Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.

Avapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The approval was based on the NAVIGATOR trial, which revealed overall response rates of more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation due to neuro-cognitive side effects. These patients have no therapeutic alternative and face a dismal prognosis. Notable, little is known about this drug's binding mode and its medicinal chemistry development, which is instrumental for the development of the next generation of drugs. Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.

The dissociation of (a+c) misfit dislocations at the InGaN/GaN interface.

In hexagonal materials, (a+c) dislocations are typically observed to dissociate into partial dislocations. Edge (a+c) dislocations are introduced into (0001) nitride semiconductor layers by the process of plastic relaxation. As there is an increasing interest in obtaining relaxed InGaN buffer layers for the deposition of high In content structures, the study of the dissociation mechanism of misfit (a+c) dislocations laying at the InGaN/GaN interface is then crucial for understanding their nucleation and glide mechanisms. In the case of the presented plastically relaxed InGaN layers deposited on GaN substrates, we observe a trigonal network of (a+c) dislocations extending at the interface with a rotation of 3° from <1 1 ¯ $\bar 1$ 00> directions. High-resolution microscopy studies show that these dislocations are dissociated into two Frank-Shockley 1/6<2 2 ¯ $\bar 2$ 03> partial dislocations with the I1 BSF spreading between them. Atomistic simulations of a dissociated edge (a+c) dislocation revealed a 3/5-atom ring structure for the cores of both partial dislocations. The observed separation between two partial dislocations must result from the climb of at least one of the dislocations during the dissociation process, possibly induced by the mismatch stress in the InGaN layer.

Primary laparoscopic fundoplication in selected patients with gastroesophageal reflux disease.

BACKGROUND: Despite proton pump inhibitors being a powerful therapeutic tool, laparoscopic fundoplication (LF) has proven successful in the treatment of gastroesophageal reflux disease (GERD), through mechanical augmentation of a weak antireflux barrier and the advantages of minimally invasive access. A critical patient selection for LF, based on thorough preoperative assessment, is important for the management of GERD-patients. The purpose of this study is to provide an overview on the management of GERD-patients treated by primary LF in a specialized center and to illustrate the possible outcome after several years. METHODS: Patients were selected after going through diagnostic workup consisting of patient's history and physical examination, upper gastrointestinal endoscopy, assessment of gastrointestinal Quality of Life Index, screening for somatoform disorders, functional assessment by esophageal manometry, (impedance)-24-hour-pH-monitoring, and selective radiographic studies. The indication for LF was based on EAES-guidelines. Either a floppy and short Nissen fundoplication was performed or a posterior Toupet-hemifundoplication was chosen. A long-term follow-up assessment was attempted after surgery. RESULTS: In total, n = 1131 patients were evaluated (603 males; 528 females; mean age; 48.3 years; and mean body mass index: 27). The mean duration between onset of symptoms and surgery was 8 years. Nissen: n = 873, Toupet: n = 258; conversion rateerativ: 0.5%; morbidity 4%, mortality: 1 (1131). Mean follow-up (n = 898; 79%): 5.6 years; pre/post-op results: esophagitis: 66%/12.1%; Gastrointestinal Quality of Life Index: median: 92/119; daily proton pump inhibitors-intake after surgery: 8%; and operative revisions 4.3%. CONCLUSIONS: In conclusion, our data show that careful patient selection for laparoscopic fundoplication and well-established technical concepts of mechanical sphincter augmentation can provide satisfying results in the majority of patients with severe GERD.

Human cytomegalovirus multiple-strain infections and viral population diversity in haematopoietic stem cell transplant recipients analysed by high-throughput sequencing.

Human cytomegalovirus (HCMV) is an important opportunistic pathogen in allogeneic haematopoietic stem cell transplant (HSCT) recipients. High-throughput sequencing of target-enriched libraries was performed to characterise the diversity of HCMV strains present in this high-risk group. Forty-four HCMV-DNA-positive plasma specimens (median viral input load 321 IU per library) collected at defined time points from 23 HSCT recipients within 80 days of transplantation were sequenced. The genotype distribution for 12 hypervariable HCMV genes and the number of HCMV strains present (i.e. single- vs. multiple-strain infection) were determined for 29 samples from 16 recipients. Multiple-strain infection was observed in seven of these 16 recipients, and five of these seven recipients had the donor (D)/recipient (R) HCMV-serostatus combination D + R + . A very broad range of genotypes was detected, with an intrahost composition that was generally stable over time. Multiple-strain infection was not associated with particular virological or clinical features, such as altered levels or duration of antigenaemia, development of acute graft-versus-host disease or increased mortality. In conclusion, despite relatively low viral plasma loads, a high frequency of multiple-strain HCMV infection and a high strain complexity were demonstrated in systematically collected clinical samples from this cohort early after HSCT. However, robust evaluation of the pathogenic role of intrahost viral diversity and multiple-strain infection will require studies enrolling larger numbers of recipients.

Double-Unit Superomedio-Central (DUS) Pedicle Inverted-T Reduction Mammaplasty in Gigantomastia: A 7-year Single-Center Retrospective Study.

INTRODUCTION: Reduction mammaplasty in patients with gigantomastia is challenging. The Double-Unit technique with a Superomedio-Central pedicle and inverted-T incision is the standard technique for reduction mammaplasty in our clinic. The aim of this study was to review our approach in cases with gigantomastia in comparison with the current literature. PATIENTS AND METHODS: From 01/2011 to 12/2017, we performed 831 reduction mammaplasties in 630 patients. The Double-Unit  Superomedio-Central  (DUS) pedicle and inverted-T incision was implemented as a standard procedure for gigantomastia. Patient demographics and the outcome parameters complication rate, patient satisfaction with the aesthetic result, nipple sensibility, and surgical revision rate were obtained and retrospectively analyzed. RESULTS: In 37 patients, 55 reduction mammaplasties were performed with more than 1000 g per breast. Mean resection weight was 1311 g on right side and 1289 g on left side. Mean age was 52.5 years, mean body mass index was 32.8 kg/m2, mean sternal-notch-to-nipple distance was 38.3 cm. A free NAC graft was necessary in four breasts. Overall complication rate was 14.5%; secondary surgical revision rate was 12.7%. 91% of the patients were "very satisfied" and "satisfied" with the aesthetic result. Nipple sensibility was rated "high" and "medium" in 83%. CONCLUSION: The Double-Unit technique with a Superomedio-Central pedicle and inverted-T incision is very effective to achieve volume reduction and aesthetically pleasing reproducible results with a low complication rate in cases with gigantomastia. LEVEL OF EVIDENCE: Level of Evidence This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Development of the ion cyclotron emission diagnostic for the W7-X stellarator.

An ion cyclotron emission (ICE) diagnostic is prepared for installation into the W7-X stellarator, with the aim to be operated in the 2022 experimental campaign. The design is based on the successful ICE diagnostic on the ASDEX Upgrade tokamak. The new diagnostic consists of four B-dot probes, mounted about 72° toroidally away (one module) from the neutral beam injector, with an unobstructed plasma view. Two of the B-dot probes are oriented parallel to the local magnetic field, aimed to detect fast magnetosonic waves. The remaining two probes are oriented poloidally, with the aim to detect slow waves. The radio frequency (RF) signals picked up by the probes are transferred via 50 Ω vacuum-compatible coaxial cables to RF detectors. Narrow band notch filters are used to protect the detectors from possible RF waves launched by the W7-X antenna. The signal will be sampled with a four-channel fast analog-to-digital converter with 14 bit depth and 1 GSample/s sampling rate. The diagnostic's phase-frequency characteristic is properly measured in order to allow measuring the wave vectors of the picked up waves.

[The 8th edition of the TNM staging system-a curse or a blessing for oropharyngeal carcinoma?] / Die 8. Version der TNM-Klassifikation ­ Fluch oder Segen für das Oropharynxkarzinom?

At the beginning of 2017, the 8th edition of the TNM classification was presented. For oropharyngeal carcinoma, this was accompanied by a paradigm shift, as a separation of the classification depending on the association with human papillomavirus (HPV) status has been established. By considering the literature, this paper provides an overview of the characteristics of HPV-associated carcinomas, the new features of the TNM classification, and the existing points of discussion. The revision has improved the prognostic significance of the TNM classification; however, there are still tumor- and patient-dependent influencing factors that must be considered for future versions.

