The mental health-related barriers and benefits to exercise in adults with and without chronic pain.

Background: Qualitative evidence points to the importance of both mental health-related barriers and benefits to exercise in chronic pain, yet this bidirectional relationship has not been established quantitatively. Methods: 89 adults with chronic pain (75 female, Age: M = 34.7, SD=13.2), and 89 demographically-matched individuals without chronic pain (73 female, Age: M = 32.0, SD=13.3) self-reported demographic and health information, mental health-related barriers and benefits to exercise, and leisure-time exercise activity. Results: Adults with chronic pain had significantly higher scores on mental health-related barriers to exercise, and lower leisure-time exercise participation than adults without chronic pain. The groups did not differ on mental health-related benefits of exercise scores. Benefits scores positively predicted exercise, yet there was a significant negative interaction between pain and benefit scores, indicating a weaker positive relationship between benefits and exercise for adults with chronic pain than for those without chronic pain. Barrier scores significantly negatively predicted exercise engagement, but did not interact significantly with chronic pain. Conclusion: Mental health-related barriers and benefits to exercise are important considerations when prescribing exercise for adults with chronic pain. Adults with chronic pain may require individualised support to address mental health-related barriers to leisure-time exercise.

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates.

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.

Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells.

Sphingolipid metabolism is dysregulated in many cancers, allowing cells to evade apoptosis through increased sphingosine-1-phosphate (S1P) and decreased ceramides. Ceramidases hydrolyze ceramides to sphingosine, which is phosphorylated by sphingosine kinases to generate S1P. The S1P allows cells to evade apoptosis by shifting the equilibrium away from ceramides, which favor cell death. One tumor type that exhibits a shift in the sphingolipid balance towards S1P is glioblastoma (GBM), a highly aggressive brain tumor. GBMs almost always recur despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Understanding sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target dysregulation of sphingolipid metabolism in GBM. Carmofur, a derivative of 5-fluorouracil, inhibits acid ceramidase (ASAH1), a key enzyme in the production of S1P, and is in use outside the USA to treat colorectal cancer. We find that the mRNA for ASAH1, but not other ceramidases, is elevated in recurrent GBM. When TMZ-resistant GBM cells were treated with carmofur, decreased cell growth and increased apoptosis were observed along with cell cycle perturbations. RNA-sequencing identified decreases in cell cycle control pathways that were specific to TMZ-resistant cells. Furthermore, the transcription factor and G1 to S phase regulator, E2F8, was upregulated in TMZ-resistant versus parental GBM cells and inhibited by carmofur treatment in TMZ-resistant GBM cells, specifically. These data suggest a possible role for E2F8 as a mediator of carmofur effects in the context of TMZ resistance. These data suggest the potential utility of normalizing the sphingolipid balance in the context of recurrent GBM.

Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas.

Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1ß in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow-derived myeloid cells (BMDMs). In contrast, no requirement for IL-1ß was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti-IL-1ß or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.

A Histopathological Study of the Spectrum of Skin Lesions in a Tertiary Care Hospital: A Retrospective Study.

Background The skin is the largest organ of the body with many different functions. All age groups are affected by skin diseases, which are widespread in underdeveloped nations. From a straightforward vesicular non-neoplastic lesion to a catastrophic neoplastic lesion, skin disorders exhibit a wide variety of geographic patterns. To make an accurate diagnosis, identify etiological agents, and assist a dermatologist or clinician in selecting the best course of treatment, a skin biopsy must undergo histopathological analysis. The present study was conducted to investigate the histological diagnosis of skin lesions, establish the distribution by age and sex, identify the most prevalent skin lesions, and further subclassify the most prevalent condition. Methodology A retrospective, cross-sectional study was conducted in the Department of Pathology at Datta Meghe Medical College, Wanadongari, Nagpur over the course of a year. Hematoxylin and eosin were used to stain a total of 50 skin biopsy samples, with special stain when necessary, and then examined. Results The study involved a total of 50 patients, with 39 (78%) males and 11 (22%) females. With 16 (32%) cases in the 21-30-year age group, the early age group preponderance was recorded. Overall, 16 (32%) cases had microbial diseases, followed by eight (16%) cases with non-infectious vesicobullous diseases and vesicopustular disease, and five (10%) cases with non-infectious erythematous papular and squamous disease. In 12 (24%) cases, leprosy was the most prevalent microbiological disease. In five (10%) cases, pemphigus vulgaris was the most prevalent vesicobullous condition. Psoriasis, which was present in two (4%) cases, was the most common non-infectious erythematous papular and squamous disease. Squamous cell carcinoma, which was seen in seven (14%) cases, was the most prevalent neoplastic lesion. Conclusions In skin lesions, males outnumbered females. Patients in the younger age groups were most commonly involved. Leprosy and squamous cell carcinoma were, respectively, the most prevalent non-neoplastic and neoplastic skin lesions in our study.

