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Author Contributions

Conceptualization, A.J.D., J.C.A., I.R. and M.B.; methodology, M.A.R., J.D., F.J.O., C.C.-R. and M.R.-R.M.; software, M.J.B., N.G.-G., E.S.-S. and C.C.-R.; validation A.J.D., J.C.A. and I.R.; formal analysis, M.J.B., N.G.-G. and E.S.-S.; resources, A.J.D., J.C.A., I.R. and J.D.; data curation, M.J.B., N.G.-G., M.B., J.D. and C.C.-R.; writing—original draft preparation, A.J.D., E.S.-S., M.A.R., I.R. and J.D.; writing—review and editing, M.R.-R.M., F.J.O., M.B. and J.C.A.; visualization, A.J.D., I.R., F.J.O. and M.R.-R.M.; supervision, A.J.D., I.R., F.J.O. and M.R.-R.M. All authors have read and agreed to the published version of the manuscript.

PMC10648681

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki (2013), and approved by the Institutional Ethics Committee of Cádiz (protocol code 0159-N-20 02-25-2020).

PMC10648681

Informed Consent Statement

Informed consent was obtained from all patients involved in the study.

PMC10648681

Data Availability Statement

The data are collected in a database prepared by the research team.

PMC10648681

Conflicts of Interest

The authors declare no conflict of interest.

PMC10648681

References

fatigue, chronic illness, muscle damage, psoriatic, psoriasis

CHRONIC ILLNESS, PSORIASIS

Baseline characteristics of psoriatic patients in the intervention and control groups.Note: Results were expressed as mean (SD). PASI: psoriasis area severity index score BMI: body mass index expressed as kg/mSerum lipid profile, glycemia, and markers of muscle damage at baseline (pre intervention) and at the end of the study (post intervention) in male adults with psoriasis.Note: Results expressed as mean (SD). LDL-c: low density lipoprotein-cholesterol expressed as mg/dl; HDL-c: high density lipoprotein-cholesterol expressed as mg/dl; TG: triglycerides expressed as mg/dl; Gly: glycemia expressed as mg/dl; CK: creatine kinase activity expressed as U/L; Mb: myoglobin concentration expressed as ng/mL. Influence of the aerobic training program on FACIT-fatigue, HAQ-DI, and VAS scores in psoriatic patients at baseline and after completing the intervention program.Note: FACIT-fatigue: functional assessment of chronic illness therapy fatigue scale; HAQ-DI: health assessment questionnaire-disability index; VAS: visual analogue scale.

PMC10648681

ABSTRACT

PMC10487390

Introduction

BRAIN METASTASES, METASTATIC BREAST CANCER

Around 25% of metastatic breast cancer (mBC) patients develop brain metastases, which vastly affects their overall survival and quality of life. According to the current clinical guidelines, regular magnetic resonance imaging screening is not recommended unless patients have recognized central nervous system–related symptoms.

PMC10487390

Patient Presentation

cancer, fatigue

BRAIN METASTASES, CANCER

The patient participated in the EFFECT study, a randomized controlled trial aimed to assess the effects of a 9-month structured, individualized and supervised exercise intervention on quality of life, fatigue and other cancer and treatment-related side effects in patients with mBC. She attended the training sessions regularly and was supervised by the same trainer throughout the exercise program. In month 7 of participation, her exercise trainer detected subtle symptoms (e.g., changes in movement pattern, eye movement or balance), which had not been noticed or reported by the patient herself or her family, and which were unlikely to have been detected by the oncologist or other health care providers at that point since symptoms were exercise related. When suspicion of brain metastases was brought to the attention of the oncologist by the exercise trainer, the response was immediate, and led to early detection and treatment of brain metastases.

PMC10487390

Conclusion and clinical implications

cancer

BRAIN METASTASES, CANCER

The brain metastases of this patient were detected earlier due to the recognition of subtle symptoms detected by her exercise trainer and the trust and rapid action by the clinician. The implementation of physical exercise programs for cancer patients requires well-trained professionals who know how to recognize possible alterations in patients and also, good communication between trainers and the medical team to enable the necessary actions to be taken.

PMC10487390

Key Words

seizures, breast cancer, vomiting, nausea,, headache

ONCOLOGY, BRAIN METASTASES, METASTATIC BREAST CANCER, BREAST CANCER

The incidence of brain metastases (BM) from breast cancer has increased in recent decades due to improved survival rates for metastatic breast cancer (mBC) and advances in neuroimaging leading to earlier detection (According to the American Society of Clinical Oncology and the European Society for Medical Oncology, regular magnetic resonance imaging (MRI) screening is not recommended unless patients have central nervous system (CNS)-related symptoms (most commonly: headache, nausea, vomiting, focal deficits, or seizures (Here, we describe a case in which BM of mBC were detected early in a patient who participated in a physical exercise program supervised by a qualified exercise trainer, as part of a randomized controlled trial (RCT). As a result of the close monitoring throughout the intervention, the exercise trainer detected new symptoms, which had not been noticed or reported by the patient herself or her family, and which were unlikely to have been detected by the oncologist at that point. The trainer alerted the oncologist who then acted promptly.

PMC10487390

CASE REPORT

cancer, comorbidity, infratentorial lesion, primary breast cancer

BRAIN METASTASIS, HYPERCHOLESTEROLEMIA, CANCER, DISEASE, ONCOLOGY

A 75-yr-old woman with a diagnosis of mBC (ER+, PR-, HER2-; Ki-67 10%) participated in the EFFECT study (The woman was diagnosed with primary breast cancer in 2014, which had disseminated to the liver in 2016, to the bone in 2017 and to lymph nodes and the kidney in 2020. She had undergone chemotherapy, radiotherapy to the pelvis, endocrine therapy, immunotherapy, and bisphosphonate treatment. At the time of randomization to the intervention group of the EFFECT study (August 2020), she was on her third line of mBC treatment receiving Palbociclib and Fulvestrant. The only known comorbidity was hypercholesterolemia, since 2017, for which she was treated with simvastatin.The patient attended the training sessions regularly (86%, 43 of 50 sessions). She was supervised by the same exercise trainer throughout the exercise program. In month 7 of the intervention, the patient’s performance declined unexpectedly. During the training session, the trainer recognized some changes and symptoms that were not in line with her previous performance and included failure to complete walking on a line, one leg stand or dual-tasking exercises during the balance component, requiring longer resting intervals or a decrease in intensity (i.e., workload) while performing the high intensity interval protocol during aerobic training. In addition, the patient seemed a little sleepier and her eye movements seemed slower than usual, especially when she was lying down. She also shared a complaint that sometimes her legs did not “listen to her” when she wanted to start walking and that she felt a “bit groggy,” but she did not seem to be overly concerned by it. Initially, the patient attributed these insidious changes to the fluctuations inherent to the disease and its treatments; however, the trainer advised her to talk to her oncologist.Four weeks later, during a training session, the patient began to make slight superfluous movements with her arms during the bench press exercise. Hence, the trainer encouraged the patient again to speak with her oncologist about these symptoms during the appointment she had that same day, but she did not do so. The patient did not seem to care and was not fully aware of the changes that were happening to her. Hence, these symptoms remained unrecognized by the medical team and the patient’s cancer treatment remained unchanged. Suspecting BM based on the signs that indicated the patient’s neurological functioning was deteriorating, the trainer sought approval from the patient 3 d later, to contact the oncologist and discuss her concerns. The oncologist responded immediately by ordering a brain MRI.Five days after the communication between the trainer and the oncologist, the MRI confirmed BM (Fig. (A) Axial T1 weighted image without gadolinium. (B) Coronal T1 weighted image without gadolinium. (C) Axial T1 weighted image after gadolinium. (D) Coronal T1-weighted image after gadolinium showing an infratentorial lesion suspected for brain metastasis.The new treatment plan included radiotherapy and chemotherapy. At the start of whole brain radiation, 4 wk after the MRI was performed, regular physical examination still showed no obvious signs of CNS involvement. Neither the patient nor her husband believed that there has been a marked deterioration over time. The patient died 5 months after diagnosis of BM. Following the CARE case reports guidelines, a timeline is provided in Figure Timeline of the case report. ECOG, Eastern Cooperative Oncology Group.

