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 .

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.

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.

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.

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.

Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132.

Epoxyeicosatrienoic acids (EETs) are lipid-derived signaling molecules with cardioprotective and vasodilatory actions. We recently showed that 11,12-EET enhances hematopoietic induction and engraftment in mice and zebrafish. EETs are known to signal via G protein-coupled receptors, with evidence supporting the existence of a specific high-affinity receptor. Identification of a hematopoietic-specific EET receptor would enable genetic interrogation of EET signaling pathways, and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify an EET receptor based on the expression of G protein-coupled receptors in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are expressed in three EET-responsive cell lines, but not expressed in an EET-unresponsive line. Of these, only recombinant GPR132 showed EET-responsiveness in vitro, using a luminescence-based ß-arrestin recruitment assay. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. In contrast to high-affinity EET receptors, GPR132 is reported to respond to additional hydroxy-fatty acids in vitro, and we found that these same hydroxy-fatty acids enhance hematopoiesis in the zebrafish. We conducted structure-activity relationship analyses using both cell culture and zebrafish assays on diverse medium-chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, whereas unoxygenated or saturated fatty acids had lower activity. Absence of the carbon-1 position carboxylic acid prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of oxygenated polyunsaturated fatty acids to enhance both embryonic and adult hematopoiesis.

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.

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors.

Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.

GDC-0810 Pharmacokinetics and Transporter-Mediated Drug Interaction Evaluation with an Endogenous Biomarker in the First-in-Human, Dose Escalation Study.

GDC-0810 (Cheeti et al., 2018) is an orally bioavailable, selective estrogen receptor (ER) degrader developed to treat ER-positive breast cancer. A first-in-human (FIH) dose escalation phase I study (n = 41) was conducted to characterize the pharmacokinetics (PK) of GDC-0810 and its two major metabolites. GDC-0810 demonstrated linear PK from 100 to 600 mg given once daily. The mean terminal half-life following a single 600 mg dose was approximately 8 hours. Since GDC-0810 is a potent in vitro inhibitor of organic anion transporting polypeptide (OATP) 1B1/3, the kinetic profile of coproporphyrin I (CPI), a promising endogenous biomarker for OATP1B1/3, was analyzed retrospectively in a subset of the plasma samples collected in the same FIH study. CPI exhibited a GDC-0810 dose-dependent increase, suggesting in vivo inhibition of OATP1B transporters. To quantitatively predict the magnitude of OATP1B-mediated drug-drug interactions (DDIs) with pravastatin (a known OATP1B substrate), the in vivo unbound inhibition constant was first estimated using a one-compartment model, and then incorporated to a physiologically based pharmacokinetic model. The model showed some underestimation of the magnitude of the DDI when compared with a clinical DDI study result, while prediction had a relatively large uncertainty due to the small effect size, limited sample size, and variability in CPI kinetics. In conclusion, this study characterized the pharmacokinetic profiles of GDC-0810 in breast cancer patients and demonstrated the utility of CPI in detecting OATP1B-mediated DDIs of a new molecular entity as early as FIH study. SIGNIFICANCE STATEMENT: Endogenous biomarkers of transporters have recently been shown to be promising tools in evaluating the risk of clinical transporter-mediated DDIs. This is the first study to report a pharmacokinetic interaction between an investigational molecule and a transporter biomarker in a first-in-human study. The observed interaction and model-based analysis and the prediction provide important insights on the novel approach to quantitatively predict transporter-mediated DDIs as early as FIH studies in the clinical development.

Cognitive screening in treatment-naïve HIV-infected individuals in Hong Kong - a single center study.

BACKGROUND: HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known. METHODS: Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment. RESULTS: Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p < 0.001) but their MoCA performance was similar at both assessments. Of note, 17 participants in this subgroup scored below the IHDS cut-off at both assessments. CONCLUSIONS: Poor IHDS performance, and likely cognitive impairment, was frequently observed in treatment-naïve HIV-infected individuals in our locality. A considerable proportion continued to score below the IHDS cut-off at 6 months after cART. Depression was frequently observed in this vulnerable population and was associated with poor IHDS performance.

Activating attachment representations during memory retrieval modulates intrusive traumatic memories.

Although priming mental representations of attachment security reduces arousal, research has not examined the effect of attachment on the retrieval of emotionally arousing memories. This study investigated the effect of priming attachment security on the retrieval of emotional memories. Seventy-five participants viewed negative and neutral images, and two days later received either an attachment prime or a control prime immediately prior to free recall of the images. Two days later, participants reported how frequently they experienced intrusions of the negative images. The attachment group had less distress, and reported fewer subsequent intrusions than the control group. Attachment style moderated these effects such that individuals with an avoidant attachment style were not impacted by the attachment prime. These findings suggest that priming attachment security decreases distress during memory reactivation, and this may reduce subsequent intrusive memories.

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors.

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

Impact of fetal and childhood mercury exposure on immune status in children.

