The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys  1.13 (0.69–1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205.Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS ( In an open-label, randomized controlled trial, normothermic machine perfusion of kidneys from donation after circulatory death was found to be feasible and safe but did not reduce the rate of delayed graft function compared to static cold storage. One response to this has been the increasing use of kidneys from donation after circulatory death (DCD) donors2.Kidney transplantation is one of the major successes of modern medicine in the 20th century, transforming and extending the lives of many thousands of patients. However, a longstanding limitation of kidney transplantation is that the supply of transplantable organs does not meet demand4. This involves flushing the kidney to remove donor blood, cooling with a preservation solution at 4 °C and storage on ice while arrangements are made for transplantation. SCS works by reducing the metabolic rate to around 5% of normal, but because this occurs in an anoxic environment, anerobic metabolism ensues5. This leads to the depletion of cellular energy in the form of adenosine triphosphate (ATP) and the accumulation of succinate, which drives the production of the reactive oxygen species that underlie ischemia reperfusion injury6. SCS is simple, effective and inexpensive and is still the standard of care in the United Kingdom (UK). However, prolonged cold ischemic injury can lead to acute tubular necrosis, the clinical consequence of which is delayed graft function (DGF), requiring a period of post-transplant dialysis support.For more than 50 years, the traditional method of pre-transplant kidney preservation has been static cold storage (SCS) in ice7. These factors lead to higher rates of DCD grafts never functioning (primary non-function (PNF)) and higher rates of DGF. There is evidence that DGF increases the risk of acute rejection, prolongs hospital stay and could adversely affect long-term allograft survival rates9.DCD takes place after cessation of cardiac activity in the donor, leading to an inevitable period of warm ischemia, which can cause acute kidney injury. In addition, DCD kidneys are more susceptible to cold storage injury10. This maintains an organ in a near-physiological state, restoring function ex vivo and, therefore, allowing functional testing. Experimental studies using animal models suggest that kidney NMP has a conditioning effect with maintenance of more stable acid–base homeostasis and a reduction in renal tubular injury, when compared to SCS11. NMP also enables a degree of metabolic resuscitation by replenishing ATP levels that have been depleted because of a combination of warm and cold ischemia12.Normothermic machine perfusion (NMP) is an emerging technique that uses cardiopulmonary bypass technology with extracorporeal membrane oxygenation to perfuse kidneys with a warmed and oxygenated red-cell-based plasma-free solution13. As a result, NMP is finding increasing clinical application in liver transplantation. The technology is rapidly developing as a method of assessment and treatment to increase organ utilization and has proved to be more cost-effective than SCS15. There is currently a paucity of evidence for NMP in kidney transplantation. Nonetheless, with high rates of kidney discard16, there is clear potential for the introduction of NMP technology.The first randomized controlled trial of NMP in liver transplantation demonstrated that, compared to conventional SCS, NMP reduced early allograft dysfunction. There was no effect on bile duct complications, graft survival and patient survival17. Here we report the first multicenter, randomized controlled trial comparing NMP with conventional SCS in DCD kidney transplantation. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant.Our non-randomized pilot study in kidney transplantation suggested that a 1-h period of NMP, delivered at the end of the cold storage period and immediately before transplantation, reduced the rate of DGF in extended criteria donor kidneysThe characteristics of the donors and recipients are detailed in Table P = 0.44; Fisher’s exact test).In total, 168 kidneys were allocated to SCS and 170 to NMP. In the SCS arm, one kidney received NMP due to the surgeon’s preference. In the NMP arm, 25 kidneys did not receive NMP. In 14 cases, this was due to the inability to secure a cannula into or around the renal artery; in eight cases, this was due to logistics with access to theater or time constraints; in one case, this was due to the surgeon’s preference; in one case, this was due to damage to the renal artery; and in one case, the kidney was transplanted as a dual transplant. A total of 21 kidneys in the SCS arm and 27 kidneys in the NMP arm were not transplanted ; 21 kidneys that were one of a pair in the trial that were transplanted in the incorrect order to which they were randomized (due to logistics); and 13 kidneys that were randomized to NMP did not receive 60 min of NMP. All of the participants who experienced a protocol deviation were included in the modified intention-to-treat (MITT) analysis but were excluded from the per-protocol analysis. Four cases had to be excluded from all risk-adjusted modeling, as one of the risk adjustment factors was missing  , DGF occurred in 83 of 142 (58.5%) patients in the SCS arm and 82 of 135 (60.7%) patients in the NMP arm. No difference was observed between the arms (adjusted odds ratio (OR) ) 1.13 (0.69–1.84), P = 0.62; Table In the MITT analysis, excluding PNF (SCS Nine participants had PNF (three in the SCS arm and six in the NMP arm) and were excluded from subsequent analyses. In the SCS arm, two patients had a vascular thrombosis, and one had cortical necrosis. In the NMP arm, one patient had a vascular thrombosis; two patients had acute rejection; and, in three cases, the reason was unknown. No significant difference was observed in the number of patients who experienced PNF between the treatment arms for both the MITT analysis (adjusted OR (95% CI) 2.34 (0.56–9.86); Table Patients who experienced DGF were excluded from the outcomes and analyses for functional DGF, creatinine reduction ratio on post-transplant day 2 (CRR2) and creatinine reduction ratio on post-transplant day 5 (CRR5). The median duration of DGF was 6 (2–9) days in the SCS arm and 4 (1–9) days in the NMP arm. No significant difference was observed between the groups in the MITT (adjusted hazard ratio (HR) (95% CI) 0.97 (0.70–1.34); Table The total number of patients who had biopsy-proven acute rejection was 19 in the SCS group and 24 in the NMP group. The unadjusted mean number of biopsy-proven acute rejection episodes per patient was numerically higher in the NMP arm compared to the SCS arm  but was not statistically different (adjusted rate ratio (95% CI) 1.57 (0.83–2.95) for the MITT population; Table P values from the time by treatment interaction term: serum creatinine 0.19 and 0.096, respectively, and eGFR P = 0.42 and P = 0.15, respectively; Supplementary Table Serum creatinine and estimated glomerular filtration rate (eGFR) were not statistically significant at 1, 3, 6 or 12 months after transplant in the MITT or per-protocol analyses  1.44 (0.33–6.36)); Fig. For safety outcomes, the total number of incidences of biopsy-proven acute rejection, renal artery or venous thrombosis, complications of the renal transplant biopsy and the number of hospital admissions for any recognized complication of the renal transplant, including renal graft dysfunction, infection, surgery related or due to immunosuppression, were the same in both arms of the study (unadjusted mean SCS 0.7 ± 1.2 versus NMP 0.7 ± 1.2 (rate ratio (95% CI) 1.06 0.73–1.52)) for the MITT analysis population; Table –1.52) foThe median renal blood flow was 180 ml/min/100 g (interquartile range (IQR) 120–230), and the median arterial pressure was 76 mmHg (IQR 74–80). The median amount of urine produced was 95 ml (IQR 50–180). The quality assessment score was applied to each of the analyzed kidneys. Forty-six percent had an assessment score of 2 of more. When adjusting for cold ischemic time, donor age, left/right kidney and transplant center, no significant difference in DGF was observed between those kidneys that scored a 1 versus 2 or more in the assessment score (adjusted OR (95% CI) 1.02 (0.47–2.24); Supplementary Table P = 0.510 and P = 0.722, respectively; Table P = 0.90 for the interaction term; Supplementary Table P = 0.8149; Supplementary Table In a sub-analysis including nine PNF cases in the MITT cohort and six in the per-protocol cohort, no significant difference was observed in rates of DGF between the study arms  113.5 (1–514) minutes in NMP kidneys with initial graft function versus 134.6 (8–696) minutes in NMP kidneys with DGF; We compared a 1-h period of NMP with conventional SCS for kidney transplantation from DCD donors. The NMP protocol had no effect on the primary endpoint, which was the incidence of DGF, defined as the requirement for dialysis in the first 7 d after transplant. No significant statistical differences were observed in the rates of acute rejection, renal function at 12 months, patient survival or graft survival. Our study also demonstrated that NMP is a safe procedure, as no significant differences were observed in complication rates when compared to SCS, and no adverse events were directly atrributable to NMP.10, the first non-randomized pilot study suggested that a 1-h period of NMP could substantially reduce the rate of DGF17. Other non-randomized studies of NMP have recently demonstrated DGF rates in the region of 30%, which was lower than expected for kidneys from this donor source20. In our trial, the rates of DGF were high, at around 60%, in both the NMP and SCS groups. These rates are not unusual and are similar to data previously reported in UK and European randomized trials of hypothermic machine perfusion (HMP) in DCD kidney transplantation23. Also, two recent large studies of controlled DCD kidney transplants in the Netherlands (n = 406 patients)24 and the UK (n = 225 patients)25 reported DGF rates of 67% and 65%, respectively, providing up-to-date contemporary data that are consistent with our trial outcomes. Although lower rates of DGF in DCD kidney transplants have been reported in the UK, these were derived from registry data, which are incomplete and of variable quality compared to the actuality of data collected in the setting of a prospective clinical trial2.After the introduction of ex vivo NMP for donor kidneys into clinical practice24. We were not able to study the effects of hypotension after the withdrawal of life-sustaining treatment in our trial because the blood pressure during the agonal phase is not routinely recorded in the UK.There are several possible causes of the high rates of DGF described here and in some of the previous literature. Physiological parameters during the agonal period, defined as the time between withdrawal of treatment and circulatory arrest, are likely to be critical. In the UK, withdrawal of treatment comprises disconnection from the ventilator and stopping inotropes but, in many centers, does not include removal of the endotracheal tube. Continuing support of the airway in this way can prolong the agonal period. Even more importantly, severe and prolonged hypotension during the agonal period and the consequent inadequate organ perfusion causes additional warm ischemic injury and has been shown to be associated with higher DGF rates in DCD kidneys26, it does not consider severity. In particular, this definition includes patients who undergo a single early postoperative dialysis for hyperkalemia or fluid overload, irrespective of their initial graft function. This overestimates the rate of clinically relevant DGF because there is evidence that a single postoperative dialysis has no effect on long-term transplant outcomes27. If patients receiving a single postoperative dialysis were excluded from the analysis, the rates of DGF in both treatment arms were less than 50%, but there were still no significant differences between the SCS and NMP groups.The high rates of DGF reported here are also related to defining DGF as the requirement for dialysis in the first 7 d after transplant. Although this is the simplest and most widely used definition of DGF29. Although these results are notable, the effects of NRP have yet to be investigated in a randomized controlled trial, and the series reported may have an element of selection and observation bias. In our trial, NRP was a specific exclusion criterion to remove it as a potentially confounding variable.The use of normothermic regional perfusion (NRP), which restores oxygenated blood flow to the abdominal organs in situ after cardiac arrest, has yielded even lower DGF rates of 23–30%31, it has not been widely adopted in many countries, including the UK. Comparison of NMP and HMP is an important future direction, and there is currently a trial ongoing to address this 32.Conventional SCS was used as the control arm in this study because it is the standard of care in the UK. Although HMP has been shown to reduce the rate of DGF in DCD kidneys when compared to SCS17. Further justification for a short period of NMP was based on experimental work using porcine kidneys, which demonstrated that brief periods of NMP restored depleted cellular ATP levels12. This was reinforced by a study of human kidneys declined for transplantation that showed an increase in the expression of glycolytic pathway and oxidative phosphorylation genes, suggesting that NMP has the potential to increase cellular capacity to generate ATP and restore homeostasis33.There are several possible explanations for the lack of effect of NMP on DGF rates. A 1-h period of NMP may not be long enough to reverse the effects of cold ischemia on renal tubular cells. The rationale for our trial design was based on pilot clinical data suggesting that 1 h of NMP could significantly reduce the rate of DGF in DCD kidneys34. The feasibility of a 24-h period of NMP has been demonstrated using a urine recirculation protocol in discarded human kidneys35, but there are currently no published clinical studies of prolonged NMP.There is limited evidence to define the optimal duration of NMP. One experimental study suggested that 1 h of NMP is not as beneficial as more prolonged periods of perfusionThe original intention in our protocol was to deliver a short period of NMP immediately before the kidney was transplanted, but this was not always achieved because of the logistics of preparing patients for transplant surgery. After 1 h of NMP, the kidney was re-flushed with cold preservation solution and placed back on ice for a variable second period of cold storage until removal from ice for implantation. The mean duration of this second cold time was just over 2 h, and, although this may not influence outcome, longer additional cold storage would eventually counteract any beneficial effects of NMP. Post hoc analysis demonstrated that there was no difference in the duration of the second cold ischemic period in NMP kidneys with or without DGF.13. However, this presents an appreciable logistical challenge, and, currently, the most common practice is to transport livers in cold storage and then perform NMP for a few hours before transplantation36. Future studies in kidney transplantation will need to address the place of more prolonged periods of NMP using protocols similar to the current practice in liver transplantation.In liver transplantation, donor livers have been maintained by NMP for the full duration of the preservation period37. Nonetheless, global transcriptomic studies have clearly demonstrated the opposite effect, with upregulation of several immune and inflammatory pathway genes in human kidneys. More detailed analysis of the transcriptomics data demonstrated that kidneys with a lower expression of oxidative phosphorylation pathways and enhanced upregulation of inflammatory cytokines and chemokines were more likely to have longer periods of DGF compared to those that had immediate graft function or just 1 d of DGF33. We have also shown that the addition of a cytokine filter to the NMP circuit attenuates the expression of inflammatory genes in human kidneys, and this has potential for clinical application in the future33.The induction of inflammation during NMP is another potential reason for the lack of its effect on the rate of DGF. The red-cell-based perfusate used in the NMP system was designed to create an anti-inflammatory environment without platelets, white cells or complement38. Nonetheless, complex renal arterial anatomy or heavily diseased aortic patches sometimes makes cannulation impossible or increases the risk of causing damage such as an arterial dissection. In this early experience, we took a cautious approach and chose not to perform NMP in higher-risk circumstances. More complex arterial perfusion techniques, such as anastomosing the renal arterial system to a tissue-banked deceased donor artery to create a discardable conduit for perfusion, are possibilities in the future that could increase the rate of implementing NMP. The intention-to-treat analysis takes account of the non-performance of NMP on the outcome of the trial.Our trial has several