Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?

• Central fatigue is accepted as a contributor to overall athletic performance, yet little research directly investigates post-exercise recovery strategies targeting the brain • Current post-exercise recovery strategies likely impact on the brain through a range of mechanisms, but improvements to these strategies is needed • Research is required to optimize post-exercise recovery with a focus on the brain Post-exercise recovery has largely focused on peripheral mechanisms of fatigue, but there is growing acceptance that fatigue is also contributed to through central mechanisms which demands that attention should be paid to optimizing recovery of the brain. In this narrative review we assemble evidence for the role that many currently utilized recovery strategies may have on the brain, as well as potential mechanisms for their action. The review provides discussion of how common nutritional strategies as well as physical modalities and methods to reduce mental fatigue are likely to interact with the brain, and offer an opportunity for subsequent improved performance. We aim to highlight the fact that many recovery strategies have been designed with the periphery in mind, and that refinement of current methods are likely to provide improvements in minimizing brain fatigue. Whilst we offer a number of recommendations, it is evident that there are many opportunities for improving the research, and practical guidelines in this area

IntPred: a structure-based predictor of protein–protein interaction sites

Motivation Protein–protein interactions are vital for protein function with the average protein having between three and ten interacting partners. Knowledge of precise protein– protein interfaces comes from crystal structures deposited in the Protein Data Bank (PDB), but only 50% of structures in the PDB are complexes. There is therefore a need to predict protein–protein interfaces in silico and various methods for this purpose. Here we explore the use of a predictor based on structural features and which exploits random forest machine learning, comparing its performance with a number of popular established methods. Results On an independent test set of obligate and transient complexes, our IntPred predictor performs well (MCC = 0.370, ACC = 0.811, SPEC = 0.916, SENS = 0.411) and compares favourably with other methods. Overall, IntPred ranks second of six methods tested with SPPIDER having slightly better overall performance (MCC = 0.410, ACC = 0.759, SPEC = 0.783, SENS = 0.676), but considerably worse specificity than IntPred. As with SPPIDER, using an independent test set of obligate complexes enhanced performance (MCC = 0.381) while performance is somewhat reduced on a dataset of transient complexes (MCC = 0.303). The trade-off between sensitivity and specificity compared with SPPIDER suggests that the choice of the appropriate tool is application-dependent. Availability and implementation IntPred is implemented in Perl and may be downloaded for local use or run via a web server at www.bioinf.org.uk/intpred/. Supplementary information Supplementary data are available at Bioinformatics online

IntPred: a structure-based predictor of protein-protein interaction sites

Motivation Protein–protein interactions are vital for protein function with the average protein having between three and ten interacting partners. Knowledge of precise protein–protein interfaces comes from crystal structures deposited in the Protein Data Bank (PDB), but only 50% of structures in the PDB are complexes. There is therefore a need to predict protein–protein interfaces in silico and various methods for this purpose. Here we explore the use of a predictor based on structural features and which exploits random forest machine learning, comparing its performance with a number of popular established methods. Results On an independent test set of obligate and transient complexes, our IntPred predictor performs well (MCC = 0.370, ACC = 0.811, SPEC = 0.916, SENS = 0.411) and compares favourably with other methods. Overall, IntPred ranks second of six methods tested with SPPIDER having slightly better overall performance (MCC = 0.410, ACC = 0.759, SPEC = 0.783, SENS = 0.676), but considerably worse specificity than IntPred. As with SPPIDER, using an independent test set of obligate complexes enhanced performance (MCC = 0.381) while performance is somewhat reduced on a dataset of transient complexes (MCC = 0.303). The trade-off between sensitivity and specificity compared with SPPIDER suggests that the choice of the appropriate tool is application-dependent

The contributions of molecular vibrations and higher triplet levels to the intersystem crossing mechanism in metal-free organic emitters.

Intense, simultaneous, room temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF) is observed in a series of donor-acceptor-donor (D–A–D) molecules. This dual-luminescence is stronger in the “angular” isomers, compared to their “linear” regioisomers, which is consistent with an enhanced intersystem crossing (ISC) in the former. Herein, we demonstrate that the small energy gap between the triplet levels, T1-Tn, below the lowest singlet state, S1, in the “angular” regioisomers, enhances the coupling between S1 and T1 states and favors ISC and reverse ISC (rISC). This is consistent with a spin-vibronic mechanism. In the absence of this “triplet ladder”, due to the larger energy difference between T1 and Tn in the “linear” regioisomers, the ISC and rISC are not efficient. Remarkably the enhancement on the ISC rate in the “angular” regioisomers is accompanied by an increase on the rate of internal conversion (IC). These results highlight the contributions of higher triplet excited states and molecular vibronic coupling to harvest triplet states in organic compounds, and casts the TADF and RTP mechanisms into a common conceptual framework

Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (ProCAID)

Purpose: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. Patients and Methods: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. Results: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. Conclusion: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme