Oncotype DX testing has reduced the use of adjuvant chemotherapy in node‐negative early breast cancer but less is known about its impact in node positive patients.This study aimed to investigate the impact of Oncotype DX gene assay testing on the decision to offer adjuvant chemotherapy in oestrogen positive, human epidermal growth factor receptor 2 negative, 1–3 lymph node positive patients.Retrospective review of all node positive patients who underwent Oncotype DX testing at a single centre. Clinicopathological data, as well as estimated survival benefit data (from the PREDICT tool), was evaluated by a multidisciplinary group of surgeons and oncologists. Treatment decisions based on clinicopathological data were compared to recurrence scores (RS). A cut off RS > 30 was used to offer adjuvant chemotherapy.The 69 patients were identified, of which 9 (13%) had an RS > 30 and assigned a high‐genomic risk of recurrence. The 32 patients (46.4%) were offered adjuvant chemotherapy. Overall based on the use of the RS, the decision to offer adjuvant chemotherapy changed in 36% of patients, and ultimately 24 patients (34.7%) would have been spared chemotherapy.Using clinicopathological data alone to make decisions regarding adjuvant chemotherapy in node positive breast cancer leads to overtreatment. Additional information on tumour biology as assessed by the Oncotype DX RS helps to select those patients who will benefit from adjuvant chemotherapy and spare patients from unnecessary chemotherapy. More recently, gene expression profiling which captures tumour biology has been increasingly used to aid clinical decision‐making.The Oncotype DX test  is a reverse transcriptase polymerase chain reaction based assay which measures the expression of a panel of 21 genes  and generates a recurrence score (RS)–a value from 0 to 100.Previous work with ER+, HER2‐, node‐negative patients has shown that the RS accurately predicts the benefit of adjuvant chemotherapy helping identify patients who would not benefit from the addition of chemotherapy to adjuvant endocrine therapy. In the landmark TAILORx trial, it was shown that ER+, HER2‐, node‐negative women with RS 0–15, and women above age 50 with RS 0–25 did not benefit from adjuvant chemotherapy with no difference in survival compared to endocrine therapy alone.More recently, attention has turned to the utility of the RS in node positive patients, to try to identify patients who would benefit from adjuvant chemotherapy.Retrospective data from the SWOG‐8814 trial found that only ER+, HER2‐, node positive patients identified as high risk, which was defined as a RS >30, benefitted from the addition of adjuvant chemotherapy compared to tamoxifen alone.The prospective WSG/planB trial showed that node positive patients with a RS < 11 had excellent (94.3%) 5‐year disease free survival without chemotherapy.From these studies, it is clear that gene expression profiling has a role in guiding treatment selection of node positive patients to identify those patients who would not benefit from chemotherapy.Decisions about breast cancer treatment are made by a multidisciplinary team (MDT) including breast surgeons and oncologists. In addition to clinicopathological data, standard UK practice is to use, a prognostication tool such as PREDICT to aid decision making.Our breast cancer MDT is one of the early adopters of Oncotype DX testing in a selected group of node positive patients since 2014. Patients were selected for Oncotype DX testing if the MDT felt there was a benefit in further information to aid decision making of adjuvant chemotherapy.The current study aims to examine the real‐life impact of Oncotype DX testing on the decision to offer adjuvant chemotherapy to ER+ HER2‐ node positive patients compared to decisions made by a simulated MDT based solely on clinicopathological data.2A retrospective cohort study was conducted at Norfolk and Norwich University Hospitals NHS Trust, a tertiary teaching hospital treating approximately 700 new breast cancer patients per year. All patients with ER+, HER2‐, 1–3 lymph node positive breast cancer who underwent Oncotype DX testing between July 2014 and April 2020 were identified from a prospectively maintained database. All patients underwent appropriate surgery to remove the primary breast tumour and either sentinel lymph node biopsy or axillary clearance. Patients were selected to undergo Oncotype testing by a contemporaneous MDT if it was felt that additional information from the test would guide decisions to offer or omit adjuvant chemotherapy in patients with intermediate‐risk. Patients with micrometastases or isolated tumour cells were excluded. Patients with four or more lymph nodes and/or distant metastases were excluded.breast.predict.nhs.uk).Clinical data were collected for each patient including age, multifocality of disease, tumour histology, tumour grade, size of tumour, presence of lymphovascular invasion, ER positivity/Allred Quick score, number of positive nodes and details of treatment to date. Furthermore, estimates of 10‐year survival and the added benefit of adjuvant chemotherapy were recorded for all patients using the online PREDICT tool  performed on each tumour were also collected.A simulated MDT panel composed of three members  reviewed the available clinicopathological for each patient and estimated survival data, before making a recommendation of whether to offer adjuvant chemotherapy or not. PREDICT scores were available to the simulated MDT members. The members of the MDT panel were blinded to the RS for each patient.The simulated MDT decision to offer adjuvant chemotherapy was compared to the RS recommendation for chemotherapy. A RS of greater than 30 was used to select high‐risk patients who would benefit from chemotherapy based on previous studies.The two decisions were compared for each patient aiming to examine the impact of the Oncotype DX test in real life.2.1p value of <.05 was taken as statistical significance. The Mann–Whitney U test was used for continuous variables, whilst Fisher's exact test and Chi‐squared test was used for categorical variables.Statistical analysis was performed using Microsoft Excel . A 2.2A cost analysis to assess the financial impact of Oncotype testing was performed using previously published sources. The current list price to the NHS for the Oncotype DX test is £2580.3A total of 69 patients with ER+, HER2‐, and 1–3 lymph node positive breast cancer were referred for Oncotype DX testing during the period between July 2014 and April 2020. The median age was 61 years . Fifty‐five patients (79.7%) had one positive lymph node, 12 patients (17.3%) had two positive lymph nodes and two patients had three positive lymph nodes. The median Oncotype DX RS was 16 with a range of 0–63.In 32 patients (46.4%), the simulated MDT recommended adjuvant chemotherapy. Figure Table p = .0353) and with a higher tumour grade (p = .0003). No patients in the high‐genomic risk group had Grade 1 tumours. Estimated additional 10‐year overall survival benefit as calculated using the PREDICT tool was moderately correlated with RS . All patients with a PREDICT score indicating >5% survival benefit with chemotherapy were recommended to undergo adjuvant chemotherapy by the simulated MDT  were more likely to present with symptoms (Concordance between the MDT decision and RS recommendation regarding the decision to offer adjuvant chemotherapy to patients or not was reached in 44 patients (63.7%). Conversely, discordance between the MDT decision and RS was observed in 25 patients (36.3%). In the vast majority of these cases (24/25 patients) the simulated MDT recommended offering adjuvant chemotherapy to patients with a low RS, indicating that these patients are unlikely to benefit from chemotherapy. Overall, based on the use of the RS the decision to offer adjuvant chemotherapy changed in 36% of patients, and ultimately 24 patients (34.7%) would have been spared chemotherapy.The simulated MDT outcomes were compared to the real life contemporaneous outcomes where the MDT panel had knowledge of Oncotype scores. All patients in the high RS group who were recommended for adjuvant chemotherapy actually received chemotherapy. In the low RS group, 5 out of 24 patients recommended for adjuvant chemotherapy by the simulated MDT underwent chemotherapy in real life.Using the current NHS list price, the Oncotype DX test costs £2580, which reflects a total cost of £178 020 to test our cohort. From previous studies, the cost of a course of adjuvant chemotherapy in breast cancer is estimated to be between £3866.17 and £4863.70 depending on regimen.Excluding patients with favourable PREDICT scores from Oncotype testing may improve cost effectiveness. Omitting the 25 patients that had a predicted survival benefit of ≤2% after the addition of adjuvant chemotherapy (and who the simulated MDT did not recommend chemotherapy to) would yield a cost of £113 520 to Oncotype test the remainder of patients, and is more comparable to the chemotherapy savings. However, one patient in the favourable PREDICT score cohort had a RS > 30 and would have potentially missed out on chemotherapy.4Our study shows that the Oncotype DX test changed the decision to offer adjuvant chemotherapy in more than one‐third of patients with ER+ HER2‐ tumours and 1–3 involved nodes. In the vast majority of cases, the MDT recommended adjuvant chemotherapy to patients with low RS scores. This is broadly in keeping with other studies looking at treatment decisions in node‐negative breast cancer.Few published studies have examined the role of Oncotype Dx testing in the node positive setting. Interim results of a UK based trial show that the decision to administer adjuvant chemotherapy changed in 74% of patients, sparing them from chemotherapy.Similar to other studies, we found that the majority of node‐positive patients have a low‐risk genomic signature as assessed by the Oncotype Dx test. Despite this, over 50% of patients in the low risk group with an RS <18 were offered adjuvant chemotherapy by the MDT.A significant proportion of patients fell into the intermediate‐risk group with an RS 18–30, and there are ongoing trials to determine whether there is a subgroup of these patients who may benefit from adjuvant chemotherapy. The patients in this group represent a real challenge for breast MDTs. The highly anticipated results from the RxPONDER trial will help inform the role of adjuvant chemotherapy in patients with RS <25.There is also variability in the RS cut‐off values used amongst different studies. The initial SWOG‐8814 trial used a definition of RS > 30 to define patients at high risk of recurrence,We found a moderately positive correlation between estimated additional 10‐year overall survival benefit based on PREDICT and RS. To the best of our knowledge, this is the first to examine this relationship in node‐positive patients. Previous studies in node‐negative patients have shown a correlation between RS and low‐risk patients, but discordance in high‐risk patients.This study is one of the very few showing real‐life data on the effect of Oncotype test on adjuvant chemotherapy decisions in 1–3 node positive patients. The management of micrometastases or isolated tumour cells in the axilla remains contentiousThere are some limitations in this study. Firstly, a relatively small number of node positive patients were tested and the study was retrospective in nature. There is also selection bias, as the contemporaneous MDT selected patients for Oncotype DX testing on a case by case basis where the decision to offer adjuvant chemotherapy was uncertain and genomic testing was felt to aid decision making.Additionally, our study did not measure the oncologic or long‐term outcomes in this group of patients as our main focus is on assessing the impact of Oncotype on the decision to offer adjuvant chemotherapy.Our present study does not show clear‐cut cost‐effectiveness in node‐positive patients, which had been reported by other studies.Another limitation of our study is that patient preferences were not taken into account in the cost effectiveness of oncotype testing and chemotherapy usage.The strengths of this study are that it reflects the real‐life practice and decision making by using actual patient data with members of the simulated MDT panel blinded to the RS to minimise bias. Our study shows that the use of Oncotype DX in selected node positive patients reduces adjuvant chemotherapy use by objectively identifying those patients with a high risk of recurrence.The use of gene assays in the management of node‐negative breast cancer has been enshrined in multiple national and international guidelines. NICE guidelines have recommended Oncotype DX testing as an option for node‐negative patients with intermediate‐risk of recurrence to help aid decisions about adjuvant chemotherapy.Advances in modern oncology with the increasing use of targeted therapies and novel prognostic markers will ultimately result in more personalised approaches to the treatment of breast cancer patients. Gene‐based assays such as Oncotype DX provide additional valuable information on individual tumour biology and prognosis. Given the short and long term toxicity associated with adjuvant chemotherapy, it is imperative to identify patients who have a high risk of recurrence and therefore most likely to benefit, as well as identify low‐risk patients in whom chemotherapy can be safely omitted. Our study shows that decision‐making based solely on clinicopathological data may lead to overtreatment of node positive patients. However, prospective randomised trial data is still lacking. The results of ongoing trials, such as RxPonder, are eagerly anticipated to fully inform the role of Oncotype DX testing in node positive patients.The authors have stated explicitly that there are no conflicts of interest in connection with this article.Mohamed Rabie: Data curation (supporting); formal analysis (supporting); software (supporting); writing – review and editing (supporting). Konstantinos Geropantas: Data curation ; investigation ; writing – review and editing . Susanna Alexander: Data curation ; formal analysis ; writing – review and editing . Simon Pain: Data curation ; formal analysis ; writing – review and editing . Mina Youssef: Conceptualization ; data curation ; formal analysis ; investigation ; methodology ; project administration ; writing – review and editing .All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Our study was registered as a clinical audit and did not require any formal ethical approval.Figure S1 Table showing breakdown of MDT decisions for adjuvant chemotherapy stratified by PREDICT score survival benefit and RS.Click here for additional data file.