Leveraging stewardship to promote ceftriaxone use in severe infections with low- and no-risk AmpC Enterobacterales.

AmpC ß-lactamases are associated with development of ceftriaxone resistance despite initial in vitro susceptibility, but the risk of AmpC derepression is not equal among Enterobacterales. The purpose of this study was to evaluate the impact of an AmpC stewardship intervention on the definitive treatment of low- and no-risk Enterobacterales. This was an IRB-approved, single pre-test, post-test quasi-experiment at a 5-hospital system. An AmpC stewardship intervention was implemented in July 2022 and included prescriber education, the removal of microbiology comments indicating potential for ceftriaxone resistance on therapy, and the modification of a blood PCR comment for Serratia marcescens to recommend ceftriaxone. Adults ≥18 years pre-intervention (July 2021 to December 2021) and post-intervention (July 2022 to December 2022) who received ≥72 hours of inpatient definitive therapy and had non-urine cultures growing low- and no-risk organisms (S. marcescens, Providencia spp., Citrobacter koseri, Citrobacter amalonaticus, or Morganella morganii) were included. The primary endpoint was definitive treatment with ceftriaxone. A total of 224 patients were included; 115 (51%) in pre-intervention and 109 (49%) in post-intervention. Definitive ceftriaxone therapy was prescribed more frequently after intervention [6 (5%) vs 72 (66%), P < 0.001]. After adjustment for critical illness, patients in the post-group were more likely to receive definitive ceftriaxone (adjOR, 34.7; 95% CI, 13.9-86.6). The proportion of patients requiring retreatment was 18 (15%) and 11 (10%) for pre- and post-intervention patients (P = 0.22), and ceftriaxone resistance within 30 days occurred in 5 (4%) and 2 (2%) patients in the pre- and post-group (P = 0.45). An antimicrobial stewardship intervention was associated with increased ceftriaxone prescribing and similar patient outcomes for low- and no-risk AmpC Enterobacterales.

Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities.

Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined. Therefore, we sought to understand the ability of TTFields to disrupt the growth patterns of and induce kinomic landscape shifts in TMZ-sensitive and -resistant GBM cells. We determined that TTFields significantly decreased the growth of TMZ-sensitive and -resistant cells. Kinomic profiling predicted kinases that were induced or repressed by TTFields, suggesting possible therapy-specific vulnerabilities. Serving as a potential pro-survival mechanism for TTFields, kinomics predicted the increased activity of platelet-derived growth-factor receptor alpha (PDGFRα). We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches.

Evaluating the Use of PROMs in Paediatric Orthopaedic Registries.

Patient-reported outcome measures (PROMs) provide structured information on the patient's health experience and facilitate shared clinical decision-making. Registries that collect PROMs generate essential information about the clinical course and efficacy of interventions. Whilst PROMs are increasingly being used in adult orthopaedic registries, their use in paediatric orthopaedic registries is not well known. The purpose of this systematic review was to identify the frequency and scope of registries that collect PROMs in paediatric orthopaedic patient groups. In July 2023, six databases were systematically searched to identify studies that collected PROMs using a registry amongst patients aged under 18 years with orthopaedic diagnoses. Of 3190 identified articles, 128 unique registries were identified. Three were exclusively paediatric, 27 were majority paediatric, and the remainder included a minority of paediatric patients. One hundred and twenty-eight registries collected 72 different PROMs, and 58% of these PROMs were not validated for a paediatric population. The largest group of orthopaedic registries collected PROMs on knee ligament injuries (21%). There are few reported dedicated orthopaedic registries collecting PROMs in paediatric populations. The majority of PROMs collected amongst paediatric populations by orthopaedic registries are not validated for patients under the age of 18 years. The use of non-validated PROMs by registries greatly impedes their utility and impact. Dedicated orthopaedic registries collecting paediatric-validated PROMs are needed to increase health knowledge, improve decision-making between patients and healthcare providers, and optimise orthopaedic management.

Nematicidal Properties of Chitosan Nanoformulation.

