoLC) education are recommended for all health care (e.g., physicians, nurses, and allied health practitioners) and social care professionals (e.g., social workers) to ensure the quality of services. However, less attention has been afforded to generic, in contrast to specialized, EoLC education. This study evaluated the effectiveness of a series of short-term generic EoLC educational programs for health and social care professionals. METHOD: A pre-post survey design was adopted, focusing on different EoLC core competences. RESULTS: Significant improvement was observed in all perceived competences after the educational programs, regardless of participants' occupation or EoLC experience. Perceived competence in self-care was rated significantly higher than all other competences prior to the programs. Healthcare professionals rated significantly higher on competence in symptom management than social workers. Scores on communication skill and self-care competences were significantly higher following longer (i.e., 16-24 hours) than shorter (i.e., 4-8 hours) programs. CONCLUSION: Generalist palliative/EoLC educational programs may enable health and social care professionals to refresh and extend their knowledge and skills and enhance their perceived competence in providing EoLC. Further research on generalist palliative/EoLC education is needed to examine the impact of continuing training on professionals' actual practice in EoLC and palliative care.

A Local Review on the Use of a Bio-Psycho-Social Model in School-Based Mental Health Promotion.

Background: Schools are a key setting for student well-being promotion. Various school-based mental health programs have been implemented worldwide, with greater emphasis placed on psychological and social aspects. The bio-psycho-social model provides a holistic and integrated view of mental health based on theory and research evidence. Given the importance of considering all three dimensions in mental health promotion, this study explored reasons for the relative neglect of this approach by studying the early phase of school well-being program development and implementation. Method: In total, 77 Hong Kong government-funded student well-being programs implemented in 2000-2009 were reviewed for the use of biological, psychological, and social interventions. Questionnaires and interviews were conducted to explore program leaders' usage and views regarding theoretical frameworks and evidence-based practice and program evaluation. Challenges encountered in the initial stage of school well-being program development and implementation were identified and analyzed. Results: Of the 77 programs reviewed, only 5 addressed all three bio-psycho-social factors of mental health. A significantly greater number of programs addressed psychological (n = 63) and social (n = 40) factors compared to those that covered biological factors of mental health (n = 13). Of 24 program implementers who responded to the online survey, 75% claimed to have studied or applied a theoretical framework yet only 41.7% considered evidence-based practices to be important. The majority of interviewed participants valued their own practical experience over theory and research evidence. Many programs lacked rigorous evaluation of clear objectives and measurable outcomes, thus the mechanisms of change and program effectiveness were uncertain. Perceived barriers to program adoption and continuation were identified. Conclusion: This study highlighted a neglect of the biological contribution to mental health in school well-being promotion initiatives, possibly due to lack of theoretical knowledge and evidence-based practice among program leaders and implementers in the early phase of school mental health promotion. The bio-psycho-social model should therefore be recommended for student well-being programs as a holistic and integrated theory of mental health underpinning program objectives, mechanisms of change, and measurable outcomes. To develop effective practices in student well-being promotion, more thorough documentation, a rigorous evaluation framework, and support for frontline educators to evaluate their practices were recommended.

Prenatal methylmercury exposure is associated with decrease heart rate variability in children.

BACKGROUND: Although several epidemiological studies have suggested mercury (Hg) might be associated with cardiotoxicity, the impact of Hg exposure on cardiac autonomic activity and blood pressure in children has not been investigated at Hg exposure levels equivalent to the Environmental Protection Agency (EPA) reference dose. OBJECTIVE: To investigate the association between low dose prenatal and recent methylmercury (MeHg) exposures and cardiac autonomic function and blood pressure with adjustment for factors such as fish consumption among children from a high fish consumption coastal city. METHODS: Children aged 7-8 years were recruited from the birth cohort of our previous study. Heart rate variability (HRV), resting heart rate (RHR) and blood pressure were measured as surrogate markers of cardiac autonomic function. Cord blood and current whole blood Hg concentration were used as biomarkers of prenatal and recent MeHg exposure, respectively. Recent fish consumption information was estimated with a food frequency questionnaire. RESULTS: Among 604 children, median cord blood and whole blood Hg concentrations were 45.9 nmol/L (IQR: 32.8-65.03 nmol/L) and 13.57 nmol/L (IQR: 9.29-19.72 nmol/L), respectively. Our results demonstrated that prenatal MeHg exposure was associated with decreased HRV (i.e. low CVRR, SDRR, and RMSSD), reflecting reduced parasympathetic activity (i.e. low CCVHF and HF), and a sympathovagal balance shift toward sympathetic predominance (i.e. high %LF and LF/HF ratio). Adjustment of recent fish consumption further increased the significance and magnitude of the adverse associations of MeHg. CONCLUSION: The results of this study suggest that prenatal MeHg exposure is associated with decreased parasympathetic modulation of cardiac autonomic function in children.

Factors facilitating positive outcomes in community-based end-of-life care: A cross-sectional qualitative study of patients and family caregivers.

