Sex-based trajectories of health system use in lonely and not lonely older people: A population-based cohort study.

BACKGROUND: There is growing interest in understanding the care needs of lonely people but studies are limited and examine healthcare settings separately. We estimated and compared healthcare trajectories in lonely and not lonely older female and male respondents to a national health survey. METHODS: We conducted a retrospective cohort study of community-dwelling, Ontario respondents (65+ years) to the 2008/2009 Canadian Community Health Survey-Healthy Aging. Respondents were classified at baseline as not lonely, moderately lonely, or severely lonely using the Three-Item Loneliness Scale and then linked with health administrative data to assess healthcare transitions over a 12 -year observation period. Annual risks of moving from the community to inpatient, long-stay home care, long-term care settings-and death-were estimated across loneliness levels using sex-stratified multistate models. RESULTS: Of 2684 respondents (58.8% female sex; mean age 77 years [standard deviation: 8]), 635 (23.7%) experienced moderate loneliness and 420 (15.6%) severe loneliness. Fewer lonely respondents remained in the community with no transitions (not lonely, 20.3%; moderately lonely, 17.5%; and severely lonely, 12.6%). Annual transition risks from the community to home care and long-term care were higher in female respondents and increased with loneliness severity for both sexes (e.g., 2-year home care risk: 6.1% [95% CI 5.5-6.6], 8.4% [95% CI 7.4-9.5] and 9.4% [95% CI 8.2-10.9] in female respondents, and 3.5% [95% CI 3.1-3.9], 5.0% [95% CI 4.0-6.0], and 5.4% [95% CI 4.0-6.8] in male respondents; 5-year long-term care risk: 9.2% [95% CI 8.0-10.8], 11.1% [95% CI 9.3-13.6] and 12.2% [95% CI 9.9-15.3] [female], and 5.3% [95% CI 4.2-6.7], 9.1% [95% CI 6.8-12.5], and 10.9% [95% CI 7.9-16.3] [male]). CONCLUSIONS: Lonely older female and male respondents were more likely to need home care and long-term care, with severely lonely female respondents having the highest probability of moving to these settings.

Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC.

Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.

Mitigation of BMP-induced inflammation in craniofacial bone regeneration and improvement of bone parameters by dietary hesperidin.

Based on anti-inflammatory and osteogenic properties of hesperidin (HE), we hypothesized its systemic administration could be a cost-effective method of improving BMP-induced bone regeneration. Sprague-Dawley rats were allocated into 4 groups (n = 10/group): a 5-mm critical-sized mandible defect + collagen scaffold or, scaffold + 1 µg of BMP2 with and without dietary HE at 100 mg/kg. HE was administered by oral gavage 4 weeks prior to surgeries until euthanasia at day 7 or 14 post-surgery. The healing tissue within the defect collected at day 7 was subjected to gene expression analysis. Mandibles harvested at day 14 were subjected to microcomputed tomography and histology. HE + BMP2-treated rats had a statistically significant decrease in expression of inflammatory genes compared to BMP2 alone. The high-dose BMP2 alone caused cystic-like regeneration with incomplete defect closure. HE + BMP2 showed virtually complete bone fusion. Collagen fibril birefringence pattern (red color) under polarized light indicated high organization in BMP2-induced newly formed bone (NFB) in HE-supplemented group (p < 0.05). Clear changes in osteocyte lacunae as well as a statistically significant increase in osteoclasts were found around NFB in HE-treated rats. A significant increase in trabecular volume and thickness, and trabecular and cortical density was found in femurs of HE-supplemented rats (p < 0.05). Our findings show, for the first time, that dietary HE has a remarkable modulatory role in the function of locally delivered high-dose BMP2 in bone regeneration possibly via control of inflammation, osteogenesis, changes in osteocyte and osteoclast function and collagen maturation in regenerated and native bone. In conclusion, HE had a significant skeletal bone sparing effect and the ability to provide a more effective BMP-induced craniofacial regeneration.

In Operando Visualization of Elementary Turnovers in Photocatalytic Organic Synthesis.

