Exosomal ROR1 in peritoneal fluid identifies peritoneal disseminated PDAC and is associated with poor survival.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters. Methods: Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed. Results: PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482). Conclusion: With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.

Comparison of 3D-Printed Single Crown Outcomes Among Different Computer-Aided Design Software Programs.

PURPOSE: Low-cost resin 3D printers have been used to produce affordable interim single crowns in public and private dental practices. The purpose of this study was to assess the impact of different computer-aided design (CAD) software programs on 3D trueness, microscopic marginal and internal gaps, time to design, and interproximal contacts of low-cost 3D-printed single crowns. MATERIALS AND METHODS: This in vitro study was performed on a total of 90 standardized resin-prepared teeth adapted to a dental manikin. For comparison among CAD software programs, 45 tooth preparations received 3D-printed crowns designed with one of three CAD software programs by an experienced technician and identified as groups TRIOS (n = 15), EXOCAD (n = 15), and ZZ (Zirkonzahn; n = 15). To assess interoperator reproducibility, 15 additional crowns were designed by a dental clinician (group ZZ-DENT) and 15 by a dental prosthetic technician (group ZZ-PROS), both with basic 1-week CAD/CAM training. Finally, as a control group, 15 crowns were milled using a high-end five-axis milling device (group ZZ-CONTROL). Statistically significant differences for 3D trueness, microscopic gaps, time to design, and interproximal contacts among groups were assessed with the Kruskal-Wallis test. RESULTS: No statistically significant differences in 3D trueness or marginal or internal gaps were found, either among different software programs or CAD operators (P > .05). However, Group TRIOS took significantly longer to design than EXOCAD and ZZ groups (P = .001). Less-experienced operators were significantly outperformed in time and interproximal contacts (P = .001) by the CAD technician using the same software program. Finally, control milled crowns (ZZ-CONTROL) significantly outperformed the respective 3D-printed copies (ZZ) in all assessed variables (P < .001). CONCLUSIONS: Different CAD software programs may affect the time required to design, but they do not significantly affect clinical outcomes of low-cost 3D-printed resin crowns if designed by an experienced CAD technician.

Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy.

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.

Stability of ten serum tumor markers after one year of storage at -18°C.

OBJECTIVES: The storage of serum tumor markers (STM) at -18 °C for one year has been a legal requirement in France since 1999, but has been abolished in 2022. This raises the question of the relevance of maintaining these biobanks in terms of conditions of storage. These should only be implemented after validation; in order to maintain the integrity of the biological sample and must be controlled over time according to the laboratory's procedures. The aim of the study was to assess the suitability of storing 10 STMs by evaluating their stability after one year of storage at -18 °C. METHODS: A new immuno-enzymatic assay (A+1) was conducted on samples that had been stored at -18 °C for one year after an initial assay (A) of one of the following STMs: carcino-embryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 125 (CA125), carbohydrate antigen 15-3 (CA15-3), carbohydrate antigen 19-9 (CA19-9), total (TPSA), and free (FPSA) prostate-specific antigen, calcitonin (CT), thyroglobulin (TG), and neuro-specific enolase (NSE). The results were confronted to four different permissible error sources. RESULTS: In total, 1148 A+1 assays were performed. A strong correlation between A+1 and A values was found for all analytes, but with a statistically significant reduction in the mean A+1 concentration compared to the mean A concentration in 7/10 STMs. The bias induced by conservation seems to be technically unsustainable if we rely on the repositories closest to the current analytical performances. CONCLUSIONS: These results support the discontinuation of mandatory STM biobank storage at -18 °C, which requires considerable technical time and organizational effort.

Cardiac MR modelling of systolic and diastolic blood pressure.

