YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model

More options are needed for the effective treatment of melanoma. In a previous study, we discovered the small molecule drug YK-4-279 almost completely inhibited tumor progression in the BrafCA;Tyr-CreERT2;Ptenflox/flox transgenic mouse model. YK-4-279 had no effect on tumor initiation but blocked progression of invasive melanoma. Our current study was designed as a treatment model, where YK-4-279 was administered during pigmented lesion formation. The study design included the use of three groups: (1) a control group that received only DMSO without a drug (MOCK), (2) mice following our prior studies with YK-4-279 administered at the time of tumor induction (YK-4-279), and (3) mice treated during tumor initiation (YK-4-279 delay). While the MOCK mice had progression of tumors, both YK-4-279 and YK-4-279 delay groups had a significant block or delay of progression. The majority of mice in the YK-4-279 groups had a block of progression, while the YK-4-279 delay group had either a partial block (60% in male mice or 29% in females) or a delay in disease progression in females (28 days in controls to 50 days in YK-4-279 delay group). Here, we demonstrate that YK-4-279 has a significant impact on blocking or delaying tumor progression in a pre-clinical treatment model of melanoma.

Time from first seen in specialist care to surgery does not influence survival outcome in patients with upfront resected pancreatic adenocarcinoma

Background This study evaluated the impact of time to surgery (TTS) on overall survival (OS), disease free survival (DFS) and postoperative complication rate in patients with upfront resected pancreatic adenocarcinoma (PA). Methods We retrospectively included patients who underwent upfront surgery for PA between January 1, 2004 and December 31, 2014 from four French centers. TTS was defined as the number of days between the date of the first consultation in specialist care and the date of surgery. DFS for a 14-day TTS was the primary endpoint. We also analyzed survival depending on different delay cut-offs (7, 14, 28, 60 and 75 days). Results A total of 168 patients were included. 59 patients (35%) underwent an upfront surgery within 14 days. Patients in the higher delay group (> 14 days) had significantly more vein resections and endoscopic biliary drainage. Adjusted OS (p = 0.44), DFS (p = 0.99), fistulas (p = 0.41), hemorrhage (p = 0.59) and severe post-operative complications (p = 0.82) were not different according to TTS (> 14 days). Other delay cut-offs had no impact on OS or DFS. Discussion TTS seems to have no impact on OS, DFS and 90-day postoperative morbidity.

Grunt Vocalizations in Children With Disabilities: Relationships With Assessed Cognition and Language

Purpose The purpose of this study was to investigate the relationship of the grunt vocalizations to cognitive and expressive language status in children with disabilities. Children with typical development produce communicative grunts at the onset of referential word production and comprehension at 14–16 months of age and continue to use this vocalization for communication as they develop language. Method All grunt vocalizations produced by 26 children with disabilities (mental age: 3–56 months; communicative age: 47–69 months) were identified from video-recorded seminaturalistic play sessions. Grunts were identified as accompanying effort or attention or as communicative bids. Participants were grouped as prelinguistic, emergent, language delay, and language competent based on standardized assessments of cognitive and language level. The Mann–Whitney U test (1947) compared groups to determine the relationships between grunt production and cognitive and language status. Results As hypothesized, participants in the language delay group produced significantly more communicative grunts than those in the language competent group ( W = 39, p = .028 < .05). The children with a cognitive and language level lower than 9 months (prelinguistic group) failed to produce communicative grunts. Conclusions The results document grunt production in children with disabilities in the same contexts as typical children and support the hypothesized relationship between assessed cognition and language and communicative grunt production. These results require replication. This vocalization, if recognized in treatment, may unlock verbal communication in many nonverbal children with disabilities. Future longitudinal research should include controlled intervention to determine the potential effectiveness of building broader communicative skills on this simple vocalization.

Time to Surgery Does Not Influence Survival Outcome in Patients With Upfront Resected Pancreatic Adenocarcinoma

BackgroundThis study evaluated the impact of time to surgery (TTS) on overall survival (OS), disease free survival (DFS) and postoperative complication rate in patients with upfront resected pancreatic adenocarcinoma (PA).MethodsWe retrospectively included patients who underwent upfront surgery for PA between January 1, 2004 and December 31, 2014 from four French centers. TTS was defined as the number of days between the date of the first consultation in specialist care and the date of surgery. DFS for a 14-day TTS was the primary endpoint. We also analyzed survival depending on different delay cut-offs (7, 14, 28, 60 and 75 days).ResultsA total of 168 patients were included. 59 patients (35%) underwent an upfront surgery within 14 days. Patients in the higher delay group had significantly more vein resections and endoscopic biliary drainage. Adjusted OS (p = 0.44), DFS (p = 0.99), fistulas (p = 0.41), hemorrhage (p = 0.59) and severe post-operative complications (p = 0.82) were similar in both groups. Other delay cut-offs had no impact on OS or DFS.DiscussionTTS seems to have no impact on OS, DFS and 90-day postoperative morbidity.

