Assessing the extent and determinants of socioeconomic inequalities in epilepsy in the UK: a systematic review and meta-analysis of evidence.

BACKGROUND: Socioeconomic inequalities in epilepsy incidence and its adverse outcomes are documented internationally, yet the extent of inequalities and factors influencing the association can differ between countries. A UK public health response to epilepsy, which prevents epilepsy without widening inequalities, is required. However, the data on UK epilepsy inequalities have not been synthesised in a review and the underlying determinants are unknown. METHODS: In this systematic review and meta-analysis, we searched six bibliographic databases (MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus) and grey literature published between Jan 1, 1980, and Feb 21, 2024, to identify UK studies reporting epilepsy incidence or epilepsy-related adverse outcomes by socioeconomic factors (individual level or area level). We included longitudinal cohort studies, studies using routinely collected health-care data, cross-sectional studies, and matched cohort studies and excluded conference abstracts and studies not reporting empirical results in the review and meta-analysis. Multiple reviewers (KJB, EC, SER, WOP, and RHT) independently screened studies, KJB extracted data from included studies and a second reviewer (SM or EC) checked data extraction. We used Critical Appraisal Skills Programme checklists to assess quality. We used random-effects meta-analysis to pool incident rate ratios (IRRs) and synthesised results on adverse outcomes narratively. This study was registered on PROPSPERO (CRD42023394143). FINDINGS: We identified 2471 unique studies from database searches. We included 26 studies, ten of which reported epilepsy incidence and 16 reported epilepsy-related adverse outcomes according to socioeconomic factors. Misclassification, participation, and interpretive biases were identified as study quality limitations. Meta-analyses showed an association between socioeconomic deprivation and epilepsy incidence, with greater risks of epilepsy incidence in groups of high-deprivation (IRR 1·34 [95% CI 1·16-1·56]; I2=85%) and medium-deprivation (IRR 1·23 [95% CI 1·08-1·39]; I2=63%) compared with low-deprivation groups. This association persisted in the studies that only included children (high vs low: IRR 1·36 [95% CI 1·19-1·57]; I2=0%). Only two studies examined factors influencing epilepsy incidence. There is limited evidence regarding UK inequalities in adverse outcomes. INTERPRETATION: Socioeconomic inequalities in epilepsy incidence are evident in the UK. To develop an evidence-based public health response to epilepsy, further research is needed to understand the populations affected, factors determining the association, and the extent of inequalities in adverse outcomes. FUNDING: Epilepsy Research Institute UK.

Phylogenetic systematics of Vigna sensu stricto in the context of Physostigma and allies.

PREMISE: Vigna includes economically vital crops and wild species. Molecular systematic studies of Vigna species resulted in generic segregates of many New World (NW) species. However, limited Old World (OW) sampling left questions regarding inter- and intraspecific relationships in Vigna s.s. METHODS: African species, including the putative sister genus Physostigma, were comprehensively sampled within the context of NW relatives. Maximum likelihood and Bayesian inference analyses of the chloroplast matK-trnK and nuclear ribosomal ITS/5.8 S (ITS) DNA regions were undertaken to resolve OW Vigna taxonomic questions. Divergence dates were estimated using BEAST to date key nodes in the phylogeny. RESULTS: Analyses of matK and ITS data supported five clades of Vigna s.s.: subg. Lasiospron, a reduced subg. Vigna, subg. Haydonia, subg. Ceratotropis, an enlarged subg. Plectrotropis, and a clade including V. kirkii and V. stenophylla. Genome size estimates of 601 Mb for V. kirkii are near the overall mean of the genus, whereas V. stenophylla had a larger genome (810 Mb), similar to some Vigna subg. Ceratotropis or Plectrotropis species. CONCLUSIONS: Former subg. Vigna is reduced to yellow- and blue-flowered species and subg. Plectrotropis is enlarged to mostly all white-, pink-, and purple-flowered species. The age of the split between NW and OW Vigna lineages is ~6-7 Myr. Genome size estimates cannot rule out a polyploid or hybrid origin for V. stenophylla, potentially involving extinct lineage ancestors of Vigna subg. Ceratotropis or Plectrotropis, as indicated by network and phylogenetic analyses. Taxonomic revisions are suggested based on these results.

