In the absence quality metrics for end-of-life care in pediatric cardiac intensive care units (CICUs), how do interdisciplinary staff perceive quality of dying and death (QODD)?In this cross-sectional survey study of 713 medical professionals involved in 60 deaths in the CICU, the pediatric intensive care unit (PICU)–QODD instrument was a reliable and valid measure of QODD in CICUs, with overall positive perceptions of QODD yet negative perceptions of the 7 days prior. Lower PICU-QODD scores were reported by nursing or allied health staff, by less experienced staff, for patients with cardiac-surgical admissions and comorbidities, and for deaths following treatment limitation or misaligned with family wishes.These data could guide strategies to improve staff well-being and end-of-life experiences. This cross-sectional study evaluates the Pediatric Intensive Care Unit Quality of Dying and Death instrument and examines differences between disciplines and end-of-life circumstances. Lack of pediatric end-of-life care quality indicators and challenges ascertaining family perspectives make staff perceptions valuable. Cardiac intensive care unit (CICU) interdisciplinary staff play an integral role supporting children and families at end of life.To evaluate the Pediatric Intensive Care Unit Quality of Dying and Death (PICU-QODD) instrument and examine differences between disciplines and end-of-life circumstances.This cross-sectional survey included staff at a single center involved in pediatric CICU deaths from July 1, 2019, to June 30, 2021.Staff demographic characteristics, intensity of end-of-life care , mode of death , and palliative care involvement.PICU-QODD instrument standardized score ; global rating of quality of the moment of death and 7 days prior  and mode-of-death alignment with family wishes.P < .001) and for less experienced staff . Mean PICU-QODD scores were lower for patients with comorbidities, surgical admissions, death following treatment limitation, or death misaligned with family wishes. No difference was observed with palliative care involvement. High-intensity care, compared with low-intensity care, was associated with lower median (IQR) rating of the quality of the 7 days prior to death  and of the moment of death .Of 60 patient deaths , 33 (55%) received intense care. Of 713 surveys (72% response rate), 246 (35%) were from nurses, 208 (29%) from medical practitioners, and 259 (36%) from allied health professionals. Clinical experience varied (298 [42%] ≤5 years). Median (IQR) PICU-QODD score was 93 (84-97); and quality of the moment of death and 7 days prior scores were 9 (7-10) and 5 (2-7), respectively. Cronbach α ranged from 0.87  to 0.92 , and PICU-QODD scores significantly correlated with global rating and alignment questions. Mean (SD) PICU-QODD scores were more than 3 points lower for nursing and allied health compared with medical practitioners (nursing staff: 88.3 [10.6]; allied health: 88.9 [9.6]; medical practitioner: 91.9 [7.8]; In this cross-sectional survey study of CICU staff, the PICU-QODD showed promise as a reliable and valid clinician measure of quality of dying and death in the CICU. Overall QODD was positively perceived, with lower rated quality of 7 days prior to death and variation by staff and patient characteristics. Our data could guide strategies to meaningfully improve CICU staff well-being and end-of-life experiences for patients and families. Second, interdisciplinary  and interprofessional  practitioners with differing experience, perceptions of benefits and burdens, and acceptability of outcomes work together. Third, responsibility for decision-making for pediatric CICU patients is shared by families and teams.16 Furthermore, low mortality means survival is expected, even in severe critical illness.17 Finally, childhood death violates the natural generational cycle and results in profound grief in bereaved families. These complexities contribute to conflict, may adversely affect staff perceptions of end-of-life care, and contribute to moral injury.Despite medical and surgical advancements, congenital and acquired heart disease remains a leading cause of childhood mortality.19 CICU staff play an integral role supporting children and their families at end of life, yet despite complexity, no studies, to our knowledge, have examined interdisciplinary perceptions of CICU QODD, and no universally accepted end-of-life outcome measures exist in this setting.20 In the absence of quality indicators and with challenges ascertaining family perspectives, staff perceptions of the quality of end-of-life care are highly valuable to inform optimal care delivery.21Quality of dying and death (QODD) is a construct that evaluates perceptions of end-of-life care with measurement tools validated for adults and pediatric intensive care units (PICUs).22 We evaluated staff perceptions of QODD in the CICU and differences between disciplines and end-of-life circumstances.Exploring interdisciplinary perceptions of QODD offers an opportunity to identify strategies to positively affect end-of-life experiences for children with heart disease and their families and staff well-being.STROBE) reporting guideline for cross-sectional studies. All CICU deaths over a 2-year period  were included. Interdisciplinary staff directly involved in patient management in the 72 hours before death or as continuity clinicians  were identified by the bereavement coordinator, approached, and invited to participate. Staff included bedside nurses, allied health staff , and medical practitioners   . Respons25 The PICU version better captures contextual differences in pediatric end-of-life care following modifications based on clinician and bereaved family interviews . Second, acknowledging contemporary focus on end-of-life goal-concordant care,28 we introduced an ad hoc question to ascertain knowledge of and alignment of the mode of death with the family’s wishes  as well as 2 global rating questions querying quality of the moment of death and quality of life in the 7 days prior .19 Finally, staff had the opportunity for free text responses.For this CICU study, we made several PICU-QODD instrument modifications based on pilot data and to incorporate suggestions from prior instrument use.19 As the PICU-QODD score was validated in the PICU population, we first attempted to validate the instrument in the pediatric CICU. We assessed performance by reporting proportions of surveys with an invalid score, a score of 0 or 100, and skewness of score distribution. Commonly used criteria suggest that less than 15% of surveys should be missing responses, less than 15% should take a value of 0 or 100, and skewness should not exceed 2.29 Internal consistency of individual items was assessed using Cronbach α. To evaluate construct validity, we examined Spearman correlations between the standardized score and global quality ratings; we would expect these measures to be positively correlated. We also calculated standardized scores for surveys on which respondents reported that the death did vs did not align with family wishes; we would expect that the median score should be higher for aligned deaths.A standardized PICU-QODD score (range 0 to 100) was calculated for surveys with at least 80% responses by summing individual item scores, dividing by the number of questions answered, and multiplying by 10.3Patient-level data collected from electronic medical records included demographic characteristics, diagnoses, palliative care involvement, and medical therapies used over the 7 days prior to death. Medical therapies included cardiopulmonary resuscitation (CPR), mechanical support (ECMO or ventricular assist device [VAD]), invasive or noninvasive ventilation (NIV), level of awareness, sedative and paralytic infusions, mobility , inotropes, and enteral nutrition . Medical intensity of end-of-life care was dichotomized as low or high. Low intensity included patients not requiring CPR, ECMO, or VAD; inotropes without respiratory support; or NIV or invasive ventilation with a maximum of 1 inotrope. High intensity was defined as requiring invasive ventilation with more than 1 inotrope, having an open chest, or receiving ECMO or CPR during the 24 hours prior to death. Mode of death was categorized as maximal resuscitation with CPR, treatment limitation (death despite ongoing cardiorespiratory support), discontinuation of life-sustaining therapy (active cessation of cardiorespiratory support), comfort care only (no interventions), and brain death.19 Secondary outcomes included individual instrument questions evaluating pain control, symptom management, and conflict; global rating questions; and alignment. Associations between survey responses and patient and staff characteristics were evaluated using univariate regression analyses with Huber-White estimates of the model coefficient SEs to account for correlation among multiple surveys completed for the same patient. Linear regression was used for the standardized PICU-QODD score and ordinal regression for individual items. To evaluate potential confounding because of missing data and response bias, sensitivity analyses were performed calculating PICU-QODD scores using all surveys and surveys with greater than 50% completion rate, as well as bivariate models adjusting for discipline. Unit of analysis is at the decedent level and all survey data analyses account for within-patient correlation. Analyses were performed in Stata version 16 (StataCorp). All tests were 2-sided and conducted at the .05 level of significance.We summarized categorical variables using frequencies and percentages, ordinal scores using medians and IQRs, and continuous variables using means and standard deviations or medians and IQRs. The standardized PICU-QODD score was the primary outcome.Sixty patient deaths occurred during the study  . Thirty-For 60 deaths, 713 surveys were completed of 994 distributed . Disciplines and clinical experience of staff completing surveys and nonrespondents are shown . RespondQuality of life in the last 7 days of life was the lowest rated item , with 5 the mode (121 responses [18%]) and 0 (terrible) the next most frequent response (82 responses [13%]). In contrast, the moment of death was positively perceived  with 10  the mode (111 [40%]). The lowest individual PICU-QODD item scores related to presence of pain  or troubling symptoms . Mode of death was commonly aligned with perceived families wishes (516 of 577 responses [89%]).P < .001) . Scores for patients with genetic or noncardiac congenital comorbidities  were lower , as were those with surgical  admissions . Compared with discontinuation of life-sustaining therapy , scores were 5.0 points lower when death followed treatment limitation . Involvement of palliative care, high intensity of medical care, and ECMO or invasive procedures prior to death were not significantly associated with PICU-QODD scores  standardized PICU-QODD