Cost-Effectiveness of Nivolumab Plus Ipilimumab for the First-Line Treatment of Intermediate/Poor-Risk Advanced and/or Metastatic Renal Cell Carcinoma in Switzerland.

OBJECTIVE: This study assessed the cost-effectiveness of nivolumab plus ipilimumab versus both sunitinib and pazopanib for the treatment of first-line unresectable advanced renal cell carcinoma (aRCC) from a healthcare system perspective in Switzerland. METHODS: A three-state partitioned survival model, consisting of progression-free, progressed disease, and death, was constructed. Efficacy estimates were based on data from the CheckMate 214 trial (NCT02231749) with a minimum follow-up of 42 months. Two Swiss oncologists were consulted to determine disease management resource use. Costs were derived from the Swiss tariff lists for outpatient (TARMED Online Browser 1.09) and inpatient (2020 data from Swiss diagnosis-related groups) treatments. Drug acquisition costs (ex-factory prices) were obtained from the March 2020 price list published by the Swiss Federal Office of Public Health. Treatment-specific EQ-5D-3L-based utilities were derived from CheckMate 214 using a French value set as a proxy for Switzerland. The model utilized a 1-week cycle length and a 40-year time horizon, with costs and effects discounted by 3.0% per annum. One-way sensitivity analyses, probabilistic analysis, and scenario analyses assessed the robustness of the results. RESULTS: Nivolumab plus ipilimumab yielded incremental 1.43 life-years and 1.36 lifetime discounted quality-adjusted life-years (QALYs) relative to sunitinib and pazopanib at an additional cost of 147,453 Swiss Francs (CHF) and CHF145,643, respectively. With an incremental cost-utility ratio of CHF108,326 per QALY gained versus sunitinib, and CHF106,996 per QALY gained versus pazopanib, the nivolumab plus ipilimumab combination can be considered a cost-effective option for the treatment of patients with aRCC in Switzerland, with a willingness-to-pay threshold of CHF200,000. Sensitivity and scenario analyses confirmed the robustness of the deterministic results. CONCLUSIONS: This study showed that nivolumab plus ipilimumab, which represents one of the standard-of-care first-line treatments for intermediate- or poor-risk aRCC patients, is a life-extending and cost-effective treatment option for patients in Switzerland.

Evidence for massive methane hydrate destabilization during the penultimate interglacial warming.

The stability of widespread methane hydrates in shallow subsurface sediments of the marine continental margins is sensitive to temperature increases experienced by upper intermediate waters. Destabilization of methane hydrates and ensuing release of methane would produce climatic feedbacks amplifying and accelerating global warming. Hence, improved assessment of ongoing intermediate water warming is crucially important, especially that resulting from a weakening of Atlantic meridional overturning circulation (AMOC). Our study provides an independent paleoclimatic perspective by reconstructing the thermal structure and imprint of methane oxidation throughout a water column of 1,300 m. We studied a sediment sequence from the eastern equatorial Atlantic (Gulf of Guinea), a region containing abundant shallow subsurface methane hydrates. We focused on the early part of the penultimate interglacial and present a hitherto undocumented and remarkably large intermediate water warming of 6.8 °C in response to a brief episode of meltwater-induced, modest AMOC weakening centered at 126,000 to 125,000 y ago. The warming of intermediate waters to 14 °C significantly exceeds the stability field of methane hydrates. In conjunction with this warming, our study reveals an anomalously low δ13C spike throughout the entire water column, recorded as primary signatures in single and pooled shells of multitaxa foraminifers. This extremely negative δ13C excursion was almost certainly the result of massive destabilization of methane hydrates. This study documents and connects a sequence of climatic events and climatic feedback processes associated with and triggered by the penultimate climate warming that can serve as a paleoanalog for modern ongoing warming.

Characteristics and outcomes of sepsis patients with and without COVID-19.

