This randomized clinical trial evaluates the association between patient characteristics and effectiveness of a mailed human papillomavirus self-sampling kit intervention on screening uptake. Is the effectiveness of mailed human papillomavirus self-sampling kits vs usual care (in-clinic screening reminders) on cervical cancer screening uptake modified by patient characteristics?In this secondary analysis of randomized clinical trial data, mailed kits were associated with significantly increased screening vs usual care within all subgroups of age, race and ethnicity, screening history, and other sociodemographic and health characteristics. Relative effects were greater with longer vs shorter duration of underscreening.These findings suggest mailing kits increases screening across patient characteristics, with opportunities to optimize self-sampling for priority subgroups. Mailing human papillomavirus (HPV) self-sampling kits increases cervical cancer screening participation, but effects may differ across subpopulations. Subpopulation data can inform US health care system implementation.To identify patient characteristics that modify effectiveness of a mailed kit intervention at increasing screening.This was a secondary analysis of data from the Home-Based Options to Make Cervical Cancer Screening Easy (HOME) randomized clinical trial conducted from 2014 to 2018 at Kaiser Permanente Washington. Data analysis was performed from March 2018 to May 2022. Individuals aged 30 to 64 years with female sex, health plan enrollment longer than 3 years and 5 months, a current primary care clinician, and no Papanicolaou test within the prior 3 years and 5 months were identified through electronic medical records and randomized (1:1) to the control or intervention group.The control group received usual care Papanicolaou screening reminders and outreach. The intervention group received usual care plus an unsolicited mailed HPV self-sampling kit.Screening uptake was captured within 6 months after randomization. Baseline patient characteristics  were extracted from the electronic medical record.Of 19 734 individuals , 9843 were randomized to the intervention group, and 9891 were randomized to the control group. Screening uptake was 26.3%  in the intervention group vs 17.4%  in the control group . Although absolute differences in uptake by group varied little by screening history, relative effects were greater with longer vs shorter time since last Papanicolaou test . Relative effects were greater in participants overdue  vs up-to-date with mammography , although absolute difference was greater in the up-to-date group. Differences by age were not significant, with RRs of 1.33 to 1.48 across 5-year age groups in participants 30 to 54, vs 1.60  in participants 55 to 59 and 1.77  in participants 60 to 64 years. Among those mailed kits, there were differences in kit use vs in-clinic screening by age, race, plan enrollment duration, underscreening duration, and colorectal cancer screening adherence.In this secondary analysis of a randomized clinical trial, clinically important improvements in screening uptake were observed for all subgroups. Differences in magnitude of intervention effect and kit use highlighted opportunities to optimize HPV self-sampling for priority groups.NCT02005510ClinicalTrials.gov Identifier:  International population-based trials in Europe and Australia have consistently demonstrated that mailing self-sampling kits increases screening participation compared with clinic-based screening invitations.28 Accelerated by the COVID-19 pandemic, multiple countries have incorporated HPV self-sampling options into their cervical cancer screening programs.31The 2018 US Preventive Services Task Force cervical cancer screening guidelines added primary human papillomavirus (HPV)–only screening as a recommended option for individuals aged 30 to 65 years.32 was the first trial to evaluate pragmatic effectiveness of a programmatic mailed HPV self-sampling kit outreach strategy in a US health care system. Mailing kits to underscreened individuals increased screening compared with usual care reminders and outreach.33 However, nearly three-quarters of individuals in the intervention group did not screen, and the increase in screening associated with the intervention was in the lower range of estimates from international trials,28 highlighting improvement opportunities. Limited data from international trials suggest potential differences in population subgroups that are best reached through HPV self-sampling.40 To inform US health care system implementation, the objective of this secondary data analysis was to identify patient characteristics that modify the mailed kit intervention’s effectiveness at increasing screening uptake.Home-Based Options to Make Cervical Cancer Screening Easy (HOME)33 we evaluated whether patient characteristics modified effectiveness of a mailed HPV kit intervention at increasing screening uptake. HOME was approved by Kaiser Permanente Washington (KPWA) and University of Washington institutional review boards. Design details were described previously.32 Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed  data to identify individuals with female sex, aged 30 to 64 years, with an intact uterus, continuously enrolled at KPWA for 3 years and 5 months or more, and with no Papanicoloau test within 3 years and 5 months. Individuals were excluded if they were on a do-not-contact list for research, were pregnant, or had an “interpreter needed” flag. All eligible individuals were enrolled under a full waiver of consent 5 months after receiving an annual preventive services reminder letter indicating they were due or overdue for screening. Patients were randomly allocated 1:1 to the intervention or control group. To meet sample size targets, control group participants were reassessed for eligibility and rerandomization 1 year after randomization. Control group participants received usual care outreach to attend Papanicoloau screening (described previously)41 BMI, tobacco use, Charlson Comorbidity Index,42 and Healthcare Effectiveness Data and Information Set–defined adherence to guideline-recommended mammography43 (restricted to those aged 52-64 years) and colorectal cancer (CRC) screening44 (restricted to those aged 51-64 years). Given documented racial and ethnic disparities in cervical cancer screening in the US,22 race and ethnicity were analyzed to identify potential differences in intervention effectiveness across groups.Screening uptake was a prespecified secondary outcome in the original randomized clinical trial captured 6 or fewer months after randomization from EMR data and defined as follows: (1) in-clinic screening; (2) self-sampling HPV 16/18-positive; (3) self-sampling HPV-negative; or (4) self-sampling HPV-positive for non-HPV 16/18 types only or unsatisfactory, followed by in-clinic screening. Patient characteristics at randomization were also derived from EMR data: age, race and ethnicity , health plan enrollment duration, time since last Papanicolaou test stratified by health plan enrollment duration, US Census block median household income, travel time to primary care clinic,32 we used intention-to-treat (ITT) log-binomial regression to estimate risk differences and relative risks (RRs) with 95% CIs for associations between randomization group and screening, and evaluate patient-characteristic-by-randomization group interactions. CONSORT guidelines recommend reporting both absolute and relative effect sizes as complementary measures.45 Relative and absolute intervention effect sizes may differ across patient subgroups with varying baseline outcome rates, and absolute differences may be particularly relevant for informing health care system decision-making. Each observation was treated separately in analysis according to group assignment, as per the ITT, with robust variance estimates used to account for within-participant correlation due to rerandomized participants contributing more than 1 observation period. Denominators for each group included all participants randomized, minus the small number who opted out of medical record review or were identified after randomization as ineligible. Statistical significance was defined as a 2-sided P < .05.As prespecified in our analysis plan,2 tests. We also tested for patient-characteristic-by-randomization group interactions for in-clinic screening (screening in-clinic in the intervention group vs screening in-clinic in the control group) using log-binomial regression and robust variance estimates. Analyses were conducted after the trial ended between March 2018 to May 2022 using SAS statistical software version 9.4 (SAS Institute).In posthoc analysis, we estimated screening uptake within the intervention group by modality (initiating screening by kit return vs in-clinic), and tested for patient-characteristic-by-modality interactions using χ33The total number of randomized participants was 20 230 . We retrP for interaction ≤ .005 for all comparisons). Relative differences in intervention effect size are impacted by screening uptake in the control group, which ranged from 2.7% to 10.3% in participants with no prior screening to 27.0% to 29.0% in those with less than 5 years since last screen. Conversely, absolute differences varied little by screening history . The relative effect of the intervention was also greater in participants overdue  vs up-to-date  for mammography, although the absolute difference was greater in the up-to-date (13.6%) vs not up-to-date (7.9%) group. There were no significant differences in relative effect of the intervention by age, with RRs ranging from 1.33 to 1.48 across 5-year age groups in participants aged 30 to 54 years, vs RRs of 1.60  in participants aged 55 to 59 years and 1.77  in participants aged 60 to 64 years. No other significant patient-characteristic-by-randomization group interactions were found.Screening uptake was higher in the intervention group  vs the control group , corresponding to a RR of 1.51  and absolute screening uptake difference of 8.9% . Across patient characteristics, nearly all stratum-specific RR and absolute risk differences showed clinically relevant and statistically significant increases in screening between groups . The