Search Results (39)

Background/Objectives: Response to immune checkpoint inhibitors (ICIs) is associated with several biological pathways, including tumor immunogenicity and antitumor immunity. Identifying host factors involved in these pathways may guide personalized ICI treatment. Methods: We describe the application of chromatin conformation assays to blood from patients with advanced urothelial carcinoma from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). This trial demonstrated a significant survival benefit with avelumab maintenance plus best supportive care (BSC) vs. BSC alone following non-progression with platinum-based chemotherapy as first-line therapy. Blood-based chromatin conformation markers (CCMs) were screened for associations with high/low immune effector gene expression in tumors and for interactions with outcomes and tumor mutation burden. Results: Candidate CCMs included genes involved in several immune response pathways, such as POU2F2, which encodes a transcription factor that regulates B-cell maturation. Conclusions: Our findings suggest that polygenic host factors may affect response to ICIs and support further investigation of chromatin conformation assays. Full article

Purpose: Assess mental health professionals’ attitudes regarding the timing and characteristics of therapeutic interventions for children whose parents have incurable cancer, and whether professionals would use artificial intelligence (AI) in these interventions. Methods: Professionals were surveyed about their therapeutic approaches to caring for children when parents have incurable cancer under different scenarios. Data from N = 294 (69% male, 72% white, 26% Latine, 56% rural or underserved communities) physicians, psychologists, social workers, hospital chaplains, community health workers, and others were analyzed. Attitudes surrounding the timing and characteristics of interventions across the parent’s cancer journey were compared, including how professionals believed interventions should attend to dimensions of the child or family, and if, how, and when AI technology could be introduced. Results: Across 10 dimensions of childhood, (1) the child’s premorbid exposure to traumatic events, (2) a surviving parent’s presence, and (3) the child’s age were important factors to consider when making mental health care decisions in this context. The professionals reported being more likely to introduce therapeutic resources as early as possible in the parent’s illness (i.e., upon diagnosis). Regarding the use of AI, 87% foresaw its role in supporting children’s mental health. While 93.2% agreed that a grieving child could be helped by interacting with an AI-generated likeness of the deceased parent, when AI’s use was contextualized in providing support for a child who lost a parent to cancer, only 49% believed AI was appropriate. The participants were conflicted over when AI could be first introduced, either upon a parent’s illness diagnosis (19.4%), during a parent’s treatment (19.0%), or as part of a parent’s hospice care (12.6%). None believed it to be appropriate following the loss of the parent to cancer. Conclusions: AI is increasingly present in children’s daily lives and quickly infiltrating health care with widely accessible mental health chatbots. Concerns about privacy, the accuracy of information, and the anthropomorphism of AI tools by children give professionals pause before introducing such technology. Proceeding with great caution is urged until more is known about the impact of AI on children’s mental health, grief, and psychological well-being in the context of parental cancer. Full article

Introduction: Cardiopulmonary exercise testing (CPET) is the gold-standard assessment of functional capacity and predicts postoperative outcomes in major abdominal and thoracic surgery, as well as in older individuals undergoing elective surgery for colorectal cancer. However, CPET is resource-intensive and not universally available. Simpler objective assessments of functional capacity, such as Clinical Frailty Scale (CFS) scoring, predict postoperative complications and may be useful in aiding shared decision and perioperative planning. Objectives: This study aimed to assess local cohort data and investigate the association between Clinical Frailty Scoring, CPET outcomes, and length of hospital stay. Methods: We conducted a retrospective cohort analysis of all patients who had received a cardiopulmonary exercise test as part of their preoperative assessment for major abdominal and thoracic surgery between May 2018 and December 2022 in four district general hospitals. Results: This study featured 174 patients, age 73 (mean), CFS 3 (mean), who underwent CPET with associated CFS scoring. The CFS scores were weakly correlated with the anaerobic threshold, VO₂ peak, and ventilatory equivalents, coefficients measuring −0.34, −0.36, and 0.31 (all p < 0.001), respectively. Linear regression demonstrated a negative coefficient for the association of CFS with the VO₂ peak and the AT, measuring −1.22 and −1.70, respectively, both p < 0.001. The CFS score was not predictive of 1-year mortality in this group. In a subgroup analysis (n = 59), there was no association between the CFS score and the length of stay. Conclusions: Our data suggest a weak relationship between the CFS score and the CPET results. Further investigations with larger prospective datasets are required to explore the use of CFS as a surrogate for CPET and its use as an independent predictor for perioperative outcomes. This study supports the limited literature available on this subject. Full article