limitations. It was designed as an open-label study because of the logistics of the NMP technique. Blinding of the surgical team was not possible because NMP was performed in the operating room while the transplant recipient was being prepared for surgery. However, the perfusion teams were not involved in data analysis. We were unable to perform NMP in 14 kidneys (8.2%) randomized to this treatment arm because of concerns over the technical aspects of cannulating the renal arterial system. The alternatives for arterial perfusion are the use of an aortic patch clamp or direct cannulation of the renal artery. The former is more favorable as it allows perfusion of multiple renal arteries without loss of the aortic patch for subsequent anastomosis in the recipientAs NMP requires cannulation of the renal blood vessels, there is potential to cause endothelial damage. There is also a risk of transmitting infection during the period in which the kidney is perfused in an ex vivo organ chamber. In our trial, NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. No significant differences were observed between the groups in terms of recipient safety outcomes. The incidence of renal arterial or venous thrombosis was very low, and there were few complications related to the renal transplant biopsies. Complications associated with kidney transplantation that require hospitalization are common and were categorized into graft dysfunction, infection, related to surgery or immunosuppression based.In conclusion, a 1-h period of NMP after SCS does not reduce the risk of DGF in DCD kidney transplants. Nonetheless, we have demonstrated that this new technology for kidney preservation is feasible, safe and suitable for clinical application. This trial delivers the first, essential step in exploring the broader potential of NMP in kidney transplantation.ISRCTN15821205. An independent DMC monitored the progress of the trial. The trial design and methods were published previously39.This investigator-led, randomized controlled, open-label trial was approved by the UK National Research Ethics Service and local institutional review boards (REC 15/EE/0356), with trial registration number Eligible patients enrolled on the transplant waiting list and allocated a suitably matched kidney were enrolled at four UK transplant centers. Inclusion criteria included recipients 18 years of age or older with end-stage renal failure requiring their first or second kidney transplant who received a kidney from Maastricht category III or IV DCD donors 18 years of age or older. Exclusion criteria included recipients receiving a third or subsequent kidney transplant, multi-organ transplants, dual kidney transplants, pediatric en bloc kidney transplants and kidneys preserved by HMP. Two additional exclusion criteria were introduced on 13 October 2017: donors who underwent normothermic regional perfusion or one of a pair already randomized as a single kidney in the trial. This was approved by the Research Ethics Service, local institutional review boards and the TSC. All patients provided written informed consent.Patients were randomly assigned in a 1:1 ratio to 1-h NMP or SCS. The randomization list was created by the trial statistician in SAS Enterprise Guide (version 5.1) with SAS 9.4, stratified by transplant center and using randomly permuted blocks of fixed size 2 and 4 for single and pairs of kidneys, respectively. In cases where paired kidneys from the same donor were transplanted in the same transplant center, the randomization was stratified by kidney (right or left) so that one kidney was randomly allocated to each treatment and in which order they should be transplanted. The randomization process was facilitated using an Interactive Web Response System. After the assignment of treatment arms, no one in the trial was blinded to the treatment allocation.Kidneys were retrieved by National Health Service Blood and Transplant (NHSBT) National Organ Retrieval Service teams, and, after flushing with cold preservation solution, they were stored on ice until transplanted.NMP was performed at the transplanting center for 1 h using a customized pediatric cardiopulmonary bypass system. Kidneys were perfused with an oxygenated red-cell-based solution supplemented with a crystalloid solution and amino acids. Details are documented in the Kidneys were transplanted into either iliac fossa with anastomosis of the artery to the common, external or internal iliac arteries. The vein was anastomosed to either the common or the external iliac vein. The ureteric anastomosis was performed as an extravesical onlay over a double J stent.−1. Levels were analysed at 1, 3, 6 and 12 months after transplant. Patients received mycophenolate mofetil (CellCept) 500 mg twice daily orally and prednisolone 20 mg once daily orally. The dose of prednisolone was tapered to 5 mg once daily by 2–6 weeks after transplantation.A standard immunosuppressive protocol was used in all four trial centers. All patients received induction therapy with basiliximab 20 mg IV given on the day of transplantation and on the fourth postoperative day. All patients received methylprednisolone 500 mg IV at induction of anaesthesia. Maintenance immunosuppression was given as triple therapy with tacrolimus, mycophenolic acid and prednisolone. Tacrolimus was administered at a dose of 0.1 mg/kg/day orally either in two divided doses (adoport) or as a single daily dose (advagraf). Tacrolimus trough blood levels were measured at least twice weekly, and the therapeutic target range in the first 3 months after transplant was 5–10 ng mlThe primary outcome measure was DGF, defined as the requirement for dialysis in the first week after transplantation. Secondary outcome measures included incidence of PNF; duration of DGF; functional DGF defined as less than 10% fall in serum creatinine for three consecutive days in the first week after transplantation; CRR2 (creatinine day 1 − creatinine day 2 / creatinine day 1 × 100), CRR5 (creatinine day 1 − creatinine day 5 / creatinine day 1 × 100); duration of hospital stay; serum creatinine and eGFR at 1, 3, 6 and 12 months using the Modification of Diet in Renal Disease (MDRD) 4 variable equation; and patient and allograft survival up to 12 months after transplant. For safety outcomes, the total number of incidences of biopsy-proven acute rejection, renal artery or venous thrombosis, complications of the renal transplant biopsy and the number of hospital admissions for any recognized complication of the renal transplant, including renal graft dysfunction, infection, surgery related or due to the immunosuppression, were recorded.Data were collected by each of the participating transplant centers using an online secure database hosted by the NHSBT Clinical Trials Unit.The NHSBT Clinical Trials Unit supported the design, data management and analysis of the trial. Historical data spanning a 5-year period for three participating centers showed that the overall rate of DGF in DCD kidney transplants was 50%. This was used as the baseline rate. In a pilot series of kidney transplants from extended criteria donors (ECDs), 18 kidneys undergoing SCS followed by 1 h of NMP were compared to a historical control group of 47 ECD transplants after SCS alone. The DGF rates were 1/18 (6%) in the NMP group compared to 17/47 (36%) in the SCS group. Using a fixed sample size study, with interim analyses after 124 and 248 participants had been enrolled and reached 7 d after transplant, a total of 370 patients receiving a DCD kidney were required to detect a 30% relative reduction in DGF (from 50% to 35%) with a power of 80%, a statistical significance of α = 0.05 and 1:1 allocation. To allow for a study withdrawal rate of 7.5%, a maximum of 400 patients were needed for recruitment. There would be no sample size re-estimation during the trial.A group sequential design, with O’Brien–Fleming stopping rules , was used to allow the DMC to review the primary outcome for evidence of harm, benefit or futility. Two unadjusted interim analyses were performed—the first after 124 patients were randomized and reached 7 d after randomization and the second after 248 patients were randomized and reached 7 d after randomization. The stopping rules were used as a guideline, alongside the other safety data available to the DMC, as an overall assessment of the trial. The interim analyses were performed by the trial statistician who was unblinded to the treatment arm, and these results were presented to the DMC only. The DMC reported its recommendations, without disclosing any trial results, to the TSC, which made the final decision regarding continuation of the trial.The population