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Peptides are an emerging modality for developing therapeutics that can either agonize or antagonize cellular pathways associated with disease, yet peptides often suffer from poor chemical and physical stability, which limits their potential. However, naturally occurring disulfide-constrained peptides (DCPs) and de novo designed Hyperstable Constrained Peptides (HCPs) exhibiting highly stable and drug-like scaffolds, making them attractive therapeutic modalities. Previously, we established a robust platform for discovering peptide therapeutics by utilizing multiple DCPs as scaffolds. However, we realized that those libraries could be further improved by considering the foldability of peptide scaffolds for library design. We hypothesized that specific sequence patterns within the peptide scaffolds played a crucial role in spontaneous folding into a stable topology, and thus, these sequences should not be subject to randomization in the original library design. Therefore, we developed a method for designing highly diverse DCP libraries while preserving the inherent foldability of each scaffold. To achieve this, we first generated a large-scale dataset from yeast surface display (YSD) combined with shotgun alanine scan experiments to train a machine-learning (ML) model based on techniques used for natural language understanding. Then we validated the ML model with experiments, showing that it is able to not only predict the foldability of peptides with high accuracy across a broad range of sequences but also pinpoint residues critical for foldability. Using the insights gained from the alanine scanning experiment as well as prediction model, we designed a new peptide library based on a de novo-designed HCP, which was optimized for enhanced folding efficiency. Subsequent panning trials using this library yielded promising hits having good folding properties. In summary, this work advances peptide or small protein domain library design practices. These findings could pave the way for the efficient development of peptide-based therapeutics in the future.

Abstract Developmental Coordination Disorder (DCD) is a common neurodevelopmental disorder featuring deficits in motor coordination and motor timing among children. Deficits in rhythmic tracking, including perceptually tracking and synchronizing action with auditory rhythms, have been studied in a wide range of motor disorders, providing a foundation for developing rehabilitation programs incorporating auditory rhythms. We tested whether DCD also features these auditory-motor deficits among 7–10 year-old children. In a speech recognition task with no overt motor component, modulating the speech rhythm interfered more with the performance of children at risk for DCD than typically developing (TD) children. A set of auditory-motor tapping tasks further showed that, although children at risk for DCD performed worse than TD children in general, the presence of an auditory rhythmic cue (isochronous metronome or music) facilitated the temporal consistency of tapping. Finally, accuracy in the recognition of rhythmically modulated speech and tapping consistency correlated with performance on the standardized motor assessment. Together, the results show auditory rhythmic regularity benefits auditory perception and auditory-motor coordination in children at risk for DCD. This provides a foundation for future clinical studies to develop evidence-based interventions involving auditory-motor rhythmic coordination for children with DCD.

Abstract Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~ 7 to 8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~ 5 to 20 nm, ~1 kbp) fold into chromatin packing domains (~ 100 to 200 nm, ~ 100 to 1000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p

Music and speech are complex and distinct auditory signals that are both foundational to the human experience. The mechanisms underpinning each domain are widely investigated. However, what perceptual mechanism transforms a sound into music or speech and how basic acoustic information is required to distinguish between them remain open questions. Here, we hypothesized that a sound's amplitude modulation (AM), an essential temporal acoustic feature driving the auditory system across processing levels, is critical for distinguishing music and speech. Specifically, in contrast to paradigms using naturalistic acoustic signals (that can be challenging to interpret), we used a noise-probing approach to untangle the auditory mechanism: If AM rate and regularity are critical for perceptually distinguishing music and speech, judging artificially noise-synthesized ambiguous audio signals should align with their AM parameters. Across 4 experiments (N = 335), signals with a higher peak AM frequency tend to be judged as speech, lower as music. Interestingly, this principle is consistently used by all listeners for speech judgments, but only by musically sophisticated listeners for music. In addition, signals with more regular AM are judged as music over speech, and this feature is more critical for music judgment, regardless of musical sophistication. The data suggest that the auditory system can rely on a low-level acoustic property as basic as AM to distinguish music from speech, a simple principle that provokes both neurophysiological and evolutionary experiments and speculations.

