Urge incontinence. Quality of life and patients' valuation of symptom reduction.

OBJECTIVE: Previous studies have demonstrated the effect of incontinence, and urge incontinence in particular, on patients' quality of life. This study assessed the effects of urge incontinence on quality of life and measured the value of a reduction in symptoms. DESIGN: A self-administered questionnaire was mailed to 591 patients with urge or mixed incontinence. 495 (83.8%) surveys were returned with complete quality of life and symptom data. Of the total sample, 411 patients received the willingness-to-pay (WTP) survey, from which 257 (62.53%) returns were judged complete and reliable. Information was collected about the number of micturitions and urinary leakages. Health-related quality of life (HR-QOL) was measured using the Short Form 36 (SF-36) Health Survey. Socioeconomic characteristics were also recorded. Value was assessed with a binary WTP question. MAIN OUTCOME MEASURES AND RESULTS: Quality of life among the sample population was significantly lower in 5 of 8 dimensions compared with the general US population, and was significantly related to the severity of the symptoms in 6 of 8 dimensions. The median (mean) willingness to pay was $US27.24 ($US87.74) per month for a 25% reduction in micturitions and leakages, and $US75.92 ($US244.54) per month for a 50% reduction in micturitions and leakages. As expected, the willingness to pay was significantly related to the size of the reduction in micturitions and leakages, and household income. CONCLUSIONS: Patients with incontinence perceive substantial benefits from a reduction in the number of micturitions and leakages.     

The Enterprise,a massive transposon carrying Spok meiotic drive genes

The genomes of eukaryotes are full of parasitic sequences known as transposable elements (TEs). Here, we report the discovery of a putative giant tyrosine-recombinase-mobilized DNA transposon, Enterprise, from the model fungus Podospora anserina. Previously, we described a large genomic feature called the Spok block which is notable due to the presence of meiotic drive genes of the Spok gene family. The Spok block ranges from 110 kb to 247 kb and can be present in at least four different genomic locations within P. anserina, despite what is an otherwise highly conserved genome structure. We propose that the reason for its varying positions is that the Spok block is not only capable of meiotic drive but is also capable of transposition. More precisely, the Spok block represents a unique case where the Enterprise has captured the Spoks, thereby parasitizing a resident genomic parasite to become a genomic hyperparasite. Furthermore, we demonstrate that Enterprise (without the Spoks) is found in other fungal lineages, where it can be as large as 70 kb. Lastly, we provide experimental evidence that the Spok block is deleterious, with detrimental effects on spore production in strains which carry it. This union of meiotic drivers and a transposon has created a selfish element of impressive size in Podospora, challenging our perception of how TEs influence genome evolution and broadening the horizons in terms of what the upper limit of transposition may be.

Transposable elements (TEs) are major agents of change in eukaryotic genomes. Their ability to selfishly parasitize their host replication machinery has large impacts on both genome size and on gene regulation (Chénais et al. 2012). In extreme cases, TEs can contribute up to 85% of genomic content (Schnable et al. 2009), and expansion and reduction of TEs can result in rapid changes in both genome size and architecture (Haas et al. 2009; Möller and Stukenbrock 2017; Talla et al. 2017). Generally, TEs have small sizes (∼50–12,000 bp) and accomplish these large-scale changes through their sheer number. For example, there are ∼1.1 million Alu elements in the human genome, which have had a large impact on genome evolution (Jurka 2004; Bennett et al. 2008). The largest known cases among Class I retrotransposons are long terminal repeat (LTR) elements that can be as large as 30 kb, but among Class II DNA transposons, Mavericks/Polintons are known to grow as large as 40 kb through the capture of additional open reading frames (ORFs) (Arkhipova and Yushenova 2019). Recently, a behemoth TE named Teratorn was described in teleost fish; it can be up to 182 kb in length, dwarfing all other known TEs. Teratorn has achieved this impressive size by fusing a piggyBac DNA transposon with a herpesvirus, thereby blurring the line between TEs and viruses (Inoue et al. 2017, 2018). Truly massive transposons may be lurking in the depths of many eukaryotic genomes, but the limitations of short-read genome sequencing technologies and the lack of population-level high-quality assemblies may make them difficult to identify.The Spok block is a large genomic feature that was first identified thanks to the presence of the spore killing (Spok) genes in species from the genus Podospora (Grognet et al. 2014; Vogan et al. 2019). The Spoks are selfish genetic elements that bias their transmission to the next generation in a process known as meiotic drive. Here, drive occurs by inducing the death of spores that do not inherit them, through a single protein that operates as both a toxin and an antidote (Grognet et al. 2014; Vogan et al. 2019). The first Spok gene described, Spok1, was discovered in Podospora comata (Grognet et al. 2014). In P. anserina, the homologous gene Spok2 is found at high population frequencies, whereas two other genes of the Spok family, Spok3 and Spok4, are at low to intermediate frequencies (Vogan et al. 2019). Unlike Spok1 and Spok2, however, Spok3 and Spok4 are always associated with a large genomic region (the Spok block). The Spok block can be located at different chromosomal locations in different individuals but is never found more than once in natural strains. The number of Spok genes and the location of the Spok block (which carries Spok3, Spok4, or both) define the overall meiotic driver behavior of a given genome, which can be classified into the so-called Podospora spore killers or Psks (van der Gaag et al. 2000; Vogan et al. 2019). The Spok block stands out not only because of its size, typically around 150 kb, but also because there is otherwise high genome collinearity among strains of P. anserina and with the related species P. comata and P. pauciseta (Vogan et al. 2019).The fact that the Spok block is found at unique genomic positions between otherwise highly similar strains is of prime interest as each novel Spok block position creates a unique meiotic drive type (Psk) due to the intricacies of meiosis in Podospora (Vogan et al. 2019). We therefore set out to determine the mechanism through which the Spok block relocates throughout the genome. Additionally, we annotated the gene content of the various Spok blocks to describe their composition and understand what represents the minimal component of the Spok block. Lastly, we conducted fitness assays to investigate whether the presence of the Spok block imparts any detrimental effects upon the host.     