scores were 3.5 and 3.0 points lower for nursing and allied health staff, respectively  . Compare P = .01 , B. WhenD scores .P = .001; moment of death: 8 [4-10] vs low intensity 9 [8-10] P = .001) (P = .02) (P = .002), while there was no statistical difference between scores from medical and allied health staff (P = .42)  , C. MediP = .02) , D. NursSimilar associations and coefficients were observed in sensitivity analyses using varying survey completion criteria for standardized PICU-QODD calculation and bivariate models adjusting for discipline  may augment the ability to determine clinically meaningful differences. Given known challenges obtaining data from bereaved family members, there are clear benefits using instruments evaluating clinician perspectives as a proxy.21 As CICU staff have likely experienced multiple patient deaths (relative to families), their comparative perspectives are highly valuable. Availability of a validated, reliable outcome measure will help drive efforts to improve quality of end-of-life care. Furthermore, staff well-being has been named a health care crisis.40 End-of-life care is a frequent driver of moral injury, demanding consideration of team perceptions.6 The impressive response rate indicates that CICU team members are eager and willing to share their insights. Further research using the PICU-QODD instrument is needed to confirm utility as a core pediatric end-of-life outcome measure, explore correlation with family bereavement outcomes, and the impact on staff well-being.While defining high-quality end-of-life care is a key research priority, no metrics focus on the unique needs of the CICU population.19 Divergence in clinician’s perceptions of QODD overall and moment of death vs the 7 days prior warrants further exploration. These findings are consistent with bereaved parent survey results, in which 50% described their child’s overall quality of life in the last month as poor or fair, while 70% of parents agreed their child experienced a good death.21 This implies both staff and parents and guardians perceive burdens of intensive interventions yet tolerate them when death is the alternative.5 These findings raise the question as to whether this high-risk, high-reward strategy may be negatively reflected upon after death for both staff and parents and guardians.20 Perceptions of higher quality of death following discontinuation of life-sustaining therapy compared with limitations of therapy may be attributable to greater certainty and control over the timing when death is imminent. In adult ICUs, data supports early palliative care integration and less invasive interventions result in better end-of-life experience for staff.42 Palliative care involvement in CICUs results in less intense therapies at end-of-life.20 Both these factors were associated with positive perceptions of quality of life in the 7 days prior to death in our study, and QODD was perceived highly when staff felt mode of death was aligned with the family’s wishes. This reinforces prioritizing goal-concordant care and suggests that interventions focused integrating palliative care principles concurrent with disease-directed therapy and augmenting team communication surrounding family’s goals of care may improve staff perceptions of the dying experience.43The quality of dying and death construct focuses on the final stage of illness and death experience.44 Variable perception across interdisciplinary staff may relate to different lengths of time with a given patient, diversity of experiences, and events witnessed during ICU admissions.23 In our CICU, nurses along with a respiratory therapist (responsible for ventilatory and ECMO care), manage moment-to-moment care and directly perform invasive interventions. Thus, it is understandable that staff spending the greatest amount of time at the bedside more negatively perceive QODD. Our findings of alignment with family wishes strongly influencing perceptions further substantiate how family fears surrounding the death of their loved one and unrealistic expectations significantly contribute to staff distress.45 Nurses with less clinical experience also tend to perceive high levels of stress and emotional responses to dying and death.48 This may relate to lack of previous dying or death experiences or inadequate preparatory training.46 Traditionally, nursing education programs have focused on health promotion with less preparation in coping with and managing end of life.48 In response, international nursing organizations have emphasized importance of robust palliative care instruction in curricula.46 Simulation training may better prepare staff with effective communication and clinical skills.49 Finally, nursing and allied health staff may experience frustration about their limited role and participation in end-of-life decision-making.44 Interdisciplinary team support and institutional practices including joint approaches to symptom control, routine team meetings, ethical competency training, and robust discussions sharing perspectives may overcome these challenges.52Despite high overall scores, our findings highlight a disconnect between perceptions of CICU QODD according to discipline and clinical experience. These observations are reflected in other critical care settings, although limited data exist for allied health professionals.51 we did not co-assess these scores owing to time constraints to increase survey completion. Additionally, we intended to evaluate staff perceptions and acknowledge this study does not reflect parent and guardian perceptions or prospective symptom assessment.This study has limitations. It was conducted in a single-center quaternary US institution known for innovation, limiting generalizability. While the overall response rate for end-of-life survey methods was remarkable and sensitivity analyses suggest our findings would not change substantially if more surveys had been completed, results could be influenced by responder and recall bias. Also, because we were unable to account for correlation among the responses given by the same health care professional, SEs of regression coefficients might be underestimated. Although end-of-life care is a recognized driver of moral distress and burnout, with most ethical issues and conflict in critical care settings arising in this context,In this cross-sectional survey study of CICU staff, the PICU-QODD instrument was found to be a reliable and valid clinician measure of QODD. CICU interdisciplinary staff positively perceived QODD and quality of the moment of death yet had a negative perception of the 7 days prior. Significantly lower scores were reported by nursing or allied health professionals, staff with less clinical experience, and patients who received high-intensity care at end-of-life. More data are needed to establish PICU-QODD as a core end-of-life outcome measure. Our findings offer an opportunity to guide strategies to meaningfully improve staff well-being and patient and family end-of-life experiences.


We aimed to investigate the postoperative trend in blood pressure (BP)-related outcomes [BP and antihypertensive (AHT) drug use] during the year following adrenalectomy for primary aldosteronism (PA) to determine the optimal timing for outcome assessment and to determine the necessary follow-up length.Since the course of BP-related outcomes after adrenalectomy is unknown, the optimal timing of outcome assessment and follow-up duration are not clear.In this retrospective single center cohort study, we used a prospectively collected database with all patients referred for difficult-to-control-hypertension-analysis. All patients diagnosed with PA who underwent adrenalectomy were included. AHT drug use [in defined daily dose (DDD)] and home blood pressure measurements (HBPMs) during the first postoperative year were collected. A mixed-effects model was developed to assess the stability of DDD and HBPM over time and adjust for potential confounders.In total 1784 patients were assessed for difficult-to-control-hypertension of whom 41 were included. Both the DDD and HBPM showed the strongest decrease in the first postoperative month  compared with preoperative values . Thereafter, both outcomes showed a stable course from 4 to 6 months  up to 12 months postoperatively .This study showed that AHT drug use and HBPM decreased substantially within the first month after adrenalectomy for PA and afterwards generally remained stable during the year following adrenalectomy. We propose that BP-related outcomes can be assessed reliably early after adrenalectomy and question the need for routine long-term follow-up in referral centers. Primary aldosteronism (PA) has an estimated prevalence of 3% to 13% among the hypertensive population.Due to a lack of robust scientific evidence, the timing and duration of postoperative BP monitoring are guided by expert consensus. Nevertheless, the 2016 Endocrine Society Clinical Practice Guideline (CPG) suggests monitoring of BP 1 to 6 months after surgery.Therefore, we aimed to investigate the postoperative trend of BP-related outcomes in the first postoperative year after adrenalectomy for PA to determine the ideal timing for outcome assessment and to determine the necessary follow-up length. We hypothesized that BP-related outcomes after adrenalectomy for PA decrease early after surgery and will thereafter remain stable during the year following adrenalectomy in the majority of the patients.This study is reported with guidance of the Strengthening The Reporting of OBservational Studies in Epidemiology (STROBE) statement.9For this retrospective cohort study, the prospectively collected data including all consecutive patients with difficult-to-control hypertension referred to the Department of Vascular Medicine of the University Medical Center Utrecht, The Netherlands, between January 2010 and November 2020 was used. Difficult-to-control hypertension was defined as hypertension unresponsive to treatment according to the current guidelines and/or the presence of end-organ damage or vascular complications.http://links.lww.com/SLA/E108.The “Analysis of Complicated Hypertension” diagnostic protocol is a standardized protocol designed for the diagnosis of – or to rule out – secondary forms of hypertension including PA. The protocol has been extensively described before.Computed tomography (CT) and/or adrenal venous sampling (AVS) were performed to distinguish between a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia according to the Endocrine Society CPG. Patients underwent a posterior retroperitoneoscopic total adrenalectomy, however, when unfeasible an open total adrenalectomy was performed.https://www.whocc.no/atc_ddd_index). HBPM were measured within daily practice care and not via standardized protocol. In case of multiple HBPM within 1 period, the mean systolic and diastolic BP was calculated by dividing the sum of all measurements by the number