relWithin the intervention group, 12.2% of participants (1201 of 9843 participants) initiated screening by kit and 14.4% (1419 of 9843 participants) did so in-clinic, corresponding to 45.8% (1201 of 2620 screenings) of intervention group screenings initiated by kit and 54.2% (1419 of 2620 screenings) initiated in-clinic. Screening modality differed by age, race, plan enrollment duration, time since last Papanicolaou test, and CRC screening adherence; all characteristic-by-modality interactions were significant, as shown in P = .003). No other significant characteristic-by-randomization group interactions were seen for in-clinic screening in the intervention vs control group.Across most characteristics, in-clinic screening in the control group was higher than in-clinic screening in the intervention group . The betIn this secondary analysis of randomized clinical trial data, mailing unsolicited HPV kits to underscreened individuals increased screening compared with usual care within all subgroups evaluated. Cervical cancer screening history and mammography adherence were the only patient characteristics that modified the intervention effect. Overall, the majority of intervention group participants remained unscreened. Within the intervention group, the proportion of screened participants choosing kits vs in-clinic screening differed by several patient characteristics, highlighting opportunities to optimize self-sampling for priority groups.28 the proportion of HOME intervention group participants who screened by kit vs in-clinic was smaller, and differences in screening between groups was in the lower range of estimates from international trials.28 Thus, we sought to identify patient characteristics that modified the intervention effect or were differentially associated with kit uptake. The intervention effect was modified by cervical cancer screening history. Relative increases in screening were greater with longer vs shorter time since last screen, and greatest in individuals with no prior screening. In the intervention group, choice of screening modality varied by screening history. Individuals without prior screening were most likely to screen by kit vs in-clinic, followed by those with longer vs shorter time since last screening. International trials (with population-based registries to document screening history) demonstrated that mailing kits to long-term nonattenders increases screening participation,49 and some51 but not all48 showed larger relative effects with longer vs shorter nonattendance duration. However, relative differences in intervention effect size are impacted by screening uptake in the control group, which in HOME ranged from 3% to 10% in participants with no prior screening to 27% to 29% in those overdue by less than 2 years. Of note, absolute differences in screening by randomization group varied little by screening history. It is unsurprising that we observed differences in underlying screening uptake and modality in the US vs other international settings, because (1) the US lacks centralized national cancer screening programs, and (2) there are different implementation challenges and opportunities for HPV self-sampling.Although screening uptake in the mailed kit group (26.3%) was similar to screening uptake in underscreened individuals in a meta-analysis of international trials (25%),24 We found that mailed kits were effective at increasing cervical screening uptake in difficult-to-reach individuals who were also overdue for other recommended cancer screening. Relative intervention effect was greater in those overdue vs up-to-date with mammography, and there was a similar but nonsignificant difference by CRC screening adherence. Importantly, however, absolute differences in cervical screening uptake between groups were smaller for participants overdue for these other cancer screenings vs up-to-date. Results highlight the need for multipronged interventions to reduce cervical cancer underscreening in difficult-to-reach individuals, and potential opportunities for interventions targeting multiple care gaps . We previously evaluated whether the HOME intervention impacted subsequent receipt of other recommended screening. Although the intervention had no impact on mammography or CRC screening compared with usual care, intervention group participants who completed a kit were more likely to receive mammography or CRC screening than those who remained unscreened for cervical cancer.53Cervical, breast, and CRC underscreening are associated and share common correlates.15 and KPWA14 data show that among individuals aged 30 to 65 years, cervical cancer screening adherence declines with increasing age. HPV self-sampling may address barriers in older individuals related to negative prior screening experiences,55 embarrassment,56 or discomfort from speculum examinations that may be exacerbated by age-related vaginal atrophy and menopause.57 Associations between age and response to mailed HPV kits have been inconsistent across international studies, highlighting the importance of setting-specific data to inform implementation strategies.61We also saw a difference in intervention effect by age, with the largest relative and absolute increases in screening in the oldest groups, although the differences were not statistically significant. Additionally, compared with younger participants, older participants who were mailed kits were also significantly more likely to screen by kit vs in-clinic. US population-level65 that likely contribute to disparities in cervical cancer incidence and mortality.66 Screening barriers and patient-reported reasons for underscreening also vary by race and ethnicity, which may contribute to differences in intervention effectiveness across subpopulations.67 In HOME, neither race nor ethnicity modified the intervention effect on screening uptake. Within the intervention group, however, differences were seen. Kit uptake was highest in White participants and lowest in Native Hawaiian/other Pacific Islander and American Indian/Alaska Native participants. Additionally, the proportion of screened participants who returned kits ranged from a low of 24.2% in Native Hawaiian/other Pacific Islander participants to a high of 47.6% in White participants. Results suggest opportunities to increase self-sampling uptake in racial and ethnic subgroups by tailoring outreach strategies and/or kit components. Other studies reported differences in acceptance or uptake of self-sampling by race or ethnicity.68 There is also heterogeneity within racial and ethnic groups that we were unable to evaluate, but that may contribute to differences in screening rates and intervention effectiveness. Additionally, lower cervical cancer screening rates have been associated with limited English proficiency (in majority English-speaking countries) and recent immigrant status.70 HOME excluded individuals who require a language interpreter , precluding comparisons between those with and without limited English proficiency. In addition, we did not have data on country of birth (and the language restriction likely would have excluded most recent immigrants).In the US, there are documented disparities in cervical cancer screening rates by race and ethnicity17 tobacco use,18 and comorbidities26 are associated with underscreening, yet our results suggest HPV self-sampling can effectively increase screening participation in patients with these characteristics. Additionally, results did not vary by clinic travel time (with the caveat that most participants lived in urban settings).Intervention effectiveness did not differ by BMI, tobacco use, or comorbidities, and among those mailed kits, no significant differences in kit vs in-clinic screening uptake were observed by these patient characteristics. Higher BMI,71 including integration of the intervention into existing clinical protocols. Furthermore, to reduce participation bias and enhance generalizability, we enrolled all individuals identified as eligible through EMR data under a waiver of consent. Only 1.2% of intervention group participants opted out of medical record review and were excluded from this analysis of patient characteristic modifiers.A strength of this study is the pragmatic trial design,72 Additionally, there is potential for misclassification of patient characteristics derived from EMR data, especially race and ethnicity.73Mailing HPV kits through a research study rather than as standard care may have positively or negatively impacted screening uptake, and impacts may have been differential by patient characteristics. Additionally, the recommendation to attend in-clinic screening even after a negative self-sampling result may have negatively impacted screening uptake, with potential for differential impacts by patient characteristics. In addition to English language proficiency and country of birth, we were also unable to evaluate household income and education level due to limitations of EMR data. We used geocoded US Census tract household income, which has limitations as a proxy for individual-level household income.Within a US health care system, a mailed HPV kit intervention was associated with an 8.9% increase in screening compared with usual care, with clinically important increases observed across all sociodemographic and health characteristics evaluated. Although we identified some patient characteristics that modified intervention effectiveness, there were notable differences when comparing relative vs absolute effects. Absolute effects may be particularly relevant for health care system decision making around how to allocate resources for maximal impact on screening rates and cervical cancer prevention in high-risk groups. We also noticed differences in kit use by several patient characteristics, highlighting opportunities to optimize HPV self-sampling for priority subgroups. Most individuals in the intervention group remained underscreened, and uptake was particularly low (≤10%) in patient subgroups defined by long duration of cervical cancer underscreening, Native Hawaiian/other Pacific Islander or American Indian/Alaska Native race, and nonadherence to breast or CRC screening. Tailored interventions to reduce cervical cancer underscreening in these priority populations are needed.