BACKGROUND: Delivery of community-based end-of-life care for patients and family members has been recognized as an important public health care approach. Despite differences in different healthcare settings and the significance of a person-centered approach, little research has investigated facilitators of community-based end-of-life care from the perspective of service recipients. In particular, there has been limited exploration of strategies to ensure positive outcomes at an operational level. AIM: To explore factors facilitating positive end-of-life care provision in community-based settings and how these are achieved in practice, from the perspectives of patients and family caregivers. DESIGN: A qualitative cross-sectional descriptive study was undertaken through semi-structured interviews with patients and family caregivers subjected to thematic analysis. SETTING/PARTICIPANTS: Ten patients and 16 family caregivers were recruited from an end-of-life community care program provided by four non-governmental organizations in Hong Kong. RESULTS: Seven core themes were identified: positive emotions about the relationship, positive appraisals of the relationship, care through inquiring about recipients' circumstances, instrumentality of care (i.e. information, coaching on care, practical help, psychological support, multiple activities), comprehensiveness of care (i.e. diversity, post-death care, family-level wellbeing), structure of care (i.e. timely follow-up, well-developed system), and qualities of workers. CONCLUSIONS: Improvement in service quality might be achieved through alternating the perceptions or emotional reactions of care recipients toward care providers and increased use of sensitive inquiry. Comprehensive care and positive outcomes might be facilitated by addressing the dualities of care by providing diverse choices in pre-death and post-death care.

Development and psychometric validation of a comprehensive end-of-life care competence scale: A study based on three-year surveys of health and social care professionals in Hong Kong.

OBJECTIVE: This study aimed to develop an assessment tool measuring comprehensive interdisciplinary competence in end-of-life care (EoLC) and investigate its content, construct validity, reliability, and their correlates. METHOD: Items of the Comprehensive End-of-Life Care Competence Scale (CECCS) were developed according to a comprehensive core competence framework in EoLC and refined by a multi-disciplinary panel of experts. The psychometric properties were further tested through region-wide surveys of self-administered questionnaires completed by health and social care professionals in Hong Kong. RESULTS: Participants comprised social workers, nurses, physicians, and allied health care professionals (445 participants in 2016, 410 in 2017, and 523 in 2018). Factor analysis validated the construct of the questionnaire which encompassed 26 items describing EoLC core competences in seven domains with satisfactory internal reliability (confirmatory factor analysis: χ2/df = 3.12, GFI = 0.85, TLI = 0.93, CFI = 0.94, RMSEA = 0.07; Cronbach's alphas ranged from 0.89 to 0.97): overarching value & knowledge, communication skills, symptom management, psychosocial and community care, end-of-life decision-making, bereavement care, and self-care. Higher perceived levels in these competences were correlated with a higher level of job meaningfulness and satisfaction (r ranged from 0.17 to 0.39, p < 0.01) and correlated with lower perceived stress (r ranged from -0.11 to -0.28, p < 0.05). Regression analysis found that age and work involvement in EoLC were positively associated with the perceived competences in all domains; professionals working in hospices reported higher levels of competence than workers in other settings; social workers showed lower perceived competences in symptom management, but higher levels in bereavement care than other health care professionals. SIGNIFICANCE OF RESULTS: The validity and internal reliability of CECCS were demonstrated. The levels of perceived competences working in EoLC were significantly associated with professionals' job-related well-being. Practically, there is still room for improvement in comprehensive competences among health and social care workers in Hong Kong.

Bilateral Paragangliomas in the Setting of Autonomic Dysfunction: A Case Report.

In 2018, a 59-year-old female patient presented with hoarseness in her voice, headache, intermittent pain in her right side, difficulty of right arm movement, left side neck pain, difficulty controlling hypertension of unknown etiology, and a large mass on the upper left side of her neck with a smaller mass on the right side. MRI of the neck revealed masses at each carotid bifurcation. These were determined to be bilateral paragangliomas. Paragangliomas are rare tumors, and bilateral ones tremendously so. The patient underwent radiation over 2 years, resulting in the successful shrinking and stabilization of both masses. Since completing radiation, the patient reported improvement in her memory, and her blood pressure has stabilized with medication.

A phase Ib open-label dose escalation study of the safety, pharmacokinetics, and pharmacodynamics of cobimetinib (GDC-0973) and ipatasertib (GDC-0068) in patients with locally advanced or metastatic solid tumors.