of BP measurements within that period. At final follow-up, patients were classified as complete, partial or absent clinical/biochemical success using the PASO consensus criteria.13Follow-up data regarding AHT and HBPM were collected preoperatively and for at least 12 months after the adrenalectomy, stratified into 6 postoperative periods of follow-up . Frequency of follow-up visits were based on individual care plan. The type and dosage of AHT were used to calculate the “defined daily dose” (DDD), which is a measure of the average maintenance dose for a drug. Calculation of DDD was based on the WHO ATC/DDD index 2021  for variables that were not normally distributed. Categorical variables were presented as counts (percentage). Since repetitive follow-up data per patient were collected, a linear mixed-effects model was developed. Follow-up time was entered as fixed effect and the patients were random effects. The Akaike Information Criterion was used for model fitting, since a lower Akaike Information Criterion value indicates better quality of fit. The autoregressive(1) was used as covariance structure, which has homogenous variances and correlations that decline exponentially with distance. This means that the variability in a measurement is constant at every follow-up period, but that 2 consecutive measurements are more correlated than ones further away. The model was adjusted for family history of hypertension, target organ damage, preoperative AVS performed, and the plasma aldosterone concentration. In case a preoperative HBPM was missing, the preoperative daytime ABPM was used as preoperative baseline HBPM value. Patients with at least 2 HBPM or DDD were eligible for the mixed-effects model. Fixed effects estimates were reported with SE and 95% confidence intervals (CI). Statistical analyses were performed with the IBM SPSS Statistics 26.0 software . Figures were generated with GraphPad Prism version 8.3 .http://links.lww.com/SLA/E108. A preoperative HBPM and ABPM with medication was available in 15 patients (mean 158/98 mm Hg) and 26 patients (mean 150/91 mm Hg), respectively. The median preoperative AHT use was 4.2DDD (2.4–6.1). In 39 (95.1%) of the patients the ARR was measured. Thirty-nine (95.1%) of the patients underwent a SIT, which had a positive result for PA in 32 (82.1%) patients and an intermediary result in 7 (17.9%) cases. CT and AVS were performed in 87.8% and 68.3% of the patients, respectively. Twenty-three (56.1%) patients underwent both CT and AVS. All patients underwent a total unilateral adrenalectomy and did not have previous adrenal surgery on the contralateral adrenal gland in their medical history. There were no cases of postoperative adrenal insufficiency (Addison’s disease).The prospective database of all consecutive patients with difficult-to-control-hypertension contained 1784 patients. A total of 1156 patients underwent the “Analysis of Complicated Hypertension” diagnostic protocol. Of these 1156 patients, 43 (3.7%) underwent unilateral adrenalectomy for PA. Two of these patients underwent surgery elsewhere and were therefore excluded from the cohort. Baseline characteristics of the 41 included patients are reported in Table Forty-one patients were eligible for the mixed-effects model analysis. Twenty patients did not need any AHT directly postoperative, of which in 11 patients small dosages of AHT were started during follow-up. Figure Thirty-six patients were eligible for the mixed-effects model analysis. The mean HBPM for each patient at the respective follow-up intervals was computed from a median of 2 1–3) measurements. Figure  measuremCure rates could be calculated for 37 patients. Clinical cure, partial clinical success and absent clinical success rates according to the PASO consensus criteria at final follow-up were 4 (10.8%), 29 (78.4%), and 4 (10.8%). In 17 (41.5%) patients, data was available on the postoperative biochemical situation. Of these patients, 16 (94.1%) had complete biochemical success and 1 (5.9%) showed absent biochemical success.In this longitudinal retrospective cohort study, the postoperative trend in BP-related outcomes (HBPM and AHT) during the first year after adrenalectomy for PA was investigated using a mixed-effects model to account for repetitive measurements, follow-up variability and intermediate missing data.The trend of AHT use – expressed as DDD – showed that most AHT were successfully discontinued directly after surgery. Twenty patients had no AHT postoperatively, of which in 11 patients eventually small dosages of AHT were restarted during follow-up. In the other patients none or only minor adjustments in AHT were necessary. This resulted in a modest increase in DDD from the second postoperative month until >12 months. Nevertheless, on group level AHT use showed statistically a stable course during the year following adrenalectomy.HBPM was used to investigate the postoperative BP trend. This trend showed the greatest decrease in BP within the first month after adrenalectomy. Thereafter, HBPM remained stable during the first year of follow-up with only minor fluctuations in mean BP, which resemble the expected BP variability between 2 measurement moments.The PASO study group and the 2016 Endocrine Society CPG both suggest follow-up up to 1 year after surgery. These suggestions were mainly based on expert opinion.The major strength of this study is the prospective routine collection of diagnostic work-up variables, which largely reflect current clinical practice and are the same for all patients. Moreover, most of the patients in this study were diagnosed according to the Endocrine Society CPG and underwent SIT regardless of the ARR outcome, which strongly reduced the influence of verification bias. Another strength is the use of HBPM. Specialists in the field of BP monitoring use the HBPM often in daily clinical practice and treatment decisions are frequently based on the HBPM instead of OBPM. Out-of-office BP measurements (ABPM/HBPM) have the advantage of substantially reducing the white-coat effect and are better in predicting cardiovascular morbidity and mortality. HBPM is more suitable to assess day-to-day BP variability for longer periods of time and to increase patient’s engagement and their adherence to treatment.This study showed that AHT use and HBPM decreased substantially within the first month after adrenalectomy for PA and afterwards generally remained stable during the year following adrenalectomy. This confirms the treatment effect expectations in the Endocrine Society CPG. In addition, we propose that BP-related outcomes can be assessed reliably early after adrenalectomy and question the need for routine long-term follow-up in referral centers in well-regulated patients as these patients could be monitored by their family physician.François Pattou First, I would like to thank the selection committee for the privilege of reviewing this very interesting paper. The authors should be commended for having conducted this precise retrospective analysis of postoperative outcome of adrenalectomy for primary aldosteronism in a single center series of 37 patients. Their data surely confirm the excellent results of surgery resulting in complete biochemical cure in more than 90% of cases and clinical success, according to the current definition, also in 90% of cases. Importantly, the authors showed that successful blood pressure-related outcomes can be reliably assessed as early as one month after adrenalectomy, and later, monitored by primary care physicians. This, therefore, questions the necessity of long follow-up in (expensive) expert referral centers. This is important and very good news for operated patients.I thank the authors for having carefully addressed most of the comments raised during the reviewing process by the three reviewers. However, I still have a few remaining questions:First, it is likely that some patients with documented primary aldosteronism from this large cohort of patients with severe hypertension were followed medically and not operated. How different were the baseline characteristics of these non-operated patients and/or the long-term outcomes from those among the operated cases?Second, ten patients  had a final diagnosis of adrenal hyperplasia, alone or associated with an authentical adenoma. Were their blood pressure related outcomes different from those with a single adenoma, especially in the long-term?Finally, distinguishing a unilateral aldosterone producing adenoma from bilateral hyperplasia is essential. For that purpose, adrenal venous sampling was performed in two thirds of the cases in your study. In order to reduce the need for this invasive procedure, other authors propose Nor-iodo-cholesterol (NP-59) adrenal scintigraphy as an alternative test to confirm unilateral aldosterone production. Do you have any experience with this alternative test? Overall, what strategy do you advise in terms of a lateralization test beyond a CT scan?Response From Diederik Suurd Thank you for your kind comments. To address the first question about the non-operative primary aldosteronism patients, we chose to only focus on the surgically treated patients in this cohort. However, indeed, the other patients in this large database were treated medically. We identified another 23 primary aldosteronism patients, who were all treated medically, in this cohort. This number is not what you would expect to obtain for medically treated patients. You would expect 80 or 90 medically treated patients, but these were not identified in this prospective database. However, the baseline characteristics of these 23 patients did not differ, in terms of preoperative blood pressure and antihypertensives. As I already said, we wanted to determine the effect of surgery. Therefore, we did not extract the long-term follow-up for the medically treated patients.Second, regarding the different outcomes between adrenal hyperplasia or single adenoma, we didn’t perform a subgroup analysis between those two groups, but we did look at long-term blood-pressure outcomes. The group of patients with adrenal hyperplasia performed similarly to the group with single adenoma. 100% of the patients with adrenal hyperplasia clearly benefitted from surgery.Third, regarding lateralization techniques, distinguishing between left- or right-sided primary aldosteronism is very important. At our institution, we strive to perform a CT and adrenal venous sampling for every patient. However, for the adrenal venous sampling, we have to refer to another academic hospital in the Netherlands. Sometimes, this is just not feasible. Regarding the NP-59, we have no experience with this technique at our center. That said, currently, we are working on a new PET-CT tracer, named Pentixafor, to see whether this tracer is suitable for distinguishing between left- and right-sided primary aldosteronism. We hope to present the results within the next few months or year.