AIMS: Blood pressure (BP) is a crucial factor in cardiovascular health and can affect cardiac imaging assessments. However, standard outpatient cardiovascular MR (CMR) imaging procedures do not typically include BP measurements prior to image acquisition. This study proposes that brachial systolic BP (SBP) and diastolic BP (DBP) can be modelled using patient characteristics and CMR data. METHODS: In this multicentre study, 57 patients from the PREFER-CMR registry and 163 patients from other registries were used as the derivation cohort. All subjects had their brachial SBP and DBP measured using a sphygmomanometer. Multivariate linear regression analysis was applied to predict brachial BP. The model was subsequently validated in a cohort of 169 healthy individuals. RESULTS: Age and left ventricular ejection fraction were associated with SBP. Aortic forward flow, body surface area and left ventricular mass index were associated with DBP. When applied to the validation cohort, the correlation coefficient between CMR-derived SBP and brachial SBP was (r=0.16, 95% CI 0.011 to 0.305, p=0.03), and CMR-derived DBP and brachial DBP was (r=0.27, 95% CI 0.122 to 0.403, p=0.0004). The area under the curve (AUC) for CMR-derived SBP to predict SBP>120 mmHg was 0.59, p=0.038. Moreover, CMR-derived DBP to predict DBP>80 mmHg had an AUC of 0.64, p=0.002. CONCLUSION: CMR-derived SBP and DBP models can estimate brachial SBP and DBP. Such models may allow efficient prospective collection, as well as retrospective estimation of BP, which should be incorporated into assessments due to its critical effect on load-dependent parameters.

Seroprevalence and risk factors of Peste des petits ruminants in different production systems in Uganda.

Peste des petits ruminants (PPR) is a highly contagious and fatal disease of mostly domestic goats and sheep. First reported in Uganda in 2007, the extent of peste des petits ruminants virus (PPRV) exposure, geographical distribution and risk factors of its transmission and spread are not clearly understood. In this study, we used cluster random sampling methodology to select study villages from three districts representing three different production systems along Uganda's "cattle corridor". Between October and December 2022, 2520 goat and sheep serum samples were collected from 252 households with no history of PPR vaccination in the past one year. The household heads were interviewed to assess possible risk factors of PPRV transmission using a structured questionnaire. The serum samples were screened with a commercial competitive enzyme-linked immunosorbent assay (cELISA) for PPRV antibodies. The determined overall true seroprevalence of PPRV was 27.3% [95% CI: 25.4-29.1]. The seroprevalence of PPRV antibodies in different production systems was 44.1% [95% CI: 40.6-47.7], 31.7% [95% CI: 28.4-35.0] and 6.1% [95% CI: 4.4-7.9] for pastoral, agropastoral and mixed crop-livestock production systems respectively. A mixed-effects multivariable logistic regression model revealed strong statistical evidence of association between female animals and PPRV antibody seropositivity compared to males [OR= 2.45, 95% CI: 1.7-3.5, p < 0.001]. The likelihood of being PPRV antibody seropositive significantly increased with increasing small ruminant age. Animals older than 3 years were more than three times as likely to be PPRV seropositive compared to animals aged under 1 year [OR= 3.41, 95% CI: 2.39-4.85, p < 0.001]. There was no statistical evidence of association between small ruminant species and PPRV antibody seropositivity (p = 0.423). Village flocks that interacted with neighboring flocks daily during grazing (IRR = 1.59, 95% CI: 1.19-2.13) and watering around swamps (IRR = 1.59, 95% CI: 1.19-2.13) were highly correlated with increased number of PPRV seropositive animals as compared to flocks that were more restricted in grazing and watered around other water sources other than swamps. Flocks from pastoral and agropastoral production systems were more than 10 times more likely to have seropositive animals than mixed crop-livestock flocks. Targeting PPR control interventions (vaccination and livestock movement control) to pastoral and agro-pastoral small ruminant production systems that are very prone to PPR incursions is recommended to prevent PPRV spread to low-risk smallholder mixed crop-livestock production systems.

PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models.

Unabated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis. Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains. Mechanistically, we show that PLK1 orchestrated the microtubule-organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL-1ß production in in vivo inflammatory models, including LPS-induced endotoxemia and monosodium urate-induced peritonitis in mice. Our results uncover a role of PLK1 in regulating NLRP3 inflammasome activation during interphase and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.

