A group-based intervention for diabetes-related emotional distress among emerging adults with type 1 diabetes: A pilot study.

AIMS: To assess diabetes-related emotional distress (DD) in emerging adults with type 1 diabetes (T1D) and assess a group-based intervention's impact. METHODS: To investigate DD we used data from the Problem Areas in Diabetes Questionnaire comprising 20 items (PAID-20). Furthermore, changes in the WHO Well-Being Index comprising five items (WHO-5) and glycated haemoglobin (HbA1c) were analysed. The intervention was evaluated using follow-up data from the emerging adults who participated. RESULTS: From 2021 to 2023, we screened 180 emerging adults using PAID-20. DD (PAID-20≥30) was prevalent in 25.0 % (95 % CI 18.9; 32.0 %), and associated with the female sex, higher HbA1c and WHO-5 < 50. Continuous subcutaneous insulin infusion at baseline was associated with PAID-20<30. 21 individuals attended a group-based intervention. At one-week follow up PAID-20 was reduced (29.1 ± 15.4 vs. 41.3 ± 12.1 at baseline, p = 0.003), and at nine-twelve months' follow-up HbA1c was reduced (59.3 ± 15.3 mmol/mol vs. 68.0 ± 17.4 mmol/mol at baseline, p = 0.012). CONCLUSIONS: This pilot study demonstrated that 25 % of the investigated emerging adults with T1D experienced DD (PAID-20≥30) associated with four clinical factors. We found a reduction in HbA1c and a short-term reduction in PAID-20 following the group-based intervention.

Outcome of adjuvant immunotherapy in a real-world nation-wide cohort of patients with melanoma.

BACKGROUND: Clinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. METHODS: Observational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). RESULTS: Between November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24-28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75-81), 66% (63-70), and 59% (55-63); MSS was 97% (95-98), 93% (91-95), and 87% (84-90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. CONCLUSION: Survival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Blood flow restricted walking in patients suffering from intermittent claudication: a case series feasibility and safety study.

To examine the feasibility and safety of blood flow restricted walking (BFR-W) in patients with intermittent claudication (IC). Moreover, to evaluate changes in objective performance-based and self-reported functioning following 12 weeks of BFR-W. Materials and methods: Sixteen patients with IC were recruited from two departments of vascular surgery. The BFR-W programme implied the application of a pneumatic cuff around the proximal part of the affected limb at 60% limb occlusion pressure in five intervals of 2 min, four times per week for 12 weeks. Feasibility was evaluated by adherence and completion rates of the BFR-W programme. Safety was evaluated by adverse events, ankle-brachial index (ABI) at baseline and follow-up, and pain on a numerical rating scale (NRS pain) before and 2 min after training sessions. Furthermore, changes in performance between baseline and follow-up were evaluated with the 30 seconds sit-to-stand test (30STS), the 6-minute walk test (6MWT) and the IC questionnaire (ICQ). Results: Fifteen out of 16 patients completed the 12-week BFR-W programme and adherence was 92.8% (95% CI: 83.4; 100%). One adverse event unrelated to the intervention was reported causing one patient to terminate the programme 2 weeks prematurely. Mean NRS pain 2 min following BFR-W was 1.8 (95% CI [1.7-2]). ABI, 30STS, 6MWT and ICQ score were improved at follow-up. Conclusions: BFR-W is feasible and appears to be safe in terms of completion rate, adherence to the training protocol, and adverse events in patients with IC. Further investigation of the effectiveness and safety of BFR-W compared to regular walking exercise is needed.

Congenital malformations among offspring of women with type 1 diabetes who use insulin pumps: a prospective cohort study.