Diabetes self-management education exposure and glycated haemoglobin levels among Marshallese participants in a randomized controlled study.

AIMS: A randomized control trial (RCT) of diabetes self-management education (DSME), undertaken by a community-based participatory research (CBPR) partnership between the University of Arkansas for Medical Sciences (UAMS) and the Marshallese community in Arkansas. The RCT examined the effect of hours of intervention exposure, with the hypothesis that increased exposure is one reason the Adapted-Family DSME was found to be more effective than the Standard DSME. METHODS: Some 221 Marshallese with type 2 diabetes were randomized to an Adapted-Family DSME group (in-home setting) (n = 110) or a Standard DMSE group (community setting) (n = 111). The Adapted-Family DSME included 10 h of education that covered the core self-care elements recommended by the American Diabetes Association (ADA) and American Association of Diabetes Educators' (AADE) recommendations. The Standard DSME included 10 h of intervention with all ADA and AADE core elements. RESULTS: The number of hours of intervention exposure in the Adapted-Family DSME arm (mean = 8.0; median = 10.0) was significantly higher than the number of hours of intervention received in the Standard DSME arm (mean = 1.5; median = 0.0). As hypothesized, higher exposure was associated with a significant reduction in HbA1c in a model including only study arm and exposure (P = 0.01), and in a model including study arm, exposure, and all demographic variables (P = 0.046). CONCLUSIONS: This finding is consistent with previous reviews that showed increased exposure to DSME produced improved glycaemic control and ≥ 10 h of DSME produces clinically meaningful reductions in HbA1c .

Poly (Butyl Acrylate)-Graft-Polystyrene Synthesis by Free-Radical Polymerization: Interplay between Structure, Morphology, Mechanical, and Optical Properties.

We report a new method of preparation of poly (butyl acrylate)-g-polystyrene/polystyrene blends by free-radical polymerization. Copolymerization of glycidyl (meth)acrylate with butyl acrylate is followed by a polymer analogous reaction of this copolymer with acrylic acid and subsequent copolymerization of the modified backbone with styrene. Investigation on the number of reactive groups per backbone chain and its molecular weight allows grafting efficiencies of about 35% to be reached, as well as low cross-linking. Blends of nanophase-separated copolymers having a backbone with Mn of around 50 kg/mol and 4 reactive groups per chain are transparent, with haze as low as 14%, tensile strength of around 22 MPa, and elongations at the break of around 3%. Correlation between morphology determined by transmission electron microscopy and properties of the blend is established.

Role of hole confinement in the recombination properties of InGaN quantum structures.

We study the isolated contribution of hole localization for well-known charge carrier recombination properties observed in conventional, polar InGaN quantum wells (QWs). This involves the interplay of charge carrier localization and non-radiative transitions, a non-exponential decay of the emission and a specific temperature dependence of the emission, denoted as "s-shape". We investigate two dimensional In0.25Ga0.75N QWs of single monolayer (ML) thickness, stacked in a superlattice with GaN barriers of 6, 12, 25 and 50 MLs. Our results are based on scanning and high-resolution transmission electron microscopy (STEM and HR-TEM), continuous-wave (CW) and time-resolved photoluminescence (TRPL) measurements as well as density functional theory (DFT) calculations. We show that the recombination processes in our structures are not affected by polarization fields and electron localization. Nevertheless, we observe all the aforementioned recombination properties typically found in standard polar InGaN quantum wells. Via decreasing the GaN barrier width to 6 MLs and below, the localization of holes in our QWs is strongly reduced. This enhances the influence of non-radiative recombination, resulting in a decreased lifetime of the emission, a weaker spectral dependence of the decay time and a reduced s-shape of the emission peak. These findings suggest that single exponential decay observed in non-polar QWs might be related to an increasing influence of non-radiative transitions.

How accurately do routinely reported HIV viral load suppression proportions reflect progress towards the 90-90-90 target in the population on antiretroviral treatment in Khayelitsha, South Africa?

