Short- and long-term direct and indirect costs of illness after ostomy creation - a Swedish nationwide registry study.

BACKGROUND: Despite advance in care of people with an ostomy, related complications remain prevalent. The objective of this study was to examine short- and long-term healthcare resource utilization and associated costs after ostomy creation. METHODS: This observational study was based on retrospectively collected data from national and regional Swedish registries. The population consisted of people living in Sweden, who had an ostomy created. The earliest index date was 1 January 2006, and people were followed for ten years, until death, reversal of temporary ostomy, termination of purchases of ostomy products, or end of study, which was 31 December 2019. Each person with an ostomy was matched with two controls from the general population based on age, gender, and region. RESULTS: In total, 40,988 persons were included: 19,645 with colostomy, 16,408 with ileostomy, and 4,935 with urostomy. The underlying diseases for colostomy and ileostomy creations were primarily bowel cancer, 50.0% and 55.8% respectively, and additionally inflammatory bowel disease for 20.6% of ileostomies. The underlying cause for urostomy creation was mainly bladder cancer (85.0%). In the first year after ostomy creation (excl. index admission), the total mean healthcare cost was 329,200 SEK per person with colostomy, 330,800 SEK for ileostomy, and 254,100 SEK for urostomy (100 SEK was equivalent to 9.58 EUR). Although the annual mean healthcare cost decreased over time, it remained significantly elevated compared to controls, even after 10 years, with hospitalization being the main cost driver. The artificial opening was responsible for 19.3-22.8% of 30-day readmissions after ostomy creation and for 19.7-21.4% of hospitalizations during the entire study period. For the ileostomy group, dehydration was responsible for 13.0% of 30-day readmissions and 4.5% of hospitalization during the study period. CONCLUSIONS: This study reported a high disease burden for persons with an ostomy. This had a substantial impact on the healthcare cost for at least ten years after ostomy creation. Working ability seemed to be negatively impacted, indicated by increased cost of sickness absence and early retirement. This calls for improved management and support of ostomy care for the benefit of the affected persons and for the cost of society.

Protein kinase A controls yeast growth in visible light.

BACKGROUND: A wide variety of photosynthetic and non-photosynthetic species sense and respond to light, having developed protective mechanisms to adapt to damaging effects on DNA and proteins. While the biology of UV light-induced damage has been well studied, cellular responses to stress from visible light (400-700 nm) remain poorly understood despite being a regular part of the life cycle of many organisms. Here, we developed a high-throughput method for measuring growth under visible light stress and used it to screen for light sensitivity in the yeast gene deletion collection. RESULTS: We found genes involved in HOG pathway signaling, RNA polymerase II transcription, translation, diphthamide modifications of the translational elongation factor eEF2, and the oxidative stress response to be required for light resistance. Reduced nuclear localization of the transcription factor Msn2 and lower glycogen accumulation indicated higher protein kinase A (cAMP-dependent protein kinase, PKA) activity in many light-sensitive gene deletion strains. We therefore used an ectopic fluorescent PKA reporter and mutants with constitutively altered PKA activity to show that repression of PKA is essential for resistance to visible light. CONCLUSION: We conclude that yeast photobiology is multifaceted and that protein kinase A plays a key role in the ability of cells to grow upon visible light exposure. We propose that visible light impacts on the biology and evolution of many non-photosynthetic organisms and have practical implications for how organisms are studied in the laboratory, with or without illumination.

Trait variation in yeast is defined by population history.

A fundamental goal in biology is to achieve a mechanistic understanding of how and to what extent ecological variation imposes selection for distinct traits and favors the fixation of specific genetic variants. Key to such an understanding is the detailed mapping of the natural genomic and phenomic space and a bridging of the gap that separates these worlds. Here we chart a high-resolution map of natural trait variation in one of the most important genetic model organisms, the budding yeast Saccharomyces cerevisiae, and its closest wild relatives and trace the genetic basis and timing of major phenotype changing events in its recent history. We show that natural trait variation in S. cerevisiae exceeds that of its relatives, despite limited genetic variation, and follows the population history rather than the source environment. In particular, the West African population is phenotypically unique, with an extreme abundance of low-performance alleles, notably a premature translational termination signal in GAL3 that cause inability to utilize galactose. Our observations suggest that many S. cerevisiae traits may be the consequence of genetic drift rather than selection, in line with the assumption that natural yeast lineages are remnants of recent population bottlenecks. Disconcertingly, the universal type strain S288C was found to be highly atypical, highlighting the danger of extrapolating gene-trait connections obtained in mosaic, lab-domesticated lineages to the species as a whole. Overall, this study represents a step towards an in-depth understanding of the causal relationship between co-variation in ecology, selection pressure, natural traits, molecular mechanism, and alleles in a key model organism.

An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.

INTRODUCTION: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.

Quantitative proteomics of yeast post-Golgi vesicles reveals a discriminating role for Sro7p in protein secretion.