Background: Enhanced Recovery after Surgery for mastectomy has resulted in increased use of outpatient same-day mastectomy (SDM). Whether SDM leads to increased readmissions or reoperations is not well documented. This study examines national data to compare outcomes of SDM to an overnight stay.Methods: We analyzed the American College of Surgeons National Surgical Quality Improvement Program Participant Use Data File from 2016 to 2018 for all mastectomy cases. Cases with a length of stay (LOS) >1 day were excluded. Cases were then categorized into 2 LOS cohorts: SDM vs 1-day LOS.Results: A total of 22,642 cases (80.8% 1-day LOS vs 19.2% SDM) were identified for the final analysis. Patients in the 1-day LOS group were more likely to be older , be female , and have greater comorbidity  compared to the SDM group. Multivariate analysis demonstrated no difference in risk for 30-day wound complications between the SDM and 1-day LOS groups. The risks for 30-day medical complications , reoperations , and readmissions  were higher in the 1-day LOS group. Even after excluding patients undergoing reoperation on the day of surgery, the risk for reoperations  remained higher in the 1-day LOS group. Characteristics associated with 1-day LOS were hypertension, steroid use, diabetes, dyspnea, dependent functional status, bilateral procedures, and breast reconstruction.Conclusion: We demonstrate that SDM is a safe procedure, with no increase in risk for 30-day postoperative complications. Appropriate patients should be offered SDM. Enhanced Recovery after Surgery (ERAS) for mastectomy has resulted in increased use of outpatient same-day mastectomy (SDM). SDM protocols have been described11 but have not been widely adopted across health care systems in the United States.Breast cancer is the most common malignancy among women in the United States, with an estimated 276,480 new cases diagnosed in 2020.16 However, whether the safety of SDM demonstrated at single integrated health care centers is generalizable to other institutions at the national level remains unclear. The primary purpose of this study was to examine 30-day outcomes of SDM using a large national database. The secondary outcome was to identify patient and operative factors associated with 1-day length of stay (LOS).The coronavirus disease 2019 pandemic has driven health care systems toward delivering more efficient, less costly, and safer patient care. The pandemic forced many institutions to re-examine their approach and criteria for patients who truly require an overnight hospital stay, and this effort increased interest in developing and implementing SDM protocols that minimize the need for an overnight hospital stay.We obtained institutional review board approval for this retrospective analysis utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Participant Use Data File from 2016 to 2018. Mastectomy cases were selected using Current Procedural Terminology codes 19303 and 19304 . We included elective procedures and only those with clean wounds (wound class I). Emergency cases and patients admitted with sepsis were excluded. We excluded cases with an LOS >1 day as these patients were likely to either have comorbidities that rendered them ineligible for SDM or may have already experienced a complication. Therefore, cases with an LOS >1 day were excluded to avoid bias to our data. The total number of eligible cases for this analysis was 22,642. Cases were categorized into 2 groups: SDM vs 1-day LOS. SDM was defined as patients discharged on the day of surgery, while 1-day LOS was defined as patients who stayed overnight and were discharged on postoperative day 1.The primary outcomes were 30-day total wound and medical complications, readmissions, and reoperations. Wound complications included superficial incisional surgical site infection (SSI), deep incisional SSI, organ space SSI, and wound disruption. Medical complications were defined as pneumonia, pulmonary embolism, urinary tract infection, cerebrovascular accident, myocardial infarction, bleeding transfusions, deep vein thrombosis/thrombophlebitis, sepsis, septic shock, reintubation, failure to wean off ventilator >48 hours, renal insufficiency, renal failure, and cardiac arrest requiring cardiopulmonary resuscitation. Secondary outcomes were patient and operative factors associated with 1-day LOS. The ACS NSQIP database does not collect hospital costs as a variable. We were also unable to collect our institutional cost data to provide any meaningful cost analysis of SDM vs 1-day LOS.t test to analyze differences in continuous variables . Multivariate analysis controlled for differences in comorbidity between groups and identified patient and procedure characteristics associated with 1-day LOS. All analyses were performed using SPSS Statistics, version 25 (IBM). A P value ≤0.05 was treated as statistically significant.We first analyzed the data by examining for any outliers and overall general trends. Next, descriptive statistics were used to examine the distribution of each outcome of interest. The Pearson chi-squared and two-sided Fisher exact tests analyzed differences in categorical variables between groups. Categorical variables included sex, race, comorbidity , functional status, American Society of Anesthesiologists (ASA) classification, and 30-day postoperative complications. We used P<0.01), be female , and have greater comorbidity  compared to the SDM group  were identified for the final analysis. Patients in the 1-day LOS group were more likely to be older  (data not shown).To avoid risk of bias by including patients with complications in the 1-day LOS group, we performed a subset analysis excluding patients with a day-of-surgery return to the operating room. Even after excluding these patients, the risk of reoperations remained higher in the 1-day LOS group , and scopolamine. Intraoperative regional nerve blocks can be successfully achieved with long-acting anesthetics, such as liposomal bupivacaine via a multilevel midaxillary intercostal nerve block.22 Cognitive impairment prior to surgery and decline in activities of daily living prior to surgery are both independent risk factors associated with 1-year functional decline after breast cancer surgery.22 Preoperative shoulder range of motion exercises reduce postoperative pain and expedite recovery after mastectomy.23 Diabetes has also been shown to increase the risk of postoperative complications and lengthen LOS for patients undergoing breast reconstruction.24Several patient characteristics are associated with 1-day LOS. Partially or totally dependent patients are likely to remain in the hospital longer because of their increased need for support to complete activities of daily living.27 Neoadjuvant chemotherapy, immediate breast reconstruction, or bilateral mastectomy does not increase the risk for hospital readmissions.28Operative characteristics correlating with 1-day LOS were bilateral procedures and breast reconstruction. We believe that the main reason for an overnight hospital stay is the concern for patient safety. Studies have shown that admitting breast reconstruction patients overnight does not prevent short-term complications, and early discharge has been shown to be quite safe in this population.28 High-volume breast surgeons who use perioperative intravenous acetaminophen and opioids in ERAS protocols increase the likelihood of SDM.28The above findings are consistent with a 2021 study that identified increased age, ASA class 3 or 4, bilateral operation, immediate reconstruction, estimated blood loss >100 mL, perioperative NSAIDs, and perioperative gabapentin to be associated with a lower likelihood for SDM.Our institutional patient selection criteria for SDM include unilateral or bilateral mastectomy, with or without sentinel lymph node biopsy; simple or complete mastectomy; and modified radical mastectomy, with or without immediate breast reconstruction. Patients excluded from our SDM protocol include those undergoing free-flap breast reconstruction and patients with significant medical comorbidities and/or inadequate family support systems. A case-by-case decision is made for patients on anticoagulation, on neoadjuvant chemotherapy, or with extensive disease burden in the axilla.29 As such, we believe that the dataset is a reliable source to investigate outcomes after SDM at the national level. As with any retrospective database study, we have no means of identifying the intention-to-treat grouping for cases. Consequently, confounding factors may exist that we were unable to control for in this study. Additionally, selection bias is likely regarding the patients eligible for SDM, as SDM is still in an early adoption phase, and only optimal candidates are probably being selected for SDM. Finally, the ACS NSQIP does not collect or report hospital costs. We were also unable to collect our institutional cost data to provide any meaningful cost analysis of SDM vs 1-day LOS.Our study has limitations. The ACS NSQIP database is only a cross-section of all mastectomy cases performed nationally each year. The 2018 dataset contained 1,020,511 cases submitted from 722 participating sites.This study demonstrates that SDM is a safe procedure, with no increase in risk for adverse 30-day postoperative complications. The risk of total wound complications was similar between the SDM and 1-day LOS groups. The risk for 30-day medical complications, readmissions, and reoperations was lower in the SDM group compared to the 1-day LOS group. Bilateral procedures, inclusive of immediate breast reconstruction, can be safely performed as an SDM procedure.


Attention-Deficit/Hyperactivity Disorder (ADHD) affects approximately 4.4% of adults in the US and impacts multiple domains of daily life including education, workplace performance and interpersonal relationships. Although an increasing number of individuals with ADHD are now entering later life, there is very little research on how ADHD risk may impact cognitive function during aging. As such, there is value in understanding the association between polygenic risk for ADHD and cognition during different stages of later life. This study utilized data from the Health and Retirement Study which surveys 37,000 Americans biennially and aimed to determine if there was an influence of ADHD risk on cognitive performance when individuals were young-old (ages 65-74) or middle-old (ages 75-84). Only participants who responded in 2006, 2016, and to the Venous Blood Study were selected. The resulting sample size of 403 African-ancestry individuals (AA) and 2286 European-ancestry individuals (EA) was compared on executive function-focused measures as well as delayed recall measures. Results showed that there was no significant effect of ADHD risk on memory-related measures at both time-points for AA and EA individuals. However, there was a statistically significant association between ADHD risk and performance on the executive function measure for EA older adults who were middle-old (p = 0.028), but not when they were young-old; no such association was observed for AA adults. This finding suggests that ADHD risk may influence cognition among older adults and has significant implications for treatment and care of individuals with ADHD throughout the life course.