Abstract The proper regulation of muscle stem cell (MuSC) fate by cues from the niche is essential for regeneration of skeletal muscle. How pro-regenerative niche factors control the dynamics of MuSC fate decisions remains unknown due to limitations of population-level endpoint assays. To address this knowledge gap, we developed a dual fluorescence imaging time lapse (Dual-FLIT) microscopy approach that leverages machine learning classification strategies to track single cell fate decisions with high temporal resolution. Using two fluorescent reporters that read out maintenance of stemness and myogenic commitment, we constructed detailed lineage trees for individual MuSCs and their progeny, classifying each division event as symmetric self-renewing, asymmetric, or symmetric committed. Our analysis reveals that treatment with the lipid metabolite, prostaglandin E2 (PGE2), accelerates the rate of MuSC proliferation over time, while biasing division events toward symmetric self-renewal. In contrast, the IL6 family member, Oncostatin M (OSM), decreases the proliferation rate after the first generation, while blocking myogenic commitment. These insights into the dynamics of MuSC regulation by niche cues were uniquely enabled by our Dual-FLIT approach. We anticipate that similar binary live cell readouts derived from Dual-FLIT will markedly expand our understanding of how niche factors control tissue regeneration in real time.

PURPOSEPediatric leukemia outcomes are poor in most low- and middle-income countries (LMICs) and exacerbated by health care systems ill equipped to manage cancer. Effective leukemia management in LMICs involves curating epidemiologic data; providing health care workforce specialty training; developing evidence-based treatments and supportive care programs; safeguarding access to medications and equipment; providing patient and family psychosocial, financial, and nutritional support; partnering with nongovernmental organizations, and ensuring treatment adherence.METHODSIn 2013, through a partnership between North-American and Mexican institutions, we used the WHO Framework for Action, a health systems strengthening model to implement a leukemia care sustainable program aimed at improving acute lymphoblastic leukemia (ALL) outcomes at a public hospital in Mexico. We prospectively assessed clinical features, risk classification, and survival outcomes in children with ALL at Hospital General-Tijuana from 2008 to 2012 (preimplementation) and from 2013 to 2017 (postimplementation). We also evaluated program sustainability indicators.RESULTSOur approach led to a fully-staffed leukemia service, sustainable training programs, evidence-based and data-driven projects to improve clinical outcomes, and funding for medications, supplies, and personnel through local partnerships. Preimplementation and postimplementation 5-year overall survival for the entire cohort of children with ALL, children with standard-risk ALL, and children with high-risk ALL improved from 59% to 65% (P = .023), 73% to 100% (P < .001), and 48% to 55% (P = .031), respectively. All sustainability indicators improved between 2013 and 2017.CONCLUSIONUsing the health systems strengthening WHO Framework for Action model, we improved leukemia care and survival in a public hospital in Mexico across the US-Mexico border. We provide a model for the development of similar programs in LMICs to sustainably improve leukemia and other cancer outcomes.

With the growing complexity of the U.S. health care system, highly motivated medical directors with strong leadership skills are vital to the success of health care facilities. Presently, there are no articles assessing a plastic surgeon's qualifications for the role of medical director. In addition, there is a paucity of literature comparing the responsibilities of medical directors across various types of health care institutions. Herein, we outline why plastic surgeons have the unique skillset to succeed in this role and highlight the differences between medical director positions across the vast landscape of health care. While the intricacies of this position vary greatly across different landscapes of the health care industry, successful medical directors lead by following a set of universal principles predisposing them for success. Plastic surgeons innately exhibit a subset of particular traits deeming them suitable candidates for the medical director position. While transitioning from the role of a surgeon to that of a medical director does require some show of adaptation, plastic surgeons are ultimately highly likely to find intrinsic benefit from serving as a medical director.

Introduction In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary.Methods Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley’s K analysis, a methodology adapted from ecology.Results Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor–stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR −0.5 to 5.1); stage III: 1.4 (IQR −0.3 to 3.5); stage IV: 0.6 (IQR −2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS–hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p

Diagnosis and management of proliferative diabetic retinopathy are reliant upon retinal imaging. A systematic literature review of non-invasive imaging to guide diagnosis and treatment of proliferative diabetic retinopathy was performed. There is a trend of moving away from invasive (e.g., fundus fluorescein angiography) to non-invasive (e.g., wide-field optical coherence tomography (OCT), OCT angiography and colour fundus photography) imaging modalities to allow for more objective assessments that can be readily repeated in a time-efficient manner without compromising patient safety. Such quantitative assessments generating large amounts of data could benefit from artificial intelligence approaches to aid clinical decision making. These non-invasive imaging modalities continue to improve both in terms of the quality of image acquisition and progress in image interpretation. It is important that newer non-invasive imaging modalities are appropriately validated in large-scale prospective observational studies or randomised clinical trials.