Supplementing investigator‐specified variables with large numbers of empirically identified features that collectively serve as ‘proxies’ for unspecified or unmeasured factors can often improve confounding control in studies utilizing administrative healthcare databases. Consequently, there has been a recent focus on the development of data‐driven methods for high‐dimensional proxy confounder adjustment in pharmacoepidemiologic research. In this paper, we survey current approaches and recent advancements for high‐dimensional proxy confounder adjustment in healthcare database studies.We discuss considerations underpinning three areas for high‐dimensional proxy confounder adjustment: (1) feature generation—transforming raw data into covariates (or features) to be used for proxy adjustment; (2) covariate prioritization, selection, and adjustment; and (3) diagnostic assessment. We discuss challenges and avenues of future development within each area.There is a large literature on methods for high‐dimensional confounder prioritization/selection, but relatively little has been written on best practices for feature generation and diagnostic assessment. Consequently, these areas have particular limitations and challenges.There is a growing body of evidence showing that machine‐learning algorithms for high‐dimensional proxy‐confounder adjustment can supplement investigator‐specified variables to improve confounding control compared to adjustment based on investigator‐specified variables alone. However, more research is needed on best practices for feature generation and diagnostic assessment when applying methods for high‐dimensional proxy confounder adjustment in pharmacoepidemiologic studies. To improve confounding control in healthcare database studies, data‐driven algorithms can be used to leverage the large volume of information in healthcare databases to generate and identify features that indirectly capture information on unmeasured or unspecified confounding factors (proxy confounders).Three areas to consider for data‐driven high‐dimensional proxy confounder adjustment include: (1) feature generation—transforming raw data into covariates (or features) to be used for proxy adjustment; (2) covariate prioritization, selection and adjustment; and (3) diagnostic assessment.There is a large literature on methods for high‐dimensional confounder prioritization/selection, but relatively little has been written on best practices for feature generation and diagnostic assessment. Consequently, these areas have particular limitations and challenges when applying machine learning algorithms for high‐dimensional proxy confounder adjustment.A fundamental obstacle in studies that utilize administrative healthcare databases is unmeasured confounding bias stemming from nonrandomized treatment choices and poorly measured comorbidities. Failing to adjust for important confounding factors can make it difficult to differentiate between outcomes that are due to drug effects or a result of the underlying conditions for which the drug was prescribed. Traditional approaches for confounding adjustment rely on the investigator to specify all factors that may confound a causal treatment‐outcome association. However, adjustment based on investigator‐specified covariates alone is often inadequate because some important confounding factors are often unknown. Furthermore, because routine‐care databases are not collected for research purposes, many important confounding factors are not directly measured in these data sources. To reduce bias caused by unspecified or unmeasured confounders, many studies have proposed using data‐driven algorithms to identify and control for large numbers of variables that are indirectly associated with unmeasured (or unspecified) confounders ('proxy' confounders). Here, discuss various aspects of high‐dimensional proxy confounder adjustment and give an overview of the current literature. We give particular focus on methods that have been impactful in pharmacoepidemiology research.1Routinely‐collected healthcare data are increasingly being used to generate real‐world evidence (RWE) to inform decision making in clinical practice, drug development, and health policy.To improve confounding control in healthcare database studies, data‐driven algorithms can be used to leverage the large volume of information in these data sources to generate and identify features that indirectly capture information on unmeasured or unspecified confounding factors (proxy confounders).While researcher‐specified confounders are identified using expert background knowledge, empirical or proxy confounders are identified using empirical associations and coding patterns observed in the data. There is a growing body of evidence showing that complementing researcher‐specified variables with empirically‐identified proxy confounders improves confounding control compared to adjustment based on researcher‐specified confounders alone.In this paper, we discuss the considerations underpinning three areas for data‐driven high‐dimensional proxy confounder adjustment: (1) feature generation—transforming raw data into covariates (or features) to be used for proxy adjustment; 2) covariate prioritization, selection and adjustment; and (3) diagnostic assessment  that best capture confounder information. Several approaches for feature generation of proxy confounders have been applied in the pharmacoepidemiologic literature. These have ranged from very simple approaches that generate binary indicators representing whether or not a given code occurs during a pre‐defined exposure assessment period,Instead of generating features based on health concepts, an alternative approach is to generate features based on empirical associations and longitudinal coding patterns observed in the data. Such approaches can be more flexible since they can be independent of the coding system and do not rely on a common data model.By taking into account the frequency of occurrence of various codes during the covariate assessment period, the hdPS tries to capture information on the intensity of the medical event or drug dispensing. In theory, algorithms could consider more complex longitudinal coding patterns to try and capture additional confounder information. For example, recent work has proposed using neural networks to model a patient's full course of care to consider temporal sequences of a specific course of treatment.2.1An important limitation of current high‐dimensional proxy confounder adjustment approaches is that they can only use structured electronic healthcare information. However, much of the essential confounder information, such as patient‐reported symptoms, severity, stage and prognosis of the disease, and functional status, is frequently recorded in free‐text notes or reports in electronic health records (EHRs) that are substantially underutilized for confounding adjustment.An additional challenge to utilizing EHR data for high‐dimensional confounding control is missing data. While both healthcare claims and EHR data are susceptible to missing information, EHR data is particularly vulnerable due to a lack of continuity and completeness of health records caused by patients seeking care at different delivery systems.3Once proxy variables have been generated through transformations of the raw data, some degree of dimension reduction is needed to prioritize and select variables for adjustment. Reducing the dimension of covariates is necessary to avoid problems of nonoverlap when adjusting for high‐dimensional sets of covariates.3.1over adjusting” for variables that can harm the properties of estimators without reducing bias , here we focus on targeted learning tools and regularized regression as these have been the most widely used approaches in the pharmacoepidemiology literature.3.2.1Regularized regression models use penalized maximum likelihood estimation to shrink imprecise model coefficients toward zero. LASSO is the most commonly used regularized regression model for variable selection in high‐dimensional covariate datasets.3.2.2super learning can be utilized to identify a small number of optimally performing prediction algorithms that generally perform best for a given data structure. Previous work has combined Super Learning with proxy confounder adjustment in high‐dimensional covariate spaces.Super Learning is an ensemble ML algorithm for prediction modeling that forms a set of predicted values based on the optimal weighted combination of a set of user‐specified prediction models in terms of minimizing cross validated predictive performance.3.2.3over‐adjustment” to improve the properties of estimators by reducing the likelihood of controlling for variables that are conditionally independent of the outcome after adjusting for a set of previously identified confounders. Recent work has developed adaptations of CTMLE that are computationally scalable to large healthcare databases.Collaborative targeted maximum likelihood estimation (CTMLE) is an extension of the doubly robust targeted maximum likelihood estimation (TMLE) method.3.3causal forest and X‐learner, a meta‐algorithm that uses ML methods as an intermediate step in an efficient estimation algorithm.Once proxy confounders have been prioritized and selected, researchers must determine a method for adjustment and causal estimation. Propensity score methods  using logistic regression for estimation of the propensity score function have become the most common approach for adjustment of selected proxy confounders in the medical literature.3.3.1Widely used doubly robust methods include TMLE, augmented inverse probability weighting (AIPW), and double ML .Recent work has further shown that the use of flexible nonparametric ML models for the estimation of nuisance functions  comes at a cost of slow convergence rates. This slow convergence is particularly problematic within singly robust estimation methods and can yield effect estimates with poor statistical properties with performance deteriorating as the dimension of the data increases .4Evaluating the validity of causal analyses for high‐dimensional proxy adjustment remains challenging but is essential to improving robustness and validity of estimated effects.4.1A process to estimate ML model performance using out‐of‐sample data, such as cross validation, are often recommended to assess model robustness and generalizability and to examine the characteristics of the inferred models to verify the importance of domain‐relevant variables. Below we focus on additional measures with specific importance to causal model diagnostics.4.1.1Calibration plots depict the average predicted versus observed  probability of the studied event in subsets of entities , to evaluate the accuracy of the predicted probabilities.C‐statistic , a measure of classification accuracy, is commonly used in standard ML applications. For outcome models, it can be used to assess prediction accuracy over the observed treatment assignment . For propensity models its utility is less straightforward: an extreme (close to 0 or 1) value, corresponding to a highly discriminative model, may indicate a potential violation of positivity; and, conversely, a value around 0.5, suggesting the model cannot discriminate between treatment groups, is not necessarily a sign for inaccurate model, but potentially good covariate overlap. As a result, some researchers recommended to avoid using C‐statistic in propensity model diagnostics.4.1.2R2) or mean squared error.The performance of continuous outcome models can be assessed in each observed treatment group (and observed outcomes) and assuming causal assumptions are met, using standard measures such as the coefficient of determination R2 or mean4.2Previous work has shown that