Patient satisfaction after rhinoplasty is a growing area of research. The FACE-Q Rhinoplasty Module, used to assess these values, requires translation to national languages.Fourteen questions assessing the Satisfaction with Nose Scale and Adverse Effects Checklist of FACE-Q Rhinoplasty Module were translated to Norwegian with adherence to the Mapi Research Trust guidelines. Answers were processed by QuestBack anonymously. Of the 243 patients undergoing rhinoplasty at Oslo Plastic Surgery Clinic, 214 patients were reachable by e-mail.Response rates to the pre- and postoperative questionnaire were 23% and 32%, respectively. Responses for somewhat or very satisfied with the nose (pre- versus postoperative) were: overall size of the nose (16.3% versus 61.7%); how straight the nose looks (22.4% versus. 58.3%); how well the nose suits the face (12.2% versus 60%); length of the nose (20.4% versus 68.4%); width of the nose at the bottom (26.6% versus 55%); bridge of the nose (14.3% versus 55%); how the nose looks in photographs (10.2% versus 50%), and tip of the nose (16.3% versus 48.3%). Adverse effects (pre- versus postoperative) were moderate or extreme difficulty breathing through the nose (28.6% versus 35%); tenderness (6.1% versus 23.7%); skin of the nose looking thick or swollen (14.6% versus 30.5%); and unnatural bumps or hollows on the nose (55.1% versus 53.3%).Satisfaction levels in rhinoplasty patients are not as high as in other cosmetic surgery procedures, such as breast augmentation. However, compared with baseline, satisfaction levels showed great improvement postoperatively. The Rhinoplasty Module seems useful in evaluating outcome of rhinoplasty. We encourage application of this clinical outcome of rhinoplasty in and among centers. However, the nose is not just a facial beauty feature, but a critical sensory organ vital to one of the essential functions of life: breathing.2 Rhinoplasty is one of the most complex procedures in plastic surgery.5 It is also one of the earliest known surgeries performed to increase a patient’s quality of life (QoL) after a disease-or trauma-related deformity of the nose by restoring functional and aesthetic capacities.6 Despite a 2% decrease in the number of rhinoplasties performed, this procedure still remains one of the most popular cosmetic plastic surgeries. In 2017, more than 218,000 nose-reshaping operations were performed in the United States.7The nose is a distinctive facial feature of immense aesthetic importance to the identity of every human being.The ultimate goal of aesthetic rhinoplasty is to create a harmonious and natural-appearing nose that assimilates into the surrounding face with no visible sign of previous intervention and that allows a patient to breathe comfortably without restriction.8 Though the importance of these measures remains, evaluation of patient satisfaction and QoL are becoming increasingly relevant in cosmetic and reconstructive surgery.13 Comprehensive assessment of surgical outcome demands rigorously developed patient questionnaires that have sufficient reliability, validity, and responsiveness,8 as these would facilitate the comparison of techniques, the quantification of positive outcomes, and allow for identification of individuals that most likely benefit from the respective surgery.12 As implied by Pusic et al,8 data yielded from patient questionnaires that are not psychometrically tested (“ad hoc questionnaires”) may not be viable for making confident conclusions on the impact and effectiveness of plastic surgery due to lacking reliability and validity.Postoperative complications and mortality rates have traditionally served as mainstay in clinical outcome research.14, for which several questionnaires are used . However, information on structural validity and internal consistency are lacking for many of these instruments,18 and none includes a wide variety of questions to evaluate separate parts of the nose and how this feature reflects QoL before and after surgery.Many studies are performed to evaluate the effects of rhinoplasty on the patients’ life19 is an instrument designed to evaluate patient-reported outcomes (PRO) before and after undergoing rhinoplasty and to assess adverse effects regarding the nose. This module requires translation to national languages.20The FACE-Q rhinoplasty moduleThe present study was conducted to evaluate patient satisfaction with the outer appearance of the nose, its function, and changes. The first of our 2 main goals was to apply an internationally validated tool for rhinoplasty to evaluate the outcomes of the procedure. This article is a detailed guide for rhinosurgeons who want to validate the FACE-Q rhinoplasty module in their country, including the whole translation process: stages and nuances, validation process, and study methods. By using this tool in daily practice, surgeons are able to collect fully anonymous responses from patients and build solid evidence-based data regarding their methods, techniques, and strategies. The second goal was to measure QoL of patients in relation to rhinoplasty. Patients were given an opportunity to rate how their satisfaction with the nasal appearance has changed after surgery. Moreover, we believe that common adverse events of rhinoplasty are also an important aspect to be considered when discussing changes in QoL. The anonymous style of the evaluation ensured honesty and objectivity from the patients when answering the questions. In light of the fact that many publications reporting technical details often do not include satisfaction of PRO conducted anonymously, we hope this work will contribute new knowledge to the rhinoplasty field.A total of 243 patients who underwent rhinoplasty at the Oslo Plastic Surgery Clinic between 2007 and 2016 had a valid e-mail address and were contacted to enroll in the study. Patients who were followed up <1 year and those not reachable by e-mail were excluded from the study.The FACE-Q rhinoplasty module is a part of the FACE-Q scales and is owned by Memorial Sloan Kettering Cancer Center , which holds the copyright of the original and all translated versions of the questionnaire. It consists of 14 validated questions that were divided into 2 separate matrixes to measure PRO: Satisfaction with Nose (10 items) and Adverse Effects Regarding the Nose (4 items). (Table Satisfaction with Nose) concern patient satisfaction with the current appearance of the nose and the week before completing the questionnaire. For each question, patients were asked to rate their level of satisfaction/dissatisfaction on a scale of 1 to 4  (Table Adverse Effects Regarding the Nose) deals with problems patients might be experiencing the preceding week. Four answer options were provided  Phase 1 was the forward translation step for which 2 local professional translators, both American and Norwegian, with previous experience in English-Norwegian translation work, and a local project manager were recruited. In this step, each translator independently produced a forward translation (English to Norwegian), yielding forward versions A1 and A2. Based on the 2 forward translations, 1 pooled Norwegian version (forward version B) was created. Both translators and the local project manager were involved in this process, and no interpretation problems were experienced. Phase 2 was the backward translation step in which an independent translator interpreted and retranslated the pooled Norwegian version (forward version B) into the language of origin. The newly obtained English version was then compared with the source questionnaire by the “backward translator” and the local project manager. These matched perfectly and, therefore, no adaptations of the first Norwegian version were necessary (forward version C). Phase 3 was intended for validation of the Norwegian version and involved 8 patients who were native speakers of the target language, obtaining forward version D. After harmonization of the target language versions with each other and with the original by professional translators representing all the countries involved and final proofreading, the final version was obtained. A quality control step by the Mapi Research Trust was performed during all stages , was used to automatically process survey answers anonymously and return the results in form of diagrams and figures to the authors. The e-mail addresses of all patients were registered in the clinic records, enabling us to send the questionnaire via e-mail.This study did not require approval by an institutional review board because it was conducted anonymously. Patients gave their consent to use their answers anonymously.The authors followed the guiding principles from the Declaration of Helsinki.Of the total 243 patients  undergoing rhinoplasty at our clinic, 214 were reachable via e-mail. The mean age of patients was 28.5 years (range 17–68). Mean follow-up time was 4.6 years (range 1–12). The preoperative questionnaire was completed by 49 of 214 patients (response rate: 23%) and the postoperative questionnaire by 60 of 185 patients (response rate: 32%).Before the operation, few patients were “somewhat” or “very satisfied” with “the overall size of the nose” 16.3%); “how straight the nose looked” (22.4%); “how well the nose suited the face” (12.2%); “the length of the nose” (20.4%); “the width of the nose at the bottom” (from nostril to nostril) (26.6%); “how the bridge of the nose looked” (where eyeglasses sit) (14.3%); “how the tip of the nose looked” (16.3%); “the shape of the nose in profile” (side view) (8.2%); “how the nose looked in photographs” (10.2%); and “how the nose looked from every angle” (6.3%).  