The Cost Effectiveness of Levodopa-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson's Disease in England.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disease, which significantly impacts patients' quality of life and is associated with high treatment and direct healthcare costs. In England, levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of levodopa-responsive advanced Parkinson's disease with troublesome motor fluctuations when available combinations of medicinal products are unsatisfactory. OBJECTIVE: We aimed to determine the cost effectiveness of LCIG compared to the standard of care for patients with advanced Parkinson's disease in England, using real-world data. METHODS: A Markov model was adapted from previous published studies, using the perspective of the English National Health System and Personal and Social Services to evaluate the cost effectiveness of LCIG compared to standard of care in patients with advanced Parkinson's disease over a 20-year time horizon. The model comprised 25 health states, defined by a combination of the Hoehn and Yahr scale, and waking time spent in OFF-time. The base case considered an initial cohort of patients with an Hoehn and Yahr score of ≥ 3, and > 4 h OFF-time. Standard of care comprised standard oral therapies, and a proportion of patients were assumed to be treated with subcutaneous apomorphine infusion or injection in addition to oral therapies. Efficacy inputs were based on LCIG clinical trials where possible. Resource use and utility values were based on results of a large-scale observational study, and costs were derived from the latest published UK data, valued at 2017 prices. The EuroQol five-dimensions-3-level (EQ-5D-3L) instrument was used to measure utilities. Costs and quality-adjusted life-years were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Total costs and quality-adjusted life-years gained for LCIG vs standard of care were £586,832 vs £554,022, and 2.82 vs 1.43, respectively. The incremental cost-effectiveness ratio for LCIG compared to standard of care was £23,649/quality-adjusted life-year. Results were sensitive to the healthcare resource utilisation based on real-world data, and long-term efficacy of LCIG. CONCLUSIONS: The base-case incremental cost-effectiveness ratio was estimated to be within the acceptable thresholds for cost effectiveness considered for England.

Enhanced recovery programmes versus conventional care in bariatric surgery: A systematic literature review and meta-analysis.

BACKGROUND: With obesity prevalence projected to increase, the demand for bariatric surgery will consequently rise. Enhanced recovery programmes aim for improved recovery, earlier discharge, and more efficient use of resources following surgery. This systematic literature review aimed to evaluate the evidence available on the effects of enhanced recovery programmes after three common bariatric procedures: laparoscopic Roux-en-Y gastric bypass (LRYGB), laparoscopic sleeve gastrectomy (LSG), and one anastomosis gastric bypass (OAGB). METHODS: MEDLINE, Embase, the Cochrane Library and the National Health Service Economic Evaluation Database were searched for studies published in 2012-2019 comparing outcomes with enhanced recovery programmes versus conventional care after bariatric surgery in Europe, the Middle East and Africa. Data were extracted and meta-analyses or descriptive analyses performed when appropriate using R. RESULTS: Of 1152 screened articles, seven relevant studies including 3592 patients were identified. Six reported outcomes for 1434 patients undergoing LRYGB; however, as only individual studies reported on LSG and OAGB these could not be included in the analyses. The meta-analysis revealed a significantly shorter mean duration of hospital-stay for LRYGB enhanced recovery programmes than conventional care (mean difference [95% CI]: -1.34 days [-2.01, -0.67]; p<0.0001), supported by sensitivity analysis excluding retrospective studies. Meta-analysis found no significant difference in 30-day readmission rate (risk ratio [95% CI]: 1.39 [0.84, 2.28]; p = 0.2010). Complication rates were inconsistently reported by Clavien-Dindo grade, but descriptive analysis showed generally higher low-grade rates for enhanced recovery programmes; the trend reversed for high-grade complications. Reoperation rates were rarely reported; no significant differences were seen. CONCLUSION: These results support enhanced recovery programmes allowing shorter inpatient stay without significant differences in readmission rate following LRYGB, although complication and reoperation rate comparisons were inconclusive. Further research is needed to fill current data gaps including the lack of studies on LSG and OAGB.

