Multistakeholder engagement is crucial for conducting health services research. Delphi‐based methodologies combining iterative rounds of questions with feedback on and discussion of group results are a well‐documented approach to multistakeholder engagement. This study develops hypotheses about the impact of panel composition and topic on the propensity and meaningfulness of response changes in multistakeholder modified‐Delphi panels.We conducted three online modified‐Delphi (OMD) multistakeholder panels using the same protocol. We assigned 60 maternal and child health professionals to a homogeneous  panel, 60 pregnant or postpartum women (patients) to a homogeneous panel, and 30 professionals and 30 patients to a mixed panel. In Round 1, participants rated the seriousness of 11 maternal and child health outcomes using a 0–100 scale and explained their ratings. In Round 2, participants saw their own and their panel's Round 1 results and discussed them using asynchronous, anonymous discussion boards moderated by the study investigators. In Round 3, participants revised their original ratings. Our outcome measures included binary indicators of response changes to ratings of the low, medium and high severity maternal and child health outcomes and their meaningfulness, measured by a change of 10 or more points.Participants changed 818 of 1491 (55%) of responses; the majority of response changes were meaningful. Patterns of response changes were different for patients and professionals and for different levels of outcome seriousness. Using study results and the literature, we developed three hypotheses. First, OMD participants, regardless of their stakeholder group, are more likely to change their responses on preference‐sensitive topics where there is a range of viable alternatives or perspectives. Second, patients are more likely to change their responses and to do so meaningfully in mixed panels, whereas professionals are more likely to do so in homogeneous panels. Third, the association between panel composition and response change varies according to the topic .Results of our work not only helped generate empirically derived hypotheses to be tested in future research but also offer practical recommendations for designing multistakeholder OMD panels.Pregnant or postpartum women were involved in this study. We use the propensity and meaningfulness of response changes after stakeholders receive statistical feedback and discuss their original responses with others as a measure of panel impact on individual stakeholder judgments. To reach the study goals, we use the data from three OMD panels that engaged patients and professionals around the severity of maternal and child health outcomes linked to gestational weight gain.22.1In October–November 2019, we conducted three concurrent OMD panels: a panel of 60 professionals, a panel of 60 patients and a mixed panel of 30 professionals and 30 patients. This panel size is consistent with the recommendations for the optimal number of participants in each OMD panel.not serious at all) to 100 (very serious) and explained their responses . We considered a change of 10 or more points to be meaningful because it moves a response from one decile to another on the 100‐point scale.Our main predictor variable is the composition of the panel a participant was randomized into .strongly disagree, 2 = disagree, 3 = slightly disagree, 4 = neutral, 5 = slightly agree, 6 = agree, 7 = strongly agree, to rate their agreement with the following statements:1.Participation in this study was satisfying.2.The charts helped me understand how my responses compared to those of other participants.3.Round 2 discussion changed my perspective on the study topics.Our control variables include three measures of stakeholders' participation experiences, such as overall satisfaction and perceptions of the impact of two key features of the OMD panels most relevant to the goals of this study—statistical feedback as presented in charts and perceived ability of online discussions to change participant responses. Participants used 7‐point Likert scales, where 1 = As in previous studies, we dichotomized responses and considered those scoring an item as 5, 6 or 7 as having positive participation experiences.Other control variables include participants' race (White vs. other) and age.2.4n = 1491 response changes). We then stratified all analyses by health outcome severity levels, which we considered as different panel topics. High severity outcomes included infant death, stillbirth, preterm birth and pre‐eclampsia (n = 537 response changes). Medium severity outcomes included obesity in women, childhood obesity, gestational diabetes and metabolic syndrome in women (n = 542 response changes). Finally, low severity outcomes included small‐for‐gestational‐age (SGA) birth, large‐for‐gestational‐age birth and unplanned caesarean delivery (n = 412 response changes). Additional details on outcome severity can be found elsewhere.We used mixed‐effect logistic regression to estimate the panel composition effects on the presence and meaningfulness of response changes. All models were clustered at the individual level to address within‐participant correlations, and robust standard errors were produced. We first ran all the models using the seriousness ratings of all pregnancy outcomes combined  answered at least one question in both rating rounds. Of these 143 participants, 73 (51%) were health care professionals and 70 (49%) were patients. Of 73 professionals, 46 (63%) were in the homogeneous panel and 27 (37%) were in the mixed panel. Of 70 patients, 47 (67%) were in the homogeneous panel and 23 (33%) were in the mixed panel. More detailed information on participation rates could be found elsewhere.n = 131, 92%) were female and roughly two‐thirds  were White  and had a doctoral degree . Two‐fifths (n = 29) of all professionals had 15 or more years of experience, 36% (n = 26) had 10–14 years, and 25% (n = 18) had 5–9 years of experience. The majority of 70 patients in our study had a master's or doctoral degree  and reported being pregnant within the past 2 years ; and slightly less than half  reported having two or more prior pregnancies.Of 143 study participants, almost all , thought that the charts showing the distribution of Round 1 responses helped them understand how their responses compared to those of other participants , and felt that the discussions changed their perspective . Of the 1491 questions that participants answered twice, responses to 55% (n = 818) of all questions changed in Round 3 , compared to their responses in the homogeneous panel , a higher proportion of professionals' responses in the homogeneous panel changed meaningfully , compared to their responses in the mixed panel . These results suggest a differential effect according to panel type. Moreover, the patterns of response changes differed by topic: A higher percentage of responses have been changed and altered by 10 or more points for medium and low severity outcomes than for high severity outcomes across all participant and panel types.3.4Table Those satisfied with their participation were less likely than their less satisfied counterparts to change ratings on medium severity outcomes , whereas those who felt that charts helped them understand how their responses compared to those of others were less likely to change their ratings on low severity questions . We note that small sample sizes led to imprecise estimates.Figure Table Although perceived usefulness of charts reduced the likelihood of meaningful response changes on low severity outcomes , participation satisfaction made participants marginally less likely to change their responses by 10 or more points on medium severity outcomes .Figure 4We analysed the impact of panel composition and topic on the presence and meaningfulness of response changes in OMD panels using the data on the severity of maternal and child health outcomes linked to gestational weight gain as a case study. Our results show that professionals and patients rating the seriousness of maternal and child health outcomes changed more than half of their original responses and that the majority of response changes  were meaningful. This finding suggests that the exposure to and the discussion of the perspective of other participants affect individual judgments about outcome severity.In contrast to previous research that suggested that personal characteristics of OMD panellists were not associated with response changes,Our results also illustrate heterogeneity in the impacts of panel composition on response changes and their meaningfulness based on panel topic, operationalized as outcome severity. While we saw some patterns, we cannot, with certainty, say that certain types of stakeholders are more likely than others to change their responses on certain topics. Nonetheless, our study design provides a unique opportunity to generate hypotheses to be tested in future research.we hypothesize that participants in OMD panels, regardless of their stakeholder group, are more likely to change their responses for certain preference‐sensitive topics, such as those where there is a range of viable alternatives or perspectives. In our study, the likelihood and meaningfulness of response changes were affected by the nature of maternal and child health outcomes considered. Moreover, participants had the lowest probability of changing their responses and doing so meaningfully while rating outcomes deemed ‘severe’ by participants. There is little if any debate that infant death and stillbirth are serious health outcomes. Therefore, it is not surprising that our participants rated these outcomes highly in Round 1 and that their perspectives did not change greatly after the discussion round. At the same time, individual judgments about less severe outcomes, such as gestational diabetes and SGA birth, were more affected by the perspectives of other participants. For example, while some patients may have initially focused more on the short‐term impact of gestational diabetes thinking that it resolves after delivery, exposure to a professional perspective may have brought to the fore concerns about risks of complications during delivery and increased risk of Type 2 diabetes after child‐bearing years.First, we hypothesize that, regardless of the panel topic, stakeholders may be more likely to change their responses in different panel types: Patients may be more likely to change their responses and to do so meaningfully in mixed panels, whereas professionals may be more likely to do so in homogeneous panels. The fact that patients generally had the highest probability of changing their responses in the mixed panel may be an illustration of collaborative learning, which takes place in diverse stakeholder panels that focus on important issues. Stakeholders can learn from the perspective of a different group and change their responses based on new ideas they may not have considered.Second, Although unexpected and somewhat methodologically undesirable, professionals in our study were more likely to change their responses and to do so meaningfully in the homogeneous panel. This finding, however, is not too surprising given that shared decision‐making often suffers from ‘selective paternalism’—a situation where healthcare professionals step outside of shared decision‐making to choose a course of action they think would work best for their patient, but that discounts hearing an alternative patient perspective.we hypothesize that the association between panel composition and response change may vary according to the topic. Panel composition may play a bigger role in panels on somewhat less serious or consequential, but still important health topics. In our study, marginal effects of panel composition varied by the outcome type: While patients in the mixed panel were more likely to change their responses and to do so meaningfully on medium and low severity outcomes, the reverse was true for high severity outcomes. Professionals in the homogeneous panel generally had higher probabilities of changing their responses and doing so meaningfully than professionals in the mixed panel. This was true across topics with one exception: Professionals in the mixed panel had a higher probability of changing their responses on low severity outcomes. Although these findings support our hypothesis that patients and professionals learn under different circumstances, it offers an important nuance—mutual learning may happen in diverse panels, but only for certain types of outcomes. While previous research shows that there are no statistically significant differences between patient/caregiver and clinician/research experiences with OMD panels or their willingness to use OMD in the future,Third, Our study has important limitations. Our analysis was limited to three OMDs that engaged pregnant and postpartum women and health professionals on the topic of maternal and child health outcomes. We note that the women who participated in our study were highly educated. Therefore, the patterns of findings may be different in panels that engage different stakeholders and/or focus on other topics. Moreover, not all study participants answered the same questions twice or provided responses to satisfaction questions, which limited our sample size. Nonetheless, attrition is common in OMD panels, and our participation rates were higher than in other panels.5We recognize that our study cannot provide conclusive answers to our research questions. That is why we consider our study results, and the empirical data it relies on, as the necessary basis for formulating evidence‐informed hypotheses about panel composition and topics that should be tested in future research. Nonetheless, we believe that our results offer a number of practical recommendations, presented in Figure Dmitry Khodyakov is a leader of the ExpertLens team. ExpertLens is a RAND‐developed online modified‐Delphi platform used to collect data in this study.All authors contributed to the study conception and design. Dmitry Khodyakov led the data collection, designed the analytic procedures and drafted the paper; Sujeong Park conducted all analyses, created all tables and figures and helped draft the paper; Jennifer A. Hutcheon and Lisa M. Bodnar obtained funding, designed the overall study, advised on the analytic procedures, reviewed and revised earlier drafts of the manuscript; Sara M. Parisi participated in the data collection and reviewed and revised earlier drafts of the manuscript. All coauthors reviewed and approved the final version of the manuscriptSupporting information.Click here for additional data file.