BACKGROUND: Mercury exposure have been shown to affect immune status in animals as reflected by cytokine expression. It is unclear whether low levels of exposure during fetal and/or childhood periods could impact on immune status in humans. OBJECTIVES: To test the hypothesis that fetal and childhood mercury exposure is associated with childhood cytokine profiles and to investigate whether childhood selenium levels interact with any of the associations found. METHODS: Children were recruited from a previously established birth cohort between the ages of 6-9 years for assessment and measurement of blood mercury, selenium and cytokine profile (interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13 and TNF-alpha). Multivariable linear regression models were used to assess the adjusted association of cord blood mercury concentration and current mercury concentrations with levels of the cytokine levels. We tested whether the association with current mercury level varied by current selenium level and cord blood mercury level. RESULTS: IL-10 was negatively associated with current blood mercury concentration. The effect was greatest in cases with low cord blood mercury and low current selenium concentrations. None of the other cytokine levels were associated with either cord blood or current blood mercury concentrations, except that cord blood mercury was negatively associated with IL-6. CONCLUSIONS: Childhood mercury exposure was negatively associated with childhood IL-10 levels. It is postulated that while selenium is protective, low levels of fetal mercury exposure may increase the degree of this negative association during childhood. Further studies into the clinical significance of these findings are required.

Skin autofluorescence associates with vascular calcification in chronic kidney disease.

OBJECTIVE: This study aims to evaluate the relationship between tissue advanced glycation end products, as reflected by skin autofluorescence, and vascular calcification in chronic kidney disease. APPROACH AND RESULTS: Three hundred patients with stage 3 to 5 chronic kidney disease underwent multislice computed tomography to estimate total coronary artery calcium score (CACS) and had tissue advanced glycation end product assessed using a skin autofluorescence reader. Intact parathyroid hormone (P<0.001) displaced estimated glomerular filtration rate as third most significant factor associated with skin autofluorescence after age (P<0.001) and diabetes mellitus (P<0.001) in multiple regression analysis. On univariate multinomial logistic regression analysis, every 1-U increase in skin autofluorescence was associated with a 7.43-fold (95% confidence intervals, 3.59-15.37; P<0.001) increased odds of having CACS ≥400 compared with those with zero CACS. Skin autofluorescence retained significance in predicting CACS ≥400 (odds ratio, 3.63; 95% confidence intervals, 1.44-9.18; P=0.006) when adjusting for age, sex, serum calcium, phosphate, albumin, C-reactive protein, lipids, blood pressure, estimated glomerular filtration rate, and intact parathyroid hormone but marginally lost significance when additionally adjusting for diabetes mellitus (odds ratio, 2.23; 95% confidence intervals, 0.81-6.14; P=0.1). Combination of diabetes mellitus and higher intact parathyroid hormone was associated with greater skin autofluorescence and CACS versus those without diabetes mellitus and having lower intact parathyroid hormone. CONCLUSIONS: Tissue advanced glycation end product, as reflected by skin autofluorescence, showed a significant novel association with vascular calcification in chronic kidney disease. These data suggest that increased tissue advanced glycation end product may contribute to vascular calcification in chronic kidney disease and diabetes mellitus and warrant further experimental investigation.

Effect of paricalcitol on left ventricular mass and function in CKD--the OPERA trial.

Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 µg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus -4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 µg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.

Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study.

BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech.

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.

Heart failure with preserved or reduced ejection fraction in patients treated with peritoneal dialysis.

BACKGROUND: Heart failure is one of the most frequent complications in dialysis patients. However, little is known of the significance of the entity "heart failure with preserved ejection fraction" (HFPEF) in this population. This study aimed to determine the prevalence, clinical profiles, and long-term outcomes of peritoneal dialysis patients with HFPEF. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 220 patients treated with peritoneal dialysis were recruited from a university teaching hospital in Hong Kong. PREDICTOR: Heart failure was defined clinically based on the presence of: (1) symptoms and signs, including dyspnea, increased jugular venous pressure, and basal crepitations; (2) radiographic evidence of pulmonary venous congestion or interstitial edema; and (3) resolution of symptoms, signs, and radiographic changes with hypertonic peritoneal dialysis exchanges. Based on a combination of clinical history of heart failure and echocardiography-derived ejection fraction, patients were classified as having no heart failure, HFPEF, and heart failure with reduced ejection fraction (HFREF). OUTCOMES: All-cause mortality, cardiac death, heart failure, and fatal or nonfatal cardiovascular events. MEASUREMENTS: All patients underwent 2-dimensional echocardiography and tissue Doppler imaging at baseline and were followed up prospectively for clinical events for 4 years. RESULTS: 86 (39%) patients had heart failure, of whom 54.7% had preserved ejection fraction ≥50% and 45.3% had reduced ejection fraction <50%. Patients with HFPEF were intermediate between those with no heart failure and those with HFREF in terms of blood pressure, prevalence of coronary artery disease, diabetes, cardiac biomarkers, left ventricular mass, volume, and ratio of early mitral inflow velocity to peak mitral annulus velocity. In the multivariable Cox regression analysis, patients with HFPEF showed an increased adjusted HR for cardiac death (2.57; 95% CI, 1.20-5.50), heart failure (HR, 2.25; 95% CI, 1.28-3.96), and fatal or nonfatal cardiovascular event (HR, 2.01; 95% CI, 1.26-3.21) compared with those with no heart failure, but the risk was lower compared with those with HFREF. LIMITATIONS: The study included prevalent peritoneal dialysis patients and may introduce survival bias. CONCLUSIONS: HFPEF is common in peritoneal dialysis patients (∼55% of all heart failure) and is associated with increased risk of mortality and adverse cardiovascular outcomes compared with those with no heart failure, although the risk was lower than in patients with HFREF. This entity needs to be more recognized in peritoneal dialysis patients.