Focused Ultrasound Thalamotomy and Other Interventions for Medication-Refractory Essential Tremor: An Indirect Comparison of Short-Term Impact on Health-Related Quality of Life.

BACKGROUND: Up to 50% of essential tremor patients are refractory to medication and require alternative treatment to achieve tremor relief. This study aimed to identify and analyze evidence supporting the use of the emerging magnetic resonance-guided focused ultrasound (MRgFUS) compared to alternative stimulatory and ablative interventions for the treatment of medication-refractory essential tremor: radiofrequency thalamotomy, unilateral deep brain stimulation (DBS), and stereotactic radiosurgery. METHODS: A systematic literature review was conducted to identify clinical, health-related quality of life (HRQoL), and economic evidence for each intervention. Because of the lack of comparative evidence captured, a feasibility assessment was performed to determine possible comparisons between interventions, and newly established matching-adjusted indirect comparison and simulated treatment comparison techniques were used to conduct a comparison between unilateral DBS aggregate data and MRgFUS individual patient data. RESULTS: The systematic literature review identified 1,559 records, and screening yielded 46 relevant articles. The captured studies demonstrated that radiofrequency thalamotomy, DBS, stereotactic radiosurgery, and MRgFUS all exhibit clinical efficacy, with variation in onset and duration of tremor relief, and are each associated with a unique safety profile. The matching-adjusted indirect comparison and simulated treatment comparison results demonstrated no evidence of a difference in efficacy (measured by Clinical Rating Scale for Tremor Total) and HRQoL (measured by Clinical Rating Scale for Tremor Part C) outcomes between MRgFUS and unilateral DBS in the short term (≤12 months). CONCLUSIONS: This study provides preliminary evidence that MRgFUS could elicit similar short-term tremor- and HRQoL-related benefits to DBS, the current standard of care, and allowed for the first robust statistical comparison between these interventions.

Cryopreservation studies of an artificial co-culture between the cobalamin-requiring green alga Lobomonas rostrata and the bacterium Mesorhizobium loti.

Algal-bacterial co-cultures, rather than cultures of algae alone, are regarded as having the potential to enhance productivity and stability in industrial algal cultivation. As with other inocula in biotechnology, to avoid loss of production strains, it is important to develop preservation methods for the long-term storage of these cultures, and one of the most commonly used approaches is cryopreservation. However, whilst there are many reports of cryopreserved xenic algal cultures, little work has been reported on the intentional preservation of both algae and beneficial bacteria in xenic cultures. Instead, studies have focused on the development of methods to conserve the algal strain(s) present, or to avoid overgrowth of bacteria in xenic isolates during the post-thaw recovery phase. Here, we have established a co-cryopreservation method for the long-term storage of both partners in a unialgal-bacterial co-culture. This is an artificial model mutualism between the alga Lobomonas rostrata and the bacterium Mesorhizobium loti, which provides vitamin B12 (cobalamin) to the alga in return for photosynthate. Using a Planer Kryo 360 controlled-rate cooler, post-thaw viability (PTV) values of 72% were obtained for the co-culture, compared to 91% for the axenic alga. The cultures were successfully revived after 6 months storage in liquid nitrogen, and continued to exhibit mutualism. Furthermore, the alga could be cryopreserved with non-symbiotic bacteria, without bacterial overgrowth occurring. It was also possible to use less controllable passive freezer chambers to cryopreserve the co-cultures, although the PTV was lower. Finally, we demonstrated that an optimised cryopreservation method may be used to prevent the overgrowth potential of non-symbiotic, adventitious bacteria in both axenic and co-cultures of L. rostrata after thawing.

SMAD4-dependent polysome RNA recruitment in human pancreatic cancer cells.

