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Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 107cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients (n= 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038.

This ERIC (Educational Resources Information Center) monograph updates and expands upon earlier ERIC publications on the topic of instructional development (ID) models. This monograph presents a brief history of ID models, describes a taxonomy for classifying them, provides examples from each of the categories in the taxonomy, and describes trends in their content and focus. The 13 models described in the book are representative of the ID literature and reflect most of the main concepts found in other models. Specific models are described and discussed in each of three orientations: (1) classroom--Gerlach and Ely; Kemp, Morrison, and Ross; Heinich, Molenda, Russell, and Smaldino; and Reiser and Dick; (2) product--Van Patten; Leshin, Pollock, and Reigeluth; and Bergman and Moore; and (3) system--IDI (Instructional Development Institute); IPISD (Interservices Procedures for Instructional Systems Development); Diamond; Smith and Ragan; Gentry IPDM (Instructional Project Development and Management); and Dick and Carey. Eighteen figures illustrate the core elements of ID, portrayals of the ID process, Rapid Prototyping model, Layers of Necessity model, taxonomy of ID models based on selected characteristics, and 12 of the 13 reviewed models. An annotated bibliography of ERIC documents and journal articles, in addition to ordering information and background information on ERIC are provided. (Contains 54 references.) (SWC)

This paper, which updates and expands on the first edition (1981), begins by presenting a definition of instructional development (ID) and a discussion of its origins. A taxonomy for classifying ID models is then suggested, and it is noted that most ID models have been subjected to only a limited degree of testing. The 12 ID models that are reviewed are divided into the three categories specified by the taxonomy as they focus on the classroom, the product, and the systems. Specific models are described and discussed in each of these categories: (1) classroom--Gerlach and Ely; Heinich, Molenda, and Russell; Dick and Reiser; and Kemp; (2) product--Van Patten; Leshin, Pollock, and Reigeluth; and Bergman and Moore; and (3) systems--IDI (Instructional Development Institute); ISPISD (Inservices Procedures for Instructional Systems Development); Dick and Carey; Seels and Glasgow; and Diamond. The taxonomy and 11 of the 12 models are depicted in 12 figures. A guide to searching ERIC for ID models is provided in the Foreword, and the annotated ERIC bibliography lists 19 journal articles and 14 documents. Instructions for obtaining copies of ERIC documents and journal articles are included. (30 references) (DB)

Rainy Lake, located in Ontario and Minnesota, offers a multitude of fishing opportunities. The lake is known for its excellent multispecies fishing, including pike, walleye, smallmouth bass, muskie, crappie, and more. It has three unique basins - the north and south arms, and Redgut Bay - each with its own fishing hotspots. Rainy Lake is less crowded than other lakes in the area and is well-charted, making it easy to navigate. Visitors can choose from a variety of resorts and accommodations, and there are also options for ice fishing during the winter months. [Extracted from the article]

From antiquity to contemporary times, artists have served as society’s defence against unbridled technological adoption. As stressed by Marshall McLuhan, artists are those individuals who aid society in understanding the conditions of our time. In literate times the poet and the painter assumed such responsibilities, but in the digital era the artist becomes something altogether different. McLuhan defined the artists broadly as an individual in any field who was able to provide insightful information into the human actions and consciousness of their time. Similarly, Paglia argued analysts must combine ‘high with popular art, the noble with the sleazy’ (1991: 34). Thus, we are left with two pressing questions: who are the artists of the millennium? Can they still save us? The following article sought to trace who we should be considered artists in the twenty-first century and exactly what they have accomplished, or failed to accomplish, in making society aware of shifting sense ratios. Though Benjamin (1969)might bemoan the obsolescence of authenticity and aura in art, Paglia astutely points out the ‘popular culture reclaims what high culture shuts out’ (1991: 34). Therefore, a survey of both high and popular art will probe the abilities and limits of artists and their art to make society aware of the effects of technological change.

Neopetrotaurines A–C (1–3), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a Neopetrosiasp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond 1H–13C and 1H–15N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range 1H–13C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A–C (1–3) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.

Reports of T cell malignancies after CAR-T cell therapy should be investigated, but existing data from follow-up studies suggest a low risk compared with other cancer treatments.

Because poor posture is a common instigating factor in back, shoulder, and neck pain, the rhomboid muscles should be considered in a complete physical evaluation. Previous techniques for treating a rhomboid tender point have addressed only one of the two main actions of the muscle, specifically retraction of the scapula utilizing shoulder abduction. This modified supine counterstrain technique for the rhomboid tender point incorporates both scapular retraction as well as superior, medial rotation of the inferior border of the scapula without abduction, providing a comprehensive treatment to accommodate patients with shoulder movement restrictions. This article discusses indications, contraindications, treatment, and a list of problem-solving strategies for the rhomboid tender point.