BackgroundPosttraumatic stress disorder (PTSD) among US military veterans can adversely impact their concerned significant others (CSOs; eg, family members and romantic partners). Mobile apps can be tailored to support CSO mental health through psychoeducation, coping skills, and stress monitoring. ObjectiveThis study assessed the feasibility, acceptability, and potential efficacy of PTSD Family Coach 1.0, a free, publicly available app that includes psychoeducation, stress management tools, self-assessments, and features for connecting to alternative supports, compared with a psychoeducation-only version of the app for cohabitating CSOs of veterans with PTSD. MethodsA total of 200 participants with an average age of 39 (SD 8.44) years, primarily female (193/200, 97%), and White (160/200, 80%) were randomized to self-guided use of either PTSD Family Coach 1.0 (n=104) or a psychoeducation-only app (n=96) for 4 weeks. Caregiver burden, stress, depression, anxiety, beliefs about treatment, CSO self-efficacy, and relationship functioning assessed using measures of dyadic adjustment, social constraints, and communication danger signs were administered via a web survey at baseline and after treatment. User satisfaction and app helpfulness were assessed after treatment. Data were analyzed using linear mixed methods. ResultsOverall, 50.5% (101/200) of randomized participants used their allocated app. Participants found PTSD Family Coach 1.0 somewhat satisfying (mean 4.88, SD 1.11) and moderately helpful (mean 2.99, SD 0.97) to use. Linear mixed effects models revealed no significant differences in outcomes by condition for caregiver burden (P=.45; Cohen d=0.1, 95% CI −0.2 to 0.4), stress (P=.64; Cohen d=0.1, 95% CI −0.4 to 0.6), depression (P=.93; Cohen d= 0.0, 95% CI −0.3 to 0.3), anxiety (P=.55; Cohen d=−0.1, 95% CI −0.4 to 0.2), beliefs about treatment (P=.71; Cohen d=0.1, 95% CI −0.2 to 0.3), partner self-efficacy (P=.59; Cohen d=−0.1, 95% CI −0.4 to 0.2), dyadic adjustment (P=.08; Cohen d=−0.2, 95% CI −0.5 to 0.0), social constraints (P=.05; Cohen d=0.3, 95% CI 0.0-0.6), or communication danger signs (P=.90; Cohen d=−0.0, 95% CI −0.3 to 0.3). Post hoc analyses collapsing across conditions revealed a significant between-group effect on stress for app users versus nonusers (β=−3.62; t281=−2.27; P=.02). ConclusionsApproximately half of the randomized participants never used their allocated app, and participants in the PTSD Family Coach 1.0 condition only opened the app approximately 4 times over 4 weeks, suggesting limitations to this app version’s feasibility. PTSD Family Coach 1.0 users reported moderately favorable impressions of the app, suggesting preliminary acceptability. Regarding efficacy, no significant difference was found between PTSD Family Coach 1.0 users and psychoeducation app users across any outcome of interest. Post hoc analyses suggested that app use regardless of treatment condition was associated with reduced stress. Further research that improves app feasibility and establishes efficacy in targeting the domains most relevant to CSOs is warranted. Trial RegistrationClinicalTrials.gov NCT02486705; https://clinicaltrials.gov/ct2/show/NCT02486705

The number of people living with diabetes is expected to rise to 578 million by 2030 and to 700 million by 2045, exacting a severe socioeconomic burden on healthcare systems around the globe. This is also reflected in the increasing numbers of people with ocular complications of diabetes (namely, diabetic macular oedema (DMO) and diabetic retinopathy (DR)). In one study examining the global prevalence of DR, 35% of people with diabetes had some form of DR, 7% had PDR, 7% had DMO, and 10% were affected by these vision-threatening stages. In many regions of the world (Australia included), DR is one of the top three leading causes of vision loss amongst working age adults (20–74 years). In the management of DMO, the landmark ETDRS study demonstrated that moderate visual loss, defined as doubling of the visual angle, can be reduced by 50% or more by focal/grid laser photocoagulation. However, over the last 20 years, antivascular endothelial growth factor (VEGF) and corticosteroid therapies have emerged as alternative options for the management of DMO and provided patients with choices that have higher chances of improving vision than laser alone. In Australia, since the 2008 NHMRC guidelines, there have been significant developments in both the treatment options and treatment schedules for DMO. This working group was therefore assembled to review and address the current management options available in Australia.

