Fumaric acid production from fermented oil palm empty fruit bunches using fungal isolate K20: a comparison between free and immobilized cells.

This study investigated the potential of using steam-exploded oil palm empty fruit bunches (EFB) as a renewable feedstock for producing fumaric acid (FA), a food additive widely used for flavor and preservation, through a separate hydrolysis and fermentation process using the fungal isolate K20. The efficiency of FA production by free and immobilized cells was compared. The maximum FA concentration (3.25 g/L), with 0.034 g/L/h productivity, was observed after incubation with the free cells for 96 h. Furthermore, the production was scaled up in a 3-L air-lift fermenter using oil palm EFB-derived glucose as the substrate. The FA concentration, yield, and productivity from 100 g/L initial oil palm EFB-derived glucose were 44 g/L, 0.39 g/g, and 0.41 g/L/h, respectively. The potential for scaling up the fermentation process indicates favorable results, which could have significant implications for industrial applications.

Incorporation of black phosphorus nanosheets into poly(propylene fumarate) biodegradable bone cement to enhance bioactivity and osteogenesis.

BACKGROUND: Injectable bone cement is commonly used in clinical orthopaedics to fill bone defects, treat vertebral compression fractures, and fix joint prostheses during joint replacement surgery. Poly(propylene fumarate) (PPF) has been proposed as a biodegradable and injectable alternative to polymethylmethacrylate (PMMA) bone cement. Recently, there has been considerable interest in two-dimensional (2D) black phosphorus nanomaterials (BPNSs) in the biomedical field due to their excellent photothermal and osteogenic properties. In this study, we investigated the biological and physicochemical qualities of BPNSs mixed with PPF bone cement created through thermal cross-linking. METHODS: PPF was prepared through a two-step process, and BPNSs were prepared via a liquid phase stripping method. BP/PPF was subsequently prepared through thermal cross-linking, and its characteristics were thoroughly analysed. The mechanical properties, cytocompatibility, osteogenic performance, degradation performance, photothermal performance, and in vivo toxicity of BP/PPF were evaluated. RESULTS: BP/PPF exhibited low cytotoxicity levels and mechanical properties similar to that of bone, whereas the inclusion of BPNSs promoted preosteoblast adherence, proliferation, and differentiation on the surface of the bone cement. Furthermore, 200 BP/PPF demonstrated superior cytocompatibility and osteogenic effects, leading to the degradation of PPF bone cement and enabling it to possess photothermal properties. When exposed to an 808-nm laser, the temperature of the bone cement increased to 45-55 °C. Furthermore, haematoxylin and eosin-stained sections from the in vivo toxicity test did not display any anomalous tissue changes. CONCLUSION: BP/PPF exhibited mechanical properties similar to that of bone: outstanding photothermal properties, cytocompatibility, and osteoinductivity. BP/PPF serves as an effective degradable bone cement and holds great potential in the field of bone regeneration.

Assessment of breast cancer chemotherapy dose reduction in an integrated healthcare delivery system.

PURPOSE: Most cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear. METHODS: In 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy. RESULTS: Overall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years. CONCLUSION: Results offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

Supplementation with Amino Acid Sources Facilitates Fermentative Growth of Shewanella oneidensis MR-1 in Defined Media.

Shewanella oneidensis MR-1 is a facultative anaerobe that grows by respiration using a variety of electron acceptors. This organism serves as a model to study how bacteria thrive in redox-stratified environments. A glucose-utilizing engineered derivative of MR-1 has been reported to be unable to grow in glucose minimal medium (GMM) in the absence of electron acceptors, despite this strain having a complete set of genes for reconstructing glucose to lactate fermentative pathways. To gain insights into why MR-1 is incapable of fermentative growth, this study examined a hypothesis that this strain is programmed to repress the expression of some carbon metabolic genes in the absence of electron acceptors. Comparative transcriptomic analyses of the MR-1 derivative were conducted in the presence and absence of fumarate as an electron acceptor, and these found that the expression of many genes involved in carbon metabolism required for cell growth, including several tricarboxylic acid (TCA) cycle genes, was significantly downregulated in the absence of fumarate. This finding suggests a possibility that MR-1 is unable to grow fermentatively on glucose in minimal media owing to the shortage of nutrients essential for cell growth, such as amino acids. This idea was demonstrated in subsequent experiments that showed that the MR-1 derivative fermentatively grows in GMM containing tryptone or a defined mixture of amino acids. We suggest that gene regulatory circuits in MR-1 are tuned to minimize energy consumption under electron acceptor-depleted conditions, and that this results in defective fermentative growth in minimal media. IMPORTANCE It is an enigma why S. oneidensis MR-1 is incapable of fermentative growth despite having complete sets of genes for reconstructing fermentative pathways. Understanding the molecular mechanisms behind this defect will facilitate the development of novel fermentation technologies for the production of value-added chemicals from biomass feedstocks, such as electro-fermentation. The information provided in this study will also improve our understanding of the ecological strategies of bacteria living in redox-stratified environments.

