The global epidemic of type 2 diabetes (T2D) and obesity has been translated into pregnancy, with approximately 18% of women being diagnosed worldwide with Gestational Diabetes Mellitus (GDM). Whilst preventive strategies have proven effective in the non-pregnant context, attrition rates are high and there is an urgent need to develop a customized, pragmatic lifestyle intervention for women both during and after pregnancy. Diet and exercise modification, behavioral support, and Commercial Weight Management Organizations have been strongly recommended to aid postpartum weight reduction for mothers with previous GDM, subsequently reducing their risk of developing obesity and T2D. This study, informed by a previous pilot study, aims to determine the effectiveness of a pragmatic pregnancy and postpartum lifestyle modification program for overweight women with previous GDM (PAIGE2) to reduce body weight at 12 months postpartum.2 recruited during pregnancy. The lifestyle intervention involves a one-hour virtual educational program (to take place at 32-36 weeks gestation). Postpartum, the intervention will include monthly phone calls, weekly motivational text messages, weekly step counts, and referral for three months to a Commercial Weight Management Organization (Slimming World). The control arm will receive usual care as offered by the local maternity hospital. The primary outcome is weight loss at 12 months postpartum. Study visits for anthropometric and clinical measurements, fasting blood samples, questionnaires pertaining to health, wellbeing and physical activity will take place at 6 weeks, 6- and 12-months postpartum. Focus groups will be conducted with intervention mothers’ post-intervention to determine the acceptability of the study design including utility of a Commercial Weight Management Organization, feasibility of remote patient contact, family involvement and patient satisfaction.This paper summarizes the protocol for the PAIGE2 study, which has been developed based on results from a pilot study (PAIGE). A six center, two parallel arm, 12-month, randomized controlled trial will be conducted across Northern Ireland and the Republic of Ireland (3 centers each), involving 340 women with GDM and body mass index ≥25 kg/mThe PAIGE2 study will address the gaps in previously conducted research and, if positive, has the potential to have major public health implications for the prevention of future GDM and subsequent T2D.https://clinicaltrials.gov/ct2/show/NCT04579016?term=NCT04579016&draw=2&rank=1, identifier NCT04579016. Women wIn addition to the maternal health implications of GDM and obesity, babies born to mothers with GDM display increased rates of macrosomia, congenital malformations, admission to intensive care and fetal death , 9. In tLifestyle modification can inhibit or impede the development of T2D in high risk non-pregnant persons , wherebyIn the Diabetes Prevention Program (DPP) 10-year follow up, it was reported that although women with a history of GDM experienced less weight loss compared with the general DPP population, they experienced a 35% decrease in T2D development as a result of an intensive lifestyle intervention . HoweverThere is increasing evidence that step count-based programs are successful in instigating increased ambulatory activity both among the general public and those with T2D for up to 6 months . On the 2) or losing 5% of pre-gravid weight (if BMI ≥ 25.0 kg/m2). Overall, “significantly more women in the intervention group met the weight loss goal and displayed larger increases in physical activity levels compared with the usual care group”  has been operating in collaboration with Primary Care Trusts and National Health Service (NHS) Trusts, proposing a subsidized plan to provide free membership for 12 weeks to patients referred by their health care professionals. This project, involving 34,271 patients, was recently audited, and showed an average percentage weight change of -4.0% with a mean number of sessions attended of 8.9. For patients attending at least 10-12 sessions , the mean percentage weight change was -5.5%. Weight gain was reduced in 92.1% of referred patients. The report concluded that referral to a CWMO is a feasible alternative for NHS weight management strategies, which accomplishes clinically effective weight loss . Slimminvs 0.7 kg respectively; p=0.02) supporting its clinical utility. A larger, definitive trial was recommended to confirm the validity of the intervention. Importantly, the intervention would seek to investigate whether a lifestyle change program for overweight and obese women with previous GDM (delivered in combination with Slimming World and the NHS), could be effective in achieving weight loss, and in the longer term, potentially a reduction in the risk of T2D.After consideration of the collated evidence and recommendations from governing bodies, a pragmatic pilot multicomponent randomized postpartum lifestyle modification program for overweight women with previous GDM (PAIGE) in combination with the CWMO Slimming World and the NHS was conducted between 2013-2014 . The res2The objective of this study is to investigate the impact of a pragmatic lifestyle intervention during, and post pregnancy compared with routine care, on weight reduction at 12 months postnatal in overweight women with previous GDM (PAIGE2). The primary outcome will be the percentage maternal weight loss over a 12-month period. Secondary outcomes will include maternal glucose tolerance, anthropometry, number of steps per day, and several questionnaires detailing physical activity and health and wellbeing, to assess clinical, anthropometric and lifestyle- related health and well-being measures. This protocol follows the reporting guidelines of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist and World Health Organization Trial Registration Data Set (33.13.1.1The study has been designed and developed based on results of a recently completed pilot RCT (PAIGE) . The stuThe PAIGE2 research proposal has been reviewed by women with GDM during a recent pregnancy prior to submission thus ensuring that researchers complete the circle of patient involvement in the proposal. In addition, service users and the public will be closely involved in the study and women with a history of GDM will be invited to sit on the Project Board. The involvement of users within the research process will be an important guide to local researchers in finalizing wording for patient information sheets, local recruitment strategies and in relation to supporting women while on the intervention.3.1.2A six center, two parallel arm, randomized controlled trial, with an equal allocation ratio of intervention to control group participants will be conducted. The six centers will include antenatal-metabolic clinics at the Royal Jubilee Maternity Service, Belfast; Ulster Hospital, Dundonald; Antrim Area Hospital; Our Lady of Lourdes Hospital, Drogheda; Sligo University Hospital and Letterkenny University Hospital.3.1.32, recently diagnosed with GDM using IADPSG criteria , they will be randomized either to the lifestyle intervention or to usual care.Before their routine 32–36-week gestation antenatal diabetes clinic appointment, women will be contacted by a member of the PAIGE2 research team Informed consent will take place approximately 2-6 weeks after the patient is first given a patient information sheet, by a member of the PAIGE2 research team. The PAIGE2 researcher will ensure that the participants have read and understood the participant information sheet, offer further explanation, if necessary, confirm eligibility and obtain written consent prior to their enrolment in the PAIGE2 study. Only after consent has been provided by the women, will any member of the PAIGE2 research team have access to the woman’s health information. If the women have a partner, they will be given the opportunity to be involved in the study, subject to written consent.3.1.4via telephone or video call. Weeks will be allocated at random, using a restricted randomization developed earlier. To minimize the risk of manipulation, allocations will only be made available to recruitment centers on the morning of the visit in sufficient time for necessary administrative arrangements to be made. Women who agree to participate at 32–36-week gestation but who did not subsequently turn up for their postnatal follow-ups must be considered as having been recruited but lost to follow-up. Due to the nature of the intervention, the study cannot be blinded. The number of women randomized to each schedule will be reviewed regularly by the trial statistician to ensure that approximately equal numbers are assigned to treatment group. Should a serious imbalance develop, an additional intervention or control week will be added as appropriate.To streamline the organization of the intervention, economize on staff time and avoid contamination effects, women will be randomized to treatment group according to the week they attend for review at the joint diabetes antenatal clinic at 32-26 week’s gestation. Delivery of the intervention or control program will take place weekly at each site in person or 3.1.5Inclusion and exclusion criteria for this study are similar to that of the original PAIGE study .Women aged ≥18 years.2 at <14 weeks gestation.Booking BMI ≥25 kg/mGDM diagnosed in the current pregnancy. GDM will be defined by the WHO (2013) criteria  fasting.Women will only continue to be included in the study if their fasting plasma glucose the morning after delivery or at 6 weeks postpartum is either normal or consistent with impaired fasting plasma glucose outside of pregnancy .  .3.1.6Pregnancy in which an anomaly has been detected on the 20-week fetal anomaly scan.History of diabetes outside of pregnancy or FPG ≥7 mmol/l the morning after delivery or at 6 weeks postpartum History of heart, liver, or chronic renal disease.Medications that adversely affect glucose tolerance .Inability to participate in moderate physical activity outside of pregnancy.Moderate/severe depressive illness or excess alcohol consumption.Inability to understand adequately verbal explanations or written information in English, or special communication needs.Women who are planning another pregnancy within the next 12 months following delivery.Women who are intending to attend a CWMO program after pregnancy.Exclusion criteria for early postpartum glucose testing will include massive postpartum hemorrhage, steroid treatment prior to delivery or patient refusal.3.1.7Assuming the same variability in weight loss as was observed in the pilot study  . This voucher can be used by the participant to attend a local or online group of their choosing, run by Slimming World, for 12 consecutive weeks. Slimming World is group-based, and the mothers can enroll at any time. Meetings convene in community locations or online and are usually 90 minutes in duration. Mothers can also avail of a website, magazines and one to one telephone support from a Slimming World consultant or other Slimming World members. Like the original PAIGE study , the wom3.2.2Women in the control arm will receive routine antenatal care as offered by their individual maternity hospital. When the study is concluded, the control group will be offered referral to Slimming World (12 consecutive weeks) free of charge and will be given access to the educational resources from the one-hour educational session.3.2.3The study will involve four data collection appointments with the participants, as depicted in 3.2.3.1Timepoint one will be the first study contact and will take place over the phone before 32-36 weeks gestation. Informed consent will be obtained at this point, followed by collection of baseline clinical and demographic data and questionnaire completion. Relevant clinical and obstetric data will be abstracted from patient notes and recorded in study specific case report forms.Those women randomized to the lifestyle intervention will be enrolled into the study in small groups where they will receive an educational program lasting around one hour (as described above). They will also be given an activity tracking device (Fitbit) to allow them to become familiar with this technology during pregnancy. This device will either be posted to participating women or