the use of prediction model diagnostics alone to guide model selection and validity assessment can lead to suboptimal performance for causal inference.4.2.1An important usage for propensity models for high‐dimensional proxy adjustment is to examine the positivity assumption. This assumption states that every individual has a non‐zero probability to be assigned to any treatment conditional on a sufficient set of covariates. A comparison of propensity score distributions can help in identifying  sub‐populations where violations or near violations of the positivity assumption occur.4.2.2Propensity score modeling aims to facilitate matching, reweighting or stratification to emulate a random assignment of individuals to treatment groups. Therefore, several studies explored methods to directly evaluate balancing of covariates among these groups.The application of balance diagnostics for high‐dimensional propensity scores is more challenging as it is unclear on which set of variables balance should be assessed. A large literature has shown that balancing variables that are independent of the outcome except through treatment  harms the properties of estimators.4.2.3Recent studies have suggested methods to assess the overall accuracy of effect estimation using control and synthetic control studies.Simulation frameworks for model validation in causal inference have largely been based on use of the parametric bootstrap. Such approaches bootstrap subjects from the observed data structure, then use modeled relationships from the original data to inject causal relations between a subset of variables while leaving all other associations among variables unchanged. With treatment‐outcome associations known by design and patterns of confounding that mimic the observed data structure, synthetic datasets have become increasingly popular to provide a benchmark for comparing statistical methods for causal inference.Franklin et al.While simulations can be useful for tailoring analytic choices for causal inference, they also have limitations that deserve attention. Schuler et al.Wasserstein Generative Adversarial Networks (WGANs) is an alternative approach to generating synthetic data for simulation‐based model validation in causal inference.Another approach that has become increasingly popular for evaluating models for confounder adjustment is the use of real negative controls—exposure‐outcome pairs that are not, as far as we know, causally related.4.2.4Estimating an effect from observational data involves multiple, at times somewhat arbitrary, modeling decisions and assumptions, for example, with respect to the definition of confounders, exposures, and outcomes or the statistical analysis.5In this paper, we have provided an overview of high‐dimensional proxy confounder adjustment in studies utilizing electronic healthcare databases. We have focused on three areas for proxy adjustment: (1) feature generation, (2) covariate prioritization, selection, and adjustment, and (3) validity assessment. We have discussed recent ML extensions and paths for future research within each area. Much attention has been given to the development of ML tools for confounder selection and adjustment for high‐dimensional proxy adjustment. These tools have great potential to improve confounding control in healthcare database studies. However, less attention has been given to advancing methods for feature generation and validity assessment for proxy confounder adjustment. Future research is warranted to investigate the optimal methods that extract the relevant confounding information to generate features for proxy adjustment while preserving scalability and data‐adaptability to large healthcare databases. Future research is also needed in the development of diagnostic methods to evaluate and compare the validity of alternative approaches to high‐dimensional proxy adjustment in healthcare database studies.Finally, although ML tools can be beneficial in identifying empirical associations among large numbers of covariates, empirical associations by themselves are not sufficient to determine causal relations.Richard Wyss, Chen Yanover, and Tal El‐Hay drafted the manuscript. All authors revised the manuscript for important intellectual content and approved the final manuscript to be submitted for publication.Funding to support this manuscript development was provided by the International Society for Pharmacoepidemiology (ISPE).Robert W. Platt has consulted for Amgen, Biogen, Merck, Nant Pharma, and Pfizer. Dimitri Bennett is an employee of Takeda. Grammati Sari is employed by Visible Analytics Ltd. Hongbo Yuan is an employee of CADTH. Andrew R. Zullo receives research grant funding from Sanofi Pasteur to support research on infections and vaccinations in nursing homes unrelated to this manuscript. Mugdha Gokhale is a full‐time employee of Merck and owns stocks in Merck. Elisabetta Patorno is supported by a career development grant K08AG055670 from the National Institute on Aging. She is researcher of a researcher‐initiated grant to the Brigham and Women's Hospital from Boehringer Ingelheim, not directly related to the topic of the submitted work.


Although a large‐caliber endoscope (LCE) is indispensable for through‐the‐scope placement of a self‐expandable metallic stent (SEMS) in patients with malignant colonic obstruction (MCO), inaccessibility of the target obstructing lesion (TOL) by the endoscope is a significant cause of unsuccessful procedures. We herein present a novel salvage procedure when the TOL is not directly accessible by an LCE in conditions such as coexisting peritoneal carcinomatosis involving the colon. The salvage procedure, termed over‐the‐catheter endoscope replacement (OCER), starts with an ultraslim endoscope suitable for deep insertion beyond a tortuous colon for traversing a guidewire through the TOL. The ultraslim endoscope is then withdrawn and replaced by an LCE through the following steps. An endoscopic retrograde cholangiopancreatography catheter is preloaded in the LCE, the catheter alone is passed over the guidewire already traversed through the TOL, and the LCE is navigated over the catheter as far as possible toward the TOL to deliver the SEMS delivery system in a standard through‐the‐scope manner or further in an over‐the‐wire manner even if LCE insertion is incomplete. Among the 165 patients with MCO who underwent stenting during our study period, OCER led to successful procedures in all nine patients whose TOLs were initially inaccessible because of colon‐involving peritoneal carcinomatosis. By utilizing the functions of distinctive endoscopes in a unique and complementary way, OCER can be a practical salvage option for challenging cases of MCO that are highly prone to unsuccessful palliation by conventional SEMS placement. Colonic self‐expandable metallic stent (SEMS) placement is an alternative to surgical intervention in the management of malignant colonic obstruction (MCO), especially in palliative settings.The initial step of the conventional TTS procedure is to access the target obstructing lesion (TOL) by inserting a large‐caliber endoscope (LCE) with a large working channel that accommodates the SEMS delivery system.We herein present a salvage procedure termed over‐the‐catheter endoscope replacement (OCER) for failed insertion of the LCE to the TOL during conventional SEMS placement in patients with MCO. OCER allows the choice of an ultraslim endoscopeFrom January 2014 to August 2020, a total of 165 patients with MCO diagnosed by their symptoms, medical histories, and computed tomography findings consecutively underwent colonic SEMS placement unless surgical intervention was favored Fig. 12, 13We classified the endoscopes into four groups based on their caliber and size of their working channel relevant to different functions in OCER Table . Groups Groups 3 and 4 comprised ultraslim endoscopes that did not accommodate a SEMS delivery system. These endoscopes were used in the first part of the salvage procedure because of their high insertability. We prioritized the use of the Group 3 endoscope , which is an ultraslim colonoscope with a 9.2 mm tip and a 2.8 mm channel that accommodates not only a guidewire  but also an ERCP catheter  for fluoroscopic examination of the stricture and better passage of the guidewire through the stricture. However, when the TOL was still inaccessible with the Group 3 endoscope, we selected a Group 4 endoscope to take advantage of its even slimmer shape (5.9 mm tip and 2.0–2.4 mm channel) to access the TOL, although only one Group 4 endoscope model, EG‐580NW  had a 2.4 mm channel large enough to pass the ERCP catheter. The whole endoscopy system had to be exchanged when switching to Group 4 endoscopes because of their compatibility with the endoscopy systems, which could have been avoided if endoscopes from the same manufacturer had been available for Group 4. All endoscopic procedures were performed under conscious sedation (intravenous midazolam plus pethidine hydrochloride) using carbon dioxide insufflation in a fluoroscopy‐equipped therapeutic endoscopy unit. All operators who performed the SEMS placement procedures, including OCER, were board‐certified endoscopists with 11–15 years of experience in gastrointestinal endoscopy at the beginning of the study period. The principal interventional endoscopist (Y.S.), who had extensive experience in gastrointestinal stenting, endoscopic submucosal dissection, ERCP, and papillectomy, performed the role of endoscopist or supervisor in most of the SEMS placement procedures  throughout the study period.The indication for OCER was the inability to insert an LCE to the TOL, resulting in failure of conventional SEMS placement Fig. ‐1,B‐1. OThe latter part of OCER begins by withdrawing the inserted endoscope and the ERCP catheter, leaving only the guidewire in the colon. Then, outside the body, after inserting the ERCP catheter into the channel of the LCE  until it protrudes from the scope tip Fig. ‐3a,B‐3a,Finally, the last step is removal of the catheter from the endoscopic channel, keeping the guidewire in place, followed by passage of the SEMS delivery system through the stricture Fig. ‐4b,B‐4b n = 4) and extracolorectal (n = 5) origins (Table n = 3) and extrinsic (n = 6) nature at the transverse colon (n = 5) and sigmoid colon (n = 4) due to computed tomography‐confirmed coexisting peritoneal carcinomatosis  were selected. Insertion to the TOL failed in three of these cases. However, after Group 4 endoscopes were chosen for these three patients, insertion to the TOL was successful, ultimately resulting in access to the TOL in all nine patients  or partial (n = 3) replacement  , which has high insertabilityFor the second step, the unique use of the ERCP catheter plays a critical role. It is extremely important to advance solely the catheter first, which very smoothly follows the guidewire. This smooth advancement is facilitated by its 1.6 mm tip that gradually tapers to a 2.3 mm body, with the distal flexible part of 28 cm having no metal stylet within the lumen. Once the catheter has been inserted along the guidewire, the catheter body has adequate rigidity because of the metal stylet contained within, over which the LCE is efficiently navigated. We speculate that the catheter keeps the colonic tortuous segment straight and linear to the advancing endoscope, avoiding angulation, friction, and loss of force transmission. In six of nine patients, the LCE reached the TOL (complete replacement), overcoming the relative luminal narrowing by invasion and the abnormal tissue fixation by adhesion that had initially hindered its advancement. In three patients, however, the LCE became stuck in a region of absolute narrowing, leaving a distance to the TOL . However, SEMS placement succeeded in a remotely controlled manner  have become available.Our herein‐described new salvage procedure is unique in maximizing the functions of different caliber endoscopes in a complementary way while requiring only endoscopes and devices already widely available. Thus, the introduction of OCER would be more feasible for most institutions routinely practicing endoscopic stenting than, for instance, switching to a radiological “over‐the‐wire” procedure for SEMS placement, which requires distinct expertise and has not been confirmed to be helpful in patients who have MCO with peritoneal carcinomatosis. Indeed, OCER might be applicable to various clinical situations in which an LCE is favored but difficult to insert to the target.There were some limitations in the present study. First, OCER has evolved from a single‐center experience, which might have resulted in a biased selection of those indicated for endoscopic stenting among the whole MCO patient cohort. However, the procedures for consecutive patients sent for stenting were not declined by our endoscopists unless there were absolute contraindications; therefore, patients who underwent OCER are thought to represent a group of patients encountered with some frequency when managing MCO. Second, the number of OCER cases included in this analysis was small; indeed, only nine patients in our study cohort were indicated for OCER because of TOL inaccessibility. However, these patients accounted for the largest portion of the impending technical failures 9 out of 12, Fig. 2, Fig. 1In conclusion, OCER is a potentially feasible and valuable option for salvage of SEMS placement in patients with coexisting MCO and peritoneal carcinomatosis. Improvement in the technical success rate of SEMS placement by OCER has important implications, especially for the palliative care of patients who are poor surgical candidates.AUTHOR E.I. has received lecture honoraria from Takeda Pharmaceutical Co., Ltd and belongs to an endowed course supported by the following companies: Ono Pharmaceutical Co., Ltd, Miyarisan Pharmaceutical Co. Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd, Terumo Corporation, Fancl International, Inc., and Ohga Pharmacy. The other authors declare no conflict of interest for this article.None.Figure S1 Flowchart of endoscope selection in nine patients who underwent the salvage procedure (over‐the‐catheter endoscope replacement [OCER]). First, ultraslim Group 3 endoscopes (n = 9) were selected. Group 4 endoscopes were selected after the failed insertion of Group 3 endoscopes to the target obstructing lesion (TOL). Ultimately, access to the TOL was successful in all nine patients, which was followed by the successful passage of a guidewire (GW) through the strictures and successful self‐expandable metallic stent (SEMS) placement. ERCP, endoscopic retrograde cholangiopancreatography; LCE, large‐caliber endoscope.Click here for additional data file.Figure S2 A representative patient (case 1) with malignant colonic obstruction (MCO) with coexisting peritoneal carcinomatosis undergoing self‐expandable metallic stent (SEMS) placement using over‐the‐catheter endoscope replacement (OCER). (A) The MCO associated with peritoneal carcinomatosis was observed at the splenic flexure on computed tomography (yellow arrowhead). Massive ascites and coexisting intrapelvic carcinomatosis were seen (red arrowhead).  Representative images showing SEMS placement using OCER. An ultraslim endoscope (Group 3) was inserted to the target obstructing lesion , followed by an endoscopic retrograde cholangiopancreatography catheter combined with a guidewire  passed through the stricture. Although the replaced large‐caliber endoscope could not be advanced past the sigmoid colon by OCER , SEMS placement using a 10F delivery system was completed in a remotely controlled manner .Click here for additional data file.Table S1 Clinical characteristics of the 165 patients who underwent endoscopic stenting during the study period.Click here for additional data file.


The increasing need for speech therapy due to our ageing population raises the demand on therapeutical resources. To meet this demand, innovative delivery of speech training is required. eHealth applications may provide a solution, as intensified and prolonged training is only possible and affordable in patients’ home environment.This study explores the effects on speech intelligibility of game‐based speech training that provides automatic feedback on loudness, pitch and pronunciation. Additionally, we investigate how satisfied patients are with the game‐based speech training and how they experience the automatic feedback. Furthermore, patients’ preferences for game‐based speech training compared with face‐to‐face training are explored.Eight adult dysarthric speakers with Parkinson's disease (PD) completed a 4‐week game‐based speech training in their home environment. For each speaker, 24 speech utterances were audio recorded 4 weeks before (T1), immediately before (T2) and immediately after (T3) the training. All speech samples were rated on speech intelligibility by 10 untrained listeners, by comparing them with the corresponding utterances realized by a healthy speaker. Changes over time were analysed using a linear mixed‐effects analysis. Patient satisfaction with the game and the automatic feedback was assessed using a questionnaire. The preferences of patients were collected using a paired comparisons procedure in which the patients were asked whether they would prefer game‐based or face‐to‐face speech training in four hypothetical scenarios with different hypothesized levels of speech improvement.While there was no significant difference in speech intelligibility ratings between T1 and T2, we did find one between T2 and T3. At T3, speech intelligibility was rated higher than at T2, indicating positive effects of the game‐based speech training. Patients generally seemed satisfied with the game as average ratings were above 7 on a 10‐point rating scale. Generally, patients agreed with the automatic feedback and could use it to positively change the way they spoke. Patients prefer the training that provides the highest hypothetical improvement, and thus do not prefer face‐to‐face above game‐based therapy.The results of this study suggest that dysarthric speakers due to PD see game‐based speech therapy as a valid alternative for face‐to‐face therapy and that it leads to an average improvement in speech intelligibility. For an optimal effect and user satisfaction it should preferably not be used in isolation but in combination with face‐to‐face training. In this manner, the strengths of both therapeutic deliveries can be harnessed.Dysarthric speech in patients with PD is known to benefit from intensified and long‐term speech therapy. The increasing need for speech therapy due to our ageing population raises the demand on therapeutical resources making highly frequent and long‐term therapy difficult. eHealth provides the opportunity to intensify and prolong speech training in patients’ home environment. A drill‐and‐practice method was employed and investigated in a web‐based speech application, indicating positive effects on speech intelligibility. However, participants indicated a lack of variation in exercises making the training less enjoyable. Other research showed that serious games can increase enjoyment during training.The results of this study show that it is possible to develop a serious game that can be successfully used for speech training by patients with dysarthria due to PD. Comparing speech intelligibility ratings before and after training, we observed significant improvements in speech intelligibility ratings. Patients generally agree with the automatic feedback and can use it to positively change the way they speak. Average ratings were above 7 on a 10‐point scale, indicating that patients are satisfied with the game. Patients prefer the type of training (game based or face to face) that provides the highest hypothetical improvement.The results of this study suggest that game‐based speech training can improve speech intelligibility in patients. This indicates that it can be considered a suitable approach in the treatment of patients with dysarthria due to PD. Patients do not prefer game‐based training above face‐to‐face training in all scenarios. For that reason, for every patient one should carefully consider how to optimally combine game‐based and face‐to‐face training. The application of eHealth for patients with acquired neurological diseases has been gaining interest in the field of rehabilitation for the last two decades. eHealth is ‘the cost‐effective and secure use of information and communications technologies in support of health and health‐related fields, including health‐care services, health surveillance, health literature, and health education, knowledge and research’, , Dysarthric speech in patients with PD is known to benefit from intensified and long‐term training . From this, a disbalance between speech therapeutical resources and the need for speech therapy may emerge that does not allow for highly frequent and long‐term therapy, leading to a potential deprivation of optimal speech rehabilitation. As a consequence, dysarthric patients experience detrimental effects of low speech intelligibility and are highly motivated for practising their speech to support them in regaining societal participation.eHealth provides the opportunity to both intensify and prolong speech motor training in patients’ home environment. This allows self‐management of speech training and, hence, the long‐term improvement and maintenance of enhanced speech intelligibility. Nevertheless, the absence of a therapist, providing instant feedback and a therapeutic relationship, and the need for patients to operate an eHealth device, may result in barriers for effective speech training. It is therefore vital to investigate the efficacy of eHealth‐based speech training before investigating how such barriers can be removed. The importance of providing evidence for eHealth‐based speech training in patients with acquired neurological diseases is even more obvious given the current Covid‐19 pandemic (2020–22), which demands physical  distance between therapists and their patients for an—as yet—unknown period of time.There are various ways of practising speech through eHealth. A drill‐and‐practice method was employed and investigated in a web‐based speech application  a serious game (Treasure Hunters) for patients with dysarthria due to PD or stroke was developed and evaluated. The goal of this game was to improve speech intelligibility in functional communication of these patients . The game targets elderly patients, because this group is largely representative of the population of patients with dysarthria due to PD. Both patients and speech therapists were involved at multiple stages of the game design and development process.Treasure Hunters 2 is based on PLVT and aims to provide intensive speech training focusing on increasing loudness at a low pitch, and improving articulation. It has been developed in collaboration with Creative Care Lab at Waag Society  notification is shown in red in Figure Spreek lager) notification at the same location. It is shown in blue to ease its identification.While playing, the players continuously received automatic feedback on voice loudness and pitch by means of speech analysis algorithms. We merged the feedback on voice loudness with the circular shaped view of the playing field to have it in the focus of players’ attention. The view grew larger and smaller depending on whether the player spoke loud enough or too soft. This way, we aimed to intrinsically motivate players to speak loud