A conceptual model for chronic hepatitis B and content validity of the Hepatitis B Quality of Life (HBQOL) instrument.

BACKGROUND: There is increased emphasis on incorporating patient perspectives and patient-relevant endpoints in drug development. We developed a conceptual model of the impact of chronic hepatitis B (CHB) on patients' lives and evaluated the content validity of the Hepatitis B Quality of Life (HBQOL) instrument, a patient-reported outcome tool for use in clinical studies, as a patient-relevant endpoint to measure health-related quality of life in patients with CHB. METHODS: A literature review of qualitative studies of patient experience with CHB and concept elicitation telephone interviews with patients with CHB in the United Kingdom were used to develop a conceptual model of the experience and impact of living with CHB. The content validity of the HBQOL was evaluated using cognitive debriefing techniques. RESULTS: The qualitative literature review (N = 43 publications) showed that patients with CHB experience emotional/psychological impacts. During concept elicitation interviews (N = 24), fatigue was the most commonly reported symptom, and most participants were worried/anxious about virus transmission and disease progression/death. A conceptual model of patients' experiences with CHB was developed. The conceptual relevance and comprehensibility of the HBQOL were supported, though limitations, including the lack of a self-stigma item and recall period, were noted for future improvement. CONCLUSIONS: The conceptual model shows that patients with CHB experience emotional/psychological impacts that affect their lifestyles, relationships, and work/schooling. The cognitive debriefing interviews support the content validity of the HBQOL as a conceptually relevant patient-reported outcome measure of health-related quality of life.

A canine case of Ehrlichia canis infection without a history of being in an endemic area in Japan.

A mixed-breed, 8-year-old male dog developed neutropenia, thrombocytopenia, and hyperglobulinemia. Bone marrow hyperplasia and splenic plasmacytosis were cytologically observed. The dog had never been outside of Tokyo or Shizuoka Prefecture. Splenectomy was performed to confirm and remove the cause of splenic plasmacytosis. A histopathological diagnosis of splenic plasmacytoma was made; however, serum protein electrophoresis showed polyclonal gammopathy. Further screening was performed, and Ehrlichia canis infection was confirmed. The dog was treated with doxycycline for 5 weeks. After the antibiotic therapy, no relapse of neutropenia, thrombocytopenia, hyperglobulinemia, or positive polymerase chain reaction result of E. canis infection was observed for 3 years. Careful attention should be given to ehrlichiosis when exploring the cause of pancytopenia or hyperglobulinemia, regardless of the travel history.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Treatment-Resistant Depression in Real-World Clinical Practice: A Systematic Literature Review of Data from 2012 to 2022.

OBJECTIVE: Real-world evidence in treatment-resistant depression (TRD; commonly defined as non-response to ≥ 2 consecutive treatments at adequate dosage and duration) is lacking. A systematic literature review was conducted to understand disease burden and treatment outcomes for patients with TRD, studied in a real-world setting over the last decade. DATA SOURCES: A literature search was conducted in May 2022 in MEDLINE, Embase, The Cochrane Libraries and PsycINFO, comprising studies published from 2012 to 2022. Bibliographies of all relevant identified systematic reviews and relevant conference proceedings from 2020 to 2022 were manually hand-searched. STUDY SELECTION: Real-world studies, including cohort, cross-sectional, case-control, chart review and registry studies, published in English and reporting outcomes in adults with TRD, were included. DATA EXTRACTION: Extracted data included study and baseline disease characteristics, treatment type, treatment response, clinical outcomes and health-related quality of life. RESULTS: Twenty studies were included. Criteria for TRD varied, but patients typically experienced long-lasting depression (range 1.4 to 16.5 years). Across studies, mean disease severity scores demonstrated moderate to severe depression, reflecting a high burden of disease at baseline. Remission rates were typically low but generally increased with longer follow-up durations. However, the heterogeneity of interventions, follow-up durations (range 2 weeks to 9.4 years) and assessment tools precluded their quantitative synthesis. Studies were frequently limited by low sample size (range 14 to 411 patients) and health-related quality of life was infrequently assessed. CONCLUSIONS: There is a lack of clinical consensus regarding the definition, assessment and monitoring of TRD in real-world practice. Nevertheless, TRD carries a high burden of illness and there is an unmet need for faster and more effective treatments. To better understand the personal burden of affected patients, future studies would benefit from standardisation of severity assessment and measures of treatment effectiveness, as well as greater consideration of health-related quality of life.