The transition to a circular economy has a major impact on waste management and the reuse of materials. New mandatory recycling targets for plastics will lead to a high availability of recyclates. For these recyclates, useful applications need to be found. One potential application for recyclates is blow molding bottles as packaging for non-food contents. This study investigates commercially available post-consumer high-density polyethylene recyclates together with virgin blow molding grades in terms of their short-term mechanical properties and environmental stress cracking resistance. While the short-term mechanical properties showed only slightly lower performance than the tested virgin grades, the overall environmental stress cracking failure times of the recyclates were much lower compared to virgin materials, even though the crack-growth kinetics could be similar. Although neither the tensile nor the notched impact strength results of the two polyethylene recyclates revealed large differences, the stress intensity-factor-dependent crack-growth rates of both materials were significantly different. The current endeavors of the European Commission towards a circular economy have led to several regulations concerning packaging products ,2. The rPolyolefin waste is notorious for its difficulty of separation due to the overlapping densities of the various polyolefins ,9. Thus,Virgin blow molding PE-HD grades have melt mass-flow rates (MFRs) of between 0.25 g/10 min and 0.80 g/10 min  followed by white. Both colors are used for natural or white products, respectively, or for subsequent coloration. Some suppliers offer color separated recyclate grades. Due to the lack of color separation and thus the color mixing of differently colored flakes, the most common colors on the post-consumer recyclate market are shades of grey. Commercially available rPE-HDs from post-consumer packaging waste usually have higher MFRs, as they consist of different sources of PE waste and include injection-molded products, for instance, caps and closures. While the MFR, tensile, and impact properties can typically be found in the datasheets of rPE-HDs, ESCR is a rarely declared property.Several standardized test methods for the experimental characterization of the ESCR of PE-HD are in use. These test methods make use of accelerating media and/or test temperatures to shorten testing times. A widely used test method, the full-notch creep test (ISO 16770) , uses elTwo virgin blow molding PE-HD grades in the form of pellets, as can be seen in Considering the two basic constraints, color and MFR, two rPE-HD grades were purchased from two different European suppliers based on their white (rPE-A) and natural (rPE-B) colors and MFRs, which are in the range of the benchmark virgin grades. The recyclates were delivered as pellets, as can be seen in Differences in specimen preparation, conditioning, and testing often impede objective comparisons between material data of different suppliers. Moreover, small lot-to-lot variations can occur even for virgin grades. Therefore, within the scope of this study, all basic properties were characterized by identical parameters for better comparability and accurate structure–property–performance relationships.The MFR measurements were conducted at 190 °C and with both 2.16 kg and 5 kg static loads on the melt flow indexer Mflow  according to ISO 1133-1 . Cuts weAccording to ISO 17855-2 , tensileFor cracked round bar (CRB) specimen production according to ISO 18489  for the Differential scanning calorimetry (DSC) measurements were carried out on the differential scanning calorimeter DSC 8500 . Measurements were made according to ISO 11357-1  and ISO A differential thermal analysis instrument from PerkinElmer, the DSC 4000, was utilized to characterize the oxidation induction temperature (dynamic OIT) according to ISO 11357-6 . SamplesThe thermogravimetric analysis (TGA) was performed on an STA 6000 simultaneous thermal analyzer , according to ISO 11358-1 [The tensile properties, tensile modulus, yield stress, and strain at break, were examined with a universal testing machine Zwick/Roell AllroundLine Z05 equipped with a Zwick/Roell multi-extensometer strain measurement system. Test parameters and MPS were used according to ISO 527-1 , ISO 527Impact properties were determined according to ISO 179-1  on a ZwiI,ini) were used to achieve testing times between 10 and 100 h. As testing environments, deionized water with 10 m% Igepal CO-630  and air, both at 40 °C, were used. A specifically constructed testing chamber for environmentally superimposed CRB experiments, made from stainless steel and glass [As the authors have the experience and machinery to conduct cracked round bar fatigue crack-growth (FCG) experiments in harsh media conditions , the chond glass , was empI with the crack-growth rate. The ΔKI value depends on the geometry, applied force range, and initial crack length as can be seen in the Equations (1)–(3) developed by Benthem and Koiter [I is a normalized value for the load affecting the crack tip.I is the initial stress-intensity factor range in loading Mode I [An in situ optical measurement of the crack length over the whole circumference of the specimen was utilized for investigations of crack growth . With thd Koiter  and usedI in MPa × m0.5. One CRB specimen was tested per material and medium.Characteristic double logarithmic FCG kinetic curves were plotted providing the relation between the FCG rate, da/dN in mm/cycle, and the stress-intensity factor range, ΔKThe MFRs for all materials are presented for 190 °C and 2.16 kg and for 190 °C and 5 kg in The DSC measurements on MPS specimens were only conducted for the recyclates with the goal to determine foreign polymer melting peaks. The thermograms were stacked so they could be looked at individually and they show that all three samples from three individual MPS exhibited comparable results, as illustrated in The DSC measurements of samples cut from the bars which are used for the manufacturing of CRB specimens were conducted to determine the melting enthalpy of the PE phase. Contrary to the measurements conducted on samples taken from MPS, the first heating run is shown instead of the second heating run. In this way, the effect of the tempering on the materials morphology could be investigated. The PP melting enthalpy is not shown for these tests as the low sample volume and missing homogenization step (injection molding) leads to high scattering of the quantifiable PP melting enthalpy in rPE-A. In comparison, the homogenization by injection molding of MPS distributes the PP contamination to each DSC sample, hence creates, despite the small sample volume, appropriate specimens for detecting trace amounts of contamination.While there are no significant differences in the melting temperatures, all materials showed a distinct rise in PE melting enthalpy due to the tempering process, as can be seen in the thermograms shown in A higher dynamic OIT shows a higher resistance to thermo-oxidative degradation and can be used as an indicator for the effectiveness of stabilizers incorporated into the material as they affect the material’s vulnerability to harsh oxidative environments . FurtherThe DSC thermograms in synthetic air together with the calculated dynamic OITs are shown in 2 from CaCO3 which would also explain the white color of rPE-A [TGA was used to show the inorganic contamination level of the materials. Unfilled polyolefins are expected to show no pyrolysis residue . rPE-A, of rPE-A .Tensile tests are a good and quick measure to gain an overview of the mechanical performance of materials. Recyclers seldom have the machinery to produce compression molded specimens for tensile or Charpy tests, hence, in their datasheets, they depict values from injection molded specimens. There is a discrepancy in the mechanical parameters between differently produced specimens with higher values usually for compression molded specimens , at leasThe tensile moduli show a clear distinction between the virgin and recycled PE-HD grades. Both virgin grades show higher tensile moduli (vPE-1 with 977 MPa and vPE-2 with 1020 MPa) than the two recyclates (rPE-A with 939 MPa and rPE-B with 914 MPa). The yield stresses show a different trend. vPE-1 (25.2 MPa), rPE-A (24.8 MPa) and rPE-B (25.3 MPa) show similar yield stresses while vPE-2 exceeds them with a very high value of 28.7 MPa. The strain at break values mimic the MFR trend shown in While the measured properties cannot be directly compared to the datasheet values of virgin grades due to their different manufacturing process (injection molded instead of compression molded), the comparison of the virgin blow molding grades to the recyclates which were produced with the same parameters show that the recyclates investigated lie within the range of virgin PE-HD blow molding grades.The impact strength can be measured according to several standardized methods with varying loading principles, geometries, and testing temperatures. One of the most used methods in Europe, as can be seen in summary datasheets of European suppliers ,15, is t2, followed by vPE-1 with 35.9 kJ/m2, rPE-B with 26.8 kJ/m2, and finally rPE-A with 23.5 kJ/m2. The lower values of the recyclates, especially of rPE-A, could again be explained by contamination within the polymer matrix [The Charpy notched impact strengths of all materials are depicted in r matrix , as alsor matrix . On averThe ESCR is a combination of two superimposed damage mechanisms, slow crack growth due to mechanical loading  and environmentally (both media and temperature) induced acceleration of that slow crack growth. The testing method presented within this paper is a first approach to combine a customary ESCR-testing medium -dependent crack-growth rate development in the solution of deionized water with 10 m% Igepal CO-630 is shown in I was the crack length. Hence, each measurement started at the bottom (low crack-growth rate) left . As the crack propagated, ΔKI and the crack-growth rate rose. vPE-1, vPE-2 and rPE-B showed crack-growth rates of similar magnitude while rPE-A showed an around five times higher crack-growth rate at a similar ΔKI. Compared to vPE-1, vPE-2 and rPE-B showed much higher crack-growth rates at lower ΔKI values, which explains the much higher crack-growth time (total failure time minus crack initiation time, shown in The stress-intensity factor range (ΔKI. vPE-1 and vPE-2 are indistinguishable from each other, indicating a similar slow crack-growth resistance. rPE-B shows distinctly higher crack-growth rates at low ΔKI values, significantly shortening its crack-growth time compared to the virgin PEs. rPE-A again shows the highest crack-growth rate of all materials, revealing its low resistance to slow crack growth.The crack-growth kinetics of the measurements in air, which are shown in By combining the findings of the results section, the following statements concerning the performance of both PE-HD recyclates can be made: the MFRs of the investigated recyclates suggest a feedstock of blow-molded PE-HD product waste. rPE-B shows the lower MFR of both recyclates. Both the DSC see  and the I values. The crack-growth rate at these low ΔKI values marked the beginning of crack growth directly after the crack initiation time. In this case, the crack propagated in the plastic zone which was exposed to the environment during the whole crack initiation time. In contrast, higher ΔKI values showed crack growth at higher crack lengths, that is, plastic zones which were not exposed to the environment during crack initiation. The flatter slope of rPE-B in the air measurement could, therefore, indicate that rPE-B was significantly more damaged during crack initiation in air than the other materials, which could also be explained by its lower dynamic OIT value, as seen in The cracked round bar experiments at 40 °C in air were conducted for investigation of the effect of Igepal CO-630 on the testing time and crack-growth kinetics. A comparison of both environments can be seen in These above-drawn conclusions imply that 40 °C warm air induces more local aging in PE than 40 °C Igepal solution. The availability and mobility of oxygen is certainly higher in air than in the liquid surfactant mixture. Moreover, the crack-growth-accelerating effect of Igepal CO-630, elaborated upon in the literature, can be attributed to its reduction of the “frictional resistance to chain slippage” , and notWith the presented properties of the various tested PE-HD virgin blow molding grades and recyclates, the applicability of recyclates for blow molding applications can only be estimated in terms of their mechanical properties. The processability with existing blow molding processes was not investigated in this paper and should also be considered when it comes to replacing virgin materials with recyclates. While the short-term mechanical properties measured by tensile and impact tests show promising results, the resistance to slow crack growth and the ESCR of recyclates may be much worse compared to virgin materials. The effect of Igepal CO-630 on the ESCR of recyclates complicates the evaluation and interpretation of the results. While the crack-growth kinetics of the recyclate rPE-B and the virgin grades look comparable, the testing time and, here specifically, the crack initiation time for the recyclate was much shorter. Shorter testing times could also be expected for other ESCR methods where only testing time and not crack-growth rate is investigated. It can be assumed that contamination found within recyclates contributes to an accelerated crack initiation and therefore they are essential for the materials’ ESCR performance. This effect could be verified by future testing on intentionally contaminated PE-HD virgin grades.