used for efficacy analyses was a MITT population including all randomized patients who received a transplant. This was a change from the original protocol because it was deemed illogical to include those participants who did not receive a transplant, as no outcome data were available. Primary and secondary outcomes were also analyzed per protocol, which excluded any participant who did not receive a transplant, was randomized in error, experienced a protocol deviation or was withdrawn from the trial . For both analysis populations, results were presented by randomized treatment, and all ratios and mean differences were presented as NMP versus SCS.P values less than 0.05 were considered statistically significant. SAS Enterprise Guide (version 7.15) with SAS 9.4 was used to conduct all analyses. It was pre-specified in the statistical analysis plan that multiple comparisons would be performed, potentially increasing the probability of observing a statistically significant result by chance, but that no adjustments would be made to account for multiple testing.All analyses were adjusted for cold ischemic time, donor age, left/right kidney and transplant center . All tests were two-sided, and The primary outcome was analyzed using an adjusted logistic regression model and excluded participants who experienced PNF. The data for this outcome were complete, and, therefore, it was not necessary to undertake any of the methods proposed in the statistical analysis plan for assessing the impact of these missing data.Secondary and safety outcome measures were analyzed using logistic regression model , Cox proportional hazards model , normal linear regression model  and negative binomial model (biopsy-proven acute rejection and safety outcomes). Missing secondary outcome measures were not imputed and were excluded from the relevant analyses, except for eGFR. Full details can be found in the statistical analysis plan. To ensure model assumptions were met, residual plots were examined.After NMP, kidneys were allocated a score of 1–5 based on the macroscopic appearance, mean renal blood flow and urine production. A lower value indicated a better score  on DGF in the MITT analysis, we used the same model as that used for the primary outcome but with the inclusion of the pre-transplant dialysis term, and we also assessed the interaction between treatment group and pre-dialysis status.iii.Some patients received a single post-transplant dialysis as a safety measure in response to hyperkalemia or fluid overload, irrespective of renal function. To take account of this, we analyzed the effect of excluding patients who received a single post-transplant dialysis on DGF rates.iv.We also analysed the effect of excluding pre-dialysis patients from CRR2 calculations in both the MITT and per-protocol analyses.v.The duration of the second cold ischemic period after NMP was variable, and this might have influenced the rate of DGF. We, therefore, compared the duration of second cold ischemic time in kidneys with initial function and DGF after NMP.vi.2 at the 1-, 3-, 6- and 12-month timepoints for patients with PNF, ongoing DGF, graft loss or death40.To take account of missing eGFR data in the MITT analysis, we imputed a value of 8.5 ml/min/1.73 mFurther information on research design is available in the Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02376-7.Supplementary InformationText, tables, protocol and statistical plan.Reporting Summary


Mindful parenting programs are effective in reducing parenting stress. More efficient offerings may increase accessibility. The current single case study aimed to determine the feasibility, acceptability and initial effects of a brief, online mindful parenting program. Six parents, recruited from the community, completed a 4-week online mindful parenting program (Two Hearts). Feasibility and acceptability were assessed by participant program evaluation, retention, engagement with program materials , and home practice. Parents completed primary outcome measurements of parenting stress, and general distress, at pre- and post-intervention, and 4-week follow-up. Individual level reliable change index and clinically significant change were calculated for outcome measures. All parents were retained through the study; all participants reported obtaining something of lasting value from the training. Program adherence varied over time. At post-intervention, four parents reported 40–50 minutes practice per week; two parents reported 10–15 minutes practice per week. At follow-up, 50% of parents reported 30–50 minutes practice per week. Three parents showed a reliable reduction in parenting stress; two of these parents demonstrated clinically significant change. Improvements in parent general distress were indicated in half the sample. Two parents experienced a clinically significant increase in parenting stress and/or general distress. In conclusion, the Two Hearts program demonstrated good acceptability, and may be a feasible and effective program for some parents. Program adherence and dosage require further investigation. The role of acute stressors  must be also considered. A brief (4-week) online mindful parenting program demonstrates good acceptability for parents.Such an intervention may reduce parenting stress and general distress in community populations.Issues of feasibility, adherence and dosage in online mindful parenting programs require further investigation. More recently, mindful parenting programs have also been developed, which differ from MBIs through application of established mindfulness interventions solely to a parenting context.Many people report, that while often rewarding, parenting is also a source of stress; this stress can negatively impact parenting skills  referred to secondary child mental health care found improvements in parent and child internalizing symptoms, child externalizing symptoms, parental stress, parenting and co-parenting  for a number of parent  and child (behavior problems and wellbeing) outcomes were found , Potharst et. al., In addition to providing shorter interventions, another adaptation to the MPP to improve accessibility may be to deliver the program in an online format. In a qualitative investigation of facilitators and barriers to engagement in a mindful parenting intervention, Ruuskanen, Leitch, Sciberras, and Evans  reportedIn the current pilot study, we aimed to assess the feasibility, including initial efficacy, of a brief-format MPP – the Two Hearts program – that comprises four online modules for a community population of parents. Consistent with published guidelines on determining the feasibility of novel interventions  and home practices. While a guideline of 20 minutes home practice per day 5 days per week was encouraged, an exploratory approach for evaluating program adherence was utilized, given home practice variability reported in previous online MPP research , T2 (immediately post-intervention), and T3 (four weeks after completion of the intervention). Dependent variables were program feasibility and acceptability, parenting stress, parent general distress, mindful parenting, general mindful awareness, and self-compassion. Ethical approval was obtained from the Griffith University Human Research Ethics Committee  and all participants gave signed informed consent. The study was conducted April to June of 2020 in Australia; during initial Covid-19 restrictions . An unplanned semi-structured telephone interview was consequently added by the first author in response to these unexpected events, with program participants to determine their preferences for program format  moving forward within the bounds of the unexpected restrictions. This led to moving the initially planned in-person program to an online asynchronous program which recruited families deemed acceptable in telephone interviews with variations approved by the ethical approval board prior to implementation. This telephone interview was undertaken to improve program acceptance and feasibility of the revised format in response to restrictions arising from the pandemic.N = 6) were recruited from broad community advertisements targeting parents of preschoolers with anxiety for inclusion in another MPP study. Parents who did not meet criteria for that study  were offered the opportunity to participate in the current study. Inclusion criteria for the current study were being an adult parent aged 18 or older of children aged 5–16 years old, with proficient English, who were able to access online materials and commit to the program practices, and who were not participating in another parenting training program. Pseudonyms have been used to protect participant