Many people continue to experience depression even after trying two or more medications. This is called treatment-resistant depression (TRD). Most of the information we have on TRD comes from clinical trials, which take place under tightly-controlled conditions. It is important to understand the effects of TRD and TRD treatments on people in their day-to-day lives. Researchers studying people's day-to-day lives call this researching in a "real-world setting". We searched for studies carried out in real-world settings in the last 10 years. We found 20 relevant studies. As these studies were in real-world settings, there were many differences between them, including differences in how TRD was diagnosed, the treatments used, how long people were monitored and how results were measured. This made it difficult to compare how successful different treatments were. Most studies included a small number of people and monitored them for a relatively short time. We found people with TRD had usually lived with it for many years and their symptoms were moderate or severe. Only two studies asked people how TRD affected their lives. These two studies found health-related quality of life and work productivity was low. Most studies found lots of people still had symptoms of depression after treatment. However, symptoms typically improved more when studies monitored people for a longer time. To improve our knowledge of TRD, future studies should monitor more people for longer and use the same ways of measuring results. They should also ask how TRD affects people's daily lives.

Metabolome analysis reveals that cyclic adenosine diphosphate ribose contributes to the regulation of differentiation in mice adipocyte.

Adipocytes play a key role in energy storage and homeostasis. Although the role of transcription factors in adipocyte differentiation is known, the effect of endogenous metabolites of low molecular weight remains unclear. Here, we analyzed time-dependent changes in the levels of these metabolites throughout adipocyte differentiation, using metabolome analysis, and demonstrated that there is a positive correlation between cyclic adenosine diphosphate ribose (cADPR) and Pparγ mRNA expression used as a marker of differentiation. We also found that the treatment of C3H10T1/2 adipocytes with cADPR increased the mRNA expression of those marker genes and the accumulation of triglycerides. Furthermore, inhibition of ryanodine receptors (RyR), which are activated by cADPR, caused a significant reduction in mRNA expression levels of the marker genes and triglyceride accumulation in adipocytes. Our findings show that cADPR accelerates adipocytic differentiation via RyR pathway.

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Metabolomics reveals inosine 5'-monophosphate is increased during mice adipocyte browning.

Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid, an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil, a prodrug of mycophenolic acid, to mice and demonstrated that mycophenolate mofetil induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.

Improving work detection by segmentation heuristics pre-training on factory operations video.

The measurement of work time for individual tasks by using video has made a significant contribution to a framework for productivity improvement such as value stream mapping (VSM). In the past, the work time has been often measured manually, but this process is quite costly and labor-intensive. For these reasons, automation of work analysis at the worksite is needed. There are two main methods for computing spatio-temporal information: by 3D-CNN, and by temporal computation using LSTM after feature extraction in the spatial domain by 2D-CNN. These methods has high computational cost but high model representational power, and the latter has low computational cost but relatively low model representational power. In the manufacturing industry, the use of local computers to make inferences is often required for practicality and confidentiality reasons, necessitating a low computational cost, and so the latter, a lightweight model, needs to have improved performance. Therefore, in this paper, we propose a method that pre-trains the image encoder module of a work detection model using an image segmentation model. This is based on the CNN-LSTM structure, which separates spatial and temporal computation and enables us to include heuristics such as workers' body parts and work tools in the CNN module. Experimental results demonstrate that our pre-training method reduces over-fitting and provides a greater improvement in detection performance than pre-training on ImageNet.

Quantification of ustalic acid, a chemotaxonomic marker, in Tricholoma ustale using liquid chromatography-mass spectrometry.