Effects of dietary disodium fumarate supplementation on muscle quality, chemical composition, oxidative stress and lipid metabolism of Hu sheep induced by high concentrate diet.

Long-term feeding of high-concentrate (HC) diet causes the decrease of rumen pH, and induces subacute rumen acidosis (SARA), which results in metabolic disorders in sheep. This not only reduces animal performance, but also increases the risk of oxidative stress and inflammatory reaction. Disodium fumarate can improve the rumen buffering capacity and increase rumen pH. This experiment was conducted to investigate the effects of high concentrate diet on muscle quality, chemical composition, oxidative damage and lipid metabolism of Hu sheep, and the regulating effect of disodium fumarate. The results showed that HC diet induced SARA by reducing rumen pH value, thus causing oxidative stress and lipid metabolism disorder in longissimus lumborum (LL) muscle of Hu sheep, which also reduced meat quality by increasing shear force, drip loss, cooking loss, chewiness and hardness, and reducing the contents of crude fat and crude protein in LL muscle. However, disodium fumarate can improve meat quality of SARA Hu sheep by regulating rumen pH, inhibiting muscle oxidative stress and promoting lipid metabolism.

Bioenergetic State of Escherichia coli Controls Aminoglycoside Susceptibility.

Aminoglycosides (AG) have been used against Gram-negative bacteria for decades. Yet, how bacterial metabolism and environmental conditions modify AG toxicity is poorly understood. Here, we show that the level of AG susceptibility varies depending on the nature of the respiratory chain that Escherichia coli uses for growth, i.e., oxygen, nitrate, or fumarate. We show that all components of the fumarate respiratory chain, namely, hydrogenases 2 and 3, the formate hydrogenlyase complex, menaquinone, and fumarate reductase are required for AG-mediated killing under fumarate respiratory conditions. In addition, we show that the AAA+ ATPase RavA and its Von Wildebrand domain-containing partner, ViaA, are essential for AG to act under fumarate respiratory conditions. This effect was true for all AG that were tested but not for antibiotics from other classes. In addition, we show that the sensitizing effect of RavA-ViaA is due to increased gentamicin uptake in a proton motive force-dependent manner. Interestingly, the sensitizing effect of RavA-ViaA was prominent in poor energy conservation conditions, i.e., with fumarate, but dispensable under high energy conservation conditions, i.e., in the presence of nitrate or oxygen. We propose that RavA-ViaA can facilitate uptake of AG across the membrane in low-energy cellular states. IMPORTANCE Antibiotic resistance is a major public health, social, and economic problem. Aminoglycosides (AG) are known to be highly effective against Gram-negative bacteria, but their use is limited to life-threatening infections because of their nephrotoxicity and ototoxicity at therapeutic dose. Elucidation of AG-sensitization mechanisms in bacteria would allow reduced effective doses of AG. Here, we have identified the molecular components involved in anaerobic fumarate respiration that are required for AG to kill. In addition to oxidoreductases and menaquinone, this includes new molecular players, RavA, an AAA+ ATPase, and ViaA, its partner that has the VWA motif. Remarkably, the influence of RavA-ViaA on AG susceptibility varies according to the type of bioenergetic metabolism used by E. coli. This is a significant advance because anaerobiosis is well known to reduce the antibacterial activity of AG. This study highlights the critical importance of the relationship between culture conditions, metabolism, and antibiotic susceptibility.

Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes.

BACKGROUND: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. METHODS: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. RESULTS: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR. CONCLUSIONS: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.

[The preliminary application of vonoprazan fumarate on laryngopharyngeal reflux disease].