HIV-1 subtypes have distinct geographical distributions, with subtypes A, C, and D and inter-subtype recombinants circulating in sub-Saharan Africa. Historically, individuals living with subtype A viruses exhibit slower CD4 decline and progression to AIDS diagnosis. Despite this, there are few authentic infectious molecular clones (IMCs) of subtype A or AC recombinant transmitted founder (TF) viruses with which to investigate viral impacts on pathogenesis. In this study, we constructed 16 authentic subtype A1 and 4 A1C recombinant IMCs from the IAVI Rwandan Protocol C acute infection cohort and characterized these viruses phenotypically. The virus replicative capacity (RC) scores varied over 50-fold, but the natural substitution of non-consensus amino acids in the p17(MA) domain of Gag was generally linked to higher RC levels. Sensitivity to a panel of broadly neutralizing antibodies (bNAbs) showed that all but one TF was sensitive to N6, which targets the CD4 binding site, while bNAbs PG16 and PGT 128 had a similar level of potency but reduced breadth against our panel of viruses. In contrast, bNAb 10E8V4 revealed high breadth but much lower potency. This panel of well-characterized, authentic subtype A and AC recombinant IMCs provides a resource for studies on the role of the virus subtype in HIV-1 transmission, pathogenesis, and vaccine design. Full article

The use of acellular nerve allografts (ANAs) to reconstruct long nerve gaps (>3 cm) is associated with limited axon regeneration. To understand why ANA length might limit regeneration, we focused on identifying differences in the regenerative and vascular microenvironment that develop within ANAs based on their length. A rat sciatic nerve gap model was repaired with either short (2 cm) or long (4 cm) ANAs, and histomorphometry was used to measure myelinated axon regeneration and blood vessel morphology at various timepoints (2-, 4- and 8-weeks). Both groups demonstrated robust axonal regeneration within the proximal graft region, which continued across the mid-distal graft of short ANAs as time progressed. By 8 weeks, long ANAs had limited regeneration across the ANA and into the distal nerve (98 vs. 7583 axons in short ANAs). Interestingly, blood vessels within the mid-distal graft of long ANAs underwent morphological changes characteristic of an inflammatory pathology by 8 weeks post surgery. Gene expression analysis revealed an increased expression of pro-inflammatory cytokines within the mid-distal graft region of long vs. short ANAs, which coincided with pathological changes in blood vessels. Our data show evidence of limited axonal regeneration and the development of a pro-inflammatory environment within long ANAs. Full article

Studies of Phytophthora impact in forests generally focus on individual species without recognition that Phytophthora occur in multispecies communities. This study investigated community structure of Phytophthora species in the rhizosphere of Agathis australis (kauri) in Te Wao Nui o Tiriwa/Waitākere Ranges, New Zealand, in the context of kauri dieback disease expression. Soil sampling and tree monitoring were conducted on 767 randomly selected mature kauri trees. Phytophthora species were detected using both soil baiting and DNA metabarcoding of environmental DNA (eDNA). Four species were detected with soil baiting (P. agathidicida, P. cinnamomi, P. multivora, and P. pseudocryptogea/P. cryptogea) and an additional three species with metabarcoding (P. kernoviae, P. cactorum/P. aleatoria and an unknown clade 7 species). Phytophthora cinnamomi was the most abundant species and was distributed throughout the forest. Both P. multivora and P. agathidicida were limited to forest edges, suggesting more recent introductions. P. agathidicida presence was strongly correlated with declining canopy health, confirming its role as the main driver of kauri dieback. The limited distribution of P. agathidicida and infrequent detections (11.0% samples) suggests that that this species is spreading as an introduced invasive pathogen and provide hope that with strategic management (including track upgrades and closures, restricting access to uninfected areas, and continual monitoring) uninfected areas of the forest can be protected. The frequent detections of P. cinnamomi and P. multivora from symptomatic trees in the absence of P. agathidicida suggest more research is needed to understand their roles in kauri forest health. Full article