The development of methods for the detection and qualification of toxic substances in mushrooms is a rapidly growing research area in forensic toxicology. This study aimed to determine liquid chromatographic and mass spectrometric conditions applicable to the analysis of ustalic acid (UA) in Tricholoma ustale. We used HPLC coupled with single quadrupole mass spectrometry (Q-MS) with electrospray ionization in its negative ion mode to analyze UA. We performed HPLC separations on a C18 reversed-phase column with gradient elution using mobile phases containing water, acetonitrile, and formic acid. The MS showed that UA formed the deprotonated molecular ion [M-H]- at m/z 337, which was sufficient for the quantitative analysis of the compound. The average recovery rates of UA from four edible mushrooms (Flammulina velutipes, Pleurotus eryngii, Lentinula edodes, and Grifola frondosa) to which 10.0 µg/g of UA was added were 108%, 104%, 108%, and 107%, respectively, and the relative standard deviation values ranged from 4.1 to 6.4%. Quantitative analysis of UA in three systematically collected individual mushrooms of T. ustale revealed 41.9-155.7 ppm in each dry material. We also explored the fragmentation behaviors of UA in triple quadrupole mass spectrometry and the proposed structures for the product ions. The data suggest that conventional Q-MS with authenticated UA would be able to identify this compound in T. ustale when used for the immediate inspection of incidences of poisoning. Confirmation of the presence of UA in T. ustale would ultimately allow for the chemotaxonomic discrimination of Tricholoma species.

Development of a simple and reliable high-performance liquid chromatography-tandem mass spectrometry approach to simultaneously detect grains specified in food allergen labeling regulation on processed food commodities.

An analytical approach using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to simultaneously detect Fagopyrum esculentum Moench (buckwheat) and cereals containing gluten (Triticum species including wheat and spelt, rye, barley, and oats) that were specified in regulations for food allergen labeling on processed foods. Trypsin-digested peptides were purified from different processed food commodities and heptapeptides derived from buckwheat 13S globulin (GFIVQAR, m/z 395.8 [precursor] > 177.0 [product]) and Triticum low molecular weight glutenin (QIPEQSR, m/z 429.3 [precursor] > 616.2 [product]) were specifically detected each species at levels as low as 0.050-0.056 µg/L and 0.028-0.032 µg/L, respectively. Detection of these synthetic peptides was quantitative to over 100 µg/L by reference to the synthetic peptide calibration curves and at recovery rates, 76.6 ± 4.1%-104.8 ± 17.1% and 82.4 ± 2.0%-105.8 ± 5.3%, for GFIVQAR and QIPEQSR, respectively, when 1-1,000 µg of these peptides were spiked into a retort tomato sauce for pasta or dried instant soup. In combination with LC-MS/MS detection methods specific to other cereals containing gluten (rye, barley, and oats), the developed analytical approach was applicable to a wide variety of processed food commodities for food allergen labeling.

Taxonomic revision of the Japanese Tricholoma ustale and closely related species based on molecular phylogenetic and morphological data.

"Kakishimeji" identified as Tricholoma ustale and belonging to Tricholoma sect. Genuina is a common poisonous mushroom in Japan. Kakishimeji contains the toxic compound ustalic acid and causes digestive trouble. However, this fungus is consumed in some regions of Japan without any digestive issues. We clarified the probable species complex of Kakishimeji based on a phylogenetic analysis. We collected 89 basidioma specimens of Kakishimeji and related species from various forest sites in Japan and conducted phylogenetic analyses using 7 nuclear and mitochondrial gene sequences. Kakishimeji was found to consist of four distinct phylogenetic clades based on all DNA regions tested. Of these, two clades included European T. stans and T. albobrunneum type specimens. Another two clades consisted of sister clades to T. pessundatum and T. ustaloides. In addition, all four phylogenetic clades of Kakishimeji had different spore and basidium sizes. Therefore, we regarded the latter two clades as two new Tricholoma species: T. kakishimeji and T. kakishimejioides.

Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes.