confidentiality. See Table Participants . Program evaluation was administered at T2 and T3. All assessments were completed via online surveys .Two Hearts program content was selected from the MPP  twice per week during the intervention period and once per week in the follow-up period. Program videos were delivered by a provisional Psychologist, with training in mindfulness- and compassion-based psychotherapeutic approaches, 10 years established mindfulness practice and meditation, 7 years’ experience as an Iyengar Yoga student, and completion of a MPP workshop.The outline of the Two Hearts program is presented in Table Did you feel you got something of lasting value or importance as a result of taking the training?”) was analyzed using descriptive statistics , and home practice data were used to evaluate what was feasible. To evaluate acceptability, Item 1 of the Program Evaluation . Module 3 videos were the least watched; the program content to which these videos related  was one of the most highly rated (T2 M = 9.67).All parents remained engaged in the study to completion at T3 . Engagement with the online videos is summarized in Table Program adherence varied considerably. Parents were encouraged to complete 20 minutes of home practice per day, 5 days per week. Two parents practiced 10 to 15 minutes per week on average (Elizabeth and Vanessa) and the remaining parents practiced 40 to 50 minutes per week. At T3 adherence had declined, however, half of the sample continued to practice 30 to 50 minutes per week in the follow-up period.Do you feel you got something of lasting value or importance as a result of taking this training?, and a high overall training importance rating, although this decreased somewhat at T3. In addition, all parents reported that they have become more conscious as a result of the training (Item 3) and have an intention to continue with mindful parenting practice . These results were sustained at follow-up, however, one parent (Elizabeth) reported that she had not made any changes as a result of the training at T3 (Item 2). In general, most parents rated all components as important (≥7); Frank and Elizabeth assigned lower ratings than other parents across many program elements, and this was also reflected in their overall rating of training importance . While Frank, Sally, and Vanessa gave lower ratings to Text Reminders (3–6), other parents rated this element highly (10).Program evaluation results are presented in Table Four of six parents  utilized the optional support sessions. These sessions, including their individual ‘opt in’ nature, were included in the program in response to parents’ requests, and as part of the adjustments made due to COVID-19. This program component was thus designed to improve program acceptability. In terms of uptake, one session occurred in the week of Module 1 (Vanessa). Three sessions occurred in the week of Module 3 . A 30-minute unscheduled phone call with Linda also took place in the week following Module 3. Themes of these sessions included discussion of: program adherence ); barriers to practice ; adjusting unhelpful expectations of self in regards to mindfulness skills and implementation; tailoring practices to specific parenting challenges; clarification of mindfulness aims  and processes .Table At T2 and T3, three of six parents  reported reliable improvements in parenting stress, and two of these  also achieved clinically significant change, moving from the clinical to normal range. As Rebecca’s scores were in the normal range across all three time points, clinical change was not possible. Linda and Vanessa did not demonstrate reliable beneficial effects, and both were in the normal range across time points. Elizabeth experienced reliable worsening of parenting stress at T3, and her T1 clinical range parenting stress score was maintained at follow-up. Both Elizabeth and Linda reported  that they had experienced significant personal stressors in the evaluation period.At the total score and anxiety subscale score levels, two parents  of six achieved reliable reductions in general distress at T2 and T3  demonstrated reliable beneficial change in their mindful parenting. At T3, half the sample continued to show positive change in their mindful parenting, however, one parent (Elizabeth) who had initially shown improvements at T2 no longer did so at T3, and one other parent  who did not show reliable change at T2, did at T3.Three parents  showed an increase in general mindful awareness, and three showed a decrease , from T1 to T2. At T3, five parents had experienced an increase in general mindful awareness with only Elizabeth not showing a reduction compared to T1.Four parents  experienced a beneficial increase in self-compassion, and two (Elizabeth and Linda) experienced a decrease, from T1 to T2. At T3, all parents except Linda demonstrated an increase in self-compassion, who experienced a decrease, compared to T1.The current study delivered a brief online MPP training, the Two Hearts program, over a 4-week period to a community sample of parents. The study aimed to assess program feasibility and acceptability to parents, as well as initial effects on parenting stress and distress, and effects on the secondary outcomes of mindful parenting, general mindful awareness, and self-compassion. The results indicated that program acceptability was adequate. Further, levels of feasible engagement in the program are outlined, and preliminary findings indicate the program may deliver beneficial reductions in parenting stress and distress.A key outcome was that parents found the program acceptable. At T3, five of six parents  reported they had found lasting value in the program and had made subsequent changes to their parenting/lifestyle. With nil drop out from the study, retention was also good, and compares favorably with Potharst et al., N = 43, average 14.94 minutes per week, range 0–120 minutes). In general, given the results of the current study, a feasible amount of home practice for an online MPP appears to be significantly less than traditional MBIs , however, at T3, home practice had generally reduced; while two parents completed at least 45 minutes practice per week (Frank and Linda), two parents reported negligible practice (0–2 minutes). Although parents’ home practice was less than the guideline suggested to them, it was higher than Potharst et al., Partial support for predicted initial effects were found. Reductions in parenting stress at T2 and T3 were achieved by half the sample . Reductions in parent general distress at T2 and T3 were also achieved in three of six parents’ anxiety scores , however, only two parents  demonstrated reliable anxiety reductions at T3. Further, only two parents experienced significant reductions in total distress scores at T2 and T3 . Previous research has indicated that there is a direct link between amount of home practice and whether intervention effects are achieved: the more practice an individual does, the better their outcome  would have benefited from earlier and more targeted support. Previous research indeed, has found that targeted interpersonal support such as ‘check ins’ from peers and trainers were identified by parents as being useful for their program engagement  to determine statistical significance, this result provides initial evidence that improvements in self-compassion or general mindful awareness may also contribute to initial effects.Initial effects for the Two Hearts program compare favorably to 8-week MPPs of more traditional and online formats. Preventative MPPs following a more traditional in-person delivery over 8-weeks have also demonstrated small reductions in parenting stress  and related stressors  were present. It is unclear what impact this situation had on parents’ motivation and capacity to engage in the program, or the effects achieved. Sensitivity to change was a limitation of the measurements utilized in this study, for the community sample . There is also a paucity of outcome measures in the field of mindfulness, and noted psychometric limitations from previous research  as well as an absence of normative data for secondary measures which precluded calculation of reliable change indexes for these measures.The video engagement data is only aggregate and anonymized, and therefore does not provide an indication of individual participant engagement. Finally, it is unclear if program format, duration, or feasibility (or a combination of these elements), impacted some parent’s outcomes. For example, program feasibility may not have been sufficient to achieve adequate dosage . The small sample size also obscures an understanding of home practice