Ischemia with no obstructive coronary arteries (INOCA) is a relatively newly discovered ischemic phenotype that affects patients similarly to obstructive coronary artery disease (CAD) but has a unique pathophysiology and epidemiology. Patients with INOCA present with ischemic signs and symptoms but no obstructive CAD seen on coronary CTA or invasive coronary angiography, which can assess epicardial vessels. The mechanisms of INOCA can be grouped into three endotypes: coronary microvascular dysfunction, epicardial coronary vasospasm, or a combination of both. Accurate and comprehensive assessment of both epicardial and microvascular disease in suspected cases of INOCA is crucial for providing targeted therapy and improving outcomes in this underrepresented population. This review aims to clarify the complex pathophysiology of INOCA, present an overview of invasive and non-invasive diagnostic methods, and examine contemporary approaches for coronary perfusion assessment using cardiac magnetic resonance (CMR). We also explore how recent advancements in quantitative CMR can potentially revolutionize the evaluation of suspected INOCA by offering a rapid, accurate, and non-invasive diagnostic approach, thereby reducing the alarming number of cases that go undetected.

Objective:. This Delphi exercise aimed to gather consensus surrounding risk factors, diagnosis, and management of chyle leaks after esophagectomy and to develop recommendations for clinical practice. Background:. Chyle leaks following esophagectomy for malignancy are uncommon. Although they are associated with increased morbidity and mortality, diagnosis and management of these patients remain controversial and a challenge globally. Methods:. This was a modified Delphi exercise was delivered to clinicians across the oesophagogastric anastomosis collaborative. A 5-staged iterative process was used to gather consensus on clinical practice, including a scoping systematic review (stage 1), 2 rounds of anonymous electronic voting (stages 2 and 3), data-based analysis (stage 4), and guideline and consensus development (stage 5). Stratified analyses were performed by surgeon specialty and surgeon volume. Results:. In stage 1, the steering committee proposed areas of uncertainty across 5 domains: risk factors, intraoperative techniques, and postoperative management (ie, diagnosis, severity, and treatment). In stages 2 and 3, 275 and 250 respondents respectively participated in online voting. Consensus was achieved on intraoperative thoracic duct ligation, postoperative diagnosis by milky chest drain output and biochemical testing with triglycerides and chylomicrons, assessing severity with volume of chest drain over 24 hours and a step-up approach in the management of chyle leaks. Stratified analyses demonstrated consistent results. In stage 4, data from the Oesophagogastric Anastomosis Audit demonstrated that chyle leaks occurred in 5.4% (122/2247). Increasing chyle leak grades were associated with higher rates of pulmonary complications, return to theater, prolonged length of stay, and 90-day mortality. In stage 5, 41 surgeons developed a set of recommendations in the intraoperative techniques, diagnosis, and management of chyle leaks. Conclusions:. Several areas of consensus were reached surrounding diagnosis and management of chyle leaks following esophagectomy for malignancy. Guidance in clinical practice through adaptation of recommendations from this consensus may help in the prevention of, timely diagnosis, and management of chyle leaks.

The Pentose Phosphate Pathway (PPP), a metabolic offshoot of the glycolytic pathway, provides protective metabolites and molecules essential for cell redox balance and survival. Transketolase (TKT) is the critical enzyme that controls the extent of “traffic flow” through the PPP. Here, we explored the role of TKT in maintaining the health of the human retina. We found that Müller cells were the primary retinal cell type expressing TKT in the human retina. We further explored the role of TKT in human Müller cells by knocking down its expression in primary cultured Müller cells (huPMCs), isolated from the human retina (11 human donors in total), under light-induced oxidative stress. TKT knockdown and light stress reduced TKT enzymatic activities and the overall metabolic activities of huPMCs with no detectable cell death. TKT knockdown restrained the PPP traffic flow, reduced the expression of NAD(P)H Quinone Dehydrogenase 1 (NQO1), impaired the antioxidative response of NRF2 to light stress and aggravated the endoplasmic reticulum (ER) stress. TKT knockdown also inhibited overall glucose intake, reduced expression of Dihydrolipoamide dehydrogenase (DLD) and impaired the energy supply of the huPMCs. In summary, Müller cell-mediated TKT activity plays a critical protective role in the stressed retina. Knockdown of TKT disrupted the PPP and impaired overall glucose utilisation by huPMCs and rendered huPMCs more vulnerable to light stress by impairing energy supply and antioxidative NRF2 responses.