Early, intensive rehabilitation improves gross motor function after perinatal stroke: results of a randomized controlled trial

Background: Perinatal stroke injures motor regions of the brain, compromising movement for life. Early, intensive, active interventions for the upper extremity are efficacious, but interventions for the lower extremity (LE) remain infrequent and understudied. Objective: To determine the efficacy of ELEVATE – Engaging the Lower Extremity Via Active Therapy Early – on gross motor function, as compared to usual care. Methods: We conducted a single–blind, two–arm, randomized controlled trial (RCT), with the Immediate Group receiving the intervention while the Delay Group served as a three–month waitlist-control. A separate cohort living beyond commuting distance was trained by their parents with guidance from physical therapists. Participants were 8 months to 3 years old, with MRI–confirmed perinatal ischemic stroke and early signs of hemiparesis. The intervention was play–based, focused on weight–bearing, balance and walking for 1 hour/day, 4 days/week for 12 weeks. The primary outcome was the Gross Motor Function Measure–66 (GMFM–66). Secondary outcomes included steps and gait analyses. Final follow–up occurred at age four. Results: Thirty–four children participated (25 RCT, 9 Parent-trained). The improvement in GMFM–66 over 12 weeks was greater for the Immediate than the Delay Group (average change 3.4 units higher) and greater in younger children. Average step counts reached 1370–3750 steps/session in the last week of training for all children. Parent–trained children also improved but with greater variability. Conclusions: Early, activity–intensive LE therapy for young children with perinatal stroke is feasible and improves gross motor function in the short term. Longer term improvement may require additional bouts of intervention.

Sleep and testing both strengthen and distort story recollection

Over time, memories lose episodic detail and become distorted, a process with serious ramifications for topics such as eyewitness identification. What are the processes which contribute to such transformation over time? We investigated the roles of post learning sleep and retrieval practice in memory accuracy, transformation, and distortion, using a naturalistic story recollection task. Undergraduate students listened to a recording of the “War of the Ghosts”, a Native American folktale, and were assigned to either a retrieval practice or listen only study condition, and either a sleep or wake delay group. Sleep and retrieval practice independently resulted in more story elements being recalled accurately, and fewer importations of non-story elements, than the wake, no retrieval practice group. However, sleep and retrieval practice also led to more inferences of non-presented, but story related information. These findings suggest that both sleep and retrieval practice contribute equally to narrative memory stabilization and distortion.

P532 Delay of maintenance infliximab increases the risk of relapse in Crohn’s disease during the COVID-19 pandemic

Background Scheduled maintenance infliximab (IFX) therapies were frequently delayed during the COVID-19 pandemic. The unusual situation allowed us to study the influence of decreased treatment adherence on Crohn’s disease (CD). This retrospective study aimed to evaluate the effect of IFX delay on relapse in Crohn’s disease (CD) patients. Methods 166 CD patients with maintenance IFX between January 25, 2020, and April 25, 2020, were retrospectively enrolled. Demographic and clinical characteristics were recorded. Relapse was defined as clinical disease relapse or biochemical disease relapse (C-reactive protein (CRP) level ≥5 mg/L without other, non-IBD related explanation). Associations between relapse and IFX delay were analyzed. Results A retrospective cohort study was conducted, including 166 CD patients receiving maintenance IFX infusion during the COVID-19 pandemic. Of all, 135 (81.3%) had delayed their IFX infusion. Only 31 (18.7%) followed the schedule infusion during the COVID-19 pandemic. The median time of the IFX delay was 18.6±17.1 days. The relapse rate in the IFX-delay group was significantly higher than the group without delay (25.9% versus 5.5%, P＜0.02). During a median IFX delay interval of 46 days (95% CI 20.9–71.1), the ratio of relapse increased with the increase of IFX delay intervals. Delay interval had a cumulative effect on disease recurrence. We proposed interval prolongation resulted in a significant IFX trough concentration reduction. Conclusion Our study provided real-world evidence of influence on relapse of IFX delay in CD patients undergone maintenance therapy. It might help the IBD specialists arrange reasonable IFX treatment intervals for patients.