BACKGROUND: The aim of this study was to describe and compare clinical characteristics and outcomes in critically ill septic patients with and without COVID-19. METHODS: From February 2020 to March 2021, patients from surgical and medical ICUs at the University Hospital Dresden were screened for sepsis. Patient characteristics and outcomes were assessed descriptively. Patient survival was analyzed using the Kaplan-Meier estimator. Associations between in-hospital mortality and risk factors were modeled using robust Poisson regression, which facilitates derivation of adjusted relative risks. RESULTS: In 177 ICU patients treated for sepsis, COVID-19 was diagnosed and compared to 191 septic ICU patients without COVID-19. Age and sex did not differ significantly between sepsis patients with and without COVID-19, but SOFA score at ICU admission was significantly higher in septic COVID-19 patients. In-hospital mortality was significantly higher in COVID-19 patients with 59% compared to 29% in Non-COVID patients. Statistical analysis resulted in an adjusted relative risk for in-hospital mortality of 1.74 (95%-CI=1.35-2-24) in the presence of COVID-19 compared to other septic patients. Age, procalcitonin maximum value over 2 ng/ml, need for renal replacement therapy, need for invasive ventilation and septic shock were identified as additional risk factors for in-hospital mortality. CONCLUSION: COVID-19 was identified as independent risk factor for higher in-hospital mortality in sepsis patients. The need for invasive ventilation and renal replacement therapy as well as the presence of septic shock and higher PCT should be considered to identify high-risk patients.

Higher sea surface temperature in the Indian Ocean during the Last Interglacial weakened the South Asian monsoon.

SignificanceUnderstanding the drivers of South Asian monsoon intensity is pivotal for improving climate forecasting under global warming scenarios. Solar insolation is assumed to be the dominant driver of monsoon variability in warm climate regimes, but this has not been verified by proxy data. We report a South Asian monsoon rainfall record spanning the last ∼130 kyr in the Ganges-Brahmaputra-Meghna river catchment. Our multiproxy data reveal that the South Asian monsoon was weaker during the Last Interglacial (130 to 115 ka)-despite higher insolation-than during the Holocene (11.6 ka to present), thus questioning the widely accepted model assumption. Our work implies that Indian Ocean warming may increase the occurrence of severe monsoon failures in South Asia.

Smaller fish species in a warm and oxygen-poor Humboldt Current system.

Climate change is expected to result in smaller fish size, but the influence of fishing has made it difficult to substantiate the theorized link between size and ocean warming and deoxygenation. We reconstructed the fish community and oceanographic conditions of the most recent global warm period (last interglacial; 130 to 116 thousand years before present) by using sediments from the northern Humboldt Current system off the coast of Peru, a hotspot of small pelagic fish productivity. In contrast to the present-day anchovy-dominated state, the last interglacial was characterized by considerably smaller (mesopelagic and goby-like) fishes and very low anchovy abundance. These small fish species are more difficult to harvest and are less palatable than anchovies, indicating that our rapidly warming world poses a threat to the global fish supply.

Shewanella putrefaciens, a rare human pathogen: A review from a clinical perspective.

Shewanella putrefaciens is a gramnegative, facultatively anaerobic, rod shaped bacterium. It belongs to the class of the Gammaproteobacteria and was first described in 1931. S. putrefaciens is part of the marine microflora and especially present in moderate and warm climates. The bacterium is a rare oppurtonistic human pathogen associated mainly with intra-abdominal as well as skin and soft tissue infections. However, it has also been reported in association with more severe diseases such as pneumonia, intracerebral and ocular infections and endocarditis. In these cases the clinical courses are often associated with underlying, predisposing diseases and risk factors. For successful treatment of S. putrefaciens, a combination of appropriate local therapy, e.g. surgical treatment or drainage, and antibiotic therapy should be performed. Since multiple resistances to antibiotics are described, the results of the antimicrobial susceptibility testing must be considered for effective therapy as well. Furthermore, a main challenge in clinical practice is the accurate microbiological identification, and especially the correct differentiation between S. putrefaciens and S. algae. Under certain circumstances, Shewanella-infections can have severe, sometimes even fatal consequences. Therefore, we decided to present the current state of knowledge as well as further aspects with regard to future diagnostics, therapy and research.