feasibility. No parent was able to complete the home practice guideline  and, while some parents were able to complete around 45 minutes practice per week, others did not. While previous research has shown no association between MBI contact hours and effect sizes , it is notable that parents who A novel – and important, given its online format – aspect of this study was the reporting of engagement with video material. The availability of such data provides an overview of how the sample of parents interact with this part of the program. Future research could track individual participant engagement information . Dose effects should also be explored in future research of brief, online MBIs for parents, which may support parents’ well-being, parenting skills, and other important outcomes, via an efficient, affordable, and accessible therapeutic option. Whilst initial efficacy and effects are important to determine, further feasibility research is also vital to contribute to the improved design and relevance of MPPs, and thus increase engagement and reach of such supports.In terms of assessment of effects and particular populations, measures designed for nonclinical populations (e.g., Depression, Anxiety and Stress Scale, Lovibond & Lovibond, The Two Hearts program may be a feasible and acceptable option for parents and may deliver beneficial reductions in parenting stress and general distress for some parents. It remains unclear what role factors such as program adherence, dosage, sample and selection of outcome measures, and program format may have on intervention effects in a brief online MPP. There is also a need for sensitive measurement of broader well-being outcomes, to determine the potential benefits of a program like Two Hearts, and which populations may best be served by such an intervention. Future research in this area could support parents’ well-being, parenting skills, and other important outcomes, via an efficient, affordable, and accessible therapeutic option.


Science industries, such as the health and medical industry, are experiencing increases in competition regarding commercializing, patenting, and funding of scientific outputs. As such, scientists are facing increased expectation to engage in academic entrepreneurship. OrganoVIR (Organoids for Virus Research) is a Horizon2020 Innovative Training Network (ITN) that aims to train Early Stage Researchers (ESRs) to lead innovation in the field of human organoids for virus research. To assist them in this process, OrganoVIR introduced a pre-Master of Business Administration program that introduced OrganoVIR’s ESRs to the tools and knowledge necessary to navigate the competitive industry. In this article, we describe this innovative pre-Master of Business Administration program and highlight the importance as well as the need for having a pre-Master of Business Administration programs in a scientific training network. The views expressed in this article are those of the author(s). Publication in Open Research Europe does not imply endorsement of the European Commission.The science industry is arguably one of the most competitive industries in the world. Nowadays, scientists are competing to commercialize, patent their research and obtain funding for future research. OrganoVIR, a Horizon2020 Innovative Training Network (ITN) under the EU Horizon 2020 research program, trains 15 Early Stage researchers (ESRs) to lead innovation in the field of human organoids for virology in Europe. Through one of its training programs, the innovative OrganoVIR pre-Master of Business Administration program aims to introduce the next generation of scientists to the European labour market. The implementation of this program marked the first time that a pre-Master of Business Administration (pre-MBA) program was successfully incorporated in a scientific training network. The OrganoVIR pre-MBA program is curated through collaboration with the Amsterdam Business School in the Netherlands. The program consisted of five modules: Process Improvement in Healthcare, Competitive Strategy, Marketing Strategy, Crisis Management, Navigating Life in Pharma Organizations and Writing a Business Plan. With this article, we aim to demonstrate the importance of integrating a pre-MBA program into a scientific ITN. Furthermore, we would like to encourage other ITNs operating within the science industry to also integrate a pre-MBA program into their scientific training program.OrganoVIR (Organoids for Virus Research), coordinated by Dr. Katja Wolthers and Prof. Dr. Dasja Pajkrt, is a Horizon2020 Innovative Training Network (ITN) under the EU Horizon 2020 research program. OrganoVIR aims to make human organoids a superior model for virus research and to transform the virology landscape.OrganoVIR trains 15 Early Stage Researchers (ESRs) to lead innovation in the field of human organoids for virology in Europe. The OrganoVIR training program consists of three pillars that build up scientific, human and business skills for applying organoids for virus research. The three training pillars will enable the ESRs to lead innovation in the field of organoids for virus research and to hold a unique position within the European labour market.Humanizing Science: seven actions for PhD students to become next generation, future-proof scientist  which was previously reported in was passed in 1980 in the United States of America (U.S.), there has been an apparent increase in the commercialization of science  well-being; 2) purpose in life; 3) identity; 4) values and beliefs; 5) emotional competences; 6) leadership behaviour; and 7) ethical dilemmas. The OrganoVIR pre-MBA programme focuses on the education of OrganoVIR’s ESRs with the aim to equip them with entrepreneurial and business analytic skills. This way, this next generation of scientists will be able to operate within commercial settings. The pre-MBA program consists of the following modules: 1) Process Improvement in Healthcare, 2) Competitive Strategy, 3) Marketing Strategy, 4) Crisis Management and Navigating Life in Pharma Organizations and 5) Writing a Business Plan.The OrganoVIR pre-MBA program has a different training purpose compared to the OrganoVIR PDP. In a previous study about the OrganoVIR PDP . In this module, OrganoVIR’s ESRs learn to solve problems by using their professional, science-like skills. OrganoVIR’s ESRs were guided to analyse the causes of problems, understand quantitative problem definitions and perform data-based diagnoses.The Lean Six Sigma, a structure for organizing improvement activities, incorporates the most effective approaches which offer a structure to establish an effective and continuous improvement . Each lecture focuses on the different tools and techniques of Lean Six Sigma. Additionally, topics regarding the organization of process improvement were discussed including; organizational structure, project management, deployment, political force field, and managing resistance.The science industry is competitive regarding influence, faculty positions, funding, publications, and students . Over thThis module revolved around two questions. First, “why do some organizations have advantages over their competitors?” and second, “What can managers do to build and maintain such competitive advantages?”. To answer these questions, the module introduced topics such as planned and emergent strategy, strategy process , and the difference between inside-out and outside-in approaches to strategy.Through interactive sessions in this module, OrganoVIR’s ESRs answered the two questions by learning to apply strategic processes, theories and tools to their own case study. In essence, during this module the ESRs learned the following: 1) how strategy, competition, value creation and value capturing drive the performance of organizations; 2) the main processes, theories and tools of competitive strategy; 3) the main strengths and weaknesses of these processes, theories and tools; 4) how to diagnose strategy issues in case-based and real-life organizations; 5) utilise the processes, theories and tools in order to improve the strategy of case-based and real-life organizations.The healthcare industry is constantly transitioning. In this phase of transition in the industry, the role of marketing strategy is changing as well. Although traditional marketing focused on identifying the market, customer segment, and products, it is also important to make a difference and to attract customers and patients with an appealing value proposition. Currently, marketing involves understanding customer behaviour and their emotional needs, providing a compelling service that is equivalent to valuable experience