was particularly high in the outcomes measure “the shape of the nose in the profile/side view” (79.6%), followed by “how the nose looks in photographs” (75.5) and “how the tip of the nose looks” (69.4%). No patient was “very satisfied” with “how the nose looked from every angle.”Postoperatively, considerably more patients were “somewhat” or “very satisfied” with all Satisfaction with Nose items. Figs. –12 PostoTotal scale scores pre- and postrhinoplasty are provided in Figure Preoperative adverse effects regarding the nose were moderate or extreme “difficulty breathing through the nose” (28.6%), “tenderness such as when wearing sunglasses” (6.1%), “the skin of the nose looking thick or swollen” (14.6%), and “unnatural bumps or hollows on the nose” (55.1%).Adverse effects were generally rated more severe after undergoing surgery: moderate or extreme “difficulty breathing through the nose” (35%), “tenderness such as when wearing sunglasses” (23.7%), “the skin of the nose looking thick or swollen” (30.5%), and “unnatural bumps or hollows on the nose” (53.3%) Figs. –17. FeweTotal scale scores pre- and postrhinoplasty are provided in Figure 23 Exempt of interpretation by clinicians, these instruments provide insight into subjective perspectives of the patients in relation to satisfaction, QoL, and adverse effects after a procedure.24 PROMs enable patients to directly express their level of satisfaction and also aid physicians in the intricate process of clinical decision-making to improve outcomes.27 This is of particular interest in the field of rhinosurgery, in which understanding of the expectations and concerns of patients is especially important to accomplish satisfactory results.29In aesthetic outcome evaluation, the tide is turning from objective and physician-reported outcomes measures, such as comparison of pre- and postoperative photographs, toward patient-reported outcomes measures (PROMs).5 Quantification of PRO satisfaction would enable the surgeon to assess the success for each technique from a patient perspective and determine the technique with the best outcome.24Rhinoplasty undoubtedly represents one of the most difficult cosmetic surgeries.19 Ultimately, it is the patient who has to be happy with the result.30Evaluation of outcomes from the patient’s point of view is relevant to cosmetic surgery, given that many essential items such as appearance and function are evaluated best through self-assessment by the patient.By application of PROs in the clinical practice, physicians are obliged to be meticulous in patient consultation, that is, assessing patient expectations, considering their feasibility, and explaining the realistic results to patients. Furthermore, constant patient feedback about the satisfaction with the postoperative results and adverse effects following surgery allows surgeons to analyze strengths and weaknesses of their surgical approach and may contribute to technique advancement, for example, by efforts to reduce trauma.19 This tool is designed to specifically evaluate cosmetic and psychosocial aspects associated with rhinoplasty, and it has been suggested to be the most suitable instrument to evaluate aesthetic outcome.18The FACE-Q rhinoplasty Module is a rigorously developed PRO instrument to evaluate QoL and that complies with the requirements of international guidelines.31 To yield an appropriate Norwegian version of the FACE-Q rhinoplasty module, steps were followed strictly in accordance with international translation recommendations by Mapi Research Trust21 ,” “how well the nose suits the face,” and “how the nose looks in photos” showed the best discriminating power between rhinoplasty patients and the control group. In accordance, these items, together with “shape of the nose in profile (side view),” showed the highest rates of preoperative dissatisfaction in the patients of the current study. The authors concluded that these items might best reflect the general appearance of the nose, combining all dysmorphoses and problems in relation to the dorsal hump, a frequent prominent feature of the nose.29Radulesco et al19 demonstrated that “the skin of your nose looking thick or swollen” was the most commonly experienced adverse effect after rhinoplasty; more than half the patients were affected. This concurs with data from the current study: 23.7% of patients were affected mildly; 22%, moderately; and 8.5%, extremely by a thick/swollen appearance of the skin of the postoperative nose. This finding is hardly surprising, given that skin swelling is considered normal sequela after surgery.33Klassen et al19 slightly >40% of patients were bothered by postoperative tenderness  in the present study. Klassen et al19 revealed that this adverse effect was associated with time since surgery. More than 60% of the patients reported a little, moderate, or extreme difficulty breathing through the nose postoperatively. A possible explanation for this finding might be that transient edema is a normal effect after surgery that causes nasal airway obstruction over a certain period. Notably, the number of respondents who reported extreme difficulty breathing through the nose preoperatively decreased even slightly after surgery. This might be attributable to the fact that the underlying cause in these patients, such as septal deviation, was corrected through surgery.In keeping with previous findings,33We found it important to assess preexisting adverse effects to illustrate that many of the mentioned items had been present before patients underwent surgery. Some of the items assessed in the FACE-Q adverse events checklist stem from the same underlying cause. For example, difficulty breathing and swollen/thick skin might be caused collectively by postoperative edema. Patients tend to report the more frequent (often transient) adverse effects that are seen as inevitable sequelae of the operation rather than as severe complications.33 pointed out that many more possible complications after rhinoplasty, such as epistaxis, septal hematoma, infection, telangiectasia, and skin necrosis, are documented in the literature. However, many of these physician-reported effects are seldom and rarely experienced by the individual patient. It is conceivable that information about adverse events stemming from experience reports of other patients might be more relevant to the patient. This becomes evident from the abundant online communities that have blossomed in popularity over the past decade, in which members report their plastic surgery experience to others. Therefore, preoperative patient consultation should not only involve data from physician-reported adverse events but also from PRO, to deepen patient understanding of what to expect most realistically from the procedure.33Fleury et alFew studies in rhinoplasty follow-up with patients scientifically and anonymously. However, it is important for evaluation of different techniques and noting the levels of satisfaction among patients. This might enable rhinosurgeons to learn more about patient needs and expectations, thereby reducing complaints and complications.30 as individuals who have very low34 or higher/above normal scores are predicted to be less satisfied after surgery.29 Another strength of the current study lies in its anonymous design, which reduces bias and makes data more reliable. Patients do not feel coerced into stressing preoperative adverse events regarding the nose to warrant surgery.Assessment of preoperative values for satisfaction with the nasal appearance and preexisting adverse effects enables surgeons to identify patients who will potentially be less satisfied with the surgical outcome,Furthermore, all patients were operated on by the same surgeon (A.K.) in a single practice, allowing for good comparability between results. Last, the translation process was conducted with strict adherence to the international guidelines and therefore brings forth a ready tool to be used by other surgeons in Norway and can serve as guidelines for other colleagues.The following limitations were encountered in the study. The response rate of patients in the study was relatively low. Patients who are less satisfied with the outcome are potentially more willing to respond to the questionnaire to diminish scores and assure their grievance about the outcome.This might bias the results toward a poorer outcome.29Inherent in the retrospective design of the current study, most questionnaires (including those assessing the preoperative status) were completed postoperatively, whereas few were completed before the surgery. Ideally, the surveys are provided preoperatively and at consistent times postoperatively to provide the most reliable data. Operations were performed over a considerable period, which makes outcomes less comparable. Changes in satisfaction with the nasal appearance may fluctuate over time. A long time after surgery, respondents might rate the outcome less favorably than earlier in the postsurgical period, when the improvement to the preoperative state was more evident. Furthermore, the presence of adverse effects was assessed only at 1 specific time point which varied considerably among patients. Longer after the surgery, adverse effects might be less present than nearer the time of the operation. Evaluation of adverse events at multiple time points and synchronized between patients would thus be useful to reveal potential changes. Last, the Satisfaction with Nostrils questionnaire was not applied in the current study because this scale might not be suitable for all patients wishing to undergo rhinoplasty.The FACE-Q rhinoplasty module was translated into Norwegian by strict adherence to the translation method used by Mapi Research Trust and the results of its application in our daily practice are presented.Our findings indicate that the FACE-Q rhinoplasty module has great potential in measuring pre- and postoperative QoL in patients electing to undergo rhinoplasty. Provisional results of patient satisfaction levels after aesthetic rhinoplasty seem modest compared with the reported outcomes of other cosmetic procedures, such as breast implantation and augmentation mastopexy. This implies that preoperative counseling must allude to the relatively high percentage of patients who are not fully satisfied. Nevertheless, compared with baseline, substantial improvement in satisfaction could be noted.Additional data from rhinoplasty patients and the normal population in the form of multicenter studies will be necessary to further delineate the importance of this outcomes instrument and to conclude with greater certainty. Therefore, we encourage our colleagues from all over the world to conduct rhinoplasty studies based on PROMs.The authors thank Cathrine W. Knudsen, MD, PhD, for her contribution to the translation process.


Are shortened durations of adjuvant chemotherapy associated with decreased survival among patients with stage II and III colon cancer?In this systematic review and meta-analysis of 22 studies comprising 43 671 patients, shortened durations of adjuvant chemotherapy were not associated with worse survival in studies involving combination regimens (the current standard of care) among patients with stage III colon cancer. Conversely, the standard 6 months of chemotherapy was associated with improved survival among patients prescribed monotherapy.Shorter durations of adjuvant chemotherapy may not adversely alter survival among patients with stage III colon cancer treated with combination therapy; patients prescribed monotherapy should be encouraged to complete the entire 6 months of treatment. This systematic review and meta-analysis investigates the association between the duration of adjuvant chemotherapy and survival among individuals diagnosed as having stage II and III colon cancer. The results from the recent International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration have led some clinicians to adopt shorter durations of adjuvant chemotherapy for patients with stage III colon cancer. The extent to which these findings are supported by other data is unknown.To conduct a systematic review and meta-analysis of randomized and observational studies investigating the association between the duration of adjuvant chemotherapy and survival among individuals diagnosed as having stage II and III colon cancer (PROSPERO protocol CRD42018108711]).Abstracts published in English between 2003 and 2018 within the MEDLINE, Embase, CENTRAL, and CINAHL databases were reviewed by 2 authors. Also searched were conference proceedings and the indexes of high-impact oncology journals.Studies were excluded if they did not present original data; focused on animal populations, on cancers in sites other than the colon, or on patients with stage 0, I, or IV disease; did not examine a 5-flourouracil–based monotherapy or combination therapy; or did not evaluate the association between treatment duration and survival. The search identified 2341 articles, from which 2 randomized trials and 20 observational studies were included in the meta-analysis.This study followed the PRISMA and MOOSE reporting guidelines. The risk of bias was assessed by 2 authors using the Cochrane and Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tools. The results were synthesized using a random-effects model.The primary and secondary outcomes were overall survival and disease-free survival, respectively. It was hypothesized a priori that 3 months of chemotherapy would be as effective as 6 months of chemotherapy.Twenty-two studies were included in the meta-analysis, representing 43 671 patients. The inclusion of patients with stage II disease or with rectal cancer was identified as a source of heterogeneity. After restricting the analysis to patients with stage III colon cancer, there was no association between the duration of chemotherapy and overall survival among studies involving FOLFOX  or CAPOX  regimens . Among studies focused exclusively on monotherapy, the standard 6-month regimen relative to a 3-month regimen was associated with improved survival .Shortened durations of chemotherapy may reduce survival among patients with stage III colon cancer prescribed monotherapy but not a combination regimen. In addition, the results from this investigation are not generalizable to adjuvant monotherapies, which are still prescribed to patients unable to tolerate oxaliplatin. As such, the results from studies examining adjuvant monotherapies or overall survival and from investigations conducted within real-world settings may help to support the findings from the IDEA collaboration1 and strengthen recommendations within clinical practice guidelines.Identifying shorter durations of chemotherapy that minimize adverse effects while maintaining clinical efficacy could lead to improved patient outcomes and cost savings. To address this issue, a recent pooled analysis of 6 randomized trials sought to assess the noninferiority of 3 months of adjuvant FOLFOX  or CAPOX  chemotherapy relative to the 6-month standard among patients with stage III colon cancer.3 published in 2010 found that 9 to 12 months of adjuvant chemotherapy was not more effective than 3 to 6 months. That review article did not compare durations of chemotherapy that were less than 6 months, include patients treated with FOLFOX or CAPOX (the current standards of care among patients with stage III colon cancer),2 or synthesize the results from observational studies. A more recent review article4 examining adjuvant chemotherapy duration was conducted; however, that review article was not systematic and did not include a meta-analysis of the evidence base. To address these limitations, we performed a systematic review and meta-analysis of randomized and observational studies that have examined the association between the duration of adjuvant chemotherapy and overall or disease-free survival among patients with stage II and III colon cancer. We hypothesized a priori that 3 months of chemotherapy would be as effective as 6 months of chemotherapy.Existing review articles on this topic are limited. A meta-analysisCRD42018108711), the international prospective register of systematic reviews.5 The present study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)6 and the Meta-analysis of Observational Studies in Epidemiology (MOOSE)7 guidelines.We previously registered a protocol for this systematic review and meta-analysis with PROSPERO  monotherapy or combination therapy  and overall or disease-free survival among individuals diagnosed as having stage II or III colon cancer. Studies were excluded if they were a review article, commentary, editorial, protocol, case series, or case report; were conducted in a nonhuman  or laboratory  population; were focused exclusively on patients with cancers in sites other than the colon; were focused on early-stage (stage 0 or I) or metastatic (stage IV) tumors; failed to examine adjuvant chemotherapy duration or discontinuation; examined a therapy other than those previously described; or if a survival outcome was not reported.We systematically searched the MEDLINE, Embase, CENTRAL, and CINAHL databases using a query that was developed by one of us (D.J.B.) in collaboration with a research librarian. This query was previously registered with PROSPERO and is available in eAppendix 1 in the Annals of Oncology, JAMA Oncology, Journal of Clinical Oncology, Cancer, Journal of Oncology Practice, and Lancet Oncology.In addition to our database search, we scanned the references of the included articles, the conference proceedings of the American Society of Clinical Oncology, and the indexes of the following oncology journals: The assessment of eligibility was conducted independently by 2 of us (D.J.B. and C.A.C.). Titles and abstracts were first screened for relevance, and then a full-text screen was undertaken. At both stages, agreement between the 2 reviewers was assessed using the percentage agreement and κ statistics. Disagreements between the 2 were resolved through discussion. Non–English language articles with abstracts written in English that were deemed eligible for full-text review were translated and assessed for eligibility.Data extraction was carried out by the first author (D.J.B.). The results of this extraction were reviewed by another author (D.E.O.) for accuracy. We attempted to contact authors in cases where the hazard ratio (HR) and corresponding 95% CI were not reported or readily estimable using the available data. These emails were sent on December 6, 2018. Articles were not included in the quantitative synthesis if the authors were unable to provide an estimate suitable for meta-analysis or if the authors could not be reached.8 and the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool.9 The final decision regarding the risk of bias for each study was reached through discussion by the 2 authors. Regarding the ROBINS-I tool, we developed a list of confounders a priori that would be relevant to the studies included in this systematic review and meta-analysis. We separated confounders into the following 2 categories according to our certainty that their adjustment was necessary to produce an unbiased effect estimate: (1) important confounders—type of chemotherapy, age, sex, site (colon or rectum), and tumor stage; and (2) potential confounders—comorbidity, performance status, body mass index, tumor location, tumor grade, period of diagnosis, time from surgery to the initiation of chemotherapy, presence of postoperative complications, dose delays, and dose reductions. We did not identify any relevant cointerventions. With respect to bias arising from selection into the study, a low-risk designation was given if the index time was defined as the start of chemotherapy initiation and if the inclusion of participants was not potentially related to the exposure and outcome.The risk of bias was assessed independently by 2 of us (D.J.B. and D.E.O.) using the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials10 we estimated the change in the log HR per 3 additional months of chemotherapy as follows: β = [ln(HR) / (x1 − x0)]*3, where x1 and x0 refer to the median duration (in months) of the upper and lower categories, respectively. We similarly estimated the corresponding SE as follows: SE(β) = {(ln[upper 95% CI] – ln[lower 95% CI]) / ([x1 − x0]*3.92)}*3. When estimating the β coefficient and its SE, the multiplication by 3 was done so that they corresponded to the change in the log HR per 3 additional months of chemotherapy as opposed to the change in the log HR per 1 additional month of chemotherapy. Additional information regarding the derivation of effect estimates in situations where the HR and 95% CI were not directly reported can be found in eAppendix 2 in the To account for differences in the definitions of chemotherapy completion, we converted each measure of association to an estimate of the change in the log HR per 3 additional months of chemotherapy. We first estimated the median number of months of chemotherapy for each duration category using the middle value of the range of the category. In situations where the number of cycles was used to define categories of duration, clinical standards were used to determine the corresponding duration . As done in a previous systematic review and meta-analysis,11 The presence of publication bias was assessed via funnel plots and with the Begg test12 and the Egger test.13 We used the I2 statistic, the τ2 estimate, and a χ2 test to assess heterogeneity within this evidence base.14 To identify sources of heterogeneity, we conducted subgroup analyses by treatment-related variables (chemotherapy regimen and the middle period of diagnosis), patient characteristics , tumor features (percentage with colon cancer and percentage with stage III cancer), and study characteristics . Analyses were performed using the metafor package in R Studio (version 1.1.419).15 Statistical significance was defined at the .05 threshold, and all statistical tests were 2-sided.The primary and secondary outcomes of interest were overall survival and disease-free survival, respectively. To facilitate the pooling of the results from randomized and observational studies, we focused on per-protocol effect estimates. Given the expected between-study heterogeneity due to differences in patient populations, a random-effects DerSimonian-Laird model was used to estimate the average measure of association. In situations in which a study reported effect estimates for independent subgroups, the subgroups were treated as individual studies in the meta-analysis. In addition to 95% CIs, we also estimated the 95% prediction intervals. As previously discussed, prediction intervals should be reported when conducting random-effects meta-analysis because they provide a range of effect estimates that one would expect to observe in a clinical setting similar to those in the meta-analysis.23 and 25 observational studies48) were deemed eligible for inclusion. There was strong agreement between the 2 reviewers at both the initial screen and the full-text screen (percentage agreement >90% and κ > 0.6).A PRISMA flow diagram of the inclusion of studies is shown in eFigure 1 in the 1 and the studies by Chau et al17 and by Ito et al.20 Among these studies, per-protocol estimates were only available for the IDEA collaboration1 and for the study by Ito et al.20 The investigation by Chau et al17 did not examine different durations of the same treatment modality. Therefore, we were only able to include the results from the IDEA collaboration1 and from the study by Ito et al20 in the meta-analysis.Among the 9 randomized trials, only 3 investigated durations of chemotherapy shorter than the current 6-month standard, specifically the IDEA collaboration25 and by Yaich et al47 because we were unable to obtain an effect estimate suitable for inclusion in the meta-analysis and we were unable to reach these authors for further details regarding their findings. In addition, we excluded the studies by Satkunam et al40 and by Tashiro et al43 due to clinical heterogeneity in the exposure definition. Specifically, these researchers did not strictly examine the duration of the prescribed chemotherapy regimen; rather, they studied a composite exposure that included dose reductions and dose modifications, such as a periodic dose omission. Last, we excluded the study by Dobie et al28 because they explored cancer-specific mortality and did not report an estimate specific to overall survival or disease-free survival.Among the 25 observational studies identified by our search strategy, 5 were excluded from the meta-analysis. Specifically, we excluded the studies by Ahn et al48 representing 43 671 patients diagnosed between 1987 and 2015. Of these 22 studies, 19 examined overall survival, and 12 examined disease-free survival. Descriptive characteristics are listed in In total, 2 randomized trials and 20 observational studies were included in the meta-analysis,49 The risk of bias in the other domains was deemed to be low. Among the 20 observational studies included in the meta-analysis, 12 were judged to have a serious risk of bias due to confounding (n = 9) or selection into the study (n = 3). The remaining 8 studies were deemed to have a moderate risk of bias. None of the studies in this evidence base were judged to have a high or critical risk of bias.The results from the study quality assessment are listed in P = .37) or the Egger test . With respect to disease-free survival, there was a suggestion of possible publication bias arising from a lack of small studies with estimates centered around the null  . The results from the subgroup analysis are summarized in There was moderate to substantial heterogeneity within this evidence base for the primary outcome  or CAPOX (n = 1) and disease-free survival among patients with stage III colon cancer were imprecise but consistent with the subgroup analyses of the IDEA collaboration.2 of 3 to 6 months of adjuvant combination therapy, depending on the regimen and tumor substage, or 6 months of adjuvant monotherapy if the patient is not a suitable candidate for oxaliplatin therapy. When revising these guidelines to account for the recent findings from the IDEA collaboration,1 concerns were raised regarding the underestimation of the treatment effect arising from the use of disease-free survival as opposed to overall survival.2 Although disease-free survival has been shown to be a good surrogate end point for overall survival in this patient population,50 we found that the magnitude of the average measure of association tended to be larger when examining overall survival as opposed to disease-free survival, which provides some support for these concerns. This discrepancy may be larger if publication bias was present among the estimates of disease-free survival as suggested in our analyses. However, differences between studies with respect to the degree of bias and precision may also account for this discrepancy.These findings support recommendations made by the National Comprehensive Cancer Network1 focused on overall survival will help to address concerns regarding the reliance on disease-free survival. Ancillary per-protocol analyses of the IDEA collaboration1 that address nonadherence and censoring using modern statistical techniques, such as structural nested failure-time models and inverse probability of censoring weights, would also help to strengthen the evidence.49 Future observational studies from large real-world data sets could examine the association between chemotherapy duration and overall survival among strata defined within the subgroup analyses of the IDEA collaboration.1 Such granularity from well-conducted studies could further strengthen the evidence surrounding the targeting of adjuvant chemotherapies for patients with stage III colon cancer. Although adjuvant chemotherapy is offered to high-risk patients with stage II colon cancer,51 additional research regarding the optimal duration of adjuvant treatment within this patient population is needed.Additional research could further strengthen current clinical practice guidelines. Mature results from the IDEA collaboration45 in the evidence base explored 3 or more categories of chemotherapy duration. To facilitate further meta-analysis, the median duration, the number of events, and the total number of patients or person-years at risk within each exposure category should be reported.52 In addition, studies should attempt to minimize the risk of bias due to confounding by adjusting for a greater number of confounders. The identification of sets of confounders that could be controlled for in the analysis can be guided by a directed acyclic graph.54 Researchers should be aware that comparisons of different durations of chemotherapy in real-world settings may be limited by immortal time bias.55 Specifically, there will be a period of immortal time among the longer-duration group and thus a survival benefit if the start of follow-up is defined as the date of diagnosis, the date of surgery, or the date of chemotherapy initiation and the exposure is treated as time invariant. To address this issue, we recommend that the index time be defined as the date of chemotherapy initiation and that the duration of treatment be modeled as a time-varying covariate. Among the observational studies included in this evidence base, only 1 study36 modeled chemotherapy duration as a time-varying covariate. Some studies excluded patients lost to follow-up, which may have resulted in selection bias. These patients should be included in the analyses, and inverse probability of censoring weights could be used to address differential loss to follow-up.56 In addition, the number of patients censored and lost to follow-up should be reported so that risk of bias can be better assessed. This information was not available in several of the studies included in this systematic review and meta-analysis. When comparing durations of chemotherapy, differences regarding dose reductions, omissions, or delays should be explored within the analysis. We propose that such differences may be conceptualized as different versions of the treatment or as time-varying confounders.57Based on our review of the evidence to date, we propose a series of recommendations for improving the conduct of studies of adjuvant chemotherapy duration in real-world settings. Future studies could explore the duration of chemotherapy as an ordinal variable with 3 or more groups to allow for the exploration of a threshold effect. We had initially planned to conduct a nonlinear dose-response meta-analysis, but only 5 studiesThis investigation has limitations that should be recognized. First, the results of this meta-analysis are likely biased due to residual confounding. A large proportion of the observational studies included in the meta-analysis (45%) were judged to have a serious risk of bias because they did not adjust for 1 or more of the important confounders we identified a priori. Second, the absence of an association among the subset of studies examining overall survival may be due to a lack of statistical power arising from a limited sample size. Third, the results of our meta-analysis may not be generalizable to patients with stage II disease. Although identified as a source of heterogeneity, there were insufficient data to examine the association of interest among patients with stage II colon cancer. As such, our results should only be generalized to patients with stage III colon cancer.While additional research is needed, the evidence to date suggests that shortened durations of adjuvant chemotherapy may not negatively alter survival among patients with stage III colon cancer who are prescribed FOLFOX or CAPOX. Conversely, the standard 6 months of adjuvant chemotherapy is associated with improved survival among patients treated who are prescribed monotherapy.


Supplemental Digital Content is available in the text. Cerebral microbleeds are linked to cognitive decline, but it remains unclear how they impair neuronal function. Infarction is not typically observed near microbleeds, suggesting more subtle mechanisms, such as inflammation, may play a role. Because of their small size and largely asymptomatic nature, real-time detection and study of spontaneous cerebral microbleeds in humans and animal models are difficult.We used in vivo 2-photon microscopy through a chronic cranial window in adult mice to follow the inflammatory response after a cortical microhemorrhage of ≈100 µm diameter, induced by rupturing a targeted cortical arteriole with a laser.+ and CCR2+ macrophages, ultimately originating from the invasion of blood-borne monocytes, were also found near the lesion. We found a coordinated pattern of microglia migration and proliferation, where microglia within 200 µm of the microhemorrhage migrated toward the lesion over hours to days. In contrast, microglia proliferation was not observed until ≈40 hours after the lesion and occurred primarily in a shell-shaped region where the migration of microglia decreased their local density. These data suggest that local microglia density changes may trigger proliferation. Astrocytes activated in a similar region as microglia but delayed by a few days. By 2 weeks, this inflammatory response had largely resolved.The inflammatory response included the invasion of blood-borne leukocytes, the migration and proliferation of brain-resident microglia, and the activation of astrocytes. Nearly all inflammatory cells responding to the microhemorrhage were brain-resident microglia, but a small number of CX3CR1Although microhemorrhages are small in size, the brain responds to a single bleed with an inflammatory response that involves brain-resident and blood-derived cells, persists for weeks, and may impact the adjacent brain microenvironment. We found that microhemorrhages do not lead to nearby cell death or degeneration of dendritic arbors11 or to long-term loss of neural responsivity.12 We did observe an increase in the density of inflammatory cells near the lesion although the classes of cells involved and their origin was not determined.11 Consistent with this, the few postmortem studies of CMBs in the literature tend to report increased presence of inflammatory cells rather than significant tissue infarction.15 Here, we used a laser-induced microhemorrhage model and 2-photon excited fluorescence imaging to examine the inflammatory response after a microhemorrhage, identifying some of the cell types involved, their spatiotemporal dynamics, and the mechanisms leading to increased inflammatory cell density near the lesion.In recent work, we have used a laser-based approach to induce CMBs in the cortex of rodentsonline-only Data Supplement.The data that support the findings of this study are available from the corresponding author on reasonable request. All animal experiments were conducted in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals published by National Institutes of Health, and all animal procedures were approved by the Cornell University Institutional Animal Care and Use Committee (protocol numbers 2009-0043 and 2015-0029). Detailed Materials and Methods are provided in the 12 We irradiated the edge of the vessel lumen with short bursts of tightly-focused femtosecond laser pulses with sufficient energy to cause ionization of the material at the laser focus. When targeting ≈20 µm diameter penetrating arterioles, an ≈100 µm diameter CMB was reliably produced in the cortex12 , comparable to the size of the smaller bleeds found in postmortem human brain.16 This laser irradiation deposited relatively little total energy, so there was minimal collateral damage to surrounding tissue from the laser itself. The ruptured wall of the targeted vessel clotted within a few seconds and restricted the size of the hematoma.11 Blood flow in the targeted penetrating was not disrupted, so there is no ischemic injury in this model.10 This approach allows us to control the time and location of a CMB in the cortex, allowing the use of in vivo 2-photon excited fluorescence microscopy to follow the cellular response to the injury. We followed the invasion, migration, and proliferation of various classes of inflammatory cells at the lesion site over hours to weeks using 2-photon excited fluorescence imaging. We also quantified microglia proliferation and confirmed distance and time-dependent cell density changes after the lesion using histological approaches in animals that were euthanized at different time points after inducing a microhemorrhage. Finally, we developed phenomenological computational models of the microglia response to the microhemorrhage based on the migration and proliferation rates we observed.To study the inflammatory response to a brain microhemorrhage, we implanted a chronic, glass-covered cranial window over the cortex of adult mice. To distinguish the response of different classes of inflammatory cells to a CMB, we used transgenic fluorescent reporter mouse lines and bone marrow transplant chimeras to label different classes of inflammatory cells. After 3 weeks of recovery, we used a laser-based approach to rupture targeted penetrating arterioles, vessels that branch from the surface arteriole network and dive into the brain to feed capillary beds.18 Previous work has suggested there are 2 broad classes of these circulating monocytes, inflammatory monocytes, which express CCR2 and exhibit phagocytic, proteolytic, and inflammatory functions, and patrolling monocytes, which express CX3CR1 and tend to attenuate inflammation and participate in wound healing.19 In wild-type mice receiving bone marrow from Cx3cr1GFP/+ mice (Cx3cr1GFP/+→wild-type mice), primarily patrolling monocytes were labeled. We observed a small number of GFP (green fluorescent protein)–positive cells (CX3CR1+ Mo/MΦ) in the brain tissue near the microhemorrhage beginning a few days to weeks after the lesion , we observed the presence of a few labeled cells (CCR2+ Mo/MΦ) near the injury beginning 1 to 2 days after the lesion  are among the most numerous blood-borne immune cells infiltrating the brain lesion.21 and to respond to local injuries.22 Without an injury, we saw no significant change in microglia location over weeks (imaged in Cx3cr1GFP/+ mice) although the spatial pattern made by their processes changed significantly, consistent with surveillance behavior21 . However, in the presence of a microhemorrhage, microglia extended processes toward the microhemorrhage within minutes . In Cx3cr1GFP/+ mice receiving bone marrow transplant from wild-type mice (wild-type→Cx3cr1GFP/+), microglia were GFP labeled (as well as a reduced fraction of patrolling monocytes because of incomplete chimerism). The density of GFP-labeled cells within 100 µm of bleed increased for the first 2 days . We also observed proliferation of some microglia using time-lapse 2-photon excited fluorescence imaging at times 40 hours or later after the injury, as evidenced by the presence of 2 microglia at the location of a single, larger microglia from the previous time point . To quantify the role of proliferation in the microglia density increase, we used 5-ethynyl-2′-deoxyuridine labeling and immunohistology approaches . Interestingly, we found microglia proliferated predominantly in an ≈100 µm wide shell with an ≈175 µm radius that surrounded the targeted penetrating arteriole  and the proliferation probabilities that were assessed histologically  to determine whether we could account for the microglia density changes near the lesion. First, we used our experimental measurements to extract probability distributions for microglia migration distances  and microglia proliferation , validating this simulation approach . We found that the simulation predicted the observed spatial distribution of microglia proliferation using a 50% volume increase as the threshold value to trigger a proliferative event  is still debatable, this approach is widely used. After creating laser-induced microhemorrhages in y Figure A. Over ty Figure B. Consis9 However, in previous studies with the laser-induced microhemorrhage model used here, we found that these small bleeds cause neither the death of nearby neurons nor the degeneration of their dendritic arbors.11 We also found that although neurons near the injury initially lost their ability to respond to a stimulus, they recovered within hours.12 We did find that microhemorrhages led to a rapidly-initiated inflammatory response, as indicated by an increased density of CX3CR1+ cells in the vicinity of the lesion, that was sustained for weeks.11 In this work, we used a series of in vivo imaging and histological studies to follow the behavior of several different inflammatory cell types after the induction of ≈100 µm sized hemorrhages in healthy adult mice. The initial inflammatory response was dominated by brain-resident microglia, which exhibited a coordinated pattern of migration and proliferation that led to an increased density of microglia near the lesion over hours to days (primarily by migration from the surrounding tissue) while later recovering the density of microglia in the surrounding tissue (by proliferation). We also found reactive astrocytes over a similar spatial region as microglia but with the response delayed by a few days relative to microglia. The delayed astrocyte activation could be explained by the recent finding that activated, inflammatory microglia induce astrocyte activation by releasing cytokines.23 A small number of Mo/MΦ were also identified in the brain near the lesion, with CCR2+ Mo/MΦ found in the first couple of days, and CX3CR1+ Mo/MΦ found later, over days to weeks after the injury.The presence of CMBs is highly correlated with cognitive impairment and functional decline.25 However, in response to inflammatory stimuli, this healthy glial-mediated rewiring can be altered. For example, under ischemic stress microglia exhibited prolonged contact with synapses and were found to phagocytize synaptic components.25 Moreover, activation of microglia and astrocytes results in the secretion of cytotoxic factors, cytokines, chemokines, growth factors, and even neurotransmitters that tune inflammatory cell function, recruit additional leukocytes, and may also be neurotoxic and interfere with neuronal function.29 Infiltrated monocytes may also secrete factors that modulate learning and memory.29 Thus, activation and redistribution of inflammatory cells near a CMB, the phagocytic activity of these cells, and the signaling factors they secrete all likely affect the behavior of nearby neurons and other cells. The accumulation of such events may contribute to the cognitive effects associated with CMBs.There are several mechanisms by which the inflammation we observe after a microhemorrhage could impact neural function. In healthy brain, microglia and astrocytes play an active role in remodeling synaptic circuits.21 Through this surveillance, microglia detect subtle changes in the microenvironment and react to a broad variety of insults, sensed with an array of surface receptors, including purigenic22 and fractalkine30 receptors. Like other tissue-resident macrophages, microglia maintain their population locally by proliferative self-renewal,34 with sporadic proliferation under normal conditions and clonal expansion under prolonged and severe pathological conditions.34 Here, through a series of in vivo analyses, we describe the concerted spatiotemporal response of microglial migration and proliferation in a focal injury model. We observed proliferation of microglia predominantly in regions where the density of microglia declined because of migration of other microglia toward the lesion, suggesting that microglia may sense their local density and proliferate when the density decreases. It is not clear how microglia might sense such changes in density, but it has been reported that microglial processes repel one another when they make contact.21 Proliferation occurred primarily at a region and time relative to the CMB in which microglia had a ramified morphology, suggesting that it is the resting-state microglia, rather than the activated microglia responding to an injury, that tend to proliferate. This proliferation compensated for the decreased microglia density because of migration toward the injury. This coordinated pattern of migration and proliferation suggests a way that microglia may maintain their characteristic organization and cellular density in nonoverlapping domains after a nearby focal injury. Further work needs to be done to uncover the specific molecular mechanisms underlying this coordinated pattern of migration and proliferation in microglia, as well as to follow the fate of activated microglia after the injury.In the healthy brain, microglia are intercalated throughout the entire parenchyma and are arranged in nonoverlapping domains, which they surveil by extending and retracting processes.+ and CCR2+ Mo/MΦ after a microhemorrhage, but we studied the response of these cells in separate reporter mice, preventing us from elucidating the role of phenotype switching in Mo/MΦ cells. In a focal ischemic model, it has been reported that many CCR2+ Mo/MΦ that had invaded after the stroke later transdifferentiated to CX3CR1+ Mo/MΦ20. Our data align with these findings in that CCR2+ Mo/MΦ are the majority blood-derived cell type present early after injury, and CX3CR1+ Mo/MΦ are more dominant at later time points. It remains unclear, however, whether CCR2+ Mo/MΦ switched to CX3CR1+ Mo/MΦ or whether CX3CR1+ Mo/MΦ separately invaded. In addition, we cannot rule out the invasion of other blood-borne leukocytes although their numbers would likely be low given that the total number of labeled cells found in UBC-GFP→wild-type bone marrow transplant mice approximately matched the sum of cells found in CX3CR1GFP/+→wild-type bone marrow transplant mice and CCR2RFP/+ mice. In addition, endogenous brain cells other than microglia and astrocytes, such as oligodendrocytes and perivascular macrophages, could have also participated in the initiation and resolution of inflammatory responses caused by laser-induced microhemorrhages, all of which needs further work. Finally, our work was conducted in healthy adult animals, and the cascade of inflammatory response may differ considerably in older mice35 or in animals with comorbidities, such as cerebral amyloid angiopathy.36Our study elucidated the response of a subset of inflammatory cells after a femtosecond laser-induced microbleed, but our work leaves some aspects of the inflammatory response unresolved. We characterized the time course of the appearance of CX3CR111 nor loss of responsiveness to external stimuli,12 this prolonged inflammatory response could cause subtle modulation of normal brain function, and the accumulation of such events could underlie cognitive decline.Here in this work, a single event of bleeding from a penetrating arteriole induced an inflammatory response that spanned more than a week and was characterized by microglia and later astrocyte activation, as well as the presence of monocyte-derived tissue macrophages of different phenotypes. Although this small bleed does not cause direct neuronal degenerationConfocal images were acquired through the Cornell University Biotechnology Resource Center, with New York State Stem Cell Science (CO29155) and National Institutes of Health (S10OD018516) funding for the shared Zeiss LSM880 confocal/multiphoton microscope. We thank Sylvie Allen and Kevin Yager in the Cornell Center for Animal Resources and Education for assistance with the mouse irradiation for bone marrow transplants.This work was supported by the National Institutes of Health grants NS080098 (Dr Schaffer), NS081179 (Dr Anrather), and American Heart Association grant 16PRE27600010 (Dr Ahn).None.