Pancreatic cancer is the fourth leading cause of cancer death in the United States because most patients are diagnosed too late in the course of the disease to be treated effectively. Thus, there is a pressing need to more clearly understand how gene expression is regulated in cancer cells and to identify new biomarkers and therapeutic targets. Translational regulation is thought to occur primarily through non-SMAD directed signaling pathways. We tested the hypothesis that SMAD4-dependent signaling does play a role in the regulation of mRNA entry into polysomes and that novel candidate genes in pancreatic cancer could be identified using polysome RNA from the human pancreatic cancer cell line BxPC3 with or without a functional SMAD4 gene. We found that (i) differentially expressed whole cell and cytoplasm RNA levels are both poor predictors of polysome RNA levels; (ii) for a majority of RNAs, differential RNA levels are regulated independently in the nucleus, cytoplasm, and polysomes; (iii) for most of the remaining polysome RNA, levels are regulated via a "tagging" of the RNAs in the nucleus for rapid entry into the polysomes; (iv) a SMAD4-dependent pathway appears to indeed play a role in regulating mRNA entry into polysomes; and (v) a gene list derived from differentially expressed polysome RNA in BxPC3 cells generated new candidate genes and cell pathways potentially related to pancreatic cancer.

Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet.

BACKGROUND: Obesity is a growing worldwide problem with genetic and environmental causes, and it is an underlying basis for many diseases. Studies have shown that the toxicant-activated aryl hydrocarbon receptor (AHR) may disrupt fat metabolism and contribute to obesity. The AHR is a nuclear receptor/transcription factor that is best known for responding to environmental toxicant exposures to induce a battery of xenobiotic-metabolizing genes. OBJECTIVES: The intent of the work reported here was to test more directly the role of the AHR in obesity and fat metabolism in lieu of exogenous toxicants. METHODS: We used two congenic mouse models that differ at the Ahr gene and encode AHRs with a 10-fold difference in signaling activity. The two mouse strains were fed either a low-fat (regular) diet or a high-fat (Western) diet. RESULTS: The Western diet differentially affected body size, body fat:body mass ratios, liver size and liver metabolism, and liver mRNA and miRNA profiles. The regular diet had no significant differential effects. CONCLUSIONS: The results suggest that the AHR plays a large and broad role in obesity and associated complications, and importantly, may provide a simple and effective therapeutic strategy to combat obesity, heart disease, and other obesity-associated illnesses.

Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice.

Little is known of the environmental factors that initiate and promote disease. The aryl hydrocarbon receptor (AHR) is a key regulator of xenobiotic metabolism and plays a major role in gene/environment interactions. The AHR has also been demonstrated to carry out critical functions in development and disease. A qualitative investigation into the contribution by the AHR when stimulated to different levels of activity was undertaken to determine whether AHR-regulated gene/environment interactions are an underlying cause of cardiovascular disease. We used two congenic mouse models differing at the Ahr gene, which encodes AHRs with a 10-fold difference in signaling potencies. Benzo[a]pyrene (BaP), a pervasive environmental toxicant, atherogen, and potent agonist for the AHR, was used as the environmental agent for AHR activation. We tested the hypothesis that activation of the AHR of different signaling potencies by BaP would have differential effects on the physiology and pathology of the mouse cardiovascular system. We found that differential AHR signaling from an exposure to BaP caused lethality in mice with the low-affinity AHR, altered the growth rates of the body and several organs, induced atherosclerosis to a greater extent in mice with the high-affinity AHR, and had a huge impact on gene expression of the aorta. Our studies also demonstrated an endogenous role for AHR signaling in regulating heart size. We report a gene/environment interaction linking differential AHR signaling in the mouse to altered aorta gene expression profiles, changes in body and organ growth rates, and atherosclerosis.

Engineered biosynthesis of the antiparasitic agent frenolicin B and rationally designed analogs in a heterologous host.

The polyketide antibiotic frenolicin B harbors a biosynthetically intriguing benzoisochromanequinone core, and has been shown to exhibit promising antiparasitic activity against Eimeria tenella. To facilitate further exploration of its chemistry and biology, we constructed a biosynthetic route to frenolicin B in the heterologous host Streptomyces coelicolor CH999, despite the absence of key enzymes in the identified frenolicin gene cluster. Together with our understanding of the underlying polyketide biosynthetic pathway, this heterologous production system was exploited to produce analogs modified at the C15 position. Both the natural product and these analogs inhibited the growth of Toxoplasma gondii in a manner that reveals sensitivity to the length of the C15 substituent. The ability to construct a functional biosynthetic pathway, despite a lack of genetic information, illustrates the feasibility of a modular approach to engineering medicinally relevant polyketide products.

