Search

Abstract Background When a patient is approaching death in the intensive care unit (ICU), patients’ relatives must make a rapid transition from focusing on their beloved one’s recovery to preparation for their unavoidable death. Bereaved relatives may develop complicated grief as a consequence of this burdensome situation; however, little is known about appropriate options in quality care supporting bereaved relatives and the prevalence and predictors of complicated grief in bereaved relatives of deceased ICU patients in the Netherlands. The aim of this study is to develop and implement a multicomponent bereavement support intervention for relatives of deceased ICU patients and to evaluate the effectiveness of this intervention on complicated grief, anxiety, depression and posttraumatic stress in bereaved relatives. Methods The study will use a cross-sectional pre-post design in a 38-bed ICU in a university hospital in the Netherlands. Cohort 1 includes all reported first and second contact persons of patients who died in the ICU in 2018, which will serve as a pre-intervention baseline measurement. Based on existing policies, facilities and evidence-based practices, a nurse-led intervention will be developed and implemented during the study period. This intervention is expected to use 1) communication strategies, 2) materials to make a keepsake, and 3) a nurse-led follow-up service. Cohort 2, including all bereaved relatives in the ICU from October 2019 until March 2020, will serve as a post-intervention follow-up measurement. Both cohorts will be performed in study samples of 200 relatives per group, all participants will be invited to complete questionnaires measuring complicated grief, anxiety, depression and posttraumatic stress. Differences between the baseline and follow-up measurements will be calculated and adjusted using regression analyses. Exploratory subgroup analyses (e.g., gender, ethnicity, risk profiles, relationship with patient, length of stay) and exploratory dose response analyses will be conducted. Discussion The newly developed intervention has the potential to improve the bereavement process of the relatives of deceased ICU patients. Therefore, symptoms of grief and mental health problems such as depression, anxiety and posttraumatic stress, might decrease. Trial registration Netherlands Trial Register Registered on 27/07/2019 as NL 7875, www.trialregister.nl

Abstract Maple syrup urine disease (MSUD) leads to severe neurological deterioration unless diagnosed early and treated immediately. We have evaluated the effectiveness of 11 years of MSUD newborn screening (NBS) in the Netherlands (screening >72 hours, referral if both total leucine (Xle) and valine ≥400 μmol/L blood) and have explored possibilities for improvement by combining our data with a systematic literature review and data from Collaborative Laboratory Integrated Reports (CLIR). Dutch MSUD NBS characteristics and accuracy were determined. The hypothetical referral numbers in the Dutch population of additional screening markers suggested by CLIR were calculated. In a systematic review, articles reporting NBS leucine concentrations of confirmed patients were included. Our data showed that NBS of 1 963 465 newborns identified 4 MSUD patients and led to 118 false‐positive referrals (PPV 3.28%; incidence 1:491 000 newborns). In literature, leucine is the preferred NBS parameter. Total leucine (Xle) concentrations (mass‐spectrometry) of 53 detected and 8 false‐negative patients (sampling age within 25 hours in 3 patients) reported in literature ranged from 288 to 3376 (median 900) and 42 to 325 (median 209) μmol/L blood respectively. CLIR showed increasing Xle concentrations with sampling age and early NBS sampling and milder variant MSUD phenotypes with (nearly) normal biochemical profiles are causes of false‐negative NBS results. We evaluated the effect of additional screening markers and established the Xle/phenylalanine ratio as a promising additional marker ratio for increasing the PPV, while maintaining high sensitivity in the Dutch MSUD NBS.

Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation o f the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four-hour fasting increased liver Dio3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced Dio3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both Dio3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, Dio3 mRNA expression increased five-fold after 48-h fasting. Treatment of 3T3-L1 adip ocytes with mTOR inhibitors induced Dio3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce Dio3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.

