Treatment for preschool age children who stutter: Protocol of a randomised, non-inferiority parallel group pragmatic trial with Mini-KIDS, social cognitive behaviour treatment and the Lidcombe Program-TreatPaCS.

Stuttering is a speech disorder in which the flow of speech is disrupted by involuntary repetitions of sounds, syllables, words or phrases, stretched sounds or silent pauses in which the person is unable to produce sounds and sound transitions. Treatment success is the highest if stuttering is treated before the age of 6 years, before it develops into "persistent" stuttering. Stuttering treatment programs that focus directly on the speech of the child, like the Lidcombe Program, have shown to be effective in this age group. Mini-KIDS is also a treatment that focuses directly on the speech of the child. It is possible that capturing the increased brain plasticity at this age in combination with creating optimal conditions for recovery underlie these treatments' success rate. A treatment focusing on the cognitions, emotions and behaviour of the child, the social cognitive behaviour treatment (SCBT), is also frequently delivered in Belgium. In this study we want to compare, and collect data on the effectiveness, of these three treatment programs: Mini-KIDS, SCBT and the Lidcombe Program (protocol registered under number NCT05185726). 249 children will be allocated to one of three treatment groups. Stuttering specialists will treat the child (and guide the parents) with Mini-KIDS, the SCBT or the Lidcombe Program. They will be trained to deliver the programs meticulously. At 18 months after randomisation, the speech fluency of the child and the attitude of the child and parent(s) towards speech will be measured. It is expected that the three programs will achieve the same (near) zero levels of stuttering in nearly all children and a positive attitude towards speech at 18 months after the start of treatment. The amount of treatment hours to reach the (near) zero levels of stuttering will be compared between the different programmes. For families as well as for the health system this could generate important information.

Integration of the PD-L1 inhibitor atezolizumab and WT1/DC vaccination into standard-of-care first-line treatment for patients with epithelioid malignant pleural mesothelioma-Protocol of the Immuno-MESODEC study.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a very poor prognosis. Recently, immune checkpoint inhibition (ICI) has taken center stage in the currently ongoing revolution that is changing standard-of-care treatment for several malignancies, including MPM. As multiple arguments and accumulating lines of evidence are in support of the existence of a therapeutic synergism between chemotherapy and immunotherapy, as well as between different classes of immunotherapeutics, we designed a multicenter, single-arm, phase I/II trial in which both programmed-death-ligand 1 (PD-L1) inhibition and dendritic cell (DC) vaccination are integrated in the first-line conventional platinum/pemetrexed-based treatment scheme for epithelioid MPM patients (Immuno-MESODEC, ClinicalTrials.gov identifier NCT05765084). Fifteen treatment-naïve patients with unresectable epithelioid subtype MPM will be treated with four 3-weekly (±3 days) chemo-immunotherapy cycles. Standard-of-care chemotherapy consisting of cisplatinum (75mg/m2) and pemetrexed (500mg/m2) will be supplemented with the anti-PD-L1 antibody atezolizumab (1200 mg) and autologous Wilms' tumor 1 mRNA-electroporated dendritic cell (WT1/DC) vaccination (8-10 x 106 cells/vaccination). Additional atezolizumab (1680 mg) doses and/or WT1/DC vaccinations (8-10 x 106 cells/vaccination) can be administered optionally following completion of the chemo-immunotherapy scheme. Follow-up of patients will last for up to 90 days after final atezolizumab administration and/or WT1/DC vaccination or 24 months after diagnosis, whichever occurs later. The trial's primary endpoints are safety and feasibility, secondary endpoints are clinical efficacy and immunogenicity. This phase I/II trial will evaluate whether addition of atezolizumab and WT1/DC vaccination to frontline standard-of-care chemotherapy for the treatment of epithelioid MPM is feasible and safe. If so, this novel combination strategy should be further investigated as a promising advanced treatment option for this hard-to-treat cancer.

Long-term effects of the COVID-19 pandemic for patients with cancer.