enough by rewarding them with a larger view of the playing field making more of the immediate environment around their character visible. Figure Thresholds were used to determine when feedback on loudness and pitch should be given: for male and female participants, initial levels of intensity were set at 60 decibel or above (Rietveld and Van Heuven Brood voor de eenden). After having read the sentence in silence (to prevent possible hesitations), the player started the recording by pressing the red button at the bottom, and stopped the recording by pressing the same button again. Afterwards, the feedback screen displayed words in which a mispronunciation was detected in red, and words in which none was detected in green. Specifically for this game we developed ASR technology that calculated confidence measures at both sentence and word level  may be too difficult for players to understand and interpret in a gaming environment. Players had three attempts in total to correct any detected mispronunciations. After the third attempt, the gate opened automatically in order to not hinder the continuity of play. The screen starting the pronunciation exercise is shown in Figure A single‐group repeated measures design was used to study the effects of our game‐based speech training intervention Figure . Since tPatients with dysarthria due to PD were recruited via speech therapists, patient internet fora and Facebook groups. The patients had completed their latest face‐to‐face speech training at least two months before T1. Exclusion criteria were aphasia, reported severe cognitive problems or other disabilities that would hamper 15 min training sessions with the game. From the 15 participants who were found willing to participate, seven had to be excluded because of the aforementioned reasons.Eight participants, five male and three female, all with dysarthria due to PD, completed the intervention and were included in our study. Table In line with the PLVT protocol  on a desk stand, using a headset (Sennheiser PC 3 Chat) for voice communication. They played the game together with a co‐player through the internet. Co‐players were recruited university student assistants who studied speech and language therapy/pathology. They were instructed to act as a cooperative co‐player and to encourage the participant to speak and not to give any feedback on participants' pronunciation. They were only allowed to ask for clarification as in regular conversation . The student assistants were also instructed on how to explain the game to the participants and how to set it up in patients’ home environments.As shown in Figure In order to measure the development of participants’ speech intelligibility, speech recordings were made of the same sentences and texts. During the three recording sessions, participants’ speech was recorded while they read sentences and texts aloud. The same sentences and texts were read at all points in time. The materials to be read aloud were selected to facilitate the measurement of effects the intervention had on the intelligibility of daily speech. Those speech materials should also challenge participants in the affected speech dimensions . Our selection comprised 30 sentences containing a word with /p/, /t/ or /k/ as the initial sounds  resolution.The speech samples recorded in the speech assessment sessions were judged on intelligibility by inexperienced listeners in an adapted paired comparisons judgement task. We chose inexperienced listeners, because they represented individuals from daily life who are unfamiliar with participants and dysarthric speech in general. For each participant, 10 inexperienced listeners—university students—were asked to judge the intelligibility of the speech samples recorded at all three time points  as compared with the intelligibility of a neurologically healthy reference speaker. We chose to use neurologically intact speech as ‘anchor’ in the paired sample in order to facilitate judging the extent to which participants’ speech deviates from typical speech. We used a female reference speaker for the female participants and a male reference speaker for the male participants, both with ages similar to those of the participants (67 and 69 years). The reference speakers recorded the same speech materials as the participants, using the same model laptop and headset as the participants.In the paired comparisons judgement task, the speech sample of the participant was played first and that of the reference speaker second. Listeners were then asked to what extent the first sample was less intelligible than the second. They assigned their ratings using a 7‐point scale from –5 (the first sample was considerably less intelligible than the second) to 1. On this scale, 0 represented both samples being equally intelligible and 1 to provide the possibility to indicate that the first sample was more intelligible than the second. A negative scale was used as we believed this would be more intuitive to indicate poorer intelligibility. Similarly, a positive integer could be used to indicate better intelligibility. Various pilot rating sessions showed no problems using this scale.Speech samples for the judgement task were selected from the recorded speech materials. The recordings from the /p/, /t/ and /k/ sentences were used without changes. To increase the number of judgements for our analysis of efficacy, the recordings from the text fragments were cut at each sentence boundary, creating individual recordings that were rated separately.Recordings containing unrecoverable reading errors and (background) noise were excluded from the judgement. To further prevent bias in judgements, a selection of recordings was made that was balanced in length (expressed in number of phonemes), occurrence of non‐frequent words (lemma frequency < 10 per million), the number of occurrences of the /p/, /t/ and /k/ sounds and the number of consonant clusters. The final set contained 42 speech samples. All speech samples were normalized to an average intensity of 68 dB(A) .In total, each listener was asked to judge 126 speech samples of one, randomly assigned, participant (42 pairs per time point). The samples were digitally provided to the listeners in an OpenSesame experiment  to 5 . A higher score thus represents higher intelligibility. The original 1 score, indicating that the participant's sample was more intelligible than that of the reference speaker, was not often used . After inspection, we were confident that these were due to small regional variations in pronouncing individual speech sounds or recording conditions . For that reason, the speech samples corresponding to these judgements were considered as equally intelligible and merged with the category ‘equally intelligible’ .From the 42 sentences recorded per speaker for every time point, 24 had usable recordings available for all three measurement times. The other sentence recordings could not be used because recordings of one or multiple measurement times contained an unrecoverable event  that could bias listeners’ judgements. Consequently, judgements of 24 speech samples were used for every measurement time by 10 listeners, totalling 720 judgements per speaker.p < 0.05), while three were not. The data of these three were further investigated on irregularities , but none was found. The mean value of the 24 estimates of reliability was 0.678.For each of the eight speakers and for each time point (T1–T3) reliability of the listeners’ judgements was assessed by the intraclass correlation coefficient, ICC. This version of the ICC family assumes that both raters and objects are random factors . The results of the fit by the R‐procedure restricted maximum likelihood (REML) are given in Table Speaker, Time and their interaction were found to be significant factors  and T3 was.The participants’ user satisfaction ratings for the game are displayed in Table All participants but for one provided comments on their overall experience playing the game. They stated that they liked the game and assumed that it helped train their speech.All participants except one stated that they frequently noticed the feedback throughout the game. For the question on the quality of the feedback, the answers were mixed. All but one participant answered positively to the question whether they could use the feedback and attempted to speak louder and lower.Feedback on pronunciation was described as a positive experience by most participants as well. Five participants always agreed with the given feedback. Two sometimes disagreed and thought that the system should have detected a mispronunciation when it did not. One participant sometimes disagreed and was puzzled by why an initial pronunciation was not correct and a second was.Table Since there is an urgent need for independent, prolonged speech training in neurological patients’ home environment, this study explored the potentials of game‐based speech training for dysarthric speakers with PD.Pre‐post‐measurements indicated a statistically significant improved speech intelligibility after the intervention (T2–T3), whereas no significant changes in speech intelligibility were observed over a 4‐week period of no training prior to the intervention (T1–T2).Moreover, the dysarthric speakers graded their satisfaction regarding the interface, the ease of use, the attractiveness of the game and their satisfaction overall with Treasure Hunters 2 as a game for speech training on average with 7.37 on a 10‐point scale (no outliers). Although these preliminary results are promising, we should note that despite the statistically significant improvement, the clinical differences are relatively small. A contributing factor may have been the limited duration of our treatment. Our four weeks of treatment is based on intensive treatments in previous research as described in the Materials and Methods section. One could reason that additional weeks of treatment may improve speech intelligibility even more.Our preliminary results do not show a consistent preference for game‐based speech or traditional face‐to‐face speech training. Regardless of preferred type of training, users’ decisions on the preferred scenario seem to be affected by the hypothesized effects on speech intelligibility. That is, our results indicate that the decisive factor seems to be the beneficial effects on speech, rather than the type of speech training. Similar results were observed in previous research Beijer, . This alGenerally, the types of feedback that were used seem to be well received in our study, especially the combination of implicit and explicit feedback for loudness. That is in line with Bakker et al.  considerIn our exploration of feedback on pronunciation we employed ASR technology. As also pointed out by Bakker et al. , it is iThe duration of our speech training  might be considered limited and perhaps contributed to an incomplete view of the effects of game‐based training. Furthermore, no statements can be made about long‐term effects of our treatment.From a technological point of view we note that the calibration of the thresholds used for sentence and word verification was based on artificially generated data.Future research should entail the calibration of these thresholds on real data. The data that was collected during this study can be used for that purpose. Furthermore, future studies should include a larger number of participants to enable more robust conclusions about the effects of game‐based speech training. Also, the long‐term effects of our treatment should be the subject of future study. Previous research showed that patients with dysarthria due to stroke also benefit from intensified and prolonged training .Supplementary materialClick here for additional data file.