This review describes the main benefits of using long axial field of view (LAFOV) PET in clinical applications. As LAFOV PET is the latest development in PET instrumentation, many studies are ongoing that explore the potentials of these systems, which are characterized by ultra-high sensitivity. This review not only provides an overview of the published clinical applications using LAFOV PET so far, but also provides insight in clinical applications that are currently under investigation. Apart from the straightforward reduction in acquisition times or administered amount of radiotracer, LAFOV PET also allows for other clinical applications that to date were mostly limited to research, e.g., dual tracer imaging, whole body dynamic PET imaging, omission of CT in serial PET acquisition for repeat imaging, and studying molecular interactions between organ systems. It is expected that this generation of PET systems will significantly advance the field of nuclear medicine and molecular imaging. Since the 1970s, when the first PET systems were built, there has been a significant evolution in PET technology. Over the last couple of years, progress in development of detector technology from photomultiplier tubes to silicon-based photomultiplier (SiPM) detector elements has led to the development of commercially available digital PET/CT scanners. With the introduction of SiPM-based digital PET/CT systems, time-of-flight (TOF) improved to a range of 210–400 ps and sensitivity increased up to 20 kcps/MBq [The latest improvement in PET system technology is the development of long axial field of view (LAFOV), or so-called “total-body”, PET/CT systems. Also equipped with SiPM-based detectors, these systems surround the patient with many more detectors in the axial direction resulting in two major improvements :higher detection efficiency as more photon pairs are captured.one bed position covers all relevant organs of interest simultaneously.To date, three LAFOV systems have been introduced: the uEXPLORER   with a 1This review will elaborate further on the advantages of LAFOV and provide an overview of novel clinical applications made possible by the use of short- and long-lived positron-emitting tracers within the context of LAFOV PET. Furthermore, the typical challenges encountered when implementing and validating a LAFOV system for clinical use will be discussed.The main characteristic of novel LAFOV PET/CT scanners is the possibility to cover the whole body (uEXPLORER) or the most important part of the body within an oncological setting (from skull vertex to mid-thigh) including all relevant organs (Quadra) in one single bed position. This provides four major advantages over PET/CT systems with a conventional FOV:Decreased acquisition time and the possibility to implement fast or ultra-fast acquisition protocols, thereby reducing motion artifacts and the need for sedation in e.g. children, which is particularly useful for scanning “difficult” patients, such as patients admitted to the Intensive Care Unit (ICU), severely debilitated patients, claustrophobic patients, or patients who cannot lay still due to neurological disorders or extreme pain.The possibility to reduce administered activity of radiopharmaceuticals with, a corresponding reduction in radiation exposure, which can be of invaluable importance in small children or babies, and in pregnant women.The improved spatial resolution and increased sensitivity may lead to higher diagnostic accuracy, especially in those cases which led to false-negative scan results on conventional FOV scanners, due to e.g., a very low grade tumor or a chronic low-grade infection site.The possibility to perform whole body dynamic PET imaging, without the need for arterial blood sampling, and including all relevant organs in the large FOV, providing the possibility to look at all relevant organs and possible (tumor) lesion simultaneously.68Ga , 11C  and 15O  can be used in the context of LAFOV PET – benefiting of the high sensitivity and large coverage in several clinically relevant ways.The short half-life of commonly used radionuclides such as Obvious benefits are, e.g., to increase the number of performed scans per produced batch/production run of these tracers because of the ability to inject a lower dose, scan faster, and inject at a timepoint longer after the production run – as the very high sensitivity of LAFOV PET systems will still allow for good quality scans. As these short lived tracers can be highly costly to produce, improving the utilization per production run in a clinical or research context may also be highly relevant from a financial perspective.15O-H2O is that it potentially allows for evaluating tracer uptake throughout the body before it decays beyond detectability, which currently requires multiple injections of the same tracer for multiple bed positions in case of conventional FOV systems. Capturing tracer dynamics with a single bed position covering alle relevant organs of interest is another benefit for short half-life tracers which, for example, brings whole-body 15O-H2O perfusion measurements with a single injection within reach, which could be highly relevant in infection/inflammation, cardiovascular and oncological imaging. A practical example of LAFOV PET/CT enabling late imaging of a short-lived radiotracer within the context of recurrent prostate cancer imaging using 68Ga-PSMA is provided by Alberts et al., who compared late imaging (4 h post injection (p.i.)) with standard imaging (1 h p.i.), with the aim of improving lesion to background and contrast [Furthermore, an obvious benefit of LAFOV combined with ultra-short half-life tracers such as 68Ga-PSMA with 18F-FDG in a dual-tracer same-day imaging protocol in patients referred for 177Lu-PSMA-radioligand therapy. In this protocol patients were scanned with the Quadra LAFOV PET/CT scanner 1 h postinjection of a standard dose of 68Ga-PSMA (150 MBq) and an additional low-dose (40 MBq) 18F-FDG scan one hour thereafter – with the combined protocol identifying lesions with low 68Ga-PSMA but high 18F-FDG avidity in 1 out of 14 (7%) patients [Also, and possibly clinically one of the most relevant benefits, LAFOV allows for combining a short-lived and longer-lived radioisotope scan within the same scan session or on the same day – while still staying within clinically acceptable acquisition time and cumulative patient dose limits. A good example of this is a recent study by Alberts et al. combining patients .89Zr). Advantages of 89Zr such as the long half-life of 78.4 h, matching the pharmacokinetic behavior of antibodies, and good in vivo stability, make it suitable for labeling monoclonal antibodies (mAbs) [89Zr-immunoPET can provide whole body information on (tumor) target expression [124I, which is used for the detection of differentiated thyroid cancer [18F with an abundance of 96%) [The most commonly used long-lived radionuclide is Zirconium-89 (s (mAbs) . 89Zr-impression . Another of 96%) , 12. Hen of 96%) .89Zr-labeled mAbs [89Zr activity results in a radiation exposure of up to 25 mSv.Currently, immunoPET is used almost exclusively in research settings in oncological patients with a relatively shorter life expectancy, because of the high mean effective doses (ranging from 0.36 to 0.66 mSv/MBq) associated with led mAbs . Adminis89Zr activity so that radiation exposures below 10 mSv become possible. This could allow for the use of immunoPET not only as a last resort in oncology, but also in (younger) patients with benign or inflammatory disorders, first in a research setting, and in the future maybe also in a routine clinical setting. For 124I imaging, improved image quality could lead to improved lesion detectability in thyroid cancer.LAFOV PET opens up several possibilities in the field of PET-imaging with long-lived tracers. The increased sensitivity leads to a better signal-to-noise ratio Fig. . FurtherThe higher sensitivity of LAFOV may also enable prolonged uptake time which is expected to result in an improved (tumor) lesion-to-background ratio. Combining delayed imaging with novel radioactive agents allows extended study of in vivo biology . FurtherClinical experiences with LAFOV PET systems have been compared with analog and digital conventional FOV PET systems. As well as experiences regarding clinical optimization using LAFOV PET alone. As the PennPET explorer is still in its prototype stage, this subsection will focus on existing comparison studies between commercially available conventional FOV and LAFOV PET systems, published up to November 2022.18F-FDG, 18F-PSMA-1007, and 68Ga-DOTA-TOC examinations. The comparison showed improved lesion detectability, reduced image noise levels, and visually improved visually image quality, all in favor of the Vision Quadra. In addition, it was concluded that LAFOV images of equivalent quality to images acquired for Alberts et al.  reported18F-FDG imaging using an LAFOV Vision Quadra PET/CT was confirmed by Van Sluis et al. [This potential to reduce scan duration for oncological s et al.  in a stu68Ga-PSMA-11 at 4 h p.i. were not only feasible, but even produced improved image quality compared with conventional FOV systems.Another, previously mentioned study by Alberts et al.  on an LA89Zr-labeled mAbs showed a remarkable improvement in image quality of patients scanned 4 days post p.i. [With respect to long-lived radionuclides, immunoPET with ost p.i. . In this18F-FDG total-body imaging [18F-FDG activity) compared with conventional PET/CT imaging. Furthermore, it was shown that the system was able to acquire total-body dynamic imaging data with high temporal resolution.The first clinical experiences with the uEXPLORER have been described by Badawi et al. in 5 patients undergoing different acquisition protocols including dynamic  imaging . The uEX imaging , was fou18F-FDG protocols (1.85 MBq/kg), Chen et al. [18F-FDG total-body PET imaging in 88 oncologic patients (3.7 MBq/kg) resulted in images with sufficient quality to meet clinical diagnostic requirements [Regarding evaluation of pediatric malignancies with half-dose n et al.  found thn et al.  which isirements , althoug89Zr-labeled minibody [89Zr-labeled mAb, high quality images were obtained with the possibility of deriving parametric Patlak images. This study highlighted that it is feasible to follow in vivo migration of T-cells using LAFOV PET, which allows for exploring functional aspects such as vaccine responses, but which may also be important for immunological research in general [In addition, one study examined the pathophysiological changes in CD8 + T cell distribution in recovering COVID-19 