INTRODUCTION: Long COVID is defined as the continuation of symptoms, unexplainable by alternative diagnosis, longer than four weeks after SARS-CoV-2 infection. These symptoms might hinder daily activities and overall well-being, ultimately impacting quality of life (QoL). Several studies have reported fatigue as the most common symptom, followed by dyspnoea, headache and myalgia. Although it is assumed that long COVID affects 10-20% of SARS-CoV-2 infected individuals, recently numbers up to 60% were described for patients with cancer. This study uncovers the impact of the COVID-19 pandemic on QoL of patients with cancer and how long COVID manifests in this cohort. METHODS: A group of 96 patients with cancer was followed from March 2022 till March 2023. Online questionnaires assessing symptoms associated with long COVID, anxiety and depression (HADS), quality of life (EORTC-QLQ-C30) and cognitive functioning (CFQ) were sent every three months during this period. Furthermore, a semi-structured focus group was organised for qualitative data collection. RESULTS: Overall, these patients reported a negative impact of the enforced COVID-19 restrictions on the emotional and psychological wellbeing. Forty nine patients with cancer (51.0%) were infected with SARS-CoV-2 over the course of the study, of which 39 (79.6%) reported long COVID symptoms. The most commonly reported symptoms were myalgia (46.2%), fatigue (38.5%) and disturbed sleep (35.9%) and it was observed that male sex is associated with poor long COVID outcomes. CONCLUSION: While patients with cancer experience similar long COVID symptoms as healthy controls, the prevalence is remarkably higher possibly due to their compromised immune system and weakened physiological reserve.

Since the outbreak in Wuhan (China) at the end of 2019, the Coronavirus Disease 2019 (COVID-19) pandemic has caused instability at various levels of society. While most patients completely recover from their SARS-CoV-2 infection, 10­20% of infected persons and up to 60% of infected patients with cancer develop long COVID. Long COVID is defined as the continuation of symptoms, which cannot be explained by alternative causes, that last longer than four weeks after initial infection. Even though it is generally accepted that patients with cancer are at increased risk of developing severe COVID-19, it is still unclear how long COVID manifests and whether long COVID impacts quality of life in this cohort. Hence, this study observed that patients with cancer reported a negative impact of the enforced COVID-19 restrictions on the emotional and psychological wellbeing. While patients with cancer experience similar long COVID symptoms as healthy controls, the prevalence is remarkably higher possibly due to their compromised immune system and weakened physiological reserve.

Large-scale real-world data on a multidisciplinary approach to spinal cord stimulation for persistent spinal pain syndromes: first evaluation of the Neuro-Pain® nationwide screening and follow-up interactive register.

Introduction: Spinal cord stimulation is a common treatment option for neuropathic pain conditions. Despite its extensive use and multiple technological evolutions, long term efficacy of spinal cord stimulation is debated. Most studies on spinal cord stimulation include a rather limited number of patients and/or follow-ups over a limited period. Therefore, there is an urgent need for real-world, long-term data. Methods: In 2018, the Belgian government initiated a nationwide secure platform for the follow-up of all new and existing spinal cord stimulation therapies. This is a unique approach used worldwide. Four years after the start of centralized recording, the first global extraction of data was performed. Results: Herein, we present the findings, detailing the different steps in the centralized procedure, as well as the observed patient and treatment characteristics. Furthermore, we identified dropouts during the screening process, the reasons behind discontinuation, and the evolution of key indicators during the trial period. In addition, we obtained the first insights into the evolution of the clinical impact of permanent implants on the overall functioning and quality of life of patients in the long-term. Discussion: Although these findings are the results of the first data extraction, some interesting conclusions can be drawn. The long-term outcomes of neuromodulation are complex and subject to many variables. Future data extraction will allow us to identify these confounding factors and the early predictors of success. In addition, we will propose further optimization of the current process.

A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial.

