There is no agreed consensus on the optimal surgical treatment for pain associated with endometriosis.To compare improvement in symptoms and quality-of-life in patients undergoing excisional endometriosis surgery (EES) versus EES with hysterectomy and bilateral salpingo-oophorectomy (EES-HBSO).This study evaluated patients undergoing EES and EES-HBSO at a single endometriosis centre between 2009 and 2019. Data was obtained from the British Society for Gynaecological Endoscopy database. Adenomyosis was assessed by blinded re-analysis of imaging and/or histology data.Pain scores  and quality-of-life scores (EQ-VAS) before and after EES and EES-HBSO.We included 120 patients undergoing EES and 100 patients undergoing EES-HBSO. After controlling for baseline characteristics and the presence of adenomyosis, there was greater post-op improvement in non-cyclical pelvic pain amongst patients undergoing EES-HBSO compared to EES alone.The baseline pain scores had improved in the EES-HBSO cohort by 2.106/10 at 6 months , 2.642/10 at 12 months , and 2.548/10 at 24 months , when compared to the EES group. Greater improvement amongst EES-HBSO patients was also seen for dyspareunia, non-cyclical dyschaezia and bladder pain. Patients undergoing EES-HBSO had greater improvement in EQ-VAS, although this was no longer statistically significant after controlling for adenomyosis.EES-HBSO appears to provide greater benefit than EES alone for symptoms including non-cyclical pelvic pain as well as for quality-of-life. Further research is required to determine which patients benefit the most from EES-HBSO, and whether removal of the ovaries, uterus or both is the key to this additional benefit in symptom control. Pelvic pain associated with endometriosis impacts quality of life with limited data to support effective treatments for the condition . AmongstRecommended surgical treatment of endometriosis usually involves laparoscopic or robotic excision of visible lesions, whilst preserving the uterus and ovaries. However, some patients opt to undergo more radical treatments including removal of the uterus, cervix, tubes, and ovaries. This induces a hypoestrogenic state and amenorrhoea, as well as removing adenomyosis which may be a concurrent cause of persistent pelvic pain .Surgery for severe endometriosis is complex and associated with significant risks in the immediate operative period and longer term , includiThe British Society for Gynaecological Endoscopy (BSGE) has established specialist endometriosis centres since 2007. This progressive approach to service delivery ensures centres meet pre-specified criteria to deliver specialist care to patients with severe endometriosis. These include a minimum number of procedures per annum per surgeon, a dedicated nurse specialist, named urological and colorectal colleagues for surgical support, and an annual exemplar video evaluation. This rigorous governance structure aims to ensure that standards of clinical and surgical care are maintained through regular evaluation and the collection of standardised data across the registered centres.International guidance, based on expert opinion, recommends hysterectomy with or without removal of the ovaries for patients who no longer wish to conceive and who have failed to respond to more conservative treatments . HoweverThe aim of this study is to evaluate the effectiveness of excisional endometriosis surgery with hysterectomy and removal of ovaries (EES- HBSO) for reducing symptoms and improving quality of life in comparison to EES alone.This study evaluated prospectively collected data on patients who underwent conservative excisional surgery and hysterectomy with bilateral salpingo-oophorectomy for pain symptoms associated with deep (Need to clarify what deep endo is) endometriosis. All patients were treated at University College London Hospital (UCLH), a BSGE-accredited tertiary endometriosis centre, by three accredited surgeons, using a laparoscopic approach.We analysed prospectively-collected data originating from UCLH available on the BSGE database between January 2009 and June 2019 . Patients were divided into those who had undergone surgical excision of endometriosis (EES group) and those who had undergone surgical excision of endometriosis with removal of the uterus, tubes, cervix, and ovaries (EES-HBSO group). The decision on whether to perform EES or EES-HBSO was made in partnership with the patients on a case-by-case basis, based on their preferences, effectiveness of previous treatment, whether the patient felt that their family was complete, and other factors.The patients who underwent EES-HBSO were offered hormone replacement therapy in the absence of specific contraindications. Data from a total of 100 consecutive patients undergoing EES-HBSO were analysed from the database, with 120 age-matched consecutive controls undergoing EES. We obtained guidance from NHS Research and Ethics. As there was no randomisation, no alteration in treatment offered or generalisable results, the study was considered to be a service evaluation and a separate ethics approval was not required. All patients had prospectively consented to the sharing of their BSGE data, and this study was approved by the BSGE Scientific Advisory Group (reference ID: BSGESAG2020-3).The BSGE database collects data on clinical symptoms at baseline , and at 6-, 12-, and 24-months postoperatively. The symptoms include premenstrual pain, menstrual pain, non-cyclical pelvic pain, deep dyspareunia, cyclical dyschaezia, non-cyclical dyschaezia, lower back pain, bladder pain, pain during bladder voiding and quality of life. All patient-reported pain scores were assessed using a numeric rating scale from 0 (no pain) to 10 (most intense pain). Quality of life (QoL) scores were collected using the EuroQol visual analogue score (EQ- VAS) from 0 , according to previously published criteria. Where aBaseline characteristics and symptom scores of patients undergoing hysterectomy and conservative surgery were compared using independent samples t–tests and Chi squared test of proportions. P-values of <0.05 were considered to be statistically significant throughout.The study used a longitudinal multilevel modelling approach to investigate differences in improvement in symptom and EQVAS scores between patients undergoing EES with or without HBSO. Symptom and EQVAS scores were modelled with respect to time post-operation, using REML (restricted maximum likelihood) mixed-effect linear regression with a random intercept for each individual patient. Models were created in R using the lme function from the nmle package. Missing values were addressed with pair- wise deletion. The models were adjusted for age, smoking status, BMI, previous surgical treatment of endometriosis, diagnosis of adenomyosis and baseline symptom score.Anonymised data of 737 patients were downloaded from the BSGE database. 22 duplicates were excluded from the study, with 38 patients excluded due to incomplete data: empty records (n=23) and missing hospital numbers (n=15). Other patients were excluded because they met one of the following exclusion criteria; no recorded preoperative pain scores (n=12), none of the follow-up pain scores were recorded (n=251) or previous hysterectomy (n=10). We identified 404 eligible patients of whom 296 had EES and 108 had EES with HBSO. After age-matching there were 120 patients in the EES group and 100 patients in the EES-HBSO group. Altogether, 220 patients were included in the primary analysis.We evaluated preoperative demographics between the two groups. The mean BMI of patients undergoing EES-HBSO  was significantly higher than those in the EES group  . The mean age of patients who underwent EES and EES-HBSO were similar, 40 (SD 3.71) and 41 (SD 4.55) respectively. Current smokers represented 10% of the EES group and 8% in the EES-HBSO group (p = 0.607). History of previous surgery for endometriosis was common among both groups with 78% having had surgery in EES group and 88% in EES-HBSO group (p = 0.042). Adenomyosis was present in 44% of EES patients based on ultrasound and/or MRI findings whereas 57% of EES-HBSO patients had adenomyosis based on ultrasound, MRI and/or histology .The mean preoperative symptom scores were significantly greater amongst those undergoing EES-HBSO compared to the EES group scores for premenstrual pain ; non-cyclical pelvic pain , deep dyspareunia  and difficulty emptying bladder . All other pain scores were similar between the two groups .The follow-up rates in EES and EES-HBSO were similar: 74% and 88% at 6 months, 65% and 63% at 12 months, and 46% and 49% at 24 months respectively.When mean pain scores were assessed at 6, 12, and 24 months postoperatively there was a reduction in pain at all time points compared to the preoperative pain scores irrespective of group, with the exception of difficulty emptying the bladder in the EES group where the symptom score increased at 12 months in comparison to the preoperative pain score.Mixed effects linear regression was used to compare improvement in quality of life score (EQ-VAS) and pain scores between patients who underwent EES and patients who underwent EES-HBSO. The comparison was performed for pain scores at 6-, 12- and 24-months post-op and was adjusted for baseline characteristics of age, smoking, previous treatment of endometriosis and BMI, with and without adjustment for the effect of adenomyosis.Non-cyclical pain improved significantly from baseline by 3.042/10 at 6 months post-op , 2.515/10 at 12 months  and 2.531 at 24 months  overall. Compared to patients who underwent EES only, patients undergoing EES-HBSO had an additional improvement of 2.344/10  at 6 months post-op, 2.624/10 at 12 months post-op  and 3.119 at 24 months post-op . After also controlling for the effect of adenomyosis, patients who had a hysterectomy still improved significantly more than patients who did not have a hysterectomy .For other symptoms, the symptom scores improved significantly more for EES-HBSO patients compared to EES for dyspareunia at 12 months by 2.306/10 , non-cyclical dyschaezia at 24 months by 1.857/10 , and bladder pain at 24 months by 2.120/10 . No other differences in symptoms were significant, and EES patients did not show greater improvement in symptoms than EES- HBSO patients at any time point for any symptom.Compared to baseline, overall mean EQ-VAS scores improved by 12.398/100 points at 6 months , 12.451/100 points at 12 months  and 10.369/100 points at 24 months . Patients who underwent EES- HBSO had significantly greater improvement in EQVAS score at 24 months compared to patients who underwent EES only, by 10.285/100 points (95%CI 0.038-20.532 p=.049) . HoweverOur study demonstrates that there may be additional benefit of EES-HBSO over EES alone for the surgical treatment of pain associated with endometriosis. Patients who underwent EES-HBSO saw greater improvement in non-cyclical pain at all follow-up time-points compared to those patients undergoing EES alone. This effect remained significant even after controlling for the presence of adenomyosis. The benefit of EES-HBSO was also seen in symptom scores for deep dyspareunia, bladder pain and non-cyclical dyschaezia. EES- HBSO