Energy requirements of long-term ventilated COVID-19 patients with resolved SARS-CoV-2 infection.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can rapidly progress into acute respiratory distress syndrome accompanied by multi-organ failure requiring invasive mechanical ventilation and critical care treatment. Nutritional therapy is a fundamental pillar in the management of hospitalized patients. It is broadly acknowledged that overfeeding and underfeeding of intensive care unit (ICU) patients are associated with increased morbidity and mortality. This study aimed to assess the energy demands of long-term ventilated COVID-19 patients using indirect calorimetry and to evaluate the applicability of established predictive equations to estimate their energy expenditure. METHODS: We performed a retrospective, single-center study in 26 mechanically ventilated COVID-19 patients with resolved SARS-CoV-2 infection in three independent intensive care units. Resting energy expenditure (REE) was evaluated by repetitive indirect calorimetry (IC) measurements. Simultaneously the performance of 12 predictive equations was examined. Patient's clinical data were retrieved from electronic medical charts. Bland-Altman plots were used to assess agreement between measured and calculated REE. RESULTS: Mean mREE was 1687 kcal/day and 20.0 kcal relative to actual body weight (ABW) per day (kcal/kg/day). Longitudinal mean mREE did not change significantly over time, although mREE values had a high dispersion (SD of mREE ±487). Obese individuals were found to have significantly increased mREE, but lower energy expenditure relative to their body mass. Calculated REE showed poor agreement with mREE ranging from 33 to 54%. CONCLUSION: Resolution of SARS-CoV-2 infection confirmed by negative PCR leads to stabilization of energy demands at an average 20 kcal/kg in ventilated critically ill patients. Due to high variations in mREE and low agreement with calculated energy expenditure IC remains the gold standard for the guidance of nutritional therapy.

Fossil leaf wax hydrogen isotopes reveal variability of Atlantic and Mediterranean climate forcing on the southeast Iberian Peninsula between 6000 to 3000 cal. BP.

Many recently published papers have investigated the spatial and temporal manifestation of the 4.2 ka BP climate event at regional and global scales. However, questions with regard to the potential drivers of the associated climate change remain open. Here, we investigate the interaction between Atlantic and Mediterranean climate forcing on the south-eastern Iberian Peninsula during the mid- to late Holocene using compound-specific hydrogen isotopes from fossil leaf waxes preserved in marine sediments. Variability of hydrogen isotope values in the study area is primarily related to changes in the precipitation source and indicates three phases of increased Mediterranean sourced precipitation from 5450 to 5350 cal. BP, from 5150 to 4300 cal. BP including a short-term interruption around 4800 cal. BP, and from 3400 to 3000 cal. BP interrupted around 3200 cal. BP. These phases are in good agreement with times of prevailing positive modes of the North Atlantic Oscillation (NAO) and reduced storm activity in the Western Mediterranean suggesting that the NAO was the dominant modulator of relative variability in precipitation sources. However, as previously suggested other modes such as the Western Mediterranean Oscillation (WeMO) may have altered this overall relationship. In this regard, a decrease in Mediterranean moisture source coincident with a rapid reduction in warm season precipitation during the 4.2 ka BP event at the south-eastern Iberian Peninsula might have been related to negative WeMO conditions.

Habitat light sets the boundaries for the rapid evolution of cichlid fish vision, while sexual selection can tune it within those limits.

Cichlid fishes' famous diversity in body coloration is accompanied by a highly diverse and complex visual system. Although cichlids possess an unusually high number of seven cone opsin genes, they express only a subset of these during their ontogeny, accounting for their astonishing interspecific variation in visual sensitivities. Much of this diversity is thought to have been shaped by natural selection as cichlids inhabit a variety of habitats with distinct light environments. Also, sexual selection might have contributed to the observed visual diversity, and sexual dimorphism in coloration potentially co-evolved with sexual dimorphism in opsin expression. We investigated sex-specific opsin expression of several cichlids from Africa and the Neotropics and collected and integrated data sets on sex-specific body coloration, species-specific visual sensitivities, lens transmission and habitat light properties for some of them. We comparatively analysed this wide range of molecular and ecological data, illustrating how integrative approaches can address specific questions on the factors and mechanisms driving diversification, and the evolution of cichlid vision in particular. We found that both sexes expressed opsins at the same levels-even in sexually dimorphic cichlid species-which argues against coevolution of sexual dichromatism and differences in sex-specific visual sensitivity. Rather, a combination of environmental light properties and body coloration shaped the diversity in spectral sensitivities among cichlids. We conclude that although cichlids are particularly colourful and diverse and often sexually dimorphic, it would appear that natural rather than sexual selection is a more powerful force driving visual diversity in this hyperdiverse lineage.

Case Report: New-Onset Retinal Migraine After Transseptal Catheterization.