Objective: To evaluate the clinical effect of vonoprazan fumarate on laryngopharyngeal reflux disease (LPRD). Methods: The clinical data of 89 patients from June 2020 to January 2022, including 45 males and 44 females, aged 18-77 (45.54±13.53) years old, were retrospectively analyzed. All the patients were diagnosed as suspected LPRD according to reflux symptom index (RSI) and reflux finding score (RFS). Patients of the Vonoprazan Fumarate group were prescribed Vonoprazan Fumarate orally (20 mg, qd) for 8 weeks.Patients of the Esomeprazole group were prescribed Esomeprazole orally (20 mg, bid) for 8 weeks. RSI and RFS of all the patients before and after treatment were compared. SPSS 18.0 was used for statistics analysis. Results: Before treatment, gender, age, RSI and RFS of the two groups had no obvious differences. After treatment, RSI and RFS in both groups were alleviated significantly. In the vonorazan fumarate group, the RSI before treatment was 12.62±7.18, and after treatment was 4.74±3.87(t=6.91, P<0.001), the RFS was 10.78±2.29 before treatment and 8.24±2.45 after treatment (t=7.06, P<0.001). While in the esomeprazole group, the RSI was 13.27±6.95 before treatment and 6.02±4.28 after treatment (t=7.50, P<0.001), the RFS was 10.59±3.14 before treatment and 8.14±3.30 after treatment (t=5.41, P<0.001). There was no significant difference in the effective rate between the two groups (86.7% in the vonoprazan fumarate group and 77.3% in the esomeprazole group, χ2=1.443, P=0.486). Conclusion: Vonoprazan fumarate could effectively alleviate the symptoms and signs of LPRD patients. The effect of vonoprazan fumarate on LPRD is not inferior to Esomeprazole. It can be used as a supplement to PPI.

Cost-Effectiveness Analysis of Triple Therapy with Budesonide/ Glycopyrronium/ Formoterol Fumarate versus Dual Therapy in Patients with Chronic Obstructive Pulmonary Disease in Spain.

Objective: To evaluate the cost-effectiveness of Budesonide/Glycopyrronium/Formoterol (BUD/GLY/FOR) versus LAMA/LABA and ICS/LABA, respectively, in patients with moderate to severe COPD, from the Spanish National Healthcare System (NHS) perspective. Methods: A lifetime Markov model with monthly cycle length was developed with baseline and treatment effect data from ETHOS clinical trial, together with utility values from literature and Spanish healthcare resource costs (€, 2021). A 3% annual discount rate was used for costs and benefits. The model comprised ten health states: nine forced expiratory volume in 1 second (FEV1)-related, which were divided by three levels of severity: moderate (FEV1 ≥50% and <80%); severe (FEV1 ≥30% and <50%) and very severe (FEV1 <30%) and a death state. Each FEV1-health state was divided into no exacerbation, moderate exacerbation, and severe exacerbations. An expert panel validated data and assumptions. Outcomes were measured as incremental cost per exacerbation avoided, per life year (LY) gained, and per quality-adjusted life-year (QALY) gained (ICUR). One-way (OWSA), scenario, and probabilistic sensitivity analyses (PSA) were performed. Results: According to this cost-effectiveness analysis based on a Markov model, BUD/GLY/FOR was associated with a lower totals exacerbation per patient (12.80) compared to LAMA/LABA (13.36) and ICS/LABA (13.23) and higher LYs (10.32 vs 10.14 and 10.06, respectively) and QALYs (7.55 vs 7.41 and 7.32, respectively). The incremental costs were €850.95, and €2422.26, respectively, per exacerbation avoided, €2733.38 and €4111.15, respectively, per LY gained and €3461.19 and €4545.24 per QALY gained. OWSA showed that the model was most sensitive to the costs of treatments following discontinuation, but the ICUR remained below the cost-effectiveness threshold of €25,000 per QALY gained. In the PSA, the probability of BUD/GLY/FOR being cost-effective was 91.32% vs LAMA/LABA and 99.29% vs ICS/LABA. Conclusion: BUD/GLY/FOR is a cost-effective treatment strategy for Spanish NHS patients with COPD compared to dual therapies.

Metabolic and Microbial Community Engineering for Four-Carbon Dicarboxylic Acid Production from CO2-Derived Glycogen in the Cyanobacterium Synechocystis sp. PCC6803.