AIMS/HYPOTHESIS: Continuous subcutaneous insulin infusion by insulin pump is often superior in improving glycaemic control compared with conventional multiple daily insulin injection (MDI). However, whether pump treatment leads to improved pregnancy outcomes in terms of congenital malformations and perinatal death remains unknown. The present aim was to evaluate the risk of malformations and perinatal and neonatal death in pregnant women with type 1 diabetes treated with pump or MDI. METHODS: We performed a secondary analysis of a prospective multinational cohort of 2088 pregnant women with type 1 diabetes in a real-world setting who were treated by pump (n=750) or MDI (n=1338). ORs for offspring with congenital malformations or perinatal or neonatal death were calculated using crude data and by logistic regression on propensity score-matched data. RESULTS: At enrolment (gestational week 8; 95% CI 4, 14), pump users had a higher educational level (university degree: 37.3% vs 25.1%; p<0.001) and better glycaemic control (mean HbA1c: 51±10 mmol/mol [6.8±0.9%] vs 54±14 mmol/mol [7.1±1.3%], p<0.001) compared with MDI users. Moreover, a greater proportion of pump users had an HbA1c level below 75 mmol/mol (9%) (97.6% vs 91.9%, p<0.001), and more often reported taking folic acid supplementation (86.3% vs 74.8%; p<0.001) compared with MDI users. All clinically important potential confounders were balanced after propensity score matching, and HbA1c remained lower in pump users. The proportion of fetuses with at least one malformation was 13.5% in pump users vs 11.2% in MDI users (crude OR 1.23; 95% CI 0.94, 1.61; p=0.13; propensity score-matched (adjusted) OR 1.11; 95% CI 0.81, 1.52; p=0.52). The proportion of fetuses with at least one major malformation was 2.8% in pump users vs 3.1% in MDI users (crude OR 0.89; 95% CI 0.52, 1.51; p=0.66; adjusted OR 0.78; 95% CI 0.42, 1.45; p=0.43), and the proportions of fetuses carrying one or more minor malformations (but no major malformations) were 10.7% vs 8.1% (crude OR 1.36; 95% CI 1.00, 1.84; p=0.05; adjusted OR 1.23; 95% CI 0.87, 1.75; p=0.25). The proportions of perinatal and neonatal death were 1.6% vs 1.3% (crude OR 1.23; 95% CI 0.57, 2.67; p=0.59; adjusted OR 2.02; 95% CI 0.69, 5.93; p=0.20) and 0.3% vs 0.3% (n=2 vs n=4, p=not applicable), respectively. CONCLUSIONS/INTERPRETATIONS: Insulin pump treatment was not associated with a lower risk of congenital malformations, despite better glycaemic control in early pregnancy compared with MDI. Further studies exploring the efficacy and safety of pump treatment during pregnancy are needed.

Quality of life and mental health in real-world patients with resected stage III/IV melanoma receiving adjuvant immunotherapy.

INTRODUCTION: Treatment with immune checkpoint inhibitors (ICI) has expanded into the adjuvant setting enhancing the importance of knowledge on the immune-related toxicities and their impact on health-related quality of life (HRQoL). Large phase 3 trials of patients with resected Stage III/IV melanoma found no effect on HRQoL during adjuvant immunotherapy. This study investigates how HRQoL was affected during and after adjuvant immunotherapy in a real-world setting. METHODS: Patients with resected melanoma treated with adjuvant nivolumab from 2018 to 2021 in Denmark were identified using the Danish Metastatic Melanoma Database (DAMMED). The study was performed as a nationwide cross-sectional analysis as a questionnaire consisting of six different validated questionnaires on HRQoL, cognitive function, fatigue, depression, fear of recurrence, and decision regret was sent to all patients in March 2021. To evaluate HRQoL during and after adjuvant treatment, patients were divided into groups depending on their treatment status when answering the questionnaire; patients in active treatment for 0-6 months, patients in active treatment for >6 months, patients who ended treatment 0-6 months ago, and patients who ended treatment >6 months ago. RESULTS: A total of 271/412 (66%) patients completed the questionnaire. Patients who ended therapy 0-6 months ago had the lowest HRQoL and had more fatigue. Patients in active treatment for >6 months had lower HRQoL and more fatigue than patients who started treatment 0-6 months ago. Patients ending therapy >6 months ago had higher HRQoL and less fatigue compared to patients who ended therapy 0-6 months ago. Multivariable analysis showed an association between HRQoL and treatment status, comorbidity, civil status, and employment status. CONCLUSIONS: Adjuvant nivolumab may affect some aspects of QoL, but the influence seems temporary. Patient characteristics, such as civil status, employment status, and comorbidity were associated with HRQoL.