patients, using a minibody . When in general .90Y microspheres was investigated in two patients by Costa et al. [Finally, improvements in calculated liver dosimetry using the LAFOV uEXPLORER versus the conventional analog mCT PET/CT in transarterial radioembolization of liver tumors with a et al. . Even tha et al. . The impThe advantages of a highly sensitive LAFOV PET system over conventional PET systems in oncology can be divided in three major areas: reduction in administered activity or faster scanning in critically ill patients, prolonged time point imaging, and quantification of uptake as a marker of total tumor load. Especially in oncology, early response assessment is pivotal in distinguishing responders from non-responders. Reduction in administered activity opens the possibility to perform these response assessments more frequently. Furthermore, it opens op opportunities to perform scans with multiple different tracers to more accurately map the status of the disease. In case a patient is not responding to the treatment, a switch to an alternative treatment line can be made more swiftly, potentially resulting in less treatment related toxicity . As suchIn addition, LAFOV PET/CT scanning will contribute to a better understanding of the biodistribution of newly developed tracers, since different organ axes can be visualized and studied in one image. The addition of dynamically acquired kinetic information can play a role in the assessment of therapeutic efficacy . Further18F-FDG, the most commonly used radiopharmaceutical in clinical practice, the main advantages of an LAFOV PET/CT system is the reduction in scanning time which may lead to a higher patient throughput. It is not expected that the diagnostic accuracy, which is already high for most oncological diseases, will further increase  and fast (2 min) scans .18F-FDG tracers the benefits may be larger. For 18F-FES, used to evaluate estrogen receptor expression in patients with metastasized breast cancer, improved sensitivity may lead to a better differentiation between low and high ER expression within a single tumor lesion. Use of LAFOV may lead to improved image quality and better signal-to-noise ratios for the 68Ga-labelled tracers, as generally lower amounts of activity are inject for these types of tracers. Improved signal-to-noise ratio also holds true for 18F-FDOPA , either labeled with 68Ga or 18F, shows negligible background activity in the brain, resulting in In higher tumor to background ratios for brain metastases from gastric, breast, lung and liver cancers, and with a higher detection rate than for 18F-FDG [Using protocol . The autprotocol . It shou 18F-FDG .18F-FDG or other radiopharmaceuticals) for oncological stratification and follow-up may, at least in theory, provide in better understanding of this poorly understood syndrome as a basis for example for prevention, treatment or prognostication.The term “chemo-brain” is sometimes used to denote deficits in neuropsychological functioning, including difficulties with memory, attention, and other aspects of cognitive function, that may occur as a result of cancer treatment consisting of chemo- or systemic therapy. In the future, systematic PET imaging . AI is expected to play an increasingly critical part of imaging equipment reconstruction and post-processing pipelines in the field of nuclear medicine .A good example of the use of AI is given by a study of Ma et al., who showed that a deep learning reconstruction algorithm using raw LAFOV Quadra PET data as input had the potential to speed up image reconstruction and improve image quality without additional CT images . AnotherIn summary, in the (near) future, applying AI-based methods to the wealth of data produced by LAFOV PET/CT systems can help in improving image quality and quantification and even reduce the reliance on CT-based information  for corrections.Considering all the advantages mentioned above, one might think that buying and installing an LAFOV PET/CT system is a must, leading to lower administered activities, scanning new indications, new patient groups, scanning faster leading to a higher patient throughput. However, the last item is a big issue and does not simply come the purchase of an LAFOV PET/CT scanner. Several prerequisites have to be met , such asThis review paper aimed to provide an overview of the clinical opportunities and applications for clinical practice. Apart from improved image quality and lesion detectability with respect to conventional FOV PET/CT systems, LAFOV allows e.g., reduction in acquisition times, reduction in amount of radiotracer administration, but also delayed imaging to follow tracers including labelled mAbs in vivo over an extended period of time. Furthermore, the larger axial FOV allows simultaneous investigation of the functional crosstalk between organ systems as well as continuous dynamic PET imaging of all relevant organ structures simultaneously to map pharmacokinetic behavior of (new) tracers. The future holds many opportunities for optimizing existing clinical applications using LAFOV PET, for example with the development and application of AI-based methods, and many more that have yet to be explored and introduced.


Most participants (93.3%) completed the survey and memory quiz relatively rapidly (mean time of 8.84 minutes). Categorical regression was used to assess the contribution of COVID status, age, time post-COVID (number of months elapsed since having had COVID), symptoms, ongoing symptoms and gender, followed by non-parametric statistics. A principal component analysis explored the relationship between subjective ratings and objective memory scores. The objective memory scores were significantly correlated with participants’ own assessment of their cognitive function. The factors significantly affecting memory scores were COVID status, age, time post-COVID and ongoing symptoms. Our main finding was a significant reduction in memory scores in all COVID groups  compared to the non-COVID group. Memory scores for all COVID groups combined were significantly reduced compared to the non-COVID group in every age category 25 years and over, but not for the youngest age category (18–24 years old). We found that memory scores gradually increased over a period of 17 months post-COVID-19. However, those with ongoing COVID-19 symptoms continued to show a reduction in memory scores. Our findings demonstrate that COVID-19 negatively impacts working memory function, but only in adults aged 25 years and over. Moreover, our results suggest that working memory deficits with COVID-19 can recover over time, although impairments may persist in those with ongoing symptoms.Although coronavirus disease 2019 (COVID-19) affects the respiratory system, it can also have neurological consequences leading to cognitive deficits such as memory problems. The aim of our study was to assess the impact of COVID-19 on working memory function. We developed and implemented an online anonymous survey with a working memory quiz incorporating aspects of gamification to engage participants. 5428 participants successfully completed the survey and memory quiz between 8 Severe acute respiratory syndrome coronavirus SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), mainly affects the respiratory system, but can also impact neurological function , which c which caWorking memory, a form of short-term memory, is the dynamic process by which information is stored and retrieved while performing a task –12. WorkResearchers investigating the impact of COVID-19 on cognitive abilities have typically utilized researcher-led surveys and tests ,15–19. UThe primary aim of our study was to investigate the impact of COVID-19 on working memory function. We designed and utilized an online survey with a single working memory quiz which could be completed rapidly by participants (<15 minutes) via a variety of platforms including smartphones, tablets or personal computers (PCs). We anonymized the survey and memory quiz to maintain privacy and to increase participant recruitment. To motivate participants, we implemented aspects of gamification into the working memory quiz. In our analysis we evaluate the impact of COVID-19 status , recovery time, COVID-19 symptoms, ongoing symptoms, age and gender on objective memory scores.th of December 2020 and disseminated mainly via direct communication through personal and professional contacts as well as through local intranets and social media. Only participants who gave their active digital written informed consent were allowed to complete the survey and memory quiz. The CORONA survey and memory quiz was fully anonymous, no personal contact details were collected, and was in compliance with General Data Protection Regulations (GDPR). The data collected were stored on the Qualtrics platform where all the data were encrypted, and access authorization was restricted. Participants did not receive any compensation for completing the survey and memory quiz.The study was carried out in conformity with the Declaration of Helsinki  . Local eDuring the COVID-19 pandemic, have you had MORE problems with: Remembering things, Concentrating on simple tasks, Concentrating on complex tasks, Having a conversation, Thinking quickly, Thinking clearly, Getting tired easily after mental effort, Low mood, Fatigue.’ In addition, we used the same scale to assess whether they had more problems with vision, hearing, smell, taste, touch or pain, balance, and dizziness. Finally, they were asked to select their age range , gender, and country of current residence. No time limit was imposed upon participants to complete the survey questions.The survey/memory quiz was designed to be globally accessible, completed quickly, and engaging in order to maximize recruitment and completion. The online survey and memory quiz was developed using the Qualtrics platform accessed via a University of York license. The survey was accessible via a Uniform Resource Locator (URL) or a quick response (QR) code and was designed to work on smartphones, tablets, laptops and PCs with internet access. https://pixabay.com/ and Unsplash, https://unsplash.com/) and from the researcher’s personal image gallery. All images were edited using Adobe Photoshop CC 2015 software. Images of single-digit whole numbers were generated by the researchers using Comic Sans MS regular font. The backgrounds of all images were removed, and each image was rescaled and centralized onto a 500 x 500 pixel white background square with a black outline.We developed a visual working memory/recall task based upon modifications of the established and widely utilized visual simple picture span and the digit span tasks ,24. The Please complete the quiz in a QUIET place WITHOUT DISTRACTIONS.’ The animal category was presented first to encourage participants to engage with the memory task, followed by either the number or fruit categories (randomized). Based upon pilot testing, the object category was found to be relatively more difficult, so we opted to present this category last. For each image category, two different random images were shown consecutively. Each image was presented for 500ms and the interstimulus interval was randomly varied between 500-600ms . To determine the relative contribution of each independent variable to the objective memory scores we used categorical regression . First, we assessed the contributions of COVID status , symptoms , ongoing symptoms , age  and gender . A second categorical regression was performed on the COVID group only to evaluate the effects of time post-COVID (17 groups: ≤1 to 17 months) along with symptoms, ongoing symptoms, age and gender. Based upon the categorical regression analysis, we next examined the impact of the significant individual variables on objective memory scores utilizing non-parametric statistics: Mann Whitney U test and Kruskal-Wallis test with Dunn’s pairwise comparisons (Bonferroni corrected). Finally, we explored the relationship between subjective ratings in the survey and objective memory quiz scores. To reduce dimensionality of the 16 subjective questions, a principal component analysis (PCA) with orthogonal (varimax) rotation was performed. Relationships between variable pairs were evaluated using the Kendall’s tau-b correlation coefficients. All testing was two-tailed, and th December 2020 and 5th July 2021. Of these, 3722 participants reported not having had COVID-19, and 1706 participants reported having had COVID-19 between January 2020 and July 2021. A total of 5428 participants fully completed the CORONA survey and memory quiz between 82 = 0.035, and p < 0.001. For all participants (non-COVID and COVID groups), a categorical regression was used to determine the contributions of COVID status, COVID symptoms, ongoing symptoms, age and gender on memory scores. The analysis generated an overall regression coefficient of multiple determination of R2 = 0.04, with p < 0.001. For the COVID group only, a categorical regression was used to determine the contributions of time post-COVID (recovery time), COVID-19 symptoms, ongoing symptoms, age and gender on memory scores. The regression coefficient of multiple determination was RSince the categorical regressions revealed that the main factors affecting objective memory scores were COVID status, age, time post-COVID and ongoing symptoms, we evaluate these factors in more detail below. We used non-parametric statistics in all these subsequent analyses as a Kolmogorov-Smirnov test revealed that objective memory scores were not normally distributed .We found that objective memory scores decreased with age for both the non-COVID and COVID groups. A Kendall’s tau-b correlation showed a negative relationship between mean memory score and age for both the non-COVID  and COVID  groups across all eight age categories. All participants above 55 years old were combined to increase sample size due to the lower numbers of participants who completed the memory quiz in the higher age categories. We found that within the COVID group, objective memory scores increased with time (number of months) post-COVID. A Kendall’s tau-b correlation revealed a positive correlation between the number of months (≤1 to 17) since having had COVID and objective memory scores . 2 (120) = 50790.90, p < 0.001, indicated that correlations between items were sufficiently large for PCA. An initial analysis was run to obtain eigenvalues for each component in the data. Three components had eigenvalues over Kaiser’s criterion of 1 and in combination explained 63.49% of the variance. To reduce dimensionality and assess the intercorrelation between the subjective ratings of the 16 survey questions, a PCA with orthogonal (varimax) rotation was performed on. The Kaiser-Meyer-Olkin (KMO) measure verified the sampling adequacy for the analysis, KMO = 0.913, and all KMO values for individual items were > 0.670, which is well above the acceptable limit of .5 . BartletOur online approach led to the successful recruitment of 5428 participants over a period of seven months (68.6% non-COVID-19 and 31.4% with COVID-19). Our study indicates that the factors most affecting objective memory scores were COVID status, age, time post-COVID and ongoing symptoms. The main finding was that objective memory scores were significantly reduced in the self-reported, positive-tested and hospitalized COVID groups compared to the non-COVID group. These results suggest that COVID-19 affects working memory function. With respect to age, we found that memory scores for the COVID group were reduced compared to the non-COVID group in every age category 25 years and over, but not for the youngest age category (18–24 years old). For the COVID group, memory scores increased as the number of months elapsed since having had COVID-19, indicating that working memory deficits can recover over time. However, scores were reduced for those with ongoing COVID-19 symptoms suggesting that working memory impairments can persist in those who continue to suffer the effects of COVID-19.Our key discovery was a significant reduction in memory quiz scores in the COVID group N = 1706) compared to the non-COVID group (N = 3722). This finding provides quantitative evidence that COVID-19 negatively impacts working memory function. The reduction in memory scores is consistent with the short-term memory deficits reported in smaller scale studies using screening questionnaires, paper-based assessments or in-person testing 06 compar,18,19,26Although the difference in objective memory scores between the COVID and non-COVID group was statistically significant it was small. However, a small change in working memory might substantially impact performance of everyday tasks. To support this, we found that objective memory scores correlated strongly with participants’ own assessment of their cognitive function; participants who reported more severe subjective ratings for cognitive questions had lower objective memory scores. Moreover, participants who were hospitalized for COVID-19 showed a marked drop in objective scores and an increase in severity in the subjective ratings. In line with these results, one study reported that 55% of hospitalized patients had working memory deficits , and othIn contrast to our findings, a large-scale study found that complex cognitive functions  were generally more affected while simpler cognitive functions (basic working memory tasks) were relatively spared in those with COVID-19 . NeverthIn our study we found that objective memory scores declined with age regardless of COVID status. This shows that our memory quiz is sensitive to the well documented steady decline in working memory beyond early adulthood as has been reported in a range of other memory tasks ,14. InteIn terms of recovery from COVID-19, objective memory scores in the COVID group increased in the months following COVID. This suggests that working memory decline due to COVID-19 is not permanent but does have the capacity to improve over time. In addition, our data indicates that it takes approximately 12 months to recover from the decline in working memory to the point that scores are not significantly different to those who do not have COVID-19. Similarly, a steady recovery over 12 months was found in a study of COVID-19 survivors (N = 24) using a delayed episodic memory task .Approximately 50% of our COVID group reported having ongoing COVID symptoms while completing the survey and memory quiz. This substantial percentage has implications on the burden upon people with COVID-19 symptoms, health service providers and society. Similar ongoing symptoms have been reported in those with long COVID ,28. For One limitation with our survey and memory quiz was that it was not conducted under controlled laboratory conditions. For instance, the presence of a researcher may encourage a participant to take the survey more seriously and answer the questions accurately. However, requiring the presence of a researcher would make the study more practically challenging and would limit the number of participants that could be recruited. Furthermore, the presence of a researcher does not necessarily ensure that participants will complete all aspects of the survey and memory quiz accurately. It is also possible that participants may have been distracted during our memory quiz thereby affecting the scores. We attempted to mitigate against this possibility by instructing participants to complete the quiz in a quiet place without distractions. Nevertheless, the large number of participants in both the COVID and non-COVID groups was able to provide sufficient power to reveal a highly significant difference. Another limitation in our study is the possibility that the non-COVID group could have included participants who were COVID-19 positive but were asymptomatic.In our study, 31.4% of participants reported having had COVID-19 between January 2020 and July 2021. These included those who self-reported, tested positive and were hospitalized with COVID-19. Since COVID-19 tests were not commonly available in the earlier stages of the pandemic, we allowed participants to self-report whether they thought they may have had COVID-19. We cannot be certain whether these participants in fact had COVID-19. However, we found no significant difference in memory scores between the self-reported COVID group and those who tested positive for COVID, whereas there was a significant difference in memory scores between the self-reported COVID group and the non-COVID group. Therefore, it would be reasonable to consider that most self-reports of COVID-19 are likely to be correct.The majority of participants (93.3%) were able to finish our survey and the memory quiz within a relatively short period (mean time of 8.84 minutes). In contrast, most other investigations of COVID-19 presented multiple cognitive tasks and questionnaires ,7,18–21.While our study provides evidence that working memory is negatively impacted by COVID-19, the underlying mechanisms for this are unknown. Several pathophysiological mechanisms underlying the neurological impact of COVID-19 have been proposed, including neuroinflammation, vascular dysfunction , coagulopathy, and pre-existing co-morbidities ,29,30. IS1 File(XLSX)Click here for additional data file.