BACKGROUND: While new-onset migraine headaches and binocular visual aura have been reported after transseptal catheterization (TSC), this case suggests that retinal aura may emerge also after this procedure. CASE DESCRIPTION: This 38-year-old male with paroxysmal atrial fibrillation had received TSC and cryoablation, and subsequently developed isolated monocular aura phenomena. The first episode happened a few hours after the intervention and was not accompanied by headache or other aura phenomena. The patient's history was negative for migraine. Brain magnetic resonance imaging demonstrated 2 lacunar diffusion restrictions in the left medial cerebral artery territory that were most likely catheterization related. Over the next 14 days, 3 additional, stereotyped episodes (duration = 20-30 minutes) with zigzag lines and flickering small bright dots in the central visual field of one eye (moving laterally) occurred. A central scotoma was noted during one episode. CONCLUSIONS: This is the first case with retinal aura phenomena meeting International Classification of Headache Disorders diagnostic criteria for retinal migraine, suggesting that this rare migraine variant can be triggered by TSC.

An oceanic perspective on Greenland's recent freshwater discharge since 1850.

Instrumental data evidence an accelerating freshwater release from Arctic sea ice export and the Greenland Ice Sheet over the past three decades causing cooling and freshening in the subpolar North Atlantic region. However, evaluating the observed acceleration on a historical oceanic and climatic perspective remains challenging given the short available instrumental time series. Here we provide a marine perspective on the freshwater releases to the ocean since 1850 as reflected in the northern limb of the Subpolar Gyre. Our reconstructions suggest that the recent acceleration tracks back to the 1940s/50s and is unprecedented since 1850. The melting, initiated by the 1920s natural rise in solar irradiance, accelerated in response to a combined effect of natural and anthropogenic forcing factors. We find that Greenland's freshwater discharge has contributed to a nutrient-driven fertilization of the upper ocean and consequently increased the marine primary productivity since the 1940s/50s.

Long-Term Results After Stapled Hemorrhoidopexy: A 15-Year Follow-Up.

BACKGROUND: The stapled hemorrhoidopexy is reported to have a low recurrence while treating the major hemorrhoidal symptoms of bleeding and prolapse. The aim of this study is to obtain long-term results on the outcome of the stapled hemorrhoidopexy. METHODS: All patients with a hemorrhoidal disease grade III, who underwent stapled hemorrhoidopexy from May 1999-December 2003, were included. Data collection was based on a standardized telephone interview. In the questionnaire, we recorded information regarding the postoperative recurrence and severity of hemorrhoidal symptoms (defined as bleeding, prolapse, burning, itching and moisture), further hemorrhoidal treatments and functional results (incontinence, fecal urgency and outlet obstruction) as well as patients' satisfaction. RESULTS: Of the 257 patients, who underwent stapled hemorrhoidopexy, follow-up data were available in 140 patients. In 47.4% of the patients, a recurrence of at least one hemorrhoidal symptom was registered, whereas this recurrence was observed in 47.3% of these patients more than 10 years postoperatively. A surgical re-intervention was necessary in 15.2%. We found a postoperative new incontinence in 15.5%, a fecal urgency in 28.0% and an outlet obstruction in 9.4%. Of all patients, 62.3% were "very satisfied" with the operation. CONCLUSIONS: The results of the study revealed a relatively high recurrence of hemorrhoidal symptoms after a mean follow-up of 15 years with a high recurrence rate more than 10 years postoperatively. In consideration of not negligible risk of incontinence, fecal urgency and outlet obstruction, the indication for a stapled hemorrhoidopexy should be made well considered. However, patients' satisfaction is very high.

Minimally Invasive Parathyroidectomy without Intraoperative PTH Performed after Positive Ultrasonography as the only Diagnostic Method in Patients with Primary Hyperparathyroidism.