PMC10487390

DISCUSSION

cancer, nausea, seizures

CANCER, RARE HEADACHE

This is a case report of a patient with mBC whose BM were detected early as a result of her participation in a supervised exercise program. For this to happen, three aspects were crucial: (i) the close monitoring of the patient by an experienced exercise trainer, (ii) the established communication pathways between the trainer and the medical team, and (iii) the trust in the trainer and hence rapid action by the clinician.Although the prognosis of BM is currently considered poor, knowledge about cancer dissemination to the brain, prevention and treatments is evolving significantly (Current guidelines do not recommend MRI screening of the brain unless symptoms are present. The most common symptoms resulting from BM are headache (35%) vomiting (26%), nausea (23%), hemiparesis (22%), visual changes (13%) seizures (12%) (The benefits of physical exercise in cancer patients have been widely corroborated by the literature (To conclude, our case report supports the advantages of implementing physical exercise programs that are supervised by qualified professionals as part of routine cancer care for patients in need. This may not only lead to physical and psychological improvements but may also contribute to better patient outcomes through follow-up. We recommend close collaboration between the medical team and exercise professionals because of their unique positioning and skill set to detect subtle deteriorations in health early.

PMC10487390

PRIMARY TAKE AWAY LESSONS OF THIS CASE REPORT

gait disturbance, forceful

ONCOLOGY, DISEASE PROGRESSION

Close monitoring performed by qualified exercise trainers during supervised exercise sessions can lead to the detection of subtle but significant signs of disease progression that may not be recognized yet by clinicians, patients or their family. Early detection of disease progression can make a significant difference to the patient’s QoL and life expectancy.We recommend that changes in movement patterns that become uncoordinated or less forceful, gait disturbance, a deterioration in balance, slower or clumsier eye movements, changes in mental state or behavior (more angry, uninhibited, disconnected, sleepy, etc.), or any unexpected performance decline recognized by a trainer should be brought to the patient’s attention.The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine.We would like to thank oncologists Cristina Churruca, Isabel Álvarez and Nerea Ancizar (UGC Medical Oncology from Gipuzkoa, OSI-Donostialdea-Onkologikoa) and radiotherapist María Pagola (Fundación Onkologikoa) for their support in discussions about the importance of publishing this case report.Statements and declarations: The EFFECT study is part of the PREFERABLE project and has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 825677. The study is also funded by the National Health and Medical Research Council of Australia (2018/GNT1170698). These funding bodies do not have any role during the execution, analyses, interpretation of the data, or decision to submit the results of this study.Competing Interests: K. S. has received speaker honorarium from Adviva, Germany. The rest of authors declare that they have no competing interests.Authors Contribution: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M. P., A. M. M., and M. B. The first draft of the article was written by M. P., M. M. S., and A. M. M. All authors commented on previous versions of the article. All authors read and approved the final article.Ethics Approval: The EFFECT study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved in October 2019 by the institutional review board of the University Medical Center Utrecht, the Netherlands, and by the local ethical review boards of all participating institutions. In this case by CEIm-Euskadi under the reference PI2019202. The study was registered with

PMC10487390

REFERENCES

PMC10487390

Introduction

The learning curve in minimally invasive surgery (MIS) is steep compared to open surgery. One of the reasons is that training in the operating room in MIS is mainly limited to verbal instructions. The iSurgeon telestration device with augmented reality (AR) enables visual instructions, guidance, and feedback during MIS. This study aims to compare the effects of the iSurgeon on the training of novices performing repeated laparoscopic cholecystectomy (LC) on a porcine liver compared to traditional verbal instruction methods.

PMC10520207

Methods

COMPLICATIONS

Forty medical students were randomized into the iSurgeon and the control group. The iSurgeon group performed 10 LCs receiving interactive visual guidance. The control group performed 10 LCs receiving conventional verbal guidance. The performance assessment using Objective Structured Assessments of Technical Skills (OSATS) and Global Operative Assessment of Laparoscopic Skills (GOALS) scores, the total operating time, and complications were compared between the two groups.

PMC10520207

Results

The iSurgeon group performed LCs significantly better (global GOALS 17.3 ± 2.6 vs. 16 ± 2.6,

PMC10520207

Conclusion

COMPLICATION

Visual guidance using the telestration device with AR, iSurgeon, improves performance and lowers the complication rates in LCs in novices compared to conventional verbal expert guidance.

PMC10520207

Supplementary Information

The online version contains supplementary material available at 10.1007/s00464-023-10360-y.

PMC10520207

Keywords

STERILITY

Open Access funding enabled and organized by Projekt DEAL.Minimally invasive surgery (MIS) has brought significant benefits to patients undergoing surgical treatment [On the contrary to open surgery, the MIS learning curve is often hindered by the fact that instructions can only be given verbally due to distance, ergonomics, and sterility of the operating room (OR) [Today, MIS training can be performed outside the OR using virtual reality (VR) simulators and box trainers [Using a telestration model with augmented reality (AR) has shown benefits in surgical performance in medical students without MIS experience [The study's primary aim was to assess whether the iSurgeon has positive learning effects on MIS training in trainees with basic MIS experience performing repetitive ex vivo porcine LC compared to conventional verbal instructions.

PMC10520207

Materials and methods

PMC10520207

Study design and participants

hand gestures

This study was designed as a randomized, controlled two-arm study. The total sample size was 40 trainees. The study was performed as a part of the complementary MIS training curriculum for medical students (trainees) in their clinical years (3rd to 6th year) at Heidelberg University Medical School, Germany. The training was conducted in the MIS training center within the Department for General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Germany. The study was approved by the local ethics committee (S-436/2018).After signing a consent form, the trainees were randomized into two groups. Randomization was performed by an independent employee, otherwise not involved in planning, conducting, or analyzing the study, using a free available randomization tool (Flowchart of the randomized controlled studyAfter performing the baseline LC, each trainee performed 10 LCs within ten training sessions. The trainees within the control group only received verbal guidance, whereas those within the iSurgeon group received verbal and visual guidance using the iSurgeon (Fig. iSurgeon setup during a LC on a box-trainerTutor giving instructions during ex vivo porcine LC to the medical student with hand gestures displayed on the screen

PMC10520207

Materials

fenestrated gall bladder

COMPLICATIONS

The study was performed on a Szabo–Berci–Sackier Box Trainer and a standard laparoscopy tower (KARL STORZ GmbH & Co. KG, Tuttlingen, Germany). A study-specific task station was specifically constructed for this study. The iSurgeon was developed at the Department of General, Visceral, and Transplantation Surgery at Heidelberg University Hospital within a federally funded EXIST program and was provided for this study. For the performed LCs, a fenestrated gall bladder grasper, curved scissors, clip applicators, and laparoscopic monopolar hook electrode were used (KARL STORZ GmbH & Co. KG, Tuttlingen, Germany).In this study, the training was conducted by a medical doctor who had reached proficiency by performing at least 30 ex vivo porcine LCs himself. Furthermore, the tutor was monitored by a board-certified surgeon. Evaluation of both groups was done by one and the same tutor to avoid potential bias when evaluating the student’s performance. The tutor was also trained on how to use the iSurgeon and gave instructions on it. Evaluation of the complications and difficulty of the LCs was directly done at the end of the training to review the condition of the used organs. Furthermore, all training sessions were captured on video recordings for later performance assessments by a blinded rater.

PMC10520207

The iSurgeon

The iSurgeon is a collaborative telestration device with AR that enables interactive visual guidance during MIS procedures. With a specifically designed camera, the iSurgeon captures the tutor’s hand above the surgical field and projecting it on the operating screen. It allows tutors to draw, annotate, and provide the identification of the anatomical structures, suggests instrument handling, and helps to limit mistakes. The trainee can see the tutor’s hand and/or annotations overlaid on the surgical field on the operating screen, suggesting the next step in the MIS procedure or the plain of dissection. The iSurgeon also allows remote access, so the tutor does not have to be in the same room as the trainee. This real-time communication allows for instant feedback and helps enhance decision-making and surgical precision.