patients showed greater improvement in quality-of-life score compared to EES patients after controlling for baseline characteristics but not after controlling for the presence of adenomyosis, indicating that this additional improvement was mostly seen in patients with adenomyosis.This is the first study to compare prospectively collected long-term pain and quality of life outcomes amongst patients with deep endometriosis undergoing EES versus EES-HBSO. Previous studies have compared re-operation rates but not improvement in symptoms , while aAs an observational non-randomised study, selection bias inevitably affected results, and accordingly worse baseline pre-operative symptoms and quality of life were found amongst patients who underwent EES-HBSO compared with those who underwent EES. A limitation of our study includes lack of data on the duration of symptoms experienced by the patients, which may have differed between groups, as well as the stage of endometriosis. Patients with worse or more long-standing chronic pain would be expected to show less overall improvement than those with less severe symptoms , howeverAll patients in our study who had a hysterectomy also underwent bilateral salpingo-oophorectomy, therefore it is not clear from the data whether it is the removal of uterus or ovaries which was providing the key benefit. Further work comparing these two treatment modalities is required to determine whether symptom improvement can be attributed to surgical menopause through oophorectomy or removal of adenomyosis by hysterectomy.This data is not definitive, and a starter point for further work to confirm whether EES-HBSO may provide additional benefit over EES alone for the control of symptoms and for which patient group. Hysterectomy results in irreversible loss of fertility, so the importance of further research to inform this choice cannot be stressed enough. Ideally the benefits of hysterectomy over EES alone would be studied in a randomised controlled trial, however this may not be ethically feasible, and may still suffer from selection bias at the enrolment and follow-up stages. Additionally, although greater improvement in pain symptoms were shown amongst EES-HBSO patients even after controlling for the presence of adenomyosis, this must be treated with caution as data on adenomyosis was missing from 33% of those undergoing EES alone. While both EES and EES- HBSO patients in our cohort may have undergone pre-operative imaging, histological examination of the uterus for adenomyosis was only possible for patients undergoing EES-HBSO. As the sensitivity of TVUS and MRI for adenomyosis is only 81% and 71% respectively , this maFollow-up was not complete and fell from 81% at 6 months, to 64% at 12 months and finally to 48% at 24 months. It was decided to not contact patients in order to obtain symptom questionnaires, as this may introduce recall bias, so loss to follow-up remains a limitation of this study. Maintaining long-term follow-up is a challenge, particularly in this relatively young and mobile patient group. However, the follow-up data in our cohort was considerably more complete than the average follow-up rates of 50%, 38% and 27% at 6-, 12- and 24-months post-op respectively for the BSGE database overall .Our findings are consistent with other studies which confirm that hysterectomy is a valuable treatment option for patients with pain symptoms associated with endometriosis . A recenThese studies and ours demonstrate the utility of hysterectomy with bilateral salpingo- oophorectomy in effectively treating symptoms, improving quality of life while reducing the need for repeat surgery. This treatment strategy mirrors internationally recommended medical approaches of inducing a hypoestrogenic state . While tIt is unclear whether patients are benefitting from removal of the uterus, the ovaries or both. Historic comparative data indicates that hysterectomy with or without ovarian preservation reduces reoperation rates . HoweverAnother cause for consideration is the added operative complexity that hysterectomy entails, especially as complication rates are higher from hysterectomy for endometriosis compared to hysterectomy for other benign indications . In a laPrevious studies have also suggested the immediate risk of bladder dysfunction increases proportionately with complexity of endometriosis surgery . This maThis study presents the first and largest comparison between excision of endometriosis alone versus with hysterectomy for the treatment of deep endometriosis associated pain. Patients who underwent EES-HBSO achieved greater improvements in their symptoms and quality-of- life scores than patients undergoing solely excision of endometriosis. The added benefit in symptom control must be weighed against the complication rate and reproductive and hormonal side-effects on an individual basis. This study will help inform patients about their available choices and enable an open discussion about expectations after EES and EES-HBSO.


This cohort study assesses risk of venous thromboembolism following COVID-19 infection in individuals with vs without immune-mediated inflammatory diseases in Ontario, Canada. Are individuals with immune-mediated inflammatory diseases (IMIDs) more likely to experience a venous thromboembolism (VTE) following COVID-19 infection than individuals without IMIDs?In a matched cohort study conducted using health administrative data from Ontario, Canada, the incidence of VTE among 28 440 individuals with an IMID was 2.64 per 100 000 person-days compared with 2.18 per 100 000 person-days among 126 437 individuals without an IMID. After adjusting for having 2 or more doses of a COVID-19 vaccine, history of VTE, and comorbidities, the risk of VTE was not statistically significantly different for people with IMIDs.Following a COVID-19 diagnosis, the overall risk of VTE is low among individuals with IMIDs. Immune-mediated inflammatory diseases (IMIDs) and COVID-19 are independently associated with venous thromboembolisms (VTEs).To determine if individuals with IMIDs are at higher risk of VTE following COVID-19 infection compared with individuals without IMIDs.Population-based matched cohort study using multiple deterministically linked health administrative databases from Ontario, Canada, and including patients testing positive for COVID-19 between January 1, 2020, and December 30, 2021, and followed up until March 31, 2022. Individuals with IMIDs (n = 28 440) who tested positive for COVID-19 were matched with up to 5 individuals without an IMID (n = 126 437) who tested positive for COVID-19. Matching was based on year of birth, sex, neighborhood income, and rural/urban residence. Data analysis was performed from August 6, 2022, to August 21, 2023.Diagnosis of an IMID, identified using algorithms based on diagnostic codes, procedures, and specialist visits.The main outcome was estimated age- and sex-standardized incidence of VTE. Proportional cause-specific hazard models compared the risk of VTE in people with and without IMIDs. Death was a competing risk. Models adjusted for history of VTE, 2 or more doses of a COVID-19 vaccine 14 or more days prior to COVID-19 diagnosis, and the Charlson Comorbidity Index. Routinely collected health data were used, so the hypothesis tested was formulated after data collection but prior to being granted access to data.The study included 28 440 individuals  with an IMID diagnosed prior to first COVID-19 diagnosis, with a mean (SD) age of 52.1 (18.8) years at COVID-19 diagnosis. These individuals were matched to 126 437 controls without IMIDs. The incidence of VTE within 6 months of COVID-19 diagnosis among 28 440 individuals with an IMID was 2.64  per 100 000 person-days compared with 2.18  per 100 000 person-days among 126 437 matched individuals without IMIDs. The VTE risk was not statistically significantly different among those with vs without IMIDs .In this retrospective population-based cohort study of individuals with IMIDs following COVID-19, individuals with IMIDs did not have a higher risk of VTE compared with individuals without an IMID. These data provide reassurance to clinicians caring for individuals with IMIDs and COVID-19. Inflammatory bowel disease (IBD),13 rheumatoid arthritis,15 psoriasis,16 vasculitis,17 and multiple sclerosis18 have all been reported to be associated with higher VTE risk.Immune-mediated inflammatory diseases (IMIDs) are a heterogeneous group of chronic diseases that result from abnormal activation of the immune system, affecting 5% to 7% of people in the Western world.The interplay between COVID-19, IMIDs, and VTE remains undefined. We hypothesized that individuals with IMIDs may have an elevated risk of VTE following COVID-19. We aimed to evaluate the incidence and risk of VTE following COVID-19 in individuals with IMIDs compared with those without IMIDs using population-based health administrative data from Ontario, Canada.RECORD), an extension to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for research using routinely collected health administrative data.19This study used health administrative data from Ontario, Canada, which has a publicly funded universal health care system. Data include all health care interactions of Ontario residents with valid health cards (>99% of the population). This includes hospitalizations , procedures requiring single-day hospital admission (CIHI Same Day Surgery Database), emergency department visits , and visits to the hospital for outpatient surgeries or other procedures (CIHI Same Day Surgery Database). Data also include physician billings for all patient-physician interactions, including outpatient visits; these data include physician specialty. Data were linked deterministically to the Registered Persons Database (demographic characteristics), Ontario Cancer Registry, C19INTGR (COVID-19 testing), and COVaxON (COVID-19 vaccinations). All data are held by ICES, an independent, nonprofit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement. Data are available in uncleaned, unedited format to researchers and data analysts. The use of the data in this project is authorized under section 45 of Ontario’s Personal Health Information Protection Act (PHIPA) and does not require review by a research ethics board. This study was reported in accordance with the Reporting of Studies Conducted Using Observational Routinely Collected Health Data , sex, mean neighborhood income quintile, and rural/urban residence. Before matching, we excluded individuals without a valid Ontario health card number, date of birth, date of death (date of death preceded date of positive COVID-19 test result), or sex. We also excluded people diagnosed with a malignant neoplasm within 5 years prior to testing positive for COVID-19.Individuals testing positive for COVID-19 were identified from C19INTGR, which includes the results of all polymerase chain reaction (PCR) tests conducted in Ontario from January 1, 2020, to December 30, 2021, after which time PCR testing was limited to selected groups. Participants were followed up from the date of the first positive COVID-19 test result until VTE, death, migration out of Ontario, or end of follow-up .International