Introduction: Despite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive multiple sclerosis (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers of disability progression that are insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing of metformin for treatment of PMS. The objective of this clinical trial is to evaluate whether metformin, as add-on treatment, is superior to placebo in delaying disease progression in patients with non-active PMS. Methods and analysis: MACSiMiSE-BRAIN is a multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled clinical trial, conducted at five sites in Belgium. Enrollment of 120 patients with non-active PMS is planned. Each participant will undergo a screening visit with assessment of baseline magnetic resonance imaging (MRI), clinical tests, questionnaires, and a safety laboratory assessment. Following randomization, participants will be assigned to either the treatment (metformin) or placebo group. Subsequently, they will undergo a 96-week follow-up period. The primary outcome is change in walking speed, as measured by the Timed 25-Foot Walk Test, from baseline to 96 weeks. Secondary outcome measures include change in neurological disability (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) and hand function (9-Hole Peg test). Annual brain MRI will be performed to assess evolution in brain volumetry and diffusion metrics. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score will be additionally evaluated as an exploratory outcome. Other exploratory outcomes will consist of paramagnetic rim lesions, the 2-minute walking test and health economic analyses as well as both patient- and caregiver-reported outcomes like the EQ-5D-5L, the Multiple Sclerosis Impact Scale and the Caregiver Strain Index. Ethics and dissemination: Clinical trial authorization from regulatory agencies [Ethical Committee and Federal Agency for Medicines and Health Products (FAMHP)] was obtained after submission to the centralized European Clinical Trial Information System. The results of this clinical trial will be disseminated at scientific conferences, in peer-reviewed publications, to patient associations and the general public. Trial registration: ClinicalTrials.gov Identifier: NCT05893225, EUCT number: 2023-503190-38-00.

Adjuvant Wilms' tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms' tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety of WT1 mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG. METHODS AND ANALYSIS: 10 paediatric patients with newly diagnosed or pretreated HGG or DIPG were treated according to the trial protocol. The trial protocol consists of leukapheresis of mononuclear cells, the manufacturing of autologous WT1/DC vaccines and the combination of WT1/DC-vaccine immunotherapy with conventional antiglioma treatment. In newly diagnosed patients, this comprises chemoradiation (oral temozolomide 90 mg/m2 daily+radiotherapy 54 Gy in 1.8 Gy fractions) followed by three induction WT1/DC vaccines (8-10×106 cells/vaccine) given on a weekly basis and a chemoimmunotherapy booster phase consisting of six 28-day cycles of oral temozolomide (150-200 mg/m2 on days 1-5) and a WT1/DC vaccine on day 21. In pretreated patients, the induction and booster phase are combined with best possible antiglioma treatment at hand. Primary objectives are to assess the feasibility of the production of mRNA-electroporated WT1/DC vaccines in this patient population and to assess the safety and feasibility of combining conventional antiglioma treatment with the proposed immunotherapy. Secondary objectives are to investigate in vivo immunogenicity of WT1/DC vaccination and to assess disease-specific and general quality of life. ETHICS AND DISSEMINATION: The ethics committee of the Antwerp University Hospital and the University of Antwerp granted ethics approval. Results of the clinical trial will be shared through publication in a peer-reviewed journal and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT04911621.

Comprehensive geriatric assessment as an essential tool to register or update DNR codes in a tertiary care hospital.

PURPOSE: To investigate the prevalence of Do not Resuscitate (DNR) code registration in patients with a geriatric profile admitted to Antwerp University Hospital, a tertiary care hospital in Flanders, Belgium, and the impact of comprehensive geriatric assessment (CGA) on DNR code registration. PATIENTS AND METHODS: Retrospective analysis of a population of 543 geriatric patients (mean age 82.4 ± 5.19 years, 46.4% males) admitted to Antwerp University Hospital from 2018 to 2020 who underwent a CGA during admission. An association between DNR code registration status before and at hospital admission and age, gender, ethnicity, type of residence, clinical frailty score (CFS), cognitive and oncological status, hospital ward and stay on intensive care was studied. Admissions before and during the first wave of the pandemic were compared. RESULTS: At the time of hospital admission, a DNR code had been registered for 66.3% (360/543) of patients. Patients with a DNR code at hospital admission were older (82.7 ± 5.5 vs. 81.7 ± 4.6 years, p = 0.031), more frail (CFS 5.11 ± 1.63 vs. 4.70 ± 1.61, p = 0.006) and less likely to be admitted to intensive care. During the hospital stay, the proportion of patients with a DNR code increased to 77% before and to 85.3% after CGA (p < 0.0001). Patients were consulted about and agreed with the registered DNR code in 55.8% and 52.1% of cases, respectively. The proportion of patients with DNR codes at the time of admission or registered after CGA did not differ significantly before and after the start of the COVID-19 pandemic. CONCLUSION: After CGA, a significant increase in DNR registration was observed in hospitalized patients with a geriatric profile.