PURPOSE: To determine the patient-centered effectiveness of switching patients with persistent macular edema due to retinal vein occlusion (RVO) to aflibercept using the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). MATERIALS AND METHODS: Prospective study of eyes with persistent cystoid macular edema due to RVO despite regular treatment with bevacizumab or ranibizumab switched to aflibercept. Three loading doses of intravitreal aflibercept were administered every 4 weeks and thereafter every 8 weeks until week 48. Vision-related quality of life (VRQoL) using NEI-VFQ-25 was measured at baseline, 24 weeks, and 48 weeks following the switch. Baseline scores were compared to week 24 and 48 using paired t-test. Relationship between best-corrected visual acuity (BCVA) in the study eye and the NEI-VFQ-25 composite and subscale scores was investigated. RESULTS: Eighteen patients with RVO were enrolled in the study with a mean age of 70.3 ± 8.6 years. The mean change in BCVA and central macular thickness (CMT) from baseline to 48 weeks was +20.6 ± 5.2 Early Treatment of Diabetic Retinopathy Score letters and −109.2 ± 82.8 μm, respectively. VRQoL improved significantly, with an increase of mean NEI-VFQ composite score of 11.5 ± 9.5; the corresponding improvements in near and distant activities were 13.3 ± 19.4 and 8.4 ± 10.4, respectively (P < 0.001 for both). Logistic regression analysis demonstrated that BCVA gain of >15 letters and CMT < 300 μm at the end of the study predicted a higher change in VFQ-25. CONCLUSION: Switching eyes with persistent macular edema due to RVO to aflibercept resulted in significant improvement in visual function and patient satisfaction.

PURPOSE: To evaluate anatomical changes on ultra-wide-field fluorescein-angiography and optical coherence angiography (OCT-A) among a cohort with treatment-resistant macular edema secondary to retinal vein occlusions (RVO) switched to aflibercept. MATERIALS AND METHODS: Patients with persistent macular edema despite previous bevacizumab and/or ranibizumab were switched to aflibercept in a 48-week prospective trial. Ultra-wide-field fluorescein angiography (UWFFA) and OCT-A were performed at baseline, week-24 and week-48. The ischemic index was calculated from UWFFA and the areas of vascular perfusion. The foveal avascular zone (FAZ) were quantitatively evaluated on OCT-A. RESULTS: Eighteen patients (mean age, 70.3±8.6 years) were recruited. Mean central macular thickness (CMT) was significantly reduced at 48-weeks compared to baseline (-87.6±48.8 μm, P < 0.001 and -191.0±128.3μm, P < 0.001 among BRVO and CRVO eyes, respectively). The mean baseline ischemic index as measured on Optos wide-field angiography was 10.9%±8.3 and decreased to 5.7%±4.2 (P = 0.028), at week 48. The mean FAZ areas of the SCP and DCP reduced by -0.06 ± 0.12 mm 2 and -0.17± 0.45 mm 2 , respectively. FAZ area on OCT-A was stable in eyes with stable or improved vision but increased in size in eyes with baseline macular ischemia and those with lower gains in BCVA at week 48 (R 2 =0.719, P = 0.05 and R 2 =0.516, P = 0.01). CONCLUSION: There was a reduction in macular edema measured on OCT at 48-weeks in eyes switched to aflibercept with chronic macular edema due to retinal vein occlusion. There was also a reduction in retinal ischemia as measured using UWFFA.

How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.

Purpose: Faricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. Methods: These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. Main Outcome Measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. Conclusions: YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

Teaching elementary students how to read is undeniably crucial, yet a substantial number of children encounter difficulties despite early interventions. Cross-age tutoring, a pedagogical approach that pairs older students with younger peers, emerges as a cost-effective solution that brings academic and social benefits to both the tutor and the tutee. Consequently, cross-age tutoring programs are widely adopted globally. To maximize the effectiveness of cross-age tutoring, we offer five evidence-based recommendations tailored for its implementation. When integrated into the preparation and implementation steps, these recommendations hold the potential to significantly improve learning outcomes for both tutors and tutees.

Background Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. Objective To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). Methods Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30–180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. Results The Combat BRS system was able to achieve target range temperature (42–44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. Conclusions Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

Purpose: We report a case of a male patient with chronic ocular pain that resolved completely following peripheral nerve blocks. Observations: A 66-year-old male presented with a seven-year history of severe left eye pain and photophobia. The pain began after retinal detachment repair with scleral buckle placement. Previous treatments included topical (autologous serum tears, corticosteroids, diclofenac, cyclosporine) and oral (gabapentin, diclofenac) therapies with no pain relief. The patient's pain was so severe that he requested enucleation. After discussion, the decision was made to perform periocular nerve blocks. Prior to the procedure, the patient reported an average pain intensity of 8 out of 10 and photophobia daily. Following left supraorbital, supratrochlear, infraorbital and infratrochlear injections with bupivacaine and methylprednisolone, pain intensity and photophobia improved to 1–2 out of 10. One week later, repeat infraorbital and infratrochlear nerve blocks were given, after which time the patient reported complete resolution of symptoms that lasted for 7 months. Repeat nerve blocks were administered with repeat resolution of pain. There were no complications associated with the procedures. Conclusions and Importance: Chronic ocular pain can be a debilitating condition. Periorbital nerve blocks can provide pain relief and should be considered as a potential treatment option after medical management has failed. Keywords: Chronic ocular pain, Periocular nerve blocks, Neuropathic ocular pain