Ischemic stroke is one of the major disabling health‐care problem and multiple different approaches are needed to enhance rehabilitation, in which neural repair is the structural basement. Remote ischemic conditioning (RIC) is a strategy to trigger endogenous protect. RIC has been reported to play neuroprotective role in acute stage of stroke, but the effect of RIC on repair process remaining unclear. Several studies have discovered some overlapped mechanisms RIC and neural repair performs. This review provides a hypothesis that RIC is a potential therapeutic strategy on stroke rehabilitation by evaluating the existing evidence and puts forward some remaining questions to clarify and future researches to be performed in the field. The figure shows the speculation that chronic RIC may enhance neural repair after ischemic stroke by improving neurogenesis, angiogenesis, axonal regeneration, synaptogenesis and remyelination. AISAcute ischemic strokeAngAngiotensinBDNFbrain‐derived neurotrophic factorCNScentral nervous systemeNOSendothelial nitric oxide synthaseEPOerythropoietinGAP‐43growth‐associated protein 43HIF‐1Hypoxia inducible factor‐1iNOSinducible nitric oxide synthaseLTDlong‐term depressionLTPlong‐term potentiationmTORmammalian target of rapamycinNgbneuroglobinNOnitric oxideOPColigodendrocyte precursor cellPSD95Postsynaptic density protein‐95p‐STAT3signal transducer and activator of transcription 3 phosphorylationRICRemote ischemic conditionSTAT3signal transducer and activator of transcription 3SYNSynaptophysinTregregulatory T cellVEGFvascular endothelial growth factorVEGFRvascular endothelial growth factor receptor 21Stroke is still one of the leading causes of disability and death in the world.Remote ischemic condition (RIC) is a non‐invasive procedure by which several episodes of sublethal ischemia and reperfusion in distant organs are applied to trigger endogenous protection of important organs. In the application of RIC, it is common practice to occlude blood flow repetitively of upper limbs in human or hind limbs in rodent bilaterally. The principle of RIC is developed from ischemic conditioning in situ, which was first described by Murry et al. that cycles of myocardial ischemia and reperfusion could protect the heart from a subsequent sustained ischemic injury.RIC has shown an impressive neuroprotective function in ischemic stroke in the past few years. It has been reported that among patients treated with recombinant tissue plasmin, those who received RIC had better prognosis for 90 days than their counterparts who did not.2ClinicalTrials.gov investigating the effect of RIC on central nervous system (CNS) rehabilitation are now ongoing  applied for 4 weeks increased the expression of GAP‐43 in young rats.Neurogenesis and angiogenesis are the structural basis of neural repair, while functional connections between newborn and surviving neurons need to be established to realize effective neurological function recovery. The action potentials between neurons are conducted by axons, therefore, axonal regeneration and reconnection play a central role in poststroke recovery. In the central nervous system, the influence of RIC on axonal regeneration has not been tested yet, but encouraging results confirmed that hypoxic conditioning significantly increased the numbers of thinly myelinated regenerating axons in surgically repaired peripheral nerves.3.4Neuronal synapse formation and maturation are complex and regulated through multiple steps. In recent years, RIC has been discovered to improve synaptogenesis in stroke model. Wang et al. found that 3 cycles of RIC after cerebral artery occlusion could improve synaptogenesis in ischemic penumbra.3.5Damaged oligodendrocytes in the acute phase cause myelin loss, which is the leading cause of white matter dysfunction. Remyelination is one of the key processes in neural repair after ischemic stroke,4After summarizing the evidence that RIC can enhance neural repair  declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.


JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.The phase 3 trials of the bone anabolic drug teriparatide were prematurely terminated because of a preclinical finding of osteosarcoma in rats treated with high doses of teriparatide for near lifetime. Even so, results from these and subsequent clinical trials showed efficacy and tolerability. Based on the phase 3 results and additional preclinical investigations, Forteo (teriparatide) was approved for use in the United States with an indication for the treatment of osteoporosis in patients at high risk for fracture, a boxed warning regarding potential risk of osteosarcoma, a 2‐year lifetime limitation of use, other risk mitigations, and a requirement to assess for risk of osteosarcoma in humans treated with teriparatide. Subsequent investigations included five real‐world studies directed at assessing a connection between teriparatide and osteosarcoma risk in humans. The early studies did not identify an increased risk of osteosarcoma but were inadequate to sufficiently characterize risk, given the low incidence of this rare form of bone cancer. Learning from these efforts, two studies were undertaken using claims data to identify large cohorts of patients treated with teriparatide and assess whether these patients were found to have osteosarcoma by linking pharmacy claims data with data from cancer registries. These studies showed no increase in osteosarcoma in patients using teriparatide compared with unexposed groups, as well as to the expected population‐based background incidence of the disease. Based on this real‐world evidence and the totality of data collected from postmarketing use and other clinical investigations, the label was updated in 2020. The changes included addition of information from large observational studies using real‐world evidence, removal of the boxed warning, and a revision of the 2‐year lifetime limitation. Thus, observational studies with large sample sizes using real‐world data can provide supportive evidence to facilitate regulatory decisions including the elimination of a boxed warning. © 2022 Eli Lilly and Company.  With aging of the population, approximately 500 million people worldwide have been diagnosed with osteoporosis and the annual incidence of osteoporotic fractures is more than 8.9 million.Osteoporosis and osteoporotic fractures can result in significant morbidity, increased mortality, reduced quality of life, and health care costs.2, 3Teriparatide  is a parathyroid hormone (PTH) analog with sequence identical to the first 34 amino acids of the 84‐amino acid human parathyroid hormone. Forteo was approved in the US in 2002 for the treatment of osteoporosis in patients at high risk of fracture. Findings from a lifetime carcinogenicity study in which teriparatide caused an increased incidence of osteosarcoma (OS) in rats resulted in the United States label required to include a boxed warning, and treatment duration was limited to 2 years.6, 7This review focuses on the history of teriparatide development, identification of the potential osteosarcoma risk based on preclinical findings, studies directed at understanding whether teriparatide administration was associated with osteosarcoma risk in humans, recent updates to the teriparatide US prescribing information, and the clinical implications of those changes. It was hypothesized that patients with osteoporotic fractures would benefit from an anabolic approach using intermittent PTH that would quickly rebuild the skeleton, although the anabolic therapy fluoride had failed to reduce fracture risk, and there was scientific uncertainty about the effects of teriparatide at cortical bone sites. Clinical development of daily subcutaneous teriparatide and a 2‐year preclinical toxicology study in rodents were undertaken.Preclinical studies demonstrated the potential of intermittent administration of PTH as an anabolic agent that stimulates osteoblasts and bone remodeling.8, 9 However, this study was prematurely terminated after a median of 19 months of treatment when the long‐term toxicology study in rats showed evidence of osteosarcoma after near lifetime exposure to teriparatide. Even so, when the clinical trial data from this study was initially and subsequently evaluated, results showed reductions in vertebral fractures, nonvertebral fractures, back pain, and increased bone mineral density. A paired iliac crest bone biopsy study from a subset of patients showed an increase in trabecular bone volume and cortical thickness, and improvements in trabecular connectivity and structural model index. Post hoc analyses suggest teriparatide may be effective and safe in patients with renal insufficiency; data are limited in patients with severe renal impairment. Additional studies supported the findings that teriparatide was associated with clinical efficacy in patients with osteoporosis at high risk for fracture. Teriparatide had a novel mechanism of action compared with antiresorptive drugs and greater fracture risk reduction in a head‐to‐head fracture trial compared with a bisphosphonate. Teriparatide was generally well tolerated.A pivotal, phase 3, multinational, randomized, double‐blind, 3‐year clinical study was conducted to assess the efficacy of teriparatide in 1637 postmenopausal women with prior vertebral fracture.12 Hown = 344) were treated with once‐daily subcutaneous injections of control or supratherapeutic doses, including 5 μg/kg, 30 μg/kg, and 75 μg/kg teriparatide from ages 6 to 8 weeks. Results showed anabolism in rodent bone, with quantitative computed tomography (QCT) images showing excessive increases in bone mass with reduction and loss of the marrow space; the bone mineral content at the end of treatment was similar to that of a rod of pure bovine cortical bone. Osteosarcoma was observed in a dose‐dependent manner  for the treatment of patients with osteoporosis at high risk of fracture to ensure patients had a sufficiently high medical need for anabolic therapy to outweigh the potential risks. Additional risk mitigation strategies including adequate labeling and inclusion of a Medication Guide were put in place. Labeling of the product included a boxed warning regarding the potential risk of osteosarcoma along with a recommendation to avoid the drug in patients at high risk for osteosarcoma. Labeling also stated that use of the drug for more than 2 years over a lifetime was not recommended. Additional risk mitigation measures included a Risk Evaluation and Mitigation Strategy with an education component to ensure that patients and prescribers were aware of the safety concerns related to the preclinical toxicology findings. Additionally, a postmarketing surveillance program was required to gain further insights into the potential risk of osteosarcoma in humans.The US FDA reviewed the teriparatide New Drug Application and convened an advisory board at which there was discussion of the benefits of teriparatide versus risks related to the preclinical toxicology findings.35 TheA comprehensive program consisting of five post‐approval observational studies developed over more than 15 years was undertaken to characterize the risk of osteosarcoma among patients treated with teriparatide , age‐ and sex‐adjusted to the teriparatide‐treated population, the expected number of cases was 4.17 cases. The study observed 3 cases and an estimated