BACKGROUND: A positive and concordant result of at least two diagnostic modalities is generally recommended prior to focused parathyroidectomy. The aim of this study was to analyze the results of surgery and the accurateness of preoperative ultrasonography (US) as single localization modality in patients who underwent parathyroidectomy without the adjunct of intraoperative Parathormone (PTH) measurement. METHODS: The cases with a preoperative US as the only localization technique, who underwent parathyroidectomy between 10/1999 and 12/2017, were selected from a prospectively maintained database. Therefore, a total number of 242 patients with a mean age of 58.6 ± 13.7 years were included in the present study. US was performed by referral endocrinologist or by the surgeon during office visits. RESULTS: The overall "cure rate" was 99.2% (240 out of 242 patients). In 228/242 patients (94.2%), a drop of perioperative PTH levels consistent with the definition of cure was observed on the day of surgery. In four of the remaining 14 patients, healing was confirmed by PTH level dropping into the normal range on the first postoperative day. Eight patients were cured after a reoperation was performed at our department. Postoperative complications included one case of permanent recurrent laryngeal nerve palsy (0.4%). CONCLUSIONS: If performed by an experienced endocrinologist and/or endocrine surgeon, a positive US could be the only preoperative localization study in patients with pHPT. Moreover, the add-value of intraoperative PTH is limited. Major advantages of US are a very high accuracy, the ease of performance (accessibility) and its cost-effectiveness compared with Sesta-MIBI scintigraphy.

Labrador Sea freshening at 8.5 ka BP caused by Hudson Bay Ice Saddle collapse.

A significant reduction in the Atlantic Meridional Overturning Circulation and rapid northern Hemisphere cooling 8200 years ago have been linked to the final melting of the Laurentide Ice Sheet. Although many studies associated this cold event with the drainage of Lake Agassiz-Ojibway, recent model simulations have shown that the Hudson Bay Ice Saddle collapse would have had much larger effects on the Atlantic Meridional Overturning Circulation than the lake outburst itself. Based on a combination of Mg/Ca and oxygen isotope ratios of benthic foraminifera, this study presents the first direct evidence of a major Labrador shelfwater freshening at 8.5 ka BP, which we associate with the Hudson Bay Ice Saddle collapse. The freshening is preceded by a subsurface warming of the western Labrador Sea, which we link to the strengthening of the West Greenland Current that could concurrently have accelerated the ice saddle collapse in Hudson Bay.

Influence of Parathyroidectomy on Bone Metabolism and Bone Pain in Patients with Secondary Hyperparathyroidism.

BACKGROUND: After parathyroidectomy (PTX), hungry bone syndrome leads to hypocalcemia due to bone remineralization. The aim of this pilot study was to analyze changes in markers of bone metabolism in patients with secondary hyperparathyroidism (sHPT) after PTX and to correlate these markers with bone pain measured with a validated questionnaire. MATERIALS AND METHODS: All patients who underwent PTX for sHPT between March 2010 and February 2012 at out institution were included in this prospective observational pilot study. At the day before surgery and on the 3rd day thereafter, levels of parathyroid hormone (PTH), calcium, osteocalcin, alkaline phosphatase (AP), bone-specific AP (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), osteoprotegerin (OPG), sclerostin, fibroblast growth factor 23, and Klotho were measured. Additionally, all patients were requested to answer the Brief Pain Inventory preoperatively and on the 5th postoperative day. RESULTS: A total of 35 patients with a mean age of 49.8 years were analyzed. A significant difference between the pre- and postoperative values could be detected in PTH, calcium, BAP, TRAP5b, and sclerostin. The highest correlation of laboratory markers with bone pain was found for preoperative PTH (r = 0.3), postoperative OPG (r = 0.4), postoperative BAP (r = -0.4), and postoperative Klotho (r = -0.4). CONCLUSIONS: The present study revealed significant perioperative changes in PTH, BAP, sclerostin, and TRAP5b after PTX. These markers may serve as laboratory markers to monitor bone metabolism in patients with sHPT. PTH, OPG, and sclerostin were the parameters with the closest correlation to bone pain. However, larger prospective trials with a longer follow-up are required to confirm these results.

Shock efficacy of single and dual coil electrodes-new insights from the NORDIC ICD Trial.

