Cost-effectiveness of tezepelumab in Canada for severe asthma.

AIMS: To assess the cost-effectiveness of tezepelumab as add-on maintenance therapy compared with standard of care (SoC) for the treatment of patients with severe asthma in Canada. MATERIAL AND METHODS: A cost utility analysis was conducted using a Markov cohort model with five health states ("controlled asthma", "uncontrolled asthma", "previously controlled asthma with exacerbation", "previously uncontrolled asthma with exacerbation", and "death"). Tezepelumab plus SoC was compared to SoC (high-dose inhaled corticosteroids plus long-acting beta agonist) using efficacy estimates derived from the NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) trials. The model included the costs of therapy, administration, resource use for disease management, and adverse events. Utility estimates were calculated using a mixed-effects regression analysis of the NAVIGATOR and SOURCE trials. A Canadian public payer perspective was used with a 50-year time horizon, a 1.5% annual discount rate, and the base case analysis was conducted probabilistically. A key scenario analysis assessed the cost-effectiveness of tezepelumab compared with currently reimbursed biologics informed by an indirect treatment comparison. RESULTS: The base case analysis suggested that tezepelumab plus SoC was associated with a quality-adjusted life-year (QALY) gain of 1.077 compared with SoC alone at an incremental cost of $207,101 (2022 Canadian dollars), resulting in an incremental cost-utility ratio of $192,357/QALY. The key scenario analysis demonstrated that tezepelumab was dominant against all currently reimbursed biologics, with higher incremental QALYs (ranging from 0.062 to 0.407) and lower incremental costs (ranging from -$6,878 to -$1,974). Additionally, when compared against currently reimbursed biologics in Canada, tezepelumab had the highest probability of being cost-effective across all willingness-to-pay (WTP) thresholds. CONCLUSION: Tezepelumab provided additional life years and QALYs at additional cost compared with SoC in Canada. In addition, tezepelumab dominated (i.e. more effective, less costly) the other currently reimbursed biologics.

Cell corner middle lamella in hydroids of dendroid moss Hypnodendron menziesii gametophyte is prominently thickened: a proposed role in the mechanical support function.

MAIN CONCLUSION: Significantly thickened corner middle lamella of the hydroid cell wall in the stipe of dendroid moss Hypnodendron menziesii has a mechanical support function. The hydroid cell walls of the erect stipe of Hypnodendron menziesii were investigated using light microscopy (LM), transmission electron microscopy (TEM), and TEM-immunogold labeling in support of the proposed biomechanical function for the highly thickened cell corner middle lamellae. The statistical analyses of dimensions of hydroid cell and wall parameters revealed a strong positive correlation between the area of hydroid cell and (i) the hydroid cell walls adhering to thick corner middle lamella, (ii) the area of the thick cell wall at hydroid corners, and (iii) the maximum thickness of cell wall at hydroid corners. The total area of the thick cell wall at the hydroid corners concomitantly increased with the area of the hydroid cell wall adhering to the middle lamella, and with the increased number of hydroids surrounding a reference hydroid. The results suggest that markedly thickened middle lamellae of the hydroid cell wall in Hypnodendron likely function by preventing hydroid cells from collapsing under the tensile forces generated from the transpirational pull on the water column. The specific localization of (1→4)- ß-D-galactan and (1,5)-α-L-arabinan in the interface region of the hydroid cell wall and the thick middle lamella is consistent with these cell wall components being involved in the mechanical strengthening of the interface through firm adhesion as well as elasticity, ensuring the structural stability of this cell wall region, which may be prone to delamination/fracturing from the various internal and external pressures imposed. The copious presence of homogalacturonan in the thick middle lamella may further enhance the strength and flexibility of hydroid cell walls.

Global hospital and operative costs associated with various ventral cavity procedures: a comprehensive literature review and analysis across regions.

Objectives: The aim of this literature review was to provide a comprehensive report on hospital costs, and cost components, for a range of ventral cavity surgical procedures across three regions of focus: (1) Americas, (2) Europe, Middle East and Africa (EMEA), and (3) Asia-Pacific. Methods: A structured search was performed and utilized a combination of controlled vocabulary (e.g., "Hepatectomy", "Colectomy", "Costs and Cost Analysis") and keywords (e.g. "liver resection", "bowel removal", "economics"). Studies were considered eligible for inclusion if they reported hospital-related costs associated with the procedures of interest. Cost outcomes included operating room (OR) time costs, total OR costs, ward stay costs, total admission costs, OR cost per minute and ward cost per day. All costs were converted to 2018 USD. Results: Total admission costs were observed to be highest in the Americas, with an average cost of $15,791. The average OR time cost per minute was found to vary by region: $24.83 (Americas), $14.29 (Asia-Pacific), and $13.90 (EMEA). A cost-breakdown demonstrated that OR costs typically comprised close to 50%, or more, of hospital admission costs. This review also demonstrates that decreasing OR time by 30 min provides cost savings approximately equivalent to a 1-day reduction in ward time. Conclusion: This literature review provided a comprehensive assessment of hospital costs across various surgical procedures, approaches, and geographical regions. Our findings indicate that novel processes and healthcare technologies that aim to reduce resources such as operating time and hospital stay, can potentially provide resource savings for hospital payers.