collected from research staff at the women’s next antenatal appointment. The education program will be led by a PAIGE2 research nurse or dietitian trained in motivational interviewing and will cover topics including GDM as a risk factor for future disease, healthy eating, physical activity, fitness tracker use, methods to reduce the risk of diabetes in subsequent pregnancies in the longer term, and ideas for maximizing peer support. The program will be loosely based on that used in the DPP  and desi3.2.3.2Timepoint two is the second study contact and will take place at around 6-8 weeks postnatal when women attend routinely for OGTT. Women will be contacted at this visit to confirm their continuing willingness and eligibility to take part in PAIGE2. They will be weighed . Alternatively, if they do not provide an OGTT, a fasting plasma glucose sample will be taken. All mothers (whether they provided an OGTT or fasting plasma glucose sample) will also provide a fasting blood sample to measure lipids and renal function. An additional serum sample will be stored for future analysis. This weight will function as a baseline measurement. The women will also be invited to upload their capillary glucose monitoring (glucometer) data during pregnancy to a secure website for examination in relation to other pregnancy-related variables such as physical activity. Those in the intervention will be offered a 12-week Slimming World voucher  to be completed within the 12-month period. This voucher can be used by the person to attend a group of their choosing, for 12 consecutive weeks. Women in the treatment group will be contacted by text messages (weekly for first month and then fortnightly) to provide motivation based feedback and to assess progress towards behavioral goals including a review of the step count, sleep activity and food intake.via text will be made with the partner to feedback on their physical activity.Subsequent contact with the women will be by text or telephone a call. The frequency of contact by text message will be weekly for the initial month (to persuade the women to sign up for the CWMO) and then fortnightly for the remainder on the study. Structured telephone calls will occur monthly, and include information of physical activity, barriers to achieving their diet and physical activity goals, as well as suggested solutions. Participants who are successful during the first three-month period of enrolment with Slimming World (gauged by attending at least 9 out of 12 sessions or demonstrated weight loss), will be offered a second funded three-month membership to maximize any benefits obtained during the program. After the second free three-month Slimming World program, women will be able to continue to attend Slimming World for the rest of the study if they desire, at their own discretion. Partners of the women in the intervention arm will also be invited to participate in the trial. Partners consent will be obtained either by post or in person at the same 6-8 post gestational timepoint, and they will subsequently be offered a fitness tracking device like that of their partner. Intermittent contact 3.2.3.3At timepoints 3 and 4, the third and final study contacts, all women will be weighed (or asked to weigh themselves at home and forward their self-recorded weight to the research staff). They will also have an additional (fasting) blood sample taken, along with a measurement of their waist circumference and their blood pressure. In addition, they will be asked to complete the same questionnaires they answered at 32-36 weeks gestation.3.2.4A summary of the several measurable outcomes of this study can be found in 3.2.4.1Weight at 12 months (accounting for any difference in weight at baseline between the intervention and control groups)Body weight: Women will be weighed (to the nearest 0.1kg) when they attend their 6-8 weeks postnatal appointment performed as part of routine standard care and will act as the baseline measurement. If they are unable to attend the department for this, the women will be asked to weigh themselves at home 6-8 weeks postnatal and send their self-measured weight in a text message to the research staff.2).Height (to the nearest 0.1cm), to calculate BMI (kg/m3.2.4.21) Fasting glucoseDay 1 postnatal : A fasting venous blood sample will be taken for glucose measurement and a serum sample will be stored for future analysis.Timepoint 2 : Participants will confirm eligibility by an OGTT when they attend their postnatal routine standard care appointment, or alternatively a fasting plasma glucose sample will be taken, along with a fasting blood sample to measure lipids and renal function. An additional serum sample will be stored for future analysis.Timepoint 3  and timepoint 4 : A maternal blood sample will be taken for fasting plasma glucose, lipids, and renal function. An additional serum sample will be stored for future analysis.2) Waist circumferenceWaist circumference  (cm), hip circumference (cm).3) Step counts, change from baseline to 12 months (intervention group only).The Fitbit tracker will allow women and their partners to upload their daily data to a secure dedicated spreadsheet. Women will choose what form of activity to engage in such as walking, dancing, aerobic activity etc., and will be encouraged to set individualized step count goals based on their baseline step count. Accumulation of all activity across the day will be promoted. Sedentary participants will be encouraged to increase their activity levels by a minimum of 3,000 steps per day, equivalent to approximately half an hour of walking . Goal at4) QuestionnairesPhysical activity will also be recorded at all timepoints using two questionnaires. The International Physical Activity Questionnaire (IPAQ)  will proThe Risk Perception Survey for Developing Diabetes (RPSDD) , adaptedPsychological measures and health and wellbeing will be measured at all timepoints using the 12-Item Short-Form (SF-12v2) Health Survey .Postpartum depression will be assessed using the Edinburgh Postnatal Depression Scale at timepoints 2-4 .Motivation for change will be measured at all timepoints by asking two questions devised by the team. For women in the intervention group motivation for change will be measured both before the delivery of the one-hour educational session and after, to assess the influence of the session on motivation to change.All the questionnaires have established reliability and validity.3.2.4.3Compliance: Slimming World records include attendance, quantity of sessions and weight at first and last sessions (intervention group only).Blood Pressure: Blood pressure .Follow up analysis of those women who have a further pregnancy within 12 months to document: BMI at booking, development of GDM and birth weight.Partner weekly step count (if applicable)3.2.5All instruments will be administered to participants by the researchers and all data, including that obtained from patient notes to record usual care/treatment, will be collated on a study-specific case report form starting at the time of recruitment. Data will be maintained and managed by the PAIGE2 research team within the Belfast Health and Social Care Trust (sponsor). OGTTs and fasting blood samples will be analyzed and stored within the Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast. Trial recruitment will be monitored by the Principal Investigator and a project manager will coordinate all aspects of the trial and manage and analyze all data under their supervision. An educational clinical psychologist will provide advice on the psychological aspects of the study including motivational interviewing and a statistician will oversee randomization and data analysis. All paper and electronic records relating to the study will be retained for 5 years.3.33.3.1Primary and secondary outcomes at 12 months will be compared between the intervention and control groups using analysis of covariance to adjust for any differences at baseline and so produce an estimate of the intervention effect with 95% confidence limits. Adjustment will also be made for recruitment center and any characteristics relevant to the outcome which, by chance, show imbalance between groups. Prior to analysis, logarithmic transformations will be applied to those secondary outcome variables whose distributions show marked positive skew. A correction will be applied to standard errors of intervention effect estimates to make allowance for the clustered nature (by week) of the randomization, although analysis of the pilot study (which used the same randomization procedure) indicated that this will make little difference to the findings. To help assess the impact of non-response, sensitivity analyses will be conducted on key outcomes by multiple imputation of missing values by chained estimating equations using the commands provided in the Stata package . We will use this approach to impute 10 complete datasets and analyze them appropriately to provide results which take account of missingness. For key outcome variables, this analysis will be reported in addition to the complete case analysis. Analysis will be by intention to treat.3.3.2Women from the intervention group during their final visit will be invited to take part in focus groups (arranged for up to ten participants per group) to feedback on their experiences of the program and to suggest how the program might be improved. This feedback about will be their experience within the trial, including the research tools used, Slimming World referral, fitness tracker use, and the educational session will be important to inform any future trial design or future roll out of the intervention. Focus group sessions will be recorded using voice recorders with transcripts anonymized prior to analysis of feedback. Focus group participation will be optional and those women who take part will receive a multistore gift voucher to reimburse them for their time. All women in the intervention group will be asked to complete a questionnaire regarding feedback for the study.4The PAIGE2 study is a large-scale investigation into the implementation of an evidence-based pragmatic pregnancy and postpartum lifestyle intervention for overweight women with GDM. The study has been informed from the results of a pilot trial (PAIGE) , which pvs clinically measured body weight across the timepoints, and use of the fasting glucose immediately post-partum compared with 6 weeks postnatally to exclude diabetes. However, these will be minimized as much as possible by the research team.A potential limitation of this study may be the differing nature of the healthcare systems in Northern Ireland and the Republic of Ireland. Obtaining ethical approval from the three Republic of Ireland hospital sites may prove difficult as the Republic of Ireland has no central ethics office/structure. However, the cross-border collaboration demonstrated in this trial should provide an evidence-based evaluation on the potential impact of a pregnancy and post-pregnancy lifestyle intervention for overweight mothers with GDM in an all-Ireland context. The cross-border approach should also identify optimum service delivery for successful implementation and impact of a lifestyle intervention for weight loss and GDM on the island of Ireland. Additional limitations may include participation-related factors, such as enrolment in Slimming World etc., which may influence their progress within the intervention. In addition, there may be some disparity between self-reported The results from this study will be distributed to healthcare professionals through conference presentations and peer-reviewed journals to add to the current literature and evidence base for effective interventions to address this major public health issue.The studies involving human participants were reviewed and approved by Research Governance and approval was obtained from the Belfast Health and Social Care Trust, South Eastern Health and Social Care Trust and Northern Health and Social Care Trust (18/NI/0228). The patients/participants provided their written informed consent to participate in this study.DM, UG, HW, CP and LC contributed to the development of study protocol. BJK wrote the protocol manuscript. All authors contributed to the article and approved the submitted version.