Classification of Diseases, Ninth Revision [ICD-9] before April 1, 2002, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] on or after April 1, 2002), the specialty of the physician submitting the billing claim for physician claims, procedure codes for endoscopy (IBD only), and indication-specific medications. Validated algorithms were available for IBD,21 multiple sclerosis,22 psoriasis,23 psoriatic arthritis,23 and rheumatoid arthritis.25 See eTable 1 in ICD-10 coding system introduction). Only individuals for whom the first diagnostic code for an IMID occurred before the date of COVID-19 diagnosis were included.Individuals with at least 1 diagnosis of ankylosing spondylitis, IBD, multiple sclerosis, polymyalgia rheumatica, psoriasis, psoriatic arthritis, rheumatoid arthritis, systemic autoimmune rheumatic disease , uveitis, or vasculitis were identified using algorithms based on multiple health care encounters with disease-specific diagnostic codes  and deep vein thrombosis (DVT), were identified from emergency department and hospitalization data using ICD-9 to ICD-10 coding.30 We adapted the index to (1) include comorbidities treated in an outpatient setting and (2) remove codes used in our IMID-identification algorithms to avoid inflation of the CCI in people with IMIDs (see eTable 3 in We used the Deyo adaptation of the Charlson Comorbidity Index (CCI), converted from 31 congestive heart failure,32 or diabetes34 prior to their COVID-19 diagnosis were identified using previously validated algorithms (eTable 4 in We report (1) the total number of IMIDs ; (2) the number of IMIDs in addition to the IMID of interest ; (3) IMID duration at the time of COVID-19 diagnosis; and (4) history of VTE in the 5 years prior to COVID-19 diagnosis. Patients with any recorded diagnosis of chronic obstructive pulmonary disease,Duration of IMID was calculated as the difference between the date of IMID diagnosis  and the date of COVID-19 diagnosis and categorized . When the exact date of diagnosis was unknown , cases were assumed to be prevalent on the date of their first diagnostic code and assigned a disease duration of 5 or more years. When individuals had multiple IMIDs, IMID duration was defined as the time from the first IMID diagnosis to date of COVID-19 diagnosis.COVaxON includes information on all COVID-19 vaccines administered in Ontario, Canada, and any out-of-province vaccines reported to public health. Anyone with 2 or more vaccinations 14 or more days before their positive COVID-19 test result was considered vaccinated.35) at the time of COVID-19 diagnosis were identified from the Registered Persons Database.Sex, rural/urban residence, death prior to end of follow-up, and mean neighborhood income quintile  unadjusted, (2) adjusted for COVID-19 vaccination and history of VTE, and (3) adjusted for COVID-19 vaccination, history of VTE, and the CCI (continuous). We selected these variables as important confounders because of their impact on the magnitude of the association between IMIDs and VTE, with the number of events limiting the number of variables that could be included in a regression model.The incidence of VTE  was calculated by dividing the number of VTEs by the total person-time and reported as events per 100 000 person-days (PDs). We reported the crude and age- and sex-standardized incidence rates within 6 and 12 months of COVID-19 diagnosis using the 2017 Canadian population as the standard. Confidence intervals for both the crude and standardized incidence rates were calculated using the gamma method.Our primary analysis included individuals with any IMID. When a person had multiple IMIDs, we included them once in the analysis of all IMIDs and in disease-specific analyses. We conducted a sensitivity analysis censoring participants with a second COVID-19 diagnosis, applying a minimum look-forward period of 60 days to minimize the risk of censoring individuals following a second positive test result for the same infection. We also conducted a sensitivity analysis excluding patients with any history of VTE (after 2002).All statistical tests were 2-sided with a 5% level of significance. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc).We identified 28 440 individuals with an IMID diagnosed prior to their first COVID-19 diagnosis, who were matched to 126 437 controls. Cases and controls were comparable for matched characteristics . PatientWithin 6 months of COVID-19 diagnosis, the standardized incidence rate of VTE was 2.64  per 100 000 PDs among people with IMIDs compared with 2.18  among matched individuals without IMIDs ; Table 2In unadjusted analysis, people with IMIDs were significantly more likely to have a VTE compared with matched controls  per 100 000 PDs among individuals with IMIDs compared with 0.17  among people without IMIDs . ExtendiThe standardized incidence rates of PEs within 6 months were 0.85  per 100 000 PDs among individuals with IMIDs and 0.54  among individuals without IMIDs . The staWhile IMIDs and COVID-19 are independently associated with VTEs, we observed no additional risk of VTEs among individuals with IMIDs relative to matched individuals without IMIDs following COVID-19 diagnosis after adjusting for COVID-19 vaccination, history of VTE, and comorbidities. However, individuals with IMIDs had a higher risk of VTEs when not adjusting for comorbidities. These findings were consistent in IMID-specific analyses and when separately investigating the risks of DVT and PE.18 Studies examining the additive risk of having an IMID on the post–COVID-19 risk of VTE are sparse. A case-crossover study using health administrative data from a US Veterans Affairs health care system cohort reported that individuals with IBD had higher odds of a VTE following COVID-19  relative to the pre–COVID-19 period.37 However, this study did not compare individuals with and without IBD. Another study using Kaiser Permanente data from California also reported elevated risk in patients with IBD and COVID-19 .38 The wide confidence intervals may indicate imprecision due to smaller sample size of patients with IBD (n = 2006). In addition, this study did not control for vaccination status. Reassuringly, the overall risk of VTEs after COVID-19 in this study (0.26 per 100 person-years [PYs]) was similar to that of the current study (2.18 per 100 000 PDs = 0.8 per 100 PYs).38 In a study from the United Kingdom, the risk of thrombosis was similar among those with autoimmune conditions and propensity-matched controls who were hospitalized for COVID-19.39 Findings were similar when restricting the analysis to individuals with rheumatologic conditions. In addition, VTE incidence in patients with COVID-19 in the current study was higher than prepandemic population-based VTE rates in Canada .40Both IMIDs and COVID-19 are associated with an increased risk of VTE.The association between IMIDs and VTE following COVID-19 was substantially modified when controlling for comorbidities in the regression analysis. This suggested that comorbidities confounded the association between IMIDs and VTE in the presence of COVID-19. This is a noteworthy finding for clinicians caring for individuals with IMIDs with COVID-19. When treating patients with an IMID and COVID-19, physicians should consider both the underlying COVID-19 severity, individual risk factors, and the presence of comorbidities in determining the need for VTE prophylaxis. In the absence of severe IMID-related inflammation, VTE risk factors, and other comorbid conditions, the IMID itself should not determine the need for VTE prophylaxis.Our study is strengthened by the use of health administrative data from Canada’s most populous province, including an ethnically diverse population from a large geographic region. Since data include information for all residents eligible for provincial health care coverage (>99%), our study is representative of the Ontario population.41 Reassuringly, the results of a sensitivity analysis censoring individuals at the time of a second infection were nearly identical to our primary analysis. We also relied on PCR testing for SARS-CoV-2 to identify patients with COVID-19. We may have missed asymptomatic or mild cases, especially during times when the need for testing and/or contact tracing exceeded demand. While all Ontario residents had universal access to PCR testing at no expense, we could not assess whether patients with IMIDs were more likely to be tested than patients without IMIDs. However, all patients admitted to the hospital were routinely tested with PCR. The structure of our data does not allow us to differentiate among individuals admitted to the hospital because of COVID-19, individuals admitted for other reasons but had an incidental positive SARS-CoV-2 test result, or individuals admitted later due to longer-term complications following infection. We therefore could not account for COVID-19 severity. Two-thirds of individuals included in our study had not received 2 or more doses of a COVID-19 vaccine at the time of their infection; a substantial proportion of the individuals included in our study tested positive before vaccines were widely available. We removed IMID-related codes from the CCI to avoid inflation of the CCI in the IMID cohort. In addition, we removed people with cancer in the preceding 5 years from the cohort due to increased risk of VTE. Many other diseases that form parts of the CCI may increase the risk of VTE . However, removing patients from the cohort with these illnesses would have severely restricted the sample size. In addition, there is no reason to believe that these act as confounders, increasing the VTE risk more in patients with IMIDs than in patients without IMIDs. Our study surprisingly found that the incidence of PE was higher than that of DVT. This may be due to differences in accuracy of the codes/algorithms used to identify these subgroups of VTE. Alternatively, patients with PEs were likely hospitalized more frequently than those with DVTs, so we may have underestimated the risk of DVTs. Our study may also be at risk of residual confounding. For example, Canadian hospitalization data do not include medications. Use of anticoagulants in patients with COVID-19 and/or corticosteroid use could be unmeasured confounders that increase the risk of both severe COVID-1943 and VTEs44 in patients with IMIDs. Administrative data do not include clinical characteristics, such as whether there was active inflammation in patients with IMIDs, which may have increased the risk of VTEs.Our study has some limitations. As with all studies using health administrative data, it is subject to misclassification bias. However, we minimized this risk by using validated algorithms for most of the included IMIDs. Our study preceded the Omicron era, and therefore repeated SARS-CoV-2 infections were less common.In this matched cohort study, we found that the absolute risk of VTE was low in individuals with IMIDs, and the risk was not statistically significantly different from that of the general population after adjusting for comorbidities and vaccination status. Therefore, the presence of an IMID alone should not dictate the use of VTE prophylaxis in patients hospitalized with COVID-19.