Mindfulness can improve overall well-being by training individuals to focus on the present moment without judging their thoughts. However, it is unknown how much mindfulness practice and training are necessary to improve well-being.The primary aim of this study was to determine whether a standard 8-session web-based mindfulness-based cognitive therapy (MBCT) program, compared with a brief 3-session mindfulness intervention, improved overall participant well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants .Participants were recruited from 17 patient-powered research networks, web-based communities of stakeholders interested in a common research area. Participants were randomized to either a standard 8-session MBCT or a brief 3-session mindfulness training intervention accessed on the web. The participants were followed for 12 weeks. The primary outcome of the study was well-being, as measured by the World Health Organization—Five Well-Being Index. We hypothesized that MBCT would be superior to a brief mindfulness training.P=.80) or during the intervention period plus 12-week follow-up . During the intervention period, younger participants (P=.05) and participants who completed a higher percentage of intervention sessions (P=.005) experienced greater improvements in well-being across both interventions, with effects that were stronger for participants in the MBCT condition. Attrition was high , which is an important limitation of this study.We randomized 4411 participants, 3873 (87.80%) of whom were White and 3547 (80.41%) of female sex assigned at birth. The mean baseline World Health Organization—Five Well-Being Index score was 50.3 (SD 20.7). The average self-reported well-being in each group increased over the intervention period  as well as the full study period . Changes in self-reported well-being were not significantly different between MBCT and brief mindfulness during the intervention period (model-based difference in slopes: −0.02, 95% CI −0.24 to 0.19; Standard MBCT improved well-being but was not superior to a brief mindfulness intervention. This finding suggests that shorter mindfulness programs could yield important benefits across the general population of individuals with various medical conditions. Younger people and participants who completed more intervention sessions reported greater improvements in well-being, an effect that was more pronounced for participants in the MBCT condition. This finding suggests that standard MBCT may be a better choice for younger people as well as treatment-adherent individuals.ClinicalTrials.gov NCT03844321; https://clinicaltrials.gov/ct2/show/NCT03844321 Data from the World Happiness Report  and Gallpulation . Caregivdose of mindfulness is unknown.One of the most acceptable and effective interventions for improving one’s overall well-being are mindfulness-based treatments. Mindfulness improves well-being by cultivating awareness and being present in the moment . The effOne reasonable hypothesis is that more sessions and more time spent on practice would lead to larger treatment effects. For example, a dose-effect study found that more sessions of mindfulness were associated with greater improvement  [In particular, mindfulness-based interventions with only a few sessions (range 1-6) have been shown to increase mindfulness and decrease anxiety, depression, negative thoughts, headaches, and pain -12. One The primary aim of this study was to determine whether a standard 8-session web-based MBCT program compared with a brief 3-session mindfulness intervention improved well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants . Given that standard MBCT is the longer and more comprehensive intervention, we hypothesized that standard MBCT would be superior to a brief, 3-session mindfulness program in increasing well-being, quality of life, and functioning as well as decreasing stress, anxiety, and depression. The primary outcome measure was the World Health Organization—Five Well-Being Index (WHO-5) well-being index from baseline to 8 weeks as well as baseline to 20 weeks. There were no specific directional hypotheses for the moderator analyses.We compared the effectiveness of an 8-session MBCT program and a 3-session brief mindfulness intervention to improve overall well-being. Adults (aged ≥18 years) from 17 web-based patient-powered research networks (PPRNs)—web-based people-centered organizations that focus on specific conditions and community interests through comparative effectiveness studies —who wereThe study was hosted on a web-based platform developed by the same team that created IMoodNetwork , a PPRN Eligible participants were randomly assigned to the 8-session web-based MBCT program or a brief web-based 3-session mindfulness program. The programs consisted of individual web-based modules comprising videos and activities delivered in short, digestible sections. The layout of the intervention material was optimized, or adapted, to the size of users’ screens, and participants could therefore complete intervention and assessment sessions on a computer, tablet, or smartphone.Randomization was performed using a stratified block randomization technique with a block size of 4 to maintain an even distribution across each PPRN. Randomization was executed using the MoodNetwork platform, which was programmed by the Massachusetts General Hospital study staff. Participants were not blinded to their randomization and were informed during the informed consent process that they would be assigned to a standard 8-week mindfulness program or a brief 3-week mindfulness program. All participants followed the same assessment schedule despite having different intervention schedules; thus, the active phase for assessments (weeks 0-8) and follow-up period for assessments (weeks 9-20) were the same for the brief mindfulness group and MBCT. During the active phase, assessments were performed every 2 weeks , and during the follow-up period, assessments were performed every 2 months .The participants were prompted to return to the study platform to complete their activities and assessments via weekly email reminders. At the end of each intervention session, participants were instructed to practice mindfulness activities on most days; however, we did not gather data on how long the participants spent practicing the activities. The participants were entered into a raffle, and 5 participants were randomly selected to receive a US $200 Visa gift card., mindfulness of the breath, mindfulness of breath and body, mindfulness of thoughts and feelings, and open or choice-less awareness). Over the course of these exercises, participants learned to adopt an observing, accepting stance (mindfulness) toward difficult thoughts, feelings, and bodily sensations. Participants also learned to bring mindfulness to everyday situations and practice how to recognize and disengage from negative, ruminative thoughts.The 8-session, standard MBCT program was based on the manual developed by Segal et al , which hletting thoughts go by bringing their attention back to the sensations of the breath. Participants received guidance on how to implement this skill during their daily lives and in stressful situations.The 3-session brief mindfulness program was based on the work of Zeidan et al ,10,19 anBoth intervention groups were assigned mindfulness exercises to practice between sessions. They were also taught the core aspects of mindfulness . Participants in both groups were not able to perform more than one intervention session per week; however, they could access material from the previous weeks at any time.Participants completed self-reported assessments at 8 time points (at no time) to 5 . A score is computed by multiplying the total score by 4 (ranging from 0 to 100), with higher scores reflecting increased well-being. Participants completed this measure during each assessment period. A change of at least 10 points is estimated to be clinically meaningful [This 5-item measure assesses well-being over the course of the prior 2 weeks  . Particianingful ,21.Demographic variables including age, gender identity, sex assigned at birth, race, ethnicity, sexual orientation, marital status, employment status, and education history were measured at baseline.At baseline, participants were asked 2 questions: (1) “Do you have a history of any medical problem?” (response: yes or no); (2) “Do you have a history of any psychiatric illness?” (response: yes or no). If participants selected “yes” for having a history of a medical or psychiatric problem, they were asked to state the conditions for which they received treatment., “In the last month, how often have you been upset because of something that happened unexpectedly?” or “how often have you felt nervous and ‘stressed’?”) [never) to 4 (very often). Participants completed this measure during each assessment period. To our knowledge, estimates of minimum clinically important differences are not available.This 10-item measure evaluates an individual’s experience of stress in the past month (egssed’?”) . Particinever) to 5 . Participants completed this measure during each assessment period. A change of at least 5 points was estimated to be clinically meaningful [This questionnaire is an 8-item assessment of perceived depressive symptoms over the past week . Particianingful .never) to 5  [The questionnaire is a 4-item assessment of self-reported fear (fearfulness and panic), anxious misery (worry and dread), hyperarousal , and somatic symptoms related to arousal (racing heart and dizziness). Participants rated how often they experienced each item from 1  . Partici .never) to 1  [The questionnaire was a 4-item assessment of the perceived ability to perform one’s everyday social roles and activities. Higher scores represent fewer limitations (better abilities). Participants rated how often they had experienced each item from 5  . Partici .Five Facet Mindfulness Questionnaire is a 39-item assessment that examines 5 aspects of mindfulness: observing, describing, acting with awareness, nonjudging of inner experiences, and nonreactivity to inner experiences. Only the questions related to nonjudging of inner experience and nonreactivity were administered , and participants rated whether each item was generally true for them from 1 (never true) to 5  [The ys true) . ParticiThis questionnaire was administered in all study sessions to assess for possible adverse events and whether they were related to the study procedures .This study was registered at ClinicalTrials.gov (NCT03844321) and was approved by the Genetic Alliance Institutional Review Board (protocol #HMHY002). Informed consent was approved by the Genetic Alliance Institutional Review Board and completed on the web by the participants.P values. We fitted separate models to assess the intervention effects over the 8-week intervention period and the entire 20-week study period. Post hoc sensitivity analyses were carried out by including a fixed categorical (rather than linear) effect for time in our models, which allowed for the mean WHO-5 scores to vary over time in an