People with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach for people already on DNase is to add hypertonic saline (HS). The effects of DNase and HS used alone have been studied in randomised trials, but their effects in combination have not. This study investigates whether, for people already prescribed DNase, adding HS has additional benefit for lung function or use of intravenous antibiotics.Using UK CF Registry data from 2007 to 2018, we emulated a target trial. We included people aged 6 years and over who were prescribed DNase without HS for 2 years. We investigated the effects of combinations of DNase and HS over 5 years of follow-up. Inverse-probability-of-treatment weighting was used to control confounding. The period predated triple combination CF transmembrane conductance regulator modulators in routine care.1%) predicted were 21.1 years and 69.7 respectively. During first year of follow-up, 3799 individuals were prescribed DNase alone; 426 added HS; 57 switched to HS alone and 216 were prescribed neither. We found no evidence that adding HS improved FEV1% at 1–5 years, or use of intravenous antibiotics at 1–4 years, compared with DNase alone.4498 individuals were included. At baseline, average age and forced expiratory volume in 1 s (FEV1% or prescription of intravenous antibiotics. Our study illustrates the emulated target trial approach using CF Registry data.For individuals with CF prescribed DNase, we found no evidence that adding HS had an effect on FEV People with cystic fibrosis (CF) are often prescribed multiple long-term treatments, including mucoactive nebulisers such as DNase and hypertonic saline. The effects of DNase and hypertonic saline used alone on health outcomes have been studied in randomised trials, but the combined effects of both treatments have not been studied.We emulated a hypothetical target trial using UK CF Registry data to compare multiple treatment strategies involving DNase and hypertonic saline. The primary interest was in estimating the effect of adding hypertonic saline to DNase after 2 years, compared with continued use of DNase alone, on long-term clinical health outcomes. We found no evidence that adding hypertonic saline has an effect on forced expiratory volume in 1 s or prescription of intravenous antibiotics.We provide an example of target trial emulation to answer a clinical question for which there is no evidence from randomised controlled trials. This approach may be used to address clinical questions that are unlikely to be answered in randomised trials in the field of CF and more widely.Randomised controlled trials (RCTs) are the gold standard for evaluating the effects of treatments. However, there are many more questions relating to treatments than can reasonably be evaluated within RCTs. When there are multiple potential treatment strategies, for example, it can be challenging to recruit enough individuals in each treatment arm for sufficient power. An alternative is to use observational data to study treatment effects, and it is increasingly recognised that emulating a target trial when using observational data helps to clarify the research question and avoid common biases.CF is an inherited condition caused by mutations in the CF transmembrane conductance regulator (CFTR) gene.RCTs have investigated the effects of DNase or HS alone in CF. A recent Cochrane systematic review1%) and prescription of intravenous antibiotics. We compare outcomes measured at 1, 2, 3, 4 and 5 years of follow-up under each treatment strategy, where each treatment strategy is to be sustained up to the outcome measurement time. Previous studies have investigated the long-term effects of DNase using registry data and the findings suggest that DNase may improve the rate of decline in lung functionWe use UK CF Registry data to emulate a target trial designed to compare multiple treatment strategies involving DNase and HS and assess their long-term effects on health outcomes in people with CF. The focus is on patients already established on DNase as defined by CF Registry documentation of current prescription, and the primary aim is to investigate the causal effect of adding and continuing HS versus continuing to use DNase only on two health outcomes: lung function . The target trial framework involves describing the protocol for a randomised trial we would like to conduct if it were feasible, and then emulating that trial using the available observational data.The key components of the protocol for our target trial are outlined in 1% calculated using the Global Lung Initiative equations.Our treatments of interest are DNase and HS. At each annual review visit it is recorded whether individuals have been prescribed these treatments over the past year. Start and stop dates for long-term treatments are also available and these were used to impute any missing data on the treatments from the annual review visits. The two outcomes of interest are lung function and receipt of intravenous antibiotics. Both outcomes are recorded annually. Lung function is measured at annual visits by spirometry, with %-predicted values for FEV1%, past intravenous antibiotic use and past rate of decline in FEV1%. Except for sex, genotype and ethnicity, which we take to be fixed over time, these covariates are recorded annually. Further details on how these covariates were defined are provided in The emulation of the target trial uses existing observational data, reflecting data collected during routine clinical care and without any randomisation to treatment strategy. It is important that the analysis accounts for the lack of randomisation, as far as possible. In the observational data, the association between treatment and the outcome is suspected to be confounded by several factors. We used directed acyclic graphs to show the assumed relationships between the relevant variables in our data and to inform which variables should be considered as confounders see  in our a10.1136/thorax-2023-220031.supp1Supplementary data1% outcome, the main estimands of interest were the mean differences in FEV1% at times 1–5 years had all individuals been following treatment strategy DN&HS, vs had all individuals been following treatment strategy DN. For intravenous antibiotics, the main estimands of interest were the corresponding ORs at times 1–4 years. Note that FEV1% is measured on the day of the annual review, whereas intravenous antibiotic use over the past year is recorded. To estimate 1-year, 2-year, 3-year, 4-year and 5- year treatment effects on FEV1%, we use FEV1% recorded at the first, second, third, fourth and fifth follow-up visit, respectively. To estimate the 1-year, 2-year, 3-year and 4- year treatment effects on intravenous antibiotic use, we use information recorded at the second, third, fourth and fifth follow-up visit. Comparisons between other treatment combinations were of secondary interest. We also compared the strategy of switching to and then continuing HS (HS) and the strategy of dropping DNase (Nil) with the strategy of continuing DNase only (DN).The target trial specifies four longitudinal treatment strategies involving our two treatments of interest . Each trThe treatment effect estimands specified above were estimated using marginal structural models (MSM) estimated using inverse-probability-of-treatment weighting (IPTW).1% outcome the MSM is a linear regression model and for the intravenous antibiotic use outcome the MSM is a logistic regression model. The MSMs were fitted for all follow-up times combined with follow-up visit included as a covariate. The analysis for each outcome was conducted with and without interaction terms between treatment use and FEV1% at baseline in the MSM. The 95% CIs for the interaction terms were estimated to assess the evidence for treatment effect heterogeneity and we present treatment effects in individuals with low, moderate or high FEV1% at baseline by setting FEV1% to 40, 75 and 100, respectively. Full specification of the MSMs is provided in We assumed that consecutive visits were approximately 1 year apart. Some individuals had less than five follow-up visits after their baseline visit, due to the administrative end of follow-up, death or organ transplant. These individuals were censored at the time of death, transplant or end of follow-up. We did not use data from visits at which an individual had missing data in the outcome, or from visits at which individuals were using certain treatments . Inverse-probability-of-censoring weights were used to address censoring, and inverse-probability-of-observation weights were used to handle exclusions at a given visit due to missing outcome data or use of certain treatments. Each individual had a combined weight at each time point which combines the IPTW with these other weights. Further details on the weights are provided in We identified 5836 individuals in the UK CF Registry who had been documented as having been prescribed DNase and not prescribed HS for at least two consecutive years between 2007 and 2017. Of these, 4498 individuals met our other inclusion and exclusion criteria for the emulated trial. 1%: 66.2), whereas those prescribed DNase alone had the highest (mean FEV1% 70.1). The proportion of people who were recorded as taking no intravenous antibiotics in the year prior to baseline was highest for people prescribed neither treatment (46.3%) and lowest for individuals prescribed DNase and HS (35.4%). Individuals were observed to switch between treatment combination during the follow-up. Details on the amount of missing data by follow-up year, and on the number of people who were censored each year , or temporarily excluded due to missing outcome data, are provided in 1% (at times 1–5 years) and the odds of intravenous antibiotics versus no intravenous antibiotics (at times 1–4 years) between the two treatment strategies DN&HS vs DN . Corresponding tabulated values are provided in 1%, the mean differences are close to 0 at times 1–5, and all corresponding 95% CI contain 0. Similarly for intravenous antibiotics, the ORs are close to 1 at times 1–4, and all corresponding 95% CI contain 1. In other words, we found no evidence that adding HS would result in a different mean FEV1% or different odds of intravenous antibiotics among individuals who are already established on DNase, compared with continuing to use DNase only. For both outcomes, CIs, particularly for the later time points, were wide reflecting the uncertainty in our estimates.Although not our focus, we also considered the effect of switching from DNase to HS (HS vs DN) and the effect of dropping DNase (Nil vs DNase). Figures for these additional comparisons are provided in the 1% at baseline. 