Dynamic associations between glucose and ecological momentary cognition in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic condition characterized by glucose fluctuations. Laboratory studies suggest that cognition is reduced when glucose is very low (hypoglycemia) and very high (hyperglycemia). Until recently, technological limitations prevented researchers from understanding how naturally-occurring glucose fluctuations impact cognitive fluctuations. This study leveraged advances in continuous glucose monitoring (CGM) and cognitive ecological momentary assessment (EMA) to characterize dynamic, within-person associations between glucose and cognition in naturalistic environments. Using CGM and EMA, we obtained intensive longitudinal measurements of glucose and cognition (processing speed, sustained attention) in 200 adults with T1D. First, we used hierarchical Bayesian modeling to estimate dynamic, within-person associations between glucose and cognition. Consistent with laboratory studies, we hypothesized that cognitive performance would be reduced at low and high glucose, reflecting cognitive vulnerability to glucose fluctuations. Second, we used data-driven lasso regression to identify clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations. Large glucose fluctuations were associated with slower and less accurate processing speed, although slight glucose elevations (relative to person-level means) were associated with faster processing speed. Glucose fluctuations were not related to sustained attention. Seven clinical characteristics predicted individual differences in cognitive vulnerability to glucose fluctuations: age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and neck circumference. Results establish the impact of glucose on processing speed in naturalistic environments, suggest that minimizing glucose fluctuations is important for optimizing processing speed, and identify several clinical characteristics that may exacerbate cognitive vulnerability to glucose fluctuations.

The effect of postoperative intravenous iron in anaemic, older cardiac surgery patients on disability-free survival (AGE ANEMIA study): study protocol for a multi-centre, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Postoperative anaemia is common in older cardiac surgery patients and often caused by iron deficiency. Anaemia may negatively affect recovery after cardiac surgery. This study aims to determine the efficacy of treatment of postoperative iron deficiency anaemia (IDA) with intravenous iron (IVI) on disability 90 days after cardiac surgery in older patients. METHODS: This is a randomized placebo-controlled double-blind multi-centre trial. In total, 310 patients aged ≥ 70 years with moderate IDA on postoperative day 1 (haemoglobin 85-110 g/L and ferritin concentration < 100 µg/L or iron saturation < 20%) after uncomplicated elective cardiac surgery (aortic valve repair or coronary artery bypass graft surgery) will be included. Patients will be randomly allocated to receive either IVI (ferric derisomaltose) or placebo (sodium chloride 0.9%) on postoperative day 1 in a 1:1 ratio, stratified by centre and type of cardiac surgery. The primary outcome is disability measured by the 12-item World Health Organization Disability Assessment score 2.0 after 90 days. Secondary outcome measures are the number of postoperative red blood cell (RBC) transfusions, change in reticulocyte haemoglobin content (pg) from randomization to hospital discharge, Hb levels at discharge, hospital complications, dyspnoea (assessed with the Rose Dyspnoea Scale) and health-related quality of life (HRQL) (assessed with The Older Persons and Informal Caregivers-Short Form (TOPICS-SF) questionnaire) after 90 days and days alive and out of hospital after 90 days. Lastly, the functional outcomes (e.g. steep ramp or 6-min walk test) and Hb level after 90 days will be assessed as an exploratory endpoint. DISCUSSION: The results of this study will demonstrate whether early treatment of postoperative IDA with IVI improves disability at 90 days in older cardiac surgery patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04913649. Registered on June 4, 2021.

[Predicting postoperative mortality]. / Postoperatieve sterfte voorspellen.

This article briefly discusses the reliability of predictive models for postoperative mortality. In current practice, prediction models for postoperative mortality often have limited clinical value, because the mortality risk is generally low. Moreover, in preoperative screening there is not so much a need for predictions about the average effectiveness of an intervention or treatment for an average patient, but rather for estimating the patient's individual risk. Postoperative functional decline and loss of quality of life are often underexposed in preoperative decision making.

[Elderly patients with an abdominal aortic aneurysm; preoperative frailty-screening and a multidisciplinary approach]. / Ouderen met een aneurysma van de abdominale aorta.