PMC10520207

Laparoscopic cholecystectomy on an ex vivo porcine liver

fibrous, bile duct injury, Fibrous, luxation

After inserting the instruments and identifying critical anatomical structures, the gallbladder's neck was grasped with consequent luxation and identification of Calot's triangle (trigonum cholecystohepaticum) [The next step was the preparation of Calot's triangle blunt or with diathermy. Fibrous tissue strands could be severed under sight only. Assistance with the iSurgeon on how to and where to best start coagulating was provided. The iSurgeon system assisted in identifying the cystic duct and artery and achieving the critical view of safety (CVS). CVS is seen as the gold standard to reduce the risk of bile duct injury in LC and was defined by Strasberg in 1995 as clearance of the hepatocystic triangle of fat and fibrous tissue, exposure of the cystic plate, and two and only two structures to be seen entering the gallbladder [

PMC10520207

Outcome parameters

injury of the gallbladder, gallbladder perforation

LIVER DAMAGE, COMPLICATION, COMPLICATIONS, COMPLICATIONS

The primary outcome of the study was performance scores assessed using standardized Objective Structured Assessments of Technical Skills (OSATS) (task-specific and global) and Global Operative Assessment of Laparoscopic Skills (GOALS) (task-specific and global) scores for all LCs performed. Global and task-specific OSATS and GOALS scores are considered reliable for assessing MIS training [Secondary outcomes were intraprocedural complications evaluated at the end of each LC concerning liver damage, gallbladder perforation, damage to cystic artery and duct, placement of the clip, and total operating time. Complications relating to damage to the liver were evaluated at the end of the training by reviewing the organ and assessing the injury of the gallbladder bed and surrounding liver parenchyma. The complication rate was evaluated using a 3-point Likert scale (supplementary material). Difficulty assessment of the ex vivo porcine liver was evaluated using the visual analog scale (VAS) on a scale ranging from 1 (extremely easy) to 10 (extremely hard) according to the given anatomical conditions such as organ size, aberrations of the cystic duct or artery, the thickness of the gallbladder wall or surrounding tissue [

PMC10520207

Statistical analysis

REGRESSION

Statistical analysis and descriptive statistics were performed using the SPSS software (version 25.0, IBM SPSS Inc., Chicago, Illinois, USA), and data are given as absolute frequency and mean ± standard deviation. Differences between the LC were assessed using the t-test for independent samples in parametric data and the Mann–Whitney U test for independent samples in the case of non-parametric data. For binary endpoints, group differences were calculated using the Chi-square test. Multivariable regression was performed to assess the influence of demographic parameters and personal characteristics on surgical performance. A

PMC10520207

Secondary endpoints

major damage

SECONDARY

The secondary endpoints are presented in Table On the left: CVS achievement compared between the two groups. On the right: comparison of the LC’s successful completion within the 90 min time limit and without major damage to crucial anatomical structures

PMC10520207

Discussion

INTRAOPERATIVE COMPLICATIONS, COMPLICATION, COMPLICATIONS

Efficient training is still a challenge in the field of MIS. Several studies showed that telestration with AR showed great potential for improving surgical performance at the beginning of MIS training [There are several telestration devices with AR that have been developed to assist with surgical training and performance [In this randomized controlled study, the visual guidance with the iSurgeon contributed to significantly better performance and fewer complications in 10 repetitively performed LCs, regardless of the difficulty of the LCs, compared to the control group that had only verbal guidance. Assessment of the task-specific and global GOALS and OSATS scores showed significantly higher scores in the iSurgeon group for all LCs performed, proving that the use of the iSurgeon system with expert guidance improves MIS skills such as tissue and instrument handling, preparation, dissection as well as the flow of operation. Interestingly, this was already shown after the first LC was performed with the assistance of the iSurgeon. There are several studies that have reported a positive influence of telestration on performance [The transfer of this kind of MIS training to the OR is accompanied by potential risks of complications, especially during the learning phase of the exercising surgeon [Interestingly, trainees in the iSurgeon group performed their baseline LC significantly faster than those in the control group. Nonetheless, this was only observed in the baseline LC. The two groups had no statistically significant difference in total operating time in the following 10 LCs.Concerning safe execution of the procedures, the iSurgeon group showed more successful completion of LCs within 90 min compared to the control group. No major damage was induced on the liver, gallbladder, cystic duct, or artery, which could lead to potentially severe complications in a real-life scenario. These aspects of safe conduct during a surgical procedure correspond with findings that misunderstandings and lack of efficient communication can lead to intraoperative complications [Additionally, according to the VAS, the iSurgeon group had a significantly lower complication rate than the control group despite more challenging LCs. This demonstrates how additional iSurgeon visual guidance potentially assists trainees to perform the LCs safely. It is comprehensible that the use of the iSurgeon with visual expert guidance assisted the trainees in developing a better understanding of the anatomical structures and procedure itself, leading to a more effortless flow from one procedural move to the next independently and being able to perform the procedure more often within the given time limit.Furthermore, visual guidance helped the trainees in the iSurgeon group achieve the CVS more often, which is one of the crucial steps in LC and essential in preventing damage to the surrounding structures [Finally, the iSurgeon group had more difficult gallbladders to work with, assessed using the VAS before each training. Considering the lower rate of complications and a higher percentage of successfully performed LCs, the iSurgeon group benefitted from visual guidance even in difficult cases, making the iSurgeon a potentially valuable tool in preclinical and clinical scenarios. Telestration devices with AR, like the iSurgeon, could have an additional effect on the learning curves of surgical trainees and patients' safety. Also, the iSurgeon could show potential in training young aspiring surgeons when used in specialized training centers or upon transfer to the OR with proctoring by a senior surgeon.However, despite promising opportunities that iSurgeon offers in MIS training, its routine application in everyday MIS training is still not accessible to all institutions due to its ongoing development. To implement the iSurgeon in training centers or the OR, it is necessary to have the corresponding material and software, which could potentially make it difficult to implement such technology without the required financial support. Nevertheless, the benefit of such assistance systems in MIS training should encourage institutions to invest in further research to make such technology accessible to improve surgical performance and quality and, through that, hopefully, patient outcomes.

PMC10520207

Limitations

STERILE

Due to the nature of the study and the spatial and temporal conditions, trainees from the iSurgeon and control group occasionally worked together in the same room. Thus, the flow of information between the two groups could have been a potential bias in both directions and within the two groups. Furthermore, since the training was conducted with students in different years of medical school (3rd to 6th year), a potential bias concerning the different levels of surgical education might have occurred. The inclusion criterium was the completion of the first module of the complementary MIS training curriculum, before which none of the participants had had any laparoscopic experience, but further previous surgical education was not assessed. However, besides the total time, the performance scores were comparable in the baseline LC. It is also important to mention that the intervention group had performed the baseline LC faster compared to the control group. This puts potential bias in the randomization process. However, the performance scores and all other compared parameters of the baseline LC were comparable between the two groups. Therefore, the study proceeded according to the predefined study protocol. One of the further limitations of the study is its small sample size, which could potentially influence the outcomes of the study.Finally, one must say that the environment in the training center where the LCs on porcine livers have been performed is not entirely comparable to an OR with a sterile covered operating field and that sound levels and disruptive factors due to the operating team consisting of surgeons, anesthesiologist, and nursing staff are higher in a real-life scenario. Nevertheless, this is also a chance for implementing the iSurgeon in a real-life OR setting to allow guidance when verbal feedback is difficult. This might, therefore, result in even higher benefits from telestration with AR in real-life conditions.