1% at times 1–5 between DN&HS and DN, by FEV1% at baseline . We found no evidence of treatment effect heterogeneity by FEV1%, the estimated mean differences increase as baseline FEV1% decreases, suggesting that adding HS is more beneficial for individuals with lower FEV1%. However, the corresponding 95% CI all contain 0. Similarly, the results for the intravenous antibiotics outcome provide no evidence of an effect of adding HS to DNase at any level of FEV1%.For FEV1% or prescription of intravenous antibiotics. We found some suggestion that adding HS may benefit lung function for people with lower initial FEV1%, although the results were not statistically significant. This is in line with results of a previous study based on UK CF Registry data, which suggested that the use of DNase alone could be more beneficial for FEV1% for people with lower initial FEV1%.We used UK CF Registry data to emulate a hypothetical RCT designed to investigate the effects of multiple treatment strategies for mucoactive nebulised treatments on lung function and prescription of intravenous antibiotics in people with CF. Our primary interest was to investigate whether, for individuals already treated with DNase, adding HS has any additional benefit for these clinical health outcomes. We found no evidence of an effect  of adding HS to DNase, either in change of FEVDespite DNase and HS being commonly prescribed together in clinical practice, there have been no RCTs investigating the effects of these treatments used in combination. Hence, we demonstrate the application of target trial emulation to address a clinical question in CF for which there is no RCT evidence. The target trial framework applies the study design principles of RCTs to observational studies which helps to minimise biases that can arise due to study design and analysis choices.1% and intravenous antibiotics when dropping DNase, although results were largely non-significant. We found no evidence of an effect (in either direction) of switching to HS on intravenous days, although some evidence that switching to HS after 2 years can improve FEV1%. This result is not clinically plausible and may be impacted by unmeasured confounding, which we discuss further below. Switching to HS is a rare decision in clinical practice. The number of people prescribed HS alone reflects this , but we used intravenous antibiotic days as a proxy for exacerbations. The information on intravenous antibiotic days included both planned and unplanned intravenous and is not a direct marker of exacerbations. However, our approach is in line with previous studies using intravenous antibiotic days data from the UK CF Registry.There are several limitations to this study. A key limitation in analyses that use observational data to study treatment effects is the possibility of bias due to uncontrolled confounding. Our analyses crucially assume that we have captured all the reasons for prescribing different treatment combinations that are associated with the outcome. While our analyses have controlled for several factors considered as potential confounders, including indicators of disease severity, it is important to note the possibility of residual confounding due to factors we did not control for. There could be, for example, biological or socioeconomic factorsIn an emulated trial using observational UK CF Registry data, we saw no additional benefit to lung function or use of intravenous antibiotics when HS was added to DNase.Our findings show that the UK CF Registry can support methodology for emulated trials. Although RCTs remain the gold standard, this methodology has the potential to address questions relevant to the CF community and could be particularly useful for assessing the long-term clinical effectiveness of multiple treatment strategies, since such questions are difficult to answer using a clinical trial. In future work, UK CF Registry data combined with the target trial framework could be used to repeat our study in a post-modulator population, including in groups with and without access to, or intolerant of, CFTR modulator treatments, and to answer related questions about discontinuing treatment in those using CFTR modulators.


Using multiparametric magnetic resonance imaging, it is now possible to diagnose prostate cancer and categorize its risk. As it can accurately determine the extracapsular extension of the tumor, invasion of seminal vesicles, involvement of lymph nodes, and the potential presence of bone metastases, multiparametric magnetic resonance imaging plays a crucial role not only in the diagnosis but also in the local staging of prostate cancer. The patients with a history of negative biopsy/increasing prostate-specific antigen and the existence of further data supporting its use in biopsy-naive patients and active surveillance are the most blatant indications for multiparametric magnetic resonance imaging in guidelines. The traditional clinical examination, prostate-specific antigen tests, and systematic biopsy are all enhanced by multiparametric magnetic resonance imaging, which will miss certain cancers due to insufficient size or changes in tissue density. The use of multiparametric magnetic resonance imaging is expected to rise, and further advances in the method will be crucial for the secure adoption of targeted therapeutic ideas. Here, we give a succinct overview of multiparametric magnetic resonance imaging's application to the identification and risk classification of prostate cancer. Multiparametric magnetic resonance imaging (mpMRI) has clinical relevance in the diagnosis as ecoguided biopsy especially if supported by a correct clinical classification of the patient and an adequate risk estimate.The use of wider surgical margins to reduce the rate of positive margins or nerve-saving surgery to reduce morbidity are 2 choices that can be made based on information provided by MRI, which also helps to improve diagnostic accuracy.The best protocol for studying prostate cancer combines a high-resolution T2W sequence acquired over 2 planes  with 2 functional sequences: a dynamic sequence following intravenous contrast agent Dynamic Contrast Enhanced (DCE) administration and a weighted diffusion image acquisition (diffusion-weighted imaging).The invasion of the seminal vesicles and extracapsular disease spread, as well as a high probability of a positive surgical margin (predisposing to recurrence), lymph node, and distant metastases, are all associated with a worse outcome. Therefore, it is evident that the information gleaned from imaging plays a significant role in the choice regarding the best course of treatment .The staging of patients at high risk using next-generation imaging methods like the whole-body-MRI or PET CT is excellent and enables a better layering of the patient, allowing for the selection of the most appropriate therapy.2In Europe, the most common male cancer, after skin cancer, is prostate cancer, with an incidence of 200 per 100 000 men/year and a rather high mortality rate.3The diagnosis of prostate cancer is based on the evaluation of different parameters such as serum levels of prostate-specific antigen (PSA), rectal examination (DRE), and transrectal ultrasound-guided biopsy.5In the past, magnetic resonance imaging (MRI) has never had a large relief in the diagnosis of prostate cancer; however, recent studies have shown that multiparametric MRI (mpMRI) has clinical relevance in the diagnosis as ecoguided biopsy, especially if supported by a correct clinical classification of the patient and an adequate risk estimate.6In 2001, the routine use of MRI in pretreatment diagnosis and staging was rather controversial among urologists.7In 2008, opinions about the use of MRI in the diagnostic process began to change, considering prostate MRI, along with rectal exploration, as a possible method of diagnosis.8Since 2012, MRI of the prostate gland has been fully integrated into the instruments adopted for the staging of prostate cancer, also approved by urologists.9In order to standardize image acquisition procedures and interpretation, the European Society of Urogenital Radiology published a set of guidelines and recommendations in 2012 under the name “Prostate Imaging Reporting and Data System (PI-RADS)”; this work underwent a number of revisions and modifications over time in collaboration with the American Society of Radiology until the final version of 2019 (PI-RADS v2.1).10For years, prostate cancer staging has relied on Partin nomograms to evaluate extracapsular cancer extension, using PSA, rectal exploration, and Gleason score (GS). The nomogram of Partin combines tumor stage, GS, and PSA to predict the final pathological stage of the tumor (accuracy 70%-80%) in the preoperative stage. The Partin nomogram, however, proved inaccurate in-stage prediction in cases of PSA >20, as evidenced by the high percentage of organ-confined disease and negative lymph nodes.1This strategy exaggerates the true severity of the disease. By identifying the location and severity of the illness, MRI can aid in the development of a surgical plan. Using wider surgical margins to lower the rate of positive margins or performing nerve-sparing surgery to reduce morbidity are 2 choices made possible by this knowledge. In fact, the use of MRI in staging is considered as a level of evidence 2B and a level of recommendation A by urological guidelines.Extracapsular extension of the tumor is associated with a higher risk of positive surgical margins, biochemical recurrence, metastatic disease, and lower survival after radical prostatectomy. Therefore, having the most accurate possible evaluation of extracapsular extension before surgery is of the utmost importance to optimize clinical decision-making.11Magnetic resonance imaging has better diagnostic accuracy for extraprostatic extension than clinical parameters and even greater accuracy when MRI is combined with clinical information to estimate extraprostatic extension. Moreover, with the increase of multimodal treatment strategies for prostate cancer, it is even more important to carefully stage before treatment.The objective of our review is to provide an overview of recent innovations in the use of mpMRI, the introduction of different systems of classification of extraprostatic disease, and its role in the classification of different risk classes.13Therapeutic management of the prostate cancer population is based on a classification and staging system provided by a set of patients with similar parameters and conditions.14The American Joint Committee on Cancer devised the “Tumor, Node, Metastasis” (TNM) staging approach, which is most frequently employed and is associated with serum PSA level and Grade Group (GG) biopsy.13 Groups T1 and T2 contain tumors that are only found in the prostate gland. These subcategories include instances of asymptomatic neoplasms that are incidental to transurethral resection because they are not clinically evident (T1a–T1b) and clinically and radiologically significant (T1c-T2) in accordance with the sample's histological results.14 Locally progressed cancers that invade seminal vesicles and locoregional tissues fall under subcategories T3 and T4. 