standardized incidence ratio of 0.72 . The results showed that osteosarcoma incidence with teriparatide use was not higher than the background incidence rate. In addition, another osteosarcoma surveillance study was conducted in five Nordic countries using regional and national cancer registry data to identify osteosarcoma cases and chart review to ascertain exposure to teriparatide. Among 109 cases of osteosarcoma identified, none had a record of teriparatide use. Given the limited number of osteosarcoma cases expected within the Nordic country population, the authors note that exposure to teriparatide among patients diagnosed with osteosarcoma would only be expected if there had been a large increased risk with the use of teriparatide. Limitations for each of the studies included the number of osteosarcoma cases observed given this is a rare disease, the lack of a comparison group, and inability to control for potential confounders.The first was the Osteosarcoma Surveillance Study, a 15‐year study initiated in 2003 as a postmarketing commitment to the US FDA. The study design and findings from the first 7 years were published in 201238 andWhen teriparatide was approved for treatment of glucocorticoid‐induced osteoporosis, a new study termed the Forteo Patient Registry was added to the program in 2009. In the Forteo Patient Registry, patients receiving a Forteo prescription were requested to voluntarily register. Patients treated with Forteo were followed by linking their data to cancer registry data to identify patients developing osteosarcoma. In this study, 6180 osteosarcoma cases were linked with 75,247 patients in the Forteo Patient Registry, and no matches were found. Limitations of this study were that the study was not comparative and the number of patients enrolled was lower than the target number to evaluate the risk of developing osteosarcoma.41 The study results suggested a similar risk for osteosarcoma between teriparatide users and their unexposed comparators.Although these earlier studies did not suggest an increased risk of osteosarcoma in patients treated with teriparatide, they were inadequate to sufficiently characterize osteosarcoma risk. Accordingly, two large, population‐based, observational cohort studies were undertaken to identify a larger sample of patients treated with teriparatide using Medicare and a large commercial claims database. These pharmacy claims databases were linked to cancer registry data to identify cases of osteosarcoma among teriparatide‐treated patients. Teriparatide exposure was observed for 3 and 0 osteosarcoma cases among 379,283 and 153,316 teriparatide users, respectively.42 The Additionally, observational studies of teriparatide use (without a focus on osteosarcoma) conducted in various geographies have also not reported any cases of osteosarcoma. Thus, an increased risk of osteosarcoma has not been observed in observational studies in humans.Overall, the real‐world data collected since 2003 through 2019 showed that the incidence rate of osteosarcoma in patients treated with teriparatide (2.47 million patients) did not exceed the background incidence rate.43 Add  Table . The fin) Table .The boxeAnother change was the lifetime restriction on duration of use of teriparatide for up to 2 years was adjusted to allow patients remaining at or who have returned to having a high risk for fracture to take teriparatide beyond 2 years (Table The updates to the Forteo (teriparatide) label provide patients and clinicians with the information that an increased risk of osteosarcoma has not been observed in humans treated with teriparatide. The information from teriparatide clinical trials, observational studies, and the postmarketing surveillance program can help clinicians in benefit–risk assessments and making informed decisions on treatment strategy for patients with osteoporosis who are at high risk of fracture.Some patients who complete 24 months of treatment with teriparatide remain at high risk for fracture or return to a state of high risk for fracture after a previously completed course. These patients may benefit from additional treatment or retreatment with teriparatide. Thus, modification of the 2‐year lifetime limitation of use may provide prescribers an opportunity to tailor the treatment duration and manage their patients based on their individual needs. These included patients with osteoporosis and very high fracture risk and dependency on glucocorticoid therapy, high fracture risk and high P1NP levels after 2 years of treatment with teriparatide, high fracture risk with multiple vertebral compression fractures at baseline while none with teriparatide, adynamic renal bone disease, severe chronic obstructive pulmonary disease, and vertebral compression fractures.Recently, Miller and colleagues published some clinical situations in which treatment with teriparatide beyond 2 years may be beneficial.49 The Data are not available to guide the duration of additional treatment beyond 2 years. Therefore, the risk of osteosarcoma in humans with longer duration of treatment is not fully understood, requiring physician judgment of benefit/risk in individual patients. Consequently, the updated label reflects that use of teriparatide for more than 2 years during a patient's lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture. Observational studies using pharmacy claims data have some limitations. The limitations for the linkage studies using Medicare and commercial pharmacy claims include an inability to assess detailed baseline patient characteristics and medical histories (only prescription data were available in the study data sources) and these study designs could not completely measure and control for confounding. It is unknown whether findings from patients treated with teriparatide are relevant to other anabolic treatments, such as PTHrP analogs.There are some limitations of the currently available data for teriparatide. The efficacy and safety data beyond 2 years of treatment with teriparatide is limited both in terms of continuous treatment as well as retreatment.53 DatIn summary, the initial phase 3 trials of the bone anabolic drug teriparatide were stopped because of a preclinical finding of osteosarcoma in rats treated with high doses of teriparatide for near lifetime. Even so, teriparatide was observed to reduce fracture risk in postmenopausal women with osteoporosis and showed efficacy and tolerability in the phase 3 program and in subsequent studies with a positive benefit to risk profile. Based on the phase 3 results, additional preclinical findings, and with risk mitigations, the agent was approved for use. Subsequent studies including in real‐world settings have not identified an increased risk of osteosarcoma in humans, and the label has been updated and adjusted, including removal of the boxed warning and a revision of the 2‐year lifetime limitation. Thus, observational studies with large sample sizes using real‐world data can be an important and efficient strategy for generating evidence in support of regulatory decision making and significant label updates.All authors have completed the ICMJE uniform disclosure form. JHK, JLK, and NKS are employees of Eli Lilly and Company. AG is an employee of RTI Health Solutions.John H Krege: Conceptualization; writing – review and editing. Alicia W. Gilsenan: Data curation; formal analysis; investigation; methodology; writing – review and editing. John L Komacko: Writing – review and editing. Nicole Kellier‐Steele: Conceptualization; data curation; formal analysis; investigation; methodology; writing – review and editing.This manuscript describes retrospective data that does not require ethics committee approval.


Streptococcus pneumoniae, Influenza A, and Mycoplasma pneumoniae, who survived with intact neurological function and no long‐term adverse outcomes after a prolonged ECMO run of 86 days. To the best of our knowledge, this is one of the longer durations of ECMO with transplant‐free survival in a pediatric patient requiring respiratory support with good recovery and a good functional outcome. Allowing time for native lung recovery is pivotal for optimal recovery, despite significant lung injury due to the underlying disease process. With evolving ECMO experience, clinicians may need to re‐consider the conventional maximum duration of ECMO in children with severe respiratory failure on a case‐by‐case basis.Extracorporeal membrane oxygenation (ECMO) is a life‐saving rescue therapy used in acute respiratory failure refractory to invasive mechanical ventilation. Recent studies on positive outcomes of extended ECMO therapy are promising. We describe a case of a 2‐year 8‐month‐old female child with necrotizing pneumonia secondary to  Use of prolonged extracorporeal membrane oxygenation (ECMO) to allow native lung recovery can result in positive outcomes for pediatric patients, although clinicians need to monitor closely for complications inherent to ECMO. Pushing the boundaries with ECMO may do pediatric patients more benefit than harm on a case‐by‐case basis. She was treated with the following broad‐spectrum antibiotics: intravenous ceftriaxone, vancomycin, and oral clarithromycin. The pleural effusion was drained with a left‐sided chest tube. Despite pleural fluid drainage and treatment with broad‐spectrum antibiotics, she progressed to respiratory failure requiring intubation prior to transfer to our pediatric intensive care unit (PICU) on Day 8 of her illness.A previously healthy 2‐year 8‐month‐old Indian girl presented with a 3‐day history of fever and cough. She had completed all age‐appropriate immunizations, including three doses of the 13‐valent pneumococcal conjugate vaccine. Chest radiograph showed bilateral pneumonia complicated by pleural effusion  of 1.0, and persistent clinical lability leading to conversion to high‐frequency oscillatory ventilation (HFOV). Despite high settings on HFOV  and a trial of nitric oxide at 30 parts per million (ppm), she remained in severe respiratory failure. Her arterial blood gas showed a pH of 7.06, partial pressure of carbon dioxide (pCO2) 101 mmHg, partial pressure of oxygen (pO2) 66 mmHg, base excess (BE) of minus 2.1 mmol/L and lactate of 0.84 mmol/L with an oxygenation index (OI) of 34.8, in keeping with severe acute respiratory distress syndrome (ARDS).Her clinical condition continued to deteriorate in our PICU. Her urine and pleural fluid tested positive for s Figure . Serial Given her rapid progression of severe acute respiratory failure refractory to conventional MV, she was commenced on venovenous (VV) ECMO treatment with a size 23 French Avalon cannula via the right internal jugular vein (IJV). Post‐cannulation, ventilator settings were weaned to minimal to facilitate lung recovery. Minimal radiologic improvement in lung aeration on Day 3 of admission with poor tidal volumes indicated a suboptimal functional improvement Figure .First computed tomography (CT) scan of the thorax done on Day 7 of admission showed bilateral pulmonary consolidation, likely abscess on the right, and necrotizing pneumonia on the left, with dissection into bilateral pleural spaces, suggesting bilateral empyema Figure . A left Between Days 5 and 54 of admission, she underwent six ECMO circuit changes. These were related to fibrin clot formation and bubbles in multiple sites of the circuit, mechanical issues