Miracle-dz/UniFAR-FTUs huggingface dataset:
MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

PURPOSE The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
Not Yet Another Negative Trial–ReACTing on Recent Glioblastoma Trials

The present ReACT trial provides data from a small randomized controlled vaccination trial that in addition to other recent immunotherapy trials in glioblastoma allows sketching a rational, advanced trial design for the development of (immune) therapies in glioblastoma elaborating on but not restricting to biological monitoring and endpoints. See related article by Reardon et al., p. 1586
Synthesis and Adsorption Performance of a Hierarchical Micro-Mesoporous Carbon for Toluene Removal under Ambient Conditions

Ordered mesoporous carbons (OMCs) were synthesized in this study through a soft template method and then activated by employing different mass ratios of KOH/OMCs to obtain KOH-activated ordered mesoporous carbons (KOMCs) with hierarchical pore structures. To verify the adsorption capacity, the KOMCs have been subjected to toluene emission-reduction experiments. The KOMCs were characterized by TEM, XRD, N2 adsorption-desorption isotherms, and Raman spectroscopy. The pore structure of OMCs was found to be effectively optimized by the activation with KOH, with the BET-area and total pore volume values reaching as high as 2661 m2 g−1 and 2.14 cm3 g−1 respectively. Then, the dynamic adsorption capacity of toluene on KOMCs was investigated via breakthrough curves, which can be well described by the Yoon and Nelson (Y-N) model. The dynamic adsorption capacities of toluene exhibit the following order: OMC < KOMC-1 < KOMC-5 < KOMC-3. The sample activated by KOH/OMC with a mass ratio of 3:1 (KOMC-3) demonstrated the highest toluene adsorption capacity of 355.67 mg g−1, three times higher in comparison with the untreated carbon (104.61 mg g−1). The modified hierarchical porous carbons also exhibited good recyclability. The KOMCs with rich pore structure, high toluene adsorption capacity, and superior reusability thus display a huge potential for volatile organic compound (VOC) elimination.
WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion

WNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS in WNT5A-mediated melanoma cell invasion has not been investigated. Analyses of melanoma patient databases suggested that similar to WNT5A expression, MARCKS expression appears to be associated with increased metastasis. A relationship between the two is suggested by the findings that recombinant WNT5A (rWNT5A) induces both increased expression and phosphorylation of MARCKS, whereas WNT5A silencing does the opposite. Moreover, WNT5A-induced invasion of melanoma cells was blocked by siRNA targeting MARCKS, indicating a crucial role of MARCKS expression and/or its phosphorylation. Next, we employed a peptide inhibitor of MARCKS phosphorylation that did not affect MARCKS expression and found that it abolished WNT5A-induced melanoma cell invasion. Similarly, rWNT5A induced the accumulation of phosphorylated MARCKS in membrane protrusions at the leading edge of melanoma cells. Our results demonstrate that WNT5A-induced phosphorylation of MARCKS is not only an indicator of PKC activity but also a crucial regulator of the metastatic behavior of melanoma and therefore an attractive future antimetastatic target in melanoma patients.
Effect of the Surfactant Charge and Concentration on the Change in the Forces between Two Charged Surfaces in Surfactant Solutions by a Liquid Flow.

A combined Atomic Force Microscope (AFM)-peristaltic pump system was used to determine the effect of a flow on the forces between two negatively charged surfaces (silica particle and silicon wafer) in aqueous solutions containing surfactants. The effect of the surfactant charge on the forces was determined by using an anionic surfactant (sodium dodecyl sulfate, SDS) and a cationic surfactant (dodecyltrimethylammonium bromide, DTAB) of the same chain-length. The surfactant concentration effect was determined by using concentrations up to the critical micelle concentration. In the case of SDS, a flow reduced the range and magnitude of the repulsive forces. The force range reduction was explained by a shrinking of the diffuse layers, due to the deformation of the diffuse layer by the flow. The force magnitude reduction was explained by (1) the increased electrostatic screening due to the thinner diffuse layers, and (2) an increased adsorption of specific ions, such as Na+, to the silica surfaces. In the case of DTAB, a concentration (8.0 mM) that gave an attractive force in the absence of a flow gave a repulsive force in the presence of a flow. Comparison of AFM images of a silicon wafer in DTAB measured in the absence and presence of a liquid flow showed that the number of DTAB patches adsorbed to the silicon wafer increased with a liquid flow. The change in the forces with a flow was therefore explained by this change in the DTAB adsorption to the negatively charged surfaces. As a liquid flow can change the charge of a surface, it may be possible to control the aggregation/dispersion of charged particles via the flow rate, if the appropriate surfactant type and concentration is used.
Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma

Purpose: Rocapuldencel-T is an autologous immunotherapy prepared from mature monocyte-derived dendritic cells (DC), coelectroporated with amplified tumor RNA plus CD40L RNA. This pivotal phase III trial was initiated to investigate the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods: Patients received either Rocapuldencel-T plus standard of care (SOC) or SOC treatment alone. The primary objective compared overall survival (OS) between groups. Secondary objectives included safety assessments, progression-free survival (PFS), and tumor responses based on RECIST 1.1 criteria. Exploratory analyses included immunologic assessments and correlates with OS. Results: Between 2013 and 2016, 462 patients were randomized 2:1, 307 to the combination group and 155 to the SOC group. Median OS in the combination group was 27.7 months [95% confidence interval (CI) 23.0–35.9] and 32.4 months (95% CI, 22.5–) in the SOC group HR of 1.10 (95% CI, 0.83–1.40). PFS was 6.0 months and 7.83 months for the combination and SOC groups, respectively [HR = 1.15 (95% CI, 0.92–1.44)]. The ORR was 42.7% (95% CI, 37.1–48.4) for the combination group and 39.4% (95% CI, 31.6–47.5) for the SOC group. Median follow up was 29 months (0.4–47.7 months). On the basis of the lack of clinical efficacy, the ADAPT trial was terminated on February 17, 2017. Immune responses were detected in 70% of patients treated with Rocapuldencel-T, and the magnitude of the immune response positively correlated with OS. In addition, we report the survival-predictive value of measuring IL-12 produced by the DC vaccine and the observation that high baseline numbers of T regulatory cells are associated with improved outcomes in DC-treated patients, but are associated with poor outcomes in patients receiving SOC treatment. No serious adverse events attributed to the study medication have been reported to date. Conclusions: Rocapuldencel-T did not improve OS in patients treated with combination therapy, although the induced immune response correlated with OS. Moreover, we identified two potential survival-predictive biomarkers for patients receiving DC based immunotherapy, IL-12 produced by the DC vaccine and higher numbers of T regulatory cells present in the peripheral blood of patients with advanced RCC.
Screening for CKD To Improve Processes of Care among Nondiabetic Veterans with Hypertension: A Pragmatic Cluster-Randomized Trial.

BACKGROUND AND OBJECTIVES We conducted a pilot, pragmatic, cluster-randomized trial to evaluate feasibility and preliminary effectiveness of screening for CKD using a triple-marker approach (creatinine, cystatin C, and albumin/creatinine ratio), followed by education and guidance, to improve care of hypertensive veterans in primary care. We used the electronic health record for identification, enrollment, intervention delivery, and outcome ascertainment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We randomized 1819 veterans without diabetes but with hypertension (41 clusters) into three arms: (1) CKD screening followed by patient and provider education; (2) screening, education, plus pharmacist comanagement; or (3) usual care. The primary clinical outcome was BP change over 1 year. Implementation and process measures included proportion screened; CKD detection rate; and total and new use of renin-angiotensin system inhibitors, nonsteroidal anti-inflammatory drugs, and diuretics. RESULTS Median age was 68 years, 55% were white, 1658 (91%) had a prior creatinine measure, but only 172 (9%) had prior urine albumin/creatinine ratio, and 83 (5%) had a prior cystatin C measure. Among those in the intervention, 527 of 1215 (43%) were identified with upcoming appointments to have CKD screening. Of these, 367 (69%) completed testing. Among those tested, 77 (21%) persons had newly diagnosed CKD. After 1 year, change in systolic BP was -1 mm Hg (interquartile range, -11 to 11) in usual care, -2 mm Hg (-11 to 11) in the screen-educate arm, and -2 mm Hg (-13 to 10) in the screen-educate plus pharmacist arm; P=0.49. There were no significant differences in secondary outcomes in intention-to-treat analyses. In as-treated analyses, higher proportions of participants in the intervention arms initiated a renin-angiotensin system inhibitor (15% and 12% versus 7% in usual care, P=0.01) or diuretic (9% and 12% versus 4%, P=0.03). CONCLUSIONS The pragmatic design made identification, enrollment, and intervention delivery highly efficient. The limited ability to identify appointments resulted in inadequate between-arm differences in CKD testing rates to determine whether screening improves clinical outcomes.
Icodextrin Versus Glucose Solutions for the Once-Daily Long Dwell in Peritoneal Dialysis: An Enriched Systematic Review and Meta-analysis of Randomized Controlled Trials.