Purpose: Ocriplasmin is effective in closing macular holes due to vitreomacular traction. We present a case of macular subretinal material deposition observed with spectral-domain optical coherence tomography (SD-OCT) and multimodal imaging, following successful closure of a macular hole following intravitreal ocriplasmin injection. Observations: An 81-year-old male presented with decreased vision in the left eye due to a full-thickness macular hole secondary to vitreomacular traction. Ocriplasmin (Jetrea) was injected into the vitreous and hole closure was observed after one week. Macular subretinal material deposition developed along the outer surface of the resultant serous detachment on OCT one week post-injection. Fluorescein angiography demonstrated no expanding hyperfluorescence due to retinal or choroidal leak, or staining of the lesion. The material was mildly autofluorescent. The macular subretinal material complex spontaneously decreased with no significant effect on vision over 60 weeks. Conclusions and importance: Macular subretinal material deposition has not previously been reported following intravitreal ocriplasmin injection. This material is likely composed of photoreceptor outer segments. It is important to recognize that macular subretinal deposits can occur following intravitreal ocriplasmin injection as it may cause diagnostic confusion and potentially influence the visual and anatomical outcomes following successful hole closure.

Heart development requires compaction of the ventricular wall into a dense myocardium at mid-gestation. Here, Rhee and colleagues show that the chromatin remodeller Ino80 is critical for the formation of the coronary vasculature, and show that coronary vessels are needed for successful cardiac compaction during embryonic development.

A field trial was performed to investigate the effect of municipal biowaste biochar (MBB) on rice and wheat growth, metal bioaccumulation, and greenhouse gas emissions in a rice paddy in eastern China. MBB was amended in 2010 before rice transplanting at rates of 0 and 40 t ha-1 in a field experiment lasting one cropping year. MBB soil amendment significantly increased soil pH, total soil organic carbon, and total nitrogen. The growth and grain yield of rice and wheat was not affected with MBB application at 40 t ha-1. MBB amendment did not influence the soil availability of Pb, Cu, and Ni, but significantly increased the soil availability of Zn and decreased the soil availability of Cd during both rice and wheat seasons. While MBB did not change the bioaccumulation of Pb, Cu, and Ni, the rice and wheat Cd accumulation was significantly reduced, and wheat Zn accumulation slightly increased with MBB amendment. Furthermore, total N2O emission during both rice and wheat seasons was greatly decreased, though total seasonal CH4 emission was significantly increased in the rice season. On the other hand, soil CO2 emission remained unaffected across crop seasons. Thus, MBB can be used in rice paddy for low carbon and low-Cd grain production, but the long-term effects remain unknown.

Objectives: The accessory middle turbinate, a rare anatomical variation of the nasal cavity, have been systematically studied in adults. Presence of accessory middle turbinate and its clinical significance in a child has not been reported. We describe clinical appearance and radiologic features of accessory middle turbinate in a child. Methods: Retrospective chart review. Results: A 3-year-old boy presented to the otolaryngology clinic for evaluation of recurrent epistaxis. Anterior rhinoscopy revealed moist nasal mucosa without inflammation and bilateral prominent blood vessels on the anterior nasal septum. Nasal endoscopy showed turbinate like protuberances in bilateral middle meatus. CT images documented accessory middle turbinate in the bilateral nasal cavity. Conclusion: Otolaryngologists should be cognizant of anatomical variations of middle turbinate to achieve correct diagnosis and avoid potential complications during surgical management.

A field study involving wheat production was extended in order to study the effects of biochar (BC) amendment in paddy soil that had long-term contamination of Cd. The BC was used as an amendment in Cd-contaminated soil for its special property. BC was amended at rates of 10 to 40 t ha-1 during the rice season before rice transplantation in 2009. BC amendments increased soil pH by 0.11 to 0.24 and by 0.09 to 0.24 units, respectively, while the soil CaCl2-extracted Cd was reduced by 10.1% to 40.2% and by 10.0% to 57.0% in 2010 and 2011, respectively. Consequently, the total wheat Cd uptake was decreased by 16.8% to 37.3% and by 6.5% to 28.3%. Wheat grain Cd concentration was reduced by 24.8% to 44.2% and by 14.0% to 39.2% in 2010 and 2011, respectively. The BC application in soil reduced Cd phyto-availability in two wheat seasons possibly by raising soil pH and soil organic carbon (SOC). Therefore, BC may be used for soil remediation, but not to reduce Cd uptake to an adequate level for food production on Cd contaminated soils.