Dear Editor,In this letter, we explore the potential role of radionuclide‐based molecular imaging modalities, such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT), in evaluating abdominal aortic aneurysms (AAA). We further discuss how the developments of promising radiotracers in combination with ultra‐sensitive PET and SPECT scanners may enable the assessment of AAA formation and progression and consequently patient risk stratification and therapeutic interventions.AAA is an asymptomatic, irreversible, focal enlargement of the abdominal aorta proceeding to rupture and eventually resulting in patient death. Patients with early‐stage AAA do not exhibit evident signs or symptoms; hence, AAA is typically diagnosed during incidental health assessments or through dedicated screening programmes, such as those implemented in the USA, the UK and Sweden. Although many studies are conducted to identify more reliable and informative risk factors of AAA rupture, aortic size is the only marker utilised in clinical practice, with elective repair offered to prevent rupture once an AAA enlarges to the intervention threshold of 5.5 cm. The aortic diameter is a straightforward and convenient parameter to extract using ultrasound scanning (USS) but may not consistently correlate with prognosis, as large AAA may remain intact, while small AAA may rupture.Much of our knowledge of human AAA pathology stems from aortic tissue obtained during surgery ; therefore, theories based on findings corresponding to these tissues may not accurately reflect early‐stage disease pathology, when an effective pharmacological treatment may be offered. Indeed, one of the most significant barriers to overcoming late‐stage detection of AAA is the ability to detect early‐stage molecular mechanisms that precede physical disease manifestation. Patient management can be complicated to navigate based solely on the risk of AAA rupture as predicted using USS for aortic diameter measurements; in this case, molecular information yielded by PET and SPECT may improve the management and treatment approaches for AAA by providing more comprehensive information on the molecular processes occurring within the aortic wall that drive an aneurysm towards growth and rupture as opposed to stability. These molecular‐level data make PET and SPECT imaging attractive tools for the purposes of early risk stratification and the assessment of responses to effective low‐risk non‐invasive therapeutic interventions as adjuncts to USS‐based screening and surveillance.18F]fluorodeoxyglucose ([18F]FDG) has been shown to correlate with inflammatory markers in AAA  uptake is increased prior to pronounced aortic expansion in the angiotensin II‐induced AAA murine model, reflecting microcalcification, which may indicate an alternative biological process that can offer a surrogate signal of an effective therapy.18F]NaF localises in regions of microcalcification in patients with asymptomatic AAA, acting as a susceptibility marker of aneurysm growth and rupture and yielding proof‐of‐concept data for the practicability of a PET radiotracer other than [18F]FDG for risk stratification in patients with AAA , has been used to demonstrate that MMP‐targeted SPECT may indicate aortic wall inflammation and help predict expansion or rupture in AAA.18F]FDG uptake and supplement classical clinical parameters, such as aneurysm diameter, since AAA growth—and consequently rupture—is implied to follow a non‐linear and unpredictable trend. As PET and SPECT are currently used in the clinic for non‐AAA applications, further research on these molecular imaging modalities for patients with AAA has functional practicality for rapid clinical translation compared to the process of translating entirely novel technologies to the clinic.Basic research in AAA pathobiology continues to generate important preclinical data and novel imaging approaches to support clinical advances. Undoubtedly, the establishment of reliable and unequivocal radiotracers remains the ultimate objective of any radionuclide‐based molecular imaging study. The widely used PET radiotracer 8FfluorodA Figure .6 Meane Figure .7 In tThe road ahead for molecular imaging of AAA may be intricate, and the smooth translation of positive preclinical findings to the clinic remains a critical aim. The key obstacle to implementing SPECT for AAA imaging in the clinic lies in the relatively poorer spatial resolution of clinical SPECT scanners than that of clinical PET scanners. However, if a SPECT radiotracer provides substantially valuable information, a dedicated redesign of collimators for AAA may enable higher‐resolution clinical SPECT. Meanwhile, in addition to the extensive range of PET radiotracers already available in the market, the development of PET scanners with a substantially longer axial field of view (4–8 times longer than that of the currently most commonly available PET scanners) offers a unique opportunity in accelerating the translation of new radiotracers in the clinic.In conclusion, many aspects of AAA evolution remain poorly understood. Considering the seemingly complex heterogeneity of AAA and involvement of numerous contributory factors, anatomical and molecular imaging modalities must be considered supplementary tools in their role in AAA management. Importantly, the strength of radionuclide‐based molecular imaging is reflected in its power to shed light on the molecular evolution of AAA, which may guide the necessity for surgical repair or response to pharmacological therapies before the disease progresses to a severe and irreversible stage. To facilitate AAA risk stratification, the quest to identify the most appropriate radiotracers is an essential path towards reducing patient morbidity and identifying alternative therapies that are potentially more efficient and economical than surgical interventions.Richa Gandhi is funded by the Engineering and Physical Sciences Research Council. Marc Bailey is funded by the British Heart Foundation. Charalampos Tsoumpas is funded by the Royal Society.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


To understand the prevalence and epidemiology of paracetamol‐induced hypotension and clinical implications for contemporaneous practice.Narrative review.In May and June 2020, an open‐date literature search of English publications indexed in ProQuest, PubMed, and EBSCO was conducted with the search terms ‘acetaminophen’ and ‘hypotension’ and related search combinations  to identify peer‐reviewed publications of blood pressure changes after paracetamol administration in humans.A pattern of blood pressure reduction following the administration of paracetamol is demonstrated in the 27 studies included in this review. Haemodynamic intervention often followed persistent blood pressure reduction, and was greatest in febrile critically ill patients who received parenteral paracetamol. Nurses have reported paracetamol‐induced hypotension, through monitoring and surveillance  and acute brain injury (p < .001) had a higher risk of developing paracetamol‐induced hypotension  medical records, the temperature and haemodynamic values recorded pre‐ and postpropacetamol administration in febrile adult recipients were reviewed. Significant BP reduction occurred 30–60 min after propacetamol administration. In 10.7% of the participants, haemodynamic alterations that necessitated intervention occurred, all of which required IVF and 49% required vasopressor support. These results confirm that propacetamol provokes BP reduction in febrile patients and must therefore be carefully considered against the risk of causing haemodynamic alterations, in agreement with other research which demonstrates that paracetamol administration may not always be beneficial in febrile patients  within 60 min of paracetamol administration. Of those 16 episodes, 69% required discretionary rescue intervention with vasopressor up‐titration or IVF resuscitation. The authors concluded that the manifestation of paracetamol‐induced hypotension may be related to the ameliorating effects of treating pain or fever and the adjustment of the sympathetic tone. Similarly as in previous research, the authors suggested that parenteral paracetamol‐induced hypotension may be underreported by pharmaceutical manufacturers (Kelly et al., Many researchers have used observational methods to validate the theory of paracetamol‐induced hypotension. Though inherently credible, these studies have been enhanced by the rigour of RCTs. Kelly et al.,  supporteTo stabilize the IV form of paracetamol, most of the commercially available preparations contain mannitol, which potentially has implications in haemodynamically vulnerable populations (Chiam, Weinberg et al., More recently, Nahum et al.,  performe4.4In a retrospective study of 100 medical records from the perioperative environment, criticism of the haemodynamic safety of rapidly infused parenteral paracetamol was challenged (Needleman, 55.1The prevalence of paracetamol‐induced BP reduction and the types of therapeutic intervention, if any, that was used to manage it has been summarized Table . The advVasopressor therapy is another strategy for managing hypotension in septic shock (Walker et al., 5.2There is evidence that febrile critically ill patients are at the greatest risk of developing paracetamol‐induced hypotension, though this association is only made possible by the continuous monitoring environments these patients inhabit. Extensive research has been carried out on paracetamol‐induced hypotension in the critical care environment, whilst the availability of research pertaining to general ward environments is limited Table .Patients can and do deteriorate outside