Characterization of a novel role for the dynamin mechanoenzymes in the regulation of human sperm acrosomal exocytosis.

STUDY QUESTION: Does dynamin regulate human sperm acrosomal exocytosis? SUMMARY ANSWER: Our studies of dynamin localization and function have implicated this family of mechanoenzymes in the regulation of progesterone-induced acrosomal exocytosis in human spermatozoa. WHAT IS KNOWN ALREADY: Completion of an acrosome reaction is a prerequisite for successful fertilization in all studied mammalian species. It follows that failure to complete this unique exocytotic event represents a common aetiology in the defective spermatozoa of male infertility patients that have failed IVF in a clinical setting. Recent studies have implicated the dynamin family of mechanoenzymes as important regulators of the acrosome reaction in murine spermatozoa. The biological basis of this activity appears to rest with the ability of dynamin to polymerize around newly formed membrane vesicles and subsequently regulate the rate of fusion pore expansion. To date, however, the dynamin family of GTPases have not been studied in the spermatozoa of non-rodent species. Here, we have sought to examine the presence and functional significance of dynamin in human spermatozoa. STUDY DESIGN, SIZE, DURATION: Dynamin expression was characterized in the testis and spermatozoa of several healthy normozoospermic individuals. In addition, we assessed the influence of selective dynamin inhibition on the competence of human spermatozoa to undergo a progesterone-induced acrosome reaction. A minimum of five biological and technical replicates were performed to investigate both inter- and intra-donor variability in dynamin expression and establish statistical significance in terms of the impact of dynamin inhibition. PARTICIPANTS/MATERIALS, SETTING, METHODS: The expression and the localization of dynamin in the human testis, epididymis and mature spermatozoa were determined through the application of immunofluorescence, immunoblotting and/or electron microscopy. Human semen samples were fractionated via density gradient centrifugation and the resultant populations of good and poor quality spermatozoa were induced to capacitate and acrosome react in the presence or absence of selective dynamin inhibitors. The acrosome integrity of live spermatozoa was subsequently assessed via the use of fluorescently conjugated Arachis hypogea lectin (PNA). The influence of dynamin phosphorylation and the regulatory kinase(s) responsible for this modification in human spermatozoa were also assessed via the use of in situ proximity ligation assays and pharmacological inhibition. In all experiments, ≥100 spermatozoa were assessed/treatment group and all graphical data are presented as the mean values ± SEM, with statistical significance being determined by ANOVA. MAIN RESULTS AND THE ROLE OF CHANCE: Dynamin 1 (DNM1) and DNM2, but not DNM3, were specifically localized to the acrosomal region of the head of human spermatozoa, an ideal position from which to regulate acrosomal exocytosis. In keeping with this notion, pharmacological inhibition of DNM1 and DNM2 was able to significantly suppress the rates of acrosomal exocytosis stimulated by progesterone. Furthermore, our comparison of dynamin expression in good and poor quality spermatozoa recovered from the same ejaculate, revealed a significant reduction in the amount of DNM2 in the latter subpopulation of cells. In contrast, DNM1 was detected at equivalent levels in both subpopulations of spermatozoa. Such findings are of potential significance given that the poor quality spermatozoa proved refractory to the induction of a progesterone stimulated acrosome reaction. In seeking to identify the regulatory influence of progesterone on DNM2 function, we were able to establish that the protein is a substrate for CDK1-dependent phosphorylation. The functional significance of DNM2 phosphorylation was illustrated by the fact that pharmacological inhibition of CDK1 elicited a concomitant suppression of both DNM2-Ser764 phosphorylation and the overall rates of progesterone-induced acrosomal exocytosis. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: This was an in vitro study performed mainly on ejaculated human spermatozoa. This experimental paradigm necessarily eliminates the physiological contributions of the female reproductive tract that would normally support capacitation and acrosomal responsiveness. WIDER IMPLICATIONS OF THE FINDINGS: This study identifies a novel causative link between dynamin activity and the ability of human spermatozoa to complete a progesterone-induced acrosome reaction. Such findings encourage a more detailed analysis of the contribution of dynamin dysregulation as an underlying aetiology in infertile males whose spermatozoa are unable to penetrate the zona pellucida. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a National Health and Medical Research Council of Australia Project Grant (APP1103176) awarded to B.N. and E.A.M. The authors report no conflict of interest.

Developmental expression of the dynamin family of mechanoenzymes in the mouse epididymis.