A field experiment was conducted on the effect of biochar (BC) amendment on Cd uptake by rice (Oryza sativa L.) in a contaminated paddy in 2009 and 2010. BC was applied as a basal soil amendment before rice transplantation in 2009 at rates of 0, 10, 20, 40t ha-1, and rice yield and Cd uptake were monitored in both 2009 and 2010. The BC amendment significantly increased soil pH by 0.15-0.33 units in 2009 and 0.24-0.38 units in 2010, and decreased CaCl2 extracted Cd in soil by 32.0%-52.5% in 2009 and 5.5%-43.4% in 2010, respectively. Under BC amendment at 10, 20, 40 t ha-1, rice grain Cd concentration was observed to be reduced by 16.8%, 37.1%, and 45.0% in 2009 and by 42.7%, 39.9%, and 61.9% in 2010, while the total plant Cd uptake was found to decrease by 28.1%, 45.7%, and 54.2% in 2009 and by 14.4%, 35.9%, and 45.9% in 2010, respectively. Such effect of BC amendment on reducing Cd plant uptake has profound implications among those using bioresources for field application. Finally, BC amendment in combination with low Cd cultivars may offer a basic option to reduce Cd levels in rice as well as to reduce greenhouse gas emissions in rice agriculture in contaminated paddies.

The use of phosphates fertilizers can increase the trace element concentration in the soils, with an eventual transfer to human chain food. As indispensable tool, models can be used to identify the risks and to evaluate the effects of preventive actions. The goal of this study was to applied a mass model for trace elements, developed at the University of California - Riverside, (USA) in two cerrado soils (LVdf, a clayey soil and NQ, a Sandy Soil). The model was used as an instrument to evaluate the risks of cadmium and lead accumulation in different soils and in soybean plants, upon the application of different phosphorous sources in the soils. The simulate cadmium content after ten years of application of the reactive phosphate FR3, it reached 2.97 mg kg-1 in the LVdf. The cadmium content in the RQo was more available for the soybean plants. The model showed a greater accumulation of Cd and Pb in the clayey soil (LVdf), after ten years of application high doses of these elements through the phosphates fertilizers FR3 and FN2.

O uso agrícola é uma das alternativas eficientes para o manejo de biossólidos. Dependendo, porém, da origem (urbana e, ou, industrial) e do sistema de tratamento, biossólidos podem conter concentrações elevadas de metais pesados, que, por sua vez, podem acumular-se nos solos. O uso de condicionadores químicos pode reduzir a biodisponibilidade e a mobilidade de metais no solo e, conseqüentemente, os riscos ao meio ambiente. Neste estudo, avaliaram-se os efeitos da adição de quatro condicionadores [carbonato de cálcio (CaCO3), sulfato de Ca (CaSO4), fosfato de potássio monobásico (KH2PO4) e hidroxiapatita sintética (HA)] na retenção e distribuição de Zn, Cu e Cd em Latossolos tratados com biossólido. Considerando a baixa solubilidade, a HA foi equilibrada nos valores de pH 4, 5 e 6. Utilizaram-se amostras superficiais (0-0,2 m) de um Latossolo Vermelho acriférrico (LVwf) e de um Latossolo Amarelo distrófico (LAd). Dois gramas de terra foram colocados para reagir em câmaras-duplas de difusão com 2 g de biossólidos com teores elevados de metais. Após atingir o equilíbrio (aproximadamente sete dias), a solução foi centrifugada, filtrada e acidificada, e as concentrações de Zn, Cu e Cd foram determinadas. As fases sólidas (solo e biossólido) foram secas por congelamento e, a seguir, procedeu-se à extração seqüencial de Zn, Cu e Cd. Os condicionadores foram eficientes na remoção de Zn, Cd e, em menor proporção, de Cu da solução. Em geral, o CaCO3 foi o mais eficiente na imobilização dos metais seguido da HA (pH 6). A HA equilibrada nos valores de pH 4 e 5 não promoveu imobilização dos metais. Após a introdução dos condicionadores, a quantidade de metais no solo ligados à fração trocável foi reduzida e os teores dos metais ligados à superfície dos óxidos/carbonatos foram aumentados, sobretudo nos tratamentos em que se utilizaram CaCO3 e HA (pH 6).Land application represents an efficient alternative for disposal of biosolids. However, depending on the origin (urban and/or domestic) and the treatment system, biosolids may contain high amounts of heavy metals, which can gradually build up in the soil. Soil chemical amendments in contaminated areas can reduce the bioavailability and mobility of heavy metals and, consequently, minimize the risks of their adverse effects on the environment. The objective of this study was to evaluate the effects of four chemical amendments [calcium carbonate (CaCO3), calcium sulfate (CaSO4), monobasic potassium phosphate (KH2PO4) and synthetic hydroxyapatite (HA)] on Zn, Cu, and Cd retention and distribution in Oxisols amended with biosolid. Due to the low solubility, HA was equilibrated at pH 4, 5, and 6. Surface soil samples (0-20 cm) of a Rhodic Acrudox (RA) and a Typic Haplorthox (HP) were used. Two grams of each soil sample were equilibrated in a dual- diffusion chamber with 2 g of heavily contaminated with heavy metals. The suspension was constantly stirred for a more uniform mixing of the solutions. When the equilibrium was reached (after approximately seven days), the solution was centrifuged, filtered and acidified. Copper, Zn, and Cd concentrations in solution were determined. The solid phases (soil and biosolid) were freeze-dried and sequential extractions of Zn, Cu and Cd were performed. The chemical amendments were efficient in Zn, Cd and, to a lesser extent, Cu immobilization. Calcium carbonate followed by HA (pH 6) was, in general, the most efficient treatment in reducing metal concentrations in solution. No heavy metal immobilization was obtained by HA equilibrated at pH 4 and 5. Chemical amendments markedly reduced the amounts of metals associated with the exchangeable fraction and increased the surface oxide/carbonate pool, especially in the treatments with CaCO3 and HA (pH 6).