We report the in operando visualization of the photocatalytic turnovers on single eosin Y (EY) through a redox-induced photoblinking phenomenon. The photocatalytic cyclization of thiobenzamide (TB) catalyzed by EY was investigated. The analysis of the intensity-versus-time trajectories of single EYs revealed the kinetics and dynamics of the elementary photocatalytic turnovers and the heterogeneity of the activity of individual EYs. The quenching turnover time showed a fast population and a slow population, which could be attributed to the singlet and triplet states of photoexcited EY. The slow quenching turnovers were more dominant at higher TB concentrations. The activity heterogeneity of EYs was studied over a series of reactant concentrations. Excess quenching reagent was found to decrease the percentage of active EYs. The method can be broadly applied to studying the elementary processes of photocatalytic organic reactions in operando.

Increased glycemic variability in pregnant women with Roux-en-Y gastric bypass compared with sleeve gastrectomy.

INTRODUCTION: Bariatric surgery is associated with adverse pregnancy outcomes such as reduced birth weight and premature birth. One possible mechanism for this is increased glycemic variability (GV) which occurs after bariatric surgery. The objective of this study was to compare the effect of Roux-en-Y gastric bypass (RYGB) versus vertical sleeve gastrectomy (SG) on GV during pregnancy and to investigate the relationships of GV, type of bariatric surgery and maternal and neonatal outcomes. RESEARCH DESIGN AND METHODS: Fourteen pregnant women after RYGB and 14 after SG were investigated with continuous glucose monitoring in their second or third trimester in this observational study carried out as part of routine clinical care. RESULTS: Pregnant women with RYGB had similar mean interstitial glucose values but significantly increased indices of GV and a lower %time in range 3.9-7.8 mmol/L (70-140 mg/dL), compared with SG. CONCLUSIONS: Pregnant women who have undergone RYGB have greater GV during pregnancy compared with those who have undergone SG. Further research is needed to establish the relationship between GV and pregnancy outcomes to determine the preferred bariatric operation in women of reproductive age, and whether interventions to reduce GV might improve outcomes.

Mitigation of BMP-induced Inflammation in Craniofacial Bone Regeneration and Improvement of Bone Parameters by Dietary Hesperidin.

Based on anti-inflammatory and osteogenic properties of hesperidin (HE), we hypothesized its systemic administration could be a cost-effective method of improving BMP-induced bone regeneration. Sprague-Dawley rats were allocated into 4 groups (n=10/group): a 5-mm critical-sized mandible defect + collagen scaffold or, scaffold + 1 µg of BMP2 with and without dietary HE at 100 mg/kg. HE was administered by oral gavage 4 weeks prior to surgeries until euthanasia at day 7 or 14. The healing tissue within the defect collected at day 7 was subjected to gene expression analysis. Mandibles harvested at day 14 were subjected to microcomputed tomography and histology. HE+BMP2-treated rats had a statistically significant decrease in expression of inflammatory genes compared to BMP2 alone. The high-dose BMP2 caused cystic-like regeneration with incomplete defect closure. HE+BMP2 showed virtually complete bone fusion. Red collagen fibrils were significantly higher in BMP2-induced newly formed bone (NFB) in HE-supplemented group (p<0.05) indicating high organization. Clear changes in osteocyte lacunae as well as a statistically significant increase in osteoclasts were found around NFB in HE rats. A significant increase in trabecular volume and thickness, and trabecular and cortical density was found in femurs of HE-supplemented rats (p<0.05). Our findings show, for the first time, that dietary HE has a remarkable modulatory role in locally delivered high-dose BMP2-induced bone possibly via control of inflammation, osteogenesis, changes in osteocyte and osteoclast function and collagen maturation in regenerated and native bone. In conclusion, HE has a significant skeletal bone sparing effect and the ability to provide a more effective BMP-induced craniofacial regeneration.

A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.

The "not so good" thyroid cancer: a scoping review on risk factors associated with anxiety, depression and quality of life.

The incidence of thyroid cancer has increased in recent years, leading to a growing number of survivors facing lifelong consequences. This scoping review investigated anxiety, depression, and quality of life (QoL) in thyroid cancer survivors compared to the general population, those with benign pathology, and survivors of other types of cancers. Moreover, we aimed to identify the risk factors associated with anxiety, depression, and QoL in thyroid cancer patients. A total of 727 articles were identified through PubMed, ProQuest, Cochrane, and Google Scholar databases, and 68 articles that met the criteria were selected for data extraction. Thyroid cancer survivors have a poorer QoL compared to the general population, population with benign pathology, and survivors of other types of cancer associated with worse clinical outcomes. The main risk factors are grouped into socioeconomic factors, disease-specific factors, management factors, comorbidities, and patient perceptions. Effective communication between the patient and the medical team and behavioral interventions may reduce these risks. Despite the common perception of thyroid cancer as a "good cancer," the findings of this review demonstrate the need to address the risk factors associated with increased anxiety, depression, and lower QoL in survivors.