IR does not provide long-term benefits to patient recovery after primary uncomplicated TKA under the current rehabilitation regime.Inpatient rehabilitation (IR) is a common postoperative protocol after total knee replacement (TKA). Because IR is expensive and should therefore be justified, this study determined the difference in knee function one year after TKA in patients treated with IR or outpatient rehabilitation, fast-track rehabilitation (FTR) in particular, which also entails a reduced hospital length of stay. A total of 205 patients were included in this multi-center prospective cohort study. Of the patients, 104 had primary TKA at a German university hospital and received IR, while 101 had primary TKA at a Canadian university hospital and received FTR. Patients receiving IR or FTR were matched by pre-operative demographics and knee function. Oxford Knee Score (OKS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and EuroQol visual analogue scale (EQ-VAS) determined knee function one year after surgery. Patients receiving IR had a 2.8-point lower improvement in OKS ( Over the last two decades, the number of total joint replacement surgeries has consistently increased due to ageing in Western societies and growing numbers of people with overweight or obesity . Due to IR after TKA is common practice in Western European countries. IR usually includes 3 weeks of medical rehabilitation at a rehabilitation center to reintroduce patients to independent living and social integration. Patients receive daily physical therapy, occupational therapy, and functional training. In addition, patients are provided accommodation and daily meals. After discharge from IR, outpatient physical therapy is continued for four more weeks.Post-TKA fast-track rehabilitation (FTR) was developed with the goal of reducing costs and providing patients with a faster return to home while maintaining comparable functional outcomes. FTR entails a reduced length of stay in the hospital with discharge to home and not to IR. Outpatient physical therapy or inhouse visits by a physical therapist help patients to regain their knee function and return to an independent lifestyle, while forgoing IR can save a patient $3450 .Because of the potential cost reduction, multiple countries have steered away from utilizing IR after uncomplicated TKAs . One of Multiple studies—mainly performed outside Germany—have demonstrated equal or even improved patient joint function when FTR after TKA or total hip arthroplasty was compared to IR ,5,6,7. WAccordingly, the purpose of the study was to compare the functional improvement after TKA among patients receiving IR in Germany with patients receiving FTR in Canada. The hypothesis was that FTR results in comparable functional improvement one year after TKA. A follow-up period of one year seemed reasonable, since knee function reaches a plateau within the first postoperative year, which remains stable in the following years ,9,10,11.The study was planned and conducted as a transnational evaluation of prospectively collected data, in which the one-year clinical improvement after the Canadian FTR and the German IR following primary TKA was compared. The study was a mutual project of the orthopedic departments of University of British Columbia, Vancouver, Canada, and Julius Maximilian Universität, Würzburg, Germany. IR for the German patients took place at a preselected rehabilitation center. Canadian patients instead conducted outpatient physical therapy with corresponding home exercises or through home visits by a physical therapist.Upon receipt of approval from both the Canadian  and German  institutional ethics boards, we identified all patients between December 2019 and February 2020 who fulfilled the criteria for medical need for TKA treatment. Included were all patients with primary osteoarthritis and radiographic evidence of Kellgren–Lawrence grades II-IV osteoarthritic changes who underwent an uncomplicated unilateral TKA using the Stryker Triathlon TKA System. Patients receiving simultaneous bilateral TKAs, patients with previous fracture of the affected lower extremity, patients with metabolic or inflammatory joint disease , and patients not following the standardized postoperative rehabilitation regime were not eligible to participate in the study. Patients lost to follow-up were excluded from the final data analysis.During the above-mentioned time-period, a total of 117 TKAs were performed at the German hospital, of which the Stryker Triathlon System was used in 113. Nine patients were lost to follow-up, leaving 104 patients for final analysis. In Canada, 115 TKAs were performed in the above-mentioned time-period, all utilizing the Stryker Triathlon System; 14 patients were lost to follow-up, leaving 101 patients for final analysis .All TKAs were performed using a standard medial parapatellar approach, mechanical alignment principles, and a cruciate retaining femoral component with a cruciate retaining (CR) or cruciate-substituting polyethylene (CR-CS) Triathlon TKA system .The target hospital length-of-stay for the IR patients was 4–5 days before they were transferred to IR. IR was scheduled for three weeks and included daily physical therapy, occupational therapy, and functional training. In the FTR group, the target hospital length-of-stay was 1–2 days before home discharge and onset of outpatient rehabilitation. Outpatient rehabilitation included physical therapy twice per week for 6 weeks with instruction to perform independent exercises at home.To compare the baseline health status between the two groups the pre-operative age, sex, body mass index (BMI), and American Society of Anesthesiologists (ASA) Physical Status score were obtained. To evaluate and assess knee function and the functional improvement after TKA the following patient-reported outcome measures (PROMs) were conducted. The Oxford Knee Score (OKS) is scored from 0 (worst) to 48 (best) and assesses knee function before and after TKA. It is self-conducted by the patient and comprises 12 questions that are divided into two subscales: pain and physical function. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a self-administered questionnaire to assess pain, function, and stiffness of the knee. The descriptors range from no difficulty (0 point) to extreme difficulties (4 points). The WOMAC Score is a commonly used standardized questionnaire to evaluate the condition of patients with osteoarthritis of the knee and hip. The WOMAC is scored from 0 (best) to 96 (worst). Furthermore, the EuroQol visual analogue scale (EQ-VAS), which measures health-related quality of life, was completed by patients. It is scored from 0 (worst to 100 (best) and quantifies the patient’s perception of their health state. It is self-conducted by the patient and has 5 different dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.The difference between the OKS, WOMAC, and EQ-VAS obtained pre-operatively and at the one-year follow-up visit defined clinical improvement. The minimum clinically important difference (MCID) for OKS was 5.0, for WOMAC, 10, and for EQ-VAS, 8.0 ,13,14.In unadjusted analyses, IR and FTR were compared with pre-operative age, sex, BMI, ASA, OKS, WOMAC, and EQ-5D VAS. Binary or categorical comparisons were made via exact chi-squared tests, while continuous comparisons were made via the Wilcoxon rank-sum test. Adjusted multivariable linear regression models were fitted to predict improvements from pre-operative to follow-up in OKS, WOMAC, and EQ-5D VAS vs. rehabilitation protocol, adjusting for age, sex, BMI, ASA, and the pre-operative value of the PROM being analyzed. Fit of linear regression models were assessed via normal quantile–quantile plots of the standardized residuals. Fit of logistic regression models were assessed with the Hosmer and Lemeshow goodness-of-fit test at alpha = 0.05 . SAS sofA total of 205 patients participated in the study with available PROMs at 1-year follow-up. Patient pre-operative demographics and knee function were comparable between the FTR and IR groups .p-values of 0.001 and 0.063, respectively. The EQ-VAS tended to improve more after IR (24.2 ± 26.9) than after FTR (11.9 ± 24.2) (p = 0.281) (Patients receiving IR had a significantly lower mean improvement in OKS (14.0 ± 10.7) and a trend of lower improvement in WOMAC (−26.5 ± 25.5) than patients receiving FTR , resulting in adjusted models for = 0.281) . All difThe most important finding from the present study was that FTR after TKA did not result in inferior functional improvement when compared to IR. Indeed, patients receiving FTR showed higher improvement in PROMs than patients receiving IR. While outcomes scores at one year were higher in the FTR group regardless of the degree of improvement, this difference was not clinically significant. These results may encourage insurance companies to recommend FTR to their patients, as FTR does not compromise patient outcome.These findings agree with multiple international studies comparing outpatient and inpatient rehabilitation ,7. ProspIn addition to providing comparable functional recovery, FTR has also been shown to reduce costs . These cBecause this study favors FTR due to comparable or slightly higher functional improvement one year after TKA, it could motivate carriers of IR facilities to reorient the focus of their rehabilitation regime. One potential reason that patients after FTR achieve higher improvement than after IR is the self-guidance and patient responsibility to regain their independence and function. The self-guidance potentially improves function in two ways. (1) It fosters salutogenesis by focusing the patient towards solving problems after TKA, which include regaining range of motion, mobility, and strength . (2) It There are some limitations to this study. First, the difference in clinical improvement could be influenced by country-specific pain awareness of patients and their interpretation of functional limitations. Because the pre-operative OKS and WOMAC were not different between the two countries and because the comparison of clinical improvement was normalized to the pre-operative PROM, the country-specific influence on clinical improvement should be minimal. Second, because patients were treated by two different orthopedic surgeon teams in different countries, multiple variables can influence patient clinical improvement besides the rehabilitation protocol. To minimize the influence of other variables, we ensured that surgical technique, component alignment target, and component design were identical between patient groups. Consequently, only a single hospital participated in Germany and in Canada, which could limit the generalizability of the results. Still, these were large teaching hospitals with high volumes, and as such were representative for the comparison of the two different rehabilitation protocols. Third, a cost analysis and comparison between both rehabilitation protocols could not be made, since profoundly different reimbursement policies were used. However, the gained knowledge from this study that functional gains after TKA are not compromised by omitting IR could motivate German insurance carriers, hospital systems, and healthcare authorities to conduct prospective studies analyzing the financial impact of omitting IR after uncomplicated TKA. Fourth, shorter follow-up intervals within the first year after TKA could have provided a more detailed comparison between FTR and IR . IdeallyAmong adults undergoing primary TKA, the use of IR compared with FTR does not yield a higher improvement in knee function. These findings do not support IR for this group of patients with the current rehabilitation regime. This study can provide a thought-provoking impulse to IR carriers to reorient their focus on rehabilitation after TKA by fostering patient salutogenesis.