BACKGROUND: The Joint United Nations Programme on HIV/AIDS (UNAIDS) third 90-90-90 target requires 90% of patients on antiretroviral treatment (ART) to be virally suppressed (<1 000 copies/mL). In Khayelitsha, Cape Town, South Africa viral load (VL) suppression of <400 copies/mL was reported as 89% in 2016, but only 56% of patients had a result recorded in routine data. We conceived a VL 'cascade' to represent the steps required for an expected VL to be reported as complete in routine data and thus contribute to reported VL suppression: among those for whom a VL is 'expected', a sample must be collected and tested ('done'), a result must be 'filed' in the patient folder, 'noted' by a clinician and electronically 'captured'. The low reported completion suggested gaps along the VL cascade and cast doubt on the validity of reported suppression. OBJECTIVES: To assess the validity of routinely reported VL suppression and identify barriers to VL completion. METHODS: A retrospective cohort study between 1 July 2015 and 30 June 2016, which included all Khayelitsha patients receiving ART, with a routine VL expected, was conducted. We obtained data routinely captured on site and VL data from the laboratory system. A sample of 1 035 patient folders was reviewed. VL suppression was calculated using laboratory data, including all tests done, and compared with reported suppression based on on-site captured electronic data. Successful progression through each step on the VL cascade was estimated. We used logistic regression to identify factors associated with laboratory data and reported VL testing. RESULTS: Of 22 991 patients for whom a routine VL test was due, 84% were done, 79% filed, 76% noted and 55% captured. Using all laboratory data, VL suppression was  estimated as 82%, 87%, 89% and 91% at the 50, 200, 400 and 1 000 copies/mL thresholds, respectively, but reported suppression using captured results was 80%, 86%, 88% and 89% at those thresholds. Routine VL testing is more likely to be done in children <15 years old (adjusted odds ratio (aOR) 1.89, 95% confidence interval (CI) 1.45 - 2.48) and pregnant women (aOR 1.90, 95% CI 1.28 - 2.81) than in men, adjusted for facility. CONCLUSIONS: Despite a low reported completion, VL testing completion was high. Reported suppression using captured data was similar to suppression calculated using all laboratory data, which provided an accurate measure of progress towards the 90-90-90 target. More work is needed to reach the 16% of patients missed by routine testing.

Qualitative study of the factors impacting antimicrobial stewardship programme delivery in regional and remote hospitals.

BACKGROUND: Many regional and remote ('regional') hospitals are without the specialist services that support antimicrobial stewardship (AMS) programmes in hospitals in major cities. This can impact their ability to implement AMS activities. AIM: To identify factors that impact on the delivery of AMS programmes in regional hospitals. METHODS: Healthcare clinicians who have primary AMS responsibilities or provide AMS support to a health service or across health services with an Australian Statistical Geography Standard Remoteness classification of inner regional, outer regional, remote or very remote were recruited purposively and via snowballing. A series of focus groups and interviews were held, and the discussions were audiotaped and transcribed verbatim. The transcripts were coded by two researchers, and thematic analysis was undertaken using a framework method. FINDINGS: Four focus groups and one interview were conducted (22 participants). Six main themes that impacted on AMS programme delivery were identified: culture of independence and self-reliance by local clinicians, personal relationships, geographical location of the hospital influencing antimicrobial choice, local context, inability to meaningfully benchmark performance, and lack of resources. Possible strategies to support the delivery of AMS programmes in regional hospitals proposed by participants were categorized into two main themes: those that may be best developed or managed centrally, and those that should be a local responsibility. CONCLUSION: AMS programme delivery in regional hospitals is influenced by factors that are not present in hospitals in major cities. These findings provide a strong basis for the development of strategies to support regional hospitals to implement sustainable AMS programmes.

How accurately do routinely reported HIV viral load suppression proportions reflect progress towards the 90-90-90 target in the population on antiretroviral treatment in Khayelitsha, South Africa?