High intratumoral plasma cells content in primary prostate cancer defines a subset of tumors with potential susceptibility to immune-based treatments.

BACKGROUND: Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials. METHODS: We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival. RESULTS: We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy. CONCLUSIONS: Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment.

Estimating the total treatment effect in randomized experiments with unknown network structure.

Randomized experiments are widely used to estimate the causal effects of a proposed treatment in many areas of science, from medicine and healthcare to the physical and biological sciences, from the social sciences to engineering, and from public policy to the technology industry. Here we consider situations where classical methods for estimating the total treatment effect on a target population are considerably biased due to confounding network effects, i.e., the fact that the treatment of an individual may impact its neighbors' outcomes, an issue referred to as network interference or as nonindividualized treatment response. A key challenge in these situations is that the network is often unknown and difficult or costly to measure. We assume a potential outcomes model with heterogeneous additive network effects, encompassing a broad class of network interference sources, including spillover, peer effects, and contagion. First, we characterize the limitations in estimating the total treatment effect without knowledge of the network that drives interference. By contrast, we subsequently develop a simple estimator and efficient randomized design that outputs an unbiased estimate with low variance in situations where one is given access to average historical baseline measurements prior to the experiment. Our solution does not require knowledge of the underlying network structure, and it comes with statistical guarantees for a broad class of models. Due to their ease of interpretation and implementation, and their theoretical guarantees, we believe our results will have significant impact on the design of randomized experiments.

Rhombencephalitis in Pregnancy-A Challenging Case of Probable Listeria Infection.

Rhombencephalitis refers to inflammation of the brainstem and cerebellum, and can be caused by infections, autoimmune disorders or paraneoplastic syndromes. The most common infective cause is the bacterium Listeria monocytogenes. Listeria monocytogenes is the predominant species to cause human listeriosis, and is commonly due to the ingestion of contaminated foods. Symptoms include a mild gastroenteritis, fever (often with extreme temperature variations), headache, and myalgia. In more severe cases, invasive disease may lead to bacteraemia and neurolisteriosis. Pregnant women are more susceptible to listeriosis, which is believed to be due to pregnancy-related immune modulation. Maternal-neonatal infection with adverse pregnancy outcomes include neonatal listeriosis, spontaneous miscarriage and intrauterine fetal demise. Diagnosis may be challenging due to initial nonspecific symptoms and low sensitivity and specificity of confirmatory diagnostic laboratory tests. Here, we describe a case of rhombencephalitis in pregnancy, attributed to Listeria, and review the clinical features, diagnosis and multidisciplinary management. Lastly, we describe the immunological response to Listeria monocytogenes and show in vitro pro-inflammatory effects of Listeria monocytogenes on peripheral blood mononuclear cells and placental explants.

Systemic Dietary Hesperidin Modulation of Osteoclastogenesis, Bone Homeostasis and Periodontal Disease in Mice.

This study aimed to evaluate the effects of hesperidin (HE) on in vitro osteoclastogenesis and dietary supplementation on mouse periodontal disease and femoral bone phenotype. RAW 264.7 cells were stimulated with RANKL in the presence or absence of HE (1, 100 or 500 µM) for 5 days, and evaluated by TRAP, TUNEL and Western Blot (WB) analyses. In vivo, C57BL/6 mice were given HE via oral gavage (125, 250 and 500 mg/kg) for 4 weeks. A sterile silk ligature was placed between the first and second right maxillary molars for 10 days and microcomputed tomography (µCT), histopathological and immunohistochemical evaluation were performed. Femoral bones subjected or not to dietary HE (500 mg/kg) for 6 and 12 weeks were evaluated using µCT. In vitro, HE 500 µM reduced formation of RANKL-stimulated TRAP-positive(+) multinucleated cells (500 µM) as well as c-Fos and NFATc1 protein expression (p < 0.05), markers of osteoclasts. In vivo, dietary HE 500 mg/kg increased the alveolar bone resorption in ligated teeth (p < 0.05) and resulted in a significant increase in TRAP+ cells (p < 0.05). Gingival inflammatory infiltrate was greater in the HE 500 mg/kg group even in the absence of ligature. In femurs, HE 500 mg/kg protected trabecular and cortical bone mass at 6 weeks of treatment. In conclusion, HE impaired in vitro osteoclastogenesis, but on the contrary, oral administration of a high concentration of dietary HE increased osteoclast numbers and promoted inflammation-induced alveolar bone loss. However, HE at 500 mg/kg can promote a bone-sparing effect on skeletal bone under physiological conditions.