of critical care environments (Peet et al., 5.3Taken together, the studies included in this review provide sound evidence that paracetamol can induce a prolonged episode of hypotension in febrile critically ill patients. This effect is perceivably more apparent in patient populations with less vasomotor control. Other significant epidemiological risk factors, which are consistent with this theory, include concurrent cardiac compromise and paediatric and elderly populations. The underlying aetiology and its extent are complex and can be influenced by pre‐existing conditions, age and the native influences of septic shock (Bae et al., Unpacking this knowledge demonstrates that a corrective intervention is frequently required to maintain haemodynamic stability after the occurrence of paracetamol‐induced hypotension. Despite reports of how paracetamol‐induced hypotension is retrospectively managed, few insights have been suggested for prevention. In patients with an intrinsic tendency to develop paracetamol‐induced hypotension (Bae et al., This evidence compels the arbitrators of safe governance to determine the appropriate hospital monitoring environment to detect paracetamol‐induced hypotension, which patients might receive paracetamol and the appropriate route of administration. The practice of close haemodynamic monitoring following paracetamol administration and correction of hypovolaemia prior to paracetamol administration should be of value to clinicians and should be widely applied in the hospital environment. This not only encourages practitioners to steward a safer and more rigorous monitoring strategy to detect paracetamol‐induced hypotension, but also surmises ways to prevent the condition.5.4The outcomes of this review need to be considered in light of its limitations. The review makes recommendations for changes in governance and clinical practice, though the author did not observe actual clinical practice or consult directly with particular jurisdictions and organizations with regard to their local drug guidelines. The findings of this research may underestimate the degree of paracetamol‐induced hypotension, because no studies were performed outside of closely monitored environments. This limitation prevents comparisons of haemodynamic responses to paracetamol in less frequently monitored clinical environments. Furthermore, the majority of studies reviewed the haemodynamic effects of parenteral paracetamol, which prevents drawing accurate comparisons with the enteral form. The studies reviewed have used variable methods of BP monitoring. Furthermore, critically ill patients demonstrate differences in vasomotor tone and receive capricious amounts of IVF, which may influence the patients’ BP responses in each study. Moreover, it is feasible to suspect that a natural illness progression may result in hypotension, even in the absence of the drug. Though this review included RCTs, the majority of the sample comprised observational studies, which rely on the frequency of documented observations that predispose to inter‐study variations. Some of the publications included in this review contained only a limited documented critical appraisal, and the review itself does not contain a documented comprehensive critical appraisal of each study reviewed.6This review has important implications for future nursing practice in that paracetamol‐induced hypotension is evidenced in research and is better detected in close monitoring environments, to ensure timely intervention. There is scope for future research around paracetamol‐induced hypotension, which could include its occurrence in the general ward environment and a survey of existing acute hospital guidelines. Notably, the concept of pre‐emptive intravascular filling as a moderator variable emerges as a hypothesis, which could be usefully explored in future research.7The results of this review present a plethora of evidence that suggests a relationship between paracetamol administration and hypotension. Commensurate with the aims, this paper canvased epidemiological concepts and revealed populations that demonstrated a greater association between these variables. Furthermore, there is currently minimal contradictory research available that accurately contends the hypotension–paracetamol relationship. Despite the evidence, there is no effective system to regulate paracetamol administration, and the drug continues to be marketed without significant haemodynamic risk warnings. Overall, this review has important clinical implications for future practice and calls for a long‐awaited change in the overarching governance of this drug to protect the public and to minimize harm. This not only protects those receiving the drug, but also those administering it.The author declares that there is no conflict of interest with respect to the research, authorship and/or publication of this review.This review did not require research ethics committee approval.


Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle‐associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first‐line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T‐cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future. Cancer immunotherapies are emerging as one of the main faces in the new era of cancer treatment and personalised medicine. The cancer immunotherapy pharmaceutical industry is now worth billions of dollars and much research is now focused on harnessing their huge potential in treating a wide range of diseases. In this review, we discuss the different types of cancer immunotherapies currently licensed and in development for the treatment of hepatocellular carcinoma, their drawbacks and limitations, and future innovations that are currently being researched in order to maximise their effectiveness for use in clinical practice. These iFor patients with advanced HCC, licensed systemic multi‐targeted kinase inhibitors, including Sorafenib and Lenvatinib, are sometimes poorly tolerated due to their well‐characterised side‐effect profiles and provide minimal benefits in overall survival.Cancer immunotherapy has revolutionised the treatment of solid malignancies. Immunotherapy aims to harness an individual's immune system to selectively target and kill tumour cells.2The use of ICIs in the treatment of various cancers has stimulated marked improvements in the treatment of solid malignancies.3Targeted therapies that selectively bind to and inhibit the activity of these co‐inhibitory receptors/ligands predominantly exist in the form of recombinant monoclonal antibodies. For example, Nivolumab  and Pembrolizumab  target and bind to PD‐1; Atezolizumab  targets and binds to PD‐L1; and Ipilimumab  targets and binds to CTLA‐4.4The liver naturally exists in a relatively immunosuppressed state which is heavily regulated by the immune system given its physiological role in processing foreign materials and first‐pass metabolism. This state of immunosuppression is hijacked and further exacerbated by HCC in order to promote immune evasion and tumour cell survival. Therefore, there exists a potential opportunity for ICIs to operate within this niche and reverse this process in the tumour, whilst maintaining immunosuppression in the background liver in order to avoid hepatic autoimmunity. Several clinical trials have previously been undertaken or are currently in progress exploring the impact of ICIs in treating HCC at different stages and with different underlying aetiologies, either as a monotherapy or in various combinations Table .42, 44.1p = 0.0752) (its primary endpoint), clinical benefits of Nivolumab, including mOS and ORR, were observed in all subgroups of patients including locally advanced and metastatic disease, underlying aetiologies  and regions (Asia vs. non‐Asia) compared to Sorafenib, together with an adequate adverse event profile.There have been several clinical trials investigating the use of ICIs as monotherapies in the first or second‐line setting (following failure of Sorafenib/Lenvatinib) for advanced HCC.4.2p = 0.0238), but did show clinical benefits in mOS, progression‐free survival (PFS) and ORR, particularly in the Asian subgroup of patients.Another PD‐1 inhibitor that has been widely studied for the treatment of advanced HCC is Pembrolizumab.4.3One of the most recent PD‐1 monoclonal antibodies that have been approved for regulatory use in China for the treatment of advanced HCC in patients who previously failed first‐line treatment is Camrelizumab.5One of the possibilities as to why both the CheckMate 459 and the KEYNOTE‐240 trials did not reach their clinically predefined primary outcome endpoints was due to the fact that both trials were unable to account for the regulatory approval of the use of other second‐line targeted therapies for the treatment of advanced HCC, including Regorafenib (a multi‐target tyrosine kinase inhibitor) which was licensed for use by the FDA in 2017, whilst both clinical trials were still ongoing.One of the more recent ways in which patients are potentially stratified based on predictive response to immunotherapy is through measuring expression of specific molecular biomarkers on tumour cells.6Immune checkpoint inhibitor monotherapy in the treatment of advanced HCC may be limited by multiple treatment‐resistance mechanisms.7p < 0.001).p = 0.0009).p < 0.001).To date, one of the most successful immunotherapy combinations developed to treat advanced HCC has been Atezolizumab (a PD‐L1 inhibitor) and Bevacizumab (a circulating VEGF inhibitor). The IMbrave150 trial (NCT03434379) was a global multicentre randomised phase III clinical trial that recruited 501 patients and compared OS and PFS (the co‐primary endpoints) of