The 28th December 1908 Messina earthquake (Mw 7.1), Italy, caused >80,000 deaths and transformed earthquake science by triggering the study of earthquake environmental effects worldwide, yet its source is still a matter of debate. To constrain the geometry and kinematics of the earthquake we use elastic half-space modelling on non-planar faults, constrained by the geology and geomorphology of the Messina Strait, to replicate levelling data from 1907–1909. The novelty of our approach is that we (a) recognise the similarity between the pattern of vertical motions and that of other normal faulting earthquakes, and (b) for the first time model the levelling data using the location and geometry of a well-known offshore capable fault. Our results indicate slip on the capable fault with a dip to the east of 70° and 5 m dip-slip at depth, with slip propagating to the surface on the sea bed. Our work emphasises that geological and geomorphological observations supporting maps of capable non-planar faults should not be ignored when attempting to identify the sources of major earthquakes. It was one of the first earthquakes in Europe in the instrumental period, transforming the study of seismicity by triggering interest in earthquake environmental effects (EEE) that we now know are crucial for understanding the geometry and kinematics of a seismic source3. The epicentre was located in the Messina Strait graben, consistent with mapped environmental effects, and deformed Quaternary and Holocene geology10 31  affected the area, including the cities of Messina and Reggio Calabria, with devastating MCS intensities up to XI36. Eleven historic seismograms are available, but the spatial distribution and azimuthal coverage limit the seismological information that can be derived38. Investigations on earthquake environmental effects (EEE) have been carried out3; these included searches for ground ruptures, ground shaking, liquefaction, coastal retreat, gas emissions, slope movements both on land and submarine, acoustic and light effects and hydrological anomalies; although many environmental effects were noted, no clear surface ruptures were identified.The 283. We note that it has been suggested that many of the levelling benchmarks were reached by the tsunami25, raising concerns that some may have been disturbed. For example, contemporary coastal slumping is reported in the port of Messina . Also, the mountains along the Sicilian coast were affected by landsliding40  the offshore Messina-Taormina Fault (MTF) that is suggested to be an active normal fault as it is thought to deform Late Quaternary marine terraces and Holocene coastal notches33. There is no field evidence of recent co-seismic displacement on the onshore fault scarp of the east-dipping “Messina Fault” . Therefore, we found that including dextral slip does not significantly improve our solution. It may be possible to improve our dip-slip model by using a more sophisticated slip-distribution , already considered to be an active normal fault18. We have identified a known east-dipping fault33 in an offshore location as the likely seismic source, with a 70° dip, and 5 m slip with slip reaching the surface on the sea bed. 21, the 2006 Mozambique Earthquake (Mw 7)44, the 2008 Dangxiong Earthquake in the southern Tibetan Plateau (Mw 6.3)45, the 2008 Nima Earthquake in Tibet (Mw 6.4)46 and the 2009 L’Aquila Earthquake in Italy (Mw 6.3)47. Indeed, it is arguably a simpler scientific scenario to propose known mapped capable faults as potential earthquake sources than proposing previously-unknown and unmapped seismogenic sources. In this case, it was simply a matter of re-plotting the data to show variation in vertical motions with distance across the strike of the mapped Quaternary active and capable faults that produced the new insight  projected onto an E-W line, quasi perpendicular to the ~NNE-SSW strike of the Quaternary normal faults around the Messina Straits. We chose an E-W transect because the Quaternary faults have curvilinear traces and we have no a priori knowledge of which one or which part of them ruptured. Thus, an E-W transect was chosen to study the simplest question of whether the fault dips generally to the east or west. Figure 52. For this reason, we have questioned whether benchmarks located on the Sicilian side could have been affected by secondary processes. Indeed, previous studies39 including work by ISPRA  show that the entire Sicilian side, where the highly-fractured and deformed Palaeozoic bedrock outcrops39, is affected by landslide processes of rock fall, and in places rotational/translational rock slides40. The footwall sites mentioned above are either affected by coastal slumps . Our work should re-invigorate the drive to link mapped capable faults with historical earthquakes rather than ignoring the valuable insights that the geology and geomorphology can bring.Re-examination of levelling data from 1907–1909 reveals that the Mw 7.1 1908 Messina earthquake ruptured a 70Supplementary InformationESM1ESM2 and 3


In low- and middle-income countries, the protective effect of breastfeeding against infections is well established, but in high-income countries, the effect could be weakened by higher hygienic conditions. We aimed to examine the association between breastfeeding and infections in the first 2 years of life, in a high-income country with relatively short breastfeeding duration. Among 10,349 young children from the nationwide Etude Longitudinale Française depuis l’Enfance (ELFE) birth cohort, breastfeeding and parent-reported hospitalizations, bronchiolitis and otitis events, and antibiotic use were prospectively collected up to 2 years. Never-breastfed infants were used as reference group. Any breastfeeding for <3 months was associated with higher risks of hospitalizations from gastrointestinal infections or fever. Predominant breastfeeding for <1 month was associated with higher risk of a single hospital admission while predominant breastfeeding for ≥3 months was associated with a lower risk of long duration (≥4 nights) of hospitalization. Ever breastfeeding was associated with lower risk of antibiotic use. This study confirmed the well-known associations between breastfeeding and hospitalizations but also highlighted a strong inverse association between breastfeeding and antibiotic use. Although we cannot infer causality from this observational study, this finding is worth highlighting in a context of rising concern regarding antibiotic resistance. In 2013, infectious diseases were in the four main categories of leading causes of death among children under 5 years of age worldwide [The World Health Organization (WHO) recommends exclusive breastfeeding for 6 months, or at least the first 4 months of life . These rMore precisely, recent literature has shown that breastfeeding is related to a reduced rate of hospital admission for diarrhea and respiratory infections as well as a protective effect on otitis media in children up to 2 years old ,5. Of noThe aim of this study was to assess the association between breastfeeding duration and several indicators of infectious morbidity, in France, a high-income country with the specificity of low breastfeeding initiation rate 69.7%) and median duration below the guidelines (17 weeks among breastfeeding mothers) ,9..7% and mThis analysis was based on data from the ELFE  study, a multidisciplinary nationwide birth cohort including 18,329 children born in 2011 in France . The incThe feeding method was prospectively collected up to 2 years and the calculation of breastfeeding duration was detailed in a previous paper . As prevFor each breastfeeding definition, infants were first categorized as ever or never breastfed and then according to their breastfeeding duration .In the present study, infections were assessed with several indicators: hospitalizations; frequency of bronchiolitis and otitis events; and antibiotic use.At the 1- and 2-year phone interviews, parents reported hospitalizations in the previous year . Infants with at least one hospitalization for infectious disease were identified . Hospitalizations from infectious diseases between birth and 2 years of age were characterized by the number of events  and cumulative duration .At the 1-year phone interview, parents both reported whether the child ever had a bronchiolitis event and if the child had had at least 3 bronchiolitis events since birth. At the 2-year phone interview, parents reported whether the child had had 3 bronchiolitis episodes or more since birth. A mixed variable was computed from both interviews resulting in a 3-category variable assessing bronchiolitis events in the first 2 years of life .At the 2-year phone interview, parents reported otitis events since birth . Unfortunately, it was not possible to distinguish infant with no otitis event from those having 1 or 2 events.At the 1- and 2-year phone interviews, parents reported the frequency of antibiotic use for their child in the previous 12 months. These frequencies were then combined into a 4-category variable .Maternal and household data were collected using face-to-face interviews at the maternity unit and then by phone interview at the 2-month follow-up. Because these data were more thoroughly assessed during the 2-month interview and only marginally changed during these 2 months, we used the data collected at 2 months in our analyses. Socio-demographic characteristics collected during the maternity stay were used only when the 2-month values were missing.Maternal socio-demographic characteristics included age at the birth of her first child , education level , place of birth , and employment status . Household characteristics included income per consumption unit  and composition .Maternal health-related characteristics included smoking status during pregnancy  and pre-pregnancy body mass index (BMI) .Infant’s birth order , caesarean-section delivery, sex, twin birth, and gestational age were collected at birth from medical records. Infant’s age at first attendance at a shared childcare facility was computed from the 1-year phone interview as a 5-category variable .n = 57) and not meeting eligibility criteria (n = 1) were excluded, resulting in 17,984 eligible infants. In twin pregnancies, one twin was randomly selected (n = 287 exclusions) to avoid family clusters.Infants whose parents withdrew consent during the first year (n = 4705). We then excluded infants with missing data on breastfeeding (n = 147) and those with missing data on infections or antibiotic use (n = 1894). We also excluded infants with incomplete information for potential confounding variables (n = 889). These exclusions lead to a sample of 10,349 infants for the complete case analysis regarding parental reports of infections and antibiotic use , and variables related to study design .As early hospitalizations may lead to early breastfeeding cessation, we repeated the main analyses after excluding infants with hospitalizations occurring before the age of 2 months, leading to a sample of 9703 infants.n = 10,349). Secondly, we used multiple imputations to deal with these missing data. This method assigned data to missing measurements based on the measurement of infants with similar profiles. We assumed that data were missing at random and generated five independent datasets with the fully conditional specification method , and then calculated pooled effect estimates (SAS MIANALYSE procedure). Further details are available in To deal with missing data for potential confounding factors, we first conducted our analyses on complete cases . Statistical significance was defined as The comparison between selected families and their non-selected ELFE counterparts is available in The sample’s characteristics according to any breastfeeding duration are described in Breastfeeding status considered as a binary variable (ever vs. never) was related neither to the number of events  nor to the cumulative duration of hospitalizations or infectious causes of hospitalizations, whatever the definition of breastfeeding used (any or predominant) .Compared