Predictors of disease activity during pregnancy in women with inflammatory bowel disease-a Danish cohort study.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) activity during pregnancy is associated with adverse pregnancy outcomes. We aimed to identify key clinical characteristics that predict disease activity during pregnancy. METHODS: Between January 2008 through 2021, we identified all singleton pregnancies among women with IBD recorded in patient and birth registries at a tertiary IBD centre in Denmark. Maternal and infant data were retrieved from medical records. Demographics, Physicians Global Assessment (PGA) of disease activity 6 months prior to pregnancy and in all three trimesters of pregnancy and pregnancy outcomes were recorded. RESULTS: In 609 pregnancies, we observed 603 (99.0%) live births. Disease activity in one or more trimesters was seen in 283 women (46.5%). UC phenotype was associated with an increase in risk of disease activity (adjusted OR = 2.6 [1.8-3.9]; p < 0.001). Disease activity within 6 months prior to conceiving (169 women [27.7%]) was associated with an increased risk of continuous disease activity during pregnancy (adjusted OR of 5.3 [3.5-8.2]; p < 0.001). Disease activity during a previous pregnancy was associated with an increased risk of flares in subsequent pregnancies (adjusted OR of 3.2 [1.5-6.6]; p = 0.002). Sustained clinical remission throughout pregnancy was associated with an increased probability of normal birth term, birthweight and low risk of fetal growth restriction (FGR) and stillbirth. CONCLUSION: Predictors for disease activity include disease activity in a previous pregnancy and/or prior to conception, as well as UC phenotype. Reassuringly, women with IBD in remission are not at increased risk of adverse pregnancy outcomes.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).

Surgical experience is predictive for bladder tumour resection quality.

OBJECTIVES: To assess the resection quality of transurethral bladder tumour resection (TURBT) and the association to surgeon experience depending on the presence of detrusor muscle. METHODS: A retrospective study on 640 TURBT procedures performed at Zealand University Hospital, Denmark, from 1 January 2015 - 31 December 2016. Data included patient characteristics, procedure type, surgeon category, supervisor presence, surgical report data, pathological data, complications data and recurrence data. Analysis was performed using simple and multiple logistic regression on the association between surgeon experience and the presence of detrusor muscle in resected tissue from TURBT. RESULTS: Supervised junior residents had significant lower detrusor muscle presence (73%) compared with consultants (83%) (OR = 0.4, 95% CI = 0.21-0.83). Limitations were the retrospective design and the diversity of included TURBT. CONCLUSIONS: It was found that surgical experience predicts detrusor muscle presence and supervised junior residents performing TURBT on patients resulted in less detrusor muscle than consultants.

Role of EXO1 nuclease activity in genome maintenance, the immune response and tumor suppression in Exo1D173A mice.

DNA damage response pathways rely extensively on nuclease activity to process DNA intermediates. Exonuclease 1 (EXO1) is a pleiotropic evolutionary conserved DNA exonuclease involved in various DNA repair pathways, replication, antibody diversification, and meiosis. But, whether EXO1 facilitates these DNA metabolic processes through its enzymatic or scaffolding functions remains unclear. Here, we dissect the contribution of EXO1 enzymatic versus scaffolding activity by comparing Exo1DA/DA mice expressing a proven nuclease-dead mutant form of EXO1 to entirely EXO1-deficient Exo1-/- and EXO1 wild type Exo1+/+ mice. We show that Exo1DA/DA and Exo1-/- mice are compromised in canonical DNA repair processing, suggesting that the EXO1 enzymatic role is important for error-free DNA mismatch and double-strand break repair pathways. However, in non-canonical repair pathways, EXO1 appears to have a more nuanced function. Next-generation sequencing of heavy chain V region in B cells showed the mutation spectra of Exo1DA/DA mice to be intermediate between Exo1+/+ and Exo1-/- mice, suggesting that both catalytic and scaffolding roles of EXO1 are important for somatic hypermutation. Similarly, while overall class switch recombination in Exo1DA/DA and Exo1-/- mice was comparably defective, switch junction analysis suggests that EXO1 might fulfill an additional scaffolding function downstream of class switching. In contrast to Exo1-/- mice that are infertile, meiosis progressed normally in Exo1DA/DA and Exo1+/+ cohorts, indicating that a structural but not the nuclease function of EXO1 is critical for meiosis. However, both Exo1DA/DA and Exo1-/- mice displayed similar mortality and cancer predisposition profiles. Taken together, these data demonstrate that EXO1 has both scaffolding and enzymatic functions in distinct DNA repair processes and suggest a more composite and intricate role for EXO1 in DNA metabolic processes and disease.

Aortic distensibility is equal in prepubertal girls and boys and increases with puberty in girls.