PMC10520207

Conclusion

verbal and visual guidance completed more LCs

COMPLICATIONS

MIS training with the iSurgeon telestration system with AR showed better task-specific and overall MIS performance for the first ten repeated ex vivo LCs. Trainees with verbal and visual guidance completed more LCs within the time limit and performed fewer complications despite higher difficulty levels of the LCs compared to those receiving only verbal guidance. This study underlines the value of visual guidance using telestration with AR in MIS training. Further studies should assess the benefits of incorporating the iSurgeon clinical training on patients.

PMC10520207

Acknowledgements

The authors would like to thank the medical students at the University Heidelberg for showing remarkable interest and motivation to participate and contribute to this study.

PMC10520207

Funding

Open Access funding enabled and organized by Projekt DEAL. No funding to disclose.

PMC10520207

Declarations

PMC10520207

Disclosures

P.

Amila Cizmic, Felix Müller, Philipp Anthony Wise, Frida Häberle, Felix Gabel, Karl-Friedrich Kowalewski, Vasile Bintintan, Beat P. Müller-Stich, and Felix Nickel have no conflicts of interest or financial ties to disclose.

PMC10520207

References

PMC10520207

Objective

maltreatment, anhedonia

Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories.

PMC10411366

Methods

depression

In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale.

PMC10411366

Results

REMISSION

Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68,

PMC10411366

Conclusions

anhedonia

We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.

PMC10411366

Résumé

PMC10411366

Objectif

Les mauvais traitements dans l’enfance sont un puissant marqueur environnemental du risque d’une mauvaise réponse aux médicaments antidépresseurs (MAD). Toutefois, les mauvais traitements dans l’enfance sont une construction hétérogène qui inclut des expositions distinctes ayant des corrélats neurobiologiques et psychologiques distincts. Le but de la présente étude est d’examiner les associations différentielles de mauvais traitements émotionnels, physiques et sexuels avec les résultats des MAD et d’examiner le rôle unique de l’anhédonie qui entraîne une mauvaise réponse chez les patients qui ont des antécédents spécifiques de mauvais traitements.

PMC10411366

Méthodes

Dans un essai clinique multicentrique de la dépression majeure, 164 personnes ont été évaluées relativement aux mauvais traitements émotionnels, physiques et sexuels dans l’enfance et ont répondu à une entrevue contextuelle avec des notations indépendantes, standardisées. Toutes les personnes ont reçu 8 semaines d’escitalopram, et les non-répondants ont reçu subséquemment également une augmentation d’aripiprazole, et les résultats ont été mesurés avec des échelles d’évaluation de la dépression et une échelle d’anhédonie.

PMC10411366

Résultats

Les mauvais traitements émotionnels plus graves perpétrés par la mère étaient un prédicteur significatif et direct de probabilités plus faibles d’une rémission à 16 semaines (RC = 1,68,

PMC10411366

Conclusions

Nous identifions les mauvais traitements émotionnels comme étant une exposition précoce spécifique qui place les patients à risque accru de non-rémission par suite d’un traitement pharmacologique. En outre, nous suggérons que l’anhédonie est un domaine de symptômes principal entraînant la non-rémission chez les patients ayant des antécédents particuliers de mauvais traitements.

PMC10411366

Introduction

maltreatment, anhedonia, sexual abuse, ARI, depressive disorder, MDD, depression, Depression, disability

REMISSION, SYNDROME

Major depressive disorder (MDD) affects close to 300 million people globally and is the leading worldwide cause of disability.Childhood maltreatment, including a history of emotional, physical, and/or sexual abuse, represents a particularly promising marker. Childhood maltreatment is the strongest developmental risk factor for MDD,The real promise of personalized medicine requires consideration of the prognostic significance of individual differences at the level of the risk marker (maltreatment) and the syndrome. Therefore, part of the reason for discrepancies in findings across studies may be due to the failure to consider the heterogeneous nature of childhood maltreatment and MDD.First, childhood maltreatment is a broad construct that includes distinct exposures that are associated with distinct neurobiological correlatesTo our knowledge, no studies have examined whether treatment efficacy in depression is differentially impacted by emotional versus physical versus sexual maltreatment. Further, no studies to our knowledge have examined change in anhedonia as a differential mediator of ADM outcome in those with histories of emotional versus physical versus sexual maltreatment. These are important questions as identifying which specific childhood histories are the strongest predictors of nonresponse may identify patients to be targeted for more rigorous intervention. Further, results bearing on mechanisms have the potential to inform the development of novel treatments targeting the domains driving nonremission.We examine our research questions in the context of the 16-week, 6-site Canadian Biomarker Integration Network in Depression (CAN-BIND)-1 trial, in which patients with MDD were treated with ESC for 8 weeks; nonresponders were then augmented with aripiprazole (ARI)—a partial D2 receptor agonist that elevates dopaminergic signalling—for an additional 8 weeks.We hypothesized that (1) emotional maltreatment, particularly perpetrated by the mother, will emerge as the strongest negative predictor of remission status at week 16 relative to physical or sexual maltreatment; (2) greater severity of emotional maltreatment, but not physical or sexual maltreatment, will be significantly associated with greater odds of requiring ARI augmentation (i.e., treatment nonresponse at week 8); and (3) severity of anhedonia at week 8 will significantly mediate the relation of emotional maltreatment to week 16 remission status.

PMC10411366

Methods

PMC10411366

Participants

MDD, DSM-IV-TR, anhedonia

SECONDARY, DISORDERS

The current study involved a secondary analysis of 164 outpatients in a current episode of MDD who completed assessments of childhood maltreatment and anhedonia during the 6-site CAN-BIND-1 trial (ClinicalTrials.gov identifier: NCT01655706).Inclusion criteria were as follows: (1) 18–60 years old, (2) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for a current episode of MDD as assessed with the Mini-International Neuropsychiatric Interview,A total of 211 patients were entered into the trial and completed baseline measures.

PMC10411366

Data Analysis

ARI, anhedonia

REGRESSION, REMISSION

SPSS statistical software version 26.0 was used for all analyses. Preliminary univariate analyses identified potential demographic or clinical covariates to include in our final models. Our first research question (maltreatment predicts remission status) was tested with a logistic regression model. The dependent variable was week 16 remission status. The predictors included treatment arm (ESC vs. ESC + ARI), and physical, sexual, and emotional maltreatment scores, entered simultaneously. The resulting parameters, thus, provide an estimate of the statistical relation of the specific maltreatment type, over and above the variance accounted for by the other maltreatment types. Receiver Operating Curves (ROCs) were fit to determine which predictors maximized the sensitivity and specificity of prediction. Further, for each type of maltreatment that emerged as a significant predictor of remission, we examined in a follow-up logistic regression model whether treatment arm significantly moderated the relation of maltreatment to week 16 remission status by including the interaction term of treatment arm with the relevant childhood maltreatment variable.Our second hypothesis was tested with a logistic regression model predicting treatment arm (i.e., week 8 response) from physical, sexual, and emotional maltreatment scores, entered simultaneously. Our third hypothesis (maltreatment predicts week 16 remission through maintenance of anhedonia) was tested with mediation models conducted in PROCESS (Model 4).

