Reply to: methodological inconsistencies define thermal bottlenecks in fish life cycle

The identification of biological pattern is often complicated by the lack of methodologically consistent data with broad geographic coverage, especially when considering functional characteristics of organisms that differ greatly in body size and morphology. In our study (Dahlke et al. 2020), we addressed the problem of data scarcity by using different types of observational and experimental data together with statistical (phylogenetic) data imputation, and by placing our analysis into the context of a physiological concept, which provides a mechanism-based explanation for the observed pattern (ontogenetic shift in thermal tolerance of fish) and with respect to transition from sublethal to lethal thresholds. Here, we show with comparative examples that our results were not affected by the use of methodologically inconsistent data

Thermal bottlenecks in the life cycle define climate vulnerability of fish

Species’ vulnerability to climate change depends on the most temperature-sensitive life stages, but for major animal groups such as fish, life cycle bottlenecks are often not clearly defined. We used observational, experimental, and phylogenetic data to assess stage-specific thermal tolerance metrics for 694 marine and freshwater fish species from all climate zones. Our analysis shows that spawning adults and embryos consistently have narrower tolerance ranges than larvae and nonreproductive adults and are most vulnerable to climate warming. The sequence of stage-specific thermal tolerance corresponds with the oxygen-limitation hypothesis, suggesting a mechanistic link between ontogenetic changes in cardiorespiratory (aerobic) capacity and tolerance to temperature extremes. A logarithmic inverse correlation between the temperature dependence of physiological rates (development and oxygen consumption) and thermal tolerance range is proposed to reflect a fundamental, energetic trade-off in thermal adaptation. Scenario-based climate projections considering the most critical life stages (spawners and embryos) clearly identify the temperature requirements for reproduction as a critical bottleneck in the life cycle of fish. By 2100, depending on the Shared Socioeconomic Pathway (SSP) scenario followed, the percentages of species potentially affected by water temperatures exceeding their tolerance limit for reproduction range from ~10% (SSP 1–1.9) to ~60% (SSP 5–8.5). Efforts to meet ambitious climate targets (SSP 1–1.9) could therefore benefit many fish species and people who depend on healthy fish stocks

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Experimental data compilation, thermal tolerance and thermal responsiveness of fish species and life stages

The data files contain experimental measurements of thermal tolerance, as well as temperature-dependent development and oxygen consumption rates (i.e. thermal responsiveness) of different life stages of fish. The data were extracted from studies published between 1930 and March 2020, including marine and freshwater species from all continents and climate zones (-70° to 80° latitude). The data were analyzed to assess differences in thermal tolerance and thermal responsiveness between life stages and species living at different latitudes. A phylogenetic imputation procedure was used to predict thermal tolerance limits of life stages for which no experimental data was available. Experimental and imputed thermal tolerance data were used to estimate thermal safety margins (indicating the risk of habitat loss) of different life stages of more than 600 species under different climate change scenarios by 2100

Impact of magnetic resonance urography and ultrasonography on diagnosis and management of hydronephrosis and megaureter in paediatric patients

Background: (1) To evaluate the diagnostic value of magnetic resonance urography (MRU) in comparison with ultrasonography (US) to determine the extent of upper urinary tract dilation and (2) to evaluate the impact of MRU on therapy management. Materials and Methods: From January 2005 to December 2010, paediatric patients with hydronephrosis or megaureter who underwent MRU in addition to standard work-up imaging were included. Data were retrospectively collected and analysed in comparison with the data obtained from results by US. Results: Forty-five patients with upper urinary tract dilatation were included into the study. Twenty-six patients (58%) had a hydronephrosis and 19 patients (42%) presented with a megaureter. Diagnosis was established in all patients by multimodulary imaging work-up including micturating cysto-urethrography, MAG3 renography, US and MRU and could be confirmed in all patients who underwent surgery (n = 28). Hydronephrosis was detected in 26 of 26 patients by US (100% sensitivity) and in 25 of 26 patients (96%) by MRU (Not significant (n.s.)). Megaureter was detected in 17 of 19 patients (sensitivity 89%) by US and in 18 of 19 patients (sensitivity 95%) by MRU (n.s.). In all 45 patients, MRU had no impact on surgical or conservative management of hydronephrosis or megaureter. Conclusion: In our experience, MRU was not superior to US in detecting hydronephrosis or megaureter and had no impact on the surgical or conservative management of upper urinary tract dilation

Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma

Background Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these patients, event-free and overall survival was improved by the addition of the anti-disialoganglioside antibody dinutuximab beta (DB) following multimodal conventional therapy. However, the prognosis of patients with refractory/relapsed NB remains poor. In the past decade, immunotherapy approaches with checkpoint inhibitors were approved for patients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In preclinical models, DB resulted in an upregulation of the programmed cell death protein 1 (PD-1) checkpoint in NB cell lines and a combined treatment of DB with a murine anti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model.Case presentations Two patients were admitted with refractory metastatic NB. In the 4-year-old girl, NB was diagnosed in 2013. She completed her first-line therapy with a first remission in 2015, but suffered a relapse in 2017. Treatment with chemotherapy and DB resulted in progressive disease after transient improvement. In the 17-year-old young man, NB was first diagnosed in April 2010. After two local relapses in 2011 and 2014, a metastatic relapse and a large abdominal tumor bulk were found in 2018. Despite transient improvement with multimodal therapy, progressive metastatic disease was observed in May 2019. Both patients had a satisfactory quality of life. Therefore, treatment with DB and nivolumab was performed—in the girl from October 2018 until August 2019, in the young man since June 2019. Tolerance to treatment was excellent. The girl continues to be in complete remission 6 months after therapy was stopped. In the young man, the soft tissue lesions disappeared completely, the skeletal lesions regressed substantially after 9 months of his still ongoing treatment.Conclusions The combination of DB with the checkpoint inhibitor nivolumab led to complete and a very good partial remission in two patients with relapsed/refractory NB. Prospective trials are warranted to clarify the role of this novel approach in a larger number of patients

Fish embryo vulnerability to combined acidification and warming coincides with a low capacity for homeostatic regulation

The vulnerability of fish embryos and larvae to environmental factors is often attributed to a lack of adult-like organ systems (gills) and thus insufficient homeostatic capacity. However, experimental data supporting this hypothesis are scarce. Here, by using Atlantic cod (Gadus morhua) as a model, the relationship between embryo vulnerability (to projected ocean acidification and warming) and homeostatic capacity was explored through parallel analyses of stage-specific mortality and in vitro activity and expression of major ion pumps (ATP-synthase, Na+/K+-ATPase, H+-ATPase) and co-transporters (NBC1, NKCC1). Immunolocalization of these transporters was used to study ionocyte morphology in newly hatched larvae. Treatment-related embryo mortality until hatching (+20% due to acidification and warming) occurred primarily during an early period (gastrulation) characterized by extremely low ion transport capacity. Thereafter, embryo mortality decreased in parallel with an exponential increase in activity and expression of all investigated ion transporters. Significant changes in transporter activity and expression in response to acidification (+15% activity) and warming (−30% expression) indicate some potential for short-term acclimatization, although this is probably associated with energetic trade-offs. Interestingly, whole-larvae enzyme activity (supported by abundant epidermal ionocytes) reached levels similar to those previously measured in gill tissue of adult cod, suggesting that early-life stages without functional gills are better equipped in terms of ion homeostasis than previously thought. This study implies that the gastrulation period represents a critical transition from inherited (maternal) defenses to active homeostatic regulation, which facilitates enhanced resilience of later stages to environmental factors