unspecified fashion. We also fit post hoc marginal models via generalized estimating equations (GEEs) for the primary WHO-5 outcome, as these visually fit the raw mean trajectories more closely; these marginal GEEs used a working independence correlation structure and, similar to the prespecified mixed models, included fixed effects for intervention, time, and an intervention-by-time interaction.We used the intention-to-treat principle for all primary analyses and incorporated all available longitudinal outcomes into the mixed effects models. We used prespecified linear mixed effects models fit via maximum likelihood to examine the comparative effectiveness of the 2 mindfulness interventions on the primary well-being endpoint : random participant slopes and intercepts; and fixed effects for intervention, time, and an intervention-by-time interaction. Our primary group comparison was based on the intervention-by-time interaction, which corresponds to the between-group difference in the slopes of average well-being scores over time. We report model-based point estimates, CIs, and intervention period and the entire 20-week study period. Statistical analyses were performed using R software . We used 2-sided significance levels of .05 and reported 95% CIs for all analyses.Demographics and assessment scores measured at the beginning of the intervention period were analyzed as potential moderators of the relationship between treatment and well-being. The a priori moderators included (1) age; (2) role (PPRN member vs caregiver or family member); and (3) levels of well-being, stress, quality of life, anxiety, depression, and mindfulness. Several exploratory moderators were also analyzed: (1) sex, (2) ethnicity, (3) race, (4) education, (5) percentage of intervention sessions completed, (6) presence of medical problems, and (7) presence of psychiatric illness. To assess each moderator, we added fixed effects for the baseline moderator as well as moderator-by-time, moderator-by-intervention, and moderator-by-intervention-by-time interactions to the mixed model and used a likelihood ratio test to assess the 3-way interaction term, a term that represents the estimated differential intervention effect across levels of the moderator. Continuous moderators  were assumed to have a linear moderating relationship in the moderator regression models. Moderator analyses were also carried out across both the 8-week Owing to study start-up delays, we reduced our recruitment target from 8500 to 2117 participants. We conducted separate power calculations for the original target sample size of 8500 and for the revised sample size of 2117 with PASS 14 for Cronbach α of .05 and a range of standardized mean differences (SMDs) between our MBCT and brief mindfulness groups. We chose SMDs to be consistent with what was reported by Hoffman et al  and alloAccording to our power calculations, with 8500 participants, for a Cronbach α of .05, the power would be >80% to detect SMDs >0.12% and >90% for SMDs >0.14. After revising our target sample size to 2117, for Cronbach α of .05, the power would be >80% for SMDs greater than 0.26% and >90% for SMDs greater than 0.29. In summary, with our target sample size of 2117 participants, we were able to detect differences that were even smaller than the published estimates for what constitutes a clinically meaningful change in the WHO-5.Recruitment for the study occurred from February 27, 2019, to October 1, 2019, and the follow-up period ended on January 31, 2020. A total of 5029 participants were consented and completed the enrollment process. Among these, 593  individuals declined to participate, and 4436  were randomized to the study interventions. nonserious adverse events. No serious adverse events or nonserious adverse events were reported by participants to be related to the study. The most common category of events reported was a negative life event that was unrelated to the study .A total of 30  participants in the MBCT group and 31  in the brief mindfulness group reported experiencing one or more serious adverse events during the full study period. In addition, 33  participants in the MBCT group and 41  in the brief mindfulness group reported experiencing one or more intervention period and entire 20-week study periods  or when using a marginal model fit via GEE with linear time  or categorical time  and those with a higher percentage of intervention sessions (P=.005); these differential effects were not sustained over the full 20-week study period. For all other moderators considered , there was no evidence of a differential effect over either the 8- or 20-week period , anxiety (P=.05), and mindfulness (P=.03) were greater in the MBCT group than in the brief mindfulness intervention group over the full 20-week study period.For both treatment conditions, all secondary outcomes of anxiety, depression, perceived ability to perform social roles, perceived stress, and mindfulness improved over the intervention and study periods  and 3. AP<.001), older (P<.001), straight (P<.001), more highly educated (P=.04), and tended to have lower baseline depression (P<.001), anxiety (P<.001), and well-being (P<.001) and higher perceived ability to perform social roles (P<.001) and mindfulness (P<.001) than those who did not complete the study , significantly differed from those who did not complete the study on several baseline and clinical characteristics. Completers were disproportionately assigned male sex at birth  that found no significant differences in improvements to participant mindfulness, as well as self-compassion, positive and negative affect, anxiety and depressive symptoms, and resilience . AnotherAlthough our study did not support the hypothesis that the longer standard 8-session MBCT would be superior to the shorter mindfulness intervention, it is possible that a shorter mindfulness program is sufficient for improving well-being across a variety of patient populations ,44. For The strengths of this study include leveraging existing registries of individuals. This allowed us to recruit and consent 5029 participants quickly , with a mean of 625 participants per month. Efficient recruitment was likely due to the broad inclusion and exclusion criteria, including stakeholder input, collaboration with PPRNs already engaged in a collaborative network, and conducting a web-based study with broad outreach.not at random. This study was also limited by a lack of diversity in the study population, especially with regard to race and gender. Our results may not be generalizable to men or to people of different colors. The second limitation was the lack of support or guidance for the participants, such as technical support with the study platform or assistance with the intervention material. Third, all outcomes were self-reported, and we did not include diagnostic assessments (which could have better characterized the sample) to minimize participant burden. Fourth, given the large sample size, we were not able to reimburse the participants’ time in completing the assessments (with the exception of a raffle) or in completing the web-based intervention. The lack of incentives and technical support for the participants could have contributed to the high attrition rates. However, these limitations increase the generalizability and applicability to more general populations.The main limitation is the high attrition and low completion rates for both the intervention sessions and assessments. Although our primary results, which are based on likelihood-based mixed effects regression models, are valid under the missing at random assumption , the results could be inaccurate if endpoints are missing In summary, this study demonstrated that a web-based 8-session MBCT program was not superior to a web-based brief 3-session mindfulness program in improving the well-being of participants. Younger people and treatment-adherent individuals  may benefit more from standard-length MBCT.


Multi-agent chemotherapy , hormone receptor negative , higher grade , younger age , and later year of diagnosis  were associated with achieving pCR. Multi-agent chemotherapy was associated with higher likelihood of pCR, but this effect was modest compared to other factors. Single-agent NAC with HER2-directed therapy in selected patients may provide excellent outcome with reduced toxicity, while allowing escalated therapy in the adjuvant setting for patients with residual disease. Prospective studies are needed to determine effects of de-escalation in the neoadjuvant setting on survival and optimal selection strategies.Women with small HER2+ breast cancers may have excellent prognosis with adjuvant single-agent chemotherapy and HER2-targeted therapy. The role of de-escalated therapy in the neoadjuvant setting, however, remains uncertain. We conducted a cohort study of adult women with T1-2/cN0 HER2+ breast cancer diagnosed 2013–2016 in the National Cancer Database treated with neoadjuvant chemotherapy (NAC) and HER2-targeted therapy. Factors associated with pathologic complete response (pCR) and overall survival were examined. In total, 6994 patients were included, 32% cT1 and 68% cT2. Multi-agent NAC was given to 90% of women while single-agent NAC was given to 10% of women. pCR was achieved in 46% of cT2 patients and 43% of cT1, and in 46% of patients treated with multi-agent versus 38% single agent. Patients receiving multi-agent chemotherapy were younger, had fewer comorbidities, and had higher cT stage and grade. In all patients, pCR was associated with improved survival ( HER2+ breast cancers account for ~14% of cases2. HER2-amplification was previously associated with high recurrence rates and poor survival3; however, development of targeted therapy in the form of monoclonal antibodies and more recently antibody-drug conjugates to HER2 given in combination with cytotoxic chemotherapy has dramatically improved outcomes7.Breast cancer is among the most common cancers for women in the U.S. and a leading cause of death8. Chemotherapy and HER2-targeted therapy can be delivered in either the neoadjuvant or adjuvant setting, but neoadjuvant chemotherapy (NAC) can be used to increase eligibility for breast-conserving surgery and decrease the extent of axillary surgery9. In addition, response to neoadjuvant therapy, including pathologic complete response (pCR), strongly predicts recurrence and survival12. For patients who have residual disease after neoadjuvant therapy, escalation of therapy with adjuvant regimens, including with HER2 antibody conjugated chemotherapy (T-DM1), has been shown to increase disease-free survival, demonstrating the use of NAC to identify patients in need of more aggressive treatment14.Current standard of care for HER2+ breast cancer includes a combination of chemotherapy with HER2-targeted therapy, surgery, radiotherapy, and endocrine therapy depending on estrogen receptor status15. Trials of de-escalated neoadjuvant therapy using APT-style taxane regimens are ongoing, but multi-agent chemotherapy regimens including carboplatin or anthracyclines in addition to taxanes remain the current