Differential regulation of polysome mRNA levels in mouse Hepa-1C1C7 cells exposed to dioxin.

The environmental agent 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) causes a multitude of human illnesses. In order to more fully understand the underlying biology of TCDD toxicity, we tested the hypothesis that new candidate genes could be identified using polysome RNA from TCDD-treated mouse Hepa-1c1c7 cells. We found that (i) differentially expressed whole cell and cytoplasm RNA levels are both poor predictors of polysome RNA levels; (ii) for a majority of RNAs, differential RNA levels are regulated independently in the nucleus, cytoplasm, and polysomes; (iii) for the remaining polysome RNAs, levels are regulated via several different mechanisms, including a "tagging" of mRNAs in the nucleus for immediate polysome entry; and (iv) most importantly, a gene list derived from differentially expressed polysome RNA generated new genes and cell pathways potentially related to TCDD biology.

Cloning, sequencing, heterologous expression, and mechanistic analysis of A-74528 biosynthesis.

A-74528 is a recently discovered natural product of Streptomyces sp. SANK 61196 that inhibits 2',5'-oligoadenylate phosphodiesterase (2'-PDE), a key regulatory enzyme of the interferon pathway. Inhibition of 2'-PDE by A-74528 reduces viral replication, and therefore shows promise as a new type of antiviral drug. The complete A-74528 gene cluster, comprising 29 open reading frames, was cloned and sequenced, and shown to possess a type II polyketide synthase (PKS) at its core. Its identity was confirmed by analysis of a mutant generated by targeted disruption of a PKS gene, and by functional expression in a heterologous Streptomyces host. Remarkably, it showed exceptional end-to-end sequence identity to the gene cluster responsible for biosynthesis of fredericamycin A, a structurally unrelated antitumor antibiotic with a distinct mode of action. Whereas the fredericamycin producing strain, Streptomyces griseus, produced undetectable quantities of A-74528, the A-74528 gene cluster was capable of producing both antibiotics. The biosynthetic roles of three genes, including one that represents the only qualitative difference between the two gene clusters, were investigated by targeted gene disruption. The implications for the evolution of antibiotics with different biological activities from the same gene cluster are discussed.

Evolution of polyketide synthases in bacteria.

The emergence of resistant strains of human pathogens to current antibiotics, along with the demonstrated ability of polyketides as antimicrobial agents, provides strong motivation for understanding how polyketide antibiotics have evolved and diversified in nature. Insights into how bacterial polyketide synthases (PKSs) acquire new metabolic capabilities can guide future laboratory efforts in generating the next generation of polyketide antibiotics. Here, we examine phylogenetic and structural evidence to glean answers to two general questions regarding PKS evolution. How did the exceptionally diverse chemistry of present-day PKSs evolve? And what are the take-home messages for the biosynthetic engineer?

Synthesis and biological activity of novel pyranopyrones derived from engineered aromatic polyketides.

The 4-hydroxy-2-pyrone moiety is commonly observed in polyketides generated via biosynthetic engineering of type II polyketide synthases. To explore the synthetic utility of these 2-pyrones, four engineered polyketides (mutactin, SEK4, SEK15, and SEK15b) were isolated from appropriate derivatives of Streptomyces coelicolor CH999. As a test case, we prepared nine novel pyranopyrones through condensation reactions with either citral, 1-cyclohexene-carboxaldehyde, or S-perillaldehyde. Synthetic tricyclic pyranopyrones with simple aromatic substituents are known to possess anticancer properties. We therefore investigated whether pyranopyrone derivatives of aromatic polyketides exhibited bioactivity in a panel of three cancer cell lines. Pyranopyrones generated from SEK4 had activity comparable to that of H10, a pyranopyrone with a 3-pyridyl substituent, whereas other analogues were less active. These results suggest that the diverse library of carbo- and heterocycles available through the genetic engineering of type II polyketide synthases can serve as useful building blocks to generate unique bioactive molecules.