RATIONALE & OBJECTIVE The efficacy and safety of icodextrin versus glucose-only peritoneal dialysis (PD) regimens is unclear. The aim of this study was to compare once-daily long-dwell icodextrin versus glucose among patients with kidney failure undergoing PD. STUDY DESIGN Systematic review of randomized controlled trials (RCTs), enriched with unpublished data from investigator-initiated and industry-sponsored studies. SETTING & STUDY POPULATIONS Individuals with kidney failure receiving regular PD treatment enrolled in clinical trials of dialysate composition. SELECTION CRITERIA FOR STUDIES Medline, Embase, CENTRAL, Ichushi Web, 10 Chinese databases, clinical trials registries, conference proceedings, and citation lists from inception to November 2018. Further data were obtained from principal investigators and industry clinical study reports. DATA EXTRACTION 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument. ANALYTIC APPROACH Qualitative synthesis of demographics, measurement scales, and outcomes. Quantitative synthesis with Mantel-Haenszel risk ratios (RRs), Peto odds ratios (ORs), or (standardized) mean differences (MDs). Risk of bias of included studies at the outcome level was assessed using the Cochrane risk-of-bias tool for RCTs. RESULTS 19 RCTs that enrolled 1,693 participants were meta-analyzed. Ultrafiltration was improved with icodextrin (medium-term MD, 208.92 [95% CI, 99.69-318.14] mL/24h; high certainty of evidence), reflected also by fewer episodes of fluid overload (RR, 0.43 [95% CI, 0.24-0.78]; high certainty). Icodextrin-containing PD probably decreased mortality risk compared to glucose-only PD (Peto OR, 0.49 [95% CI, 0.24-1.00]; moderate certainty). Despite evidence of lower peritoneal glucose absorption with icodextrin-containing PD (medium-term MD, -40.84 [95% CI, -48.09 to-33.59] g/long dwell; high certainty), this did not directly translate to changes in fasting plasma glucose (-0.50 [95% CI, -1.19 to 0.18] mmol/L; low certainty) and hemoglobin A1c levels (-0.14% [95% CI, -0.34% to 0.05%]; high certainty). Safety outcomes and residual kidney function were similar in both groups; health-related quality-of-life and pain scores were inconclusive. LIMITATIONS Trial quality was variable. The follow-up period was heterogeneous, with a paucity of assessments over the long term. Mortality results are based on just 32 events and were not corroborated using time-to-event analysis of individual patient data. CONCLUSIONS Icodextrin for once-daily long-dwell PD has clinical benefit for some patients, including those not meeting ultrafiltration targets and at risk for fluid overload. Future research into patient-centered outcomes and cost-effectiveness associated with icodextrin is needed.
Listening Difficulties of Children With Cochlear Implants in Mainstream Secondary Education

Supplemental Digital Content is available in the text. Objectives: Previous research has shown that children with cochlear implants (CIs) encounter more communication difficulties than their normal-hearing (NH) peers in kindergarten and elementary schools. Yet, little is known about the potential listening difficulties that children with CIs may experience during secondary education. The aim of this study was to investigate the listening difficulties of children with a CI in mainstream secondary education and to compare these results to the difficulties of their NH peers and the difficulties observed by their teachers. Design: The Dutch version of the Listening Inventory for Education Revised (LIFE-R) was administered to 19 children (mean age = 13 years 9 months; SD = 9 months) who received a CI early in life, to their NH classmates (n = 239), and to their teachers (n = 18). All participants were enrolled in mainstream secondary education in Flanders (first to fourth grades). The Listening Inventory for Secondary Education consists of 15 typical listening situations as experienced by students (LIFEstudent) during class activities (LIFEclass) and during social activities at school (LIFEsocial). The teachers completed a separate version of the Listening Inventory for Secondary Education (LIFEteacher) and Screening Instrument for Targeting Educational Risk. Results: Participants with CIs reported significantly more listening difficulties than their NH peers. A regression model estimated that 75% of the participants with CIs were at risk of experiencing listening difficulties. The chances of experiencing listening difficulties were significantly higher in participants with CIs for 7 out of 15 listening situations. The 3 listening situations that had the highest chance of resulting in listening difficulties were (1) listening during group work, (2) listening to multimedia, and (3) listening in large-sized classrooms. Results of the teacher’s questionnaires (LIFEteacher and Screening Instrument for Targeting Educational Risk) did not show a similar significant difference in listening difficulties between participants with a CI and their NH peers. According to teachers, NH participants even obtained significantly lower scores for staying on task and for participation in class than participants with a CI. Conclusions: Although children with a CI seemingly fit in well in mainstream schools, they still experience significantly more listening difficulties than their NH peers. Low signal to noise ratios (SNRs), distortions of the speech signal (multimedia, reverberation), distance, lack of visual support, and directivity effects of the microphones were identified as difficulties for children with a CI in the classroom. As teachers may not always notice these listening difficulties, a list of practical recommendations was provided in this study, to raise awareness among teachers and to minimize the difficulties.
Identification of Pediatric Sepsis for Epidemiologic Surveillance Using Electronic Clinical Data*