In February 2023, a train derailment in Ohio caused a chemical spill and fires releasing contaminants into the air, soil, waterways, and buildings. The authors conducted a rapid response which included six field investigations and bench-scale experiments to understand the chemical identity, fate, and exposure pathways after the evacuation order was lifted. Multiple buildings were chemically contaminated and silicone wristband products inside a commercial building were found to have adsorbed derailment-related chemicals. The indoor air of this commercial building was found to be contaminated for 4.5 months after the derailment. Derailment chemicals were also found on building exteriors 5 weeks after the incident. Railcar chemicals were detected in the nearby creeks. Cleanup activities (sorbent pads, aerators) as well as creek hydraulic and environmental conditions influenced chemical fate in creeks. Creek mechanical aeration activities prompted VOC emission that contributed to human exposures and vapor intrusion. Atmospheric modeling revealed that the chemical plumes extended beyond the evacuation zone. Water was a consequential media associated with contaminant transport and human exposures found in the present study. Because the complexity, magnitude, and health threats posed to the community were not matched by efforts employed by the responding organizations, the population experienced continued exposures for months; workers as well as town visitors also experienced health symptoms. This study revealed unaddressed human exposure pathways. Also identified were crucial gaps requiring improved decision-making and technologies. Recommendations to better protect human health and the environment before and during a response to chemical incidents are provided.

The sphenopalatine (pterygopalatine) ganglion (SPG) is the most superficial ganglia to manipulate from the oral cavity. It has parasympathetic and sensory fibers directly affecting the paranasal sinuses as well as the palatine, nasal, pharyngeal, and lacrimal glands. The SPG can be manipulated intraorally by students and physicians utilizing osteopathic manipulative treatment (OMT) to relieve congestion associated with sinusitis, allergies, headaches, and upper respiratory infections. Within osteopathic medical education programs, students have anecdotally had difficulty identifying this ganglion due to its deep anatomic location and lack of direct visualization. In this article, we discuss that cadaveric dissection with a superficial to deep approach to the SPG has the ability to allow medical students and physicians to better understand the three-dimensional location and osteopathic clinical relevance of this ganglion.

Context:Individuals with SCI typically live with neurogenic bowel dysfunction and impaired colonic motility that may significantly impact health and quality of life. Bowel management often includes digital rectal stimulation (DRS) to modulate the recto-colic reflex to promote bowel emptying. This procedure can be time-consuming, caregiver-intensive, and lead to rectal trauma. This study presents a description of using electrical rectal stimulation as an alternative to DRS to help manage bowel emptying in a person with SCI.Methods:We conducted an exploratory case study with a 65-year-old male with a T4 AIS B SCI who normally relies on DRS as the main component of his regular bowel management strategy. In randomly selected bowel emptying sessions during a 6-week period, the participant received burst-pattern electrical rectal stimulation (ERS) (50 mA, 20 pulses/s at 100 Hz), via a rectal probe electrode until bowel emptying was achieved. The primary outcome measure was number of cycles of stimulation required to complete the bowel routine.Results:17 sessions were performed using ERS. In 16 sessions, a bowel movement was produced after only 1 cycle of ERS. In 13 sessions, complete bowel emptying was achieved with 2 cycles of ERS.Conclusions:ERS was associated with effective bowel emptying. This work represents the first time ERS has been used to affect bowel emptying in someone with SCI. This approach could be investigated as a tool to evaluate bowel dysfunction, and it could be further refined as a tool for improving bowel emptying.

Annular sum and difference beam patterns, produced by an array-fed ring-focus reflector (RFR), are synthesized using three different methods. An ideal planar source that produces an annular beam with the maximum possible gain is determined. The first method places the above ideal planar source in front of the RFR’s aperture. The radiated electromagnetic (EM) fields produced by the induced current on the RFR’s surface determine the feed-array source distribution. The second method directly projects the ideal planar source onto the RFR’s surface with phase adjustment. The EM fields radiated by the surface current are then employed to synthesize the source distribution of the feed array. The third method employs conjugate field matching optimization to determine the array source distribution. The difference beams are synthesized by employing Gram–Schmidt’s orthogonalization method. The second and third methods show improved performance over the first method. The array-fed RFR is advantageous over direct radiating mechanically scanned arrays, typically used in mobile receiving systems, in terms of complexity and implementation cost.