Aneurysm of the abdominal aorta is common and can be treated with endovascular repair, open surgical repair or conservative treatment. Risk-stratification and treatment decision-making can be complex in frail patients and depends largely on anatomy, life-expectancy and functional capacity. Currently, risk-stratification in the Netherlands is primarily based on comorbidities and age. Insight in a patient's resilience could provide important additional information. For this reason, St. Antonius hospital has implemented an Anaesthesia Geriatric Evaluation (AGE) to screen for frailty in high risk vascular surgery patients. Results of frailty-screening are discussed in a multi-disciplinary team (MDT) to assess perioperative risk and compose a personal treatment plan. This paper presents a case-series of three patients to illustrate the additional value of MDT care and frailty-screening in a high-risk vascular surgery population.

New insights into the cognitive effects of sleep deprivation by decomposition of a cognitive throughput task.

STUDY OBJECTIVES: A cognitive throughput task known as the Digit Symbol Substitution Test (DSST) (or Symbol Digit Modalities Test) has been used as an assay of general cognitive slowing during sleep deprivation. Here, the effects of total sleep deprivation (TSD) on specific cognitive processes involved in DSST performance, including visual search, spatial memory, paired-associate learning, and motor response, were investigated through targeted task manipulations. METHODS: A total of 12 DSST variants, designed to manipulate the use of specific cognitive processes, were implemented in two laboratory-based TSD studies with N = 59 and N = 26 subjects, respectively. In each study, the Psychomotor Vigilance Test (PVT) was administered alongside the DSST variants. RESULTS: TSD reduced cognitive throughput on all DSST variants, with response time distributions exhibiting rightward skewing. All DSST variants showed practice effects, which were however minimized by inclusion of a pause between trials. Importantly, TSD-induced impairment on the DSST variants was not uniform, with a principal component analysis revealing three factors. Diffusion model decomposition of cognitive processes revealed that inter-individual differences during TSD on a two-alternative forced choice DSST variant were different from those on the PVT. CONCLUSIONS: While reduced cognitive throughput has been interpreted to reflect general cognitive slowing, such TSD-induced impairment appears to reflect cognitive instability, like on the PVT, rather than general slowing. Further, comparisons between task variants revealed not one, but three distinct underlying processes impacted by sleep deprivation. Moreover, the practice effect on the task was found to be independent of the TSD effect and minimized by a task pacing manipulation.

Cognitive flexibility: A distinct element of performance impairment due to sleep deprivation.

In around-the-clock operations, reduced alertness due to circadian misalignment and sleep loss causes performance impairment, which can lead to catastrophic errors and accidents. There is mounting evidence that performance on different tasks is differentially affected, but the general principles underlying this differentiation are not well understood. One factor that may be particularly relevant is the degree to which tasks require executive control, that is, control over the initiation, monitoring, and termination of actions in order to achieve goals. A key aspect of this is cognitive flexibility, i.e., the deployment of cognitive control resources to adapt to changes in events. Loss of cognitive flexibility due to sleep deprivation has been attributed to "feedback blunting," meaning that feedback on behavioral outcomes has reduced salience - and that feedback is therefore less effective at driving behavior modification under changing circumstances. The cognitive mechanisms underlying feedback blunting are as yet unknown. Here we present data from an experiment that investigated the effects of sleep deprivation on performance after an unexpected reversal of stimulus-response mappings, requiring cognitive flexibility to maintain good performance. Nineteen healthy young adults completed a 4-day in-laboratory study. Subjects were randomized to either a total sleep deprivation condition (n = 11) or a control condition (n = 8). Athree-phase reversal learning decision task was administered at baseline, and again after 30.5 h of sleep deprivation, or matching well-rested control. The task was based on a go/no go task paradigm, in which stimuli were assigned to either a go (response) set or a no go (no response) set. Each phase of the task included four stimuli (two in the go set and two in the no go set). After each stimulus presentation, subjects could make a response within 750 ms or withhold their response. They were then shown feedback on the accuracy of their response. In phase 1 of the task, subjects were explicitly told which stimuli were assigned to the go and no go sets. In phases 2 and 3, new stimuli were used that were different from those used in phase 1. Subjects were not explicitly told the go/no go mappings and were instead required to use accuracy feedback to learn which stimuli were in the go and nogo sets. Phase 3 continued directly from phase 2 and retained the same stimuli as in phase 2, but there was an unannounced reversal of the stimulus-response mappings. Task results confirmed that sleep deprivation resulted in loss of cognitive flexibility through feedback blunting, and that this effect was not produced solely by (1) general performance impairment because of overwhelming sleep drive; (2) reduced working memory resources available to perform the task; (3) incomplete learning of stimulus-response mappings before the unannounced reversal; or (4) interference with stimulus identification through lapses in vigilant attention. Overall, the results suggest that sleep deprivation causes a fundamental problem with dynamic attentional control. This element of performance impairment due to sleep deprivation appears to be distinct from vigilant attention deficits, and represents a particularly significant challenge for fatigue risk management.

Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients.

This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P < 0.01). Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.

The clinical relevance of hysteroscopic polypectomy in premenopausal women with abnormal uterine bleeding.

This study assessed the efficacy of hysteroscopic polyp removal in the management of abnormal uterine bleeding (AUB) of premenopausal patients. The monthly menstrual blood loss, measured semi-objectively by the pictorial blood loss assessment chart (PBAC) and patients satisfaction were recorded prospectively preoperatively and postoperatively. Twenty-one patients were included. Median monthly PBAC-score before treatment was 288 (range 142-670) and 6 months after polyp removal 155 (range 39-560). It was concluded that hysteroscopic polyp removal in premenopausal women with AUB reduces the monthly blood loss significantly and has a high satisfaction rate on the short term.

Assessment of circadian function in fibroblasts of patients with bipolar disorder.

Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBalpha, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REV-ERBalpha and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKIdelta, CKIepsilon, GSK3alpha and GSK3beta) and the protein and phosphorylation levels of two of them (GSK3alpha and GSK3beta). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3beta phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3beta may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.

[Hysteroscopy: useful in diagnosis and surgical treatment of intrauterine lesions]. / Hysteroscopie: hulpmiddel bij diagnostiek en chirurgische behandeling van intra-uteriene afwijkingen.

Hysteroscopic surgery has an established role in the field of gynaecologic surgery. With the introduction of thinner scopes and simpler instruments part of the interventions can now be performed on an outpatient basis. Hysteroscopy can be used for the removal of polyps and myomas, endometrial resection, synechiolysis, sterilisation, septum resection and the removal of remnants from pregnancy. Hysteroscopic surgery can be an option for patients who wish to preserve the uterus and for the treatment of infertility. The complication rate associated with hysteroscopic interventions is low. The most common events are intravasation of distension fluid, uterine perforation, and haemorrhage. The complication rate depends on the complexity of the procedure.

A randomised comparison of vaginoscopic office hysteroscopy and saline infusion sonography: a patient compliance study.

OBJECTIVE: The purpose of this study was to compare patient discomfort during saline infusion sonography (SIS) and office hysteroscopy performed according to a vaginoscopic approach. DESIGN: Randomised controlled trial. SETTING: University hospital. POPULATION: Women with an indication for further investigation of the uterine cavity. METHODS: A total of 100 women randomly allocated to either SIS or vaginoscopic office hysteroscopy in an outpatient clinic. MAIN OUTCOME MEASURES: Scores on a visual analogue scale (VAS) for pain and a present pain intensity (PPI) scale, conclusiveness and success rate. RESULTS: The patients' pain scores on both the VAS and the PPI were lower for SIS when compared with office hysteroscopy (P < 0.05). However, in cases of severe pain (VAS > 7 or PPI > 2), there was no statistically significant difference between both groups. The success rate, defined as adequate inspection of the cervical canal and uterine cavity, was 94% for SIS compared with 92% for office hysteroscopy (P = 0.633). SIS, multiparity, shorter procedure time and position of the uterus in anteversion decreased pain scores among women studied. CONCLUSIONS: Both SIS and office hysteroscopy are successful procedures and well tolerated by women. SIS induces significantly less discomfort than office hysteroscopy and should therefore be considered the method of choice.

Diagnostic hysteroscopy in abnormal uterine bleeding: a systematic review and meta-analysis.