Atezolizumab and Bevacizumab against Sorafenib.8Combination monoclonal antibody therapies targeting some of the most commonly studied immune checkpoints are also currently the subject of interest in advanced clinical trials.9Whereas some clinical trials have sought to combine the use of novel immunotherapy agents, there are also several clinical trials that are combining the use of novel ICIs with previously established locoregional therapies used in the treatment of advanced HCC  is a multicentre, double‐blind, randomised phase III trial evaluating the safety and efficacy of Pembrolizumab and Lenvatinib against Lenvatinib as first‐line therapy for patients with advanced HCC, with OS and PFS being the primary endpoints.1111.1+ cytotoxic T‐lymphocytes, which are capable of direct antitumour effects.Another method in which an individual's immune system can be harnessed to selectively target and kill tumour cells is through ex‐vivo stimulation of T‐cells against TAAs.Early iterations of ACT therapies include TILs and T‐cell receptor (TCR)‐engineered T‐cells. These broadly comprise of endogenously or in vitro‐isolated T‐cells that target specific TAAs which are expanded in vitro before being transfused back into a host to generate a systemic immune response against tumour cells Figure .102, A more recent approach to ACT therapy involves engineering of chimeric antigen receptors (CARs), comprising of an extracellular single‐chain variable fragment that functions as the TAA‐recognition domain along with costimulatory molecules, a transmembrane domain and intracellular signalling domains, on T‐cells Figure .110, There are currently multiple ongoing phase I/II clinical trials examining the safety profile and tolerability of CAR T‐cells in HCC. They broadly target some of the most commonly expressed TAAs on HCC tumour cells including GPC‐3, AFP, and NY‐ESO‐1.One of the main issues surrounding CAR T‐cell therapies are the well‐characterised but serious adverse effects, including cytokine release syndrome and neurotoxicity, particularly when CAR T‐cells are delivered to individuals systemically.11.2The concept of developing a so‐called anti‐cancer vaccine that primes and stimulates the adaptive immune system to target and destroy tumour cells has existed for over 60 years and is a method that has gained particular interest and traction over the past 20 years. The first anti‐cancer vaccine—sipuleucel‐T/Provenge—secured regulatory approval by the FDA for the treatment of metastatic castration‐resistant prostate cancer in 2010.It has previously been demonstrated that the surrounding tumour microenvironment in HCC is highly immunosuppressive.www.hepavac.eu), a study looking to identify further novel TAAs specific to HCC. The HepaVac‐101 trial (NCT03203005), a phase I/II clinical trial is exploring the safety, tolerability and immunogenicity of an adjuvant therapeutic anti‐cancer vaccine targeting 16 recently identified novel peptides from resected HCCs (IMA970A) in combination with a novel co‐stimulatory agent (CV8102) in patients with early‐to‐intermediate‐stage HCC following the failure of standard treatment.Early‐phase clinical trials involving DC vaccines have shown them to be generally safe and well‐tolerated when targeting TAAs expressed on HCC tumour cells, both as a primary therapy and as an adjunctive therapy in combination with other established treatments, along with being associated with improved overall efficacy and survival outcomes.12Viruses are obligate intracellular pathogens that utilise unique proteins in their machinery to undertake viral replication in target host cells before escaping generally by cellular lysis (thereby inducing cell death) in order to continue their spread. These principles, in part, have led to the creation and evolution of oncolytic viruses (OVs), which broadly exert their antitumour effects through multiple mechanisms.The most commonly studied OVs for the potential treatment of HCC in both preclinical and clinical studies include adenovirus and vesicular stomatitis virus (VSV), both due to their ability to preferentially infect HCC tumour cells, along with herpes simplex virus, Edmonston strain of the measles virus, Newcastle disease virus, and vaccinia virus.Promotion of an immunogenic environment by OVs (as discussed above) also further lends itself to complementing the immunogenic activity of ICIs which has the potential to provide an increased and/or synergistic antitumour response.13Until recently, there were very few successes in the development of systemic therapies for advanced HCC. However, rapid advances in the field of cancer immunotherapy have allowed new targeted therapies to be developed. For a long period of time, aside from Sorafenib (and more recently Lenvatinib), there remained no other first‐line treatments licensed and available for the systemic treatment of advanced HCC. This was until the recent success of the IMbrave150 clinical trial which demonstrated a clinical benefit for Atezolizumab/Bevacizumab combination therapy. Other successes within this field include the licensing and regulatory approval by the FDA of both Pembrolizumab and Nivolumab/Ipilimumab combination as second‐line therapies for the treatment of advanced HCC. Multiple clinical trials in various stages are currently in the pipeline exploring the potential use of ICIs both as monotherapies and in combination with other established treatment modalities for the treatment of advanced HCC.Whilst ICI immunotherapy leads the field in the development of new systemic therapies for treating advanced HCC, other immunotherapeutic modalities are rapidly progressing, including CAR T‐cells, DC vaccines and OVs. Much of this work has been aided by a better knowledge and understanding of the commonly expressed TAAs on HCC tumour cells and of the interplay between tumour cells and their surrounding microenvironment. Technological advances have also led to the development of the next generation of monoclonal antibodies and CAR T‐cells, improved personalisation of DC vaccines, and better genetic engineering of OVs. These more sophisticated therapies are being clinically tested to enable more specific targeting of tumour cells, better control of downstream immune responses and a reduction in off‐target effects. Moreover, several clinical trials are currently underway exploring the role of immunotherapies in the neoadjuvant and adjuvant settings in patients with early‐ and intermediate‐stage HCC, in an effort to improve treatment outcomes and prevent tumour recurrence. Outcomes from future clinical trials should also aim to investigate a similar role for immunotherapies as downstaging therapy in advanced HCC in order to potentially widen access to other treatments used for early and immediate‐stage HCC in these individuals. Future research in this field should consider the potential risks of treatment hepatotoxicity at the start of the research pipeline. Finally, determining clinically useful biomarkers as surrogate measures of immunotherapy treatment response and prognosis in HCC remains the focus of many in vitro and in vivo studies.Justin K. H. Liu and Adel Samson were involved in the initial conception and design of the manuscript. All of the authors contributed towards drafting the manuscript and approved the final version.The authors declare no conflict of interest.Ethical approval was not required for this study.


Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 has spread explosively throughout the world and has since been declared a pandemic by the World Health Organization. Although it is recommended that upper gastrointestinal endoscopies either be postponed or canceled during the pandemic because of their high risk of aerosol generation, this does not apply in emergency cases, which may include patients with coronavirus disease. In this case report, we describe the safe undertaking of an emergency upper gastrointestinal endoscopy in a patient with suspected hemorrhagic shock who tested positive for the severe acute respiratory syndrome coronavirus 2 using the polymerase chain reaction. We performed the procedure in the contamination zone of a specialized coronavirus disease ward with prespecified zones. Full personal protective equipment was worn during the procedure, as recommended by various academic societies, and careful attention was paid to the sterilization of all equipment after the procedure. Thus, emergency endoscopies can be performed safely in patients with coronavirus disease in a suitable environment by using appropriate personal protective equipment and by handling the equipment appropriately. Coronavirus disease 2019 (COVID‐19), a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), and first verified in December 2019 in Wuhan, China, has quickly spread throughout the world,A 65‐year‐old man with diabetic nephropathy and on triweekly maintenance dialysis presented to our hospital with complaints of fever and cough. Oropharyngeal swabs collected on the same day tested positive by the reverse transcriptase‐polymerase chain reaction (RT‐PCR), while computed tomography of the chest revealed infiltrative shadows in the inferior lobe of the left lung Figure . COVID‐1Amid the COVID‐19 pandemic, upper gastrointestinal endoscopies in patients with COVID‐19 should be postponed or avoided whenever possible because of the risk of transmission to medical staff.In conclusion, emergency endoscopies can be safely performed on patients with COVID‐19 in a suitable environment by using appropriate PPE and with proper handling of equipment.All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.The authors declare that they have no conflict of interest.None.