14The location of prostate cancer is categorized into 4 groups based on the recommendations of the European Urology Association.The GS is a classification method used in clinical practice to rate the aggressiveness of prostate cancer. It is decided by assigning a score (ranging from 1 to 5) to each of the two tumor parts that most accurately represent the tumor. The number 1 will be given to tumor tissue that is highly comparable to normal glandular tissue, and the score 5 will be given to a tumor that is exceedingly undifferentiated.These 2 scores are added together to get the GS, which is based on a scale from 2 to 10 that indicates how aggressively cancer cells in a sample were observed under a microscope. Tumors in grades 2 through 6 are often slow-growing and have a minimal propensity to spread further, while tumors in grades 7 through 10 are considered to be particularly aggressive.16There are certain drawbacks to Gleason's classification, though. Grades 1 and 2 are extremely uncommon. Hence, the GS has the lowest value of 6, which can be confusing because grade 1 is the lowest grade for other tumors. Additionally, a GS of 7 can be obtained from either a 3 + 4 or obviously a 4 + 3, 2 circumstances with quite different prognoses.Due to these factors, the International Society of Urological Pathology proposed a new classification system in 2016 called GG or Prostate Cancer Grade Group. This system, which derives directly from the GS with the aim of streamlining its reading and improving the prognostic result, has been gradually introduced into clinical practice.17Prostate cancers are categorized using this system into 5 prognostic degree groups. Group 1 comprises all scores below 6, which are actually very uncommon, and Gleason's 6 (3 + 3). While grade 3 indicates prostate tumors with Gleason 4 + 3, grade 2 correlates to Gleason 3 + 4. Groups of grades 4 and 5 correspond to the GS of 8 and Gleason scores of 9 and 10, respectively.The group with the highest prognostic grade correlates to the lowest grade, and this obviously simplifies prostate cancer classification and staging .20 In the proposed protocol, a dynamic sequence after intravenous contrast agent (CED) administration and diffusion-weighted imaging (DWI) with b values of 0-1000 s/mm2 is combined with a high-resolution T2W sequence acquired over 2 planes, including at least one axial  indicated that it might be a promising method for identifying malignant tumors. For example, Bittencourt et al21 found that DWI with a value of 1400 s/mm2 showed benefits in increasing rates of prostate cancer diagnosis.A simple protocol should ideally be used with 3 T equipment to decrease the signal-to-noise ratio, shorten the acquisition time, and keep an acceptable level of spatial resolution. But all of these variables can be updated and optimized by 1.5 T equipment. The endorectal coil is no longer advised due to the patient's discomfort.ne axial .14,19 Th22 An axial plane T1WI sequence stretching FOV to the aortic bifurcation must be acquired in order to assess nearby lymph nodes and bone as well as its efficacy in detecting postbiopsy prostate hemorrhage . The local T-staging of prostate cancer still requires the T2WI pattern.14 A fast-spin-echo or turbo-spin-echo to a layer thickness of 3 mm (no-gap) would also be suitable in addition to the aforementioned sequences to assess lymph nodes, vascular-nerve bundles, seminal vesicles, extraprostatic extension, and any bone metastases.23 A T2WI 3D acquisition with isotropic voxel and layer width of 1 mm would also be beneficial for a more accurate examination of the aforementioned anatomical structures near to the prostate.14To obtain a more appropriate and accurate evaluation of the imaging during synchronous sequence scrolling, it must be emphasized that each sequence must be acquired with precise scanning settings , slice thickness, and voxel).24 The PI-RADS guidelines specifically suggest the T1WI, fat-suppressed T2W or short tau inversion recovery, and DWI sequences for the assessment of metastases in WB-MRI.26As bone involvement is only detectable during the most advanced stages of the disease with bone scintigraphy (BS), recent studies have indicated that whole-body MRI (WB-MRI) may also have a better diagnostic value than BS.Whole-body-MRI has a diagnostic promise, but there are still some restrictions on how it can be used to stage prostate cancer. The high prices and lengthy scan times are the main causes of these restrictions.14 Therefore, it is clear that the decision regarding the type of medication to be given is directly influenced by the information obtained from imaging .The main objective of local staging of the disease, in accordance with the guidelines of the European Association of Urology (EAU), is to distinguish between a disease that is confined to the gland and a locally advanced one. It is recommended that only patient groups with intermediate or high risk should participate in local illness staging (T2-T3a-T3b). An increased risk of a positive surgical margin (predisposing to recurrence), extracapsular disease dissemination, invasion of the seminal vesicles, lymph node, and distant metastases are all associated with a poorer outcome.Nowadays, there are no specific scores for the locoregional staging of prostate cancer.11 identified a new score called Extra Prostatic Extension (EPE) GRADE.11 Imaging features were implemented in an EPE grading system as follows: grade 0, no suspicion for pathologic EPE; grade 1, either curvilinear contact length or capsular irregularity and bulge; grade 2, both curvilinear contact length and capsular irregularity and bulge; grade 3, frank EPE visible at MRI or invasion of adjacent anatomic structures.A recent study by Mehralivand et al11However, these results are being validated. Although the PI-RADS recommendations do not assign a probability of extraprostate extension based on a combination of these results, they do advise that you report these characteristics when analyzing prostate MRI examinations.The characteristics of MRI of extraprostatic extension are as follows:large tumor contact ;capsular bulging ;irregularity/interruption of capsule ;obliteration of the recto-prostatic angle ;asymmetry of neurovascular bundles;invasion of periprostatic fat ; andinvasion of seminal vesicles.27 because there is a close relationship between the contact of prostate cancer with the capsule and the likelihood of extraprostatic disease; in particular, for a contact up to 10 mm, the probability of extraprostatic disease is below 10%, when the contact is 15 mm, then the probability rises around 40%.In clinical practice, it may be useful to consider the results of Baco et al’s studyIf the tumor can be classified as a T3b, it is crucial to consider how the lesion interacts with the seminal vesicles. Since the seminal vesicles and the base of the prostate gland are in close proximity to one another, it is conceivable that the seminal vesicle base will be most affected by penetrated tumors at the base.The diagnostic criteria used to establish infiltration of seminal vesicles and 7 arediffuse wall thickening;parietal focal thickening;intraluminal mass;obliteration of vesicular-prostatic angle;structural change;restricted diffusion within the lumen of seminal vesicle; andpostcontrast alteration enhancement.Another anatomical structure that must be carefully studied is the neurovascular bundle that decorates posterolaterally and bilaterally to the prostate gland. The role of the urologist becomes fundamental, especially in young patients undergoing surgery for prostate adenocarcinoma. Today there are significant improvements in both disease-free survival and quality of life in terms of urinary continence and sexual potency.28“Nerve-sparing” surgery is a surgical technique that aims to remove the prostate by saving 2 bundles of nerves that flow to the sides of the gland and are directed to the penis. These nerves are responsible for erection. The purpose of “Nerve-sparing” surgery is to allow the patient to have negative margins after removal of the tumor and, at the same time, preserve sexual and urinary function while preserving the neurovascular bundle. For these reasons, it is necessary to be as precise as possible in establishing whether or not the tumor lesion infiltrates the neurovascular bundle .2829An important problem in the local staging of prostate cancer by MRI was demonstrated by a recent meta-analysis performed on almost 10 thousand patients. This study shows the sensitivity of MRI to extraprostatic disease (T3) is only 57% compared to a specificity of 91%. This is due to the incapacity of MRI to detect microscopic disease.30The MRI of the prostate is also constrained by intrinsic patient features. An organ's signal strength, which affects the quality of the image obtained, is inversely proportional to its distance from the MR system's receiving coil. Since there is an increased distance between the receiver coil and the prostate in individuals with significant obesity, the quality of the study may deteriorate to the point where it is frequently useless for diagnosing the patient's condition. Metal foreign bodies, in particular hip endo-prosthesis , are significant factors that impair the effectiveness of the mpMRI test. An accurate evaluation of the mpMRI research may even be impossible due to field distortion brought on by a metal endo-prosthesis.31 and NCCN32 agree to identify 3 risk categories .31The EAU guidelines say that it is not necessary to perform a CT for the lymph nodes, and you should not do scintigraphy for the study of bone because the prevalence of pathological lymph nodes is < 10% and so also for bone metastases.The intermediate risk includes patients with PSA between 10 and 20, a GS of 7, and palpable disease. American guidelines divide intermediate risk into favorable and unfavorable risk. It is a category of patients that is invested with different resources in terms of surgery and radiotherapy, and yet about 30% of these patients will have a recurrence. So, the therapeutic goal is to achieve oncological radicality.33The prevalence of extraprostatic disease in this group of patients rises to 20%-45%.For this reason, the radiological report must be as precise as possible by marking every area of contact of the tumor with the prostate capsule or bulging to better guide the therapeutic approach.Patients with adverse intermediate risk need to make a systemic staging, evaluating, with a cross-sectional technical, lymph node by CT and bone metastases by scintigraphy.Patients who have metastases are included in the high-risk group (PSA > 20 and GS > 7), and the clinical goal is to increase survival.18F-choline, 11C-choline, 11C-acetate, and 18F-fluciclovine have all shown promise in prostate cancer imaging, prostate-specific membrane antigen (PSMA) has shown the most promise when combined with MRI. For patients at high risk and those who are worried about a biochemical recurrence, PSMA has shown potential in the diagnosis of both localized and metastatic illness.34For men with high-risk prostate cancer who are worried about recurrence, the integration of Positron Emission Tomography (PET) and MRI scanners has opened up new possibilities for multimodal imaging, notably in the diagnosis of nodal and metastatic disease. While 35Ultra-small superparamagnetic iron oxide-enhanced MRI is one of the new imaging modalities that has demonstrated encouraging results, mostly in the context of clinical research. To evaluate the clinical