Age-associated changes in the T cell compartment are well described. However, limitations of current single-modal or bimodal single-cell assays, including flow cytometry, RNA-seq (RNA sequencing) and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile >300,000 single T cells from healthy children (aged 11–13 years) and older adults (aged 55–65 years) by using the trimodal assay TEA-seq (single-cell analysis of mRNA transcripts, surface protein epitopes and chromatin accessibility), which revealed that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4+T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8αα+T cell subset lost with age that is epigenetically poised for rapid effector responses and has distinct inhibitory, costimulatory and tissue-homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.

I tell the hunters that the cardinal sin in deer hunting is getting out of the stand for any reason, especially to go for a walk. He encouraged me to start taking my hunters out on the water to hunt deer. We drive mainland points and peninsulas as well, trying to push deer past hunters waiting at a stand. [Extracted from the article]

When a patient presents with head, neck, or respiratory concerns, the scalene muscles are not commonly considered. However, somatic dysfunctions of the anterior/middle scalenes (AMS) can be contributing to or causing these medical concerns. Although tender points within the scalene muscles have been documented within the muscle belly, they have not been documented at the insertion site. This article details how to diagnose and treat an AMS tender point with an efficient technique that requires minimal exertion and maximal comfort for both the physician and patient at a new tender point location. This article also discusses the importance of this tender point and provides a list of additional somatic dysfunctions that may be used to problem-solve a scalene tender point that fails to correct.

Enigmazole B (1) and four new analogues, cis-enigmazole B (2), dehydroenigmazole B (3), enigmimide B (4), and enigmimide A (5), were isolated from the marine sponge Cinachyrella enigmatica. Their planar structures were elucidated by detailed NMR and MS data analyses, which established 1–3to be oxazole-substituted 18-membered phosphomacrolides, while 4and 5were oxazole ring-opened congeners. The relative and absolute configurations in 1were determined by a combination of chemical transformations and spectroscopic analyses. Photooxidation of the oxazole moiety in 1gave enigmimide B (4), thus establishing that 4has the same absolute configuration of 1. Enigmazole B (1) along with analogues 2and 3showed cytotoxicity against murine IC-2 mast cells with IC50values of 3.6–7.0 μM. The enigmimides (4and 5) and dephosphoenigmazoles did not show cytotoxicity (IC50> 10 μM), implying that both the oxazole moiety and the phosphate group are necessary for the cytotoxicity of the enigmazole class macrolides.

Background: Foot pathologies can affect the kinetic chain during gait, leading to altered loading at other joints that can lead to subsequent pathologies. Although hallux valgus is the most common foot disease, little has been discussed about the biokinetic effects of hallux valgus on the foot and lower limb. This systematic review evaluated the kinematic, kinetic, and pedobarographic changes of the hallux valgus foot compared to a healthy one.Methods: Several electronic databases were searched up to January 2022, including only cross-sectional studies with clearly defined isolated hallux valgus diseases and healthy groups. Two investigators independently rated studies for methodological quality using the NIH Study Quality Assessment Tool for cross-sectional studies. Kinetic data were extracted, including temporal data, kinematics of the foot joint, kinematics of the proximal lower limb, and pedobarography. We did meta-analyses tests with a random effects model using the metafor package in R.Results: Hallux valgus patients walk slower compared to a disease-free control group −0.16 m/s (95% CI −0.27, −0.05). Hallux valgus patients exhibited significantly reduced coronal plane motion of the hindfoot-shank during preswing 1.16 degrees (95% CI 0.31, 2.00). Hallux valgus patients generated less force in the hallux region 33.48 N (95% CI 8.62, 58.35) but similar peak pressures in the hallux compared to controls. Hallux valgus patients generated less peak pressure at the medial and lateral hindfoot as compared to controls: 8.28 kPa (95% CI 2.92, 13.64) and 8.54 kPa (95% CI 3.55, 13.52), respectively.Conclusion: Although hallux valgus is a deformity of the forefoot, the kinematic changes due to the pathology are associated with significant changes in the range of motion at other joints, underscoring its importance in the kinetic chain. This is demonstrated again with the changes of peak pressure. Nevertheless, more high-quality studies are still needed to develop a fuller understanding of this pathology.

In this essay we will demonstrate that the Economy of Communion (EoC) movement provides a very good example of Humanistic Management (HM) as characterized by Domènec Melé in particular. EoC provides a unique lens through which to conceive of Humanistic Management which is extraordinarily person-centered, and which maps onto many of the key themes and principles of Humanistic Management practice. We will here present nine features of Humanistic Management which are clearly displayed in EoC scholarship and practice. We will show the commonalities of thought between EoC and HM through their parallel scholarly explanations of business practices, and also through concrete lived examples of EOC entrepreneurs. Our hope is that the Economy of Communion movement and businesses will become a fruitful source of study and investigation for further Humanistic Management research.