to never-breastfed infants, infants who were predominantly breastfed for <1 month were at higher risk of being hospitalized once, which justifies our sensitivity analysis excluding early infections. The association remained consistent after the exclusion of infants with early hospitalizations (before the age of 2 months) .Compared to never-breastfed infants, infants who were predominantly breastfed for at least 3 months were at lower risk of long duration (≥4 nights) of hospitalizations. These associations remained consistent after the exclusion of infants with early hospitalizations (before the age of 2 months).Compared to never-breastfed infants, any breastfed for 1 to <3 months infants were at higher risk of hospitalization from fever and any breastfed for <1 month infants were at higher risk of hospitalization from gastrointestinal infections. The first association disappeared after the exclusion of early hospitalization, whereas the second one remained consistent.Overall, the number of bronchiolitis events was significantly related neither to ever breastfeeding nor to breastfeeding duration. However, ever any breastfeeding tended to be related to a higher risk of 1 or 2 bronchiolitis events but not to frequent bronchiolitis events. In contrast, predominant breastfeeding duration tended to be negatively related to the risk of frequent bronchiolitis events . These tBoth any and predominant breastfeeding were not related to frequent otitis events (at least 3 in the first 2 years) .Ever breastfeeding was related to a lower risk of frequent antibiotic use (at least 2 times in the first 2 years of life), whatever the definition of breastfeeding used .Compared to no breastfeeding, breastfeeding durations (any and predominant) of at least 3 months were associated with a lower risk of frequent antibiotic use.All these associations remained after the exclusion of infants with early hospitalizations .Compared to never-breastfed infants, predominantly breastfed for <1 month infants were no longer at higher risk of a single hospitalization event (OR (95% CI) = 1.17 ) . Any breCompared to never-breastfed infants, any breastfed for ≥6 months infants were at lower risk of longer hospitalizations (≥4 nights) ).Other previously highlighted results remained consistent .In the ELFE study, predominant breastfeeding for over 3 months was related to lower risk of at least 4 nights of hospitalization up to 2 years, while any breastfeeding for over 3 months was related to higher risk of 1 or 2 bronchiolitis events in the first 2 years of age. Finally, both any and predominant breastfeeding durations were negatively associated with frequency of antibiotic use.We first examined infectious morbidity through common infectious diseases such as bronchiolitis and otitis. Unfortunately, data on diarrhea occurrence were not collected. Contrary to a previous meta-analysis conducted in industrialized countries , a lowerInfections with higher concern can be approximated with hospitalizations. A recent meta-analysis highlighted a protective effect of breastfeeding against hospitalizations from diarrhea and respiratory infections, including lower respiratory tract infection and pneumonia . More reWe are unable to provide a biological explanation for the higher risk of 1 or 2 bronchiolitis events in the first 2 years of life related to any breastfeeding but not to predominant breastfeeding. An additional sensitivity analysis adjusting for family history of allergy  did not modify the results (data not shown). A similar unexpected association was found in an Italian case–control study, with a higher breastfeeding rate among infants hospitalized for bronchiolitis than among their control counterparts .Reverse causation bias is a probable hypothesis for the highlighted higher risk of parental reported hospital admission from infection or gastrointestinal infection related to short breastfeeding duration (<1 month) compared to never breastfeeding. As early adverse health events, including hospital admission, can lead to early breastfeeding cessation, the exclusion of early cases of hospitalization allowed us to control this reverse causation bias but not fully as not all adverse health events lead to hospitalization.Finally, in the present study, antibiotic use was considered as a proxy for bacterial infections. This indicator was strongly related to breastfeeding, a longer duration being related to a lower use of antibiotics up to 2 years of age. Similar results were found in a Czech cross-sectional survey, with lower risk of early exposure to antibiotics among breastfed infants . LikewisThe ELFE study is a recent nationwide birth cohort aimed at assessing the development of healthy-born children from birth to adulthood from a broad and interdisciplinary point of view. The prospective design limits recall bias for both exposure and outcomes assessment. However, we have to acknowledge the inability to consider exclusive breastfeeding in the present study according to the WHO definition, because the use of water, water-based drinks, and fruit juice in the 0–2-month period were not collected in the ELFE study. While the study may lack specificity when assessing particular outcomes , the strength of our approach is the use of complementary indicators of infectious morbidity, with the occurrence of common infectious diseases, hospitalizations, and antibiotic use. Hospitalizations could reflect the most severe cases and allowed for controlling bias due to parental reporting. It is interesting to note that breastfeeding was more related to the duration of hospitalization than to the number of events. When matching with the national health system database will be available, it would be of great interest to conduct similar analyses based on medical care use rather than parental report. The use of antibiotics would be more specific for bacterial infections, but it remains difficult to distinguish a lower need for antibiotics from the reluctance to such use. The very large sample and the collection of detailed socio-demographic or economic data ensure good statistical power and favor control for potential confounders. Exclusion rates due to missing data for these analyses were high, but multiple imputations did not change the results.Even in the context of a high-income country with short breastfeeding duration, we highlighted a lower risk of infectious morbidity related to breastfeeding duration, especially for duration of hospitalization and antibiotic use. The strong association highlighted for antibiotic use would be of great interest in the context of rising concerns regarding antibiotic resistance.


Long-distance runners are prone to injuries including Achilles tendinopathy and medial tibial stress syndrome. We have developed an Internet comprehensive self-report questionnaire examining the medical history, injury history, and running habits of adult recreational runners.The objective of the study was to evaluate two alternative forms of test-retest reliability of a comprehensive self-report Internet questionnaire retrospectively examining the medical history, injury history, and running habits among a sample of adult recreational runners. This will contribute to the broad aims of a wider study investigating genetics and running injury.Invitations to complete an Internet questionnaire were sent by email to a convenience pilot population (test group 1). Inclusion criteria required participants to be a recreational runner age 18 or over, who ran over 15 km per week on a consistent basis. The survey questions addressed regular running habits and any injuries  of the lower limbs that resulted in discontinuation of running for a period of 2 consecutive weeks or more, within the last 2 years. Questions also addressed general health, age, sex, height, weight, and ethnic background. Participants were then asked to repeat the survey using the Internet platform again after 10-14 days. Following analysis of test group 1, we soft-launched the survey to a larger population (test group 2), through a local running club of 900 members via email platform. The same inclusion criteria applied, however, participants were asked to complete a repeat of the survey by telephone interview after 7-10 days. Selected key questions, important to clarify inclusion or exclusion from the wider genetics study, were selected to evaluate test-retest reliability. Reliability was quantified using the kappa coefficient for categorical data.In response to the invitation, 28 participants accessed the survey from test group 1, 23 completed the Internet survey on the first occasion, and 20 completed the Internet retest within 10-21 days. Test-retest reliability scored moderate to almost perfect (kappa=.41 to .99) for 19/19 of the key questions analyzed. Following the invitation, 122 participants accessed the survey from test group 2, 101 completed the Internet survey on the first occasion, and 50 were randomly selected and contacted by email inviting them to repeat the survey by telephone interview. There were 33 participants that consented to the telephone interview and 30 completed the questionnaire within 7-10 days. Test-retest reliability scored moderate to almost perfect for 18/19 (kappa=.41 to .99) and slight for 1/19 of the key questions analyzed.We successfully developed a self-reported, retrospective questionnaire, delivered using Internet software, providing stable and reliable answers. We demonstrate that our survey provides a relatively quick, easy to complete, and cost effective method to collect epidemiological data from recreational runners and evaluate these participants for inclusion into a genetic study. P<.05). The most common injuries sustained by long-distance runners were found to be Achilles tendinopathy, iIliotibial friction syndrome, and medial tibial stress syndrome [Several systematic reviews have examined the incidence rates and risk factors of running related injuries -4. Such syndrome ,2,5-7.There are two types of injury that are commonly reported in association with running and exercise: bone stress injuries  and tendon injuries (including tendinopathy and tendon rupture) ,6. In thPublished genetic studies on exercise-induced injuries primarily focus on soft tissue injuries , and theSurveys should be evaluated for reliability, a critical measurement property for health-related and physical activity variables. Reliability refers to the consistency of answers obtained by the same participant when a measurement is repeated on different occasions . Test-reInternet survey instruments are increasingly being used as a preferred method of conveniently collecting data from a wide range of participants from various locations. The reliability of survey instruments delivered on the Internet has been previously demonstrated, showing that in the instance of retrospective tobacco exposure and risk, this method of data collection is reliable . FurnessThe purpose of the study reported here is to test the test-retest reliability of an Internet survey platform from a convenience population of first responders, and pilot test participants who accepted an invitation to describe their recreational running epidemiology. This will contribute to the broad aims of the wider study, which are to recruit thousands or even tens of thousands of individuals to investigate injury epidemiology across a wide group of recreational runners in order to gain insight into how a variety of demographic factors may influence injury epidemiology; and to perform genetic assessments for the injury risk factors in a small subsample of the overall injury epidemiology study.The questionnaire administered was designed to enable recruitment as part of the wider study entitled, “The Genetics of Exercise-Induced Injuries in Tendon and Bone.” This study has very broad aims in the range of wanting to recruit very large numbers of participants to provide injury epidemiology among recreational runners, as well as performing genetic assessments for the injury risk factors in a smaller subsample of the overall injury epidemiology