The mammalian epididymis is an exceptionally long ductal system tasked with the provision of one of the most complex intraluminal fluids found in any exocrine gland. This specialized milieu is continuously modified by the combined secretory and absorptive of the surrounding epithelium and thus finely tuned for its essential roles in promoting sperm maturation and storage. While considerable effort has been focused on defining the composition of the epididymal fluid, relatively less is known about the intracellular trafficking machinery that regulates this luminal environment. Here, we characterize the ontogeny of expression of a master regulator of this machinery, the dynamin family of mechanoenzymes. Our data show that canonical dynamin isoforms were abundantly expressed in the juvenile mouse epididymis. However, in peripubertal and adult animals dynamin takes on a heterogeneous pattern of expression such that the different isoforms displayed both cell- and segment-specific localization. Thus, dynamin 1 and 3 were predominately localized in the distal epididymal segments (corpus and cauda), where they were found within clear and principal cells, respectively. In contrast, dynamin 2 was expressed throughout the epididymis, but localized to the Golgi apparatus of the principal cells in the proximal (caput) segment and the luminal border of these cells in more distal segments. These dynamin isoforms are therefore ideally positioned to play complementary, nonredundant roles in the regulation of the epididymal milieu. In support of this hypothesis, selective inhibition of dynamin altered the profile of proteins secreted from an immortalized caput epididymal cell line.

Tat-dependent translocation of an F420-binding protein of Mycobacterium tuberculosis.

F(420) is a unique cofactor present in a restricted range of microorganisms, including mycobacteria. It has been proposed that F(420) has an important role in the oxidoreductive reactions of Mycobacterium tuberculosis, possibly associated with anaerobic survival and persistence. The protein encoded by Rv0132c has a predicted N-terminal signal sequence and is annotated as an F(420)-dependent glucose-6-phosphate dehydrogenase. Here we show that Rv0132c protein does not have the annotated activity. It does, however, co-purify with F(420) during expression experiments in M. smegmatis. We also show that the Rv0132c-F(420) complex is a substrate for the Tat pathway, which mediates translocation of the complex across the cytoplasmic membrane, where Rv0132c is anchored to the cell envelope. This is the first report of any F(420)-binding protein being a substrate for the Tat pathway and of the presence of F(420) outside of the cytosol in any F(420)-producing microorganism. The Rv0132c protein and its Tat export sequence are essentially invariant in the Mycobacterium tuberculosis complex. Taken together, these results show that current understanding of F(420) biology in mycobacteria should be expanded to include activities occurring in the extra-cytoplasmic cell envelope.

Ultrastructural and molecular characterization of a bacterial symbiosis in the ecologically important scale insect family Coelostomidiidae.

Scale insects are important ecologically and as agricultural pests. The majority of scale insect taxa feed exclusively on plant phloem sap, which is carbon rich but deficient in essential amino acids. This suggests that, as seen in the related aphids and psyllids, scale insect nutrition might also depend upon bacterial symbionts, yet very little is known about scale insect-bacteria symbioses. We report here the first identification and molecular characterization of symbiotic bacteria associated with the New Zealand giant scale Coelostomidia wairoensis, using fluorescence in situ hybridization (FISH), transmission electron microscopy (TEM) and 16S rRNA gene-based analysis. Dissection and FISH confirmed the location of the bacteria in large, paired, multilobate organs in the abdominal region of the insect. TEM indicated that the dominant pleomorphic bacteria were confined to bacteriocytes in the sheath-enclosed bacteriome. Phylogenetic analysis revealed the presence of three distinct bacterial types, the bacteriome-associated B-symbiont (Bacteroidetes), an Erwinia-related symbiont (Gammaproteobacteria) and Wolbachia sp. (Alphaproteobacteria). This study extends the current knowledge of scale insect symbionts and is the first microbiological investigation of the ecologically important coelostomidiid scales.

The structure of a putative scaffolding protein of immature poxvirus particles as determined by electron microscopy suggests similarity with capsid proteins of large icosahedral DNA viruses.

Orf virus, the prototype parapoxvirus, is responsible for contagious ecthyma in sheep and goats. The central region of the viral genome codes for proteins highly conserved among vertebrate poxviruses and which are frequently essential for viral proliferation. Analysis of the recently published genome sequence of orf virus revealed that among such essential proteins, the protein orfv075 is an orthologue of D13, the rifampin resistance gene product critical for vaccinia virus morphogenesis. Previous studies showed that D13, arranged as "spicules," is necessary for the formation of vaccinia virus immature virions, a mandatory intermediate in viral maturation. We have determined the three-dimensional structure of recombinant orfv075 at approximately 25-A resolution by electron microscopy of two-dimensional crystals. orfv075 organizes as trimers with a tripod-like main body and a propeller-like smaller domain. The molecular envelope of orfv075 shows unexpectedly good agreement to that of a distant homologue, VP54, the major capsid protein of Paramecium bursaria Chlorella virus type 1. Our structural analysis suggests that orfv075 belongs in the double-barreled capsid protein family found in many double-stranded DNA icosahedral viruses and supports the hypothesis that the nonicosahedral poxviruses and the large icosahedral DNA viruses are evolutionarily related.