In this essay, we highlight 7 distinctives of EoC businesses which set them apart even from other humanistic approaches to management. Not that EoC’s distinctives make them a non-humanistic form of management, but they distinguish it with a unique set of goals and aims. These are: 1. Social and Economic Transformation Towards Unity; 2. The existential Self giving aspect—Creating a Culture of Encounter; 3. Redistributing Wealth for the Common Good; 4. Concern to Alleviate Poverty in All of Its Forms, and to Participate in Poverty; 5. EoC Entrepreneurs Participate in Poverty (The Wound and the Blessing); 6. Fraternity and the Market as a Place of Community-Building (Communion); and 7. Competitors as friends—Acting as “Starters of Cooperation.”

Calvert wanted to create fishing camps to share the beauty and excellent fishing. The Whitefish Bay area of Lake of the Woods where Ernie had two camps still has an excellent lake trout population today that attracts anglers from far and wide. Ernie was the pioneer of operating a fishing camp and his vision to share the excellent fishing in northern Ontario with the rest of the world is still being realized today. Ernie was a pharmacist and opened Calvert's Drug Store in Rainy River on the south end of the lake. [Extracted from the article]

Water quality impacts of new ion exchange point-of-entry residential softeners and their ability to be decontaminated following hydrocarbon exposure were investigated. During startup, significant amounts of total sulfur (445 ± 815 mg/L) and total organic carbon (937 ± 119 mg/L) were released into the drinking water that flowed through the softeners. Particulate organic carbon was released until the third regeneration cycle, and resin may also have been released. After one week of device use, softeners continued to cause organic carbon levels to be four to five times greater than background levels. Leached materials from the ion-exchange resin contributed to chlorine decay. When resins were exposed to hydrocarbon-contaminated water, they sorbed benzene, toluene, ethylbenzene, and xylenes (BTEX) and then desorbed the contaminants into drinking water during a 15 day flushing decontamination period. On day 15, benzene exceeded the federal drinking water limit for two of the four resins. The aged resin contributed to the greatest chlorine decay rates and sorbed and then retained the least amount of BTEX. Scale and biofilm on the aged resin likely prompted disinfectant reactivity and inhibited BTEX diffusion into the resin. Study results show that softeners exposed to hydrocarbon-contaminated water may need to be repeatedly flushed to remove BTEX contamination or be replaced. Additional work is recommended to better understand softener impacts on drinking water quality.

AbstractWe present an affine-invariant random walk for drawing uniform random samples from a convex body $\mathcal{K} \subset \mathbb{R}^n$ that uses maximum-volume inscribed ellipsoids, known as John’s ellipsoids, for the proposal distribution. Our algorithm makes steps using uniform sampling from the John’s ellipsoid of the symmetrization of $\mathcal{K}$ at the current point. We show that from a warm start, the random walk mixes in ${\widetilde{O}}\!\left(n^7\right)$ steps, where the log factors hidden in the ${\widetilde{O}}$ depend only on constants associated with the warm start and desired total variation distance to uniformity. We also prove polynomial mixing bounds starting from any fixed point xsuch that for any chord pqof $\mathcal{K}$ containing x, $\left|\log \frac{|p-x|}{|q-x|}\right|$ is bounded above by a polynomial in n.

Features PRO bass fishing looks glamourous from the outside. That means upgrading the hooks on my baits, using the proper rod and line for the technique that I'm employing, and making sure my hook-set matches my bait. While it's fun to set the hook on slack line, dropping your rod and really giving the hook-set all you have will tear a big hole in the fish's mouth or rip the bait right out. You will fish the baits you have confidence in better than the baits you haven't experienced previously. [Extracted from the article]

Seven new eremophilane sesquiterpenoids, paraconulones A–G (1–7), along with three previously reported analogues, periconianone D (8), microsphaeropsisin (9), and 4-epi-microsphaeropsisin (10), were obtained from an EtOAc extract of the marine-derived fungus Paraconiothyrium sporulosumDL-16. The structures of these compounds were elucidated by extensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and computational studies. Compounds 1, 2, and 4are the first examples of dimeric eremophilane sesquiterpenoids coupled through a C–C bond identified from microorganisms. Compounds 2–5, 7, and 10showed inhibitory effects on lipopolysaccharide-induced NO production in BV2 cells, which were comparable to the positive control curcumin.