Research shows that over summer break, students forget approximately 1 month of learning in math and reading; furthermore, some studies find that low‐income students lose ground relative to peers. Year‐round education (YRE) redistributes schooldays to shorten summer. Prior analyses pooled single‐track YRE  and multitrack YRE .Systematic search of 22 online databases in summer 2017 yielded 494 de‐duplicated results; 81 warranted full‐text examination. After applying selection criteria, nine studies met criteria but did not report data that allowed effect size calculation. Thirty studies constituted our analytic sample.Studies needed to be of K‐12 single‐track YRE , with no accompanying extended instructional time. Studies needed to be from 2001 to 2016, include outcome data, and include a comparison group.g, 58 reading g, 29 math odds ratio, and 27 reading odds ratio effect sizes.We extracted 55 math Students at single‐track YRE schools show modestly higher achievement in both math and reading—by a magnitude similar to estimates of summer learning loss—but comparable proficiency. Unexpectedly, the effect was no greater for historically disadvantaged students. Math effects may be larger in middle than elementary school, but the reason is unclear. Importantly, studies of schools that shortened summer to the fewest weeks showed the largest effects in both subjects. Achievement gains from single‐track YRE are similar in magnitude to the degree of summer learning loss documented in other studies. However, no difference was found in proficiency rates in either subject. Possible reasons for lack of effect on proficiency are discussed in the review.1.2Over the long summer break, students forget some of what they learned during the prior school year. For low‐income students, this “summer learning loss” may be especially large. One policy aimed at decreasing summer learning loss is YRE: redistributing the usual number of school days so that students have more short breaks during the school year, but a much shorter summer vacation. A specific design used to achieve this goal is single‐track YRE, which involves placing all students attending a given school on the same year‐round calendar. This review considers evidence on the effect of single‐track YRE on academic achievement—test scores and proficiency rates—of K‐12 students in math and reading from studies published between 2001 and 2016.This systematic review synthesizes the findings from 30 studies that compared the performance of students at schools using single‐track year‐round calendars to the performance of students at schools using a traditional calendar.1.2.1This review includes studies that compare achievement in single‐track year‐round schools to achievement in traditional‐calendar schools. Of a total of 39 studies on the topic, nine reported outcomes in a way that could not be combined with the 30 that this review focuses on. The studies were from 2001 to 2016 and were all of K‐12 schooling in the United States, but varied in school characteristics . None of the studies used an experimental design (random assignment); studies were about evenly split between (a) comparing one school to another that is very similar, (b) comparing one school to a nearby school, and (c) comparing students at a single school before versus after a switch to a year‐round calendar.1.31.3.1Average student achievement was higher in both reading and math at single‐track year‐round schools. Compared to a prior meta‐analysis of summer learning loss which found that students typically forget the equivalent of 1 month of learning over the summer, this review found the gain from YRE to be slightly more than this in reading and a slightly less in math. Proficiency rates were not higher in either subject; possible reasons for this are discussed in the review.1.3.2For the most part, no. Low‐income and minority students do not see greater benefit from YRE than average students in either reading or math. Elementary and middle school students show about the same gain in reading. However, we find that middle school students’ achievement in math increases more than elementary school students’ from the year‐round calendar. Because none of the included studies were experiments (and therefore factors other than duration of summer break may have been distributed non‐randomly), the certainty of these findings for smaller groups of students is lower.1.3.3Tentatively, yes: the schools that shortened summers to the fewest weeks had the largest effect on student achievement in both math and reading.1.4Single‐track YRE appears to have a benefit to student achievement that is equivalent in size to about a month of learning; this is similar in size to some ways of calculating the learning loss students experience over the traditional 10‐week summer break. In examining smaller subsets of data, which weakens the reliability of our analyses, the authors did not find YRE to be more helpful for low‐income or minority students than for the average student, but do find that YRE might have a larger effect for middle school students than elementary school students in math. Schools that shortened summer to the fewest weeks of vacation showed the greatest gain in student achievement, but the  design of the studies examined preclude us from interpreting this relationship as causal. This might indicate that schools could expect an improved student achievement gain equivalent to 1 month of learning from a year‐round calendar, with a larger improvement from shortening the summer break to 4–6 weeks in length than from shortening the summer break to 7–8 weeks.1.5The review authors searched for studies up to 2016, with electronic searches conducted in July and August 2017.22.12.1.1SDs in math and 0.11 in reading) during summer.Summer learning loss is a prominent concern in academic and public discussions of education. Summer learning loss refers to the fact that students forget material and show measurably decreased competency over the period from the end of one school year in the spring to the beginning of the following school year in the fall. Concerns focus on not only what students forget over summer vacation, but also on the instructional time that must be spent reviewing previously taught material at the beginning of each school year. Overall, summer learning loss is worse in math than in reading  students during summer months when they cannot access school resources  to distribute instructional time more evenly throughout the year while retaining the standard 180 instructional days. The National Association for Year‐Round Education (NAYRE) defines YRE by saying that it provides “more continuous learning by breaking up the long summer vacation into shorter, more frequent vacations throughout the year…The year‐round calendar is organized into instructional periods and vacation weeks that are more evenly balanced across 12 months than the traditional school calendar” (NAYRE). One common calendar example alternates 45 instructional days (9 weeks) with 10 days (2 weeks) of break; this allocation of time is called a 45‐10 calendar, and results in a summer vacation of around 6 weeks instead of 10 or more.exclusively to reallocating the 180 instructional days more evenly throughout the year.YRE is sometimes conflated with other calendar and instructional reforms, so it is important to delineate how it is distinct from seemingly similar policies. YRE is distinct from a reform that is typically called extended year, which consists of adding days to the standard American school year of 180 days. YRE also does not refer to after‐school programming, tutoring, summer school for remediation, other summer programming, or lengthening the number of instructional hours in each school day. It refers Two distinct forms of YRE are commonly used but for different reasons. Single‐track YRE, in which all students are on the same schedule, is commonly a policy response to summer learning loss and is intended to improve student learning and achievement. In multitrack YRE, students are on multiple different calendars  so that a share of students are on break at all times . Multitrack YRE is often a response to overcrowding as it increases the capacity of a school building without the cost of building new classrooms and other facilities. Because multitrack YRE is framed at addressing an issue other than summer learning loss, this review examines only the topic of single‐track YRE.Single‐track YRE calendars themselves can vary on two important axes. Single‐track YRE can be implemented in a variety of calendar structures—whether a calendar has 30 days of instruction followed by 5 of vacation , 45 days of instruction followed by 10 of vacation (45‐10), 45‐15, 60‐20, or another alternative—which could moderate the impact of the calendar type on student achievement. Single‐track YRE calendars can also differ in the duration of their summer vacation. Schools shorten their summer from the traditional 10 weeks to lengths ranging from 4 to 8 weeks; given the concern about summer learning loss, it would not be surprising for those lengths to moderate the effectiveness of single‐track YRE.Year‐round calendars have become more common across the United States in recent years. According to Skinner , from 202.3consecutive weeks for students to forget material, the degree of learning loss during the summer will be lessened, which in turn means that students will need less review after breaks and allow teachers to cover more material over the course of an academic year. The thinking of advocates is that the more‐frequent short breaks  are not long enough to engender learning loss in the same way that lengthy summer vacations do. This reveals an important assumption on the part of YRE advocates, which is that learning loss is a nonlinear function of the rate at which students forget what they have learned and time. If the relationship between time off school and learning loss are indeed linear, then YRE would not be able to counter summer learning loss because altering the calendar would not change the total amount of time that students spend in and out of school. Students would then forget a smaller amount during each break, but the total learning loss would still sum to the same annual total as on a traditional calendar. If, on the other hand, the relationship between time spent outside of school and learning loss is nonlinear, such that the degree of learning loss is minor over short periods of time but becomes more severe over longer periods, then altering the school calendar to create shorter breaks should decrease overall learning loss. If correct, distributing vacations and schooling more evenly throughout the year would allow for students’ year‐over‐year academic progress to increase with no additional days of teaching.The logic of YRE is fairly simple: by redistributing the school calendar to create shorter breaks in which there are fewer 2.4SDs depending on the exact model and analysis used. Kneese also stated that single‐track calendars appeared to have a larger effect than multitrack calendars. Cooper et al.  for only low‐income students and for only minority students?3.What is the relationship between characteristics of YRE  and the effect size estimate?Guided by prior research, this meta‐analysis examines single‐track YRE only. The main objective is to identify, across studies published in the post‐NCLB era, how single‐track YRE affects student achievement. Along with this, we investigate the effect of YRE on different subgroups of students. The summer learning loss literature shows that historically disadvantaged students fall further behind their advantaged peers over the summer. This disparity points to the possibility that the effect size of YRE, which derives in part from mitigating summer learning loss, may differ for subgroups of students. Third, given the assumption of YRE advocates that learning loss is a nonlinear function of time, we also examine the relationship between the effect single‐track YRE and the structure of the calendar implemented. We operationalize these objectives in the following research questions:44.14.1.1As is commonly the case in education research, we did not encounter any experimental studies. Much research in this area is simply mean achievement comparisons at schools with similar demographic characteristics. In order to avoid excessively restricting the size of our final sample, we included studies that use any approach to comparing academic achievement at traditional calendar schools versus single‐track year‐round schools  at the same school). Scholars disagree about the strength of cohort designs relative to matched designs  on a year‐round calendar. However, a subset of YRE evaluations use what we call 4.1.2Studies must be of K‐12 schooling (students). Both early childhood education and college have enough differences in policy and practice from K‐12 that a cross‐level merged effect would not be appropriate. The restriction to K‐12 schooling will allow for effect estimates to be for primary and secondary education, which are commonly grouped, without including studies examining modified school calendars in early childhood education, preschool, or college. Additionally, we consider studies of whole schools or of only regular‐education students (who are in some cases the only students for whom achievement data are available), but not any studies of special education students. We initially planned to separately estimate effects for U.S.