Aims: Dual coil (DC) electrodes are preferred to single coil (SC) electrodes because of an assumed higher shock efficacy. However, DC-electrodes may be associated with an increased difficulty and risk of lead extraction. We aimed to compare SC- and DC-electrodes with respect to the first shock efficacy (FSE) after implantable cardioverter defibrillator (ICD) implantation. Methods and results: One thousand and seventy-seven patients of the NORDIC ICD trial were randomly assigned to first time ICD implantation with or without defibrillation (DF) testing. The electrode configuration was determined before randomization. One thousand and sixty-seven patients eventually received an ICD, 516 (48.4%) with a SC- and 551 (51.6%) with a DC-electrode. DC-electrodes were preferentially selected in older patients, renal failure, atrial fibrillation, dual chamber, Cardiac Resynchronization Therapy (CRT) devices, angiotensin-converting-enzyme (ACE) inhibitors/angiotensin (AT) receptor blockers and without Sotalol. However, the preference of the investigational site was dominant over clinical parameters. The DF energy at the final electrode position was higher in SC-electrodes (adjusted difference +1.15 J; P = 0.005; only patients tested). Less patients with DC-electrodes required intra-operative system reconfiguration (adjusted difference -3.9; P = 0.046; only patients tested). Using mixed logistic regression, the FSE was 92.6% in SC- and 97.8% in DC-electrodes (adjusted odds ratio 4.3 (95% confidence interval [1.9, 9.8]; P < 0.001)). Conclusion: Dual coil-electrode selection mainly depends on the preference of the investigational site and seems to be preferred in older patients, renal failure, atrial fibrillation, dual chamber, and CRT devices. Patients with DC-electrodes required less intraoperative system reconfigurations. Dual coil-electrodes provided a substantially higher FSE during follow-up. Mortality rates were not significantly different in patients with DC- and SC-electrodes.

Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span.

The shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 expression in both adult (1-year-old) and old (2-year-old) mice using gene therapy can delay age-associated pathologies. To this end, we used the nonintegrative adeno-associated serotype 9 vector (AAV9), which transduces the majority of mouse tissues allowing for moderate and transient TRF1 overexpression. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues. Together, these findings suggest that rescuing naturally decreased TRF1 levels during mouse aging using AAV9-TRF1 gene therapy results in an improved mouse health span.

The Benefit of Benzodiazepine Reduction: Improving Sedation in Surgical Intensive Care.

AIMS: Sedation, as it is often required in critical care, is associated with immobilization, prolonged ventilation, and increased morbidity. Most sedation protocols are based on benzodiazepines. The presented study analyzes the benefit of benzodiazepine-free sedation. METHODS: In 2008, 134 patients were treated according to a protocol using benzodiazepine and propofol (Group 1). In 2009, we introduced a new sedation strategy based on sufentanil, nonsteroidal anti-inflammatory drugs, neuroleptics, and antidepressants, which was applied in 140 consecutive patients (Group 2). Depth of sedation, duration of mechanical ventilation, duration of Intensive Care Unit, and hospital stay were analyzed. RESULTS: Group 1 had both a longer duration of deep sedation (18.7 ± 2.5 days vs. 12.6 ± 1.85 days, P = 0.031) and a longer duration of controlled ventilation (311, 35 ± 32.69 vs. 143, 96 ± 20.76 h, P < 0.0001) than Group 2. Ventilator days were more frequent in Group 1 (653, 66 ± 98.37 h vs. 478, 89 ± 68.92 h, P = 0.128). CONCLUSIONS: The benzodiazepine-free sedation protocol has been shown to significantly reduce depth of sedation and controlled ventilation. Additional evidence is needed to ascertain reduction of ventilator days which would not only be of benefit for the patient but also for the hospital Management.

Telomere Length Defines the Cardiomyocyte Differentiation Potency of Mouse Induced Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSCs) can be differentiated in vitro and in vivo to all cardiovascular lineages and are therefore a promising cell source for cardiac regenerative therapy. However, iPSC lines do not all differentiate into cardiomyocytes (CMs) with the same efficiency. Here, we show that telomerase-competent iPSCs with relatively long telomeres and high expression of the shelterin-complex protein TRF1 (iPSChighT ) differentiate sooner and more efficiently into CMs than those with relatively short telomeres and low TRF1 expression (iPSClowT ). Ascorbic acid, an enhancer of cardiomyocyte differentiation, further increases the cardiomyocyte yield from iPSChighT but does not rescue the cardiomyogenic potential of iPSClowT . Interestingly, although iPSCslowT differentiate very poorly to the mesoderm and endoderm lineages, they differentiate very efficiently to the ectoderm lineage, indicating that cell fate can be determined by in vitro selection of iPSCs with different telomere content. Our findings highlight the importance of selecting iPSCs with ample telomere reserves in order to generate high numbers of CMs in a fast, reliable, and efficient way. Stem Cells 2017;35:362-373.