Dermatological Issues Among Individuals Receiving Palliative Care - A Review.

Skin disorders among individuals receiving palliative care may be associated with the primary condition or underlying comorbidities and patients may experience pruritus, discomfort or pain. Common conditions include xerosis, pressure ulcers, intertrigo, superficial fungal infections, telogen effluvium, pruritus, herpes zoster, eczematous disorders and edema. During end-of-life care, there is reduced skin perfusion and metabolism hence leading to susceptibility to infection, pressure and injury. Other factors affecting the skin include limited mobility, nutritional deficits and immunosuppression. Although treatment strategies for each skin condition are usually aligned with standard protocols, considerations among these patients include limited life-expectancies, potential treatment burden, drug-drug interactions as well as comfort-directed rather than cure-directed therapy. For patients with xerosis cutis, the regular use of moisturisers is recommended. The management and prevention of pressure ulcers include the strategies of skin assessment and care, pressure redistribution, nutrition and hydration and ulcer care. Superficial fungal infections require treatment with appropriate topical and/or systemic antifungals while antivirals and adjunctive treatment can be prescribed for herpes zoster. Treatment and symptom control of skin disorders in this population can improve quality of life and patients' comfort level.

Intravenous immunoglobulin is safe and effective in controlling pre-existing paraneoplastic neuromuscular diseases in cancer patients treated with immune checkpoint inhibitors: two case reports and literature review.

Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.

Sparse Bayesian Learning for End-to-End EEG Decoding.

Decoding brain activity from non-invasive electroencephalography (EEG) is crucial for brain-computer interfaces (BCIs) and the study of brain disorders. Notably, end-to-end EEG decoding has gained widespread popularity in recent years owing to the remarkable advances in deep learning research. However, many EEG studies suffer from limited sample sizes, making it difficult for existing deep learning models to effectively generalize to highly noisy EEG data. To address this fundamental limitation, this paper proposes a novel end-to-end EEG decoding algorithm that utilizes a low-rank weight matrix to encode both spatio-temporal filters and the classifier, all optimized under a principled sparse Bayesian learning (SBL) framework. Importantly, this SBL framework also enables us to learn hyperparameters that optimally penalize the model in a Bayesian fashion. The proposed decoding algorithm is systematically benchmarked on five motor imagery BCI EEG datasets ( N=192) and an emotion recognition EEG dataset ( N=45), in comparison with several contemporary algorithms, including end-to-end deep-learning-based EEG decoding algorithms. The classification results demonstrate that our algorithm significantly outperforms the competing algorithms while yielding neurophysiologically meaningful spatio-temporal patterns. Our algorithm therefore advances the state-of-the-art by providing a novel EEG-tailored machine learning tool for decoding brain activity.

Which non-infection related risk factors are associated with impaired proximal femur fracture healing in patients under the age of 70 years?

BACKGROUND/PURPOSE: Impaired healing is a feared complication with devastating outcomes for each patient. Most studies focus on geriatric fracture fixation and assess well known risk factors such as infections. However, risk factors, others than infections, and impaired healing of proximal femur fractures in non-geriatric adults are marginally assessed. Therefore, this study aimed to identify non-infection related risk factors for impaired fracture healing of proximal femur fractures in non-geriatric trauma patients. METHODS: This study included non-geriatric patients (aged 69 years and younger) who were treated between 2013 and 2020 at one academic Level 1 trauma center due to a proximal femur fracture (PFF). Patients were stratified according to AO/OTA classification. Delayed union was defined as failed callus formation on 3 out of 4 cortices after 3 to 6 months. Nonunion was defined as lack of callus-formation after 6 months, material breakage, or requirement of revision surgery. Patient follow up was 12 months. RESULTS: This study included 150 patients. Delayed union was observed in 32 (21.3%) patients and nonunion with subsequent revision surgery occurred in 14 (9.3%). With an increasing fracture classification (31 A1 up to 31 A3 type fractures), there was a significantly higher rate of delayed union. Additionally, open reduction and internal fixation (ORIF) (OR 6.17, (95% CI 1.54 to 24.70, p ≤ 0.01)) and diabetes mellitus type II (DM) (OR 5.74, (95% CI 1.39 to 23.72, p = 0.016)), were independent risk factors for delayed union. The rate of nonunion was independent of fracture morphology, patient's characteristics or comorbidities. CONCLUSION: Increasing fracture complexity, ORIF and diabetes were found to be associated with delayed union of intertrochanteric femur fractures in non-geriatric patients. However, these factors were not associated with the development of nonunion.

Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease-From Early Cancer Detection to Individualized Cancer Treatment.

Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.

Liquiritigenin promotes osteogenic differentiation and prevents bone loss via inducing auto-lysosomal degradation and inhibiting apoptosis.

Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy-apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro, and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP.

Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming.

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive. Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis. Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.

Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis.

Our perspectives on aortic stenosis (AS) are changing. Evolving from the traditional thought of a passive degenerative disease, developing a greater understanding of the condition's mechanistic underpinning has shifted the paradigm to an active disease process. This advancement from the 'wear and tear' model is a result of the growing economic and health burden of AS, particularly within industrialised countries, prompting further research. The pathophysiology of calcific AS (CAS) is complex, yet can be characterised similarly to that of atherosclerosis. Progressive remodelling involves lipid-protein complexes, with lipoprotein(a) being of particular interest for diagnostics and potential future treatment options.There is an unmet clinical need for asymptomatic patient management; no pharmacotherapies are proven to slow progression and intervention timing varies. Novel approaches are developing to address this through: (1) screening with circulating biomarkers; (2) development of drugs to slow disease progression and (3) early valve intervention guided by medical imaging. Existing biomarkers (troponin and brain natriuretic peptide) are non-specific, but cost-effective predictors of ventricular dysfunction. In addition, their integration with cardiovascular MRI can provide accurate risk stratification, aiding aortic valve replacement decision making. Currently, invasive intervention is the only treatment for AS. In comparison, the development of lipoprotein(a) lowering therapies could provide an alternative; slowing progression of CAS, preventing left ventricular dysfunction and reducing reliance on surgical intervention.The landscape of AS management is rapidly evolving. This review outlines current understanding of the pathophysiology of AS, its management and future perspectives for the condition's assessment and treatment.

Circulating Monocytes Serve as Novel Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma Patients.

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most fatal cancer diseases, widely accepted to have the most dismal prognoses. Although immunotherapy has broadly revolutionized cancer treatment, its value in PDAC appears to be relatively low. Exhibiting protumoral effects, monocytes have recently been proposed as potential targets of such immunotherapeutic regimens. However, to date, the body of evidence on monocytes' role in PDAC is scarce. Therefore, we analyzed monocytes in the peripheral blood of 58 PDAC patients prior to surgery and compared them to healthy individuals. PDAC patients showed increased levels of monocytes when compared to healthy controls In addition, patients with perineural infiltration demonstrated a higher percentage of monocytes compared to non-infiltrating tumors and PDAC G3 was associated with higher monocyte levels than PDAC G2. Patients with monocyte levels > 5% were found to have an 8.9-fold increased risk for a G3 and perineural infiltrated PDAC resulting in poorer survival compared to patients with <5% monocyte levels. Furthermore, PDAC patients showed increased expressions of CD86 and CD11c and decreased expressions of PD-L1 on monocytes compared to healthy individuals. Finally, levels of monocytes correlated positively with concentrations of IL-6 and TNF-α in plasma of PDAC patients. Based on our findings, we propose monocytes as a novel prognostic biomarker. Large-scale studies are needed to further decipher the role of monocytes in PDAC and investigate their potential as therapeutic targets.

Mindful gratitude journaling: psychological distress, quality of life and suffering in advanced cancer: a randomised controlled trial.