Current studies investigating properties of nanoparticle-reinforced polymers have shown that nanocomposites often exhibit improved properties compared to neat polymers. However, over two decades of research, using both experimental studies and modeling analyses, has not fully elucidated the mechanistic underpinnings behind these enhancements. Moreover, few studies have focused on developing an understanding among two or more polymer properties affected by incorporation of nanomaterials. In our study, we investigated the elastic and thermal properties of poly(acrylamide) hydrogels containing silica nanoparticles. Both nanoparticle concentration and size affected hydrogel properties, with similar trends in enhancements observed for elastic modulus and thermal diffusivity. We also observed significantly lower swellability for hydrogel nanocomposites relative to neat hydrogels, consistent with previous work suggesting that nanoparticles can mediate pseudo crosslinking within polymer networks. Collectively, these results indicate the ability to develop next-generation composite materials with enhanced mechanical and thermal properties by increasing the average crosslinking density using nanoparticles.

Certain trace elements are essential for humans, plants and animals, but become toxic at higher concentrations. For many trace elements, the margin of safety between beneficial and harmful is narrow. Deficiencies of trace elements are common plant nutritional problems in crop production. While most trace elements in soils are beneficial to plant growth, a buildup of trace elements may have a negative effect on whoever eats the plant. Trace elements may also degrade water quality downstream. Some are added to soils from the atmosphere, irrigation water and agricultural inputs including chemicals, biosolids, manures and compost. On cropland, important trace elements may also be depleted from the soil profile through leaching, crop harvest, surface runoff and volatilization. We calculated the levels of trace-element accumulation and depletion on the West Side of the San Joaquin Valley. Although the accumulation of chromium, cadmium, lead, mercury, nickel, copper and zinc on cropland will increase significantly over time, the rate of accumulation is slow and the added trace elements are not likely to interfere with farming in the foreseeable future. At the same time, arsenic, boron, molybdenum and selenium are being depleted from West Side soils. Elements removed in drainage water are now accumulating in evaporation ponds. To ensure desirable levels, water and soil sources of these elements must be monitored, and research into methods for limiting their accumulation and depletion should continue.

In a reaction time task, people typically slow down following an error or conflict, each called post-error slowing (PES) and post-conflict slowing (PCS). Despite many studies of the cognitive mechanisms, the neural responses of PES and PCS continue to be debated. In this study, we combined high-density array EEG and a stop-signal task to examine event-related potentials of PES and PCS in sixteen young adult participants. The results showed that the amplitude of N2 is greater during PES but not PCS. In contrast, the peak latency of N2 is longer for PCS but not PES. Furthermore, error-positivity (Pe) but not error-related negativity (ERN) was greater in the stop error trials preceding PES than non-PES trials, suggesting that PES is related to participants' awareness of the error. Together, these findings extend earlier work of cognitive control by specifying the neural correlates of PES and PCS in the stop signal task.