value of such agents, more research will be needed.Many studies show how the next-generation imaging techniques that combine the morphological data with the functional like the WB-MRI or the PET CT are excellent in the staging of patients at high risk and allow a better layering of the patient and therefore the choice of the best therapy. The phases of prostate cancer progression may need to be redefined if previously undetectable metastases are found using next-generation imaging techniques. This means that early or locally targeted systemic treatment can improve the patient's outcomes.Magnetic resonance imaging has a very important role in promoting precision oncology because it can respond to the needs of individual patients. The needs of patients with prostate cancer are very different. The low-risk patient must preserve the function and therefore sexual power and continence. Those with intermediate risk have the need to eradicate the disease and avoid recurrence. Finally, the patient with high risk has as its objective the increase of survival and therefore it is necessary to search for small metastases in order to avoid useless treatments.The use of mpMRI, integrated with patient clinical data and next-generation imaging techniques, allows you to benefit from the latest technological advances, such as robotic surgery or stereotactic radiotherapy, with the aim of obtaining a personalized medicine, integrating clinical data with imaging for a successful therapeutic strategy.Therefore, MRI is definitely a diagnostic tool in exclusively radiological hands that tends to play an increasingly important role in the diagnostic algorithms of prostate cancer.


The purpose of this study was to demonstrate a new method for quantifying the difference between predicted and achieved tooth movement with Invisalign using stable three-dimensional (3D) mandibular landmarks and dental superimposition. Cone-beam computed tomography (CBCT) scans before (T1) and after (T2) the first series of aligners, their corresponding digital models , and the ClinCheck final model of the first series as the predicted were obtained from 5 patients treated with non-extraction Invisalign therapy. After segmentation of the mandible and its dentition, T1 and T2 CBCTs were superimposed on stable anatomic structures  along with the pre-registered ClinCheck models. The 3D prediction differences between the predicted and achieved tooth position for 70 teeth with four types  were measured using a combination of software. The method employed in this study was tested to be reliable and repeatable with a very high intraclass correlation coefficient (ICC) for both intra- and inter-examiner reliability. Premolar Phi (rotation), Incisor Psi , and Molar Y  showed a significant prediction difference (P < 0.05), which is also clinically relevant. The method involving CBCT and individual crown superimposition to measure the 3D positional changes in the mandibular dentition is a robust and novel one. While, our finding in terms of the predictability of Invisalign treatment in the mandibular dentition mainly served as a crude, cursory examination, which warrants further and more rigorous investigations. With this novel methodology, it is possible to measure any amount of 3D tooth position difference in the mandibular dentition either between the simulated and the actual or with treatment and/or growth. Deliberate use of overcorrection of which specific type of tooth movement with clear aligner treatment and to what extent, might be possible with future studies. Björk was the first to use metallic implants as an alternative comparison point for regional mandibular superimposition5. In cephalograms, he also described natural stable structures of the maxilla and mandible. The tip of the chin and the following three internal structures in the mandible are deemed stable: (1) the inner cortical structure of the inferior border of the symphysis, (2) detailed structures from the mandibular canal, and (3) the lower contour of the molar germ from the time that mineralization of the crown is visible until the roots begin to form4. However, these landmarks are projections of three-dimensional (3D) structures into two-dimensional (2D) lateral films, making them unreliable, except for those located in the midsagittal plane. Using cone-beam computed tomography (CBCT) images, a study group discovered that the Björk registration was not reliable in most 3D mandibular superimposition cases6. The displacement of the mandibular canal and other “stable structures” as a result of development were some of the reasons for their argument.Measuring tooth positional changes, either as a result of orthodontic treatment and/or growth or created by a computer software simulating the proposed orthodontic treatment, is challenging and complicated by the difficulty to identify constant reference points. Without these relatively stable landmarks, it is impossible to differentiate between growth, relative movement and treatment effects or predict the accuracy of the orthodontic appliance system. Palatal structures may only be used as reference points in the maxillary dentition. In the maxilla, most studies used the third palatal ruga as the reliable registration landmark for the superimposition of maxillary digital casts7 have tried to use bilateral mandibular tori, a primarily nodular mass of dense cortical bone in adults as potential stable landmarks for mandibular dental model registration and superimposition. Albeit, mandibular tori are relatively stable within 2 or 3 years of orthodontic treatment in adult patients, the prevalence varies by ethnic origin from 0.2 to 61% 8. Furthermore, the simulation software routinely removes the non-dental structures from the digital image, and treatment management portals for clear aligners or fixed appliance systems make it impossible to use these anatomic landmarks for accurate registration. Therefore, mandibular tori can only be utilized in very few studies. Other mandibular structures, such as lingual surfaces of the alveolar process of the anterior and/or posterior teeth7 or unmoved teeth9, have also served as registration references, but apparently, neither seems to be appropriate as a reference area.An et al.10. Researchers have attempted to use CBCT to develop a method for 3D regional mandibular superimposition. Park et al. suggested a surface-to-surface matching method based on the basal bone structure of the mandible to evaluate 3D changes in the lower arch11. Dai et al. used a similar method in their study12. Ruellas et al. stated that using the mandibular body mask  was a reliable reference for 3D regional registration6. Nguyen et al. established 3D stable mandibular structures in growing patients with the aid of bone plates and discovered several anterior stable areas (the chin and symphysis regions)13. However, it has been debated whether any stable structures posterior to the symphysis area can be found to improve mandibular superimpositions. A recent study by Chen et al. attempted to identify the most stable mandibular landmarks in growing patients using CBCT scans. They found that during a growth period that averaged 4.6 years, ranging from 11.2 to 19.8 years old, the structures that appeared relatively stable and could be used in mandibular regional superimpositions included Pogonion (Pog), landmarks on the inferior part of the internal symphysis, and the mental foramen14.CBCT can provide a reliable 3D image of the cranial skeletal structures using much less radiation than conventional computed tomography (CT) scans16 or using a common-structured cranial facial coordinate system to express the 3D tooth movement12. Therefore, the purpose of this study is to introduce a novel application methodology to assess differences between the predicted and achieved mandibular tooth movement with clear aligner therapy using stable mandibular landmarks and a tooth-specific coordinate system.The ability to measure tooth movement or predict treatment outcomes helps treating clinicians visualize treatment outcomes, make real time adjustments to simulations, easily project corrections, have a better judgment on choosing an appropriate treatment plan, build necessary compensations into the virtual treatment plan, provide better interaction and communication with patients, and help with extraction or interproximal reduction decisions. While, previous studies that used 3D superimposition to assess the difference between predicted and achieved mandibular tooth movement are either lacking of stable landmarksThe informed consent was waived due to the retrospective nature of this study and the research protocol was approved by the Institutional Review Board at the University of British Columbia, Vancouver, Canada (No. H21-02474).All patients receiving orthodontic clear aligner treatment exclusively using Invisalign  during the period between Jan 2016 and Dec 2018 from a private clinic were selected.The main inclusion criteria for patient recruitment were (1) had a permanent dentition with or without third molars before treatment; (2) have completed the first series of clear aligner treatment; (3) had good-quality pre-treatment and post-treatment CBCT scans after the initial series; (4) underwent non-extraction treatment; and (5) had good compliance with the clear aligner treatment according to the chart. The main exclusion criteria were as follows: (1) an initial series of aligners not completed or had a mid-course correction; (2) incomplete or missing radiographic and dental records; (3) the chin was cut out on the CBCT scans; (4) missing tooth except third molars; (5) had an auxiliary appliance before or during aligner treatment other than attachments or elastics; (6) extraction cases; and (7) non-compliant cases.Finally, 5 patients (including 70 mandibular teeth) were selected and we collected the following records for each patient: (1) Pre-treatment (T1) CBCT; (2) post-treatment  CBCT; (3) ClinCheck initial and final stereolithographic (STL) files from the first series served as T1 and ClinCheck predicted digital models respectively; (4) ClinCheck initial STL file from the refinement series served as the T2 digital model.To superimpose the T2 achieved model on the ClinCheck predicted model, by using mandibular anatomic reference landmarks on CBCT, the following steps were followed.2, 90 kV; 6.0 mA; scan time, 15 s; and voxel size, 0.3 mm. The volume data were exported in Digital Imaging and Communications in Medicine (DICOM) format. The pre- and post-treatment mandibles were segmented, including Pog and the mental foramen, and converted to STL files using 3D Slicer software , a free, open-source software application for medical image computing17. Regions of interest (ROIs) were constructed to represent the mandible and teeth that were distinct from one another. A variety of semi-automatic and manual segmentation tools were used in the process  with the following settings: field of view (FOW), 200 × 200 mmwww.rhino3d.com; Robert McNeel & Associates, Seattle, WA, USA) was used to segment only the occlusal one-third of the clinical crowns on the ClinCheck