The essential value of long-term experimental data for hydrology and water management

We would like to thank the European Research Council ERC for funding the VeWa project and most of Tetzlaff's time (project GA 335910 VeWa). No data were used in producing this manuscript.Peer reviewedPublisher PD

Crisis and change in industrial relations in Central and Eastern Europe

This article introduces the special issue on industrial relations in Central and Eastern Europe since the financial and economic crisis. Already dependent economically on funding from the west, and lacking the robust industrial relations institutions traditional in much of Western Europe, countries in the region were particularly vulnerable. However, there are important cross-national differences, and the strategies of key actors have significantly affected the outcomes

High riverine CO2 emissions at the permafrost boundary of Western Siberia

Acknowledgements: The study was part of the JPI Climate initiative, financially supported by VR (the Swedish Research Council) grant no. 325-2014-6898 to J.K. Additional funding from RNF (RSCF) grant no. 18-17-00237, RFBR grant no. 17-55-16008 and RF Federal Target Program RFMEFI58717X0036 ‘Kolmogorov’ to O.S.P. and S.N.K. as well as NERC grant no. NE/M019896/1 to C.S. is acknowledged. The authors thank A. Sorochinskiy and A. Lim for assistance in the field, as well as M. Myrstener, M. Klaus and S. Monteux for advice on data analysis. L. Kovaleva is acknowledged for artwork.Peer reviewedPostprin

Does sand content in spawning substrate result in early larval emergence? Evidence from a lithophilic cyprinid fish

The spawning success of lithophilic salmonids is strongly influenced by the fine sediment content (‘fines’) of spawning substrates, yet knowledge on the impacts of fines on the spawning of non-salmonid lithophiles remains limited, despite their ecological and socio-economic importance in European rivers. Consequently, the aim here was to use an ex-situ experiment to investigate the impact of sand content on egg survival and timing of larval emergence of the surface-spawning cyprinid European barbel Barbus barbus. Thirty incubator boxes within a recirculating system were filled with one of five experimental sediment mixtures (0 to 40 % sand by mass) that each contained 300 fertilised eggs at a depth of 50 mm. Emerged, free-swimming larvae were captured and counted daily to assess grain size effects on larval survival and emergence. Specifically, total proportion of emerged larvae, cumulative daily proportion of emerged larvae and time required to reach 50 % emergence were measured during the study. Whilst the proportion of sand in the sediments did not have a significant impact on egg-to-emergence survival (mean survival per treatment 75 % to 79 %), it significantly affected the timing of larval emergence to the water column; early emergence was detected in treatments with elevated sand content (on average, 50 % emergence after 12 - 13 days versus 19 days in the control). Similar to findings from salmonid studies, these results suggest high sand content in spawning gravels can influence timing of larval emergence and potentially cyprinid lithophilic fish survival

Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis

Ca2+ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP3R) serve to discharge Ca2+ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP3R isoforms and protect cells from apoptosis, reducing ER Ca2+ release. However, it has not been elucidated which IP3R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP3R I, strongly suppresses IP3-mediated Ca2+ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca2+ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca2+ release. Moreover, regulating Ca2+ flux to mitochondria, Akt maintains the mitochondrial integrity and delays the trigger of apoptosis, in a type III-dependent mechanism. These results demonstrate a specific activity of Akt on IP3R III, leading to diminished Ca2+ transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt

Cost-effectiveness of Spironolactone for Adult Female Acne (SAFA): economic evaluation alongside a randomised controlled trial.

OBJECTIVE: This study aims to estimate the cost-effectiveness of oral spironolactone plus routine topical treatment compared with routine topical treatment alone for persistent acne in adult women from a British NHS perspective over 24 weeks. DESIGN: Economic evaluation undertaken alongside a pragmatic, parallel, double-blind, randomised trial. SETTING: Primary and secondary healthcare, community and social media advertising. PARTICIPANTS: Women ≥18 years with persistent facial acne judged to warrant oral antibiotic treatment. INTERVENTIONS: Participants were randomised 1:1 to 50 mg/day spironolactone (increasing to 100 mg/day after 6 weeks) or matched placebo until week 24. Participants in both groups could continue topical treatment. MAIN OUTCOME MEASURES: Cost-utility analysis assessed incremental cost per quality-adjusted life year (QALY) using the EQ-5D-5L. Cost-effectiveness analysis estimated incremental cost per unit change on the Acne-QoL symptom subscale. Adjusted analysis included randomisation stratification variables (centre, baseline severity (investigator's global assessment, IGA <3 vs ≥3)) and baseline variables (Acne-QoL symptom subscale score, resource use costs, EQ-5D score and use of topical treatments). RESULTS: Spironolactone did not appear cost-effective in the complete case analysis (n=126 spironolactone, n=109 control), compared with no active systemic treatment (adjusted incremental cost per QALY £67 191; unadjusted £34 770). Incremental cost per QALY was £27 879 (adjusted), just below the upper National Institute for Health and Care Excellence's threshold value of £30 000, where multiple imputation took account of missing data. Incremental cost per QALY for other sensitivity analyses varied around the base-case, highlighting the degree of uncertainty. The adjusted incremental cost per point change on the Acne-QoL symptom subscale for spironolactone compared with no active systemic treatment was £38.21 (complete case analysis). CONCLUSIONS: The results demonstrate a high level of uncertainty, particularly with respect to estimates of incremental QALYs. Compared with no active systemic treatment, spironolactone was estimated to be marginally cost-effective where multiple imputation was performed but was not cost-effective in complete case analysis. TRIAL REGISTRATION NUMBER: ISRCTN registry (ISRCTN12892056)

Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial

Objective: To assess the effectiveness of oral spironolactone for acne vulgaris in adult women.Design: Pragmatic, multicentre, phase 3, double blind, randomised controlled trial.Setting: Primary and secondary healthcare, and advertising in the community and on social media in England and Wales.Participants: Women (≥18 years) with facial acne for at least six months, judged to warrant oral antibiotics.Interventions: Participants were randomly assigned (1:1) to either 50 mg/day spironolactone or matched placebo until week six, increasing to 100 mg/day spironolactone or placebo until week 24. Participants could continue using topical treatment.Main outcome measures: Primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12 (range 0-30, where higher scores reflect improved QoL). Secondary outcomes were Acne-QoL at week 24, participant self-assessed improvement; investigator’s global assessment (IGA) for treatment success; and adverse reactions.Results: From 5 June 2019 to 31 August 2021, 1267 women were assessed for eligibility, 410 were randomly assigned to the intervention (n=201) or control group (n=209) and 342 were included in the primary analysis (n=176 in the intervention group and n=166 in the control group). Baseline mean age was 29.2 years (standard deviation 7.2), 28 (7%) of 389 were from ethnicities other than white, with 46% mild, 40% moderate, and 13% severe acne. Mean Acne-QoL symptom scores at baseline were 13.2 (standard deviation 4.9) and at week 12 were 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo (difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46), adjusted for baseline variables). Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo (difference 3.45 (95% confidence interval 2.16 to 4.75), adjusted). More participants in the spironolactone group reported acne improvement than in the placebo group: no significant difference was reported at week 12 (72% v 68%, odds ratio 1.16 (95% confidence interval 0.70 to 1.91)) but significant difference was noted at week 24 (82% v 63%, 2.72 (1.50 to 4.93)). Treatment success (IGA classified) at week 12 was 31 (19%) of 168 given spironolactone and nine (6%) of 160 given placebo (5.18 (2.18 to 12.28)). Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% v 12%; p=0.02). No serious adverse reactions were reported.Conclusions Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne.Trial registration ISRCTN1289205