CONTEXT: Numerous studies have shown that gratitude can reduce stress and improve quality of life. OBJECTIVE: Our study aimed to examine the effect of mindful gratitude journaling on suffering, psychological distress and quality of life of patients with advanced cancer. METHODS: We conducted a parallel-group, blinded, randomised controlled trial at the University of Malaya Medical Centre, Malaysia. Ninety-two adult patients with advanced cancer, and an overall suffering score ≥4/10 based on the Suffering Pictogram were recruited and randomly assigned to either a mindful gratitude journaling group (N=49) or a routine journaling group (N=43). RESULTS: After 1 week, there were significant reductions in the overall suffering score from the baseline in both the intervention group (mean difference in overall suffering score=-2.0, 95% CI=-2.7 to -1.4, t=-6.125, p=0.000) and the control group (mean difference in overall suffering score=-1.6, 95% CI=-2.3 to -0.8, t=-4.106, p=0.037). There were also significant improvements in the total Hospital Anxiety and Depression Scale score (mean difference=-3.4, 95% CI=-5.3 to -1.5, t=-3.525, p=0.000) and the total Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being score (mean difference=7.3, 95% CI=1.5 to 13.1, t=2.460, p=0.014) in the intervention group after 7 days, but not in the control group. CONCLUSION: The results provide evidence that 7 days of mindful gratitude journaling could positively affect the state of suffering, psychological distress and quality of life of patients with advanced cancer. TRIAL REGISTRATION NUMBER: The trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN1261800172191) and conducted in accordance with the Declaration of Helsinki.

The sleep physiology of nightmares in veterans with psychological trauma: Evaluation of a dominant model using participant-applied electroencephalography in the home environment.

Nightmares are a core feature of posttraumatic stress disorder, are poorly understood, and are associated with serious negative outcomes. Their biology has been difficult to study, and the feasibility of capturing them in the naturalistic home environment has been poor. This said, the published research and dominant scientific model has focused on nightmares as a manifestation of noradrenergic hyperarousal during rapid eye movement sleep. The current study used at-home, participant-applied devices to measure nightmare physiology in posttraumatic stress disorder treatment-seeking veterans, by examining heartrate measures as indicators of noradrenergic tone, and sleep-stage characteristics and stability in the sleep preceding time-stamped nightmare awakenings. Our data indicate the high feasibility of participant-administered, at-home measurement, and showed an unexpected stability of -rapid eye movement sleep along with no evidence of heartrate elevations in sleep preceding nightmare awakenings. Altogether, these data highlight new opportunities for the study of nightmares while questioning the sufficiency of dominant models, which to date are largely theoretically based.

Effect of trabeculectomy on the rate of progression of visual field damage.

OBJECTIVES: This study quantifies the effect of trabeculectomy on the rate of progression (RoP) of visual field (VF) damage utilising pre- and post-operative visual function as the outcome instead of surrogate outcomes of success. METHODS: Clinical and VF data from 199 sequential patients who underwent trabeculectomy between 2015 and 2016 were extracted from the network of sites of Moorfields Eye Hospital NHS Foundation Trust. Of these, we analysed 80 eyes of 74 patients who met our inclusion criteria of at least three reliable VFs before and after surgery (false positive rate <15%). The change in mean RoP (dB/year) was tested using point-wise sensitivity values through a mixed effect model with random effects on both intercepts and slopes. A broken-stick regression of sensitivity over time, with a breakpoint at the day of surgery, modelled the individual change in RoP. RESULTS: We analysed 10 [9,12] VFs per subject (Median [Interquartile Range]). At surgery, the age was 67 [57, 72] years, mean deviation was -10.84 [-14.7, -5.6] dB and the IOP was 18 [15, 20] mmHg. One year after surgery, the IOP was 10 [8,13] mmHg (p = 0.002). Mean RoP before surgery was -0.94 [-1.20, -0.69] dB/year (Mean [95% credible intervals]) and it was slowed down by 0.62 [0.26, 0.97] dB/year (p < 0.001) after surgery. CONCLUSIONS: Trabeculectomy leads to a significant reduction in the RoP of VF loss postoperatively.