standard of care in neoadjuvant therapy of HER2+ breast cancer. Multi-agent chemotherapy regimens are associated with significant side effects including nausea, vomiting, diarrhea, neuropathy, neutropenia, and cardiotoxicity, which can be worsened with HER2-targeted therapy17.On the other hand, for patients with node-negative small HER2+ breast cancers <3 cm, the APT trial demonstrated that a regimen of single-agent adjuvant paclitaxel with trastuzumab (TH) confers a very low risk of recurrence with a favorable profile of side effectsFor small, node-negative HER2+ breast cancer, the optimal treatment sequence remains unclear. NAC risks overtreatment of patients who potentially could have excellent survival and less toxicity with taxane/trastuzumab regimens in the adjuvant setting, while surgery first risks under-treatment by failing to identify patients with residual disease who could benefit from escalated adjuvant therapy. Currently, the decision for surgery/chemotherapy sequence is made in node-negative patients largely based on clinical T stage, which may not be the optimal stratification metric. We hypothesize that NAC with de-escalated taxane/trastuzumab regimens may be the preferred strategy for patients with T1/T2 N0 HER2+ breast cancer to minimize toxicity and identify patients with residual disease in need of escalated systemic therapy. In this study, we examine outcomes of women with early stage, node-negative HER2+ breast cancer treated with single (NCDB surrogate for taxane/trastuzumab) or multi-agent NAC and the association between treatment, pCR, and survival using a large national database.This study included 6994 patients diagnosed between 2013 and 2015 with clinical T1/T2, clinical N0 HER2+ breast cancer treated with NAC, and HER2-targeted therapy followed by surgical resection . On multivariable analysis prior to stratification by response to chemotherapy, pCR was significantly associated with improved survival . To determine factors, such as clinical T stage and type of chemotherapy, associated with survival after accounting for response to chemotherapy, we created separate models for patients that achieved a pCR and those with residual disease to examine independence of these factors from response to chemotherapy. In the multivariable Cox model , age >70 in comparison to age 18–39 , and Charlson Comorbidity Index ≥3 in comparison to 0  were associated with mortality, while hormone receptor positivity was associated with improved survival , which significantly increased the pCR rate over TH. Pertuzumab was approved by the FDA following our enrollment period, and the addition of a second HER2-directed agent may increase the pCR rates for early disease over those reported in our study.In patients with clinically small, node-negative breast cancers, pathologic complete response was achieved more often with multi-agent chemotherapy compared to single agent. We report overall pCR rate of 37% in patients treated with single-agent chemotherapy with HER2-directed therapy, which is in the high range of rates reported in the TH arms of prospective trials examining more advanced disease, including NeoSphere (21.5%), NeoALTTO (27%), and CALBG 40601 (45%)25, but these data indicate that pCR is a biologically informative prognostic marker in early disease as well, although the effect is small in this short timeframe. In patients that achieved a pCR, no cancer-related factors were associated with short term survival, which was only associated with comorbidities. In contrast, in patients with residual disease, tumor features including hormone receptor status and positive lymph nodes were predictive of survival, indicating that cancer mortality may be a driver of overall mortality in these patients even in this short time period. Similar to more advanced disease, these data indicate that residual disease after neoadjuvant chemotherapy in patients with early HER2+ breast cancer identifies patients at increased risk of death. Clinical T stage, which is commonly used to determine treatment (multi-agent NAC versus surgery first) in N0 patients, was not prognostic in patients achieving pCR or those with residual disease, indicating this may not be the ideal selection criterion26. Response to chemotherapy is a biologically informative prognostic marker and could be a better stratification point to inform which patients need more or less aggressive systemic therapy.Although overall survival data are immature, in this study pCR was associated with improved survival in patients with early-stage disease. The prognostic value of pCR has been well established in neoadjuvant trials of more advanced disease28. In this study, multi-agent chemotherapy was associated with an absolute increase in pCR rate of 9% compared to single agent with a modest odds ratio compared to hormone receptor status and grade. Depending on long-term survival difference between women with pCR versus residual disease and the ability to mitigate that difference with adjuvant therapy, increased rates of pCR in patients treated with multi-agent chemotherapy may not routinely justify increased toxicity upfront29. However, the relationship between pCR and survival is not uniform. Patients with hormone receptor-positive tumors are less likely to have a pCR but have improved survival. Using pCR to determine risk of recurrence may be less useful in ER+/HER2+ disease, especially in early disease where patients may have excellent outcomes with de-escalated therapy regardless of pCR status.Balancing potential benefits and side effects of chemotherapy is a key therapeutic decision. The toxicity of chemotherapy is an important component in decisions regarding continuation of therapyIn patients with residual disease, having received upfront multi-agent chemotherapy was a predictor of poor survival. This may reflect selection of patients expected to have worse outcome for multi-agent regimens, that residual disease after multi-agent NAC may be biologically worse than residual disease after single-agent NAC, or related to adverse effects of multi-agent chemotherapy. Alternatively, patients that were treated more aggressively upfront may have fewer therapeutic options in the adjuvant setting.15. More study is needed to determine optimal escalation strategies, and patients that do not need additional adjuvant therapy, for APT eligible patients residual disease after neoadjuvant chemotherapy.We found that APT eligible patients with T1 tumors, with residual disease after NAC have similar survival to patients with T2 tumors with residual disease and may represent a higher risk group than was representative of that trial. Response to therapy may contribute to shared decision-making with patients regarding an adjuvant regimen that balances the risks of additional therapy with anticipated outcomesThis study has several important limitations. NCBD data is incomplete. Information from only facilities with CoC accreditation is included, participation is voluntary, and data are reported by facilities without additional review. In addition, small sample sizes in the stratified analyses led to imprecise estimates. In this study, a minority of patients received single-agent chemotherapy, and the reasons for which those patients were selected for that therapy by the treating teams are not fully captured in the NCDB. Furthermore, information about specific therapeutic agents is missing and we are not able to determine adjuvant therapy. Lastly, recurrence data is not available from the NCDB. We report only 3-year overall survival, which may be insufficient for differences in outcomes to manifest.In this large observational cohort of early HER2+ breast cancer, multi-agent chemotherapy was associated with higher likelihood of pCR, but this effect was modest compared to other factors. Single-agent NAC with HER2-directed therapy resulted in a pCR in a substantial number of patients and may provide excellent outcome with reduced toxicity, while allowing escalated therapy in the adjuvant setting for patients with residual disease. Prospective studies are needed to determine effects of de-escalation in the neoadjuvant setting, identify patients safe for de-escalation strategies, and determine optimal escalation strategies for patients with residual disease.18. Data are collected from over 1500 Commission on Cancer (CoC) accredited facilities. We followed best practices for analyses using NCDB19.We utilized data from the American College of Surgeons and American Cancer Society 2016 National Cancer Database (NCDB) breast cancer participant use file. The NCDB is a clinical oncology database covering over 70% of incident cancers in the U.S.We identified adult women (≥18 years) with clinical T1N0 or T2N0 HER2+ malignant carcinoma of the breast between January 1, 2013 and December 31, 2015. Women were followed for up to 3 years after diagnosis. Prior years were not included due to changes in definitions for key study variables in 2013. Women were included if they were treated with NAC with HER2-targeted therapy prior to surgery and underwent either a mastectomy or breast-conserving therapy within 8 months of their breast cancer diagnosis. HER2-targeted therapy was identified using the NCDB immunotherapy variable. Women who died or were lost to follow-up within 8 months of diagnosis were excluded.Pathologic response was categorized as pathologic complete response . Individuals with missing pathologic T or N stage were treated as missing.Demographic and clinical covariates were assessed for analyses of factors associated with pCR and mortality. Demographic factors included age and race. Tumor factors included hormone receptor status, tumor grade, histology, and year of diagnosis. Comorbidity burden was assessed using the Charlson Comorbidity Index (CCI) in the NCDB file. The NCDB contains an adjuvant therapy data field, but there is only specific data on the first course of chemotherapy which in this cohort was neoadjuvant. It is additionally a composite variable of chemotherapy, hormone therapy, and immunotherapy, and was missing for the majority of patients in this study, so we did not include it in the analysis.Patient demographic and clinical characteristics were described using frequency statistics for categorical variables and medians and interquartile ranges (IQRs) for continuous variables. Pathologic response rates were described using frequency statistics, stratified by type of NAC (single vs. multi-agent). Chemotherapy is reported in the NCDB as single or multi-agent and we are unable to identify patients treated with specific drugs or regimens. HER2-directed therapy is reported separately, and so we can include only patients that received HER2-directed therapy and stratify those patients by single or multi-agent chemotherapy regimens. Factors associated with pCR to neoadjuvant therapy were assessed using a multivariable logistic regression model that included overall pCR as the dependent variable and patient demographic and clinical factors as independent variables.21. Follow-up for survival analyses was started for all women at 8 months following diagnosis, to account for variable timing of surgery and NAC initiation. To determine the significance of other clinical and pathologic features in addition to the prognostication provided by pCR, we analyzed factors associated with mortality using Cox proportional hazards regression models. Separate models were fit in women with pCR and those with residual disease. Individuals with missing covariate information were excluded from all models. All analyses were conducted using SAS Version 9.4 . The study was exempted from review by the Institutional Review Board at the University of North Carolina at Chapel Hill (IRB# 20-1493).Kaplan–Meier analyses were used to assess survival, stratifying by type of NAC (single vs. multi-agent) and pathologic response (pCR vs. no pCR). A landmark approach was used to address potential immortal time biasFurther information on research design is available in the Supplementary FilesConsort ChecklistReporting SummaryNIH Publishing Agreement