The four-carbon (C4) dicarboxylic acids, fumarate, malate, and succinate, are the most valuable targets that must be exploited for CO2-based chemical production in the move to a sustainable low-carbon future. Cyanobacteria excrete high amounts of C4 dicarboxylic acids through glycogen fermentation in a dark anoxic environment. The enhancement of metabolic flux in the reductive TCA branch in the Cyanobacterium Synechocystis sp. PCC6803 is a key issue in the C4 dicarboxylic acid production. To improve metabolic flux through the anaplerotic pathway, we have created the recombinant strain PCCK, which expresses foreign ATP-forming phosphoenolpyruvate carboxykinase (PEPck) concurrent with intrinsic phosphoenolpyruvate carboxylase (Ppc) overexpression. Expression of PEPck concurrent with Ppc led to an increase in C4 dicarboxylic acids by autofermentation. Metabolome analysis revealed that PEPck contributed to an increase in carbon flux from hexose and pentose phosphates into the TCA reductive branch. To enhance the metabolic flux in the reductive TCA branch, we examined the effect of corn-steep liquor (CSL) as a nutritional supplement on C4 dicarboxylic acid production. Surprisingly, the addition of sterilized CSL enhanced the malate production in the PCCK strain. Thereafter, the malate and fumarate excreted by the PCCK strain are converted into succinate by the CSL-settling microorganisms. Finally, high-density cultivation of cells lacking the acetate kinase gene showed the highest production of malate and fumarate (3.2 and 2.4 g/L with sterilized CSL) and succinate (5.7 g/L with non-sterile CSL) after 72 h cultivation. The present microbial community engineering is useful for succinate production by one-pot fermentation under dark anoxic conditions.

Redox Brake Regulator RedB and FnrL Function as Yin-Yang Regulators of Anaerobic-Aerobic Metabolism in Rhodobacter capsulatus.

We recently described a new member of the CRP (cyclic AMP receptor protein)/FNR (fumarate and nitrate reductase regulatory protein) family called RedB, an acronym for redox brake, that functions to limit the production of ATP and NADH. This study shows that the RedB regulon significantly overlaps the FnrL regulon, with 199 genes being either directly or indirectly regulated by both of these global regulatory proteins. Among these 199 coregulated genes, 192 are divergently regulated, indicating that RedB functions as an antagonist of FnrL. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis indicates that RedB and Fnr directly coregulate only 4 out of 199 genes. The primary mechanism for the divergent regulation of target genes thus involves indirect regulation by both RedB and FnrL (156 cases). Additional regulation involves direct binding by RedB and indirect regulation by FnrL (36 cases) or direct binding by FnrL and indirect regulation by RedB (3 cases). Analysis of physiological pathways under direct and indirect control by these global regulators demonstrates that RedB functions primarily to limit energy production, while FnrL functions to enhance energy production. This regulation includes glycolysis, gluconeogenesis, photosynthesis, hydrogen oxidation, electron transport, carbon fixation, lipid biosynthesis, and protein synthesis. Finally, we show that 75% of genomes from diverse species that code for RedB proteins also harbor genes coding for FNR homologs. This cooccurrence indicates that RedB likely has an important role in buffering FNR-mediated energy production in a broad range of species. IMPORTANCE The CRP/FNR family of regulatory proteins constitutes a large collection of related transcription factors, several of which globally regulate cellular energy production. A well-characterized example is FNR (called FnrL in Rhodobacter capsulatus), which is responsible for regulating the expression of numerous genes that promote maximal energy production and growth under anaerobic conditions. In a companion article (N. Ke, J. E. Kumka, M. Fang, B. Weaver, et al., Microbiol Spectr 10:e02353-22, 2022, https://doi.org/10.1128/Spectrum02353-22), we identified a new subgroup of the CRP/FNR family and demonstrated that a member of this new subgroup, called RedB, has a role in limiting cellular energy production. In this study, we show that numerous genes encompassing the RedB regulon significantly overlap genes that are members of the FnrL regulon. Furthermore, 97% of the genes that are members of both the RedB and FnrL regulons are divergently regulated by these two transcription factors. RedB thus functions as a buffer limiting the amount of energy production that is promoted by FnrL.

Peptide supplementation relieves stress and enhances glycolytic flux in filamentous fungi during organic acid bioproduction.

Filamentous fungi occupy a uniquely favorable position in the bioproduction of organic acids. Intracellular stress is the main stimulator in filamentous fungi to produce and accumulate organic acids with high flux. However, stress can affect the physiological activities of filamentous fungi, thereby deteriorating their fermentation performance. Herein, we report that peptide supplementation during Rhizopus oryzae fermentation significantly improved fumaric acid production. Specifically, fumaric acid productivity was elevated by approximately 100%, fermentation duration was shortened from 72 to 36 h, while maintaining the final titer. Furthermore, transcriptome profile analysis and biochemical assays indicated that the overall capabilities of the stress defense systems (enzymatic and nonenzymatic) were significantly improved in R. oryzae. Consequently, glycolytic metabolism was distinctly enhanced, which eventually resulted in improved fumaric acid production and reduced fermentation duration. We expect our findings and efforts to provide essential insights into the optimization of the fermentation performance of filamentous fungi in industrial biotechnology and fermentation engineering.

