The effects of simulated monocular and binocular vision impairment on football penalty kick performance.

Sports performance is relatively robust under high levels of binocular blur. However, the limited research studies investigating monocular impairments has shown it has a larger impact on sport performance. This research study is relevant for classification in sports for athletes with vision impairment (VI), where visual acuity (VA) from the better eye is used during classification. Across two experiments, we aimed to establish the point at which binocular and monocular impairments affected performance in a football penalty kick (PK) through simulating varying severities of degraded VA and contrast sensitivity (CS) in active football players. In experiment one, 25 footballers performed PKs as VA and CS were systematically decreased in both eyes, and in one condition, visual field (VF) was reduced. The most severe VA/CS condition and reduced VF significantly impacted outcome, ball velocity and placement (ball kicked closer to the centre of the goal) (p < 0.05). In experiment two, 29 different footballers performed PKs as VA and CS of only the dominant eye were systematically decreased and in one condition the dominant eye was occluded, and participants viewed their environment through the non-dominant eye (monocular viewing). No differences were observed when assessing monocular impairments influence on outcome, velocity and ball placement. PKs have a high resilience to VI, but binocular impairment has a more immediate effect, suggesting binocular measures should be used in classification processes in football.

From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.

Consideration of T-cell profile in the examination of statin efficacy in inflammatory diseases, neurodegeneration, and neurocognitive performance.

Statins are a cornerstone in the medical management of cardiovascular disease, yet their efficacy varies greatly between individuals. In this commentary, we outline evidence for the role of CD4+CD28null T-cell expansion as a critical moderator of the effects of statins in preventing cardiovascular events via the reduction of pathological inflammation. Given this relationship, we argue that T-cell profiles should be considered as a patient characteristic in clinical and pre-clinical studies examining statin efficacy in other age- and inflammation-related pathologies. We discuss the implications this may have for studies of statin use in numerous disease processes - notably, dementia and neurocognitive dysfunction - and the potential for T-cell profiles to be used as a prognosticator for statin efficacy in rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis.

Incidence of and risk factors for paediatric perioperative anaphylaxis in the USA.

BACKGROUND: Perioperative anaphylaxis is a serious and often life-threatening immediate hypersensitivity reaction. There are few published data on paediatric perioperative anaphylaxis (pPOA). We evaluated the incidence of and risk factors involved in the occurrence of pPOA within a large US national database. METHODS: Deidentified data from the US Nationwide Inpatient Sample from 2005 to 2014 were used to identify pPOA cases and to conduct a retrospective multivariate analysis of preselected independent variables. RESULTS: Among 3,601,180 surgeries and procedures in children aged 0-18 yr, 297 pPOA cases were identified for an incidence of one in 12,125 surgeries and procedures. Compared with controls, pPOA cases had an increased median length of stay (6 vs 2 days; P<0.001) and median hospital cost ($54 719 vs $5109; P<0.0001). The age groups between 6 and 12 yr (odds ratio [OR] 7.1; 95% confidence interval [CI] 3.9-12.9; P<0.001) and 13 and 17 yr (OR 8.5; 95% CI 4.7-15.2; P<0.001) were associated with increased odds of pPOA. Transplant (OR 46.3; 95% CI 20.8-102.9; P<0.001), cardiac (OR 16.4; 95% CI 7.5-35.9; P<0.001), and vascular (OR 15.2; 95% CI 7.5-30.7; P<0.001) procedures posed the highest risk for pPOA. Chronic pulmonary disease, coagulopathy, and fluid and electrolyte disorders were also associated with pPOA (OR 2.2; 95% CI 1.5-3.3; P<0.001). CONCLUSIONS: The incidence of pPOA was one in 12,125 cases. Risk factors included age, procedure type, and comorbidities.

Emotional preparedness for human body donor dissection in premedical education: A pilot program evaluation.