HLA-A,B,C and DR antigens in psoriasis

51 psoriasis vulgaris patients and 93 controls were tested for HLA-A,B,C and DR antigenic frequencies. Significant increases of B17, Cw6 and DR7 were documented in the patient group, as well as a decreased frequency of DR1. The significance of these findings is discussed. DR7 occurred more often together with Cw6 in psoriasis patients than in controls, which might suggest that there are at least two interacting HLA linked genes which increase the disease susceptibility and possibly one DR1 linked gene associated with resistence to the disease.     

Life underneath the VCA umbrella: Perspectives from the US Uterus Transplant Consortium

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field.     

The cost-effectiveness of the switch towards more expensive antihypertensive drugs

A switch from treatment with diuretics and beta-blockers to treatment with the more expensive ACE-inhibitors and calcium-antagonists has been noted in the hypertension field. The aim of this paper was to analyse the cost-effectiveness of this switch towards more expensive antihypertensive drugs in Sweden. The upper limit of the cost-effectiveness of ACE-inhibitors and calcium-antagonists compared with diuretics and beta-blockers was estimated by assuming that ACE-inhibitors and calcium-antagonists achieve the epidemiologically expected risk reduction for coronary heart disease. The incremental cost per life-year gained varies between approximately SEK 50,000 and approximately SEK 6,000,000 ($1 = SEK 6) in the different patient groups analysed. It is concluded that ACE-inhibitors and calcium-antagonists may be potentially cost-effective in some patient groups at a high risk of coronary heart disease. Since an improved risk reduction has not been demonstrated in clinical trials, however, ACE-inhibitors and calcium-antagonists cannot at present be recommended for hypertension treatment in any patient groups unless treatment with diuretics and beta-blockers is contraindicated.     

On the estimation of cost-effectiveness ratios

In a recent paper Birch and Gafni criticised the use of cost-effectiveness ratios in decisions about the allocation of health care resources. To support their claim that the use of cost-effectiveness ratios will not lead to the maximization of health effects for a given budget they used an example. In this paper it is pointed out that the example used contains two basic errors. The first error is the failure to exclude dominated programmes in the estimation of incremental cost-effectiveness ratios. The second error is the failure to distinguish between independent and mutually exclusive programmes. It is concluded that to get a more sober discussion about the use and interpretation of cost-effectiveness analysis it is important that the technique is used correctly.     

New estimates of the demand for health: results based on a categorical health measure and Swedish micro data.

In this paper we estimate a "Grossman" model of demand for health based on Swedish micro data. The data set consists of a random sample of over 5000 individuals taken from the Swedish adult population. Health capital is measured by a categorical measure of overall health status, and an ordered probit model is used to econometrically estimate the demand for health equation. The results are consistent with the theoretical predictions and show that the demand for health increases with income and education and decreases with age, male gender, overweight, living in big cities and being single.     

Bicyclic tripeptide mimetics with reverse turn inducing properties

Analogues of the hypertensive octapeptide angiotensin II, comprising novel constrained 5,8-bicyclic and 5,9-bicyclic tripeptide units adopting nonclassical beta-turn geometries, as deduced from theoretical conformational analysis, have been synthesized. Spontanous bicyclization upon acid-catalyzed deprotection of a model peptide, encompassing a protected omega-formyl alpha-amino acid in position 5 and cysteine residues in positions 3 and 7, revealed a strong preference for bicyclization toward the C-terminus. The bicyclic thiazolidine related angiotensin II analogues synthesized exhibited no affinity for the angiotensin II AT1 receptor.     

Angiotensin II analogues encompassing 5,9- and 5,10-fused thiazabicycloalkane tripeptide mimetics

A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precursors derived from glutamic acid as key building blocks, provides a complement to the related bicyclization previously reported, where an aspartic acid-derived precursor was employed to induce cyclization toward the C-terminal end of the peptide. Thus, the regioselectivity of the bicyclization can be altered simply by varying the chain length of the incorporated aldehyde precursor. Four analogues of the hypertensive octapeptide angiotensin II, comprising the new scaffolds in the 3-5- and 5-7-positions, were synthesized. One of these conformationally constrained angiotensin II analogues exhibited AT(1) receptor affinity (K(i) = 750 nM). Results from theoretical conformational analysis of model compounds of the bicyclic tripeptide mimetics are presented, and they demonstrate that subtle differences in geometry have a strong impact on the affinity to the AT(1) receptor.