Investigation of Oscillatoria spongeliae-dominated bacterial communities in four dictyoceratid sponges.

Certain species of marine sponges in the order Dictyoceratida harbor large populations of the cyanobacterial symbiont Oscillatoria spongeliae in the mesohyl (interior) of the sponge. We show that in four of these sponge species (Lamellodysidea herbacea, Lamellodysidea chlorea, Lendenfeldia chondrodes, and Phyllospongia papyracea) from Palau there is a consistent community of alpha-proteobacteria in addition to O. spongeliae that fall within the Rhodobacter group based on 16S rRNA gene analysis. Some of the alpha-proteobacteria in Lendenfeldia chondrodes and P. papyracea but not in the Lamellodysidea spp. contained site-specific insertions in the 16S rRNA gene. Reverse transcription-PCR experiments demonstrated that the largest insertion found in this study (63 bp) is present in the mature rRNA. Lendenfeldia chondrodes was the only sponge found to have another cyanobacterium in the tissue, a Synechocystis sp. We found that the Synechocystis sp. was present in both the pinacoderm (surface epithelial tissue) and mesohyl, in contrast to O. spongeliae, which was only found in the mesohyl through the use of specific fluorescence in situ hybridization experiments. Of the four sponge species, only P. papyracea was found to contain a significant number of gamma-proteobacteria. These results demonstrate that O. spongeliae-dominated bacterial communities in different sponge species can vary considerably and increase our understanding of the bacterial communities found in marine invertebrates.

Speciation and biosynthetic variation in four dictyoceratid sponges and their cyanobacterial symbiont, Oscillatoria spongeliae.

Four species of marine sponges (Phylum Porifera, Order Dictyoceratida), which contain the filamentous cyanobacterial symbiont Oscillatoria spongeliae, were collected from four locations in Palau. The halogenated natural products associated with the symbiont were characterized from each sample, revealing that each species contained either chlorinated peptides, brominated diphenyl ethers, or no halogenated compounds. Analysis of the host sponges and the symbionts indicated that each species of sponge contained a distinct strain of morphologically similar cyanobacteria. Although cospeciation may be present in this group, we have identified that at least one host switching event has occurred in this symbiosis. Only the strain of O. spongeliae in the sponge containing the chlorinated compounds possessed genes involved in the biosynthesis of chlorinated leucine precursors, indicating that the chemical variation observed in these animals has a genetic foundation.

Approaches to identify, clone, and express symbiont bioactive metabolite genes.

This review discusses approaches to identify, clone, and express bioactive metabolite genes from symbionts of marine invertebrates. Criteria for proving symbiotic origin of bioactive metabolites are presented, followed by a comprehensive, practically-oriented overview of techniques to be applied. The Bugula neritina/Endobugula sertula association is used as a primary example, but other symbioses are discussed. Thirty-six compounds are presented and 111 references are cited.

New cytotoxic steroidal alkaloids from the Philippine sponge Corticium niger.

Four new steroidal alkaloids, plakinamine I-K (1-3) and dihydroplakinamine K (4), were isolated from the marine sponge Corticium niger. The structures of these compounds were elucidated by interpretation of spectroscopic data. Compounds 1-4 exhibit significant in vitro cytotoxicity.

Total synthesis and evaluation of lamellarin alpha 20-Sulfate analogues.

In order to explore the influence of sulfate groups on the bioactivity profiles of marine alkaloids of the lamellarin class, three such alkaloids, lamellarin alpha, lamellarin alpha 13,20-disulfate and lamellarin H, were synthesized and their activities against HIV-1 integrase and cancer cell lines were compared with those of lamellarin alpha 20-sulfate, which is a selective inhibitor of HIV-1 integrase. Lamellarin alpha does not inhibit HIV-1 integrase but shows moderate cytotoxicity with good cell line selectivity. Lamellarin alpha 13,20-disulfate is a moderate inhibitor of both HIV-1 integrase and cancer cell lines. Lamellarin H is a more potent inhibitor of HIV-1 integrase but lacked the specificity required to be medicinally useful.