Dissection of bodies provided by donors continues to be utilized as a critical part of medical education. It also represents a rite of passage that socializes students to prepare them for the stress that comes with working in a clinical environment as a medical professional. Just as proper guidance in acquiring technical skills is critical in anatomy education, there is an important need for proper emotional guidance throughout the human dissection process. A pilot curriculum was developed by an interdisciplinary faculty team to emotionally prepare students for their first visit to the anatomy laboratory. Students were first-year foundation premedical students who had expressed an interest in visiting the laboratory. Pre- and post-visit surveys were conducted to explore students' emotional responses to a first visit to the anatomy laboratory and their utilization of coping strategies. The survey findings show an overwhelming favorable feeling in anticipation of the human gross anatomy laboratory visit. About 20% of the students experienced anxiety at the anticipation of the laboratory visit, but only 5.3% experienced anxiety during the visit. The decrease in the number of students experiencing anxiety may be attributed to the interventions introduced before and during the visit. Talking with a close friend was the main coping strategy utilized by 63% of students experiencing fear or anxiety during and after the laboratory visit. The findings from this program evaluation provide a better understanding of student emotional preparedness and utilization of coping strategies, which may help prepare and guide future students for the dissection experience.

A toolkit for a modern gynecologic oncology tissue bank.

OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.

Epigenetic signals associated with delirium replicated across four independent cohorts.

Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.

Point-of-Care Kidney and Genitourinary Ultrasound in Adults: Image Acquisition.

A range of conditions involving the kidneys and urinary bladder can cause organ-threatening complications that are preventable if diagnosed promptly with diagnostic imaging. Common imaging modalities include either computed tomography or diagnostic ultrasound. Traditionally, ultrasound of the kidney-genitourinary system has required consultative teams consisting of a sonographer performing image acquisition and a radiologist performing image interpretation. However, diagnostic point-of-care ultrasound (POCUS) has recently emerged as a useful tool to troubleshoot acute kidney injury at the bedside. Studies have shown that non-radiologists can be trained to perform diagnostic POCUS of the kidneys and bladder with high accuracy for a set number of important conditions. Currently, diagnostic POCUS of the kidney-genitourinary system remains underused in actual clinical practice. This is likely because image acquisition for this organ system is unfamiliar to most clinicians in specialties that encounter acute kidney injury, including primary care, emergency medicine, intensive care, anesthesiology, nephrology, and urology. To address this multi-specialty educational gap, this narrative review was developed by a multi-disciplinary group to provide a specialty-agnostic framework for kidney-genitourinary POCUS image acquisition: indications/contraindications, patient positioning, transducer selection, acquisition sequence, and exam limitations. Finally, we describe foundational concepts in kidney-genitourinary ultrasound image interpretation, including key abnormal findings that every bedside clinician performing this modality should know.

Impact of automated alerts on discharge opioid overprescribing after general surgery.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The objectives of this study were to identify the most performed surgical procedures associated with the highest rates of discharge opioid overprescribing and to implement an electronic health record (EHR) alert to reduce discharge opioid overprescribing. METHODS: This quality improvement, before-and-after study included patients undergoing one of the identified target procedures-laparoscopic cholecystectomy, unilateral open inguinal hernia repair, and laparoscopic appendectomy-at an academic medical center. The alert notified providers when the prescribed opioid quantity exceeded guideline recommendations. The preimplementation cohort included surgical encounters from January 2020 to December 2021. The EHR alert was implemented in May 2022 following provider education via email and in-person presentations. The postimplementation cohort included surgical encounters from May to August 2022. The primary outcome was the proportion of patients with a discharge opioid supply exceeding guideline recommendations (overprescribing). RESULTS: A total of 1,478 patients were included in the preimplementation cohort, and 141 patients were included in the postimplementation cohort. The rate of discharge opioid overprescribing decreased from 48% in the preimplementation cohort to 3% in the postimplementation cohort, with an unadjusted absolute reduction of 45% (95% confidence interval, 41% to 49%; P < 0.001) and an adjusted odds ratio of 0.03 (95% confidence interval, 0.01 to 0.08; P < 0.001). Among patients who received opioids, the mean (SD) opioid supply at discharge decreased from 92 (43) oral morphine milligram equivalents (MME) (before implementation) to 57 (20) MME (after implementation) (P < 0.001). The proportion of patients who received additional opioid prescriptions within 1 to 14 days of hospital discharge did not change (P = 0.76). CONCLUSION: Implementation of an EHR alert along with provider education can reduce discharge opioid overprescribing following general surgery.

NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten eleven translocation (TET) enzymes and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTis). NAPRT silencing was also associated with synergistic tumor cell killing with poly(ADP)-ribose polymerase inhibitors (PARPis) and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT-silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite associated hypermethylation can impact diverse cellular processes and leads to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARPis.

Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs. Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSAD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage. Results: We found an association between PRSAD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRSAD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRSAD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04). Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Characterization of Ligilactobacillus salivarius CRISPR-Cas systems.

Ligilactobacillus is a diverse genus among lactobacilli with phenotypes that reflect adaptation to various hosts. CRISPR-Cas systems are highly prevalent within lactobacilli, and Ligilactobacillus salivarius, the most abundant species of Ligilactobacillus, possesses both DNA- and RNA-targeting CRISPR-Cas systems. In this study, we explore the presence and functional properties of I-B, I-C, I-E, II-A, and III-A CRISPR-Cas systems in over 500 Ligilactobacillus genomes, emphasizing systems found in L. salivarius. We examined the I-E, II-A, and III-A CRISPR-Cas systems of two L. salivarius strains and observed occurrences of split cas genes and differences in CRISPR RNA maturation in native hosts. This prompted testing of the single Cas9 and multiprotein Cascade and Csm CRISPR-Cas effector complexes in a cell-free context to demonstrate the functionality of these systems. We also predicted self-targeting spacers within L. salivarius CRISPR-Cas systems and found that nearly a third of L. salivarius genomes possess unique self-targeting spacers that generally target elements other than prophages. With these two L. salivarius strains, we performed prophage induction coupled with RNA sequencing and discovered that the prophages residing within these strains are inducible and likely active elements, despite targeting by CRISPR-Cas systems. These findings deepen our comprehension of CRISPR-Cas systems in L. salivarius, further elucidating their relationship with associated prophages and providing a functional basis for the repurposing of these Cas effectors for bacterial manipulation. IMPORTANCE: Ligilactobacillus salivarius is a diverse bacterial species widely used in the food and dietary supplement industries. In this study, we investigate the occurrence and diversity of their adaptive immune systems, CRISPR-Cas, in over 500 genomes. We establish their function and provide insights into their role in the interplay between the bacterial host and the predatory phages that infect them. Such findings expand our knowledge about these important CRISPR-Cas immune systems widespread across the bacterial tree of life and also provide a technical basis for the repurposing of these molecular machines for the development of molecular biology tools and the manipulation and engineering of bacteria and other life forms.

A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Functional performance of a vibrotactile sensory substitution device in people with profound vision loss.

SIGNIFICANCE: This study has shown a vibrotactile sensory substitution device (SSD) prototype, VibroSight, has the potential to improve functional outcomes (i.e., obstacle avoidance, face detection) for people with profound vision loss, even with brief familiarization (<20 minutes). PURPOSE: Mobility aids such as long canes are still the mainstay of support for most people with vision loss, but they do have limitations. Emerging technologies such as SSDs are gaining widespread interest in the low vision community. The aim of this project was to assess the efficacy of a prototype vibrotactile SSD for people with profound vision loss in the face detection and obstacle avoidance tasks. METHODS: The VibroSight device was tested in a movement laboratory setting. The first task involved obstacle avoidance, in which participants were asked to walk through an obstacle course. The second was a face detection task, in which participants were asked to step toward the first face they detected. Exit interviews were also conducted to gather user experience data. Both people with low vision (n = 7) and orientation and mobility instructors (n = 4) completed the tasks. RESULTS: In obstacle avoidance task, participants were able to use the device to detect (p<0.001) and avoid (p<0.001) the obstacles within a significantly larger range, but were slower (p<0.001), when compared with without the device. In face detection task, participants demonstrated a great level of accuracy, precision, and sensitivity when using the device. Interviews revealed a positive user experience, although participants identified that they would require a lighter and compact design for real-world use. CONCLUSIONS: Overall, the results verified the functionality of vibrotactile SSD prototype. Further research is warranted to evaluate the user performance after an extended training program and to add new features, such as object recognition software algorithms, into the device.

Molecular detection of sub-microscopic infections and Plasmodium falciparum histidine-rich protein-2 and 3 gene deletions in pre-elimination settings of South Africa.