and designing a go-to-market strategy.In the Marketing Strategy module, OrganoVIR’s ESRs learned to: 1) recall and recognize the marketing frameworks, ideas and principles; 2) comprehend and translate the marketing and behaviour frameworks to a business and healthcare challenge; 3) select and synthesize the best marketing strategy tools and tactics to tackle a patient, product, service; 4) evaluate and translate perspectives from other industries to healthcare; 5) apply knowledge of marketing strategy, innovation and behaviour.This module provided the knowledge and the skills to analyze, design and execute a marketing strategy. Within the course, several practical marketing strategy topics were addressed including: 1) patient-driven marketing; 2) design value proposition and  healthcare services on the patient journey; 3) innovation in care – digital care services and innovation; 4) purpose-led marketing; 5) building brands in healthcare, brand experience and equity.Every healthcare industry encounters a crisis at some point. During a crisis, organizations temporarily go “out of control”. Crisis management offers an alternative and makes it possible for an organization to maintain control during a crisis.The first masterclass in the Crisis Management module focused on crises and the core principles of crisis management. In this masterclass, the ESRs became acquainted with various crises they might face and how to prepare for a crisis. Questions such as “how to diagnose a crisis?”, “what are the main challenges in crisis management?”, “how does a crisis impact an organization” and “how to prepare for a crisis?” were addressed in this masterclass.In the second masterclass of this module, the ESRs learned how to manage a crisis. Focusing on creating ownership and leadership, the ESRs were introduced to the core aspects of the Crisis Management Model and the key characteristics of great crisis leaders. Furthermore, the ESRs became acquainted with an effective crisis meeting approach and experienced the dynamics of a crisis during a brief crisis simulation. This masterclass addressed questions such as “how do you manage a crisis?”, “which leadership skills are needed during a crisis?” and “how to make quick and well-considered decisions?”.The pharmaceutical industry is a rapidly growing landscape. In the U.S. alone, pharmaceutical industries develop a variety of expensive new drugs every year which contribute to an increase in healthcare costs for the private sector and the federal government . The incTo help our ESRs navigate their lives through the commercial pharmaceutical industry, we began this module with the first masterclass which focused on the research and development (R&D) aspect of pharmaceutical organizations. This masterclass explored the history of the pharmaceutical industry and the pharmaceutical innovation process. During this masterclass, the ESRs learned to diagnose R&D inefficiency and potential remedies, rethink the innovation process and have discussions about existing innovation processes in healthcare., its implementation in the development of medical devices, and innovation in healthcare were discussed.The second masterclass focused on the landscape of the pharmaceutical industry, inter-organizational collaboration and entrepreneurship. OrganoVIR’s ESRs learned the importance of collaboration between in-house and external R&D, the role of small and medium-sized organizations in the biotech industry, types of collaborations in the pharma industry, and funding opportunities for entrepreneurs. Topics such as the Stage-Gate processThe third masterclass focused on social value creation, ethics, and sustainability. The masterclass began with an introduction to ethical theories and ethical dilemmas in healthcare. Ethics does not refer to ethical guidelines, but more to the philosophical questions about ethics in healthcare practices . Furthermore, OrganoVIR’s ESRs learned how the Sustainable Development Goals (SDGs) affect the healthcare landscape, the difference between social value and financial value in healthcare, and the role of patients in the healthcare innovation process.To conclude the OrganoVIR pre-MBA program, the last module focused on writing a business plan. Although writing a successful business plan can be stimulating, it can also be challenging and requires knowledge of several entrepreneurship concepts and steps. The final module introduced the basic principles of entrepreneurship and the main tools that can be used to set up a new company and write a business plan.Upon completion of this module, we found that our ESRs were able to identify and delineate the fundamental steps in the creation of a new company, from idea generation to financing. Furthermore, our ESRs learned to develop an effective business model and business plan for the new development of a new company. Finally, we also found that our ESRs were able to collaborate in a team when developing their business.The scientific industry is competitive. In this article, we have addressed how the global competition for university licensing, patenting and creation of start-up companies have increased since the Patent and Trademark act was introduced in 1980. OrganoVIR understands that implementing the pre-MBA program into a scientific training program will guide the next generation of researchers to become leading entrepreneurs in the science industry. Through the pre-MBA program, OrganoVIR’s ESRs were trained in the skills involved in managing a business such as developing competitive and marketing strategies, navigating through crisis and organizations and writing a business plan. We believe that in order to excel in the competitive labour market, the next generation of scientists must not only be trained in science but also in human skills and entrepreneurial skills. Hence, with this article, we encourage other scientific training networks to also implement a pre-MBA program as part of their training program. attached.The research aimed to aims to train Early Stage Researchers (ESRs) as part of a Horizon 2020 project to lead innovation in the field of human organoids for virus research. The research sounds interesting but needs clarifications and literature support. Some parts do not flow well due to the unclear links and the jumps between general and specific information. A funnel model should be adapted moving from general to specific information. A clear structure is recommended in the pdfThree types of skill sets are mentioned in the introduction . Can you please introduce what skills are focused in each module?I recommend adding a sentence at the end of each section introducing the activities applied in each module. Currently, the aims of the modules are clear but how it is targeted to be achieved (methods/strategies/approaches) is vague. These would really benefit the audience.To increase the validity and reliability, how the researchers know the learning was improved should be clarified, and the details mentioned above should be provided. Further details about the comments and recommendations can be found on the pdf document attachedhere. The developed pre-MBA programme includes five modules. However, rationalisation of the modules based on the current research is not enough. In each module, the need and the importance should be highlighted more in the light of the current research. In each module, the strategies used to reach the learning outcomes are not clearly stated. Currently, if I want to develop and implement a module based on this research, I am not sure how I should structure the module, what skills I should focus on and what strategies I should use, how long the modules should be or how many masterclasses the module should include. Therefore, I do not have a clear guideline. Furthermore: When the parts are clarified a bit more and enriched with recent references, the research is worth reading. I believe the research can contribute to the field.Where applicable, are recommendations and next steps explained clearly for others to follow? (Please consider whether others in the research community would be able to implement guidelines or recommendations and/or constructively engage in the debate)NoDoes the article adequately reference differing views and opinions?PartlyAre all factual statements correct, and are statements and arguments made adequately supported by citations?PartlyIs the rationale for the Open Letter provided in sufficient detail? YesIs the Open Letter written in accessible language? YesReviewer Expertise:My area of expertise includes STEM and enterprise education.