Association of Anticoagulant Choice on mortality in the Primary Treatment of Non-Cancer Venous Thromboembolism: Medicare 2011-2018.

Direct oral anticoagulants (DOACs; rivaroxaban, apixaban) and warfarin are approved for venous thromboembolism (VTE) treatment. Few direct comparisons of DOACs on risk of mortality among VTE patients exist, and for patients with concomitant conditions (e.g., kidney and liver disease) clinical guidelines are unclear. We evaluated 6-month all-cause mortality by anticoagulant prescribed for primary treatment of VTE. Using Medicare 20% sample data, we created a propensity score matched analytic dataset of 47,860 beneficiaries with non-cancer incident VTE. We used Cox regression to estimate adjusted hazard ratios (HRs) of OACs with 6-month mortality, and tested interactions by liver/kidney disease. There were 3,422 deaths over 6 months of follow-up. In adjusted models, patients prescribed rivaroxaban [HR: 0.82 (95% CI: 0.76-0.90)] had lower rates of mortality versus warfarin. There was no association comparing apixaban to warfarin [HR: 0.96 (95% CI: 0.87-1.07)]. In head-to-head comparisons of apixaban versus rivaroxaban the HR was 1.14 (95% CI: 1.01-1.28)]. Findings were similar among patients with liver and kidney disease. Overall, risk of death was similar by OAC prescribed. Though it is possible residual confounding remained, there was some suggestion of lower risk with rivaroxaban than warfarin. DOACs appear safe among VTE patients with concomitant kidney or liver disease.

Pathways to Geographic Atrophy in Non-Neovascular Age-Related Macular Degeneration.

PURPOSE: This study aimed to characterize and quantify the precursor lesions of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). METHODS: A retrospective study of eyes with a minimum 6-month follow-up prior to developing GA. Evaluations included color and autofluorescence imaging, along with spectral domain optical coherence tomography, employing definitions from the Consensus of Atrophy Meeting Group and Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group. RESULTS: There were 55 eyes of 44 patients, who had a mean age of 81.3 years at onset of atrophy; 35 (63.6%) were female. The mean duration of follow-up before and after the advent of GA was 4.9 years and 1.2 years, respectively. GA was preceded by collapse of a druse in 41 (74.5%) of eyes. Of these 29 (70.7%) were drusenoid pigment epithelial detachments. Among the eyes with regressing drusen, there were 9 with overlying vitelliform deposit, and all had concurrent subretinal drusenoid deposit (SDD), while 19 of 30 eyes with no vitelliform deposit overlying the druse had concurrent SDD, a difference that was significant (P<.001). Regression of SDD was found in 3 (5.4%) eyes, regression of vitelliform deposit associated with SDD in 6 (7.3%), and regression of vitelliform deposit in eyes concurrently harboring drusen was found in 3 (5.4%) at the site of eventual development of GA. CONCLUSIONS: GA appears to develop from multiple pathways as manifested by the many precursor lesions, all various forms of extracellular deposit, that upon regression, result in a common end stage appearance.

Identification of a family of peptidoglycan transpeptidases reveals that Clostridioides difficile requires noncanonical cross-links for viability.

Most bacteria are surrounded by a cell wall that contains peptidoglycan (PG), a large polymer composed of glycan strands held together by short peptide cross-links. There are two major types of cross-links, termed 4-3 and 3-3 based on the amino acids involved. 4-3 cross-links are created by penicillin-binding proteins, while 3-3 cross-links are created by L,D-transpeptidases (LDTs). In most bacteria, the predominant mode of cross-linking is 4-3, and these cross-links are essential for viability, while 3-3 cross-links comprise only a minor fraction and are not essential. However, in the opportunistic intestinal pathogen Clostridioides difficile, about 70% of the cross-links are 3-3. We show here that 3-3 cross-links and LDTs are essential for viability in C. difficile. We also show that C. difficile has five LDTs, three with a YkuD catalytic domain as in all previously known LDTs and two with a VanW catalytic domain, whose function was until now unknown. The five LDTs exhibit extensive functional redundancy. VanW domain proteins are found in many gram-positive bacteria but scarce in other lineages. We tested seven non-C. difficile VanW domain proteins and confirmed LDT activity in three cases. In summary, our findings uncover a previously unrecognized family of PG cross-linking enzymes, assign a catalytic function to VanW domains, and demonstrate that 3-3 cross-linking is essential for viability in C. difficile, the first time this has been shown in any bacterial species. The essentiality of LDTs in C. difficile makes them potential targets for antibiotics that kill C. difficile selectively.

