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Slipped capital femoral epiphysis (SCFE) is the most common hip disorder in adolescents, occurring in 10.8 per 100,000 children. SCFE usually occurs in those eight to 15 years of age and is one of the most commonly missed diagnoses in children. SCFE is classified as stable or unstable based on the stability of the physis. It is associated with obesity, growth spurts, and (occasionally) endocrine abnormalities such as hypothyroidism, growth hormone supplementation, hypogonadism, and panhypopituitarism. Patients with SCFE usually present with limping and poorly localized pain in the hip, groin, thigh, or knee. Diagnosis is confirmed by bilateral hip radiography, which should include anteroposterior and frog-leg views in patients with stable SCFE, and anteroposterior and cross-table lateral views in unstable SCFE. The goals of treatment are to prevent slip progression and avoid complications such as avascular necrosis, chondrolysis, and femoroacetabular impingement. Stable SCFE is usually treated using in situ screw fixation. Treatment of unstable SCFE also usually involves in situ fixation, but there is controversy about timing of surgery and the value of reduction. Postoperative rehabilitation of patients with SCFE may follow a five-phase protocol.

Landsat-based fire severity datasets are an invaluable resource for monitoring and research purposes. These gridded fire severity datasets are generally produced with pre- and post-fire imagery to estimate the degree of fire-induced ecological change. Here, we introduce methods to produce three Landsat-based fire severity metrics using the Google Earth Engine (GEE) platform: The delta normalized burn ratio (dNBR), the relativized delta normalized burn ratio (RdNBR), and the relativized burn ratio (RBR). Our methods do not rely on time-consuming a priori scene selection but instead use a mean compositing approach in which all valid pixels (e.g., cloud-free) over a pre-specified date range (pre- and post-fire) are stacked and the mean value for each pixel over each stack is used to produce the resulting fire severity datasets. This approach demonstrates that fire severity datasets can be produced with relative ease and speed compared to the standard approach in which one pre-fire and one post-fire scene are judiciously identified and used to produce fire severity datasets. We also validate the GEE-derived fire severity metrics using field-based fire severity plots for 18 fires in the western United States. These validations are compared to Landsat-based fire severity datasets produced using only one pre- and post-fire scene, which has been the standard approach in producing such datasets since their inception. Results indicate that the GEE-derived fire severity datasets generally show improved validation statistics compared to parallel versions in which only one pre-fire and one post-fire scene are used, though some of the improvements in some validations are more or less negligible. We provide code and a sample geospatial fire history layer to produce dNBR, RdNBR, and RBR for the 18 fires we evaluated. Although our approach requires that a geospatial fire history layer (i.e., fire perimeters) be produced independently and prior to applying our methods, we suggest that our GEE methodology can reasonably be implemented on hundreds to thousands of fires, thereby increasing opportunities for fire severity monitoring and research across the globe.

CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT. A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort. Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.

Nanofibrous scaffolds loaded with bioactive nanoparticles are promising materials for bone tissue engineering. In this study, composite nanofibrous membranes containing a copolymer of L-lactide and glycolide (PLGA) and diamond nanoparticles were fabricated by an electrospinning technique. PLGA was dissolved in a mixture of methylene chloride and dimethyl formamide (2:3) at a concentration of 2.3 wt%, and nanodiamond (ND) powder was added at a concentration of 0.7 wt% (about 23 wt% in dry PLGA). In the composite scaffolds, the ND particles were either arranged like beads in the central part of the fibers or formed clusters protruding from the fibers. In the PLGA-ND membranes, the fibers were thicker (diameter 270 ± 9 nm) than in pure PLGA meshes (diameter 218 ± 4 nm), but the areas of pores among these fibers were smaller than in pure PLGA samples (0.46 ± 0.02 μm(2) versus 1.28 ± 0.09 μm(2) in pure PLGA samples). The PLGA-ND membranes showed higher mechanical resistance, as demonstrated by rupture tests of load and deflection of rupture probe at failure. Both types of membranes enabled the attachment, spreading, and subsequent proliferation of human osteoblast-like MG-63 cells to a similar extent, although these values were usually lower than on polystyrene dishes. Nevertheless, the cells on both types of membranes were polygonal or spindle-like in shape, and were distributed homogeneously on the samples. From days 1-7 after seeding, their number rose continuously, and at the end of the experiment, these cells were able to create a confluent layer. At the same time, the cell viability, evaluated by a LIVE/DEAD viability/cytotoxicity kit, ranged from 92% to 97% on both types of membranes. In addition, on PLGA-ND membranes, the cells formed well developed talin-containing focal adhesion plaques. As estimated by the determination of tumor necrosis factor-alpha levels in the culture medium and concentration of intercellular adhesion molecule-1, MG-63 cells, and RAW 264.7 macrophages on these membranes did not show considerable inflammatory activity. This study shows that nanofibrous PLGA membranes loaded with diamond nanoparticles have interesting potential for use in bone tissue engineering.