Data were collected at baseline and after 150 days. The endpoints were assessed in the intention-to-treat population. Results: We enrolled 20 patients in the ProMoFasT group and 24 in the oral group. No differences in body weight, BMI or waist circumference between the two groups were found after 150 days. At follow-up, FFM (%) and MM (%) results were higher in the ProMoFasT group than the oral group  and FM (kg) and FM (%) were significantly lower in the ProMoFasT group . Insulin levels were lower in the ProMoFasT group than the oral group at follow-up . Conclusion: The ProMoFasT is more effective in improving body composition and glucometabolic markers than the same diet administered orally.Background: Protein-sparing modified fast (PSMF) diet is a very-low-carbohydrate ketogenic diet administered to patients with obesity, which preserves lean mass and suppresses appetite as well as continuous enteral feeding. Thus, we aim to evaluate the effect of the PSMF diet administered continuously by nasogastric tube (NGT) or orally. Methods: Patients with a body mass index (BMI) > 34.9 kg/m In recent decades, worldwide obesity has tripled and is currently reaching epidemic proportions, since in 2016 over 650 million people were affected by obesity . This pa2 alone or BMI ≥ 35 kg/m2 with significant comorbidities) that leads to persistent weight loss and could reduce obesity-related comorbid illnesses [Traditional approaches for managing obesity, such as lifestyle modification with a balanced Mediterranean diet, regular exercise, behavior therapy and drug administration, generally suffer from low long-term compliance ,7. Bariallnesses ,9; howevllnesses , and impllnesses ,12,13.In clinical practice, very-low-carbohydrate ketogenic diets (VLCKDs) are commonly used to achieve rapid weight loss, particularly in patients affected by severe or complicated obesity  and in patients who need rapid weight loss for severe comorbidities or for scheduled surgery ,15; moreThe protein-sparing modified fast (PSMF) diet is a VLCKD with a high-quality protein content (1.2–1.5 g/kg/day), a carbohydrate amount less than 20–30 g/day and a low-fat intake (about 10–20 g/day); additionally, it requires a significant amount of water (above two liters) as well as vitamin and mineral supplementation . AccordiThus, the continuous enteral nutrition (EN) of a high-protein diet administered through a nasogastric tube (NGT) may be a valid approach for counteracting the catabolism of lean mass . MoreoveTo date, no evidence reports a comparison between a PSMF diet administered continuously via NGT and the equivalent PSMF diet taken orally on anthropometric and body composition data in patients with obesity. Therefore, our study aims to evaluate the effect of a PSMF diet on anthropometric and body composition parameters when supplied continuously by NGT or administered per os. Secondly, we examine the impact of the PSMF diet on blood glucometabolic markers.The present study is a pilot single-center randomized clinical trial designed to test the efficacy of a PSMF diet administered via NGT (ProMoFasT) compared with the same PSMF diet taken orally in patients with obesity. Subjects were evaluated and enrolled in the Dietetics and Clinical Nutrition Unit of the IRCCS Policlinic San Martino Hospital, University of Genoa  according to the following inclusion and exclusion criteria. 2 whose age ranged from 18 to 70 years who had not previously responded to weight-lowering drugs and/or cognitive/behavioral therapy. Exclusion criteria were Type 1 Diabetes Mellitus, Types 2 Diabetes Mellitus (T2DM) treated with insulin, pregnancy and breastfeeding, kidney failure and severe chronic kidney disease, liver failure, multi-organ failure, intestinal bowel diseases, eating disorders and other severe mental illnesses, alcohol and drug abuse, active neoplasm, malignant hematological disease, severe esophagitis, voluminous symptomatic hiatal hernia , active stage of gastric and/or duodenal ulcers, previous restrictive surgery of the gastrointestinal tract, esophageal-gastro-duodenal bleeding or potential bleeding, patients treated with nonsteroidal anti-inflammatory drugs and anticoagulants and patients with contraindication to EN.We included patients with obesity with a BMI above 34.9 kg/mclinicaltrials.gov .Informed written consent for the use of personal data was obtained from patients. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the IRCCS Policlinic Hospital San Martino in Genoa  (n.reg CEA 125/10) in February 2011 and was registered on ® v.1.0, Akern 2014, Firenze, Italy). BIA analysis was performed at baseline and at the 150-day follow-up visit and included the following parameters: standardized phase angle (PA) (°), body cell mass (BCM) (kg), fat-free mass (FFM) (kg and %), muscle mass (MM) (kg and %), fat mass (FM) (kg and %), total body water (TBW) (L and %) and intracellular water (ICW) (L and %). Blood test analysis was assessed and the following data were recorded at baseline and at the follow-up visit: fasting blood glucose, fasting blood insulin, glycated hemoglobin (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), creatinine, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), potassium, calcium and phosphorus.Patients were randomized 1:1 to a PSMF diet administered continuously during 24 h via NGT (ProMoFasT) or to the same PSMF diet administered orally. The protocol included 5 cycles of active PSMF nutrition lasting 10 days alternated to 20 days of a balanced oral low-calorie diet for a total of 150 days. The PSMF diet administered in both two groups was based on a whey protein formula , a multiThe endpoints were assessed in the intention-to-treat population. After a 12-h overnight fast, an 8 French polyurethane NGT was placed in a day-hospital setting in the Dietetics and Clinical Nutrition Unit of the IRCCS Policlinic San Martino Hospital, University of Genoa, Italy. Patients were provided with tools to carry out home EN and they were elucidated about the use of the infusion pump and any possible side effects of EN.www.spss.com, accessed on 13 November 2023) was used for statistical analysis. The normality of variables was examined using a Kolmogorov–Smirnov analysis. Contingency tables and ordinal and nominal variables were used to represent frequency and percentage in the population. The median and interquartile range were used to express the results of continuous variables. Data were analyzed according to an intention-to-treat (ITT) principle, which included all 44 randomized subjects. Non-parametric tests  were used when necessary to compare continuous variables between different patient groups. For the correlation with continuous variables, the Pearson chi square (X2) test and Spearman’s rank correlation index were used to analyze nominal variables. Within-group differences from baseline to follow-up were analyzed by the Wilcoxon’s signed-rank test.IBM SPSS Statistics, Version 25.0  were randomized to the administration via NGT (ProMoFasT group), while 24 patients  were assigned to the PSMF diet administration orally  . Twelve p = 0.012 and 45.0%, IQR 37.4–49.0 vs. 36.1, IQR 33.3–41.0, p = 0.009, respectively)  .ctively)  and bothctively) . TBW (%)p = 0.001 and 6.2, IQR 5.7–6.4 vs. 5.4, IQR 5.3–5.7, p = 0.009, respectively). The fasting blood glucose and HOMA-IR were significantly reduced in both groups from baseline to follow-up visit, although no significant differences between the two groups were found among the latter parameters after 150 days. As shown in TC, LDL-C and TG plasma levels were significantly reduced, and HDL-C plasma levels were significantly increased in the ProMoFasT group from baseline to follow-up visit, while TC, HDL-C and LDL-C levels were significantly increased, and TG levels were significantly reduced in the oral group from baseline to follow-up visit. Nonetheless, no significant differences in the lipid profile were observed between the two groups after 150 days. Calcium and phosphorous levels were significantly increased in both groups from baseline to follow-up visit.VLCKDs are valid and well-recognized strategies in the treatment of severe obesity and the PSMF diet falls into this group of dietary interventions, but its peculiarity is that not only carbohydrates are restricted to less than 30 g/day, but also lipids are limited to less than 20 g/day, making proteins the primary source of calories. This dietary approach seems to have a protein-sparing effect, preventing muscle catabolism. Furthermore, the consistent administration of a whey-protein-rich diet is more effective in preventing lean mass catabolism and inducing appetite suppression ,24,25. TGiven this knowledge, we found that the PSMF diet administered by NGT is an effective and safe dietary intervention with a high level of compliance that leads to a rapid improvement in body composition parameters and glucometabolic markers when compared to administering the same diet orally. Specifically, we observed improvements in body composition parameters, with significantly lower levels of FM (kg) and FM (%) and higher levels of FFM (%), MM (%). From a pathophysiological perspective, it is known that nutrition administered via NGT determines a greater suppression of appetite in human subjects due to alterations in appetite-suppressing gut hormones, and may increase the levels of glucagon-like peptide 1 and peptide YY as reported by a recent randomized controlled trial (RCT) . AdditioThis latter remark could be supported by the conflicting results of the improvement in muscle anabolism when using intermittent boluses of amino acids versus their continuous administration . It is pAnother intriguing finding from our study was the possibility of maintaining lean body mass throughout the administration of whey protein as a sole source of protein in PSMF. Whey proteins are rich in leucine, a branched chain amino acid that stimulates human muscle protein synthesis by activating the mTOR signaling pathway independently by Insulin-like growth factor receptor 1, resulting in a muscle anabolism enhancement. Moreover, whey proteins inhibit food intake and tend to improve oxidative balance in rats with obesity as this source of proteins was associated with a slight increase in total glutathione both in the liver and in the blood as compared to a casein-based diet ,37.In our study, we observed a lower level of fasting blood insulin after 150 days of the PSMF diet in the ProMoFasT group compared to the oral group. This effect has several beneficial effects on human health, as it is well known in the literature that an insulin-sensitizing diet can improve strong outcomes in both diabetic and non-diabetic patients such as the reduction in cardiovascular mortality . The difAlthough it has been established that prolonged exposure to excessive amino acids diminished AMPK activity leading to insulin resistance , we obseAnother interesting result emerging from our study is the significant improvement in the lipid profile of the ProMoFasT group from baseline to follow-up, characterized by a decrease in LDL-C and TG and an increase in HDL-C. On the other hand, patients who received the oral PSMF diet experienced a worsening of LDL-C levels. The different results from baseline to follow-up observed in the ProMoFasT group could be attributed to the levels of fasting blood insulin, which appear to be significantly lower in the ProMoFasT group compared to the oral group. In fact, insulin has a well-recognized stimulatory influence on endogenous cholesterol synthesis . NeverthBased on our findings, calcium and phosphorus plasma levels increase in both groups from baseline to follow-up, although it is still possible to hypothesize that a protein-sparing diet may not negatively impact bone metabolism. In fact, it is well-known that a higher protein diet raises insulin-like growth factor-1, a crucial mediator of bone health , even thFinally, we observed a significant reduction in body weight, BMI and waist circumference during 150-day cycles of PSMF, whether administered via NGT or orally. In this field, a recent study suggested the effectiveness and safety of the PSMF diet as an outpatient weight loss strategy for adolescents affected by severe obesity . MoreoveTo the best of our knowledge, this is the first RCT that compared the safety and the efficacy in terms of body composition and glucometabolic improvement of a PSMF diet administered by NGT, compared to the same diet supplied orally. The limitations of our study include a small sample size and a relative high number of patients lost to follow-up; thus, the findings should be considered as preliminary. Furthermore, the lack of quality-of-life data could be another limitation of the study; in fact, quality of life encompasses significant aspects of well-being such as physical, mental, and emotional health, which are important for assessing the overall effectiveness and sustainability of any dietary intervention in a real-world setting. Another limitation was the non-statistically different distribution of male gender between the two groups, slightly favoring the ProMoFasT group and which may have an impact on the body composition. Nevertheless, we did not observe any differences among all parameters evaluated with the BIA analysis. Compared to the same PSMF diet given orally, the ProMoFasT is an effective and safe nutritional intervention that has a good compliance rate and results in improvements in body composition with an insulin-lowering effect among subjects with severe obesity. Further RCTs are needed to confirm these preliminary findings.