Windkessel function is governed by conductance artery compliance that is associated with cardiovascular disease in adults independently of other risk factors. Sex-related differences in conductance artery compliance partly explain the sex-related differences in risk of cardiovascular disease. Studies on sex-related differences in conductance artery function in prepubertal children are few and inconclusive. This study determined the conductance artery compliance and cardiac function by magnetic resonance imaging in 150 healthy children (75 girls) aged 7-10 yr. Any sex-related difference in conductance artery function was determined with correction for other potential predictors in multivariable linear regression models. Our data showed that ascending [crude mean difference 1.11 95% confidence interval (CI) (0.22; 2.01)] and descending [crude mean difference 1.10 95% CI (0.09; 1.91)] aortic distensibility were higher in girls, but differences disappeared after adjustment for pubertal status and other identified potential predictors. Systolic and diastolic blood pressure, cardiac output, left ventricle (LV) systolic function, and total peripheral resistance did not differ between the sexes. In girls, heart rate was 7 beats/min higher, whereas pulse pressure (by 2 mmHg), LV end-diastolic volume index (by 7 mL), and stroke volume (by 5 mL) were lower. LV peak filling rate indexed to LV end-diastolic volume was 0.5 s-1 higher in girls. In conclusion, prepubertal girls and boys have equal conductance artery function. Thus, the well-known sex difference in adult conductance artery function seems to develop after the onset of puberty with girls initially increasing aortic distensibility.NEW & NOTEWORTHY Although it has been suggested that sex differences in conductance artery function may exist early in childhood, this study demonstrates that the well-known, sex-related difference in conductance artery stiffness (hence Windkessel function) in adulthood is not established before puberty. Thus, healthy prepubertal girls and boys have comparable conductance artery compliance. In contrast to previous studies, our study suggests that pubertal girls develop a more distensible aorta than prepubertal children.

National Implementation of Simulator Training Improves Transurethral Resection of Bladder Tumours in Patients.

Background: Transurethral resection of bladder tumours (TURBT) is the initial diagnostic treatment for patients with bladder cancer. TURBT is not an easy procedure to master and simulator training may play a role in improving the learning curve. Objective: To implement a national training programme for simulation-based mastery learning in TURBT and explore operating theatre performance after training. Design setting and participants: From June 2019 to March 2021, 31 doctors at urology departments in Denmark performed two pretraining TURBT procedures on patients, followed by proficiency-based mastery learning on a virtual reality simulator and then two post-training TURBTs on patients. Outcome measurements and statistical analyses: Operating theatre performances were video-recorded and assessed by two independent, blinded raters using the Objective Structured Assessment for Transurethral Resection of Bladder Tumours Skills (OSATURBS) assessment tool. Paired-sample t tests were used to compare pretraining and post-training analyses and independent t tests for between-group comparisons. This trial is registered at ClinicalTrials.gov as NCT03864302. Results and limitations: Before training, novices had significantly lower performance scores in comparison to those with intermediate experience (p = 0.017) and experienced doctors (p < 0.001). After training, novices significantly improved their clinical performance score (from 11.4 to 17.1; p = 0.049, n = 10). Those with intermediate experience and experienced doctors did not benefit significantly from simulator training (p = 0.9 and p = 0.8, respectively). Conclusions: Novices improved their TURBT performance in the operating theatre after completing a proficiency-based training programme on a virtual reality simulator. Patient summary: We trained surgeons in an operation to remove bladder tumours using a virtual reality simulator. Novice doctors improved their performance significantly after the training, but the training effects for more experienced doctors were minimal. Therefore, we suggest the introduction of mandatory simulator training in the residency programme for urologists.

Toward Nurses' Transformative Agency in Transitional Care for Older Adults: A Change-Laboratory Intervention.

Mobilization of nurses' agency across healthcare sectors is needed to counter challenges associated with older adults' transitions between hospital and primary care. Based on Cultural Historical Activity theory and the Change Laboratory method, we developed a learning intervention with 16 nurses. The aim was to foster the nurses' transformative agency to improve care. Video-recording of nine learning sessions were transcribed and analyzed. Results demonstrated that shared transformative agency exhibited as an emergent phenomenon crossing sectoral boundaries as a prerequisite for change in transitional care. The nurses progressed from acting as individuals criticizing the current conditions to collectively forming a vision around a transitional care model. This was nurtured through the nurses' negotiations which included a recognition of sharing similar challenges deriving from the healthcare organization and related financial restrictions, and conflicting healthcare and nursing ideals across healthcare sectors. The evolution of transformative agency was grounded in a professional nursing identity.