Chiari I malformation: Case report of a postnatal diagnosis and literature review.

Mode of delivery and intrapartum analgesia for women with Chiari I malformation pose a challenge to the obstetrician and anaesthetist. Clinicians often advocate caesarean section delivery under general anaesthetic to prevent an uncontrolled rise in intracranial pressure or a fall in cerebrospinal fluid pressure during labour that may result in neurological complications, or rarely, brainstem herniation. This case report discusses a woman with hitherto undiagnosed Chiari I malformation who delivered by CS due to obstetric concerns, but remained asymptomatic throughout the preceding labour and in spite of multiple epidural insertion attempts. We discuss considerations for future pregnancies, and review the literature to challenge the view that women with Chiari I need planned caesarean or must avoid epidural/spinal analgesia; instead presenting evidence to support the safety and suitability of vaginal delivery and neuroaxial block in labouring parturients with this condition.

PACER lncRNA regulates COX-2 expression in lung cancer cells.

Long noncoding RNAs (lncRNAs) are known to regulate gene expression; however, in many cases, the mechanism of this regulation is unknown. One novel lncRNA relevant to inflammation and arachidonic acid (AA) metabolism is the p50-associated COX-2 extragenic RNA (PACER). We focused our research on the regulation of PACER in lung cancer. While the function of PACER is not entirely understood, PACER is known to play a role in inflammation-associated conditions. Our data suggest that PACER is critically involved in COX-2 transcription and dysregulation in lung cancer cells. Our analysis of The Cancer Genome Atlas (TCGA) expression data revealed that PACER expression is significantly higher in lung adenocarcinomas than normal lung tissues. Additionally, we discovered that elevated PACER expression strongly correlates with COX-2 expression in lung adenocarcinoma patients. Specific siRNA-mediated knockdown of PACER decreases COX-2 expression indicating a direct relationship. Additionally, we show that PACER expression is induced upon treatment with proinflammatory cytokines to mimic inflammation. Treatment with prostaglandin E2 (PGE2) induces both PACER and COX-2 expression, suggesting a PGE2-mediated feedback loop. Inhibition of COX-2 with celecoxib decreased PACER expression, confirming this self-regulatory process. Significant overlap between the COX-2 promotor and the PACER promotor led us to investigate their transcriptional regulatory mechanisms. Treatment with pharmacologic inhibitors of NF-κB or AP-1 showed a modest effect on both PACER and COX-2 expression but did not eliminate expression. These data suggest that the regulation of expression of both PACER and COX-2 is complex and intricately linked.

Diagnostic Evidence GAuge of Single cells (DEGAS): a flexible deep transfer learning framework for prioritizing cells in relation to disease.

We propose DEGAS (Diagnostic Evidence GAuge of Single cells), a novel deep transfer learning framework, to transfer disease information from patients to cells. We call such transferrable information "impressions," which allow individual cells to be associated with disease attributes like diagnosis, prognosis, and response to therapy. Using simulated data and ten diverse single-cell and patient bulk tissue transcriptomic datasets from glioblastoma multiforme (GBM), Alzheimer's disease (AD), and multiple myeloma (MM), we demonstrate the feasibility, flexibility, and broad applications of the DEGAS framework. DEGAS analysis on myeloma single-cell transcriptomics identified PHF19high myeloma cells associated with progression. Availability: https://github.com/tsteelejohnson91/DEGAS .

Endoscopic management of idiopathic subglottic stenosis in pregnancy.