Background Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.

BackgroundImmunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures.MethodsData from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method.ResultsAt 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs.ConclusionsAlthough overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN.Trial registration number NCT02231749.

Background Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated with increased cancer-risk. Psychological trauma is a common experience and a key driver of these behaviours among adults. The primary aim of this study is to evaluate the effect of trauma-informed yoga, drumming, and psychoeducation compared to control on tobacco use, alcohol use, and sugar-sweetened beverage consumption among community-based adults. Secondary aims are to evaluate the effect of these interventions compared to control on psychological and physiological stress symptomology, social connection, and coping behaviour. Methods Recruitment for this single-blinded randomized trial began in April 2019 in the Faculty of Health Sciences at the University of Lethbridge. Adults who consumed tobacco, alcohol, or sugar-sweetened beverages in the past month and live in Lethbridge, Alberta are being recruited using ads placed in public spaces. Participants are randomly allocated to a 12-session group yoga class, 12-session group drumming class, a 12-session psychoeducation class, or control. Participants attend an appointment in-person to fill out an online questionnaire package, provide a saliva sample, and complete physical measures pre-intervention, and 1-month and 6-months post-intervention. Discussion This study provides a unique opportunity to compare the impacts of two trauma-informed body-based interventions to psychoeducation and control for cancer-risk behaviour among community-based adults. The findings can be used to develop trauma-informed group interventions to reduce cancer-risk behaviour in general populations. Results are expected in 2022. Trial registration This trial was registered with ClinicalTrials.gov ISRCTN15583681 on 22 August 2019 (retrospectively registered).

In our paper titled, ‘Mean Composite Fire Severity Metrics Computed with Google Earth Engine Offer Improved Accuracy and Expanded Mapping Potential’ [...]

Research using eye tracking methods has revealed that when viewing faces, between 6 to 10 months of age, infants begin to shift visual attention from the eye region to the mouth region. Moreover, this shift varies with stimulus characteristics and infants’ experience with faces and languages. The current study examined the eye movements of a racially diverse sample of 98 infants between 7.5 and 10.5 months of age as they viewed movies of White and Asian American women reciting a nursery rhyme (the auditory component of the movies was replaced with music to eliminate the influence of the speech on infants’ looking behavior). Using an analytic approach inspired by the multiverse analysis approach, several measures from infants’ eye gaze were examined to identify patterns that were robust across different analyses. Although in general infants preferred the lower regions of the faces, i.e., the region containing the mouth, this preference depended on the stimulus characteristics and was stronger for infants whose typical experience included faces of more races and for infants who were exposed to multiple languages. These results show how we can leverage the richness of eye tracking data with infants to add to our understanding of the factors that influence infants’ visual exploration of faces.

Mental rotation is a critically important, early developing spatial skill that is related to other spatial cognitive abilities. Understanding the early development of this skill, however, requires a developmentally appropriate assessment that can be used with infants, toddlers, and young children. We present here a new eye-tracking task that uses a staircase procedure to assess mental rotation in 12-, 24-, and 36-month-old children (N = 41). To ensure that all children understood the task, the session began with training and practice, in which the children learned to fixate which of two houses a giraffe, facing either left or right, would approach. The adaptive two-up, one-down staircase procedure assessed the children’s ability to fixate the correct house when the giraffe was rotated in 30° (up) or 15° (down) increments. The procedure was successful, with most children showing evidence of mental rotation. In addition, the children were less likely to succeed as the angle of rotation increased, and the older children succeeded at higher angles of rotation than the younger children, replicating previous findings with other procedures. The present study contributes a new paradigm that can assess the development of mental rotation in young children and holds promise for yielding insights into individual differences in mental rotation.