Abstract Background Displaced victims of interpersonal violence, such as refugees, asylum seekers, and victims of sexual exploitation, are growing in numbers and are often suffering from a post-traumatic stress disorder (PTSD). At the same time, these victims are known to benefit less from trauma-focused therapy (TFT) and to be less compliant to treatment. The objective of this paper is to describe the rationale and research protocol of an ongoing trial that aims to evaluate different variables that might influence the feasibility of TFT for the study population. Specifically, perceived daily stress, emotion regulation, and mood are investigated as predictors of change in PTSD symptoms during a trauma-focused therapy (narrative exposure therapy (NET)). The feasibility of administering measures tapping these constructs repeatedly during treatment will also be evaluated. Methods/design Using an observational treatment design, 80 displaced victims of interpersonal violence will be measured before, during, and after partaking in NET. Several questionnaires tapping PTSD plus the aforementioned possible predictors of PTSD change will be administered: Post-traumatic Stress Disorder Checklist-5, Perceived Stress Scale, Difficulties in Emotion Regulation Scale-18 (pre-test, post-test, and follow-up),subscale impulsivity of the Difficulties in Emotion Regulation Scale-18, Perceived Stress Scale short version, Primary Care Post-traumatic Stress Disorder and a single Mood item (each session). Multilevel modelling will be used to examine the relation between the possible predictors and treatment outcome. Discussion The present study is the first to examine the interplay of facilitating and interfering factors possibly impacting treatment feasibility and effectiveness in displaced victims of interpersonal violence with PTSD receiving NET, using repeated measures. The current study can help to improve future treatment based on individual characteristics. Trial registration Netherlands Trial Register: NTR7353 , retrospectively registered. Date of registration: July 11, 2018.

Abstract Background The availability of interventions for bereaved parents have increased. However, most are practice based. To enhance the implementation of bereavement care for parents, an overview of interventions which are replicable and evidence-based are needed. The aim of this review is to provide an overview of well-defined bereavement interventions, focused on the parents, and delivered by regular health care professionals. Also, we explore the alignment between the interventions identified and the concepts contained in theories on grief in order to determine their theoretical evidence base. Method A systematic review was conducted using the methods PALETTE and PRISMA. The search was conducted in MEDLINE, Embase, and CINAHL. We included articles containing well-defined, replicable, paediatric bereavement interventions, focused on the parent, and performed by regular health care professionals. We excluded interventions on pathological grief, or interventions performed by healthcare professionals specialised in bereavement care. Quality appraisal was evaluated using the risk of bias, adapted risk of bias, or COREQ. In order to facilitate the evaluation of any theoretical foundation, a synthesis of ten theories about grief and loss was developed showing five key concepts: anticipatory grief, working models or plans, appraisal processes, coping, and continuing bonds. Results Twenty-one articles were included, describing fifteen interventions. Five overarching components of intervention were identified covering the content of all interventions. These were: the acknowledgement of parenthood and the child’s life; establishing keepsakes; follow-up contact; education and information, and; remembrance activities. The studies reported mainly on how to conduct, and experiences with, the interventions, but not on their effectiveness. Since most interventions lacked empirical evidence, they were evaluated against the key theoretical concepts which showed that all the components of intervention had a theoretical base. Conclusions In the absence of empirical evidence supporting the effectiveness of most interventions, their alignment with theoretical components shows support for most interventions on a conceptual level. Parents should be presented with a range of interventions, covered by a variety of theoretical components, and aimed at supporting different needs. Bereavement interventions should focus more on the continuous process of the transition parents experience in readjusting to a new reality. Trial registration This systematic review was registered in Prospero (registration number: CRD42019119241 ).