This study aimed to assess the association of birth conditions, nutritionalstatus, and childhood growth with cardiometabolic risk factors at 30 years ofage. We also evaluated whether body mass index (BMI) at 30 years mediated theassociation of weight gain in childhood with cardiometabolic risk factors. Thisis a prospective cohort study that included all live births in 1982 in hospitalsin the city of Pelotas, Rio Grande do Sul State, Brazil, whose families lived inthe urban area. Mothers were interviewed at birth, and participants werefollowed at different ages. For our analyses, we used data on weight and heightcollected at birth, 2 and 4 years and cardiovascular risk factors at 30 years.Multiple linear regressions were performed to obtain adjusted coefficients andG-formula for mediation analysis. Relative weight gain in childhood, despite theage, was positively related to mean arterial pressure, whereas relative weightgain in late childhood was positively associated with carotid intima-mediathickness, pulse wave velocity, triglycerides, non-HDL cholesterol, plasmaglucose, and C-reactive protein. BMI in adulthood captured the total effect ofrelative weight gain in the period between 2 and 4 years on carotid intima-mediathickness, triglycerides, non-HDL cholesterol, and C-reactive protein. Ourfindings reinforce the evidence that rapid relative weight gain after 2 years ofage may have long-term consequences on the risk of metabolic and cardiovasculardisorders. Moreover, the effect of linear growth has not beendisentangled from that of linear growth-independent weight gain. To the best of ourknowledge, the mediating role of body mass index (BMI) in adulthood in theassociation of conditional relative weight gain during childhood withcardiometabolic risk factors in adulthood has not been evaluated. This study aimedto assess the association of birth conditions, nutritional status, and growth duringchildhood with cardiometabolic risk factors at 30 years of age, and to examinewhether the association between relative weight gain and cardiometabolic riskfactors was mediated by BMI in adulthood.,In 1982, the maternity hospitals located in Pelotas, a southern Brazilian city, weredaily visited, and those live births whose families lived in the urban area of thecity  were examined and their mothers were interviewed soon afterchildbirth. These subjects have been prospectively followed up on several occasions,and further details on the study methodology have been published elsewhere In 1984 and 1986, all households located in the urban area of the city were visitedin search of the cohort members, and 5,161 and 4,979 individuals were evaluated,respectively. From June 2012 to February 2013, the research team tried to follow thewhole cohort and the study participants were invited to visit the research clinic tobe interviewed, examined, and to donate a random blood sample. In this study,pregnant women were excluded.At 30 years, the following cardiometabolic risk factors were assessed:https://www.omron.com) withan adapted cuff for subjects with obesity, and the average of these measurementswas used in the analyses. Average arterial pressure was estimated by: 1/3systolic blood pressure + 2/3 diastolic blood pressure Blood pressure was measured twice on the left arm. The measurement was performedusing an automatic device  was used to analyze image data. Theanalyzer also calculated the average value of 90 measurements (frames) takenfrom the 10mm-long section studied.Carotid intima-media thickness was measured at the posterior wall of the rightand left common carotid arteries in longitudinal planes using ultrasoundimaging. Photographs of a 10mm-long section of the common carotid artery weretaken, proximal to the carotid bulb. The Carotid Analyzer for Research , which is a noninvasive device thatmeasures the pulse wave velocity with a tonometric transducer.Pulse wave velocity was assessed using the SphygmoCor system .Serum glucose was measured using the colorimetric enzyme assay with K082 GlucoseMonoreagent kits  chemistry analyzer.High-sensitivity C-reactive protein was measured using the automated turbidimetrytechnique with a BS-380 .Women who used oral contraceptives were excluded from C-reactive protein analysessince oral contraceptives increase C-reactive protein levels https://www.oswaldofilizola.com.br/) that were periodicallycalibrated by the research team. Gestational age was estimated based on the dateof the last menstrual period, and birth weight for gestational age z-scores wereassessed using the Williams reference population Birth weight was assessed by the hospital staff using pediatric scales  and 4 years of age (1986), cohort members were weighted to thenearest 0.1kg using portable calibrated scales  and portable stadiometers were used to assess length/height tothe nearest 0.1cm. Weight-for-length/height, BMI-for-age, andheight/length-for-age z-scores according to age and sex were estimated using theWorld Health Organization (WHO) growth standards ,Conditional growth was assessed by regressing current size (weight orlength/height) on earlier measures of weight and length/height, and standardizedresiduals were derived by sex. Conditional variables express how a childdeviates from its expected height or weight based on its previous measures andthe growth of the same sex from the studied population. At each time point, theconditional variable represents growth during a time interval. For example,conditional relative weight at 2 years of age represents the relative weightgain from birth to 2 years of age; similarly, the conditional variable at 4years of age represents the height or relative weight gain from 2 to 4 years ofage. To estimate conditional height, the current length/height was regressed onprevious weight and length. Therefore, conditional length at 2 years of age wasestimated by regressing length-for-age z-scores at 2 years of age on birthweight. In contrast, conditional relative weight was estimated fromlength/height at that age and previous measures of length/height and weight.Thus, conditional relative weight at 2 years of age was derived by regressingweight at 2 years of age on birth weight and length at 2 years of age Family income at birth assessed the total income earned by the family members inthe month before the interview. Maternal schooling at birth was assessed incomplete years of schooling. Maternal skin color was evaluated by theinterviewer in the perinatal study and categorized into two groups(white/non-white). Mothers who reported any smoking during pregnancy wereconsidered as smokers. Maternal height was measured at the hospital in theperinatal study, using portable stadiometers. Pre-pregnancy weight was obtainedfrom the antenatal care card or reported by the mother. Information onbreastfeeding duration and age at introduction of weaning foods was collected inthe 1984 and 1986 visits. The information closest to the age of weaning was usedto minimize recall bias.https://www.cosmed.com) and height was measured with a portablestadiometer . The BMI was calculated by dividing theweight by the square height (kg/m2).BMI at 30 years, a possible mediator, was assessed in the 2012/2013 follow-upvisit. Weight was measured to the nearest 0.1kg using a scale coupled to BodPod. Asthe distribution of triglycerides and C-reactive protein were clearlyasymmetric, these variables were log-transformed. Analysis of variance (ANOVA)was used to compare means and multiple linear regression to obtain estimatesthat were adjusted for confounders . Estimates on the associationsof nutritional status in childhood and conditional growth were further adjustedto breastfeeding duration. Furthermore, for conditional length gain from birthto 2 years of age, analyses were also adjusted for birth weight according togestational age z-score. For conditional relative weight gain from birth to 2years of age, analyses were controlled for birth weight and conditional lengthgain from 0 to 2 years of age. For conditional length gain from 2 to 4 years ofage, birth weight and conditional variables from birth to 2 years of age wereincluded in the regression model. For relative weight gain from 2 to 4 years ofage, length gain for this period was further included in the model. Conditionalrelative weight and conditional height variables are not correlated to eachother and, hence, they were included together in linear regression modelswithout collinearity concerns ,Statistical analysis was performed using Stata software package, version 16.Generally, the points are randomly distributed, complying with the assumptionsof linearity, normality, and homoscedasticity.The covariates included in the models were selected a priori following aconceptual model based on the literature. In addition to verifying thecorrelation between the variables included in the models, the variance inflationfactor (VIF) was also verified for each of the regression models and there was alow possibility of multicollinearity in the models. For ordinal variables,comparisons were based on tests of heterogeneity and linear trend, and the onewith the lowest p-value was presented. Residual analyses were performed andpresented as Mediation analysis was conducted using G-formula to decompose the total effectinto natural direct and indirect effects of conditional relative weight gainfrom 2 to 4 years of age on metabolic cardiovascular risk factors at age 30.Standard errors for mediation analyses were calculated using bootstrapping with10,000 simulations. Separate models were fitted for each outcome  and mediator (BMI at 30 years of age). All models were adjusted for baseconfounders  andpost-confounders (family income at last visit). Before conducting the mediationanalyses, it was assessed whether body mass index at adulthood was modifying theassociations.Declaration ofHelsinki, and all procedures involving human subjects were approvedby Research Ethics Committee of the Faculty of Medicine, Federal University ofPelotas (protocol n. 16/12).The current study was conducted in accordance with the In the 30-year follow-up of the 1982 Pelotas birth cohort, 3,701 subjects wereevaluated, resulting in a follow-up rate of 68.1% when combined with the 325 deathsamong the cohort participants. Information on at least one exposure and outcome wasavailable for 3,619 individuals. For the conditional growth analysis, information onbirth weight, gestational age, and nutritional status at 2 and 4 years of age wasavailable for 2,479 subjects. Triglycerides were higher among subjects who were in the extreme birth weightcategories. Height-for-age z-scores at 4 years old was positively associated withtriglycerides and C-reactive protein. Triglycerides and C-reactive protein werehigher among subjects in the extreme categories of weight-for-height at 4 years ofage. Moreover, random blood glucose was higher among subjects whoseweight-for-height z-score was ≥ 2 z-score .Conditional length and relative weight gain from birth to 2 years of age were notassociated with non-HDL cholesterol, glucose, and C-reactive protein. On the otherhand, linear growth from 2 to 4 years was positively associated with triglyceridesand C-reactive protein, whereas conditional relative weight gain from the sameperiod showed a positive association with triglycerides, non-HDL cholesterol, plasmaglucose, and C-reactive protein.This study aimed to assess the association of birth conditions and early growth withmetabolic cardiovascular risk factors at age 30. Birth weight was negativelyassociated with mean arterial pressure. Regarding nutritional status in childhood,length/height in childhood was negatively associated with mean arterial pressure,whereas height-for-age z-score at 4 years old was positively associated withtriglycerides, non-HDL cholesterol, and C-reactive protein. Weight-for-height at 2years of age was not associated with the evaluated outcomes; however, at 4 years ofage, weight-for-height was positively related to blood pressure, carotidintima-media, pulse wave velocity, triglycerides, and C-reactive protein. Concerningthe association with early growth, poor linear growth during the first two years oflife was associated with lower triglycerides, whereas linear growth from 2 to 4years old was positively associated with triglycerides and C-reactive protein.Relative weight gain in childhood, despite the age, was positively related to meanarterial pressure. In late childhood, relative weight gain was positively associatedwith carotid intima-media thickness, pulse wave velocity, triglycerides, non-HDLcholesterol, plasma glucose, and C-reactive protein. Mediation analysis showed thatBMI in adulthood is an important mediator of the association of relative weight gainin childhood with cardiometabolic risk factors in early adulthood.,After controlling for confounders, birth weight was negatively associated with meanarterial pressure. A meta-analysis including 53 studies reported that the odds ofhypertension was 30%  higheramong