Supplemental Digital Content is available in the text. Objectives: A method to identify pediatric sepsis episodes that is not affected by changing diagnosis and claims-based coding practices does not exist. We derived and validated a surveillance algorithm to identify pediatric sepsis using routine clinical data and applied the algorithm to study longitudinal trends in sepsis epidemiology. Design: Retrospective observational study. Setting: Single academic children’s hospital. Patients: All emergency and hospital encounters from January 2011 to January 2019, excluding neonatal ICU and cardiac center. Exposure: Sepsis episodes identified by a surveillance algorithm using clinical data to identify infection and concurrent organ dysfunction. Interventions None. Measurements and Main Results: A surveillance algorithm was derived and validated in separate cohorts with suspected sepsis after clinician-adjudication of final sepsis diagnosis. We then applied the surveillance algorithm to determine longitudinal trends in incidence and mortality of pediatric sepsis over 8 years. Among 93,987 hospital encounters and 1,065 episodes of suspected sepsis in the derivation period, the surveillance algorithm yielded sensitivity 78% (95% CI, 72–84%), specificity 76% (95% CI, 74–79%), positive predictive value 41% (95% CI, 36–46%), and negative predictive value 94% (95% CI, 92–96%). In the validation period, the surveillance algorithm yielded sensitivity 84% (95% CI, 77–92%), specificity of 65% (95% CI, 59–70%), positive predictive value 43% (95% CI, 35–50%), and negative predictive value 93% (95% CI, 90–97%). Notably, most “false-positives” were deemed clinically relevant sepsis cases after manual review. The hospital-wide incidence of sepsis was 0.69% (95% CI, 0.67–0.71%), and the inpatient incidence was 2.8% (95% CI, 2.7–2.9%). Risk-adjusted sepsis incidence, without bias from changing diagnosis or coding practices, increased over time (adjusted incidence rate ratio per year 1.07; 95% CI, 1.06–1.08; p < 0.001). Mortality was 6.7% and did not change over time (adjusted odds ratio per year 0.98; 95% CI, 0.93–1.03; p = 0.38). Conclusions: An algorithm using routine clinical data provided an objective, efficient, and reliable method for pediatric sepsis surveillance. An increased sepsis incidence and stable mortality, free from influence of changes in diagnosis or billing practices, were evident.
Spectral-Temporal Trade-Off in Vocoded Sentence Recognition: Effects of Age, Hearing Thresholds, and Working Memory

Supplemental Digital Content is available in the text. Objectives: Cochlear implant (CI) signal processing degrades the spectral components of speech. This requires CI users to rely primarily on temporal cues, specifically, amplitude modulations within the temporal envelope, to recognize speech. Auditory temporal processing ability for envelope modulations worsens with advancing age, which may put older CI users at a disadvantage compared with younger users. To evaluate how potential age-related limitations for processing temporal envelope modulations impact spectrally degraded sentence recognition, noise-vocoded sentences were presented to younger and older normal-hearing listeners in quiet. Envelope modulation rates were varied from 10 to 500 Hz by adjusting the low-pass filter cutoff frequency (LPF). The goal of this study was to evaluate if age impacts recognition of noise-vocoded speech and if this age-related limitation existed for a specific range of envelope modulation rates. Design: Noise-vocoded sentence recognition in quiet was measured as a function of number of spectral channels (4, 6, 8, and 12 channels) and LPF (10, 20, 50, 75, 150, 375, and 500 Hz) in 15 younger normal-hearing listeners and 15 older near-normal-hearing listeners. Hearing thresholds and working memory were assessed to determine the extent to which these factors were related to recognition of noise-vocoded sentences. Results: Younger listeners achieved significantly higher sentence recognition scores than older listeners overall. Performance improved in both groups as the number of spectral channels and LPF increased. As the number of spectral channels increased, the differences in sentence recognition scores between groups decreased. A spectral-temporal trade-off was observed in both groups in which performance in the 8- and 12-channel conditions plateaued with lower-frequency amplitude modulations compared with the 4- and 6-channel conditions. There was no interaction between age group and LPF, suggesting that both groups obtained similar improvements in performance with increasing LPF. The lack of an interaction between age and LPF may be due to the nature of the task of recognizing sentences in quiet. Audiometric thresholds were the only significant predictor of vocoded sentence recognition. Although performance on the working memory task declined with advancing age, working memory scores did not predict sentence recognition. Conclusions: Younger listeners outperformed older listeners for recognizing noise-vocoded sentences in quiet. The negative impact of age was reduced when ample spectral information was available. Age-related limitations for recognizing vocoded sentences were not affected by the temporal envelope modulation rate of the signal, but instead, appear to be related to a generalized task limitation or to reduced audibility of the signal.