Det er nødvendigt at mobilisere sygeplejerskers ejerskab for udvikling på tværs af sundhedssektorer for at imødegå udfordringer i ældre medicinske patienters overgange mellem hospital og primærsektor. Med udgangspunkt i virksomhedsteori og Change Laboratory metoden udviklede vi en læringsintervention for 16 sygeplejersker. Formålet var at fremme sygeplejerskernes transformative ejerskab for at kunne forbedre sygeplejen. Vi transskriberede og analyserede videooptagelser af ni læringssessioner. Resultaterne viste et spirende fælles transformativt ejerskab blandt sygeplejerskerne på tværs af sektorer som en forudsætning for at kunne forandre den tværsektorielle pleje. Sygeplejerskerne gjorde fremskridt idet de flyttede sig fra at give individuel kritik af forholdende, til at samarbejde om at skabe en fælles vision for pleje ved overgange.Fremskridtet opstod, fordi sygeplejerskerne erkendte, at de på tværs af sektorer delte de samme udfordringer, som er forårsaget af organiseringen af sundhedsvæsenet og økonomiske begrænsninger samt modstridende idealer mellem sundhedsvæsenet og sygeplejeidealer på tværs af sundhedssektorer. Udviklingen af sygeplejerskernes transformerende ejerskab var forankret i en sygeplejefaglig professionsidentitet.

Kinetics of activation marker expression after in vitro polyclonal stimulation of chicken peripheral T cells.

A comprehensive analysis of T cell activation markers in chicken is lacking. Kinetics of T cell activation markers (CD25, CD28, CD5, MHC-II, CD44, and CD45) in response to in vitro stimulation of peripheral blood mononuclear cells with concanavalin A (Con A) were evaluated between two chicken lines selected for high and low levels of mannose-binding lectin in serum (L10H and L10L, respectively) by flow cytometry. L10H chickens showed a stronger response to Con A based on the frequency of T cell blasts in both the CD4+ and CD8+ compartment. The majority of the proliferating CD4+ and CD8+ T cells expressed CD25. Proliferating T cells were seen both in the CD4+ MHC-II+/- and CD8+ MHC-II+/- population. For both CD4+ and CD8+ T cells, frequencies of CD25+ and MHC-II+ T cells were increased 24 h after stimulation. CD28+ frequencies were only increased on CD8+ T cells 48 h after stimulation. An increase in the relative surface expression based on mean fluorescence intensity (MFI) upon activation was observed for most markers except CD5. For CD4+ T cells, CD28 expression increased 24 h after stimulation whereas MHC-II expression increased after 48 h. For CD8+ T cells, a tendency toward an increase in CD25 expression was observed. CD28 expression started to increase 24 h after stimulation and only a transient peak in MHC-II expression on CD8+ T cells was observed after 24 h. CD44 and CD45 expressed on CD4+ and CD8+ T cells increased 24-72 h after stimulation. In summary, the frequency of CD25+ and MHC-II+ T cells were shown to be early markers (24 h) for in vitro activation of both CD4+ and CD8+ T cells. Frequency of CD28+ T cells was a later marker (48 h) and only for CD8+ T cells. Surface expression of all markers (MFI) increased permanently or transiently upon activation except for CD5.

Validation of a Novel Assessment Tool Identifying Proficiency in Transurethral Bladder Tumor Resection: The OSATURBS Assessment Tool.

Background: Competence in transurethral resection of bladder tumors (TURB) is critical in bladder cancer management and should be ensured before independent practice. Objective: To develop an assessment tool for TURB and explore validity evidence in a clinical context. Design, Setting, and Participants: From July 2019 to March 2021, a total of 33 volunteer doctors from three hospitals were included after exemption from the regional ethics committee (REG-008-2018). Participants performed two TURB procedures on patients with bladder tumors. A newly developed assessment tool (Objective Structured Assessment for Transurethral Resection of Bladder Tumors Skills, OSATURBS) was used for direct observation assessment (DOA), self-assessment (SA), and blinded video assessment (VA). Outcome Measurements and Statistical Analysis: Cronbach's alpha and Pearson's r were calculated for across items internal consistency reliability, inter-rater reliability, and test-retest reliability. Correlation between OSATURBS scores and the operative experience was calculated with Pearson's r and a pass/fail score was established. Differences in assessment scores were explored with paired t-test and independent samples t-test. Results and Limitations: The internal consistency reliability across items Cronbach's alpha was 0.94 (n = 260, p < 0.001). Inter-rater reliability was 0.80 (n = 64, p < 0.001). Test-retest correlation was high, r = 0.71 (n = 32, p < 0.001). Relationship with TURB experience was high, r = 0.71 (n = 32, p < 0.001). Pass/fail score was 19 points. DOAs were strongly correlated with video ratings (r = 0.85, p < 0.001) but with a significant social bias with lower scores for inexperienced and higher scores for experienced participants. Participants tended to overestimate their own performances. Conclusions: OSATURBS tool for TURB can be used for assessment of surgical proficiency in the clinical setting. DOA and SA are biased, and blinded VA of TURB performances is advised. Clinical Trials NCT03864302.