PMC10411366

Childhood Maltreatment and Week 8 Response

ARI

REGRESSION

A multivariate logistic regression model predicting need for ARI augmentation at week 8 (i.e., week 8 response) from severity of emotional, physical, and sexual maltreatment, entered as a block, was not significant, χ

PMC10411366

Childhood Maltreatment, Week 8 Anhedonia, and Week 16 Remission

anhedonia

REMISSION

However, lower scores on the week 8 DARS residual (i.e., less change from baseline, and thus, greater severity of week 8 anhedonia) were significantly correlated with greater severity of emotional maltreatment, Greater severity of (a) emotional maltreatment and (b) physical maltreatment predicted less change in anhedonia from baseline to week 8, which subsequently significantly predicted a greater likelihood of nonremission to escitalopram or escitalopram + aripiprazole at week 16. Parameter estimates for indirect effects are provided in the text. *Follow-up mediation models revealed that the indirect effect on week 16 remission status through a change in anhedonia was An open question raised by the models above is to what extent the mediation effects are

PMC10411366

Discussion

anhedonia, ARI, treatment-refractory, MDD, depression, depressive recall

EVENTS, MALTREATMENT, REMISSION

In a large multicentre trial that included rigorous contextual assessment of childhood maltreatment history, we found that greater severity of mother-perpetrated emotional maltreatment directly predicted lower odds of remission following 16 weeks of treatment with ESC or ESC + ARI. Further, emotional maltreatment perpetrated by the father and physical maltreatment were indirectly associated with remission status through greater severity of (less change in) anhedonia from baseline to week 8. The current design provided a particularly conservative test of our research question. The effect of emotional maltreatment was robust when controlling for overlapping variance with physical and sexual maltreatment, and ROC analysis indicated that a model containing only physical and sexual maltreatment did not predict remission better than chance. Further, the effect of emotional maltreatment on remission at week 16 was robust even over and above the very strong association of response at week 8. Previous cross-sectional research has found that emotional maltreatment is also significantly more strongly associated than other forms of maltreatment with the onset and severity of MDD.Higher severity of emotional and physical maltreatment was associated with greater severity of (less change in) anhedonia following 8 weeks of ESC treatment. Further, the relations of emotional maltreatment perpetrated by the father and physical maltreatment to remission status were significantly Symptoms of anhedonia are more strongly related to threat neurocircuitry than are symptoms of general distress in depression.Maltreatment predicted remission over and above treatment arm (ESC vs. ESC + ARI). Therefore, childhood maltreatment may represent a marker of a more treatment-refractory set of patients who warrant multilevel investigation. In particular, future research is needed to examine other treatment strategies (e.g., new pharmacotherapy augmentation strategiesLimitations include the retrospective nature of the CECA, which raises concerns about depressive recall bias. However, contextual interview measures of childhood maltreatment are less subject to recall bias than traditional self-report measures because ratings are independent and standardized to anchored exemplars.Further, the MADRS includes 1 item related to anhedonia (item 8 “Inability to feel”), raising the potential that our mediator may be confounded with our outcome. However, our measure of anhedonia assesses the much broader domain, capturing interest, motivation, effort, and enjoyment of rewards across several areas of life. Nevertheless, conclusions would be strengthened through future research including behavioural tasks or neurophysiological markers of anhedonia. Finally, it was beyond our scope to examine the developmental timing of maltreatment, proximal stressful life events, or additional psychobiological factors that could potentially mediate or moderate the relation between childhood maltreatment and treatment response.Childhood maltreatment is widely regarded as one of the strongest risk factors for the onset and treatment resistance of MDD. The current results identify which specific early exposures place patients at the greatest risk, thereby allowing these patients to be assigned for more rigorous intervention. Further, they have the potential to inform the development of novel treatments targeting the domains driving nonremission, specifically anhedonia, with the ultimate goal of reducing the burden associated with MDD.

PMC10411366

References

PMC10411366

Objectives

T2DM, Diabetes

TYPE 2 DIABETES MELLITUS, DIABETES

Edited by: Yan Shu, University of Maryland, United StatesReviewed by: Haoyan Chen, Shanghai Jiao Tong University, China; Jian Zhou, Shanghai Jiao Tong University, China; Yuqian Bao, Shanghai Jiao Tong University, China†These authors have contributed equally to this workThis article was submitted to Systems Endocrinology, a section of the journal Frontiers in EndocrinologyThe purpose of this study was to assess the incidence of type 2 diabetes mellitus (T2DM) after 6 years in patients with IGT who received early probiotic intervention in the Probiotics Prevention Diabetes Program (PPDP) trial.

PMC9982119

Methods

T2DM

77 patients with IGT in the PPDP trial were randomized to either probiotic or placebo. After the completion of the trial, 39 non-T2DM patients were invited to follow up glucose metabolism after the next 4 years. The incidence of T2DM in each group was assessed using Kaplan-Meier analysis. The 16S rDNA sequencing technology was used to analyze gut microbiota’s structural composition and abundance changes between the groups.

PMC9982119

Results

T2DM

The cumulative incidence of T2DM was 59.1% with probiotic treatment versus 54.5% with placebo within 6 years, there was no significant difference in the risk of developing T2DM between the two groups (

PMC9982119

Conclusions

T2DM

Supplemental probiotic therapy does not reduce the risk of IGT conversion to T2DM.

PMC9982119

Clinical Trial Registration

PMC9982119

Introduction

T2DM, prediabetes

IMPAIRED GLUCOSE TOLERANCE, TYPE 2 DIABETES MELLITUS, PREDIABETES

Compared with normal glucose tolerance (NGT), people with prediabetes, especially impaired glucose tolerance (IGT), have a higher risk of developing type 2 diabetes mellitus (T2DM). Early intervention can significantly reduce the probability of developing T2DM in the IGT population (After the PPDP trial was completed, participants without T2DM were invited to follow up for 4 years. The objective of the PPDP Follow-On study was to observe the effect of early probiotic intervention on the conversion of T2DM after 6 years.

PMC9982119

Research design and methods

PMC9982119

PPDP study

T2DM

SECONDARY

The design and primary results of the PPDP study have been reported previously (Feces of the two groups before and after intervention were collected. The 16S rDNA sequencing technology was used to analyze intestinal microbiota’s structural composition and abundance changes. The primary outcome was the cumulative prevalence of T2DM in the two groups. The secondary endpoints were the possible changes in the proportion of microbiota. The study was registered in the Chinese clinical trial registry (ChiCTR-TRC-13004024).

PMC9982119

PPDP follow-on study

T2DM, blood tumor

After the completion of the initial PPDP study, patients who with undiagnosed T2DM continue to be invited to participate in the PPDP Follow-On study without probiotics intervention. A total of 39 non-T2DM patients agreed to follow up glucose metabolism for next 4 years. Patients were asked to monitor fasting and postprandial blood glucose by themselves. At the 4th year, OGTT were assessed at the outpatient department of Shanghai East Hospital. Finally, 36 patients finished the next 4-year follow-up, 2 patients withdrew due to loss of contact, and 1 patient died due to a blood tumor, with a dropout rate of 4.2%. The detailed patient flow of the original trial (PPDP) and follow-on study is summarized in Flow diagram for PPDP follow-on study.The primary outcome was the cumulative incidence of T2DM in the two groups during the 6 years. The PPDP study and the PPDP Follow-On study were reviewed and approved by the hospital’s ethics committee and all patients signed informed consent.

PMC9982119

16S rRNA gene sequencing and analysis

Fresh fecal samples were collected and bacteria’s 16S rRNA gene sequence was detected using paired-end configuration on an Illumina MiSeq system (Illumina, San Diego, USA). Briefly, microbial DNA was extracted and DNA quality was examined by agarose gel electrophoresis. The V3-V4 regions of the bacteria’s 16S rRNA gene were amplified by PCR. The sequencing was performed using paired-end configuration on an Illumina MiSeq system (Illumina, San Diego, USA). Raw fastq files were demultiplexed, and then data was filtered to ensure quality. The taxonomy of each 16S rRNA gene sequence was analyzed by RDP Classifier (

PMC9982119

Statistical analyses

Statistical analyses were performed by SPSS version 23.0 (IBM Corp, Armonk, NY, USA) and GraphPad Prism version 8.0 (San Diego, California, USA). Continuous data were described as means ± standard deviation, and inter-group comparison was performed with a t-test or analysis of variance. All continuous data were abnormally distributed. Categorical data were described as n (%), and inter-group comparisons were analyzed by χ

PMC9982119

Results

PMC9982119

Baseline characteristics

T2DM

INSULIN RESISTANCE

The baseline characteristics of the Probiotics group and Placebo group in the PPDP study have been presented in the previous article (9). Specifically, there were no significant differences in sex composition, age, body mass index (BMI), blood pressure, heart rate, liver function, blood lipid profile, FPG, post-glucose load plasma glucose, glycated hemoglobin A1c(HbA1c), fasting serum insulin (FINS) and the homeostasis model assessment of insulin resistance (HOMA-IR) between the two groups.At the end of the PPDP study, there remained 39 patients with undiagnosed T2DM (21 patients in the Probiotics group and 18 in the Placebo group). The characteristics of undiagnosed T2DM patients at the end of 2-year follow up between the probiotics and placebo groups were shown in Characteristics of undiagnosed T2DM patients at the end of 2-year follow up between the Probiotics and Placebo groups.ALT, Alanine aminotransferase; BMI, body mass index; DBP, Diastolic blood pressure; FPG, fasting plasma glucose; FINS, fasting insulin; HOMA-IR, homeostasis model assessment of insulin resistance; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, Triglyceride; SCr, serum creatinine; 30minPG, 30-minute-plasma glucose post-glucose load; 2hPG, 2-h-plasma glucose post-glucose load; 30mINS, 30-minute-insulin post-glucose load; 2hINS, 2-hour-insulin post-glucose load.Categorical data were described as n (%). Continuous data are presented as mean ± SD.*P values<0.05 were considered significant.