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Summary: The article discusses the OrganoVIR (Organoids for Virus Research) program, a Horizon2020 Innovative Training Network (ITN) that aims to train Early Stage Researchers (ESRs) in the field of human organoids for virus research. The focus is on the introduction of a pre-Master of Business Administration (pre-MBA) program within OrganoVIR to equip ESRs with entrepreneurial and managerial skills, acknowledging the increasing expectation for scientists to engage in academic entrepreneurship. The program is unique in its approach, as no other scientific training network has implemented a pre-MBA as part of its training. The pre-MBA program consists of five modules: Process Improvement in Healthcare, Competitive Strategy, Marketing Strategy, Crisis Management, and Navigating Life in Pharma Organizations. Additionally, a module on Writing a Business Plan concludes the program. Each module aims to provide ESRs with practical skills and knowledge needed to excel in commercial settings.RecommendationsWhile the article provides a comprehensive overview of the pre-MBA program, it could benefit from including concrete outcomes or success stories of ESRs who have completed the program. Providing data on how the program has benefited participants and their subsequent careers would strengthen the article's argument for the importance of pre-MBA programs.To further emphasize the uniqueness and effectiveness of the OrganoVIR pre-MBA program, the authors could compare it to alternative approaches or models for training scientists in entrepreneurship. This could include discussing the strengths and weaknesses of different approaches and why the pre-MBA model was chosen.The article acknowledges the need for pre-MBA programs but does not directly address potential criticisms or concerns. For a more balanced perspective, the authors could discuss any drawbacks or challenges associated with integrating business education into scientific training and propose strategies to mitigate these issues.Where applicable, are recommendations and next steps explained clearly for others to follow? (Please consider whether others in the research community would be able to implement guidelines or recommendations and/or constructively engage in the debate)PartlyDoes the article adequately reference differing views and opinions?PartlyAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the rationale for the Open Letter provided in sufficient detail? YesIs the Open Letter written in accessible language? YesReviewer Expertise:academic/technology entrepreneurship, entrepreneurial leadership, entrepreneurship educationI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. I appreciate the privilege of reviewing the submission titled 'When Science Meets Entrepreneurship' and would like to extend my gratitude for this opportunity. This paper delves into the compelling intersection of science and entrepreneurship, with a specific focus on the induction of an entrepreneurship curriculum for Early-Stage Researchers (ESRs). While the paper contains valuable insights, I believe there is potential for further enhancement to truly elevate its impact and contribution to the field. In this feedback, I aim to provide constructive suggestions and insights to help refine and strengthen the paper. First, I believe the paper could benefit from greater clarity regarding its research questions and the contributions it aims to offer. Clarifying how this paper fills gaps in existing knowledge would enhance its overall contribution. It would be nice if there is a clear explanation how the current programme addresses the challenges faced by academic scientists. Alternatively, if the authors could devote more attention to identifying current debates in entrepreneurship education for scientists and explaining how the newly designed pre-MBA modules can address these challenges, the paper would undoubtedly provide greater value. Another avenue to strengthen the paper's contribution is by introducing novelty. While I agree with the paper's assertion that introducing entrepreneurship to pre-MBA courses is relatively new, it is worth noting that entrepreneurship is already a common skill taught in many MBA programs and training courses for academic entrepreneurship. Given the shortage of entrepreneurship skills and knowledge among scientists, coupled with a growing emphasis on knowledge commercialization in Europe, numerous initiatives have emerged to enrich and expand the entrepreneurship capabilities of researchers, academics, and scientists. I believe it is crucial to distinguish this program from previous or existing initiatives. Also it would be advantageous to highlight the uniqueness of the proposed program within this broader context, such as its relevance to the Organovir project. Once the research objectives are well-established, the next step is to find a theoretical framework that can serve as the foundation for the curriculum design. This does not necessarily mean the authors must find pedagogical theories to support the design, but they can explain the rationale behind selecting particular modules contents. Since the pre-MBA program includes modules such as "Process Improvement in Healthcare," "Marketing," and "Navigating Life," it would be highly informative to understand the rationale behind the development of these modules and how they integrate within the entrepreneurial narrative of the program. Moreover, the section on "Writing a Business Plan" deserves more in-depth explanation. Entrepreneurship pedagogy has evolved significantly over the past few decades, with various contemporary approaches that go beyond mere business plan writing. I am confident that this module incorporates unique approaches or contextual elements that are worth showcasing. Regarding the conclusion, it would be valuable to include an evaluation of the program and provide recommendations. As far as I can discern, there have been no significant breakthroughs in teaching entrepreneurship to scientists in general. Therefore, if this pre-MBA program has specific measurable criteria or successful stories, it would be worthwhile to mention them in this section. Finally, the introduction appears somewhat lengthy compared to the overall content. A more concise introduction that clearly communicates the research objectives, reasons for conducting the research, and the intended contributions of the paper would be preferable.Where applicable, are recommendations and next steps explained clearly for others to follow? (Please consider whether others in the research community would be able to implement guidelines or recommendations and/or constructively engage in the debate)PartlyDoes the article adequately reference differing views and opinions?PartlyAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the rationale for the Open Letter provided in sufficient detail? PartlyIs the Open Letter written in accessible language? YesReviewer Expertise:Entrepreneurship, Academic entrepreneurship.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. This brief article describes the ongoing attempts by various policymakers to bridge the gap between knowledge discovery and application. It follows the Edinburgh-Standford link which was directed at harnessing the entrepreneurial and innovation ecosystem of the Silicon Valley experts through collaborative research linkages with their Scottish counterparts.  In broad strokes, the paper describes a variant of the quest to embed business skills in research practices of early career scientists. The novelty here is the introduction of pre-MBA program to anchor the scientific training networks.   Though very promising, as the pre-MBA program practicalizes 'science-business', it remains to be seen how the transition from pre-MBA to actual practice works for the early scientists. In spite of this reservation, this paper provides a translatable approach that is likely to become a cost effective model, compared to the integration of a fully-fledged MBA masterclass model, to moving knowledge to the marketplace.Where applicable, are recommendations and next steps explained clearly for others to follow? (Please consider whether others in the research community would be able to implement guidelines or recommendations and/or constructively engage in the debate)YesDoes the article adequately reference differing views and opinions?YesAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the rationale for the Open Letter provided in sufficient detail? YesIs the Open Letter written in accessible language? YesReviewer Expertise:Triple Helix, Globalisation and Innovation Policy, Public Policy, Sociology of Science and KnowledgeI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.