AIMS: To describe the use of laser, endoscopic balloon dilatation with jet ventilation anaesthesia in the treatment of pregnant women with idiopathic subglottic stenosis. MATERIALS AND METHODS: This is a case review of pregnant women with idiopathic subglottic stenosis, presenting to a tertiary referral centre with worsening breathlessness. Data were extracted from patient case notes. RESULTS: Four women underwent surgical management of subglottic stenosis in pregnancy. One patient required two procedures during the course of their pregnancy due to restenosis. All women had improvement in symptoms post-operatively and went on to deliver healthy babies at term. CONCLUSION: Endoscopic balloon dilatation of idiopathic subglottic stenosis is a safe and viable treatment option in pregnancy and should be offered as first-line treatment in symptomatic women.

TPSC: a module detection method based on topology potential and spectral clustering in weighted networks and its application in gene co-expression module discovery.

BACKGROUND: Gene co-expression networks are widely studied in the biomedical field, with algorithms such as WGCNA and lmQCM having been developed to detect co-expressed modules. However, these algorithms have limitations such as insufficient granularity and unbalanced module size, which prevent full acquisition of knowledge from data mining. In addition, it is difficult to incorporate prior knowledge in current co-expression module detection algorithms. RESULTS: In this paper, we propose a novel module detection algorithm based on topology potential and spectral clustering algorithm to detect co-expressed modules in gene co-expression networks. By testing on TCGA data, our novel method can provide more complete coverage of genes, more balanced module size and finer granularity than current methods in detecting modules with significant overall survival difference. In addition, the proposed algorithm can identify modules by incorporating prior knowledge. CONCLUSION: In summary, we developed a method to obtain as much as possible information from networks with increased input coverage and the ability to detect more size-balanced and granular modules. In addition, our method can integrate data from different sources. Our proposed method performs better than current methods with complete coverage of input genes and finer granularity. Moreover, this method is designed not only for gene co-expression networks but can also be applied to any general fully connected weighted network.

Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma.

Neoantigen peptides arising from genetic alterations may serve as targets for personalized cancer vaccines and as positive predictors of response to immune checkpoint therapy. Mutations in genes regulating RNA splicing are common in hematological malignancies leading to dysregulated splicing and intron retention (IR). In this study, we investigated IR as a potential source of tumor neoantigens in multiple myeloma (MM) patients and the relationship of IR-induced neoantigens (IR-neoAg) with clinical outcomes. MM-specific IR events were identified in RNA-sequencing data from the Multiple Myeloma Research Foundation CoMMpass study after removing IR events that also occurred in normal plasma cells. We quantified the IR-neoAg load by assessing IR-induced novel peptides that were predicted to bind to major histocompatibility complex (MHC) molecules. We found that high IR-neoAg load was associated with poor overall survival in both newly diagnosed and relapsed MM patients. Further analyses revealed that poor outcome in MM patients with high IR-neoAg load was associated with high expression levels of T-cell co-inhibitory molecules and elevated interferon signaling activity. We also found that MM cells exhibiting high IR levels had lower MHC-II protein abundance and treatment of MM cells with a spliceosome inhibitor resulted in increased MHC-I protein abundance. Our findings suggest that IR-neoAg may represent a novel biomarker of MM patient clinical outcome and further that targeting RNA splicing may serve as a potential therapeutic strategy to prevent MM immune escape and promote response to checkpoint blockade.

Mechanism-Centric Approaches for Biomarker Detection and Precision Therapeutics in Cancer.

Biomarker discovery is at the heart of personalized treatment planning and cancer precision therapeutics, encompassing disease classification and prognosis, prediction of treatment response, and therapeutic targeting. However, many biomarkers represent passenger rather than driver alterations, limiting their utilization as functional units for therapeutic targeting. We suggest that identification of driver biomarkers through mechanism-centric approaches, which take into account upstream and downstream regulatory mechanisms, is fundamental to the discovery of functionally meaningful markers. Here, we examine computational approaches that identify mechanism-centric biomarkers elucidated from gene co-expression networks, regulatory networks (e.g., transcriptional regulation), protein-protein interaction (PPI) networks, and molecular pathways. We discuss their objectives, advantages over gene-centric approaches, and known limitations. Future directions highlight the importance of input and model interpretability, method and data integration, and the role of recently introduced technological advantages, such as single-cell sequencing, which are central for effective biomarker discovery and time-cautious precision therapeutics.