Efficacy and Safety of Rupatadine Fumarate Combined with Acupoint Application in Allergic Rhinitis Complicated with Diabetes.

The prevalence of allergic rhinitis has exhibited an upward trend, and diabetes is a common endocrine metabolic disorder. Treatment of allergic rhinitis complicated with diabetes has been marginally explored. This study aimed to observe the effect of rupatadine fumarate combined with acupoint application in the treatment of allergic rhinitis complicated with diabetes and its effect on serum IgE levels. Totally 80 patients with allergic rhinitis complicated with diabetes admitted to our hospital from December 2019 to December 2020 were recruited and assigned to receive either rupatadine fumarate (control group) or rupatadine fumarate plus acupoint application (research group). The clinical observation indexes of the two groups of patients before and after treatment were analyzed, and the clinical efficacy of the two groups was evaluated. Rupatadine fumarate plus acupoint application was associated with a significantly higher efficacy (23 cases of markedly effective, 14 cases of effective, and 3 cases of ineffective) versus rupatadine fumarate alone (14 cases of markedly effective, 16 cases of effective, and 10 cases of ineffective) (χ 2 = 4.501, p = 0.034). The immunoglobulin E (IgE) and nasal mucosal eosinophils (EOS) levels of the two groups of patients after treatment decreased significantly, and the research group had lower results (p < 0.05). Patients in the research group showed significantly lower syndrome scores than those in the control group (p < 0.05). Rupatadine fumarate plus acupoint application resulted in significantly lower physical sign scores and interleukin-4 (IL-4) levels and higher levels of interferon-gamma (INF-γ) versus rupatadine fumarate alone (p < 0.05). The two groups showed a similar incidence of adverse events (p > 0.05). Rupatadine fumarate plus acupoint application may offer a viable alternative for the treatment of allergic rhinitis as it alleviates the clinical symptoms, improves the treatment efficiency, and enhances the anti-allergic effect of the drug, with a high safety profile.

Economic Evaluation of Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate for the Treatment of Moderate to Very Severe Chronic Obstructive Pulmonary Disease in China Using a Semi-Markov Model.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease with considerable clinical and socioeconomic impact. Budesonide/glycopyrrolate/formoterol fumarate (BGF) is a newly approved pharmacotherapy for COPD in China that has been shown to improve lung function and reduce the risk of exacerbations, but the cost-effectiveness of BGF remains unknown. The objective of this study was to evaluate the cost-effectiveness of BGF in patients with moderate to very severe COPD from a Chinese healthcare system perspective. METHODS: A semi-Markov model was developed to compare the costs and benefit of treatment with BGF versus a composite comparator of long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) therapies. Clinical inputs for BGF and the composite comparator were based on the KRONOS study (NCT02497001) and a network meta-analysis. Cost inputs were derived from published literature and Chinese government documents, supplemented by expert opinion where necessary. Health-related quality-of-life inputs were also obtained based on the KRONOS study. Lifetime costs, number of exacerbations, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. Costs were measured in 2020 Chinese Yuan (CN¥) and converted into US dollars (US$). Scenario analyses and sensitivity analyses were conducted. RESULTS: Over the lifetime horizon, BGF treatment led to fewer moderate and severe exacerbations (4.01 and 0.87, respectively) versus the composite comparator (8.42 and 2.04, respectively), with a base-case ICER of CN¥13,685.94 (US$1983.47) per QALY gained. Scenario analyses considering different population and utilities resulted in ICERs ranging from dominant to CN¥13,673.91 (US$1981.73). Extensive sensitivity analyses indicated robust base-case results since all analyses yielded ICERs below the conservative cost-effectiveness threshold of one times the Chinese per capita gross domestic product (CN¥72,447.00 [US$10,499.57], 2020). CONCLUSION: Triple therapy with BGF was predicted to improve outcomes and be a cost-effective treatment option compared with LAMA/LABA therapies for patients with moderate to very severe COPD in China.

Comorbidity and Therapeutic Approaches in Patients with Necrobiosis Lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease. OBJECTIVES: We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy. MATERIALS AND METHODS: Comorbidity and the efficacy of the applied treatment was assessed for 98 patients. RESULTS: We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy. CONCLUSION: Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.

Unconventional treatment options in psoriasis: A review.