PMC9982119

Comparison of the incidence of T2DM

T2DM

In the next 4 years, there were 6 patients in the Probiotics group and 5 patients in the Placebo group who developed T2DM. Thus, the cumulative incidence of T2DM was 59.1% in the probiotic group and 54.5% in the placebo group within 6 years. As shown in Kaplan-Meier analysis of the cumulative incidence of T2DM within 6 years between the probiotics and placebo group.At the end of the 6-year follow-up, patients were grouped according to whether T2DM occurred. The age of the T2DM group was significantly older than the non-T2DM group (57.2 vs 53.7 years,

PMC9982119

COX regression analysis of risk factors for T2DM

T2DM

REGRESSION

COX regression model was used to analyze the risk factors affecting the development of T2DM. Probiotic intervention or not, age, gender, BMI, waist circumference, blood pressure, liver function, blood lipid, blood glucose, serum insulin and HbA1c were used as covariates, and results showed that 30-minute post-glucose load insulin level was a factor affecting the conversion of IGT to T2DM (HR=0.954, 95%CI 0.915-0.994, COX regression analysis of risk factors for T2DM after 6 years.

PMC9982119

Gut microbiota analysis

T2DM

According to the informed consent and research protocol, fecal samples were collected at baseline (day 0) and the end of the 2-year follow-up visit. The 16S rDNA sequencing technology was used to analyze gut microbiota’s structural composition and abundance changes. A total of 32 stool samples in the Probiotic group and 22 in the Placebo group were collected. In this study, the differences in operational taxonomic units (OTUs) abundance among the probiotic group and the placebo group were compared. The Venn diagram showed that 435 of the total 972 genera were shared among the 4 groups (Composition and diversity of gut microbiota before and after two years probiotics or placebo intervention. Composition and diversity of gut microbiota in T2DM patients and non-T2DM patients before and after two years of probiotics intervention. The mean proportion of subdoligranulum and monoglobus in the T2DM group was significantly lower than that of the non-T2DM group both at bas `eline and after the intervention. The proportion of collinsella was lower in the T2DM group (Analysis of significantly altered gut microbiota and specific species microbiot in T2DM patients and non-T2DM patients after two years of probiotics intervention. Functional prediction and comparison of gut microbiota between T2DM and non-T2DM groups.

PMC9982119

Discussion

obesity, gestational diabetes, metabolic diseases, metabolic disease, T2DM, diabetes

METABOLIC DISEASES, OBESITY, GESTATIONAL DIABETES, DIABETES

IGT is closely associated with metabolic disease progression. According to the epidemiological data, about 70% of IGT patients progress to DM within 5 years in China (The treatment of metabolic diseases with probiotics is a hot topic in intestinal microbiota research. However, there are fewer studies on probiotics for the prevention and treatment of IGT patients. We previously observed that probiotics supplementation for IGT patients for 2 years did not significantly reduce the risk of IGT conversion to T2DM in the PPDP study (Although the relationship between the gut microbial ecological imbalance and the development of obesity and diabetes is being extensively explored, the conclusions of various studies are different. The results of randomized controlled studies on pregnant women with gestational diabetes or obesity showed that probiotic intervention had no effect on glycemic control, but might improve lipid metabolism (The gut microbiota profile may be related to and responsive to a particular dietary pattern (There are some limitations in our study. First, this was a small sample size study that enrolled a limited number of patients with IGT. More clinical and laboratory studies using large-size samples and long-term observation are needed to confirm the role of probiotics in developing IGT into DM. Second, the results of the study of Bifico used in this study as a probiotic supplement for Chinese patients are not representative of the effects of other strains on other people or races. Third, the study did not document lifestyle factors, such as diet and exercise, which might have influenced blood sugar outcomes. There is also no recorded family history of T2DM, which is a very strong risk factor for developing T2DM. However, the placebo control designed in this study could compensate for this effect to the greatest extent. To provide preliminary data that could drive more conclusive testing. Therefore, high-quality, large-scale, multicenter randomized controlled trials with longer follow-up are needed to compare safety and efficacy further.

PMC9982119

Conclusions

Lactobacillus acidophilus

Nevertheless, the results of this study suggest that supplementation with active probiotics of Bifidobacterium, Lactobacillus acidophilus and Enterococcus faecalis is safe, although it does not reduce the risk of IGT conversion to DM. More clinical and laboratory studies using large samples and long-term observation are needed to explore the effects of different probiotic strains on IGT. This pilot study was designed to provide preliminary data to conduct more conclusive hypothesis testing.

PMC9982119

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: NCBI BioProject [

PMC9982119

Ethics statement

The studies involving human participants were reviewed and approved by the institutional review board of Shanghai East Hospital and was conducted in accordance with the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.

PMC9982119

Author contributions

BF designed the study and oversaw the project implementation. QY conceived and carried out experiments. WH and YT participated in data analyses, interpretation and writing publications. XUL, YY and XIL participated in data collection, data analyses and interpretation and writing publications. All authors were involved in writing the paper and had final approval of the submitted and published versions.

PMC9982119

Acknowledgments

We were grateful to the participants and nurses in the Department of endocrinology of Shanghai East hospital for participating in this study.

PMC9982119

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

PMC9982119

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

PMC9982119

Supplementary material

The Supplementary Material for this article can be found online at: Click here for additional data file.

PMC9982119

References

PMC9982119

Subject terms

coronavirus disease 2019

SECONDARY, CORONAVIRUS DISEASE 2019

Large clinical trials often generate complex and large datasets which need to be presented frequently throughout the trial for interim analysis or to inform a data safety monitory board (DSMB). In addition, reliable and traceability are required to ensure reproducibility in pharmacometric data analysis. A reproducible pharmacometric analysis workflow was developed during a large clinical trial involving 1000 participants over one year testing Bacillus Calmette-Guérin (BCG) (re)vaccination in coronavirus disease 2019 (COVID-19) morbidity and mortality in frontline health care workers. The workflow was designed to review data iteratively during the trial, compile frequent reports to the DSMB, and prepare for rapid pharmacometric analysis. Clinical trial datasets (n = 41) were transferred iteratively throughout the trial for review. An RMarkdown based pharmacometric processing script was written to automatically generate reports for evaluation by the DSMB. Reports were compiled, reviewed, and sent to the DSMB on average three days after the data cut-off, reflecting the trial progress in real-time. The script was also utilized to prepare for the trial pharmacometric analyses. The same source data was used to create analysis datasets in NONMEM format and to support model script development. The primary endpoint analysis was completed three days after data lock and unblinding, and the secondary endpoint analyses two weeks later. The constructive collaboration between clinical, data management, and pharmacometric teams enabled this efficient, timely, and reproducible pharmacometrics workflow.Open access funding provided by Uppsala University.