PANoptosis opens new treatment options for allergic bronchopulmonary aspergillosis.

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a rare airway disorder primarily affecting patients with asthma and cystic fibrosis. Persistent airway inflammation brought on by Aspergillus fumigatus exacerbates the underlying condition and can cause significant respiratory damage. Treatments center on reducing inflammation with the use of corticosteroids and antifungals. PANoptosis is a new concept in the field of cell death and inflammation that posits the existence of cross talk and a master control system for the 3 programmed cell death (PCD) pathways, namely, apoptosis, pyroptosis, and necroptosis. This concept has revolutionized the understanding of PCD and opened new avenues for its exploration. Studies show that Aspergillus is one of the pathogens that is capable of activating PANoptosis via the Z-DNA binding protein 1 (ZBP1) pathway and plays an active role in the inflammation caused by this organism. Objective: This article explores the nature of inflammation in ABPA and ways in which PCD could lead to novel treatment options. Method: PubMed was used to review the literature surrounding Aspergillus infection-related inflammation and PANoptosis. Results: There is evidence that apoptosis and pyroptosis protect against Aspergillus-induced inflammation, whereas necroptosis promotes inflammation. Conclusion: Experimental medications, in particular, necroptosis inhibitors such as necrosulfonamide and necrostatin-1, should be studied for use in the treatment of ABPA.

Consensus recommendations for systemic therapies in the management of relapsed Ewing sarcoma: A report from the National Ewing Sarcoma Tumor Board.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs.

Maternal history of childhood maltreatment and pregnancy weight outcomes.

BACKGROUND: Childhood maltreatment is associated with elevated adult weight. It is unclear whether this association extends to pregnancy, a critical window for the development of obesity. METHODS: We examined associations of childhood maltreatment histories with pre-pregnancy BMI and gestational weight gain among women who had participated for >20 years in a longitudinal cohort.At age 26-35 participants reported childhood maltreatment (physical, sexual, and emotional abuse; emotional neglect) and, 5 years later, about pre-pregnancy weight and gestational weight gain for previous pregnancies (n=656). Modified Poisson regression models were used to estimate associations of maltreatment history with pre-pregnancy BMI and gestational weight gain z-scores, adjusting for sociodemographics. We used Multivariate Imputation by Chained Equations to adjust outcome measures for misclassification using data from an internal validation study. RESULTS: Before misclassification adjustment, results indicated a higher risk of pre-pregnancy BMI ≥30 kg/m2 in women with certain types of maltreatment (e.g., emotional abuse RR=2.4; 95% CI: 1.5, 3.7) compared with women without that maltreatment type. After misclassification adjustment, estimates were attenuated but still modestly elevated (e.g., emotional abuse RR=1.7; 95% CI: 1.1, 2.7). Misclassification-adjusted estimates for maltreatment associations with gestational weight gain z-scores were close to the null and imprecise. CONCLUSIONS: Findings suggest an association of maltreatment with pre-pregnancy BMI ≥30 kg/m2 but not with high gestational weight gain. Results suggest a potential need for equitable interventions that can support all women, including those with maltreatment histories, as they enter pregnancy.

Treatment Adherence Rates and Long-Term Mortality in a Quaternary Multidisciplinary Heart Team: An Observational Cohort.