models to improve the precision of superimposition by using a smaller and reliable part of the tooth structure.The initial and final STL files of the first series of aligner treatment were exported from ClinCheck software directly with a dental superimposition feature. The initial STL file from the refinement ClinCheck was also exported separately as T2 digital model. Rhinoceros software  and aligned accordingly. The ClinCheck initial model was registered on the dentition part of T1 CBCT model together with ClinCheck predicted model, and T2 actual model was integrated with T2 CBCT model based on dentition superimposition  RMS. The acceptable deviation from the perfect fit was RMS ≤ 0.05.Rough alignment of T1 and T2 CBCT models Fig.  was regiWith the request to hide all models except the ClinCheck predicted and T2 actual model, the final superimposition of the actual and predicted mandibular models were obtained Fig. .Figure 5To assess the 3D tooth positional difference of each mandibular tooth between the superimposed achieved model and ClinCheck predicted model, the single tooth registration was also performed in CloudCompare, each fit providing the transformation needed to move that tooth from its achieved to its predicted position. Each movement was expressed relative to a world coordinate system. We used a cuboidal template within which the surface of the achieved tooth crown was oriented so its occlusal and facial surfaces aligned with the world axes, and its bounding-box center coincided with the world origin. An example of the individual tooth registration is shown in Fig. In Fig. The differences between the predicted and achieved tooth position of these seventy teeth from 5 patients were measured and grouped into four groups according to different tooth types: incisor, canine, premolar and molar.All measurements of the 70 teeth were performed by one examiner (A.A.). We randomly selected six teeth and reassessed by the same and a second examiner. Intra- and inter-examiner reliability were tested using intraclass correlation coefficients (ICC) and Bland–Altman analyses.T test was used to test whether or not the sample mean of a sample is significantly different from a pre-specified mean (here it is zero). To adjust for multiple tooth comparisons, we applied a Bonferroni correction to the p-values and the P value was set at 0.05. The analyses were performed using the R statistical package  through RStudio (version 1.4.1103).One-sample All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was reviewed, informed consent was waived and the research protocol was approved by the Institutional Research Board at University of British Columbia, Vancouver, Canada (No. H21-02474).Since this is a retrospective study, inform consent was waivered. All data collected were de-identified.Table Tables The ICC value for inter-examiner agreement is very high, with a value of 0.996, which nearly reaches 1. Examining the Bland–Altman plot Fig. , we see The ICC value for the intra-examiner agreement is also very high, with a value of 0.999. The Bland–Altman plot Fig.  does not22, the Orthodontics Model Grading System24, CBCT25, or Simulator Software26. These assessment tools may provide a general assessment when lacking a stable reference structure for superimposition. In the present study, we used multiple software for different purposes.Previously, several studies used different assessment tools to evaluate the effectiveness of clear aligner therapy. For example, the Toot0068Measure program (Align Technology)3DSlicer was used to segment CBCT images. CloudCompare was used to measure the linear and angular difference between objects with respect to the six components of the transformation matrix . In the present study, it is essential to discuss the CouldCompare registration process to interpret the findings appropriately. To measure the difference between the ClinCheck predicated and actual tooth movement, we used the transformation matrix approach. This approach provides a standardized metric to measure the difference between the ClinCheck-predicted tooth and the actual post-treatment tooth.Cartesian coordinate systems relative to an object in space can be extrinsic or intrinsic. A World Coordinate System is extrinsic, and a Local one is intrinsic. The numerical descriptors needed to the change in pose according to a coordinate system include displacements along, and rotations around the three defined axes that pass through a common origin, so they could be described within a World or Local frame. CloudCompare always uses the platform’s World Coordinates for all calculations; however, calculations based on Local coordinates depend on user-specification of that object’s origin and axes and are typically based on its physical features. If the moving object is not located at the World’s origin, any rotations around it alter the object’s position in World space in addition to any translational movement. This unwanted effect can be avoided if the object is initially centred on the World origin and aligned to World axes before it is moved, and effectively creates a Local coordinate system that is coincident with the World one. In our registration sequence, both predicted and achieved teeth were posed initially and the tooth to be moved (predicted tooth) was positioned at CloudCompare’s origin, and its known anatomical features coincided with CloudCompare’s axes Fig. . The sofInvisalign system provides transformation measurements that describe the difference between the ClinCheck pre-treatment and predicted teeth; however, we are not aware of the convention system that Invisalign uses for their measurements. Therefore, comparing their measurement data with our findings wouldn’t be a valid option for our analysis. Moreover, the coordinate system could be utilized differently for measurements, such as using a transformation matrix based on a tooth-based Cartesian system or measuring tooth-orientations expressed as lines, axes or vectors (polar coordinate system).Overall, the results of this study showed that the mean prediction differences of X , Z , and Theta ) are not statistically different across all teeth types Table .27. In addition, Simon et al. conducted a study to assess the efficacy of an aligner technique regarding incisor torque, premolar derotation, and molar distalization. They found the lowest accurate tooth is premolar derotation with 40%28. One might think this partly due to the old aligner materials involved. However, in our study, we included only cases that were treated with the newer Invisalign aligner material (SmartTrack) and also found that derotation of the 1st premolar is less accurate with Invisalign system.In the present study, the premolars showed the only statistically significant prediction difference with Phi (rotation tooth movement). Rossini and colleagues published a systematic review in 2015 to evaluate the efficacy of clear aligner treatment in controlling orthodontic tooth movement. They reviewed relevant studies starting from 2000 to mid-2014. They found that rotation tooth movement is challenging, with an accuracy of 36%28. However, our findings didn’t show an accuracy between the predicted and achieved distalization. We also found that there is a statically significant difference in the Psi  between the incisors of the ClinCheck predicted model and the post-treatment model superimposition. This is different from Lombardo et al.29 work indicating that mesiodistal tipping is quite accurate. This difference could be explained either by the different clear aligner system  or measurement methodology, with sample size discrepancy as another potential factor.In terms of Y , in our study, we found a statically significant difference in mesiodistal transitional movements between the molars of the ClinCheck predicted model and the post-treatment model superimposition (in the positive direction). This indicates that the positions of the achieved post-treatment teeth were more distally in relation to the ClinCheck predicted teeth. These findings agree with the efficacy of Invisalign for distalizing molarsSome strengths could be associated with this study. First, this study used a novel methodology utilizing the mandibular body to superimpose the ClinCheck initial model along with its final predicted model over the post-treatment models. Second, utilizing accurate superimposition software such as CloudCompare would minimize the risk of measurement bias. This study presents some limitations, such as the small sample size, which is expected due to the difficulty to obtain pre-and post-treatment (at refinement) CBCT images for orthodontic patients. This is mainly due to the need for justification for taking images with high radiation doses at pre- and post-treatment (refinement) time points. Recently, Align Tech has added the CBCT feature to their ClinCheck. Hopefully, with the future introduction of low-dose radiation CBCT, it might be feasible to assess the tooth movement, including the roots and their relation to the basal bone.Another limitation is the retrospective nature of the study, which makes the selection bias a possibility. In addition, patient compliance was difficult to control in our sample collections. Additional limitation of this study, which applies to studies with a similar design, is assessing the tooth movements of several teeth on the same patients. This would question if the tooth movements are induced mainly by the effect of aligners, or also by the effect of the adjacent teeth movements. In theory, to avoid this limitation, one tooth and one tooth movement should be measured in each participant, which will require an ample sample size or fewer tooth movements to measure. Alternatively, using statistics that account for matching and clustering effects, such as multivariate models, would be an optimal solution. However, this would require an adequate sample size as well. Finally, the resultant tooth movements could be influenced by the experiences of the clinicians with the treatment plan using Invisalign. Furthermore, using multiple software makes the process complicated and prone to errors. Each model segmentation and measurement would take up to a few hours to complete. Finally, as the best fit technique is used, the differences between the predicted and achieved tooth position may appear small, but they do not represent the prediction position of the teeth within the bone and in the face.In this study we aimed to demonstrate a robust novel methodology which can be employed to quantify 3D tooth positional difference either with orthodontic treatment or with growth by using CBCT and dental superimposition based on stable anatomic landmarks. However, the findings in terms of the prediction of Invisalign treatment in the mandibular teeth in non-extraction cases are potentially weak, which merits further and more rigorous investigations not only due to the limited sample size but also because that ClinCheck is more of a tool to design clinicians’ biomechanics rather than merely a tool for visualization of the predicted treatment outcomes when planning clear aligner therapy.