We here report the first comparative proteomics of purified yeast post-Golgi vesicles (PGVs). Vesicle samples isolated from PGV-accumulating sec6-4 mutants were treated with isobaric tags (iTRAQ) for subsequent quantitative tandem mass spectrometric analysis of protein content. After background subtraction, a total of 66 vesicle-associated proteins were identified, including known or assumed vesicle residents as well as a fraction not previously known to be PGV associated. Vesicles isolated from cells lacking the polarity protein Sro7p contained essentially the same catalogue of proteins but showed a reduced content of a subset of cargo proteins, in agreement with a previously shown selective role for Sro7p in cargo sorting.

Inequalities in pharmacologic treatment of spasticity in Sweden - health economic consequences of closing the treatment gap.

BACKGROUND: The Swedish Healthcare Act states that patients should have equal access to healthcare. This study addresses at how this translates to pharmacological treatment of adult spasticity, including injections with botulinum toxin A (BoNT-A) and pumps for intrathecal baclofen (ITB). To address potential economic incentives for treatment differences, the results are also set into a health economic perspective. Thus, the current study provides a detailed and comprehensive overview for informed decision- and policymaking. METHODS: Botulinum toxin use was retrieved from sales data. Clinical practice regarding mean BoNT-A treatment dose and proportion used for spasticity indication were validated in five county councils, while the number of ITB pumps were mapped for all county councils. Published costs and quality of life data was used for estimating required responder rates for cost-balance or cost-effectiveness. RESULTS: The proportion of patients treated with BoNT-A varied between 5.8% and 13.6% across healthcare regions, with a mean of 9.2% on a national level. The reported number of ITB pumps per 100,000 inhabitants varied between 3.6 and 14.1 across healthcare regions, with a national mean of 6/100,000. The estimated incremental cost for reaching treatment equity was EUR 1,976,773 per year for BoNT-A and EUR 3,326,692 for ITB pumps. Based on expected cost-savings, responder rates ranging between 4% and 15% cancelled out the incremental cost for BoNT-A. Assuming no cost-savings, responder rates of 14% or 36% was required for cost-effectiveness. CONCLUSIONS: There is a marked variation in pharmacologic treatment of adult spasticity in Sweden. Overall, the results indicate an underuse of treatment and need for harmonisation of clinical practice. Furthermore, the incremental cost for reaching treatment equity is likely to be offset by spasticity-associated cost-savings.

The yeast tumor suppressor homologue Sro7p is required for targeting of the sodium pumping ATPase to the cell surface.

The SRO7/SOP1 encoded tumor suppressor homologue of Saccharomyces cerevisiae is required for maintenance of ion homeostasis in cells exposed to NaCl stress. Here we show that the NaCl sensitivity of the sro7Delta mutant is due to defective sorting of Ena1p, the main sodium pump in yeast. On exposure of sro7Delta mutants to NaCl stress, Ena1p fails to be targeted to the cell surface, but is instead routed to the vacuole for degradation via the multivesicular endosome pathway. SRO7-deficient mutants accumulate post-Golgi vesicles at high salinity, in agreement with a previously described role for Sro7p in late exocytosis. However, Ena1p is not sorted into these post-Golgi vesicles, in contrast to what is observed for the vesicles that accumulate when exocytosis is blocked in sec6-4 mutants at high salinity. These observations imply that Sro7p has a previously unrecognized role for sorting of specific proteins into the exocytic pathway. Screening for multicopy suppressors identified RSN1, encoding a transmembrane protein of unknown function. Overexpression of RSN1 restores NaCl tolerance of sro7Delta mutants by retargeting Ena1p to the plasma membrane. We propose a model in which blocked exocytic sorting in sro7Delta mutants, gives rise to quality control-mediated routing of Ena1p to the vacuole.

Cost Effectiveness of Nusinersen in the Treatment of Patients with Infantile-Onset and Later-Onset Spinal Muscular Atrophy in Sweden.