Resveratrol (RSV) has recently attracted keen interest because of its pleiotropic effects. It exerts a wide range of health-promoting effects. In addition to health-promoting effects, RSV possesses anti-carcinogenic activity. However, a non-physiological concentration is needed to achieve an anti-cancer effect, and its in vivo bioavailability is low. Therefore, the clinical application of phytochemicals requires alternative candidates that induce the desired effects at a lower concentration and with increased bioavailability. We previously reported a low IC50 of vaticanol C (VTC), an RSV tetramer, among 12 RSV derivatives (Ito T. et al, 2003). However, the precise mechanism involved remains to be determined. Here, we screened an in-house chemical library bearing RSV building blocks ranging from dimers to octamers for cytotoxic effects in several leukemia and cancer cell lines and their anti-cancer drug-resistant sublines. Among the compounds, VTC exhibited the highest cytotoxicity, which was partially inhibited by a caspase 3 inhibitor, Z-VAD-FMK. VTC decreased the expression of sphingosine kinase 1, sphingosine kinase 2 and glucosylceramide synthase by transcriptional or post-transcriptional mechanisms, and increased cellular ceramides/dihydroceramides and decreased sphingosine 1-phosphate (S1P). VTC-induced sphingolipid rheostat modulation (the ratio of ceramide/S1P) is thought to be involved in cellular apoptosis. Indeed, exogenous S1P addition modulated VTC cytotoxicity significantly. A combination of SPHK1, SPHK2, and GCS chemical inhibitors induced sphingolipid rheostat modulation, cell growth suppression, and cytotoxicity similar to that of VTC. These results suggest the involvement of sphingolipid metabolism in VTC-induced cytotoxicity, and indicate VTC is a promising prototype for translational research.

Correction to: Resveratrol oligomer structure in Dipterocarpaceaeous plants.

The article Resveratrol oligomer structure in Dipterocarpaceaeous plants.

Resveratrol oligomer structure in Dipterocarpaceaeous plants.

Oligostilbenoids are a group of natural products derived from the oxidative coupling of C6-C2-C6 units found in some plant families. A structurally diverse chemical pool is produced after the successive regioselective and stereoselective oligomerization of resveratrol. This review describes the current status and knowledge of the structure of resveratrol oligomers (ROs) in Dipterocarpaceaeous plants (DPs). Beginning with the recently validated formation of ROs in DPs, each downstream conversion is described from the perspective of the resveratrol coupling mode. Particular emphasis is placed upon the regioselectivity of monomer- and dimer-derived radical-radical coupling processes, which are responsible for producing dimers, trimers, and tetramers with various cyclic frame skeletons, as well as related processes that result in highly condensed scaffolds, such as hexamers and octamers. Trimers in oxidized, dearomatized, and rearranged forms are also summarized, as well as the biogenic relationship between the compounds. Furthermore, emphasis is placed on the O- and C-glucosides of ROs, as well as on the hetero-coupled ROs. In addition, several stereoisomers that originate from asymmetric carbons and the stereochemistry with respect to the conformation due to the chiral axis are described. Besides, NMR spectroscopic properties such as coalescence and anisotropy are briefly described. Approaches to determine absolute configuration are also summarized.

Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

BACKGROUND: LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA) + prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos + ADT arm could switch to AA + P + ADT during an open-label extension. As in other studies where switching is allowed, statistical adjustments are needed to assess the real benefit of new drugs. PATIENTS AND METHODS: This was a post hoc analysis to estimate the true survival benefit of AA + P + ADT in patients with newly diagnosed mCSPC by applying statistical adjustments commonly used to adjust for treatment switching. RESULTS: Of 112 patients still receiving placebos + ADT at the first interim analysis, 72 switched to AA + P + ADT during the open-label extension. Final analysis was conducted after median follow-up of 51.8 months. Compared to the placebos + ADT arm, the risk of death in the AA + P + ADT arm was 34% lower [hazard ratio (HR) = 0.663 (95% confidence interval 0.566-0.778)] by unadjusted intent-to-treat analysis, 37% lower [HR = 0.629 (95% confidence interval 0.526-0.753)] by rank preserving structure failure time modeling, and 38% lower [HR = 0.616 (95% confidence interval 0.524-0.724)] by inverse probability of censoring weights. CONCLUSIONS: Analyses adjusting for treatment switching using two different statistical approaches confirm the improved survival benefit of adding AA + P to ADT in patients with newly diagnosed mCSPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01715285.