Background & Aims: Bile acids are important metabolic signaling molecules. Bile acid receptor activation promotes body weight loss and improves glycemic control. The incretin hormone GLP-1 and thyroid hormone activation of T4 to T3 have been suggested as important contributors. Here, we identify the hepatic bile acid uptake transporter Na+ taurocholate co-transporting polypeptide (NTCP) as target to prolong postprandial bile acid signaling. Methods: Organic anion transporting polypeptide (OATP)1a/1b KO mice with or without reconstitution with human OATP1B1 in the liver were treated with the NTCP inhibitor Myrcludex B for 3.5 weeks after the onset of obesity induced by high fat diet-feeding. Furthermore, radiolabeled T4 was injected to determine the role of NTCP and OATPs in thyroid hormone clearance from plasma. Results: Inhibition of NTCP by Myrcludex B in obese Oatp1a/1b KO mice inhibited hepatic clearance of bile acids from portal and systemic blood, stimulated GLP-1 secretion, reduced body weight, and decreased (hepatic) adiposity. NTCP inhibition did not affect hepatic T4 uptake nor lead to increased thyroid hormone activation. Myrcludex B treatment increased fecal energy output, explaining body weight reductions amongst unaltered food intake and energy expenditure. Conclusions: Pharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

Non-fatal traffic accidents may give rise to mental health problems, including posttraumatic stress (PTS) and depression. Clinical evidence suggests that victims may also experience grief reactions associated with the sudden changes and losses caused by such accidents. The aim of this study was to examine whether there are unique patterns of symptoms of PTS, depression, and grief among victims of non-fatal traffic accidents. We also investigated associations of emerging symptom patterns with sociodemographic variables and characteristics of the accident, and with transdiagnostic variables, including self-efficacy, difficulties in emotion regulation, and trauma rumination. Participants (N = 328, Mage = 32.6, SDage = 17.5 years, 66% female) completed self-report measures tapping the study variables. Using latent class analysis (including symptoms of PTS, depression, and grief), three classes were identified: a no symptoms class (Class 1; 59.1%), a moderate PTS and grief class (Class 2; 23.1%), and a severe symptoms class (Class 3; 17.7%). Summed symptom scores and functional impairment were lowest in Class 1, higher in Class 2, and highest in Class 3. Psychological variables were similarly ordered with the healthiest scores in Class 1, poorer scores in Class 2, and the worst scores in Class 3. Different sociodemographic and accident related variables differentiated between classes, including age, education, and time since the accident. In a regression including all significant univariate predictors, trauma rumination differentiated Class 2 from Class 1, all three psychological variables differentiated Class 3 from Class 1, and difficulties with emotion regulation and trauma rumination differentiated Class 3 from Class 2. This study demonstrates that most people respond resiliently to non-fatal traffic accident. Yet, approximately one in three victims experiences moderate to severe mental health symptoms. Increasing PTS coincided with similarly increasing grief, indicating that grief may be considered in interventions for victims of traffic accidents. Trauma rumination strongly predicted class membership and appears a critical treatment target to alleviate distress.

Introduction: When grief reactions after bereavement are so intense that they impair daily functioning, a diagnosis of disturbed grief may apply. Slightly differing criteria-sets for disturbed grief are included in the ICD-11, the DSM-5, and its forthcoming text revision, DSM-5-TR. We examined psychometric properties of a new self-report measure, the 22-item Traumatic Grief Inventory-Self Report Plus (TGI-SR+), that assesses these criteria sets for Persistent Complex Bereavement Disorder (PCBD) as per DSM-5, and Prolonged Grief Disorder (PGD) as defined in ICD-11 and DSM-5-TR. Material and methods: We examined the: i) factor structure, ii) internal consistency, iii) temporal stability, iv) convergent validity, v) known-groups validity, vi) probable caseness, and vii) optimal clinical cut-off scores in two Dutch bereaved samples. Sample 1 consisted of 278 adults, bereaved by various causes. Sample 2 included 270 adults who lost loved ones in a traffic accident. Results: We found support for a 3-factor PCBD model, 1-factor DSM-5-TR model, and 1-factor ICD-11 PGD model. The DSM-5 PCBD, DSM-5-TR PGD, and ICD-11 PGD items demonstrated good internal consistency and temporal stability. Associations between disturbed grief symptoms and posttraumatic stress and depression levels supported convergent validity. Associations between demographic/loss-related variables and disturbed grief symptoms supported known-groups validity. Optimal clinical cut-offs for the TGI-SR+ total score were ≥ 75, ≥71, and ≥ 75 for probable caseness of DSM-5 PCBD, DSM-5-TR PGD, and ICD-11 PGD, respectively. Discussion: While replication of our findings in diverse bereaved samples is needed, we conclude that the TGI-SR+ is a reliable and valid measure to assess symptoms of DSM-5 PCBD, DSM-5-TR PGD, and ICD-11 PGD.

Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3′-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.

Chronic hemodynamic overload of the heart induces ventricular hypertrophy that may be either compensatory or progress to decompensation and heart failure. The gradual impairment of ventricular function is, at least in part, the result of a reduction of cardiac thyroid-hormone (TH) action. Here, we examined the proposed roles of increased cardiac expression of the TH-inactivating enzyme deiodinase type 3 (D3) and reduced plasma TH levels in diminishing cardiac TH levels. Using minipumps, mice were infused for one and two weeks with isoproterenol (ISO) alone or in combination with phenylephrine (PE). Remodeling of the heart induced by these adrenergic agonists was assessed by echocardiography. Left ventricular (LV) tissue and plasma TH levels (T4 and T3) were determined using liquid chromatography-tandem mass spectrometry. LV D3 activity was determined by conversion of radiolabeled substrate and quantification following HPLC. The results show that ISO induced compensated LV hypertrophy with maintained cardiac output. Plasma levels of T4 and T3 remained normal, but LV hormone levels were reduced by approximately 30% after two weeks, while LV D3 activity was not significantly increased. ISO + PE induced decompensated LV hypertrophy with diminished cardiac output. Plasma levels of T4 and T3 were substantially reduced after one and two weeks, together with a more than 50% reduction of hormone levels in the LV. D3 activity was increased after one week and returned to control levels after two weeks. These data show for the first time that relative to controls, decompensated LV hypertrophy with diminished cardiac output is associated with a greater reduction of cardiac TH levels than compensated hypertrophy with maintained cardiac output. LV D3 activity is unlikely to account for these reductions after two weeks in either condition. Whereas the mechanism of the mild reduction in compensated hypertrophy is unclear, changes in systemic TH homeostasis appear to determine the marked drop in LV TH levels and associated impairment of ventricular function in decompensated hypertrophy.

Objective: Thyroid hormones (TH) are essential for the homeostatic control of energy metabolism and the regulation of body temperature. The hypothalamic–pituitary–thyroid (HPT) axis is regulated by negative feedback mechanisms, ensuring that TH levels are maintained at a constant level. However, the feedback mechanisms underlying the resetting of the HPT axis regulation in the control of body temperature are still not fully understood. Here, we aimed to determine the thermoregulatory response in hypothyroid mice to different environmental temperatures and the underlying mechanisms. Methods: Distinct thermogenic challenges were induced in hypothyroid female C57BL/6N and leptin-deficient ob/ob mice through housing at either room temperature or thermoneutrality. The thermogenic and metabolic effects were analyzed through metabolic chambers, 18F-FDG-PET/MRI, infrared thermography, metabolic profiling, histology, gene expression and Western blot analysis. Results: In hypothyroid mice maintained at room temperature, high leptin serum levels induce a pyrexic effect leading to the stabilization of body temperature through brown adipose tissue thermogenesis and white adipose tissue browning. Housing at thermoneutrality leads to the normalization of leptin levels and a reduction of the central temperature set point, resulting in decreased thermogenesis in brown and white adipose tissue and skeletal muscle and a significant decline in body temperature. Furthermore, anapyrexia in hypothyroid leptin-deficient ob/ob mice indicates that besides its pyrexic actions, leptin exerts a stimulatory effect on the HPT axis to stabilize the remaining TH serum levels in hypothyroid mice. Conclusion: This study led to the identification of a previously unknown endocrine loop in which leptin acts in concert with the HPT axis to stabilize body temperature in hypothyroid mice.