‐only results and international results.4.1.3Year‐round calendars are not all the same. The most important distinction in type is whether a calendar is single‐ or multitrack. On a single‐track calendar, all students and teachers are on the same schedule (track). The school building either has all students present or none present on each day, and the building only has students in it for 180 days per year. Single‐track YRE is typically framed as an academic reform to improve student achievement. In contrast, multitrack YRE is typically implemented in response to overcrowding when there is no funding available for additional classroom space. On a multitrack calendar, some of the students  are on vacation at any given time, while the other students  are in school. The tracks rotate through their time in school and on vacation, which allows a school with capacity for 900 students to serve 1,200 students on a rotating basis.Multitrack calendars introduce disadvantages that are unique to having multiple tracks. Administrators and support staff need to serve all tracks, and may bear a heavier workload than on a traditional calendar  math achievement scores and (b) reading achievement scores, measured both by mean scores (including both mean scores and mean percentile scores) and by percent proficiency or other dichotomous outcomes.Supplementary analyses examine growth as an outcome (instead of only single‐year achievement scores). Growth scores are not consistently available in studies included in the final sample, so growth analyses are suggestive rather than comprehensive.4.1.6We consider only studies that examined outcomes while students were still attending the year‐round school. This restriction excluded only a single dissertation, which examined the high school achievement of students who had attended a year‐round elementary school.4.1.7We examine studies in which single‐track YRE was the only schedule‐based intervention. Studies cannot be evaluations of extended instructional time . It is not infrequent for schools or school districts to make multiple changes at once. However, it would not be possible to identify what share of a change in student performance was due to a year‐round calendar  and what share was due to additional days of instruction. We therefore only include studies of schools on year‐round calendars without extended instructional time or other simultaneous calendar reforms.4.24.2.1ERICPsycARTICLESPsycEXTRAPsychINFOProQuest Research LibraryProQuest Dissertations & Theses GlobalDissertations & Theses @ CIC InstitutionsEducation Administration AbstractsEducation Full TextSocial Sciences Citation IndexSociological AbstractsPolicyFileInternational Bibliography of the Social SciencesPeriodicals Index OnlineEconLitSociology DatabasePRISMASocial Services AbstractsPAIS InternationalGoogle ScholarGoogle Web of ScienceOur general/starting‐point search terms for this meta‐analysis include those used by Cooper et al. , augmentWe include a database search log in an online appendix to this review. This log contains, for each database that was searched, the terms, phrases, and Boolean operators that were used to identify relevant studies; fields that were searched; and restrictions or filters that were used. The log also includes comments on the search strategy used for each database to describe any database‐specific procedures that were used to identify studies. Finally, the log indicates the number of records that were retrieved from each database along with the number of full‐text studies that were downloaded from this pool. At all steps, our search process adhered to best practices in research synthesis as outlined by the Campbell Collaboration  to identify additional grey literature from pertinent websites. Those sites include the more than 50 (excluding higher education‐specific resources) listed in the Campbell information retrieval guide .Studies must include quantitative achievement data.Studies must include a comparison group.Studies must be of K‐12 schooling in the United StatesThe results from the initial search included a large number of works that were not actually studies warranting inclusion in this meta‐analysis. Four selection criteria, adapted from those used by Cooper et al. , were apFigure 4.3.2SD, and sample size (N) for the treatment and control groups, or N and percent proficient. When necessary, we extracted data from other analyses such as F tests and analysis of variance (ANOVA). When multiple estimates were provided instead of a single overall treatment/control estimate  we extracted the data for multiple effect size estimates from that study. In addition to full‐school statistics, where available, we extracted the data necessary for calculating effect sizes for subgroups of the full sample: for low‐SES students only (24 estimates from 10 studies) and for racial minorityWe extracted the student outcome data needed for calculating the effect size(s) from each study. In most cases this was mean score, To consider our second research question, we recorded two independent variables of interest: calendar structure and the duration of summer break. Single‐track YRE calendars can differ from each other on two important axes: calendar structure and the length of summer break. Single‐track YRE can be implemented in a variety of calendar structures—whether a calendar has 30 days of instruction followed by 5 of vacation , 45 days of instruction followed by 10 of vacation (45‐10), 45‐15, 60‐20, or another alternative—which could moderate the impact of the calendar type on student achievement. Unfortunately, calendar structure was inconsistently reported. Of studies in the final sample, only 12 (40%) reported a single calendar structure implemented in all treatment schools. Another six (21%) reported the combined performance of multiple schools following different calendar structures. Though 11 (38%) did not provide calendar structure information, we contacted authors and were able to add structure information for eight of them. Table Single‐track YRE calendars can also differ in the length of their summer vacation. Schools shorten their summer from the traditional 10 weeks to lengths ranging from 4 to 8 weeks. Given that single‐track YRE is predicated on diminishing summer learning loss, it would not be surprising for those lengths to moderate the effectiveness of single‐track YRE. The consistency with which studies reported the year’s longest break resembled that of calendar structure, with 14 (47%) reporting a break length and another 2 (7%) reporting the combined performance of multiple schools with breaks of different lengths. Again, we contacted authors and gained supplementary un‐published data from 4 (14% of) authors about the length of summer break, but for 10 studies (34%) no data were available. The studied schools with available summer length data show large variation in that length: one as short as 4 weeks, three at 5 weeks, six at 6 weeks, two at 7 weeks, and four at 8 weeks long.For each study, we recorded standard information on the study and report itself. This included the report author, year of publication or release, published/unpublished status, and the matching protocol used to identify the comparison school(s). For the treatment schools examined, this included the state in which the schools were located, years of student testing data included, and the type of score used for the outcome measurement. We also recorded sample/student characteristics associated with each estimate. For studies that separately reported the outcomes for multiple student groups, we recorded these data separately for each estimate within those studies. We coded the grade range of the students tested, a value for school type , the percent of treatment‐group students that were Hispanic or African‐American (subsequently referred to as “minority”), and the percent of treatment‐group students that were eligible for FRPL or otherwise were designated low‐income.4.3.3Examining the studies included in this meta‐analysis revealed two potential sources of bias in our results: publication bias and bias arising from the internal validity of included studies. While publication bias is a concern in any meta‐analysis, we argue that the risk of publication bias in this review is low because the majority of studies in the final sample are unpublished dissertations and reports. While this does not mean that publication bias can be definitively ruled out, we are confident that the present meta‐analysis includes all the relevant and available research on YRE from 2001 to 2016. However, bias stemming from identification strategy is of greater concern because the designs and/or analytical strategies employed by studies retained in this meta‐analysis may pose a threat to their internal validity. Reviewing the studies retained for this meta‐analysis, we observe three different strategies used for identifying comparison groups: geographic proximity, student cohorts, and using student and/or school characteristics to identify a comparison group. While there are strengths and weaknesses to each approach, the degree to which geographically selected comparison cases make for a valid counterfactual is unclear. On one hand, selecting proximate schools and/or districts for comparison could meaningfully account for a range of contextual factors. On the other, student characteristics and achievement may vary considerably over even small spatial differences which, if not accounted for in a study’s analytical strategy, may bias estimated effects, though it is difficult to determine the direction and magnitude of such bias.To investigate this issue, in the results, we conduct separate analyses of those studies that simply used geographic proximity to identify a comparison group, studies that used a cohort design to assess how a particular school’s (or how particular schools’) performance changed after conversion to a year‐round calendar, and studies that used a matching protocol. Comparing these results, we find that the estimated effect sizes are consistently positive, but that the magnitude of these effect sizes vary significantly based on identification strategy. Specifically, analyses restricted to studies that use geographic proximity obtain larger effect sizes and cohort designs produce more varied effect sizes than do matching protocols. As a result, the overall effect sizes we observe may be biased, though the direction of this bias is unclear.Formal tools for assessing bias in meta‐analysis were developed based on meta‐analyses of randomized controlled trials (RCTs) with, for example, differing approaches to randomization or single‐ versus double‐blind treatment assignment. For instance, the Cochrane Collaboration risk of bias tool  that are misaligned with observational studies of school‐level policy change  there is serious risk of bias. The schools and communities that decide to switch to YRE may have characteristics that interact with the effectiveness of the new calendar (as both are likely related to a community’s attitude toward education). This possible bias due to