such as movement of the cannula resulting in change of depth, and air embolism. Her circuit changes were complicated by hemodynamic instability requiring inotropic support and short periods of cardio‐pulmonary resuscitation. A repeat CT of the thorax performed on Day 33 of admission Figure  showed sGiven the absence of multiorgan dysfunction  and CT scan of the brain showing no intracranial bleed on Day 62 of her ECMO run (despite prolonged heparin use on ECMO), an extensive discussion with the family was undertaken regarding the appropriateness of continued ECMO support. This was to reinforce that there were no further options of pediatric lung transplant offered in our center and the high risk of complications with continuation of ECMO. A consensus on continuing ECMO was reached between the medical team and parents given the potential for her lung recovery with time. Furthermore, a decision was made to terminate the ECMO if she developed any irreversible organ injury or intracranial complications.A trial off VV ECMO decannulation was attempted on Day 69 of her ECMO run, which she failed after she developed significant desaturations. On Day 76 of her ECMO run, she was converted to venoarterial (VA) ECMO via a right femoral arterial cannulation. Venous cannulation was done through the right atrium as the right femoral vein was of inadequate caliber to allow for full advancement of the venous cannula to provide adequate flow. The decision to convert to VA ECO was made firstly due to inability to wean off ECMO in view of high ventilatory settings, and secondly in view of highly friable neck tissue over the internal jugular veins on the right neck due to prolonged use as well as lack of other suitable sites for venous cannulation owing to size and central line placement. Moreover, during the last circuit change on Day 71 of ECMO, she desaturated to 0% and required 5 min of cardio‐pulmonary resuscitation, indicating that her reserves were poor and making her hemodynamic status tenuous. While we acknowledge that conversion from VV to VA ECMO at this juncture is unusual, our case highlights the challenge with pediatric ECMO cannulation in prolonged runs.In the days following VA ECMO cannulation, she was noted to have significant radiological improvement in lung aeration and tidal volumes (up to 4 ml/kg). She was successfully decannulated on Day 10 of VA ECMO to conventional MV, completing a total of 86 days of ECMO. Before decannulation, she underwent two flexible bronchoscopies, bronchoalveolar lavage for pulmonary toileting and intensive chest physiotherapy to optimize lung recruitment.Post‐decannulation of ECMO, she remained on conventional MV. Apart from an inferior vena cava (IVC) thrombus requiring subcutaneous enoxaparin treatment, she did not have any other ECMO‐related complications. She remained sedated for the entire duration of the ECMO run, requiring prolonged infusions of benzodiazepines and opioids owing to movement of the neck cannula and frequent complications of air entrainment.2O on room air as her respiratory status improved. She was allowed periods of de‐venting with the physiotherapist. CT thorax performed 2 months post‐ECMO  ventilation for 12 days and subsequently converted to continuous positive airway pressure (CPAP) of +7 cm HO Figure  showed rO Figure . She remO Figure  done 4 mAfter recuperating from her prolonged illness, she resumed school and regular physical activities a year after discharge. At her most recent outpatient review in the respiratory clinic 37 months 20 days after her PICU admission, there were no reported respiratory symptoms with exertion. No spirometry test was performed yet given the age.3Since 1993, ECMO survival trends for pediatric patients with acute respiratory failure, without any underlying comorbidities, have been improving.Our patient survived after 86 days of combined VV and VA ECMO, which is one of the most prolonged pediatric ECMO runs with a favorable outcome in terms of a transplant‐free survival, in a center which does not offer transplant. The longest documented duration is 394 days in a 13‐year‐old awaiting cardiac transplantation in 2021, who eventually received a cardiac transplant.Positive prognostic factors specific to this case were the absence of pre‐existing comorbidities, female gender, absence of multi‐organ failure,The nature of underlying disease process also affects outcomes of prolonged ECMO as the rate of lung recovery will be faster in patients with ARDS secondary to viral pneumonia or pulmonary hypertension compared with ARDS secondary to complications of malignancies or associated treatment.Our case also enables clinicians to reflect on the need for surgery and lung transplant for patients with significant lung destruction secondary to necrotizing pneumonia. These procedures carry their innate complications. Giving a longer duration for the patient's lung to recover is important, although it is hard to predict the exact duration needed, as it is often patient‐dependent. Lung recovery strategies such as regular chest physiotherapy and secretions management also play an often‐underestimated pivotal role in helping the lungs recover.For complex cases such as our patient requiring prolonged ECMO support, there can be a myriad of factors affecting ECMO outcome including patient factors such as age and gender, underlying primary diagnosis and disease related as well as treatment related factors, duration of MV, advancements in ECMO technologies and institution‐based expertise.On a case‐by‐case basis, the team has to be prepared to deal with the issues with regular and open conversations with family and relevant stakeholders involved such as the cardiothoracic surgeons, cardiology, and respiratory teams. Continued engagement with the family to ensure a shared decision‐making process in challenging patients, for whom there is a lack of robust evidence‐based protocols to guide key decisions such as duration of or discontinuation of ECMO, at regular critical intervals are important in contributing to better outcomes for these children.Thankfully, this child had a good functional outcome owing to the cohesive ECMO team comprising of doctors, nurses and allied health, the collaboration between multiple subspecialties and the unwavering faith of the family. Neurological examinations done at her follow‐up visit were normal although no formal neurodevelopmental test has been performed yet.4Further large‐cohort studies analyzing mortality outcomes or validated scoring systems of children receiving prolonged ECMO for acute respiratory failure, particularly necrotizing pneumonia, would help guide clinical decision‐making for intensivists in terms of duration of therapy and endpoints of treatment. Our experience suggests that prolonged use of ECMO may be justified in children with pediatric ARDS resulting from severe necrotizing pneumonia in the absence of significant comorbidities and multiorgan dysfunction. However, one has to acknowledge that there are challenges associated with a long ECMO run and this has to be applied on a case‐by‐case basis.PRR, SC, YHT, BT, JHL, APM, OKK, and AKP contributed to the conception of this report, revised the manuscript critically, approved its final version. PRR was responsible for drafting the manuscript.All authors declare that no conflict of interest exists.Written informed consent was obtained from the patient's parents to publish this report in accordance with the journal's patient consent policy.


The coronavirus disease 2019 (COVID‐19) pandemic is the latest in a series of global high‐consequence respiratory virus outbreaks. In prior years, we faced the emergence of severe acute respiratory syndrome (SARS) during 2002–2003,For COVID‐19, early pandemic public health responses focussed on nonpharmaceutical interventions, and control measures were implemented globally to limit viral spread and slow down any potential overwhelming of healthcare systems. These interventions included border closures and travel restrictions, closing of day‐care centres, schools, restaurants and shops, the cancellation of mass events, mandatory wearing of face masks and numerous physical isolation measures. The near‐simultaneous global implementation of these nonpharmaceutical interventions helped to slow down the community transmission of SARS‐CoV‐2, mitigated the burden of disease on healthcare resources and allowed time to develop vaccines and treatments. An unexpected but positive phenomenon resulting from the mass implementation of these pandemic measures was the significant drop in non‐COVID‐19 respiratory viral infections and gastrointestinal viral infections globally.An astounding decrease in influenza virus infections in both northern and southern hemispheres was by far one of the most noteworthy changes in non‐COVID‐19 disease incidence during the pandemic period.Clinical & Translational Immunology, we seek to highlight important non‐COVID‐19 vaccine papers from the past year that aimed at combating ongoing respiratory threats and improving protection in the coming years.With the progressive removal of pandemic measures, these decreases in disease incidence have not been sustained. For example, the partial relaxing of measures over the summer period between 2021 and 2022 caused an unseasonal spike in influenza cases in the Southern Hemisphere, and infection levels are now back to prepandemic levels.et al.The Special Feature Review by Elkashif et al.Similarly targeting intranasal delivery, the Special Feature Review by Williams et al.et al. specifically demonstrate how crucial the timing of vaccination is for individuals that are B‐cell‐depleted, to ensure sufficient vaccine‐mediated protection. B‐cell depletion is an effective therapy for autoimmune diseases and for B‐cell malignancies, but this therapy also leaves the patient highly susceptible to infections, particularly with respiratory pathogens. This effect is known and can often be intentionally countered with specific vaccinations around the time of depletion. Ercoli et al. investigated the effect of vaccinating either prior to or immediately after B‐cell depletion therapy and found that protection against the respiratory bacterium Streptococcus pneumoniae was most robust when vaccines were administered prior to depletion. Specifically, B‐cell depletion after Prevnar‐13 vaccination had little effect on both Prevnar‐induced serological responses and protection of animals against pneumococcal pneumonia. However, if a patient is unable to receive vaccinations because of safety concerns or clinical issues, Ercoli et al. also demonstrated that vaccination immediately after B‐cell depletion still offers partial protective efficacy, at least in the short term. This was not simply because of retained T‐cell immunity, as additional T‐cell depletion did not abrogate the ongoing partial protection against S. pneumoniae.Finally, an Original Article from Ercoli Overall, we have made remarkable progress over the last 2 years in creating new tools and improving our understanding of SARS‐CoV‐2 – knowledge that can now be applied to other respiratory infectious diseases. In addition to improved surveillance, communication plans, quarantine practises and public health protocols, the global deployment of effective vaccines is one of the most meaningful strategies we have to protect lives and limit global disease spread.