The effects of increased therapy time on cognition and mood in frail patients with a stroke who rehabilitate on rehabilitation units of nursing homes in the Netherlands: a protocol of a comparative study

BACKGROUND: Recovery after stroke is dependent on how much time can be spent on rehabilitation. Recently, we found that therapy time for older stroke patients on a rehabilitation unit of a nursing home could be increased significantly from 8.6 to at least 13 hours a week. This increase was attained by the implementation of interventions, focused on strength, mobility and balance. Nurses carried out these exercises with the patients during their daily activities. The aim of the present study is to investigate if increased therapy time has a positive effect on cognition, mood (depression and anxiety), and ADL in stroke patients. METHODS: A comparative single blind controlled study will be applied. Patients suffering from a stroke and staying on one of the rehabilitation units of the nursing homes are eligible for participation. Participants belong to the intervention group if they stay in two nursing homes where four interventions of the Clinical Nursing Rehabilitation Stroke Guideline were implemented. Participants who stay in two nursing homes where therapy is given according to the Dutch stroke Guideline, are included in the control group. Clinical neuropsychologists will assess patients’ cognitive functioning, level of depression (mood) and anxiety. Nurses will assess a Barthel Index score on a weekly basis (ADL). These variables are measured at baseline, after 8 weeks and at the moment when participants are discharged from the nursing home. DISCUSSION: The present study evaluates the effect of increased therapy time on cognition, mood (level of depression and anxiety), and ADL in stroke patients. When positive effects will be found this study can guide policy makers and practitioners on how to implement more therapy time on rehabilitation wards of nursing homes. TRIAL REGISTRATION: TNR Our study has been documented in the Dutch Trial Registration, TC = 3871

Immunomodulation for ARDS:Insights From Proteomics in COVID-19

Background: The success of targeted immunomodulation in COVID-19 underscores its potential for ARDS resulting from other causes. However, it is important to understand both its targeted and broader impacts on the inflammatory host response. To guide future ARDS studies, we explored this in patients with COVID-19 using targeted proteomics.Research Question: How do different immune modulators affect the immune profiles of patients who are critically ill with COVID-19-related ARDS? Study Design and Methods: In this multicenter cohort study, we used 2 Dutch biorepositories to compare patients with COVID-19 with acute respiratory failure treated with: no immunotherapy (n = 18), corticosteroids (n = 21), anakinra plus corticosteroids (n = 9), or tocilizumab plus corticosteroids (n = 22). Plasma proteins related to inflammation and cardiovascular injury were measured using proximity extension assays on ICU days 0 through 1, ICU days 2 through 4 (T3), and ICU days 6 through 8 (T7) after treatment initiation. Results: We observed lower expression of inflammatory biomarkers immediately after tocilizumab administration and from T3 onward after anakinra administration. After treatment with corticosteroids alone, fewer inflammatory biomarkers were suppressed, and only at T3. Multivariate analyses at T3 identified tumor necrosis factor-related apoptosis-inducing ligand, IL-1 receptor-like 2, and tumor necrosis factor β as markedly increased and proto-oncogene tyrosine-protein kinase (SRC) and serine/threonine kinase 4 (STK4) as decreased, solely after tocilizumab. At T7, lower concentrations of 2,4-dienoyl-CoA reductase 1, signaling lymphocytic activation molecule family member 7, SRC, and STK4 were observed in patients treated with tocilizumab or anakinra, whereas interferon γ, chemokine (C-X-C motif) ligand 9, and chemokine (C-C motif) ligand 19 were decreased only after anakinra treatment. Interpretation: In this exploratory study, adding tocilizumab or anakinra to corticosteroids triggered a much broader immunoregulatory response than can be explained by their receptor-specific actions. The response after tocilizumab occurred more rapidly than that after anakinra, offering a potential advantage in the time-sensitive ICU setting. Additionally, tocilizumab preserved the interferon pathway, crucial for antiviral defense, whereas anakinra suppressed it.</p

Immunobiological effects of tocilizumab across respiratory subphenotypes in COVID-19 ARDS