confounding is of greater concern than any other areas. Because the policy change occurred at the school level, individual students likely introduced little or no bias in the selection of participants into the study. Our selection criteria deliberately excluded studies with multiple intervention types, so our analyses have low risk of bias from the classification of interventions. Missing data and selective reporting are both discussed above. Because the same standardized tests were used in YRE and traditional calendar schools, (a) the studies in our final sample have relatively low risk of bias in outcome measurement, and (b) the bias introduced by standardized testing is common to education research.The Cochrane Collaboration Risk Of Bias In Non‐Randomized Studies—of Interventions (ROBINS‐I) is has partial applicability to studies examining outcomes before and after a universally applied (within schools) policy change  and is mostly unpublished dissertations.The final sample in reading was 58 4.3.5The final sample in this meta‐analysis included a small enough number of studies that it was straightforward to assess whether any covered the same state in the same years of testing. In such a case, the studies—for those that anonymized the results—could feasibly of the same students. Two studies, by Kellems and Oppel, are merged because they precisely duplicate the population: the same Indiana school system in the same year. Otherwise, <1% of records could feasibly be the same students.The structure of the data from our final sample complicated selecting a final model for estimating the average effect size for single‐track YRE. The effect sizes extracted from studies with multiple estimates were heterogeneous in their structure. Twelve studies reported one estimate, the remainder had more than one estimate, but not with a consistent hierarchical relationship. Several provided multiple grades of data for the same year, multiple years of data for the same grade, or reported multiple races for the same grade in multiple years. While those data structures do not create statistical dependencies in the estimates, three studies provided estimates following the same cohort of students (or multiple cohorts) for multiple years, which would have correlated errors among the repeated measures of the same students if all estimates were included in a weighted average. Common approaches to meta‐analytic calculations for studies with multiple effect size estimates were not appropriate for these data, but robust variance estimate (RVE) was.Several typical techniques for resolving within‐study dependence are not suitable to the single‐track YRE effect sizes. It is common to calculate a simple or weighted average of multiple effects size estimates from a study in order to produce a single estimate for that study  based on other studies in the analytic sample with the same outcome .Studies that did not report all data necessary to calculate an effect size were handled in one of three ways. First, authors were contacted in order to seek supplemental information to allow for standard calculations. For a subset of studies whose authors could not provide additional data, the 4.3.7τ2 and ω2. In RVE analysis using hierarchical weights, ω2 is a measure of variation in within‐study (within‐cluster) estimates of effect. τ2, instead, estimates variance between clusters, and is therefore more similar to the meta‐analytic measures of heterogeneity with which readers may be more familiar.We tested for heterogeneity among the effect size estimates provided by the studies in our final sample using both 4.3.8g estimate for continuous measures of achievement and once to produce an estimated odds ratio for dichotomous measures of proficiency.Hedges et al.  discuss 4.3.9The analytic sample for this synthesis included 30 studies. Three sets of analyses were conducted on their effect sizes. First, we conducted a main effect calculation, using RVE to calculate a cross‐study weighted average (correctly accounting for correlated errors) for continuous and dichotomous outcomes in reading and math. We then conducted analyses of this same structure restricted only to estimates for low‐income students and only to estimates for minority students, because the literature on summer learning loss might predict YRE to provide greater benefit to historically disadvantaged students. We also conducted analysis of this structure divided by grade span, to assess whether there appear to be differential effects in elementary and middle schools.Any difference in the effect of YRE for elementary‐aged children relative to middle school and high school may relate to differences in cognitive and memory development between elementary and middle school. Although much cognitive development occurs before school enrollment, memory function continues to develop during later childhood  is not large enough to meet the guidelines for having an independent variable (in addition to the main effect estimate) in the RVE meta‐regression  on two separate occasions  and calculated the effect size estimate and variance using each set of figures, achieving intrarater reliability over 0.96 and correcting all nonmatching estimates. After applying all restrictions, the resulting sample included 30 studies.5.1.2Table g effect size estimates are from the only two studies of schools that retained an 8‐week break for summer, rather than a shorter break . The 30 studies examined predominantly 45‐10 or 45‐15 calendars serving students in grades 3–5. Only three studies included grades earlier than three, and only three studies examined high school students.Both tables illustrate the weak reporting of calendar structure and summer length in primary studies of YRE. Descriptively, it is of interest that Table 5.1.3The descriptive features of the studies whose results could not be included in our meta‐analytic calculations are similar to those of the included studies. These nine studies are primarily of late elementary grades, conducted in a variety of states and with weak reporting of calendar structure and summer vacation length. Table 5.2g estimates that are more than twice as large as those in the full sample of studies, although proficiency estimates are marginally smaller. Cohort comparison analyses produce larger‐magnitude effect size estimates in reading, but an insignificantly negative g estimate (near zero) in math. The results for studies using matching look very like the estimates across all identification strategies: insignificant estimates for dichotomous outcomes (though with slightly larger point estimates than for the full sample of studies), +0.09 for math, and +0.11 for reading. These patterns indicate that identification strategies do differentially introduce bias into the estimates of YRE’s effect.For both dichotomous and continuous outcomes, Table 5.35.3.1g estimates are large relative to the estimated size of summer learning loss (estimated at 0.11 in reading and 0.16 in math), but counter to expectations, the estimate for reading  is larger than the estimate for math  for the full sample. Both estimates reveal minimal underlying heterogeneity, with τ2 values of 0.0055 in reading and 0 in math.For each study that included multiple estimates we used inverse‐variance weights to calculate a single effect size for each study to display in Table τ2 estimates variance between clusters and is therefore similar to the meta‐analytic measures of heterogeneity with which readers may be more familiar. The estimates for τ2 in RVE models of dichotomous outcomes are much larger than for Hedges’ g. This is not surprising, given how sensitive proficiency rates are to shifts in cut scores. For the mean difference analyses, estimates for τ2 are in general quite small: zero for four of the estimates in Table SD estimates—estimates of how stable or varied the true effect is—for each model  versus 0.06 , both with τ2 values of 0). This could be because elementary math skills like addition or multiplication may be more likely to be used during summer months than middle‐school math like algebra. In addition to estimates mostly smaller than for the full sample, the low‐SES and minority estimates show slightly elevated τ2 values, indicating the least precision and greatest heterogeneity of any set of effect sizes. Given that estimates for subgroups are based on a small sample, they should not be interpreted as conclusive; but they do suggest that the conceptualization of YRE as particularly effective for historically disadvantaged students may be an over‐simplification of a more nuanced situation.Given that summer learning loss is most evident among students from disadvantaged groups, the estimated effects for low‐income and minority students are unexpectedly about the same magnitude or smaller than for the full sample, and are not statistically significant. For low‐income students, we find an effect size of 0.06 in math  and 0.13 in reading . For minority students we find an effect size of 0.13 in math  and 0.10 in reading . That the estimated effect size is larger in math than in reading for the minority subsamples, and that it is larger than the full‐sample estimate, is more aligned with predictions. However, we hesitate to interpret too much based on this one of the four coefficients for historically disadvantaged students. In reading, the estimated effects in elementary grades  and middle grades  are very similar, with the This set of findings aligns with recent research adding nuance to our understanding of summer learning loss (which YRE is primarily intended to decrease). Individual works are neither systematic nor conclusive, but have shown larger losses in elementary than middle grades  associated with a lower estimated effect size, seeming to indicate that as summer is shorter, summer learning loss does indeed diminish. This finding, moreover, seems to align with the implicit theory of YRE advocates mentioned above, that the length of the longest break from school may determine the extent of learning loss, with forgetting having a nonlinear relationship to break length. If further analyses reinforce this understanding, that would emphasize the importance of reduced length of longest break as the critical mechanism for mitigating learning loss.Despite the incomplete reporting of calendar structure and summer length, we conducted preliminary analyses of how calendar characteristics relate to study estimates. Table Year‐over‐year growth is in several respects a better measure of policy effectiveness than achievement or proficiency. However, just seven of the studies in the final sample report a form of growth, so assessment of the relationship between YRE and growth must be considered tentative. Additionally, the studies have different growth‐related outcome variables—including school‐level change in percent proficient, cohort change in percent proficient, student‐level change in proficiency status, school‐level growth in mean score, student‐level growth in score, growth relative to predicted value—which makes producing an estimated average effect seem unwise. Instead, the individual study findings are summarized in Table 66.16.1.1Across analyses, single‐track YRE consistently shows no effect on dichotomous outcomes but shows a positive effect on average achievement in both reading and math. The estimates are relatively stable for elementary schools, middle schools, minority students, and low‐SES students, but vary slightly depending on calendar characteristics and studies’ identification strategies. These estimates for subgroups may be less precise because of the smaller number of studies included in each calculation, and other explanatory factors may not have been distributed randomly, as none of the primary studies employed an experimental design. Overall, though, the magnitude of achievement increase from single‐track YRE is comparable to the estimated magnitude of summer learning loss.6.2There are two important analyses that could not be completed in as rigorous a method as would be preferred with the data available because of extensive under‐reporting of calendar characteristics. The summer vacation of schools in the final sample for this meta‐analysis ranges from as short as 4 weeks to a high of 8 weeks, with vacations as long as 10 