study.The platform used to deliver the survey was the Internet and commercial survey software (SurveyGizmo). The Internet survey was advertised through appropriate forums relevant to the intended population to analyze sporting injuries and training practices. Participants provided us with data on their demographics and running injuries, but the survey provides a platform for determining whether a participant met the wider genetics study’s inclusion and exclusion criteria. Participation was entirely voluntary and required consent to participate in the research processes described by checking a required “I ACCEPT” box necessary to access the questionnaire. Further information about the project was made available via a check box diverting the participant to another screen with all relevant information and contact details for further clarification if required.On accepting conditions of participation in this project, participants were taken to the questionnaire and instructed that it would take no more than 30 minutes to complete. The software used allowed participants to exit the survey at any time and complete at a later date, allowing participants to provide their data at the time most suitable to them. A questionnaire was deemed complete when the participant had answered all required questions (customized within the software) and participants had submitted their questionnaire by checking the “SUBMIT” tab inserted at the end of the questionnaire.The questionnaire developed here combined new items of assessment with adapted versions of the SCOFF questionnaire for examining eating disorders . The fulIn addition, participants were asked to report on their general health, provide any knowledge of existing conditions or diseases, and any known antibiotic or prescribed drug administration. They were asked to describe their regular dietary practices including sport supplement use, as well as any body weight fluctuations. Participants were also asked to report their age, sex, height, weight, and ethnic background to collect demographic data for further epidemiology analysis.Some of the key variables, important to clarify inclusion or exclusion from the wider genetics study previously mentioned, were then selected for test-retest reliability here . QuestioInitial recruitment involved inviting a convenience sample of participants into a pilot group. Invitation to complete “The Genetics of Exercise-Induced Injuries in Tendon and Bone Study” survey was via email platform including an outline of the purpose of the study and providing potential participants with a link to the Internet survey. Participants were recruited from within our association or among associated colleagues. Inclusion criteria for participants included being a recreational runner aged 18 or over, who ran over 15 km/week on a consistent basis.In response to the invitation, 28 participants accessed and consented to the conditions of the study as logged by SurveyGizmo. Of these participants, 23 completed the first survey on the first occasion, and after 10-14 days were invited by email to repeat the survey for a second time, 20 completed within 10-21 days after the date of the first completion. This group was deemed test group 1 and were subjected to the Internet-Internet test-retest method.After data from test group 1 suggested that reliability was more than moderate for 19/19 of the variables analyzed, we then sought to maximize the variability in response and strength in reliability of our questionnaire by soft launching the survey to a wider population using a different test-retest method. We invited a larger convenience sample of participants by promoting the wider genetics study through a local running club of 900 members via email platform as described earlier for group 1. The same inclusion criteria were applied and participant information was provided at the commencement of the survey, and checking the box “I ACCEPT” resulted in access to the Internet survey and provided informed consent.In response to the invitation, 122 participants accessed and consented to the conditions of the study as logged by SurveyGizmo. Of these participants, 101 completed the first survey on the Internet on the first occasion. Of these participants, 50 were randomly selected and contacted by email platform inviting them to repeat the survey by telephone interview. In response to this invitation, 33 participants agreed to the repeat by telephone interview within 7-10 days of Internet completion and 30 answered the call within 14 days and completed the questionnaire on the second occasion. This group was deemed test group 2 and participants were subjected to the Internet-phone test-retest method.Descriptive statistics were used to describe the cohort characteristics of participants for each group, and reported as a percentage (%) of total participant number within the group illustrated. Some of the key variables important to clarify inclusion or exclusion from the wider genetics study previously mentioned were then selected for test-retest reliability and scored using the kappa statistic, with asymptotic standard error . ReliabiThis self-report questionnaire worked toward the development of a standardized instrument via which participants not only provide us with data on their demographics and running injuries, but also provide us with a platform for determining whether interested participants meet the wider genetics study’s inclusion criteria. This study analyzed the test-retest reliability of key inclusion/exclusion criteria for the wider genetics study, collected with the developed survey involving the 2 groups. The choice of different methods for test-retest analysis of each group is discussed in the “Methods” section. The results of both approaches scored using the kappa statistic, with asymptotic standard error, the valid number of responses, and number of response options, are highlighted here.There were 20 participants that fulfilled group 1 criteria by completing the survey on the Internet then again on the Internet within 21 days after the first completion. Participants were between 18-68 years of age, with an equal distribution of males  and females . As much as 45% (9/20) of participants recorded that they had been running for 6 years or less and the remaining 55% (11/20), 8 years or more. Their running habits were variable, with 50% (10/20) predominantly running 15-30 km/week, 25% (5/20) running 30-40 km/week, and 25% (5/20) running 40 km or more per week .There were 30 participants that fulfilled group 2 criteria by completing the survey on the Internet then again by phone interview within 14 days after Internet completion. Participants were between 18 and 67 years of age, with an almost equal distribution of males  and females . There were 40% (12/30) of participants that had been running for 6 years or less and the remaining 60% (18/30) 10 years or more. Their running habits were similar to test group 1 with 43% (13/30) predominantly running 15-30 km/week, 30% (9/30) 30-40 km/week, and 27% (8/30) 40 km or more per week .Reliability was almost perfect for the type of terrain run on (kappa=.863), injuries of the lower limbs reported in the last 2 years (kappa>.99), and the number of these lower limb injuries diagnosed in the same time frame (kappa>.99). Reliability was also almost perfect for the injury being diagnosed by a doctor (kappa=.820), the injury being a bone stress injury (kappa>.99), reporting any hip/knee/ankle surgery (kappa=.857), and the use of orthotics while running (kappa>.99). Reliability was substantial for the number of years running on a regular basis (kappa=.791), average kilometer run per week (kappa=.684), other sports or intentional exercise participated in regularly in the last 2 years (kappa=.773), and reporting the injury as an Achilles tendon injury (kappa=.625). Reliability was moderate for being diagnosed by a physiotherapist , any knowledge of being treated with calcium tablets (kappa=.886), any knowledge of being treated with vitamin D supplementation (kappa>.99), reporting on whether participants followed a gluten-free diet (kappa>.99), or stating any food allergies or avoidances (kappa>.99). Reliability for any knowledge of being treated with corticosteroid medication (kappa=.492) or quinolone (kappa=.468) was moderate .The reliability of running habit and running injury key variables in test group 1 was more variable than that of test group 1 . ReliabiOverall, reliability was lower for general health questions reported in test group 2 in comparison to test group 1 . ReliabiThe wider study, for which this survey will provide epidemiology information and a participant cohort to recruit from, will be the first, to our knowledge, to examine the genetic predisposition of tendon and bone injury in adult recreational runners. Recruitment for the larger study will involve the use of this survey, tested here initially for test-retest reliability. The results indicate that the self-reported questionnaire, delivered using the Internet commercial software, provided stable and reliable answers for many of the most important measures required for recruiting to the larger study on tendon and bone injury.The Internet delivery of a retrospective injury study is a convenient method for remote collection of data from participants and has been used successfully in the analysis of sports-induced injuries in surfing  and stroPoor reliability of the question addressing treatment with quinolone may suggest poor understanding of or unfamiliarity with “quinolone” upon first exposure to the question. It is known that test-retest reliability can be influenced by many factors. Interpretation of a question, such as familiarity of content or ambiguity, as well as memory can cause random answers . QuestioRespondent fatigue is a well-known phenomenon affecting survey participants . We deveResults when addressing the 2 different test groups should be considered in the context of several limitations. Our study contained a different number of participants in each group with a variable distribution of age. This limitation resulted from the sequential manner of recruitment of the two groups, inviting participation from within our networks for test group 1, then soft launching to recruit a larger group from the running club for test group 2.There was a slightly higher test-retest reliability for test group 1, in which the survey was repeated using the same Internet platform. It is possible that this was due to learning effects, or that the retest was administered in exactly the same format.The slightly lower test-retest reliability for group 2, in which the survey was administered by the Internet platform and then followed up by a telephone call, may be related to the wording of the question over the telephone by the interviewer compared to the participants reading the computer screen. During the telephone assessment, it is also possible that participants felt more uncomfortable answering sensitive questions or got confused in regards to what constitutes a response for each question asked. Our findings indicate that using 2 test-retest protocols resulted in participants providing the same information with high reliability for the survey administered in this study. Maintaining consistency of the protocol, however, can improve test-retest reliability.We successfully developed an Internet survey to meet the recruitment needs of the larger genetic injury study. We tested its reliability using 2 different test-retest methods and used a participant sample targeted to our needs  in aid of focusing our findings to support our larger study. We had equal gender participation and a broad range of running habits and participants with reportable Achilles and bone stress injuries. Despite the aforementioned limitations, the results of this reliability study demonstrate that the Internet survey developed does provide a relatively quick, easy to complete, and cost-effective method to collect epidemiological data from recreational runners and evaluate these participants for inclusion into a genetic study.