Adherence to subcutaneous immunotherapy with aeroallergens in real-life practice during the COVID-19 pandemic

Background: The success of subcutaneous immunotherapy (SCIT) mostly depends on regular injections. Our aim was to investigate adherence to SCIT with aeroallergens during the COVID-19 pandemic and demonstrate clinical consequences of treatment disruptions in real-life. Methods: Visual analogue scale for quality of life (VAS-QoL), VAS for symptom scores (VAS-symptom), medication scores (MSs) and total symptom scores (TSS-6) were recorded during the pandemic in 327 adult allergic rhinitis and/or asthmatic patients receiving maintenance SCIT and these scores were compared with the pre-pandemic data. Patients were grouped according to SCIT administration intervals; no delay (Group 1), <2 months (Group 2), and ≥2 month intervals (Group 3). Results: 104 (31.8%) patients (Group 3) were considered as non-adherent which was mostly related to receiving SCIT with HDMs and using public transportation for reaching the hospital. Median MS, VAS-symptom and TSS-6 scores of Group 3 patients during the pandemic were higher than the pre-pandemic scores (p=0.005, p<0.001, p<0.001, respectively) whereas median VAS-QoL scores of Group 3 during the pandemic were lower than the pre-pandemic scores (p<0.001). Median TSS-6 and VAS-symptom scores were the highest in Group 3 compared to other groups (p<0.001 for each comparison). Median VAS-QoL scores were the lowest in Group 3 compared to Group 1 and Group 2 (p<0.001, p=0.043, respectively). Conclusion: When precautions in allergy clinics are carefully applied, adherence to SCIT can be high during a pandemic. Patients must be warned about adhering to SCIT injections since delays in SCIT administration can deteriorate clinical symptoms.

The timing of continuous renal replacement therapy initiation in sepsis-associated acute kidney injury in the intensive care unit: the CRTSAKI Study (Continuous RRT Timing in Sepsis-associated AKI in ICU): study protocol for a multicentre, randomised controlled trial

IntroductionAcute kidney injury (AKI) is one of the most common organ dysfunction in sepsis, and increases the risk of unfavourable outcomes. Renal replacement therapy (RRT) is the predominant treatment for sepsis-associated AKI (SAKI). However, to date, no prospective randomised study has adequately addressed whether initiating RRT earlier will attenuate renal injury and improve the outcome of sepsis. The objective of the trial is to compare the early strategy with delayed strategy on the outcomes in patients with SAKI in the intensive care unit (ICU).Methods and analysisThis is a large-scale, multicentre, randomised controlled trial about SAKI. In total, 460 patients with sepsis and evidence of AKI stage 2 of Kidney Disease Improving Global Outcomes (KDIGO) will be recruited and equally randomised into the early group and the delay group in a ratio of 1:1. In the early group, continuous RRT (CRRT) will be started immediately after randomisation. In the delay group, CRRT will initiated if at least one of the following criteria was met: stage 3 of KDIGO, severe hyperkalaemia, pulmonary oedema, blood urea nitrogen level higher than 112 mg/dL after randomisation. The primary outcome is overall survival in a 90-day follow-up period (90-day all-cause mortality). Other end points include 28-day, 60-day and 1-year mortality, recovery rate of renal function by day 28 and day 90, ICU and hospital length of stay, the numbers of CRRT-free days, mechanical ventilation-free days and vasopressor-free days, the rate of complications potentially related to CRRT, CRRT-related cost, and concentrations of inflammatory mediators in serum.Ethics and disseminationThe trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2017–31-ks-01). Participants will be screened and enrolled from patients in the ICU with SAKI by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations.Trial registrationNCT03175328.

Efektivitas Metode Fonik terhadap Penurunan Tingkat Keterlambatan Bicara Anak Usia 4-5 Tahun

This research examines the effectiviness of phonic method on reducing the level of speech delay in children aged 4-5 years at Integrated Islamic Kinderganten Al Ummah Gresik. Phonic method is a developed by optimizing all language skills, listening, speaking, writing, and reading. Speech delay occurs when the level of speech development of a child is below the level of quality of speech development of normal children in general according tho their age. This research uses description of quantitative action research type, one group pre-test and post-test design. This research uses a non-probability sampling technique whit a suturated sampling technique. The populations were 10 children and the sample were 6 children in the severe speech delay category and 4 children in the light speech delay category. The data analysis technique used the mann-whitney test analysis. The analysis show that there is an effect of giving phonic method treatment on reducing the level of speech delay in the severe speech delay group. Whereas in the light speech delay group stated that there was no effect of giving phonic method treatment on reducing the level of speech delay. Furthermore, the gain score calculation also shows tha there is no difference in the effectiveness of giving phonic method treatment on reducing the level of speech delay in both the severe speech delay category and the light speech delay category. This suggest tha further researchers provide treatment by experts or people who are experts in their fields, and it is advisable to choose other types of research, such as experimental research, so that the result are more comprehensive.