South Africa's efforts toward eliminating malaria have positioned the country in the pre-elimination stage. Imported and sub-microscopic cases still contribute to the persistence of malaria in regions of low transmission as identified in this study where diagnostics is built largely on the use of Rapid Diagnostic Test (RDT). However, the presence of Pfhrp2/3 gene deletion is known to interfere with the accuracy of diagnosis with the use of RDT. Malaria elimination and detection of Pfhrp2/3 gene deletion in the pre-elimination setting requires accurate molecular surveillance. With the core objective of this study being the determination of the presence sub-microscopic malaria cases and deleted Pfhrp2/3 gene markers, a total of 354 samples were collected from five districts of KwaZulu Natal, South Africa. These samples were prepared for molecular analysis using primers and PCR conditions specific for amplification of 18S rRNA and msp-1gene. Positive amplicons were analysed for the presence of Pfhrp2/3 and flanking genes, along with Sanger sequencing and phylogenetic studies. Out of 354 samples collected 339 were tested negative with PfHRP2 based RDTs. Of these Pfhrp2 and Pfhrp3 gene deletions were confirmed in 94.7% (18/19) and 100% (19/19) respectively. High migration rate (75%) among the study participants was noted and phylogenetic analysis of sequenced isolates showed close evolutionary relatedness with India, United Kingdom, Iran, and Myanmar and China isolates. Molecular-based test is recommended as an essential surveillance tool for malaria management programs as the target focuses on elimination.

IFN-γ production by functionally reprogrammed Treg cells promotes anti-tumor efficacy of OX40/CD137 bispecific agonist therapy.

Regulatory T (Treg) cells are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Treg cells to contribute to anti-tumor immunity. OX40 and CD137 are expressed highly on Treg cells, activated and memory T cells, and NK cells. Here, using a novel tetravalent bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonists induce potent anti-tumor immunity partially dependent upon IFN-γ-production by functionally reprogrammed Treg cells. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Treg cells into both fragile Foxp3+ IFN-γ+ cells with decreased suppressive function, and lineage instable Foxp3- IFN-γ+ cells. Treg cell fragility is partially dependent upon IFN-γ signaling, whereas Treg cell instability is associated with reduced IL-2 signaling upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Treg cells and their progeny partially reverses the anti-tumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Treg cells into IFN-γ-producing cells contributes to the efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting co-stimulatory receptors highly expressed by Treg cells potentiate anti-tumor immunity in mouse models.

Supramolecularly-Cross-Linked Nanogel Assemblies for On-Demand, Ultrasound-Triggered Chemotherapy.

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.

The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On this data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualisable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.

The Use of Clips to Prevent Post-Polypectomy Bleeding: A Clinical Review.

GOALS: The goal of this clinical review is to provide an overview of the current literature regarding the utility of prophylactic clips in reducing postpolypectomy bleeding and to provide an expert statement regarding their appropriateness in clinical practice. BACKGROUND: Colonoscopy enables the identification and removal of premalignant and malignant lesions through polypectomy, yet complications including postpolypectomy bleeding (PPB) can arise. While various studies have explored applying clips prophylactically to prevent PPB, their effectiveness remains uncertain. STUDY: A literature search conducted in PubMed and Embase identified 671 publications discussing clip use postpolypectomy; 67 were found to be relevant after screening, reporting outcomes related to PPB. Data related to clip utilization, polyp characteristics, and adverse events were extracted and discussed. RESULTS: The current literature suggests that prophylactic clipping is most beneficial for nonpedunculated polyps ≥20 mm, especially those in the proximal colon. The utility of clipping smaller polyps and those in the distal colon remains less clear. Antithrombotic medication usage, particularly anticoagulants, has been linked to an increased risk of bleeding, prompting consideration for clip placement in this patient subgroup. While cost-effectiveness analyses may indicate potential savings, the decision to clip should be tailored to individual patient factors and polyp characteristics. CONCLUSIONS: Current research suggests that the application of prophylactic clips can be particularly beneficial in preventing delayed bleeding after removal of large nonpedunculated polyps, especially for those in the proximal colon and in patients on antithrombotic medications. In addition, for large pedunculated polyps prophylactic clipping is most effective at controlling immediate bleeding.