PMC10539503

Introduction

coronavirus disease 2019

CORONAVIRUS, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME

Clinical trial datasets are becoming larger and increasingly complex with innovative advances in biomarker including genomic, transcriptomic, proteomic, and metabolomic measurements, mobile or wearable patient surveillance, and the use of real-world dataPharmacometricians are experts in data review, processing, and analysis in clinical and preclinical pharmacology. Reproducibility, defined as reaching the same outcome when repeating an analysisThe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became a world-wide pandemic. It particularly put a serious strain on the health care system of South AfricaThe objective of this work was therefore to create a reproducible pharmacometric workflow for data processing, reporting, and analysis in order to support the data safety monitoring board (DSMB) and allow for efficient, timely, and reproducible data analysis. We focussed on understanding of, and confidence in handling the growing clinical trial dataset, fast and reliable frequent reporting of aggregated and per-arm data, and consistency between the reporting and the subsequent pharmacometric analysis dataset. We present here the reproducible pharmacometrics workflow that led to the rapid pharmacometrics analyses of the trial, which are not the focus on this work and the outcome of which are reported separately.

PMC10539503

Methods

PMC10539503

Workflow structure

The reproducible pharmacometric workflow was designed in consensus between the pharmacometricians, clinicians, and data managers within the project, and is shown in Fig. Overview of the pharmacometric reproducibility workflow. Clinical operations were the initial start of the workflow, but because of its circularity, and ongoing clinical operations throughout the trial parallel to the data processing, the workflow was performed repeatedly. The black boxes represent the clinical team, purple boxes represent the data management team, magenta boxes represent the pharmacometric team, and orange box represent the independent data safety monitoring board (DSMB). All processes were blinded until the end of the clinical trial, after which the data report per arm and the DSMB contained the unblinded data. eCRF = electronic case report form, QC = quality control.After resolving all queries, the pharmacometric processing script produced two types of output. Firstly, the script automatically generated two data reports for frequent review; an aggregated report and a per-arm closed report. The aggregated data report, with treatment arms combined to prevent investigator unblinding or bias, was presented to the data safety monitoring board (DSMB) during the open session of their meeting, where the clinical team was present. The closed data report for the DSMB conversely showed the clinical trial data separated per arm but still blinded during the trial. Second, the pharmacometric processing script prepared for the different pharmacometric analyses, by graphical exploration of the data and data parsing to datasets for non-linear mixed effects modelling, of which the results were also presented to the clinical team and the DSMB. Collaboration on, and interoperability of, the pharmacometric processing script was essential between the different members of the pharmacometric team, which are working on the same reporting and analyses in parallel. To facilitate coding within the same script, the members of the pharmacometric team worked together in a private Github repository through Github Desktop (v.2.9.4) which at the same time ensured the script’s version control.

PMC10539503

Clinical trial data

ADVERSE EVENTS, INJECTION SITE REACTION, EVENTS, RESPIRATORY TRACT INFECTION (RTI)

The clinical trial data was captured in four master databases namely Screening/enrolment, Events, Lab results, and Follow-up, which consisted of 59 datasets in total. The Screening/enrolment database contained the participant demographics, medical and social history, and trial specific information such as inclusion/exclusion criteria, informed consent, and randomization. This database was therefore essential for covariate information to be tested in subsequent analyses. In the Events database, all information on adverse events was collected. Events were categorized as injection site reaction (ISR), respiratory tract infection (RTI), or other. Events were given a health status score by the clinical team with 0 representing healthy participant, 1 representing mild symptoms, 2 representing moderate symptoms, 3 representing severe symptoms, 4 representing hospitalization, 5 representing hospitalization with supplemental oxygen, 6 representing hospitalization with mechanical ventilation, and 7 representing deathThe four master databases were transferred from the data management to the pharmacometric team through secure file transfer protocol (sFTP, WinSCP v. 5.19.3

PMC10539503

Data review

The clinical team’s QC ensured all data entries to the eCRF platform corresponded to the paper source documentation. The data management’s QC subsequently checked the eCRF platform data on MedDRA coding, duplicates, incomplete or non-QC-ed records, etc. Once data had passed the clinical and data management QCs successfully, they were transferred to the pharmacometric team. The integrated database as a result of the pharmacometric processing script was subject to a data review complementary to these QCs. The pharmacometric data review had three objectives, and was performed by running the integrated data through an R-script after which results were reviewed by members of the pharmacometrics team. First, data was reviewed to comprehend the clinical meaning of the data entries, including in the context of new data and information on COVID-19 that arose throughout the trial and the ongoing pandemic. Second, once integrated by the pharmacometric processing script, the consistency between the data entries was reviewed, e.g. to not have conflicting records from different datasets for the same timepoint. Third, a check was done to ensure the eCRF data output of the eCRF platform (Mobenzi), was correctly input into the data handling software used by the pharmacometric team (R). This more technical review considered missing values, leading spaces, spelling, lower or upper cases, and numerical or character values, among others. A dedicated R chunk in the pharmacometric processing script was developed for the data review which was updated frequently. After every data transfer, the updated integrated database was reviewed using this code and queries were directed to the data management team. After all queries were resolved and data review was passed successfully, the integrated database was used for graphical and numerical exploration in the pharmacometric processing script, as well as for the DSMB report.

PMC10539503

Reporting

Frequent reporting on the progress of the trial was critical to identify early evidence of efficacy, if present. To that aim, the reports contained graphical and tabular exploration of the data without formal interim statistical testing. To limit the time between data transfer and distributing data reports, the pharmacometric processing script was developed to automatically generate reproducible data reports. RMarkdown was used to incorporate R-based output (numeric, graphical, tabular) with written text, which was compiled into a pdf document by knitr (v.1.33

PMC10539503

Pharmacometric analysis preparation

The pharmacometric processing script was also utilized for the pharmacometric analysis preparation. The integrated database that was input for the tables and graphs in the report, was transformed into the pharmacometric analysis datasets in NONMEM v.7.4.3

PMC10539503

Results

PMC10539503

Transfer of clinical trial data

Instead of the conventional approach of receiving data for pharmacometric analysis after the trial completion, an iterative data transfer and reproducible data handling workflow was developed by consensus between the clinical, data management, and pharmacometric teams who collaborated in this clinical trial. Data QC and review responsibilities were shared between the clinical, data management, and pharmacometric teams. Figure Overview of the data management throughout the clinical trial. Number of participants on trial over time is shown in purple solid line, database locks (n = 2) are shown in black dashed lines, scheduled data review (n = 41) are shown as magenta top rug plot, first reported diagnosed COVID-19 case in South Africa is shown as grey bottom axis mark for reference.

PMC10539503

Understanding and confidence in handling through data review

COVID-19 respiratory tract infections, viral syndrome

SARS-COV-2 INFECTION, ASYMPTOMATIC SARS-COV-2 INFECTION, COVID-19 PNEUMONIA, DISEASE, EVENT, COVID-19 INFECTION, POST VIRAL SYNDROME, EVENTS, VIRAL SYNDROME, EVENTS, POST VIRAL SYNDROME