Chitosan is the second most abundant bio-polymer available in the world, second only to cellulose. It is found in crustaceous shells, e.g., those of crabs, shrimps, prawns, and fungi, as well as insect exoskeletons. The use of nanoformulations for the management of pests and diseases is receiving increased interest with the advancement of nanotechnology. Here, chitosan nanospheres were obtained from chitosan using the ionic gelation technique. The nanoformulations obtained were characterized using a particle size analyzer, Fourier transform infrared spectroscopy, and a transmission electron microscope. The efficacy of chitosan nanospheres in suppressing the root-knot nematode Meloidogyne incognita was studied. The particle size of nanospheres formulated for this study was 380.2 nm, with a polydispersity index (PI) of 0.4 and Zeta potential of 45.7 or 50.9 mV at pH 5.2. The chitosan nanospheres were spherical and the particles did not agglomerate. FTIR spectra of the chitosan nanospheres peaked at 3334 cm-1, thereby indicating the stretching of the OH and NH group. In In-vitro studies, chitosan nanospheres showed significant nematicidal activity against M. incognita. Under pot culture conditions, chitosan nanospheres (1%- active compound chitosan) at 2ml/plant decreased the nematode population in roots or soil. Compared to the control, the number of galls was reduced by 83.68%, the number of egg masses by 83.85%, the number of adult females by 66.56%, and the number of second-stage juveniles by 73.20%. In a field experiment, application of chitosan nanospheres (1%) was followed by a 18.75% increase in fruit yield compared to the non-treated control.

Developing resilient clinical trials: Lessons learned from rolling out the Get Back to Healthy trial during a pandemic.

BACKGROUND: The COVID-19 pandemic has caused wide-spread disruptions to the conduct of randomised controlled trials (RCTs), particularly those involving public health services. Using the Get Back to Healthy trial as an example, this study aimed to contextualise the challenges imposed by the COVID-19 pandemic on implementation of RCTs involving public health services in Australia, summarise the effect of common and novel contingency strategies employed to mitigate these challenges, and describe key lessons learned. METHODS: The main challenges, the effect of contingency strategies employed, and key lessons learned were summarised descriptively. RESULTS: The main COVID-19-related challenge has been slow recruitment due to the suspension of clinical services for the trial target population. This challenge has been addressed through carefully considered adjustments to trial design (i.e., expanding the trial eligibility criteria), which has markedly improved trial recruitment rates. Other challenges have included the rapid transition to remote consent and data collection methods, increased complexity of monitoring participant safety, and future statistical challenges with disentangling the impact of the COVID-19 pandemic from treatment effects. The key lessons learned are: (i) adaptations to trial design may be necessary during a pandemic; (ii) offering remote methods may encourage trial participation from all age groups during a pandemic; (iii) enhanced monitoring of safety is critical during a pandemic; (iv) statistical challenges are likely to occur and should be considered when interpreting trial results. CONCLUSION: Key lessons learned may be useful for informing the conduct of resilient RCTs, particularly those involving public health services, in the present and future.

A systematic review on clinical adaptive radiotherapy for head and neck cancer.

INTRODUCTION: Head and neck cancer (HNC) patients' anatomy may undergo significant changes during radiotherapy (RT). This potentially affects dose distribution and compromises conformity between planned and delivered dose. Adaptive radiotherapy (ART) is a promising technique to overcome this problem but requires a significant workload. This systematic review aims to estimate the clinical and dosimetric benefits of ART using prospective data. MATERIAL AND METHODS: A search on PubMed and Web of Science according to the PRISMA guidelines was made on Feb 6, 2023. Search string used was: 'adaptive radiotherapy head neck cancer'. English language filter was applied. All studies were screened for inclusion on title and abstract, and the full text was read and discussed in the research group in case of uncertainty. Inclusion criteria were a prospective ART strategy for HNC investigating clinical or dosimetric outcomes. RESULTS: A total of 1251 articles were identified of which 15 met inclusion criteria. All included studies were published between 2010 and 2023 with a substantial diversity in design, endpoints, and nomenclature. The number of patients treated with ART was small with a median of 20 patients per study (range 4 to 86), undergoing 1-2 replannings. Mean dose to the parotid glands was reduced by 0.4-7.1 Gy. Maximum dose to the spinal cord was reduced by 0.5-4.6 Gy. Only five studies reported clinical outcome and disease control was excellent. Data on toxicity were ambiguous with some studies indicating reduced acute toxicity and xerostomia, while others found reduced quality of life in patients treated with ART. CONCLUSION: The literature on clinical ART in HNC is limited. ART is associated with small reductions in doses to organs at risk, but the influence on toxicity and disease control is uncertain. There is a clear need for larger, prospective trials with a well-defined control group.

A comparison of medical and pharmacy student perspectives of a clinical interprofessional home-visit versus a virtual interprofessional workshop.