BACKGROUND: Spinal muscular atrophy is a rare neuromuscular disorder with a spectrum of severity related to age at onset and the number of SMN2 gene copies. Infantile-onset (≤ 6 months of age) is the most severe spinal muscular atrophy and is the leading monogenetic cause of infant mortality; patients with later-onset (> 6 months of age) spinal muscular atrophy can survive into adulthood. Nusinersen is a new treatment for spinal muscular atrophy. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of nusinersen for the treatment of patients with infantile-onset spinal muscular atrophy and later-onset spinal muscular atrophy in Sweden. METHODS: One Markov cohort health-state transition model was developed for each population. The infantile-onset and later-onset models were based on the efficacy results from the ENDEAR phase III trial and the CHERISH phase III trial, respectively. The cost effectiveness of nusinersen in both models was compared with standard of care in Sweden. RESULTS: For a time horizon of 40 years in the infantile-onset model and 80 years in the later-onset model, treatment with nusinersen resulted in 3.86 and 9.54 patient incremental quality-adjusted life-years and 0.02 and 2.39 caregiver incremental quality-adjusted life-years and an incremental cost of 21.9 and 38.0 million SEK (Swedish krona), respectively. These results translated into incremental cost-effectiveness ratios (including caregiver quality-adjusted life-years) of 5.64 million SEK (€551,300) and 3.19 million SEK (€311,800) per quality-adjusted life-year gained in the infantile-onset model and later-onset model, respectively. CONCLUSIONS: Treatment with nusinersen resulted in overall survival and quality-adjusted life-year benefits but with incremental costs above 21 million SEK (€2 million) [mainly associated with maintenance treatment with nusinersen over a patient's lifespan]. Nusinersen was not cost effective when using a willingness-to-pay threshold of 2 million SEK (€195,600), which has been considered in a recent discussion by the Dental and Pharmaceutical Benefits Agency as a reasonable threshold for rare disease. Nonetheless, nusinersen gained reimbursement in Sweden in 2017 for paediatric patients (below 18 years old) with spinal muscular atrophy type I-IIIa.

Health Economic Analysis of Open and Robot-assisted Laparoscopic Surgery for Prostate Cancer Within the Prospective Multicentre LAPPRO Trial.

BACKGROUND: The rapid adoption of robot-assisted laparoscopy in radical prostatectomy has preceded data regarding associated costs. Qualitative evidence regarding cost outcomes is lacking. OBJECTIVE: This study assessed how costs were affected by robot-assisted laparoscopic prostatectomy (RALP) compared with open surgery. DESIGN, SETTING, AND PARTICIPANTS: Cost analysis was based on the dataset of the LAPPRO (Laparoscopic Prostatectomy Robot Open) clinical trial, which is a prospective controlled, nonrandomised trial of patients who underwent prostatectomy at 14 centres in Sweden between September 2008 and November 2011. Currently, data are available from a follow-up period of 24 mo. INTERVENTION: In the LAPPRO trial, RALP was compared with radical retropubic prostatectomy (RRP). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Costs per surgical technique were assessed based on resource variable data from the LAPPRO database. The calculation of average costs was based on mean values; Swedish currency was converted to purchasing power parity US dollar (PPP$). All tests were two-tailed and conducted at α=0.05 significance level. RESULTS AND LIMITATIONS: The cost analysis comprised 2638 men. Based on the LAPPRO trial data, RALP was associated with an increased cost/procedure of PPP$ 3837 (95% confidence interval: 2747-4928) compared with RRP. The result was sensitive to variations in caseload. Main drivers of overall cost were robotic system cost, operation time, length of stay, and sick leave. Limitations of the study include the uneven distribution between RALP and RRP regarding procedures in public/for-profit hospitals and surgeon/centre procedural volume. CONCLUSIONS: Based on the LAPPRO trial data, this study showed that RALP was associated with an increased cost compared with RRP in Swedish health care. There are many factors influencing the costs, making the absolute result dependent on the specific setting. However, by identifying the main cost drivers and/or most influential parameters, the study provides support for informed decisions and predictions. PATIENT SUMMARY: In this study, we looked at the cost outcome when performing prostatectomies by robot-assisted laparoscopic technique compared with open surgery in Sweden. We found that the robot-assisted procedure was associated with a higher mean cost.

High-throughput biochemical fingerprinting of Saccharomyces cerevisiae by Fourier transform infrared spectroscopy.

Single-channel optical density measurements of population growth are the dominant large scale phenotyping methodology for bridging the gene-function gap in yeast. However, a substantial amount of the genetic variation induced by single allele, single gene or double gene knock-out technologies fail to manifest in detectable growth phenotypes under conditions readily testable in the laboratory. Thus, new high-throughput phenotyping technologies capable of providing information about molecular level consequences of genetic variation are sorely needed. Here we report a protocol for high-throughput Fourier transform infrared spectroscopy (FTIR) measuring biochemical fingerprints of yeast strains. It includes high-throughput cultivation for FTIR spectroscopy, FTIR measurements and spectral pre-treatment to increase measurement accuracy. We demonstrate its capacity to distinguish not only yeast genera, species and populations, but also strains that differ only by a single gene, its excellent signal-to-noise ratio and its relative robustness to measurement bias. Finally, we illustrated its applicability by determining the FTIR signatures of all viable Saccharomyces cerevisiae single gene knock-outs corresponding to lipid biosynthesis genes. Many of the examined knock-out strains showed distinct, highly reproducible FTIR phenotypes despite having no detectable growth phenotype. These phenotypes were confirmed by conventional lipid analysis and could be linked to specific changes in lipid composition. We conclude that the introduced protocol is robust to noise and bias, possible to apply on a very large scale, and capable of generating biologically meaningful biochemical fingerprints that are strain specific, even when strains lack detectable growth phenotypes. Thus, it has a substantial potential for application in the molecular functionalization of the yeast genome.