The frequent interim data QC by the clinical, data management, and pharmacometric teams was a time-saving investment. All records were subject to check after entry into the eCRF, and the clinical QC and data management combined found in 20.9% of the records that a correction was needed when the eCRF was compared to the paper source document. A total of 201 queries accounting for 10.7% of total records were found by the pharmacometrics team and resolved while the trial was ongoing. The last data check after the trial completed only resulted in 4 additional queries which were resolved in two days, after which the data could be locked. In addition to saving time after study completion, addressing queries while the study is still ongoing was also found to be advantageous because an incorrect measurement (e.g. weight) can still be re-measured and recorded. Pharmacometric analysis (magenta hexagon in Fig. Data review was challenging because of the large size of the database. The full database consisted of 20,457 records. Figure Number of eCRFs submitted per master database. Dataset architecture consisted of 4 master databases (Screening/enrolment, Events, Lab results, and Follow-up) for which the number of records is shown.Most important in the pharmacometric data review was the understanding of the clinical meaning of the data entries. For example, COVID-19 was defined as a symptomatic disease with confirmed SARS-CoV-2 infection. As such, a COVID-19 event with a health status score of 0, or a polymerase chain reaction (PCR) confirmed asymptomatic SARS-CoV-2 infections with a health status of 1 or higher, would result in a query directed to the clinical team on how to interpret these results. The records would subsequently be corrected in the next data transfer for the health status score to reflect the event definition. Another example was post viral syndrome, i.e. long COVID. A record without a preceding COVID-19 event would also result in a query.The consistency review between the different databases and datasets mostly focussed on the Events master database. The weekly health status score was captured in two different datasets; in the original Events dataset for the first observation(s) and thereafter in the Follow-up dataset. In the integrated datasets, these weekly health status scores were merged and checked for consistency. Where different health status scores for a single week were reported, or where the number of weekly scores did not equal the number of weeks an event was ongoing, a query was opened. Each event had a unique event number, so duplicate event numbers were flagged to the data management team. Consistency between Follow-up and Events master databases was important because participants self-reported COVID-19 events during the follow-up contact, which would result in a record in the Events master database when symptomatic. Consistency of dates between the Lab, Follow-up, and Events master databases was checked to prevent ongoing events after trial completion.Records were checked for missing or not applicable (NA) values. Additionally, dates (negative timepoints, the same record with different dates), MedDRA event descriptions, and spelling were checked. Spelling was a noteworthy issue where COVID-19 was recorded with 63 different spelling alternatives, including COVID-19, COVID 19, COVID, COVID-19 infection, COVID-19 pneumonia, COVID-19 respiratory tract infections, while post COVID viral syndrome was recorded in 10 different alternatives. Therefore, the MedDRA term initially utilized, but unfortunately also contained two alternative spellings for both. From this insight, the MedDRA numerical codes were included into the data processing.The initial analysis workflow evolved over time with new information and methods arising during the pandemic which were unknown at database setup. Post viral syndrome after COVID-19, also coined long COVID

PMC10539503

Interoperability

Interoperability between members of the pharmacometric team was essential to divide the work with the short timelines. The pharmacometric processing script was stored in a private Github repository where multiple coders could work simultaneously. Through Github, changes to parts of the script by team members could be reviewed and incorporated into an updated version, all while tracking these changes and being able to revert to an earlier version in case of debugging. Additionally, the file structure between pharmacometricians was standardized, so only the path to the working directory needed to be changed relative to which all other files were inputted or outputted. The path to the working directory was automatically called at the start of the script based on an if-statement with the system’s info of the user’s machine (Fig. Interoperability through standardized file structure and automatic extraction of working directory using the system’s info. The ifelse() statement can be expanded with nested ifelse() statement for more collaborators.

PMC10539503

Automatically compiled and consistent data reports

The pharmacometric team prepared the data reports for the DSMB to review the safety and efficacy of the ongoing trial. Because of the time-sensitive nature of the vaccination trial, initially biweekly reporting was proposed, which was later amended to a lower frequency by request of the DSMB and the clinical team because of reduced clinical urgency. Two types of reports were prepared. The open report showed the data aggregated which was open to review for the whole clinical trial, while the closed report showed the blinded data per study arm for the closed session of the DSMB. The pharmacometric processing script was developed to automatically generate a report based on the integrated database, to prevent repetitive manual report drafting with the suggested frequency. Using this method, a transparent and reproducible workflow was established from the raw eCRF input through to the DSMB report. RMarkdown was used to integrate the R-based processing of the integrated database with Markdown and LaTeX text compilers to create a report in pdf format in which the numerical, graphical, and tabular elements were automatically updated with each compilation (Fig. RMarkdown was used to combine text and R variables in the automatically generated report. (To create the two versions of the report in a consistent manner, an R-variable was integrated into the relevant numerical, graphical, and tabular elements where aggregated or per-arm data was reported. This had the advantage of not having to work in two RMarkdown scripts at the same time with the risk of inconsistencies and code conflicts that occur when coding even when working as diligently as possible. As a result, the open and closed reports showed the exact same data with the only difference being the presentation of these data. The switch-variable (CLOSED) was used in if-statements throughout the report to show figures and tables either aggregated or per arm (Fig. When the DSMB meeting schedule was set, a corresponding data transfer schedule was set. On average, the DSMB received the compiled and reviewed report within 3 days after the cut-off date of the data, including the final unblinded report. The DSMB repeatedly expressed their appreciation for these “excellent turnaround times.”

PMC10539503

Pharmacometric analysis preparation

RTI, SECONDARY

The pharmacometric processing script was also developed to include the pharmacometric analysis dataset creation. This resulted in a transparent, traceable, and version-controlled workflow from the raw eCRF input data to the analysis dataset in NONMEM format. Moreover, because the same script and integrated database was utilized to that aim, the datasets were consistent with the figures and tables in the DSMB reports.The reproducible workflow and subsequent confidence in handling of the data allowed for preparation of the pharmacometric analysis of the primary and secondary endpoints while the trial was still ongoing. Based on interim graphical exploration of the data, modelling strategies were developed per endpoint including which functions to test. Model scripts were written, tested, and code reviewed before the data lock. Analysis of the primary endpoint had the highest priority. Because of the reproducible workflow and preparations for the pharmacometric analysis before the data lock, the primary endpoint analysis was completed and reviewed within three days after data lock and unblinding, and shared with the DSMB and the clinical team. Analysis of the secondary endpoints, including a total of 7 time-to-event analyses for COVID-19, RTI, and hospitalization due to all causes in both intention-to-treat and per-protocol datasets, as well as an exploratory time-to-SARS-CoV2 specific vaccination analysis, was completed and reviewed within two weeks after data lock and unblinding, and presented to the DSMB and the clinical team. As we focus here on the reproducible pharmacometrics workflow, the results of these analyses are out of scope and reported separately.

PMC10539503

Discussion

SECONDARY

A reproducible pharmacometric workflow was developed here to review data iteratively during a clinical trial, report the trial data frequently to the DSMB, and prepare for the pharmacometric analyses of the primary and secondary endpoints upon trial completion to answer time-sensitive questions. Early collaboration between clinical, data management, and pharmacometric teams was established in this COVID-19 vaccination trial to ensure preparedness for the short analysis timelines. Investing in the development of this workflow paid off, as the primary endpoint analysis was completed within three days, and the secondary endpoint analyses were completed within two weeks after the data lock and unblinding. The automatically compiled open and closed reports ensured consistent and real-time presentation of the latest data when reporting to the DSMB, with on average three days between cut-off and sending the report. The DSMB repeatedly expressed their appreciation for the latest data and extensive analyses given the short timelines. The data review did not only result in confidence in handling the data, but also progressive insight with each iteration. Every single query from the data review improved the understanding of the data, their structure, and the data handling by the processing script. Additionally, through frequent interactions between the clinical, data management and pharmacometric teams, the appreciation for each other’s expertise and requirements grew which led to a very constructive environment. Drug development would benefit by moving from a conventional linear and sequential paradigm, to a more integrative approach as shown hereThe pharmacometric reproducible workflow developed here falls within a larger context of increasing awareness in reproducibility in both data and modelling. This is especially important because of the increasing size and complexity of data acquisition and data types in drug development. The FAIR principles of findability, accessibility, interoperability and reusability of data are becoming the standard

PMC10539503

Conclusion

The reproducible pharmacometric workflow we developed resulted in fast, efficient, and reliable analyses in a large clinical trial during the COVID-19 pandemic in South Africa. The constructive collaboration between clinical, data management, and pharmacometric teams enabled this efficient and robust pharmacometric data analysis which was embedded during the trial in order to support the DSMB and allowed for efficient, timely, and reproducible data analysis.

PMC10539503

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-023-43412-3.

PMC10539503

Acknowledgements

The authors gratefully acknowledge all members of the clinical and data management teams for their hard work under short timelines and for the constructive discussions. This project was part of the EDCTP2 programme supported by the European Union (grant number RIA2020EF-2968-Re-BCG-CoV-19). The computations were enabled by resources in project SNIC2020-5-524 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973.

PMC10539503

Author contributions

All authors conceptualized the work and designed the workflow. All authors wrote the manuscript and approved the final version.

PMC10539503

Funding

Open access funding provided by Uppsala University.

PMC10539503