BACKGROUND: This study was conducted to assess the accuracy and feasibility of diagnostic hysteroscopy in the evaluation of intrauterine abnormalities in women with abnormal uterine bleeding. SEARCH STRATEGY: Electronic databases were searched from 1 January 1965 to 1 January 2006 without language selection. The medical subject heading (MeSH) and textwords for the following terms were used: hysteroscopy, diagnosis, histology, histopathology, hysterectomy, biopsy, sensitivity and specificity. SETTING: University Hospital. SELECTION CRITERIA: The inclusion criteria were report on accuracy of diagnostic hysteroscopy in women with abnormal uterine bleeding compared to histology collected with guided biopsy during hysteroscopy, operative hysteroscopy or hysterectomy. DATA COLLECTION AND ANALYSIS: Electronic databases were searched for relevant studies and references were cross-checked. Validity was assessed and data were extracted independently by two authors. Heterogeneity was calculated and data were pooled. Subgroup analysis was performed according to validity criteria, study quality, menopausal state, time, setting and performance of the procedure. The pooled sensitivity, specificity, likelihood ratios, post-test probabilities and feasibility of diagnostic hysteroscopy on the prediction of uterine cavity abnormalities. Post-test probabilities were derived from the likelihood ratios and prevalence of intrauterine abnormalities among included studies. Feasibility included technical success rate and complication rate. MAIN RESULTS: One population of homogeneous data could be identified, consisting of patients with postmenopausal bleeding. In this subgroup the positive and negative likelihood ratios were 7.9 (95% CI 4.79-13.10) and 0.04 (95% CI 0.02-0.09), raising the pre-test probability from 0.61 to a post-test probability of 0.93 (95% CI 0.88-0.95) for positive results and reducing it to 0.06 (95% CI 0.03-0.13) for negative results. The pooled likelihood ratios of all studies included, calculated with the random effects model, were 6.5 (95% CI 4.1-10.4) and 0.08 (95% CI 0.07-0.10), changing the pre-test probability of 0.46 to post-test probabilities of 0.85 (95% CI 0.78-0.90) and 0.07 (0.06-0.08) for positive and negative results respectively. Subgroup analyses gave similar results. The overall success rate of diagnostic hysteroscopy was estimated at 96.9% (SD 5.2%, range 83-100%). CONCLUSIONS: This systematic review and meta-analysis shows that diagnostic hysteroscopy is both accurate and feasible in the diagnosis of intrauterine abnormalities.

Significant reduction in blood loss in patients undergoing minimal extracorporeal circulation.

Several recent studies have shown differences in blood loss and allogeneic transfusion requirements between on-pump and off-pump coronary artery bypass grafting (CABG). Recently a new concept, the mini-extracorporeal circulation, was introduced to minimize the side effects of extracorporeal circulation. Therefore, there are no data comparing the three techniques with special emphasis to blood loss and transfusion requirements. Two hundred and eighty-five patients undergoing first-time coronary artery bypass grafting were retrospectively matched for number of grafts, age and sex. Ninety-five patients underwent surgery with the off-pump CABG (OPCAB) technique, 97 patients using conventional CABG with cold cardioplegia (CCABG) and 93 patients with the mini-extracorporeal circuit with warm blood cardioplegia (MCABG). Blood loss for the CCABG group with a mean loss of 819 +/- 557 mL and the OPCAB group with a mean loss of 870 +/- 768 mL was significant different compared to the MCABG group with a mean loss of 679 +/- 290 mL. The use of units red blood cell units was significantly higher for CCABG group and OPCAB group compared to the MCABG group. On the day of operation the use of platelet concentrate was significantly higher for the CCABG group compared to MCABG group. As a consequence of improvements of several components of the mini heart lung machine, significantly less blood products are needed in MCABG patients. The expected reduced need for transfusion when the pump was completely avoided could not be confirmed in this single retrospective cohort study.

Comparison of long term outcome of patients with rheumatoid arthritis presenting with undifferentiated arthritis or with rheumatoid arthritis: an observational cohort study.

BACKGROUND: The outcome of undifferentiated arthritis (UA) ranges from remission to rheumatoid arthritis (RA) fulfilling the American College of Rheumatology (ACR) classification criteria. OBJECTIVES: To report the outcome of UA after 1 year of follow up and compare the disease course of patients who presented with UA, but evolved into RA within 1 year (UA-RA group), with that of patients who presented with RA fulfilling the ACR criteria (RA-RA group). METHODS: The diagnosis of 330 patients who presented with UA was recorded at 1 year. The UA-RA and RA-RA groups were then followed up for 3 more years. Outcome measurements were radiographic progression, disease activity, and functional capacity. RESULTS: From 330 patients who were diagnosed UA, 91 had evolved into RA at 1 year; 62 patients had presented with RA. No significant differences were detected between the UA-RA and RA-RA groups in median Sharp/van der Heijde score at baseline, radiographic progression rates, disease activity, and functional capacity. However, significantly more disease modifying antirheumatic drugs were prescribed in the RA-RA group. CONCLUSION: The disease outcome of patients who present with UA that evolves into RA within 1 year is the same as that of patients who present with RA as measured by radiographic progression, disease activity, and functional capacity.

Pneumoproteins as a lung-specific biomarker of alveolar permeability in conventional on-pump coronary artery bypass graft surgery vs mini-extracorporeal circuit: a pilot study.