Background: No Place Like Home is a clinical interprofessional education (IPE) activity whereby pharmacy and medical students conduct home visits under the guidance and supervision of a clinical preceptor to homebound patients. Purpose: We examined pharmacy and medical student perceptions of mastery of interprofessional competencies during an in-person clinical home visit pre-COVID-19 pandemic versus a virtual IPE learning activity consisting of didactic and case discussions in response to the global COVID-19 pandemic. Methods: We administered the same modified Interprofessional Collaborative Competency Attainment Survey (ICCAS) instrument, which uses a five-point Likert scale, to both the in-person and the virtual IPE students following their learning activity.   Results: We received a total of 459 completed survey responses with an overall response rate of 84%. For both groups of students, the in-person format was preferred, however, to our surprise, the results indicated that students in the virtual group reported greater perceived gain in interprofessional skills than students in the in-person group. In addition, pharmacy students perceived greater gain from the interprofessional activity and offered more thoughtful reflections about their experience. Conclusions: Even though both groups of students preferred the in-person visit, the IPE objectives were equally (for medical students) or better (for pharmacy students) absorbed in the virtual environment than the in-person clinical home visit.

Malakoplakia of the Gallbladder: A Case Report.

Histiocytes are cells that are involved in the immune responses of the body. They are unable to properly break down the bacterial material in malakoplakia, a chronic granulomatous histiocytic disease that occurs in immunocompromised patients and autoimmune conditions. Very few reports of these lesions exist, as those that occur in the gallbladder. It typically affects the urinary bladder, alimentary tract, cutaneous, hepato-biliary, and male and female genital systems. These lesions are usually incidental findings that result in patients being misdiagnosed. A 70-year-old female presented with right lower quadrant abdominal pain, and malakoplakia of the gallbladder was diagnosed. Histopathology findings revealed malakoplakia of the gallbladder, and the same was confirmed with special stains such as periodic acid-Schiff (PAS). This case highlights the role of gross and histopathology findings as a clue to the diagnosis, which helps the surgeon with further management.

GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.

The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.

Role of diagnostic stewardship in reducing healthcare-facility-onset Clostridioides difficile infections.

We describe the implementation of an electronic medical record "hard stop" to decrease inappropriate Clostridioides difficile testing across a 5-hospital health system, effectively reducing the rates of healthcare-facility-onset C. difficile infection. This novel approach included expert consultation with medical director of infection prevention and control for test-order override.

Effects of Inspiratory Muscle Warm-Up on Physical Exercise: A Systematic Review.

This study aimed to systematically review the literature to examine the effects of inspiratory-muscle warm-up (IMW) on the inspiratory, metabolic, respiratory and performance parameters of a main exercise performed by athletes and healthy and active individuals. Methods: This systematic review included randomized studies in English based on the criteria of the PICOS model. The exclusion criteria adopted were studies that applied inspiratory exercise to: i. promote long-term adaptations through inspiratory training (chronic responses); ii. obtain acute responses to inspiratory load (overload) during and in breaks from physical effort and in an inspiratory-exercise session (acute training effect); iii. evaluate the effects of IMW on participants with cardiorespiratory and/or metabolic disease. Data Sources: PubMed, Embase, MedLine, Scopus, SPORTDiscus and Google Scholar (until 17 January 2023). Results: Thirty-one studies were selected. The performance and respiratory parameters were the most investigated (77% and 74%, respectively). Positive effects of IMW were reported by 88% of the studies that investigated inspiratory parameters and 45% of those that evaluated performance parameters. Conclusions: The analyzed protocols mainly had positive effects on the inspiratory and performance parameters of the physical exercises. These positive effects of IMW are possibly associated with the contractile and biochemical properties of inspiratory muscles.

Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity.

Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.

α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.

One of the least-investigated areas of brain pathology research is glycosylation, which is a critical regulator of cell surface protein structure and function. ß-Galactoside α2,6-sialyltransferase (ST6GAL1) is the primary enzyme that α2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion, thereby modulating cell signaling and behavior. We demonstrate a potentially novel, protumorigenic role for α2,6 sialylation and ST6GAL1 in the deadly brain tumor glioblastoma (GBM). GBM cells with high α2,6 sialylation exhibited increased in vitro growth and self-renewal capacity and decreased mouse survival when orthotopically injected. α2,6 Sialylation was regulated by ST6GAL1 in GBM, and ST6GAL1 was elevated in brain tumor-initiating cells (BTICs). Knockdown of ST6GAL1 in BTICs decreased in vitro growth, self-renewal capacity, and tumorigenic potential. ST6GAL1 regulates levels of the known BTIC regulators PDGF Receptor ß (PDGFRB), Activated Leukocyte Cell Adhesion Molecule, and Neuropilin, which were confirmed to bind to a lectin-recognizing α2,6 sialic acid. Loss of ST6GAL1 was confirmed to decrease PDGFRB α2,6 sialylation, total protein levels, and the induction of phosphorylation by PDGF-BB. Thus, ST6GAL1-mediated α2,6 sialylation of a select subset of cell surface receptors, including PDGFRB, increases GBM growth.