Benign prostatic hyperplasia is the most common cause of urinary retention in men (BPH). The gold standard surgical treatment is transurethral resection of the prostate (TURP). However, due to the morbidity and mortality associated with TURP, more minimally invasive treatments, such as vaporizing the prostate with the Rezum system, have been introduced. We investigated the efficacy of Rezum in the treatment of refractory urinary retention due to BPH in this review.To conduct this review, the Cochrane methodology for systematic reviews was used. All studies that used Rezum to treat catheter-dependent patients with enlarged prostates were included. The literature search showed 111 studies, 84 of which were excluded due to non-relevance based on titles and 18 due to lack of relevance based on abstract review. Full manuscripts were reviewed in nine studies, three of which were excluded because they did not meet the inclusion criteria.This review included 301 patients in total. The rate of a successful trial of voiding post Rezum therapy was 85%. The complication rated between 3.8 and 4.3% all of which were mild and self-limited. As there was no major complication of Rezum (clavien dindo >2), the procedure-related morbidity is negligible.In this review, Rezum was found to be an efficacious and safe alternative in the treatment of refractory retention with mild complications and minimal morbidity. Benign prostatic hyperplasia (BPH) is the most common cause of voiding and lower urinary tract symptoms in men, particularly in men over the age of 60 ,2. PatieThe gold standard surgical treatment for BPH remains transurethral resection of the prostate (TURP) . HoweverThe Rezum System ablates prostatic tissue using convective water vapor energy and can be performed as an office-based procedure with local anaesthesia and oral analgesia to avoid the morbidities associated with general or even spinal anaesthesia required in TURP. The efficacy and safety of Rezum system have been reported in multiple prospective and retrospective studies as efficacy was associated with low rate of shortlived mild side effects . Due to Several studies looked into the effectiveness of Rezum in treating lower urinary tract symptoms caused by BPH, but the role of Rezum in the treatment of refractory retention remains uncertain. In this review, we evaluated the efficacy of Rezum in treating patients with refractory urinary retention due to benign prostate hyperplasia as an alternative to TURP.To conduct this review, the Cochrane methodology for systematic reviews was used ,12. The We included all studies that reported on the use of Rezum in the treatment of enlarged prostate patients with chronic retention and catheter-dependent patients. Two authors independently identified studies that were eligible for inclusion and extracted the data. The authors’ disagreement was settled by unanimous agreement. Patient demographics, prostate size, a successful voiding trial, and catheter-free rate were among the variables extracted for the patient with retention.The literature search showed 111 studies, of which 84 were eliminated due to non-relevance based on titles and 18 were eliminated due to lack of relevance based on abstract review . Full maThe inclusion criteria articles that describe the use of Rezum in the treatment of refractory urinary retention. Articles that do not have data regarding patients with retention were excluded.The studies spanned between Nov 2016 and April 2022. The included studies evaluated the efficacy of Rezum in managing enlarged prostate. The number of patients in the included articles ranged from 8 to 136 patients. All the included studies found to have low risk of bias on ROBINS-I tool.This study included 301 patients in total; all of whom had urinary retention due to enlarged prostate and were catheter-dependent; the mean age was 75.7 years (59 − 89). Mean prostate volume was 74(20–200) cc. The mean preoperative retention volume of 888(566–2100) cc was reported in three articles involving 195 patients .Table 1All patients in this review underwent Rezum procedure; the median number of vapor injections used was 10 [5–12] .The success rate of a voiding post Rezum therapy trial was 85%, as 256 out of 301 patients were catheter free after the procedure, with follow-up periods ranging between 3 and 12 months. Two articles subclassified patients according to prostate volume to < 80 ccs and > 80 ccs, the catheter-free rate of those groups was 83% and 77.5%, respectively.The outcome of patients who failed TWOC was reported in 2 articles, 10 patients had reintervention, 3 of them underwent transurethral resection of prostate; 2 of them failed TWOC after it; another 3 patients underwent redo Rezum; and all of them failed TWOC. Four of them remained catheter-dependent either SPC or CIC.Post-Rezum PVR was 144 ccs, and a post Rezum Q max of 11.6 ml/sec has reported in three studies. The post-Rezum improvement of lower urinary tract symptoms reported in five studies, the mean post-Rezum IPSS was 6.2  patients had gross haematuria and 9 (3.8%) patients had urinary tract infection; no other complications were reported.The most common cause of urinary retention in men is BPH; the incidence increases with age where men aged 70 and above are at higher risk ,20. The In this review, we studied the Rezum system’s efficacy in refractory urinary retention and found that the catheter-free rate post-Rezum is 85% (number of studies 6 and number of patients 301). The most important factor affecting the rate of successful TWOC was prostate volume, as prostate volume > 80 ccs was associated with lower catheter-free rates (number of studies 2 and number of patients 196). The catheter-free rate of the gold-started transurethral resection of the prostate in the treatment of BPH-induced urinary retention is 92% , which iThe reported suboptimal Q max and PVR post-Rezum in patients with refractory retention might be a result of an element of decreased bladder contractility as the patients who failed to void without catheter after Rezum also failed to void after going TURP or redo Rezum and remained catheter-dependent ,17,24. IThe effect on sexual function is a major determinant in the management of BPH, for instance the gold standard surgical treatment TURP results in retrograde ejaculation in 50–70% of patients . On the The adverse effects of Rezum are related to endoscopic instrumentation during the procedure. When compared to TURP, Rezum complications are mild and self-resolving that includes haematuria (11.8%), dysuria 16.9%), urgency (5.9%), frequency and acute urinary retention (3.7%) and urinary tract infection (3.7%) ,18 . On .9%, urgeIn this review, we observed that Rezum is a safe and effective alternative to TURP in the treatment of refractory urinary retention due to BPH. The main limitation of this review is the low quality of the studies included, as the majority of the studies were retrospective and had a relatively short follow-up period. In addition, some studies included patients with refractory urinary retention as a subgroup.In this review, Rezum was found to be an efficacious and safe alternative in the treatment of refractory retention with mild complications and minimal morbidity. More research is needed to prove the efficacy of Rezum as an alternative to TURP and to evaluate its long-term complications.