BACKGROUND: A multidisciplinary heart team (HT) approach to patients with complex coronary artery disease has a class IB recommendation, yet there are limited data on adherence to HT treatment recommendations and long-term clinical follow-up. The objective of this study was to assess adherence rates to HT recommendations and assess long-term mortality rates among patients with complex CAD. METHODS AND RESULTS: Six hundred eighty-four sequential HT cases for complex coronary artery disease from January 2015 to May 2017 were reviewed. After excluding cases with significant comorbid valve disease, baseline characteristics were compared based on HT treatment recommendations: optimal medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting. Adherence rates were manually extracted, and 5-year mortality rates were obtained from the Michigan Death Registry. Seventy-two percent of 405 included patients were men (mean age 66±11 years), with high rates of medical comorbidities. Estimated surgical risk scores were lowest in the coronary artery bypass grafting group. Optimal medical therapy was recommended in 138 patients (34%), percutaneous coronary intervention in 95 (23%), and coronary artery bypass grafting in 172 (42%). Adherence to HT recommendations across groups was high (96%) and did not differ between treatment groups. Over 5 years of follow-up, there were 119 deaths, resulting in a cumulative mortality rate of 29%. CONCLUSIONS: In the largest HT cohort in the United States to date, high rates of adherence to HT recommendations were observed among high-risk patients with coronary artery disease. High rates of adherence to HT recommendations were observed irrespective of treatment group recommendation, suggesting that HT recommendations were individualized and acceptable to both patients and physicians alike.

Dynamic adaptation to novelty in the brain is related to arousal and intelligence.

How does the human brain respond to novelty? Here, we address this question using fMRI data wherein human participants watch the same movie scene four times. On the first viewing, this movie scene is novel, and on later viewings it is not. We find that brain activity is lower-dimensional in response to novelty. At a finer scale, we find that this reduction in the dimensionality of brain activity is the result of increased coupling in specific brain systems, most specifically within and between the control and dorsal attention systems. Additionally, we found that novelty induced an increase in between-subject synchronization of brain activity in the same brain systems. We also find evidence that adaptation to novelty, herein operationalized as the difference between baseline coupling and novelty-response coupling, is related to fluid intelligence. Finally, using separately collected out-of-sample data, we find that the above results may be linked to psychological arousal.

Genomic landscape of malignant phyllodes tumors reveals multiple targetable opportunities.

BACKGROUND: Malignant phyllodes tumors (MPT) are rare fibroepithelial breast cancers with no known effective systemic therapy; metastatic progression portends a dismal prognosis. We sought to describe the genomic landscape of MPTs through genomic profiling and immunotherapeutic biomarker analysis. MATERIALS AND METHODS: Cases of sequenced MPT were identified from a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited laboratory (Foundation Medicine). All cases underwent genomic profiling using adaptor ligation-based, next-generation sequencing assay of 324 genes. Tumor agnostic immunotherapy biomarkers, microsatellite instability, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression were evaluated. Fisher's Exact Tests and analysis of variance were used to test for differences between groups and for continuous variables as appropriate. RESULTS: Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic. Median age was 54 years (range 14-86). The median TMB was 2.5 mut/Mb and 3 were TMB-high (≥10 mut/Mb). 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥1). Most commonly altered genes included TERT-promoter (69.7%), CDKN2A (45.9%), TP53 (37.8%), NF1 (35.6%), CDKN2B (33.3%), MED12 (28.9%), MTAP (27.7%), KMT2D (22.2%), PIK3CA (20.0%), PTEN (18.5%), and RB1 (18.5%). Several tumors harboring genomic alterations with US Food and Drug Administration-approved indications in other tumor types were found including NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. CONCLUSIONS: In the largest genomic evaluation of MPT to date, multiple clinically actionable mutations were found. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment.

Genetically Encoded, Noise-Tolerant, Auxin Biosensors in Yeast.

Auxins are crucial signaling molecules that regulate the growth, metabolism, and behavior of various organisms, most notably plants but also bacteria, fungi, and animals. Many microbes synthesize and perceive auxins, primarily indole-3-acetic acid (IAA, referred to as auxin herein), the most prevalent natural auxin, which influences their ability to colonize plants and animals. Understanding auxin biosynthesis and signaling in fungi may allow us to better control interkingdom relationships and microbiomes from agricultural soils to the human gut. Despite this importance, a biological tool for measuring auxin with high spatial and temporal resolution has not been engineered in fungi. In this study, we present a suite of genetically encoded, ratiometric, protein-based auxin biosensors designed for the model yeast Saccharomyces cerevisiae. Inspired by auxin signaling in plants, the ratiometric nature of these biosensors enhances the precision of auxin concentration measurements by minimizing clonal and growth phase variation. We used these biosensors to measure auxin production across diverse growth conditions and phases in yeast cultures and calibrated their responses to physiologically relevant levels of auxin. Future work will aim to improve the fold change and reversibility of these biosensors. These genetically encoded auxin biosensors are valuable tools for investigating auxin biosynthesis and signaling in S. cerevisiae and potentially other yeast and fungi and will also advance quantitative functional studies of the plant auxin perception machinery, from which they are built.