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5’ untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023. Full article

Tactical occupations regularly encounter life-threatening situations while on duty. Although these occupations are often trained to utilize slow breathing (SB) during intense stress, there is no evidence supporting the effects on markers of stress in response to a virtual reality active shooter training drill (VR-ASD). The purpose of the study was to determine the impact of acute SB on biomarkers of stress in response to a VR-ASD. Seventy-nine (n = 79) subjects performed either slow breathing method 1 (SB1), slow breathing method 2 (SB2), or normal breathing (control) for five minutes, both pre- and post-VR-ASD. Saliva samples were analyzed for stress markers, including α-amylase (sAA) and secretory immunoglobulin-A (SIgA). Both methods of SB resulted in significantly lower sAA concentrations at 5 (p < 0.001) and 30 min post-VR-ASD (SB1: p = 0.008; SB2: p < 0.001) compared to the control. In the control condition, the sAA concentrations were significantly elevated 5 min post-VR-ASD (p < 0.001) but did not change across time in SB1 or SB2 (p > 0.05). Thus, both SB1 and SB2 reduced the sAA response and resulted in lower concentrations post-VR-ASD. This study was pre-registered as a clinical trial (“Impact of Breathing Interventions on Stress Markers”; NCT05825846). Full article

Background: Breast reconstruction is a pivotal part of the recuperation process following a mastectomy and aims to restore both the physical aesthetic and emotional well-being of breast cancer survivors. In recent years, artificial intelligence (AI) has emerged as a revolutionary technology across numerous medical disciplines. This narrative review of the current literature and evidence analysis explores the role of AI in the domain of breast reconstruction, outlining its potential to refine surgical procedures, enhance outcomes, and streamline decision making. Methods: A systematic search on Medline (via PubMed), Cochrane Library, Web of Science, Google Scholar, Clinical Trials, and Embase databases from January 1901 to June 2023 was conducted. Results: By meticulously evaluating a selection of recent studies and engaging with inherent challenges and prospective trajectories, this review spotlights the promising role AI plays in advancing the techniques of breast reconstruction. However, issues concerning data quality, privacy, and ethical considerations pose hurdles to the seamless integration of AI in the medical field. Conclusion: The future research agenda comprises dataset standardization, AI algorithm refinement, and the implementation of prospective clinical trials and fosters cross-disciplinary partnerships. The fusion of AI with other emergent technologies like augmented reality and 3D printing could further propel progress in breast surgery. Full article

New microfluidic lab-on-a-chip capabilities are enabled by broadening the toolkit of devices that can be created using microfabrication processes. For example, complex geometries made possible by 3D printing can be used to approach microfluidic design and application in new or enhanced ways. In this paper, we demonstrate three distinct designs for microfluidic one-way (check) valves that can be fabricated using digital light processing stereolithography (DLP-SLA) with a poly(ethylene glycol) diacrylate (PEGDA) resin, each with an internal volume of 5–10 nL. By mapping flow rate to pressure in both the forward and reverse directions, we compare the different designs and their operating characteristics. We also demonstrate pumps for each one-way valve design comprised of two one-way valves with a membrane valve displacement chamber between them. An advantage of such pumps is that they require a single pneumatic input instead of three as for conventional 3D-printed pumps. We also characterize the achievable flow rate as a function of the pneumatic control signal period. We show that such pumps can be used to create a single-stage diffusion mixer with significantly reduced pneumatic drive complexity. Full article