BACKGROUND: Despite improvements of the heart-lung machine (HLM), oxidative stress and subsequent damage to the alveolar capillary membrane still occur after conventional on-pump coronary artery bypass graft (CCABG) surgery. In an attempt to further improve the conventional HLM, a mini-extracorporeal circuit (MECC) was introduced. This new concept is based on minimal volume shifts. The extent of alveolar injury that is associated with this new technique is unknown. The lung-specific biomarkers Clara-cell 16 (CC16) and KL-6 are applied in this study to quantify alveolar dysfunction in both techniques. METHODS: In a prospective observational setting, the concentrations of CC16 and KL-6 were measured during and after 10 consecutive CCABG operations and 10 consecutive coronary artery bypass graft (CABG) operations using MECC (MCABGs). These pneumoproteins were measured after the induction of anesthesia, before clamping of the ascending aorta, after unclamping of the aorta, on arrival to the ICU, and on the following days until discharge. Quantification of the differences of KL-6 and CC16 leakage through the alveolar membranes between the two techniques was realized by calculation of the Student t test. Perioperative and postoperative shunt fractions and clinical observations were monitored simultaneously. The potential value of pneumoproteins as biomarkers for quantification of alveolar permeability during CABG surgery was tested. RESULTS: Significantly reduced concentrations of CC16 were found early after MCABG as compared to CCABG surgery (p = 0.033). KL-6 showed no consistent pattern during both treatment modalities. Early after CCABG surgery, shunt fractions tended to show reduced oxygen transport over the alveolar membrane as compared to MCABG surgery. CONCLUSION: CC16 appears to be a useful biomarker for alveolar permeability during CABG surgery. Injury of the alveolar capillary membrane appears significantly reduced during MCABG surgery. Consistently early postoperative alveolar shunt fractions showed an increased value in CCABG compared to MCABG surgery in the early postoperative phase. Further randomized studies need to confirm the value of CC16 as marker in monitoring alveolar capillary damage during coronary bypass grafting.

Non-invasive tests to predict fetal anemia in Kell-alloimmunized pregnancies.

OBJECTIVES: To compare test characteristics of ultrasound and Doppler parameters in the prediction of fetal anemia in Kell-alloimmunized pregnancies. METHODS: In this prospective study, 27 fetuses at risk for anemia due to Kell alloimmunization were evaluated with ultrasound and Doppler imaging. Spleen perimeter, liver length, middle cerebral artery (MCA) peak systolic velocity and intrahepatic umbilical venous (IHUV) maximum velocity were measured. Results were compared with fetal hemoglobin values at first intrauterine blood sampling or delivery. Severe fetal anemia was defined as a hemoglobin deficit of at least 5 SD below the mean for gestational age. RESULTS: Eighteen fetuses were anemic and required intrauterine transfusions. In the other nine pregnancies no transfusions were performed; one of these fetuses was severely anemic at birth. MCA and IHUV flow velocities were the best predictors of fetal anemia in Kell alloimmunized fetuses (sensitivity 89% for each test). Sensitivities for spleen perimeter (15%) and liver length (14%) were disappointing. CONCLUSIONS: Doppler evaluation of MCA peak systolic velocity and IHUV maximum velocity can be used to reliably predict severe fetal anemia in Kell alloimmunization.

Undifferentiated arthritis--disease course assessed in several inception cohorts.

The prognosis of patients with undifferentiated arthritis (UA) may vary from self-limited to severe destructive rheumatoid arthritis (RA). Because early aggressive treatment might offer an effective means to slow disease progression in RA, it is important to identify UA patients who will develop RA and treat them as early as possible. At the same time, inappropriate treatment of patients with a more benign disease course should be avoided. Here, an overview is given of the characteristics and numbers of patients with UA who evolve into RA. UA is defined as any arthritis that has the potential for a persistent course, without fulfilling the classification criteria for specific rheumatic disorders. To compare endpoints in the different databases, the 1987 ACR criteria for RA were used. In the nine databases employing a similar definition for undifferentiated arthritis, the proportion of patients with UA that evolved into RA within 1 year varied from 6% to 55%. These differences arise in large part from differences in the inclusion criteria and in the definitions used for UA and RA. The data from the various cohorts support a hypothesis that a considerable proportion of UA patients are actually patients with RA in a very early stage. Controlled intervention studies with early antirheumatic treatment in these patients are mandatory in order to provide further insight into the natural course of UA and to define a treatment strategy that will successfully slow or prevent disease progression.