Social Determinants of Health, Tribal Payments, and Probability of Contracting COVID-19 in American Indian and Alaska Native Peoples.

Little is known about the relationships between demographic and economic social determinants of health and the probability of contracting COVID-19 in American Indian and Alaska Native (AI/AN) peoples. In addition, we do not know if and how tribal payments, unique to AI/AN peoples, are associated with the probability of contracting COVID-19. We surveyed 767 AI/AN patients of five geographically disparate health organizations that primarily served AI/AN peoples in urban settings between January and May of 2021. We used univariate modified Poisson regressions to estimate the influence of age, gender, household composition, education, household income, and tribal payments on risk of contracting COVID-19, with results presented as both risk and risk difference. Fifteen percent of the sample contracted COVID-19, and individuals who lived in households with two or more generations had an 11-percentage point elevated risk of contracting COVID-19 compared to those who lived alone. Twenty-seven percent of participants received tribal payments; receipt was associated with seven percentage points (change from 18% probability to 11% probability) lower risk of contracting COVID-19. Our findings showed interventions specifically designed to reduce the spread of COVID-19 in multigenerational households, and regular tribal payments may help improve health outcomes in urban AI/AN populations.

Evolution of Initial Treatment for Desmoid Tumors.

INTRODUCTION: Desmoid tumors (DTs) are rare, fibroblastic cell proliferations that can exhibit locally aggressive behavior but lack metastatic potential. Initial management has traditionally involved upfront resection; however, contemporary guidelines and expert panels have increasingly advocated for prioritizing active surveillance strategies. METHODS: A single-institution, retrospective chart review identified all patients diagnosed with a primary DT at any site from 2007 to 2020. The primary outcome was the initial management strategy over time. Secondary outcomes included treatment-free survival (TFS) and time to treatment (TTT) for those undergoing active surveillance, as well as recurrence-free survival (RFS) and time to recurrence for those undergoing resection. RESULTS: Overall, 103 patients were included, with 68% female and a median follow-up of 44 months [24-74]. The most common tumor locations included the abdominal wall (27%), intra-abdominal/mesenteric (25%), chest wall (19%), and extremity (10%). Initial management included resection (60%), systemic therapy (20%), active surveillance (18%), and cryoablation (2%). Rates of surgical resection significantly decreased (p < 0.001) over time, from 69.6% prior to 2018 to 29.2% after 2018. For those treated with upfront resection, 5-year RFS was 41.2%, and for patients undergoing initial active surveillance, TFS was 66.7% at 2 years, with a median TTT of 4 months [4-10]. CONCLUSIONS: This single-institution cohort at a tertiary medical center spanning over a decade demonstrates the transition to active surveillance for initial management of DTs, and highlights salient metrics in the era of surveillance. This trend mirrors recommended treatment strategies by expert panels and consensus guidelines.

Contributions of network structure, chemoarchitecture and diagnostic categories to transitions between cognitive topographies.

The mechanisms linking the brain's network structure to cognitively relevant activation patterns remain largely unknown. Here, by leveraging principles of network control, we show how the architecture of the human connectome shapes transitions between 123 experimentally defined cognitive activation maps (cognitive topographies) from the NeuroSynth meta-analytic database. Specifically, we systematically integrated large-scale multimodal neuroimaging data from functional magnetic resonance imaging, diffusion tractography, cortical morphometry and positron emission tomography to simulate how anatomically guided transitions between cognitive states can be reshaped by neurotransmitter engagement or by changes in cortical thickness. Our model incorporates neurotransmitter-receptor density maps (18 receptors and transporters) and maps of cortical thickness pertaining to a wide range of mental health, neurodegenerative, psychiatric and neurodevelopmental diagnostic categories (17,000 patients and 22,000 controls). The results provide a comprehensive look-up table charting how brain network organization and chemoarchitecture interact to manifest different cognitive topographies, and establish a principled foundation for the systematic identification of ways to promote selective transitions between cognitive topographies.