BackgroundHeller myotomy (HM) with partial fundoplication is the standard of care for achalasia cardia. However, the choice of partial fundoplication is controversial. In this study, we compared both types of fundoplication concerning subjective and objective parameters.MethodologyThis prospective comparative study comprised a total of 30 consecutive patients who underwent laparoscopic/robotic HM with either Dor fundoplication (DF) (n = 15) or Toupet fundoplication (TF) (n = 15). Preoperative baseline characteristics, intraoperative details, and postoperative complications were recorded. Patients were followed with Eckardt score, quality of life-related scores, 24-hour pH study, and high-resolution manometry (HRM) at the one-year follow-up.ResultsThere was no significant difference between the two groups regarding preoperative baseline parameters, length of hospital stay, and postoperative complications. The HM+DF group had four (27%) patients with recurrence/failure with none in the HM+TF, but it was not significant (p = 0.79). Symptom scores were similar between the groups at six and 12 months of follow-up. One patient in the HM+DF group and two in the HM+TF group had significant pathological acid reflux (p = 0.483). On HRM, HM+TF showed a trend toward significance in terms of esophagogastric junction (EGJ) relaxation (p = 0.058) with a non-significant difference in median integrated relaxation pressure (p = 0.081).ConclusionsThe study showed a trend toward lower failure rates and improved EGJ relaxation with similar reflux rates in patients who underwent HM+TF compared to HM+DF. However, long-term follow-up is required to validate our findings with well-defined subjective and objective criteria. Achalasia is a disease involving the esophagus which causes progressive degeneration of nerves leading to aperistalsis of the esophagus and failure of relaxation of the lower esophageal sphincter (LES). Because the disease process involves a gradual loss of ganglion cells in Auerbach’s plexus of the esophagus, it is essentially irreversible . ConsequPartial fundoplication is preferred after HM as it is reported that there is an increased risk of dysphagia, with no significant difference in pathological reflux after a total fundoplication . FurtherOur study aimed to compare postoperative reflux and dysphagia in patients undergoing HM and partial fundoplication with a 24-hour pH study, high-resolution manometry (HRM), and the quality of life outcome questionnaires. Integration of objective and subjective assessment of postoperative reflux may aid surgeons in selecting the ideal anti-reflux procedure and prevent complications related to asymptomatic reflux after esophageal myotomy.This prospective study was conducted in the Department of Surgical Gastroenterology at the All India Institute of Medical Sciences (AIIMS), Jodhpur (India), to compare the incidence of reflux between DF and TF in achalasia cardia after HM, as well as to determine the improvement in the quality of life. All patients undergoing minimally invasive HM with partial fundoplication from July 2018 to December 2019 were included in the study and were followed up till December 2020. Ethical clearance was attained from the Institutional Ethics Committee with reference number AIIMS/IEC/2018/777.The sample size was calculated by assuming a surgical complication proportion from the study by Torres-Villalobos et al. . The patPatients with end-stage achalasia cardia/sigmoid esophagus, previous upper abdominal surgery or peroral endoscopic myotomy (POEM), prior HM, Chagas disease or other esophageal motility disorders, uncorrectable coagulopathy, and significant comorbid conditions precluding the use of general anesthesia/American Society of Anesthesiologist (ASA) class 3-4 were excluded from the study.Clinical history of dysphagia, chest pain, chronic cough, nocturnal cough, dyspnea on exertion, and weight loss was obtained. Eckardt score and achalasia-specific quality of life (ASQOL) and gastroesophageal reflux disease health-related quality of life (GERD-HRQL) questionnaires were filled in the preoperative setting. Chicago classification of esophageal motility disorders, version 3.0, was used for defining achalasia cardia, and the diagnosis was confirmed with an oral contrast study (OCS), HRM, and upper gastrointestinal endoscopy (UGIE).Laparoscopic and robotic HM was performed with either DF or TF. The myotomy was initiated just above the esophagogastric junction (EGJ) and extended 4-5 cm proximally, followed by 2-3 cm distally onto the gastric side, such that a total myotomy length of 6-8 cm was achieved. The choice between anterior and posterior fundoplication was the surgeon’s preference. Postoperatively, patients were started on oral liquids on day one or two after OCS, and the nasogastric tube and abdominal drain were usually removed on postoperative day (POD) two or three. Patients were typically discharged by POD three or four. Patients were followed up every six months for one year, either via a physical visit to the outpatient department or telephonically, and re-assessed by the physician with the Eckardt, ASQOL, and GERD-HRQL questionnaires. At the one-year follow-up, a 24-hour pH study and manometry were done to assess reflux and dysphagia objectively.Failure was defined as a persistent Eckardt score of >3, and recurrence was described as a decrease with an Eckardt score of <3 with an increase to >3 on follow-up. Pathological reflux was defined as a DeMeester score of more than 14.7 on a 24-hour pH study.Statistical analysisData were acquired in a specified format as in a proforma and entered in SPSS version 27 /Microsoft Excel software for analysis. Measured data were expressed as median with interquartile range (IQR) at the 25th and 75th percentiles or as percentages. Chi-square or Fisher’s exact test was used for comparing proportions, whichever was applicable. Numerical data were compared using the Mann-Whitney U test. Pre- and post-intervention scores were compared using the Wilcoxon signed-rank test. A two-tailed p-value of 0.05 or less was considered statistically significant.Both HM+DF n = 15) and HM+TF (n = 15) groups had similar baseline characteristics  and four 26.7%) patients in each group underwent laparoscopic and robotic HM, respectively. The length of myotomy on the esophagus and stomach and the median hospital stay was similar between the two groups. None of our patients required readmission. Although three patients in the HM+DF group had a mucosal tear, none had clinical leaks, and all recovered uneventfully  in the HM+DF group compared to the HM+TF group (0%), this difference was not significant (p = 0.799). The Eckardt, ASQOL, and GERD-HRQL scores were not significantly different between the groups  at the one-year follow-up Table .The difference between the two groups in the 24-hour pH study was also insignificant. Two patients in the TF group and only one in the DF group had a DeMeester score of more than 14.7 (p = 0.483). On manometry, median IRP (IQR) was 16.4  mmHg in the HM+DF group and 10  mmHg in the HM+TF group (p = 0.081). EGJ relaxation was incomplete in eight patients in the HM+DF group and three in the HM+TF group. This difference seemed to tend toward significance (p = 0.058)  and objective assessments of both dysphagia and reflux.All patients in our study underwent minimally invasive surgery, either laparoscopic or robotic-assisted. Several retrospective studies have shown equivalent outcomes in comparing LHM and RHM with respect to operative time, complications, and success rates . The lenOur patients were followed up at six months and then again at 12 months after surgery, with subjective and objective assessments of dysphagia and reflux. The International Society for Diseases of the Esophagus (ISDE) guidelines recommend evaluating symptomatic improvement as the best measure of success or failure of a treatment modality . The EckFurther, few studies have shown that TF is associated with lower recurrence rates than DF . This diHealth-related quality of life is an essential tool in the assessment of functional disorders, but only a few studies in the literature report quality of life in achalasia patients ,7,18. ThGERD-HRQL is an accepted and validated questionnaire for the assessment of GERD symptoms . We emplTo objectively evaluate relief in dysphagia, we also performed HRM in our patients one year after surgery. The postoperative median IRP was higher in the HM+DF group than in the HM+TF group, but this difference was not statistically significant. This finding is akin to the results reported by Torres-Villalobos et al. . They foNevertheless, our study is fraught with limitations of the small sample size, selection bias, and a short postoperative follow-up. Additionally, postoperative endoscopy was not performed routinely unless symptomatic. However, our study is unique as it evaluated ASQOL, improvement in manometric outcomes concerning dysphagia, and assessment of reflux with the GERD-HRQL questionnaire, as well as an ambulatory 24-hour pH study together in follow-up. We believe that only symptomatic assessment may lead to underdiagnosis of postoperative GERD and its complications; hence, objective evaluation with a 24-hour pH study is essential.HM with partial fundoplication is currently the standard of care for patients with achalasia. Although the choice of fundoplication may be decided based on an individual surgeon’s preference, our study shows a trend toward lower failure rates and improved EGJ relaxation with similar pathological reflux rates in patients who underwent HM+TF compared to those who underwent HM+DF. Poor clearance of asymptomatic acid refluxate in a dilated aperistaltic esophagus of this chronic incurable disease is a matter of grave concern in the long term. We believe that future clinical research for ideal fundoplication post-myotomy should focus on objective reflux parameters rather than relying solely on symptoms during follow-up. Larger studies with longer follow-ups aimed at comparing the two fundoplications with a 24-hour pH study at follow-up may end the surgeon’s dilemma.