Psoriasis is a common skin disease that affects 1-3% of the general population. The treatment depends on body surface area involved, quality of life impairment and associated comorbidities. The treatment options include topical therapy, phototherapy, conventional systemic therapy (methotrexate, cyclosporine and acitretin), biologics and oral small molecules (apremilast and tofacitinib). Despite the availability of newer therapies such as biologics and oral small molecules, many a time, there is a paucity of treatment options due to the chronic nature of the disease, end-organ toxicity of the conventional drugs or high cost of newer drugs. In these scenarios, unconventional treatment options may be utilized as stand-alone or adjuvant therapy. In this review, we have discussed these uncommonly used treatment options in the management of psoriasis.

Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial.

BACKGROUND: Fumaric acid esters (FAEs; Fumaderm® ) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi® ) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. OBJECTIVES: To compare risankizumab treatment to FAEs in patients with psoriasis. METHODS: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. RESULTS: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. CONCLUSIONS: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

Uptake of Encapsulated Ferrous Fumarate Double Fortified Salt in the Public Distribution System in India: A Value Chain Analysis.

Food fortification is a powerful strategy to reach large populations with multiple micronutrients added to a single food vehicle. The impact depends on the sustained provision and utilization of adequately fortified food by a large population (mainly in low-income and food-insecure settings). We apply a value chain (VC) analysis framework to diagnose and address the barriers to the uptake of encapsulated ferrous fumarate double fortified salt (DFS) distributed through public-sector-led DFS interventions in India.We adapt the VC requirements framework proposed by Henson and Humphrey to identify and categorize barriers along the DFS VC as technological, market-related, and policy-related. We conducted a desk review of published and unpublished literature on DFS and information available in the public domain, semi-structured interviews with VC stakeholders from the private sector, program data from implementing organizations, and participation in multistakeholder consultations on DFS.Major supply-side barriers were under-developed private markets, inconsistent demand from public markets, unpredictable returns-on-investments, and inadequate business incentives to invest in DFS. The product's weak consumer orientation, uncreated consumer demand, low awareness of fortified foods, inadequate nutrition signaling were significant demand-side barriers. Technological barriers related to the requirement of high-grade salt for DFS production and residual organoleptic property of mild discoloration of food. Policy barriers related to inadequate and irregular financing for distributing subsidized DFS through the public distribution system; insufficient policy support for risk-sharing and managing costs associated with fortification; and a weak institutional environment for sustaining DFS interventions.Building an enabling institutional environment, demand creation through consumer awareness, strengthening institutional markets through public financing, managing cost and risks through public-private partnerships, and assuring quality during commercial scale-up are critical interventions necessary to ensure impact at scale.

Use of fumaric acid as a feed additive in quail's nutrition: its effect on growth rate, carcass, nutrient digestibility, digestive enzymes, blood metabolites, and intestinal microbiota.

To investigate the effects of dietary fumaric acid (FUA) on performance, carcasses, nutrient digestibility, blood metabolites, digestive enzymes, and cecal microbiota in Japanese quail chicks. Three hundred unsexed Japanese quail (1-wk-old) were randomly assigned to 5 groups. Supplementation of FUA in the diet of Japanese quail chicks exhibited a significant improvement in growth performance through the different experimental periods studied compared with those receiving unsupplemented one. The digestibility of crude protein (CP) and metabolizable energy (ME) were improved with 10 and 15 g/kg FUA, respectively. Apart from lipase enzyme, birds fed 5 and 15 g/kg FUA recorded higher activity of amylase. There were no significant changes among experimental groups on the relative weights of carcass, gizzard, heart, and dressing. Dietary supplementation of FUA at different levels (P> 0.05) increased total protein (TP) and globulin (GLB) concentrations and A/G % compared with control group. A significant (P < 0.01) decrease in plasma low density lipoprotein (LDL) and total cholesterol (TC) levels and increase in high density lipoprotein (HDL) concentrations were observed in chicks fed with FUA containing diets. Immunoglobulin G (IgG) (P = 0.0026) and M (IgM) (P = 0.0007) levels were greater in groups treated with either 10 or 15 g FUA/kg diet. A significant increase in plasma Ca concentration was noticed in chicks received 15 g FUA/ kg compared with the other groups. Quail chicks received diets containing FUA at different levels exhibited reduced cecal count of coliform, E. coli, and Salmonella as compared with control group. In conclusion, supplementation of fumaric acid (especially 15 g/kg diet) in quail chick diets improved their growth, digestibility of nutrients, immune response, antioxidant status, digestive enzyme, and intestinal health.