Fish according to weather conditions Before I made my first visit to the St. Lawrence River in 2019, fellow pro angler Cory Johnston told me a general rule to follow. Take care of the fish Anglers are often disappointed when new fishing regulations are implemented, especially when they are not allowed to keep as many fish as they could in the past. Pay attention to the small details because there are days when they do make a difference - the colour of your bait, the cadence of the retrieve, even the patience to fish your bait just a little bit slower that some anglers have more than others. Anglers could spot fish and put a bait in front of them before fish even knew they were there. [Extracted from the article]

Contemporary management of COPD relies on exacerbation history to risk-stratify patients for future exacerbations. Multivariable prediction models can improve the performance of risk stratification. However, the clinical utility of risk stratification can vary from one population to another.

In this article, the authors will discuss a modified anatomy-based neck and thyroid examination that allows for a more comprehensive evaluation. It is the opinion of the authors that an organ and its function are best evaluated utilizing the following steps: anatomy-based inspection and palpation, imaging, and blood tests. Approximately half of the lateral part of the thyroid is deep to the sternocleidomastoid (SCM) and sternothyroid muscles, which makes it rather difficult to palpate the entire gland utilizing prior physical examination techniques. The goal of this modified anatomy-based thyroid examination is to minimize the number of structures between the physician’s fingers and the patient’s thyroid by utilizing neck flexion, side bending, and rotation. If one approaches the thyroid from behind the patient, nodules can be missed due to the muscles and transverse processes overlaying them. The incidence of thyroid cancer in the United States is drastically increasing, which demonstrates the importance of a more thorough thyroid palpation. Our anatomy-based approach may allow for earlier detection and therefore earlier treatment.

Digital health refers to the field of using and developing technology to improve health outcomes. Digital health and digital health interventions (DHIs) within the area of intensive care and critical illness survivorship are rapidly evolving. Digital health interventions refer to technologies in clinical interventional format. A DHI could support clinicians with increasing clinical demands to have improved oversight of their patients’ recovery trajectory or potential for deterioration, improve efficiency of healthcare delivery, and/or predict patient outcomes. In this narrative review, DHIs are explored across the continuum from in the ICU (recognising and managing clinical deterioration, identifying individuals at risk of poor recovery outcomes, tailoring care of the ICU patient and supporting the emotional needs of their family) through to integration in the primary care setting (adjuncts to ICU follow-up clinics and tracking, coaching and remote monitoring). Some of the DHIs discussed in this narrative review (to name a few) include interventions delivered via: Telehealth, artificial intelligence, wearable devices, virtual reality, and mobile phone applications (apps). Additionally, exploration of DHIs used successfully in other health fields are discussed to highlight potential opportunities for adaptation to the ICU context. Finally, the review provides an overview of considerations needed in the development of new DHIs. Development should consider the intended user, barriers to technology engagement and design. In the implementation of a new DHI, the World Health Organization (WHO) Global Strategy on Digital Health and appropriate evaluation should be considered prior to scaling up. Optimal implementation of DHIs could help address the key challenges of the ICU field.

Cysteine chemoproteomic screening platforms are widely utilized for chemical probe and drug discovery campaigns. Chemoproteomic compound screens, which use a mass spectrometry–based proteomic readout, can interrogate the structure activity relationship for thousands of proteins in parallel across the proteome. The versatility of chemoproteomic screens has been demonstrated across electrophilic, nucleophilic, and reversible classes of molecules. However, a key bottleneck that remains for these approaches is the low throughput nature of the most established sample preparation workflows, which rely on many time-intensive and often error prone steps. Addressing these challenges, here we establish a novel workflow, termed CySP3-96, that pairs single-pot, solid-phase-enhanced, sample preparation (SP3) with a customized 96-well sample cleanup workflow to achieve streamlined multiplexed sample preparation. Our CySP3-96 method addresses prior volume limitations of SP3, which allows for seamless 96-well chemoproteomic sample preparation, including for large input amounts that are incompatible with prior methods. By deploying CySP3-96 to screen a focused set of 16 cysteine-reactive compounds, we identify 2633 total ligandable cysteines, including 21 not captured in CysDB. Chemoproteomic analysis of a pair of atropisomeric electrophilic kinase inhibitors reveals striking stereoselective cysteine ligandability for 67 targets across the proteome. When paired with our innovative budget friendly magnetic resin, CySP3-96 represents a versatile, low cost, and highly reproducible screening platform with widespread applications spanning all types of chemoproteomic studies.