low birth weight subjects. Since a negative association was also observed withbirth weight according to gestational age - whereas gestational age was notassociated with blood pressure - the observed association with blood pressure isprobably due to intrauterine growth restriction. Several mechanisms would explainthe association of intrauterine growth with hypertension, including chronic kidneydisease and endothelial, vascular, and metabolic abnormalities ,,,,,Regarding nutritional status in childhood, stunting at 2 and 4 years and poor lineargrowth during the first two years of life were associated with higher mean arterialpressure. On the other hand, height-for-age z-score at 4 years of age showed apositive association with triglycerides, non-HDL cholesterol, and C-reactiveprotein. Triglycerides and C-reactive protein were higher among subjects whopresented accelerated growth from 2 to 4 years. A positive association ofheight-for-age z-score and linear growth during childhood with blood pressure hasbeen previously reported ,,,,,,Concerning the negative consequences of relative weight gain in childhood, ourfindings are consistent with previous studies that have reported that fasterrelative weight gain, mainly in late childhood, is associated with the developmentof metabolic cardiovascular risk factors at adolescence and adulthood This study has several strengths, such as a large sample size and anthropometricmeasurements that were conducted at different time points during childhood. Thecohort has been prospectively followed since birth and anthropometric measurementshave been performed by a trained staff using standardized methods, reducing possiblemeasurement errors. Moreover, the conditional growth analysis allowed us to examinethe independent effects of weight and height gains at different age periods.Conditional variables are uncorrelated and expressing them as z-scores allow for adirect comparison of coefficients within regression models. To our knowledge, thisis the first study to assess the mediating role of contemporary nutritionalstatus.,,Linear growth during early childhood is positively associated with human capital inadulthood and reduces morbidity and mortality risk in late childhood


Those with cirrhosis who develop colorectal cancer (CRC) are an understudied group who may tolerate treatments poorly and are at risk of worse outcomes. This is a retrospective cohort study of 842 individuals from Ontario, Canada, with a pre-existing diagnosis of cirrhosis who underwent surgery for CRC between 2009 and 2017. Practice patterns, overall survival, and short-term morbidity and mortality were assessed. The most common cirrhosis etiology was non-alcoholic fatty liver disease (NAFLD) (52%) and alcohol-associated liver disease (29%). The model for end-stage liver disease score (MELD-Na) was available in 42% . Preoperative radiation was used in 62% of Stage II/III rectal cancer patients, while postoperative chemotherapy was used in 42% of Stage III colon cancer patients and 38% of Stage II/III rectal cancer patients. Ninety-day mortality following surgery was 12%. Five-year overall survival was 53% . Those with alcohol-associated cirrhosis  had lower survival than those with NAFLD. Those with a MELD-Na of 10+ did worse than those with a lower MELD-Na score . This study reports poor survival in those with cirrhosis who undergo treatment for CRC. Caution should be taken when considering aggressive treatment. Both liver cirrhosis and colorectal cancer are expected to rise over the next several decades, especially among young adults ,2,3. ThoTreatment of colorectal cancer in those with an existing diagnosis of cirrhosis can be a challenge. Curative intent treatment typically requires major surgical resection and may include liver-toxic chemotherapy ,5. PreviDespite the increasing incidence of both cirrhosis and colorectal cancer, there have been few contemporary studies assessing outcomes among this complex and unique group. Thus, the objectives of this study were to (1) determine the proportion of patients who receive guideline-recommended cancer treatments (such as radiation and chemotherapy); (2) determine the overall survival; (3) determine the associations between cirrhosis etiology and/or severity and survival among a cohort of patients with cirrhosis and CRC.This is a retrospective population-level study of all individuals with cirrhosis who underwent surgery for colorectal cancer in Ontario, Canada, from January 2009 to December 2017 with outcome events followed until the end of 2020. This study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .This study uses routinely collected healthcare datasets stored at ICES. These datasets include health administrative data that are routinely generated upon the delivery of a healthcare service to an individual, as well as demographic and census data. The datasets were linked at the individual level using a unique encrypted identifier and analyzed at ICES .Individuals with incident or prevalent cirrhosis were identified using a previously validated algorithm . The algPatient demographics were derived and included age at the time of surgery, sex, and socioeconomic status. Co-morbid illness was defined using the Charlson co-morbidity index. Specific pre-existing comorbidities were identified in patients based on ICES-validated definitions ,25,26,27Surgery type was categorized as resection with anastomosis, resection without anastomosis (permanent ostomy), or resection with anastomosis and proximal diversion based on the fee code that was billed in OHIP at the time of surgery . SurgicaThe primary outcomes were 5-year overall survival outcome and overall survival as a time-to-event outcome. Secondary outcomes included the receipt of guideline-recommended neoadjuvant and adjuvant therapies as described in well-established clinical practice guidelines ,5.Other short-term outcomes included in-hospital mortality, 90-day mortality, intensive care unit (ICU) admission, hospital and ICU length of stay, 90-day readmission and 90-day emergency department (ED) visit, and hepatic decompensation . These dCounts and proportions were calculated for categorical variables and means with standard deviations or medians with interquartile ranges for continuous variables. We used chi-square statistical tests to compare categorical proportions, one-way analysis of variance to compare means, and Kruskal–Wallis test as a non-parametric approach to compare median values between cancer-type groups. For cells with small numbers  ranges are presented to protect the anonymity of the patient population, as required by ICES.Postoperative outcomes were described according to cancer type along with counts and proportions for categorical outcomes and means with standard deviations or medians with interquartile ranges for continuous outcomes. In-hospital and 90-day mortality was further elucidated by the MELD-Na score. Five-year survival was evaluated using Kaplan–Meier curves and stratified according to cancer type and stage. Predictors associated with postoperative mortality during follow-up were assessed using Cox proportional hazards models. Patients were followed from the time of surgery until death or 31 December 2020. Predictors were selected a priori and evaluated for violation of the proportional hazards assumption using Schoenfeld residuals. We performed a sensitivity analysis by repeating the multivariable Cox models for predictors of postoperative mortality in a subset of the cohort that had an available MELD-Na score and included MELD-Na as a predictor of interest. We also performed a sensitivity analysis, excluding those who died within 90 days of surgery.p-value < 0.05. All data were prepared and analyzed using the SAS Enterprise Guide, Version 7.1 . Results were considered significant at n = 441, 52%), followed by ALD , viral hepatitis , and autoimmune or other . A small number had a history of hepatic decompensation . The MELD-Na was available for 353 individuals (42%), with a median score of 9 (IQR 7–11). Cancer stages included Stage I disease , Stage II disease , Stage III disease , and Stage IV disease . Most individuals underwent elective surgery . In those with colon cancer (N = 696), the most common procedure was resection with anastomosis , followed by resection and permanent ostomy . Few individuals with colon cancer underwent anastomosis and proximal diversion . Those with rectal cancer (N = 146) most commonly had a resection with a permanent ostomy  or resection with anastomosis and proximal diversion . Few individuals underwent resection and anastomosis without diversion .A total of 842 individuals with cirrhosis underwent surgery for colorectal cancer, including 696 individuals with colon cancer and 146 with rectal cancer . DemograIn those with Stage III colon cancer, approximately half  had a medical oncology assessment, with 42% (90/213) ultimately receiving adjuvant chemotherapy. In those with locally advanced rectal cancer , 70% (62/89) had a radiation oncology assessment, with 62% (55/89) receiving preoperative radiation. Similar to Stage III colon cancer, about half  of those with locally advanced disease had a medical oncology assessment and 38% (34/89) ultimately received adjuvant chemotherapy. n = 219/353, 62%), with few having a score >20 . The 90-day mortality in those with a MELD-Na <10 was 6.8% vs. 22% in those with a MELD-Na >10 (p < 0.001) (Short-term outcomes are presented in < 0.001) .The 5-year overall survival for the cohort was 53%. Cox proportional hazards regression was completed for all individuals in the cohort  and was Cox proportional hazards regression was also completed for the subgroup with MELD-Na score available at the time of surgery . Those wThe present study reports practice patterns and outcomes in those with cirrhosis who develop colorectal cancer and undergo surgical resection. The 5-year overall survival for the cohort was 53%. Cirrhosis etiology was associated with overall survival, while MELD-Na score was predictive of increased 90-day mortality. A number of other major short-term complications were common, including 90-day mortality (12%).The present study is the largest and most contemporary report of outcomes in those with cirrhosis who develop colorectal cancer and receive surgery. Several older studies have reported long-term survival ,31,32,33p = 0.082). This association persisted even after adjusting for MELD-Na in those with a score available. The reasons for this are not immediately clear from the data but could relate to individuals with ALD having a more advanced liver dysfunction that is not able to be captured using MELD alone such as the degree of ascites and hepatic encephalopathy. Further, individuals with ALD cirrhosis have historically included a higher proportion who are vulnerable due to their social determinants of health, which may influence the ability of patients with ALD to access and engage in care. An interesting finding from this work is the differences in outcomes based on the etiology of cirrhosis. Those with ALD had a worse survival compared with those with NAFLD  compared to that reported for all comers in Canada (65%), based on previous publications . The CanThis study has several strengths. Due to the relative scarcity of individuals with both a diagnosis of cirrhosis and colorectal cancer, a population-based approach allowed for the inclusion of a large number of individuals. The identification of those with cirrhosis was made using a previously validated algorithm which ensured a low risk of misclassification or inappropriate inclusion. We also identified those with colorectal cancer using the Ontario Cancer Registry, which is highly accurate. For these reasons, there was a low risk of missing individuals with pre-existing cirrhosis who developed colorectal cancer. The type and extent of treatment were determined using well-established sources, while the outcomes were determined using previously validated approaches. As the data for this study were ascertained using linked administrative databases within a single-payer universal healthcare system, loss to follow-up was minimal.Despite these strengths, several well-described limitations of population-based studies exist within this study . PertinePatients with cirrhosis who develop colorectal cancer and undergo surgical resection infrequently receive guideline-recommended treatment, have poor short-term outcomes, and have poor overall survival. Further, compared to the general population, the stage of the disease is less likely to be predictive of long-term survival, especially in those with rectal cancer. We found liver-related factors, including ALD and MELD-Na > 10, to be associated with survival. This information will assist healthcare providers in having detailed discussions with these patients and their caregivers, allowing for enhanced awareness and education pertaining to the anticipated challenges associated with treatment.