Background. The Joint United Nations Programme on HIV/AIDS (UNAIDS) third 90-90-90 target requires 90% of patients on antiretroviral treatment (ART) to be virally suppressed (<1 000 copies/mL). In Khayelitsha, Cape Town, South Africa viral load (VL) suppression of <400 copies/mL was reported as 89% in 2016, but only 56% of patients had a result recorded in routine data. We conceived a VL 'cascade' to represent the steps required for an expected VL to be reported as complete in routine data and thus contribute to reported VL suppression: among those for whom a VL is 'expected', a sample must be collected and tested ('done'), a result must be 'filed' in the patient folder, 'noted' by a clinician and electronically 'captured'. The low reported completion suggested gaps along the VL cascade and cast doubt on the validity of reported suppression.Objectives. To assess the validity of routinely reported VL suppression and identify barriers to VL completion. Methods. A retrospective cohort study between 1 July 2015 and 30 June 2016, which included all Khayelitsha patients receiving ART, with a routine VL expected, was conducted. We obtained data routinely captured on site and VL data from the laboratory system. A sample of 1 035 patient folders was reviewed. VL suppression was calculated using laboratory data, including all tests done, and compared with reported suppression based on on-site captured electronic data. Successful progression through each step on the VL cascade was estimated. We used logistic regression to identify factors associated with laboratory data and reported VL testing.Results. Of 22 991 patients for whom a routine VL test was due, 84% were done, 79% filed, 76% noted and 55% captured. Using all laboratory data, VL suppression was estimated as 82%, 87%, 89% and 91% at the 50, 200, 400 and 1 000 copies/mL thresholds, respectively, but reported suppression using captured results was 80%, 86%, 88% and 89% at those thresholds. Routine VL testing is more likely to be done in children <15 years old (adjusted odds ratio (aOR) 1.89, 95% confidence interval (CI) 1.45 - 2.48) and pregnant women (aOR 1.90, 95% CI 1.28 - 2.81) than in men, adjusted for facility. Conclusions. Despite a low reported completion, VL testing completion was high. Reported suppression using captured data was similar to suppression calculated using all laboratory data, which provided an accurate measure of progress towards the 90-90-90 target. More work is needed to reach the 16% of patients missed by routine testing

Modification of Dzyaloshinskii-Moriya-Interaction-Stabilized Domain Wall Chirality by Driving Currents.

We measure and analyze the chirality of Dzyaloshinskii-Moriya-interaction (DMI) stabilized spin textures in multilayers of Ta|Co_{20}F_{60}B_{20}|MgO. The effective DMI is measured experimentally using domain wall motion measurements, both in the presence (using spin-orbit torques) and absence of driving currents (using magnetic fields). We observe that the current-induced domain wall motion yields a change in effective DMI magnitude and opposite domain wall chirality when compared to field-induced domain wall motion (without current). We explore this effect, which we refer to as current-induced DMI, by providing possible explanations for its emergence, and explore the possibility of its manifestation in the framework of recent theoretical predictions of DMI modifications due to spin currents.

Does postexercise modelled capillary blood flow accurately reflect cardiovascular effects by different exercise intensities?

Blood flow (BF) in exercising muscles is an important factor for exercise capacity. Recently, a non-invasive method to estimate capillary BF (Qcap ) was introduced. Using this method, the Fick principle is re-arranged by using relative differences in deoxygenated haemoglobin (ΔHHb) as a surrogate for arteriovenous O2 difference and pulmonary oxygen uptake (VO2 ) instead of muscular oxygen uptake. The aim of this study was to examine (I) the relationship between Qcap and exercise intensity during and following exercise, and (II) to critically reflect the Qcap approach. Seventeen male subjects completed six bouts of cycling exercise with different exercise intensities (40-90% peak oxygen uptake, VO2peak ) in randomized order. VO2 and ΔHHb were monitored continuously during the trail. Qcap was modelled bi-exponentially, and mean response time (MRT) was calculated during recovery as well as the dissociation of modelled VO2 and Qcap recovery kinetics (MRT/τVO2 ). End-exercise Qcap increased continuously with exercise intensity. This also applied to MRT. Postexercise MRT/τVO2 increased from 40 to 60% VO2peak but remained stable thereafter. The results show that Qcap response to exercise is linearly related to exercise intensity. This is presumably due to vasoactive factors like shear-stress or endothelial-mediated vasodilation. MRT/τVO2 shows that postexercise Qcap is elevated for a longer period than VO2 , which is representative for metabolic demand following exercise ≥70% VO2peak . This is a hint for prolonged local vasodilation. According to previous studies, Qcap could not be modelled properly in some cases, which is a limitation to the method and therefore has to be interpreted with caution.