Soy hydrolysate enhances the isoproterenol-stimulated lipolytic pathway through an increase in ß-adrenergic receptor expression in adipocytes.

Activation of the adipose lipolytic pathway during lipid metabolism is mediated by protein kinase A (PKA), which responds to ß-adrenergic stimulation, leading to increased lipolysis. Soy is well known as a functional food and it is able to affect lipolysis in adipocytes. However, the mechanism by which soy components contribute to the lipolytic pathway remains to be fully elucidated. Here, we show that hydrolyzed soy enhances isoproterenol-stimulated lipolysis and activation of PKA in 3T3-L1 adipocytes. We also found that the expression of ß-adrenergic receptors, which coordinate the activation of PKA, is elevated in adipocytes differentiated in the presence of soy hydrolysate. The activity of the soy hydrolysate towards ß-adrenergic receptor expression was detected in its hydrophilic fraction. Our results suggest that the soy hydrolysate enhances the PKA pathway through the upregulation of ß-adrenergic receptor expression and thereby, increase lipolysis in adipocytes.

Patient Preferences for Metastatic Hormone-Sensitive Prostate Cancer Treatments: A Discrete Choice Experiment Among Men in Three European Countries.

INTRODUCTION: Various treatment options are available for metastatic hormone-sensitive prostate cancer. This study aimed to quantify how men with prostate cancer in the United Kingdom (UK), Germany, and Spain perceive the risks and benefits of hypothetical abiraterone acetate plus prednisone treatment and docetaxel-based chemotherapy treatment options. METHODS: A targeted literature review, exploratory interviews with prostate cancer patients and oncologists, and pre-test interviews were used to develop a discrete choice experiments (DCE). The final DCE included 32 choice sets, selected using a main-effects orthogonal design, divided into two survey blocks. Paired profiles presented hypothetical treatments for prostate cancer through six attributes that could be presented at two or four levels each. Preference estimates were estimated using a conditional logit regression model. Preference results were stratified by cancer stage. RESULTS: A total of 152 participants (mean age 69 years) completed the DCE in the UK, Germany, and Spain. Treatment effectiveness was the main concern for the patients (difference in preference estimates between 8 and 32 months 1.443). Participants wanted to avoid pain that was not well controlled (preference dummy coding estimate - 1.157). Participants valued a change from an oral medication to an intravenous treatment (change in preference estimate - 0.416) more negatively than a change from a 1% to a 5% risk of infection (change in preference estimate - 0.313). CONCLUSIONS: This study shows that treatment effectiveness and pain control were the most important attributes for patients with prostate cancer. These two attributes influenced more than 50% of their decision-making in this study. The risk of fatigue and mode of administration were least prioritised by patients. This study highlights the relative importance that Spanish, German, and British patients place on various aspects of treatment options for prostate cancer. Understanding patient preference and taking them into consideration shall help physicians when developing their treatment strategies for their patients. FUNDING: Janssen.

Qualitative and Quantitative Assessment of Patient and Carer Experience of Chemotherapy (Docetaxel) in Combination with Androgen Deprivation Therapy (ADT) for the Treatment of Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

INTRODUCTION: Recent studies suggest that docetaxel plus androgen deprivation therapy can prolong survival among men with metastatic hormone-sensitive prostate cancer (mHSPC). However, as a cytotoxic therapy, there is a need to understand the experiences of men with mHSPC receiving docetaxel and their carers in a real-world setting. METHODS: During phase 1, semi-structured qualitative interviews were conducted with men with mHSPC (n = 31) and their carers (n = 14) in Europe to elicit in-depth data concerning their experiences with docetaxel. Eighteen men were also asked to record their experiences in a diary for 7 days. During phase 2, men with mHSPC (n = 161) and carers of men with mHSPC (n = 135) completed an online survey comprising self-report questionnaires including the Cancer Therapy Satisfaction Questionnaire, Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Prostate, EuroQol-5-Dimensions and the Burden Scale for Family Caregivers (carers only). RESULTS: At the outset of therapy, men reported a willingness to take docetaxel to prolong their life, despite being fearful of the potential side effects and impacts on their daily lives. Patient and carer experiences were generally consistent with pre-treatment expectations. However, variations in individual experiences and their ability to tolerate side effects were evident. Fatigue emerged as a prominent symptom with the majority (n = 98, 60.9%) of men reporting experiencing moderate-severe fatigue in the past 24 h. Participant ratings of fatigue were strongly correlated with health-related quality of life (r = - 0.82). Nausea, diarrhoea and sore mouth were also among the most bothersome symptoms for participants. CONCLUSIONS: Findings from this study highlight that real-world experience of docetaxel may differ from that observed in clinical trials and that care must be taken to ensure that treatment options are tailored to the needs of individual patients to promote not only how long patients survive but also the quality of that survival. FUNDING: Janssen.

Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis.

AIM: Androgen deprivation therapy (ADT) has long been the gold standard for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trials have demonstrated significant survival benefits when docetaxel (DOC) or abiraterone acetate (AA) and prednisone (P) are added to ADT, necessitating comparison of these combination treatments. METHODS: A systematic review of randomised controlled trials (RCTs) of AA-/ADT-/DOC-containing treatment regimens in newly diagnosed patients with high-risk and/or high-volume mHSPC identified three RCTs (LATITUDE, CHAARTED and GETUG-AFU 15). Network meta-analyses (NMAs) using fixed effects Bayesian methods were performed to compare relative benefits of each treatment on overall survival (OS), radiographic progression-free survival (rPFS) and quality of life (QoL) measured by the Brief Pain Inventory, and the Functional Assessment of Cancer Therapy-Prostate questionnaire. One trial, STAMPEDE, was assessed in exploratory OS analyses. RESULTS: The hazard ratio (HR) for OS ranged from 0.85 to 0.92, with the Bayesian probability of AA + P + ADT being better than DOC + ADT ranging between 72% and 87%. For rPFS, the HR ranged between 0.71 and 0.76 (Bayesian probability range: 93%-97%). Exploratory analyses including STAMPEDE found similar trends. AA + P + ADT also showed improved QoL compared with DOC + ADT for at least 1 year of therapy, with results being more pronounced at 3 months. CONCLUSION: Our findings suggest that AA + P + ADT is at least as effective as DOC + ADT in reducing the risk of death in men with mHSPC and better at preventing disease progression and improving QoL. The NMA provides useful insights to clinicians and other decision-makers on the relative efficacy of treatment options for men with mHSPC.

Reduced Arogenate Dehydratase Expression: Ramifications for Photosynthesis and Metabolism.

Arogenate dehydratase (ADT) catalyzes the final step of phenylalanine (Phe) biosynthesis. Previous work showed that ADT-deficient Arabidopsis (Arabidopsis thaliana) mutants had significantly reduced lignin contents, with stronger reductions in lines that had deficiencies in more ADT isoforms. Here, by analyzing Arabidopsis ADT mutants using our phenomics facility and ultra-performance liquid chromatography-mass spectrometry-based metabolomics, we describe the effects of the modulation of ADT on photosynthetic parameters and secondary metabolism. Our data indicate that a reduced carbon flux into Phe biosynthesis in ADT mutants impairs the consumption of photosynthetically produced ATP, leading to an increased ATP/ADP ratio, the overaccumulation of transitory starch, and lower electron transport rates. The effect on electron transport rates is caused by an increase in proton motive force across the thylakoid membrane that down-regulates photosystem II activity by the high-energy quenching mechanism. Furthermore, quantitation of secondary metabolites in ADT mutants revealed reduced flavonoid, phenylpropanoid, lignan, and glucosinolate contents, including glucosinolates that are not derived from aromatic amino acids, and significantly increased contents of putative galactolipids and apocarotenoids. Additionally, we used real-time atmospheric monitoring mass spectrometry to compare respiration and carbon fixation rates between the wild type and adt3/4/5/6, our most extreme ADT knockout mutant, which revealed no significant difference in both night- and day-adapted plants. Overall, these data reveal the profound effects of altered ADT activity and Phe metabolism on secondary metabolites and photosynthesis with implications for plant improvement.