This randomized clinical trial evaluates the effect of a perturbation-based balance training treadmill intervention vs standard treadmill walking on 12-month fall rates among community-dwelling older adults. Does treadmill perturbation-based balance training (PBT) reduce daily-life fall rates among community-dwelling adults 65 years or older?In this randomized clinical trial involving 140 highly functioning older adults, those who received an 4-session PBT intervention  experienced a statistically nonsignificant 22% reduction in daily-life fall rates over a 12-month period.Findings of this trial suggest the need for future studies to investigate possible effects of current treadmill PBT on daily-life falls. Falls are common and the leading cause of injuries among older adults, but falls may be attenuated by the promising and time-efficient intervention called perturbation-based balance training (PBT).To evaluate the effects of a 4-session treadmill PBT intervention compared with regular treadmill walking on daily-life fall rates among community-dwelling older adults.This 12-month, assessor-blinded randomized clinical trial was conducted from March 2021 through December 2022 in Aalborg University in Denmark. Participants were community-dwelling adults 65 years or older and were able to walk without a walking aid. Participants were randomized to either PBT (intervention group) or treadmill walking (control group). Data analyses were based on the intention-to-treat principle.Participants who were randomized to the intervention group underwent four 20-minute sessions of PBT, including 40 slip, trip, or mixed slip and trip perturbations. Participants who were randomized to the control group performed four 20-minute sessions of treadmill walking at their preferred speed. The 3 initial training sessions were completed within the first week, whereas the fourth session was performed after 6 months.Primary outcome was the daily-life fall rates that were collected from fall calendars for the 12 months after the third training session. Secondary outcomes were the proportion of participants with at least 1 fall and recurrent falls, time to first fall, fall-related fractures, fall-related injuries, fall-related health care contacts, and daily-life slip and trip falls.A total of 140 highly functioning, community-dwelling older adults , 57 (41%) of whom had a fall in the past 12 months, were included in this trial. Perturbation training had no significant effect on daily-life fall rate  or other fall-related metrics. However, there was a significant reduction in laboratory fall rates at the posttraining assessment , 6-month follow-up , and 12-month follow-up .Results of this trial showed that participants who received an 80-minute PBT intervention experienced a statistically nonsignificant 22% reduction in daily-life fall rates. There was no significant effect on other daily-life fall-related metrics; however, a statistically significant decrease in falls was found in the laboratory setting.NCT04733222ClinicalTrials.gov Identifier:  It has been shown that just a few PBT sessions can produce substantial refinements in reactive balance control after laboratory-induced perturbations.18 Moreover, these adaptations can be retained for up to 12 months after training cessation.21 Nonetheless, the dose for optimal retention and generalization of adaptations still needs further evaluation.10 Additionally, the current evidence regarding the effects of PBT on daily-life falls is inconsistent, with some studies reporting a fall-reducing effect of nearly 50%,24 whereas other studies demonstrate no effects.33 Most of these trials were designed either as a pilot study or as an evaluation of other outcomes, resulting in small sample sizes (<50 participants per group).33 In addition, perturbation type, dose, and intensity vary between studies, limiting the ability to make recommendations for PBT.33Falling is the leading cause of injuries in older adults, and the associated costs of treatment and rehabilitation burden society substantially.4 Therefore, this randomized clinical trial (RCT) aimed to evaluate the effects of a 4-session treadmill PBT intervention compared with regular treadmill walking on daily-life fall rates among community-dwelling older adults.The recently published world guidelines for fall prevention highlight PBT as a future research priority.34 There were no important deviations from the protocol. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.35This assessor-blinded, parallel-group (1:1 ratio) RCT was conducted between March 2021 and December 2022 at a laboratory in Aalborg University in Denmark. The trial protocol was approved by the North Denmark Region Committee on Health Research Ethics and the Danish Data Protection Agency. All participants provided written informed consent. The trial protocol  and statIndividuals were recruited through radio and television advertisements and snowball sampling from March through November 2021. Eligible individuals were 65 years or older, community dwelling, and able to walk without a walking aid. Individuals were excluded if they (1) had any of the following self-reported conditions: orthopedic surgery within the past 12 months, osteoporosis or osteoporosis-related fractures , or progressive neurological disease ; (2) had an unstable medical condition that prevented safe participation; (3) had a severe cognitive impairment (score <8 in the Short Orientation-Memory-Concentration Test); or (4) were currently participating in another fall prevention trial.After the pretraining assessments, participants were randomized in a 1:1 ratio to either the PBT (intervention) group or control group . A permu36 eAppendix 1 in All participants in the PBT group were assigned to four 20-minute PBT sessions, and participants in the control group were assigned to 4 treadmill walking training sessions; the initial 2 training sessions were performed on the same day immediately after the pretraining assessments. A week later, the third training session was completed, whereas the fourth was conducted after 6 months A. The trEach of the 4 PBT sessions lasted approximately 20 minutes and consisted of 40 perturbations (20 to each leg) delivered on a uniformly moving treadmill with no lateral rails . A safety harness prevented participants from falling to the ground if they could not regain balance after a perturbation. Participants experienced only slips in the first session, only trips in the second session, and randomly ordered slips and trips (mixed perturbations) in the third and fourth sessions A. The siThe perturbation intensity was adjusted based on participants’ preferred walking speed and was divided into 5 levels with progressively longer durations (slip) or greater accelerations (trip). The intensity was increased after every fourth perturbation if (1) the combined rating of perceived anxiety and difficulty was 4 or less, (2) the participant avoided falling during the previous 4 perturbations, and (3) the participant was comfortable increasing the intensity. However, if any criterion was not met, the intensity remained unchanged  Participants made daily recordings in fall calendars and returned these calendars to the research team at the end of each month using preaddressed envelopes. All fall calendars were reviewed by a research assistant who was blinded to the group randomization. If a participant recorded a fall, the blinded research assistant interviewed the participant over the telephone to validate the fall and retrieve additional information about the circumstances and consequences of that fall.This RCT’s primary outcome was the daily-life fall rates that were collected from fall calendars for the 12 months after the third training session. A fall was defined as “an unexpected event in which the participant comes to rest on the ground, floor, or lower level.”37 A fall-related injury was any minor  or major  injury from a fall. A fall-related health care contact was defined as any contact with the health care system  associated with a fall.Secondary outcomes included the proportion of participants experiencing at least 1 fall and recurrent falls, time to first fall, fall-related fractures, fall-related injuries, fall-related health care contacts, and daily-life slip and trip falls. A fall-related fracture was a radiologically confirmed fracture from a fall.At the pretraining and posttraining assessments and the 6-month and 12-month follow-up, laboratory falls were evaluated by exposing participants to level-1 slip and trip perturbations. These perturbations were recorded in slow motion (100 fps [frames per second]) with a camera  that was positioned 2 m away, perpendicular to the center of the treadmill. The video recordings were reviewed by a blinded research assistant to determine whether the participants experienced a fall. An attempt was categorized as a fall when the participant's body posture was in a falling mode that was clearly and unambiguously stopped by the safety harness. The laboratory fall rate  was used for analysis. The personnel responsible for the training sessions (J.E.N.) registered all adverse events related to the intervention, including any injury or unpleasantness.40 The base fall rate of 0.85 was extracted from the control groups of the studies on physical exercise and fall prevention that were included in a systematic review.8An a priori sample size calculation was performed using a Poisson regression model in G*Power, version 3.1.9.4 (University of Kiel). To detect a significant (2-sided α = .05) difference between groups of 50% from a base fall rate of 0.85 with 80% power and an expected 20% dropout, a total of 140 participants, with 70 in each group, was needed. The expected effect size of 50% was based on previous PBT reports.P < .05 was considered to be significant.The statistical analyses were conducted in collaboration with an external statistician according to a preregistered statistical analysis plan using Stata, version 17.0 (StataCorp LLC). The analyses were based on the intention-to-treat principle. Two-sided 41 The between-group difference in time to first fall was analyzed with a Cox proportional hazards regression model .42 The Stata codes used for analyses are available in eAppendix 2 in Between-group differences in count outcomes were analyzed using a negative binomial regression with person-years of follow-up as an offset variable. We applied the negative binomial regression as the data fit better with this model than with the preregistered Poisson regression with bootstrapping. A sensitivity analysis using the preregistered approach was conducted. Binary daily-life fall outcomes were evaluated using Poisson regression with robust error variance.Preregistered sensitivity analyses were conducted for each daily-life fall outcome, adjusting for age, sex, and previous falls and following the per-protocol principle, among participants who completed at least 75% of the training sessions. Sensitivity analyses that were decided after data collection included fall rates after stratifying participants based on their fall history and laboratory fall rates after multiple imputations.Of the 199 individuals screened for eligibility, 140 were included  and randomized to either the PBT or control group . Fifty-sThe PBT group completed 90% and the control group completed 93% of the assigned training sessions. At least 75% (per-protocol criterion) of the training sessions were completed by 90% of the PBT group and 97% of the control group.At 12 months, the PBT group had returned 99% (71.5 person-years) and the control group had returned 97% (70.4 person-years) of fall calendars. Nineteen participants (27%) in the PBT group and 25 participants (36%) in the control group had missing laboratory fall data. Data were treated as missing at random because the reasons for missing data and the demographic characteristics of participants with missing data were similar between the 2 groups  and 78 in the control group  were reported, resulting in a nonsignificant 22% relative between-group difference in fall rates  . No signThe laboratory fall rates were similar at baseline but were significantly lower in the PBT group than in the control group at the posttraining assessment , 6-month follow-up , and 12-month follow-up . All laboratory fall rate results are shown in eTable 3 in The Poisson regression with bootstrapping yielded results that were comparable to those of the negative binomial regression for all count outcomes ,33 and 2 of these trials included only 1 type of perturbation (either slips or trips),33 diminishing the transferability of these interventions since unidirectional perturbations are not associated with improved reactive balance control after perturbations in other directions.45 However, 1 RCT investigated adding multidirectional treadmill PBT to usual balance training but showed no effects on daily-life fall rates .32 Its participants were categorized as having a high risk of falling, 70% of whom had experienced a fall in the preceding year.32 However, it has been shown that older adults with a history of falls may be less responsive to PBT than participants without a previous fall.46 In this trial, the sensitivity analysis found larger effects among participants without falls  than participants with a previous fall , suggesting that PBT may be most effective in primary prevention. However, the results join the current evidence, which has not yet demonstrated that treadmill PBT can prevent daily-life falls among community-dwelling older adults.33Of the 4 RCTs with a primary aim of investigating the effects of PBT on daily-life falls,23 Pai et al23 showed that overground PBT reduced the fall rate by 49% and any falls by 51%. This finding suggested that overground walkway PBT offers superior adaptation transferability to daily life compared with treadmill PBT. A possible explanation is that overground walkway perturbations more closely resemble daily-life situations than perturbations induced by treadmill accelerations.10 For instance, recent evidence showed that repeated trips induced by treadmill accelerations did not improve reactive balance control in a subsequent obstacle-induced trip.47 In daily life, trips occur by obstructing the swinging leg, demanding elevation or lowering of the leg before a large forward step is taken to regain balance.48 In contrast, the response following a trip from a treadmill acceleration does not necessitate such an elevation or lowering of the leg before the compensatory step is taken, leading to biomechanical differences.47 These differences may have resulted in suboptimal adaptation transferability.49 Moreover, while treadmill slip PBT has been associated with better reactive balance control following a subsequent overground slip perturbation, greater improvements and retention were found after practicing on an overground walkway.50 Although treadmills may be less task specific, they are less space consuming, cheaper, and easier to operate than overground setups, making them more clinically feasible.45 Thus, developing more task-specific treadmill perturbations  may facilitate clinically feasible and more effective PBT.While treadmill PBT did not show significant decreases in daily-life falls, overground PBT may be more effective.37 Second, there was no established dose-response association between PBT and daily-life falls. Thus, the applied intensity and dose of the PBT were selected based on previous studies showing the sustained effectiveness of PBT in laboratory falls.52 Still, generalization to daily life may require higher training doses or intensity.10 Third, due to practical limitations, laboratory falls were evaluated by visual inspection of video recordings instead of the weight supported by the safety harness.53 However, the assessor was blinded to group randomization, reducing this limitation’s potential bias. Fourth, participants were assembled from convenience sampling and included healthy older adults; thus, the results do not generalize to frail individuals with a higher risk of fall-related injuries.This trial has several limitations. First, participants were unblinded to group randomization due to the nature of training interventions. Given that the initial fall reporting was a participant-reported outcome, the lack of blinding may have contributed to fewer falls reported in the PBT group. However, daily-life falls were collected according to the recommendations of the Prevention of Falls Network Europe.In this RCT, participants who received an 80-minute PBT intervention experienced a statistically nonsignificant 22% reduction in daily-life fall rates. There was no significant effect on other daily-life fall-related metrics; however, a statistically significant decrease in falls was found in the laboratory setting. Further studies are warranted to corroborate this effect.


This is a report of unpublished data obtained from a randomized, single-blind, within-subject crossover design, neuroimaging trial comparing the effects of midazolam and ketamine on memory and pain. An experimental auditory paradigm paired with the periodic pain was used to examine auditory encoding and subsequent recognition. Psychometric surveys assessed stress, anxiety, depression, and pain behaviors. These data were collected to potentially characterize inter-subject variation during analysis. Electrodermal activity was measured to examine the association between previous pain-pairing of experimental items and autonomic responses during next day recognition memory testing, with exposure to the same auditory word items. Electrodermal responses were determined using an event-related analysis approach. These data may help shape future experiments using psychometric data to characterize individual responses or using next day electrodermal activity to determine conditioned responses to previously-experienced aversive stimuli. Specifications Table1•Researchers may apply the presented psychometric data in discerning how drug exposure influences inter-subject variation in mood and pain behaviors.•The presented electrodermal activity data demonstrate the relationship between prior painful stimulation paired with non-painful auditory stimuli and are useful to demonstrate conditions under which conditioned responses may be revealed on re-exposure to the non-painful stimuli.•Researchers investigating memory formation, in the context of periodic painful stimulation, and hoping to develop an aversive conditioning paradigm may benefit from these data.•These data may help shape future experimental designs seeking to use psychometric data to characterize individual responses or using next day electrodermal activity as a measure of conditioned responses in similar paradigms that employ aversive stimuli.2Psychometric data were collected from 25 healthy subjects at three time points: pre-scan, post-scan, and during the next day follow-up visit, in which there was no MRI scanning. Psychometric data is available except for missing pre-scan (1), post-scan (15) and next day follow-up (13) scores due to this data not being collected at these time points in the first few sessions. Tabulated final total scores are presented for each of the following questionnaires: the Brief Inventory of Perceived Stress (BIPS) Electrodermal activity data (EDA) refers to changes in the electrical properties of the skin caused by sweat secretion. It was collected during the next day sessions are provided in the supplementary materials as comma-separated value (txt) files for each subject. The file names are labeled by subject and session number . A header is displayed at the top of the text file indicating the subject and session number (as part of the file name); this is followed by the sampling rate, and then the labels and units for each acquisition channel. Five channels were recorded: CH2, CH4, CH5, CH6, and CH9. Column 1 denoted by the “min” header, represents the time (in minutes) for each sample. Column 2, titled CH2, contains the values of the raw EDA amplitudes in microsiemens. Column 3 or CH4 contains signal amplitude values in volts, corresponding to a marker for the timing of previously-heard words that were previously paired with pain. CH5 indicates timing for previously-heard non-pain words. CH6 marks the timing of new words (not heard the previous day). CH9 presents the raw amplitude values from tracing of the electrocardiograph, in millivolts.EDA data from the next day (post-scan/drug) sessions are available from 23 subjects. Missing data were due to technical issues, most commonly a lack of capturing skin responses. EDA was analyzed by the percent of EDA responses, latency, and amplitude across stimulus types with pain associations and drug conditions. The presented stimuli from the memory testing sessions are classified into three different word types: pain paired (words presented with a shock during the memory encoding sessions), non-pain paired (words not associated with a shock during memory encoding sessions), and new (words not heard during the memory encoding session). The percent of EDA responses from both midazolam and ketamine conditions are shown, according to word type . The lat33.1Subjects first completed six psychometric questionnaires  outside the scanner environment. Questionnaires were administered by research staff. This was done prior to IV start and any painful stimulation. Using a randomized, single-blind, within-subject crossover design, subjects performed the experimental paradigm in an MRI scanner  delivered to their left index finger from an electric nerve stimulator . They made categorization decisions about a series of words they were hearing; one-third of the words were paired with pain. All these words were repeated three times, in randomized order, with pain-pairing kept consistent. Following the scan, the STICSA, PASS-20, PVAQ, and PCS questionnaires were completed again.The following day, ranging 20-32 hours after the memory encoding sessions, subjects returned for a follow-up testing session. The STICSA, PASS-20, PVAQ, and PCS assessments were again completed at the beginning of the visit. EDA electrodes were placed on the left palm to detect evidence of remembered physiological responses from previously pain paired words. No painful shocks were administered during these next day follow-up sessions. Subjects performed a Remember-Know recognition paradigm 3.2EDA data were processed within the AcqKnowledge software. Electrodermal response peaks occurring following the onset of the word item stimuli were considered paired together if the following parameters were met, similar to our previous report 3.3Subjects completed psychometric questionnaires to capture the subjective experience of pain and associated subject-reported measures. The BIPS During the follow-up testing portion of the experiment that took place the next day, subjects were seated in front of a laptop computer and heard experimental word items through headphones while using keyboard (number pad) buttons to respond. This session did not take place in an MRI scanner. EDA data were collected using EL507 electrodes loaded with BIOPAC isotonic electrode gel for EDA (GEL101A). EDA acquisition was done with a BIOPAC MP160  analog to digital conversion system and captured using the accompanying software, AcqKnowledge version 5.0 . The data sampling rate was 625 Hz.3.4Healthy adults between the ages of 18 and 38 years were recruited from the Pittsburgh community and completed the study. Subjects were compensated $200 for their participation. All subjects reported having no significant memory impairments, significant hearing impairments, chronic pain, other chronic medical issues, and recent or regular use of antidepressants, antipsychotics, antihistamines, anxiolytics, stimulants, sleep aids, and analgesics. Data was collected from a total of 25 subjects  of which the average age was 25.4 years and the age range was 19–37 years. Age and sex for each subject are listed in None.The experimental protocol was approved by the University of Pittsburgh Institutional Review Board (PRO14050609) and informed consent was obtained from each subject. This study otherwise conformed to the highest standards for the responsible conduct of research, including compliance with the Declaration of Helsinki.Lindsay Zhang: Formal analysis, Writing – original draft, Visualization. Keith Vogt: Conceptualization, Methodology, Validation, Investigation, Resources, Writing – review & editing, Supervision, Project administration, Funding acquisition.