Changes of the bone structure after cap resurfacing arthroplasty of the humeral head.

INTRODUCTION: Although humeral head resurfacing with a cap is relatively common in clinical practice, clinical studies about the changes of the bone are rare. The aim of this study was to analyse qualitative and quantitative changes of the bone after cup arthroplasty. Our hypothesis is that the implant leads to a new functional load with remarkable changes of the bone underneath the cap. MATERIAL AND METHODS: Overall, 12 explanted caps with adherent bone tissues, retrieved at the revision surgery, were collected for histological examination. None of these implants were revised for loosening. Afterwards, there was a qualitative evaluation of the bone as well an assessment of established quantitative bone tissue parameters. Results were analyzed in correlation to the time to revision surgery, as well as to patient's age. RESULTS: A significant decrease of the bone volume and trabecular architecture underneath the cap was already observed after a relatively short lifetime. The quantitatively measured bone loss does not depend on the patient's age, but correlates significantly with the lifetime of the implants. In contrast to these findings within the central areas, an increased bone remodeling with bone densifications and microcallus formations was noticed at the edge of the cap in most cases. DISCUSSION: A significant reduction of the bone volume underneath the cap and remarkable changes of the trabecular architecture confirm our hypothesis. Even if these changes did not lead to a clinically relevant loosening in our series, they might influence revision surgeries. Thus, these findings might be of interest, especially when a non-stemmed reversed or anatomical revision arthroplasty with a central metaphyseal press-fit fixation is chosen. LEVEL OF EVIDENCE: IV - retrospective or historical series.

The anticipated and the lived experience of home and in-centre haemodialysis: Is there a disconnect?

This qualitative study aimed to explore home haemodialysis and in-centre haemodialysis patients' experience, to illuminate barriers and facilitators in the uptake and maintenance of home haemodialysis. Thirty-two semi-structured interviews with patients receiving home haemodialysis or in-centre haemodialysis were analysed using framework analysis. Four themes emerged: 'perceptions of self'; 'impact of haemodialysis on family'; 'perceived advantages and disadvantages of home haemodialysis and in-centre haemodialysis' and 'practical issues and negotiating haemodialysis'. The lived experience of home haemodialysis was in contrast to the lived experience of in-centre haemodialysis and to the anticipated experience of home haemodialysis, highlighting patient factors that contributed to under-usage of home haemodialysis.

End-exercise ΔHHb/ΔVO2 and post-exercise local oxygen availability in relation to exercise intensity.

Increased local blood supply is thought to be one of the mechanisms underlying oxidative adaptations to interval training regimes. The relationship of exercise intensity with local blood supply and oxygen availability has not been sufficiently evaluated yet. The aim of this study was to examine the effect of six different intensities (40-90% peak oxygen uptake, VO2peak ) on relative changes in oxygenated, deoxygenated and total haemoglobin (ΔO2 Hb, ΔHHb, ΔTHb) concentration after exercise as well as end-exercise ΔHHb/ΔVO2 as a marker for microvascular O2 distribution. Seventeen male subjects performed an experimental protocol consisting of 3 min cycling bouts at each exercise intensity in randomized order, separated by 5 min rests. ΔO2 Hb and ΔHHb were monitored with near-infrared spectroscopy of the vastus lateralis muscle, and VO2 was assessed. ΔHHb/ΔVO2 increased significantly from 40% to 60% VO2 peak and decreased from 60% to 90% VO2 peak. Post-exercise ΔTHb and ΔO2 Hb showed an overshoot in relation to pre-exercise values, which was equal after 40-60% VO2peak and rose significantly thereafter. A plateau was reached following exercise at ≥80% VO2peak . The results suggest that there is an increasing mismatch of local O2 delivery and utilization during exercise up to 60% VO2peak . This insufficient local O2 distribution is progressively improved above that intensity. Further, exercise intensities of ≥80% VO2peak induce highest local post-exercise O2 availability. These effects are likely due to improved microvascular perfusion by enhanced vasodilation, which could be mediated by higher lactate production and the accompanying acidosis.