Strenuous exercise involving eccentric muscle actions induces skeletal muscle damage resulting in delayed onset muscle soreness (DOMS). Antioxidant supplementation, such as astaxanthin (AX), may alleviate muscle injury following intense exercise. The purpose of this study was to investigate the effect of a four-week course of AX supplementation at 12 mg/day⁻¹ on subjective markers of DOMS, recovery, and performance after a bout of muscle damaging eccentric exercise. Nineteen resistance-trained men (mean ± SD: age, 22.6 ± 2.2 y) completed a between-group design with a four-week supplementation period of 12 mg/day⁻¹ of either AX or a placebo. Subjects completed four trials, with trials One and Three designed to induce muscle damage, consisting of a one repetition maximum test (1RM) for leg-press, followed by five sets of ten repetitions at 65% of 1RM. Trials Two and Four were performance trials, conducted 48 h later and consisting of repetitions to failure at 65%, 70%, and 75% of 1RM. Subjective markers of DOMS and recovery were collected at multiple timepoints post-trial for trials One and Three. Although performance was not affected (p > 0.05), AX supplementation significantly decreased subjective markers of DOMS (p = 0.01) compared to the placebo. The results demonstrated that AX may enhance recovery by reducing DOMS without detriment to performance in resistance-trained men. Full article

Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. Methods: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. Results: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients. Full article

Hydrogen peroxide (H₂O₂) is commonly used as an oxidizing, bleaching, or antiseptic agent. It is also hazardous at increased concentrations. It is therefore crucial to monitor the presence and concentration of H₂O₂, particularly in the vapor phase. However, it remains a challenge for many state-of-the-art chemical sensors (e.g., metal oxides) to detect hydrogen peroxide vapor (HPV) because of the interference of moisture in the form of humidity. Moisture, in the form of humidity, is guaranteed to be present in HPV to some extent. To meet this challenge, herein, we report a novel composite material based on poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) doped with ammonium titanyl oxalate (ATO). This material can be fabricated as a thin film on electrode substrates for use in chemiresistive sensing of HPV. The adsorbed H₂O₂ will react with ATO, causing a colorimetric response in the material body. Combining colorimetric and chemiresistive responses resulted in a more reliable dual-function sensing method that improved the selectivity and sensitivity. Moreover, the composite film of PEDOT:PSS-ATO could be coated with a layer of pure PEDOT via in situ electrochemical synthesis. The pure PEDOT layer was hydrophobic, shielding the sensor material underneath from coming into contact with moisture. This was shown to mitigate the interference of humidity when detecting H₂O₂. A combination of these material properties makes the double-layer composite film, namely PEDOT:PSS-ATO/PEDOT, an ideal sensor platform for the detection of HPV. For example, upon a 9 min exposure to HPV at a concentration of 1.9 ppm, the electrical resistance of the film increased threefold, surpassing the bounds of the safety threshold. Meanwhile, the colorimetric response observed was 2.55 (defined as the color change ratio), a ratio at which the color change could be easily seen by the naked eye and quantified. We expect that this reported dual-mode sensor will find extensive practical applications in the fields of health and security with real-time, onsite monitoring of HPV. Full article

Hydrogen peroxide (aqueous solution of H₂O₂) is one of the most used reagents i n medical sterilization, environmental disinfection, food storage, and other fields. However, hydrogen peroxide has the potential to cause serious harm to biological health and environmental safety. There are many methods (especially electrochemistry) for H₂O₂ detection in liquid phase systems, but a lack of methods for vapor detection. This is due to its colorless and tasteless nature, as well as the oxidative activity of the molecule and its coexistence with humidity. In this study, poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), one of the most commercially successful and widely used conductive polymers, was employed to fabricate an all-organic chemiresistive sensor for simple, real-time, and on-site sensing of hydrogen peroxide vapor (HPV) at room temperature. In comparison with pristine PEDOT:PSS film, the PEDOT:PSS/PEDOT film was prepared by in situ electrochemical polymerization. Upon exposure to different concentrations of HPV, it was found that the hydrophobic and porous PEDOT layer could weaken the interference of humidity in HPV sensing, resulting in a more sensitive and accurate response. At 1.0 ppm HPV concentration, the resistance signal response was increased by nearly 89% compared with the pristine PEDOT:PSS film. This PEDOT-film-based chemiresistive sensor showcases the possibility for further development of nonenzymatic HPV monitoring technology. Full article