Cardiovascular risk factors early in the course of treatment in people with type 2 diabetes without established cardiovascular disease: A population-based observational retrospective cohort study.

AIMS: To characterise the cardiovascular risk of people with type 2 diabetes without established cardiovascular disease but with risk factors, relative to those with established cardiovascular disease, to provide information on which patients could benefit from early use of glucose-lowering therapies that also reduce cardiovascular risk. METHODS: Data from people with type 2 diabetes initiating second-line glucose-lowering medication were retrieved from the UK Clinical Practice Research Datalink GOLD database and linked with Hospital Episode Statistics and Office for National Statistics (2001-2016). Cox proportional hazards models were used to estimate relative risks of major adverse cardiovascular events within groups defined by the presence of selected risk factors in people without versus with established cardiovascular disease. RESULTS: Of 53,182 individuals, 19.4% had established cardiovascular disease (i.e. a prior cardiovascular event). Over 5-7 years' follow-up, the rate of major adverse cardiovascular events was 14.0 and 49.6 events/1000 person-years without and with established cardiovascular disease, respectively (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.26, 0.29). Compared with a reference HR 1.0 for participants with established cardiovascular disease, estimated glomerular filtration rate <60 mL/min was the single factor associated with the highest risk of major adverse cardiovascular events (HR 0.75, 95% CI 0.70, 0.81) and mortality (HR 1.12, 95% CI 1.07, 1.18) in people with type 2 diabetes without established cardiovascular disease. The combination of chronic kidney disease with older age, smoking and/or dyslipidaemia was associated with a similarly high risk of cardiovascular events in people with type 2 diabetes and without cardiovascular disease compared with those having established cardiovascular disease. CONCLUSIONS: These analyses provide important information to identify people who may benefit from primary prevention of cardiovascular disease. Modifiable cardiovascular risk factors should be controlled early in all individuals with type 2 diabetes (as well as in all individuals with cardiovascular disease).

Characteristics of pregnant women with diabetes using injectable glucose-lowering drugs in the EVOLVE study.

AIMS: To examine clinical parameters, glycemic control, folic acid supplementation, and the presence of other chronic diseases during early pregnancy in the EVOLVE study population (women with pre-existing diabetes treated with injectable glucose-lowering drugs). METHODS: Cross-sectional baseline evaluation of EVOLVE: an international, multicenter, non-interventional study investigating the safety of injectable glucose-lowering drugs in pregnant women with pre-existing type 1 (T1D) or type 2 diabetes (T2D). Data were collected at enrollment visit interviews before gestational week 16. RESULTS: In total, 2383 women from 17 mainly European countries were enrolled in the study: 2122 with T1D and 261 with T2D; mean age was 31 and 33 years, and duration of diabetes was 15 and 6 years, respectively. For women with T1D or T2D, 63% and 75%, respectively, received basal and rapid-acting insulin, 36% and 3% rapid-acting insulin only, 0.7% and 14.0% basal insulin only, 0.2% and 5.4% premix insulin, 0.0% and 1.2% injectable glucagon-like peptide-1 receptor agonist treatment without insulin. In women with T1D or T2D, respectively, during early pregnancy, 59% and 62% had HbA1c <7.0% (53 mmol/mol); 16% and 36% reported not taking folic acid before or during early pregnancy. Overall, >40% of women had ≥1 chronic concomitant condition (predominantly thyroid disease or hypertension). Retinopathy was the most commonly reported diabetic complication. The most commonly reported previous pregnancy complication was miscarriage. CONCLUSIONS: Baseline data from this large multinational population of women with pre-existing diabetes indicate that sub-optimal glycemic control, poor pregnancy planning, and chronic concomitant conditions were common in early pregnancy.