Background: Two distinct longitudinal respiratory subphenotypes have recently been described in COVID-19-related acute respiratory distress syndrome (ARDS). These subphenotypes exhibit dynamic immunobiological changes that may help guide immunomodulatory interventions. However, the extent to which the immune response is determined by respiratory subphenotype in the presence of concurrent immunomodulatory treatment remains unclear. We investigated the independent and combined effects of respiratory subphenotype and tocilizumab on inflammatory response and clinical outcomes. Methods: We analyzed patients from existing COVID-19 biobanks who were consecutively admitted to the ICU and received more than 4 days of invasive mechanical ventilation between March 2020 and May 2022. Patients were classified into two previously described longitudinal respiratory subphenotypes—characterized by mechanical power, minute volume and ventilatory ratio—referred to as ‘low-power’ and ‘high-power’ subphenotypes. We analyzed how tocilizumab treatment and respiratory subphenotype were associated with endothelial and inflammatory plasma biomarkers on days 0, 4 and 7, as well as with mortality. Results: 720 patients were included, of whom 464 (64%) and 256 (36%) were assigned to the low- and high-power subphenotypes, respectively. 108 (23%) of the low-power subphenotype patients received tocilizumab, and 43 (17%) of the high-power subphenotype. 427 patients had plasma samples available. The high-power subphenotype was associated with slightly higher SP-D, thrombomodulin and TNF-RI plasma concentrations on the day of intubation compared to the low-power subphenotype, along with a more rapid increase in IL-6 and TNF-RI levels in subjects who had received tocilizumab treatment (β = 0.14 log ng/ml, p = 0.022, and β = 0.06 log ng/ml, p = 0.014, respectively). Tocilizumab treatment accounted for four times more variance in IL-6 and angiopoietin-2 levels than subphenotype, while subphenotype explained only a small proportion of the variance and slightly more than tocilizumab for TNF-RI and thrombomodulin. Subphenotype did not modify the association between tocilizumab and mortality (IPTW adjusted hazard ratio 1.18; 95%CI 0.60–2.33). Conclusion:Respiratory subphenotypes showed varying TNF-RI and IL-6 responses to tocilizumab, but these differences were only minor compared to the drug’s overall immunobiological effect. This suggests that respiratory subphenotype should not determine tocilizumab treatment decisions.</p

Brain donation in psychiatry : Results of a Dutch prospective donor program among psychiatric cohort participants

Background: Human brain tissue is crucial to study the molecular and cellular basis of psychiatric disorders. However, the current availability of human brain tissue is inadequate. Therefore, the Netherlands Brain Bank initiated a program in which almost 4.000 participants of 15 large Dutch psychiatric research cohorts were asked to register as prospective brain donors. Methods: We approached patients with schizophrenia, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, families with a child with autism or Attention Deficit Hyperactivity Disorder, healthy relatives and healthy unrelated controls, either face-to-face or by post. We investigated whether diagnosis, method of approach, age, and gender were related to the likelihood of brain-donor registration. Results: We found a striking difference in registration efficiency between the diagnosis groups. Patients with bipolar disorder and healthy relatives registered most often (25% respectively 17%), followed by unrelated controls (8%) and patients with major depressive disorder, post-traumatic stress disorder, and obsessive-compulsive disorder (9%, 6% resp. 5%). A face-to-face approach was 1.3 times more effective than a postal approach and the likelihood of registering as brain donor significantly increased with age. Gender did not make a difference. Conclusions: Between 2013 and 2016, our prospective brain-donor program for psychiatry resulted in an almost eightfold increase (from 149 to 1149) in the number of registered psychiatric patients at the Netherlands Brain Bank. Based on our results we recommend, when starting a prospective brain donor program in psychiatric patients, to focus on face to face recruitment of people in their sixties or older

BrainNet Europe's Code of Conduct for brain banking

Research utilizing human tissue and its removal at post-mortem has given rise to many controversies in the media and posed many dilemmas in the fields of law and ethics. The law often lacks clear instructions and unambiguous guidelines. The absence of a harmonized international legislation with regard to post-mortem medical procedures and donation of tissue and organs contributes to the complexity of the issue. Therefore, within the BrainNet Europe (BNE) consortium, a consortium of 19 European brain banks, we drafted an ethical Code of Conduct for brain banking that covers basic legal rules and bioethical principles involved in brain banking. Sources include laws, regulations and guidelines (Declarations, Conventions, Recommendations, Guidelines and Directives) issued by international key organizations, such as the Council of Europe, European Commission, World Medical Association and World Health Organization. The Code of Conduct addresses fundamental topics as the rights of the persons donating their tissue, the obligations of the brain bank with regard to respect and observance of such rights, informed consent, confidentiality, protection of personal data, collections of human biological material and their management, and transparency and accountability within the organization of a brain bank. The Code of Conduct for brain banking is being adopted by the BNE network prior to being enshrined in official legislation for brain banking in Europe and beyond

Effect of hydrocortisone therapy initiated 7 to 14 days after birth on mortality or bronchopulmonary dysplasia among very preterm infants receiving mechanical ventilation : a randomized clinical trial

IMPORTANCE: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. OBJECTIVE: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. INTERVENTIONS: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. RESULTS: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). CONCLUSIONS AND RELEVANCE: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. TRIAL REGISTRATION: Netherlands National Trial Register Identifier: NTR2768.status: publishe