BACKGROUND: This Phase Ib study explored combination dosing of the allosteric MEK1/2 inhibitor cobimetinib and the ATP-competitive pan-AKT inhibitor ipatasertib. METHODS: Patients with advanced solid tumors were enrolled to two dose escalation arms, each using a 3 + 3 design in 28-day cycles. In Arm A, patients received concurrent cobimetinib and ipatasertib on days 1-21. In Arm B, cobimetinib was administered intermittently with ipatasertib for 21 days. Primary objectives evaluated dose-limiting toxicities (DLTs), maximum tolerated doses (MTD), and the recommended Phase II dose (RP2D). Secondary objectives included analysis of pharmacokinetic parameters, MAPK and PI3K pathway alterations, changes in tissue biomarkers, and preliminary anti-tumor efficacy. Expansion cohorts included patients with PTEN-deficient triple-negative breast cancer and endometrial cancer. RESULTS: Among 66 patients who received ≥1 dose of study drug, all experienced an adverse event (AE). Although no DLTs were reported, 6 patients experienced Cycle 1 DLT-equivalent AEs. The most common treatment-related AEs were diarrhea, nausea, vomiting, dermatitis acneiform, and fatigue. Thirty-five (53%) patients experienced drug-related AEs of ≥ grade 3 severity. Cobimetinb/ipatasertib MTDs were 60/200 mg on Arm A and 150/300 mg on Arm B; the latter was chosen as the RP2D. No pharmacokinetic interactions were identified. Biomarker analyses indicated pathway blockade and increases in IFNγ and PD-L1 gene expression following the combination. Three patients with endometrial or ovarian cancer achieved partial response, all with PTEN-low disease and two with tumor also harboring KRAS mutation. CONCLUSION: There was limited tolerability and efficacy for this MEK and AKT inhibitor combination. Nonetheless, pharmacodynamic analyses indicated target engagement and suggest rationale for further exploration of cobimetinib or ipatasertib in combination with other anticancer agents. ClinicalTrials.gov identifier: NCT01562275.

Thoracoscopic removal of a displaced thoracoamniotic shunt in a newborn with antenatal pleural effusion-a case report.

Thoracoamniotic shunt has been considered as a treatment for antenatal pleural effusion and complication is rare. In majority of cases, the shunt can be removed uneventfully. In this article, we reported a rare complication of shunt migration resulting in the need of thoracoscopic removal at newborn period. The patient born at 39+3 weeks of gestation suffered from antenatal chylothorax detected at 28 weeks and was managed by intrauterine thoracoamniotic shunt insertion. This was complicated by shunt displacement, which caused respiratory distress after birth requiring ventilatory support and progressive pleural effusion in this patient. To prevent further neonatal compromise, thoracoscopic removal of the retained shunt was done on day 7 of life followed by post-op chest drain insertion. Post-op condition was stable with resolution of respiratory distress, and the patient was discharge on post-op day 16. We would like to remind clinicians about this potential complication of thoracoaminotic shunt, which can pose a potential risk of severe neonatal compromise, and that it can be managed by minimal invasive surgery even in the newborn period.

Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare hematopoietic disease characterized by a block in red cell differentiation. Most DBA cases are caused by mutations in ribosomal proteins and characterized by higher than normal activity of the tumor suppressor p53. Higher p53 activity is thought to contribute to DBA phenotypes by inducing apoptosis during red blood cell differentiation. Currently, there are few therapies available for patients with DBA. We performed a chemical screen using zebrafish ribosomal small subunit protein 29 (rps29) mutant embryos that have a p53-dependent anemia and identified calmodulin inhibitors that rescued the phenotype. Our studies demonstrated that calmodulin inhibitors attenuated p53 protein amount and activity. Treatment with calmodulin inhibitors led to decreased p53 translation and accumulation but does not affect p53 stability. A U.S. Food and Drug Administration-approved calmodulin inhibitor, trifluoperazine, rescued hematopoietic phenotypes of DBA models in vivo in zebrafish and mouse models. In addition, trifluoperazine rescued these phenotypes in human CD34+ hematopoietic stem and progenitor cells. Erythroid differentiation was also improved in CD34+ cells isolated from a patient with DBA. This work uncovers a potential avenue of therapeutic development for patients with DBA.

Risk perception in paranoia and anxiety: Two investigations across clinical and non-clinical populations.

OBJECTIVES: It is common, among clinical and non-clinical populations alike, for paranoia and anxiety to co-occur. It has been suggested that anxiety and its related appraisal styles may contribute to development of paranoia. We aimed to evaluate different aspects of risk perception in relation to paranoia and anxiety and to identify specific aspects that may differentiate paranoia from anxiety. This paper consists of two inter-related studies. METHODS: Study 1 compared 30 patients with persecutory delusions, 21 patients with generalized anxiety disorder and 52 healthy controls. Study 2 compared 30 non-clinical individuals with high levels of paranoia and anxiety, 28 individuals with high anxiety only and 36 healthy controls. Within each study, the two symptomatic groups were matched on level of anxiety. Four dimensions of risk perception (i.e. likelihood, harm, controllability, and intentionality) were compared across groups, as measured by the locally validated Risk Perception Questionnaire. RESULTS: In both studies, the paranoia and the anxiety groups reported an elevated perceived likelihood of negative events than controls respectively. Only the paranoia groups reported an elevated perceived harm of neutral events than controls. In Study 2, the two at-risk groups attributed more harm and intentionality to negative events than controls. CONCLUSION: Although perception of negative events was characteristic in anxiety (with or without paranoia), a biased perception of neutral events as risky was unique to the addition of paranoia. Implications to the transdiagnostic and continual view of psychopathology, and mechanism-based interventions were discussed.