weeks appearing in other studies that were excluded in this analysis. Given that a premise of YRE is that the shortened summer break combats summer learning loss, a strong theoretical case can be made that shortening summer break to only 20 weekdays would be expected to have a different impact on students than a summer break shortened but still 40–50 weekdays long. However, less than half of the studies in the final sample reported the length of the summer vacation (and did not combine schools with multiple summer lengths to produce a single estimate of effect), which precluded formal analysis of whether a shorter summer is more beneficial than a longer summer within single‐track year‐round calendars.Similarly, only half of the studies indicated which calendar structure the year‐round schools being studied used . Again, a strong theoretical case can be made that the different calendar structures  would be expected to have a different impact on students and teachers. Perhaps students on a 60‐20 calendar need a few days of review after each 4‐week break, and so some instructional days are lost to review on that calendar structure. Perhaps, instead, students on a 30‐5 calendar have reduced attention because they get no lengthy breaks during the year and have a shorter summer than students on a traditional calendar. A 45‐10 calendar might combine the strengths or combine the weaknesses of the calendars with more‐ and less‐frequent breaks. Unfortunately, because so few studies clearly reported data on calendar structure and because those that did report structure almost exclusively followed two of the structures, we could conduct only a preliminary assessment of how calendar structure links with student achievement within year‐round schools.6.3The studies included in this meta‐analysis reflect diversity in geography, grade, and calendar characteristics. However, relatively few studies used advanced analyses or quasiexperimental design. Tittermary et al.  calculat6.46.4.1A small number of foreign‐language studies were examined, with the assistance of researchers fluent in the language of those studies. However, all searches were conducted in English. As a result, it is possible that studies of year‐round calendars in non‐English‐speaking nations were not retrieved. As a result, this review should be treated primarily as having implications for United States policymaking, secondarily for other nations with similar policies and culture , and less so for other nations, particularly those with starting school calendars that differ from the 180‐day calendar in the United States. Descriptively, one of just two math mean differences below −0.04 is from the only study of Guam, which perhaps emphasizes the potential importance of cultural and policy differences that link with geographic differences.a priori thought that YRE was likely to have a  positive effect, based on its theory of action and on the findings of prior meta‐analyses. We do not believe, though, that this in any way influenced our research synthesis process, studies that were included, estimates that were calculated, or any other facet of the work.The process of meta‐analysis uses extensive reasoning, not just objective assessment that produces homogenous conclusions  beyond that. It is possible for schools to provide supplementary instruction during the frequent vacation weeks, thereby providing extended‐year school only for students who are struggling—some YRE advocates are strongly in favor of such “intersession” instruction—but doing so increases costs and challenges. YRE as purely reallocation of 180 instructional days does include face administrative barriers, and does not introduce instructional time or resources.7.1.2SD (Hanushek & Rivkin, Given the relatively low cost of adopting single‐track YRE, this analysis supports increased adoption of single‐track YRE. YRE appears able to counter much of the measured drop from summer learning loss. Additionally, the estimated effect of YRE on student achievement we find in this meta‐analysis is similar to the estimated impact on student achievement that would be expected from increasing teacher quality by one 7.2Findings that single‐track YRE has a greater effect for middle school than for elementary school need to be considered very tentative based on the smaller sample of studies and weaker model used in the grade‐span analyses. However, they are new, as none of the final sample’s studies compared effects across grades, and Cooper et al.  only looContent: Dan FitzpatrickSystematic review methods: Dan FitzpatrickStatistical analysis: Dan FitzpatrickInformation retrieval: Dan Fitzpatrick & Jason BurnsWho is responsible for the below areas? Please list their names:The work reported here was supported in part by funding from the Campbell Collaboration and in part by funding from Michigan State University and the Education Policy Center at MSU. The opinions expressed here are those of the authors and do not represent the views of any other parties.We would also like to acknowledge assistance at various stages of this work from Spyros Konstantopoulos, Terri Pigott, Josh Polanin, Carlton Fong, Gary Ritter, and David Pickup.NoneI will remain responsible for updating this review every five years or will be available to help Campbell in identifying a new researcher to conduct the update.Supplementary informationClick here for additional data file.


Treatment of extensive‐stage (ES) small cell lung cancer (SCLC) is a challenge with poor local control and dismal overall survival. Although single extrathoracic metastasis was defined as M1b according to the eighth edition of the tumour–node–metastasis (TNM) classification of lung cancer, M1b includes involvement of a single intrathoracic nonregional lymph node (LN) such as pericardial, internal mammary or paravertebral LNs. Here, we report a successful treated case of a 50‐year‐old female with ES‐SCLC with right pericardial LN involvement, cT1cN3M1b (LYM). She initially received two cycles of induction chemotherapy consisting of cis‐Diamminedichloroplatinum/cisplatin (CDDP) and etoposide and achieved a very good partial response. She then received curative chemoradiotherapy with intensity‐modulated techniques (45 Gy in 30 fractions BID), followed by an additional cycle of chemotherapy. She is free of recurrence for more than 2.5 years. This is the first reported case of intrathoracic extensive‐stage small cell lung cancer, successfully treated with intensity‐modulated radiation therapy and concurrent chemotherapy. Small cell lung cancer (SCLC) is the most common and aggressive pulmonary neuroendocrine carcinoma, accounting for about 15% of all diagnosed lung cancer cases.Although patients with SCLC have been treated with systemic chemotherapy with or without radiation therapy (RT) and a significant minority of patients with SCLC are amenable to surgical resection, immune checkpoint inhibitors have been recently incorporated into the treatment for ES‐SCLC.Intensity‐modulated RT (IMRT) is an innovative radiation technique that optimizes the dose distribution in three dimensions (3D) by focusing radiation on tumour burdens from multiple directions with nonuniform dose intensity in the radiation field, thereby reducing the dose to normal tissues around the tumour and surrounding organs.The patient was a 50‐year‐old woman. She visited the Department of Otolaryngology at a local general hospital for a lump in the neck in February of a certain year. The biopsied specimen of the right cervical LN showed SCLC; positron emission tomography‐computed tomography (PET‐CT) revealed accumulation of the right middle lobe tumour and the bilateral supraclavicular, bilateral mediastinal and right pericardiac LNs with very small amount of right pleural effusion Figure ; and braThe seventh and the eighth editions of the TNM staging system are useful in the treatment of SCLC.Consolidative TRT is recommended for ES‐SCLC patients who had a complete or good response to chemotherapy.The number of metastases is a prognostic factor, and the majority of the long‐term survivors with ES‐SCLC had been reported to have either a single metastatic site or metastases limited to contralateral hemithorax and/or contralateral cervical or axillary nodes.For the first‐line treatment of ES‐SCLC, chemoimmunotherapy of platinum and etoposide combined with anti‐PD‐L1 antibodies including atezolizumab and durvalumab has been shown to improve survival and has become the standard of care.In SCLC, better local and systemic therapies are necessary to improve OS. We here present a case of a female ES‐SCLC patient with right pericardial LN involvement. To our knowledge, this is the first case report of intrathoracic ES‐SCLC, who is successfully treated with IMRT and concurrent chemotherapy. Continued advances in multimodal therapy are essential for the optimal clinical management of ES‐SCLC.None declared.All authors contributed to the patient's therapy and/or manuscript preparation. Waki Hosoda also participated in the histological diagnosis. All the authors have read the manuscript and have approved this submission.The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.


We read with interest the personal reflection of. Hans‐Gustaf Ljunggren from the Karolinska Institute (KI) about the path towards natural killer (NK) cell‐based cancer immunotherapy.Prof. Ljunggren was among the first to describe that NK cells preferentially kill targets with low or absent MHC class I molecules and postulated the existence of MHC class I‐specific inhibitory receptors (IR), which would refrain NK cells from killing normal surrounding cells (missing self‐hypothesis).The researchers from the KI started, among others, to look at mice genetically deficient in MHC class I molecules, such as beta‐2‐microglobulin (β2m) knockout (KO) animals. According to the missing self‐concept, NK cells were expected to kill autologous cells because they lack expression of self MHC class I molecules, but this is not the case at baseline. The NK cells from such animals are tolerant towards autologous targets and unable to perform missing self‐recognition in vitro and in vivo.An equivalent to TAP‐deficient mice was described in 1994 by de la Salle et alMoins‐Teissserenc et al (5) and Furukawa et al. (1) described additional TAP‐1 and TAP‐2 deficient patients,via the interaction of HLA class I molecules with specific NK cell IR, the latter being phenotypically and functionally normal in TAP deficiency.Moins‐Teisserenc et alWhat makes this paper truly interesting and important is the observation that some skin lesions were massively infiltrated with activated NK cells.In this context, it is interesting to note that tissue NK cells have become a hot topic in recent years, again partly under the leadership of the KI. It is generally admitted that NK cells in various organs and tissues might not only migrate from peripheral blood, but that different NK cell phenotypes and even lineages might be organ specific.Although only a bit more than 30 TAP‐deficient patients have been described, the clinical presentation and their NK cells appear quite heterogeneous, as illustrated by the discordant findings of our group and those of Furukawa et alIn addition to TAP deficiency, two cases of human β2 microglobulin deficiency were presented by Ardeniz et al.Overall, NK cells from human HLA class I‐deficient patients seem to behave as their mouse counterparts . In both species, NK cells must be educated by the interaction of IR with their cognate MHC class I ligands to become functional, and, in the absence of this interaction, the cells remain hypo‐responsive. Nevertheless, when they become stimulated in an infectious and inflammatory context, major auto‐aggressive phenomena may occur.A fundamental difference is that inbred mouse strains are genetically  homogeneous, which is not the case when analysing biologic material from different, unrelated human beings. This may explain, at least in part, the discrepancies between our studies and those of Furukawa et alThe authors declare that the present letter was written in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.All authors gave important intellectual input and feedback on the Letter and approved the final submitted version. Jacques Zimmer wrote the Letter.