Progression of Peripapillary and Macular Chorioretinal Atrophy in Multifocal Choroiditis Is Associated with Periatrophic Inflammatory Plumes.

PURPOSE: To investigate peripapillary atrophy and macular chorioretinal scars in eyes affected by multifocal choroiditis and panuveitis (MCP). METHODS: This retrospective cohort study reviewed the medical records, fundus photographs, and SD-OCT scans of 31 eyes from 19 patients. RESULTS: Patients had a mean age of 45 years (range 24-69 years). The average follow-up duration was 7 years (range 2.5-14.5 years), with 14 patients undergoing immunosuppressive treatment. In the group of 31 eyes, 20 showed peripapillary plumes of ill-defined hyperreflectivity at the termination border of the retinal pigment epithelium (RPE). These plumes, extending from bare Bruch's membrane to the outer nuclear layer, sometimes undermined the adjacent RPE. They responded to corticosteroid treatment and resembled the material under the RPE in acute lesions. Among 20 eyes with these peripapillary inflammatory lesions, 16 (80%) experienced increased atrophy, in contrast to none in the eyes without these lesions (P<0.001). Similar patterns were observed at the edges of macular chorioretinal atrophy. This observation occurred in patients using immunosuppressive medication who were otherwise thought to be under adequate control. CONCLUSION: In MCP patients, previously unrecognized plumes of smoldering inflammatory activity at the borders of chorioretinal atrophy appears to be linked to atrophy expansion. The recognition of this phenomenon may require a reappraisal of treatment of multifocal choroidopathies to help mitigate expansion of atrophy in these eyes.

The mortality burden of cachexia or weight loss in patients with colorectal or pancreatic cancer: A systematic literature review.

Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.

Integrin signalling in joint development, homeostasis and osteoarthritis.

Integrins are key regulators of cell-matrix interactions during joint development and joint tissue homeostasis, as well as in the development of osteoarthritis (OA). The signalling cascades initiated by the interactions of integrins with a complex network of extracellular matrix (ECM) components and intracellular adaptor proteins orchestrate cellular responses necessary for maintaining joint tissue integrity. Dysregulated integrin signalling, triggered by matrix degradation products such as matrikines, disrupts this delicate balance, tipping the scales towards an environment conducive to OA pathogenesis. The interplay between integrin signalling and growth factor pathways further underscores the multifaceted nature of OA. Moreover, emerging insights into the role of endocytic trafficking in regulating integrin signalling add a new layer of complexity to the understanding of OA development. To harness the therapeutic potential of targeting integrins for mitigation of OA, comprehensive understanding of their molecular mechanisms across joint tissues is imperative. Ultimately, deciphering the complexities of integrin signalling will advance the ability to treat OA and alleviate its global burden.

Effects of Copper on Legionella pneumophila Revealed via Viability Assays and Proteomics.

Cu is an antimicrobial that is commonly applied to premise (i.e., building) plumbing systems for Legionella control, but the precise mechanisms of inactivation are not well defined. Here, we applied a suite of viability assays and mass spectrometry-based proteomics to assess the mechanistic effects of Cu on L. pneumophila. Although a five- to six-log reduction in culturability was observed with 5 mg/L Cu2+ exposure, cell membrane integrity only indicated a <50% reduction. Whole-cell proteomic analysis revealed that AhpD, a protein related to oxidative stress, was elevated in Cu-exposed Legionella relative to culturable cells. Other proteins related to cell membrane synthesis and motility were also higher for the Cu-exposed cells relative to controls without Cu. While the proteins related to primary metabolism decreased for the Cu-exposed cells, no significant differences in the abundance of proteins related to virulence or infectivity were found, which was consistent with the ability of VBNC cells to cause infections. Whereas the cell-membrane integrity assay provided an upper-bound measurement of viability, an amoebae co-culture assay provided a lower-bound limit. The findings have important implications for assessing Legionella risk following its exposure to copper in engineered water systems.