Apolipoprotein D and transthyretin are reduced in female adolescent offspring of women with type 1 diabetes: The EPICOM study.

AIMS: Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex-specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and that these alterations are associated with lipid profile and indices of insulin sensitivity and secretion. METHODS: A prospective nationwide follow-up study (EPICOM) in a Danish population. Blood samples were assessed from offspring of women with T1D (index offspring, n = 267, 13-20 years), and matched control offspring (n = 290). Serum proteins were analysed using a 25-plex cardio-metabolic targeted proteomics assay, which includes 12 apolipoproteins and 13 transport and inflammatory proteins. RESULTS: Apolipoprotein D (ApoD) and transthyretin (TTR) were reduced in index females as compared to female controls (-8.1%, p < 0.001 and -6.1%, p = 0.006 respectively), but not in index males (2.2%, p = 0.476 and -2.4%, p = 0.731 respectively). Sex-dependent inverse associations between exposure to maternal T1D in utero and ApoD and TTR were significant after adjusting for age, BMI-SDS and Tanner stage (OR = 0.252 [95% CI 0.085, 0.745], p = 0.013 and OR = 0.149 [95% CI 0.040, 0.553], p = 0.004). ApoD correlated to indices of insulin sensitivity and secretion in a similar sex-specific pattern in crude and adjusted analyses. CONCLUSIONS: Low ApoD may be regarded as an early risk marker of metabolic syndrome. A possible link between ApoD and cardiovascular disease needs further investigation.

Asymmetric amyloid deposition in preclinical Alzheimer's disease: A PET study.

Introduction: The typical spatial pattern of amyloid-ß (Aß) in diagnosed Alzheimer's disease (AD) is that of a symmetrical hemispheric distribution. However, Aß may be asymmetrically distributed in early stages of AD. Aß distribution on PET has previously been explored in MCI and AD, but it has yet to be directly investigated in preclinical AD (pAD). We examined how Aß was distributed in individuals with pAD and MCI using 11C-Pittsburgh Compound B (PiB) PET. Methods: In this PET study, 79 subjects were retrospectively enrolled, including 34 controls, 24 pAD, and 21 MCI. All subjects underwent APOE genotyping, 11C-PiB PET, MRI, and cognitive testing. We explored differences in Aß load, Aß lateralisation, and Aß distribution, as well as associations between Aß distribution and cognition. Results: The Aß asymmetry index (AI) differed between groups, with pAD having the highest Aß AI as compared to both controls and MCI. There was no clear Aß lateralisation in pAD, but there was a non-significant trend towards Aß being more left-lateralised in MCI. There were no correlations between the cognitive scores and Aß AI or Aß lateralisation in pAD or MCI. Conclusion: The distribution of Aß is most asymmetrical in pAD, as Aß first starts accumulating, and it then becomes less asymmetrical in MCI, when Aß has spread further, suggesting that more pronounced asymmetrical Aß distribution may be a distinguishing factor in pAD. Longitudinal studies examining the distribution of Aß across the AD continuum are needed.

Cerebral hemodynamics and capillary dysfunction in late-onset major depressive disorder.

In major depressive disorder (MDD), perfusion changes in cortico-limbic pathways are interpreted as altered neuronal activity, but they could also signify changes in neurovascular coupling due to altered capillary function. To examine capillary function in late-onset MDD, 22 patients and 22 age- and gender-matched controls underwent perfusion MRI. We measured normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), and relative transit-time heterogeneity (RTH). Resulting brain oxygenation was estimated in terms of oxygen tension and normalized metabolic rate of oxygen (nCMRO2). Patients revealed signs of capillary dysfunction (elevated RTH) in the anterior prefrontal cortex and ventral anterior cingulate cortex bilaterally and in the left insulate cortex compared to controls, bilateral hypometabolism (parallel reductions of nCBV, nCBF, and CMRO2) but preserved capillary function in the subthalamic nucleus and globus pallidus bilaterally, and hyperactivity with preserved capillary function (increased nCBF) in the cerebellum and brainstem. Our data support that perfusion changes in deep nuclei and cerebellum reflect abnormally low and high activity, respectively, in MDD patients, but suggest that microvascular pathology affects neurovascular coupling in ventral circuits. We speculate that microvascular pathology is important for our understanding of etiology of late-onset MDD as well as infererences about resulting brain activity changes.