Among the structural variants observed in metastatic colorectal cancer (mCRC), deletions (DELs) show a size preference of ~10 kb–1 Mb and are often found in common fragile sites (CFSs). To gain more insight into the biology behind the occurrence of these specific DELs in mCRC, and their possible association with outcome, we here studied them in detail in metastatic lesions of 429 CRC patients using available whole-genome sequencing and corresponding RNA-seq data. Breakpoints of DELs within CFSs are significantly more often located between two consecutive replication origins compared to DELs outside CFSs. DELs are more frequently located at the midpoint of genes inside CFSs with duplications (DUPs) at the flanks of the genes. The median expression of genes inside CFSs was significantly higher than those of similarly-sized genes outside CFSs. Patients with high numbers of these specific DELs showed a shorter progression-free survival time on platinum-containing therapy. Taken together, we propose that the observed DEL/DUP patterns in expressed genes located in CFSs are consistent with a model of transcription-dependent double-fork failure, and, importantly, that the ability to overcome the resulting stalled replication forks decreases sensitivity to platinum-containing treatment, known to induce stalled replication forks as well. Therefore, we propose that our DEL score can be used as predictive biomarker for decreased sensitivity to platinum-containing treatment, which, upon validation, may augment future therapeutic choices. Large cohorts of primary cancers analyzed by whole-genome sequencing (WGS) were recently described , yieldinFHIT and MACROD2 were most often identified (>40% of CRC cases).One result was that deletions in genes present in common fragile sites (CFS) were associated with response to therapy, and this current manuscript further investigates this. Large deletions, along with tandem duplications (DUPs), inversions, and translocations, are a class of structural variants (SVs) observed in most cancer types. In a primary pan-cancer study, these SVs have recently been extensively described, reporting high numbers of complex SVs, deletions, and tandem duplications in over 20 cancer types, including colorectal cancer. Other types of SVs are reported in virtually all cancer types, but at lower frequency. However, CFSs were only briefly discussed . Among aFHIT, WWOX, PDE4D, PARK2). In terms of the mechanism driving the genome fragility of these regions, Wilson et al. distilled their observations in cell lines to a possible model involving a transcription-dependent double-fork failure (TrDoFF) [CFSs are a decades-old observation , quickly(TrDoFF) . In shor(TrDoFF) ,16. We here aimed to have a detailed look into the role of the DELs in metastatic lesions of 429 mCRC patients, using WGS and corresponding RNA-sequencing data. We evaluated whether the instability at CFSs described in primary CRC persists in metastatic disease. We specifically studied the localization and size of DELs and DUPs, and included expression of the genes affected by these SVs. Lastly, we investigated the potential clinical consequences of these characteristics.We previously described  density RBFOX1 in p = 1.29 × 10−246, odds ratio 5.697). For TADs, 84% vs. 90% of DELs were in between TADs outside and inside hotspot regions, respectively (chi-square p = 5.96 × 10−25), and with an odds ratio of 1.738, having a much smaller effect size compared to Ini-seq peaks. A multivariable logistic regression of DELs within Ini-seq peaks and TADs with being inside or outside hotspot region as outcome variable showed odds ratios of 5.43 and 1.14 , respectively, indicating that Ini-seq peaks have an exceedingly larger role in bordering DELs in the hotspot regions. We next used previously reported locations of several potentially relevant genomic features to investigate the reason behind the preference for the DEL size, including topologically associated domains (TADs)  and siteSince it is well known that CFS regions are late-replicating, it seems reasonable that replication origins (identified by the Ini-seq peaks) are of importance for SVs therein, and it is likely that the observed preference of DEL sizes in mCRC are restricted by the location of the bordering Ini-seq peaks. A histogram of the distances between all consecutive Ini-seq peaks c showed These observations suggest that the DELs may be a consequence of stalled replication forks, the reason for their stalling likely linked to the particular genomic milieu. A potential solution for these stalled replication forks was proposed by the transcription-dependent double-fork failure (TrDoFF) model ,14, in wNAALADL2 , one of the genes with many DELs, was expressed and located between Ini-seq peaks, while the neighboring NLGN1 gene, also large (size 898 kb) and located between Ini-seq peaks, but having no accompanying DELs, was not expressed. We verified this observation genome-wide by selecting large genes (>500 kb) within and outside the 13 CFS regions but positioned between Ini-seq peaks (n = 147 genes). We showed that the median gene expression level of the genes inside the hotspot regions was significantly higher (Mann–Whitney p = 0.0013) than that of the genes outside hotspot regions . The hotspot region on chr 8 has no gene annotated to the region where DELs/DUPs are located. An uncharacterized noncoding RNA LOC105375631 is located nearby, and visual inspection of RNA-seq bam files shows some mapped reads there (data not shown).Of note, not all 13 hotspot regions contained a single large gene at the location where DELs were observed . For theIn summary, the specific DEL size and DEL/DUP position seen in mCRC appeared to be guided by two observations: (1) the origins of replication flanking the CFS regions and (2) active transcription. The TrDoFF model proposes that the combination of late replication and transcription of large genes gives rise to double-fork failure. The disentanglement of that complex yields DELs and DUPs at specific locations which precisely fit with the observations presented here. WWOX in a single sample. For samples with available RNA-seq data, we searched for sequence reads that corroborate the DEL reported at DNA level in that sample, by identifying reads that cross the junction created by the DEL. In total, 305 sequence reads were identified in 44 samples . Though WWOX, PARK2) were associated with response to platinum-containing therapy [We considered the number of DELs (10 kb–1 Mb) within the 13 hotspot regions as a biomarker for the ability to circumvent stalled replication forks. We hypothesized that such a mechanism would act on any double-fork failure, not necessarily transcription-dependent or just those in CFS regions. Since we previously observed that loss of some of the genes in hotspot regions . A subset of patients that were given platinum-containing therapy after biopsy were also previously treated with this agent , a clinical decision often taken when the patient had a relatively good response . A multivariable analysis to test the association of RSF status, prior platinum therapy, and the number of prior-treatment lines with PFS on subsequent platinum-containing therapy showed a relative hazard ratio (HR) for RSF+ of 3.01 , HR = 0.83  for prior platinum therapy and an HR of 1.58  for the number of prior-treatment lines.In total, 118 patients received platinum-containing therapy after biopsy . The group of patients with any prior treatment (platinum or other) was too small to perform a statistically meaningful analysis, with only two RSF+ patients in either prior containing platinum or prior other. These four patients did show a similar trend with a PFS < 250 days.Lastly, patients who did not receive any prior systemic treatment before biopsy also showed a significantly shorter PFS on platinum-containing therapy in RSF+ patients  also among the reported regions here. Using their pan-cancer set of primary tumors, Li et al. reported 18 CFS regions [We here describe an in-depth analysis of DELs in metastatic lesions of 429 CRC patients. The density profile of DELs in mCRC is distinct from those in metastatic breast- and prostate-cancer but bears resemblance to a profile seen in, e.g., primary esophagus and pancreas cancer , with th regions , of whic regions . In shorTo the best of our knowledge, we are the first to match observations in a large cohort of metastatic CRC patients with four essential features of the TrDoFF model: (i) sparsity of replication origins, (ii) transcription, and the (iii) presence and (iv) position of DELs and DUPs. For the latter three features, we were able to use in-house data only; for the sparsity of origins we additionally required public data (Ini-seq peaks) which were based on a replication origin mapping technique whereby newly replicated DNA is labeled and sequenced . The posIndirect clues for other contributing factors come from the observation that patients that received platinum-containing treatment prior to removal of the metastatic biopsy showed a significantly higher number of DELs in CFS. Platinum compounds induce crosslinks between two bases, either GG or AG, in DNA ,21 whileIn conclusion, we here present data that show that CFSs are still present in mCRC, providing an explanation for why DELs observed in mCRC are of a certain size, and that the observations agree with a model of transcription-dependent double-fork failure as modus operandi for DELs (and DUPs) in CFS. This ability to resolve stalled replication forks is associated with resistance to platinum-based therapy, which may provide new prospects for clinical decision making.https://github.com/lh3/bwa). Of all tumor biopsies, 98% had a coverage of at least 30 × (95% with >60 × coverage), whereas for the normal blood, 98% had >10× coverage and 94% >20 × coverage. Structural variants were called using GRIDSS v1.8.0 [https://github.com/hartwigmedical/hmftools/tree/master/isofox). Metastatic patients starting any new systemic treatment were included, and the particular treatment given to participating patients was decided by the local clinicians. The types and lines of systemic treatment given before the biopsy was taken were recorded; in total, 241 patients received a platinum-containing therapy before biopsy, mostly Oxaliplatin in combination with Capecitabine (n = 231), while 124 patients were treatment-naïve at the time of biopsy. Furthermore, response to treatment after biopsy was evaluated; 118 patients received a platinum-containing therapy after the biopsy was taken with available progression-free survival data  in the form of a combination of Oxaliplatin + Capecitabine with/without Bevacizumab). The cohort consists of 429 metastatic biopsies taken from colorectal cancer patients gathered as part of the Center for Personalized Cancer Treatment (CPCT) consortium , which was approved by the medical ethics committee of the University Medical Center Utrecht, the Netherlands [S v1.8.0 . RNA-seqp < 0.05. Stata 13.0  and R (v3.6.0) were used for the statistical analyses. R package “mcp” (https://github.com/lindeloev/mcp/) was used to perform piecewise linear regression in order to find change points in the number of deletions per sample. The midpoint between the first two changepoints was selected to indicate samples with a high nr of DELs (>20). KaryoploteR [For categorical data, a Pearson’s chi-squared test was used while continuous variables were evaluated using a Mann–Whitney U-test (MWU). All statistical tests were two-sided and considered statistically significant when yoploteR  was usedyoploteR .