Evaluation of the learning effect on the 6-min walk distance in adults with long COVID.

There was no learning effect found on 6-min walk distance (6MWD) in patients with long COVID, performing a 6-min walk test twice. However, considerable variation in the difference between the two 6MWDs was observed: only 51% showed an increase. https://bit.ly/3H70G1r.

Concurrent and Predictive Validity of the Mann Assessment of Swallowing Ability in Belgian Acute Stroke Patients Based on a 1-Year Follow-Up Study.

INTRODUCTION: The Mann Assessment of Swallowing Ability (MASA) is a standardized clinical swallowing examination, specifically developed as a diagnostic test for the presence of oropharyngeal dysphagia and aspiration in the early period after stroke onset. In the original validation study, cutoff scores of <178 and <170 points, respectively, for the identification of dysphagia and aspiration risk are reported. However, a literature search revealed that alternative cutoff scores for dysphagia and/or aspiration provide better diagnostic accuracy. The aim of this secondary data analysis study was to evaluate the concurrent and predictive validity of the MASA. METHODS: Data were derived from a Belgian cohort study of an acute stroke population (n = 151). The MASA total score (MASA-TS), which is the sum of weighted scores on the 24 items, was evaluated against the Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS) to assess concurrent validity. To assess predictive validity of the MASA-TS, pneumonia during hospitalization and over 1 year and mortality acted as a future criterion. Analyses included receiver operating characteristic curves and area under the curve (AUC). RESULTS: Diagnostic accuracy of the MASA-TS was good for dysphagia (AUC = 0.85) and for the presence of relevant aspiration risk (AUC = 0.84). Using the original cutoff scores, the MASA-TS showed perfect sensitivity (Se = 1.00) for the identification of dysphagia and aspiration but inadequate specificity (Sp) for dysphagia (Sp = 0.16) and aspiration (Sp = 0.43). After determining new MASA cutoff scores, the optimal MASA cutoff scores were ≤146 for both dysphagia and aspiration with adequate thresholds (Se = 0.71 and Sp = 0.81 for dysphagia; Se = 0.73 and Sp = 0.80 for aspiration). The MASA-TS was a significant predictor of pneumonia during hospitalization (AUC = 0.85) and 1-year follow-up (AUC = 0.86), and of mortality (AUC = 0.79). CONCLUSION: The MASA-TS showed good concurrent validity with the FEDSS. Furthermore, using new cutoff scores (≤146 for the identification of dysphagia and aspiration) lead in general to more accurate diagnostic indexes. The MASA-TS is a good predictor of aspiration pneumonia during hospitalization and 1-year follow-up and of mortality.

The impact of need-based care on formal caregivers' wellbeing in nursing homes: A cluster randomized controlled trial.

BACKGROUND: Need-based care is a structured and standardized model that supports formal caregivers in nursing homes in delivering person-centered care by responding with tailored non-pharmacological interventions on residents' unmet needs as well as having positive effects on behavioral and psychological symptoms on residents with dementia. However, limited resources as well as the shortage of caregivers in nursing homes make the implementation of need-based care challenging, especially when it comes to finding ways to spend more time with residents. The aim of this study is to evaluate the impact of the implementation of need-based care in nursing homes on formal caregivers' wellbeing. METHODS: A three-arm cluster randomized controlled trial was set up in 24 Belgian nursing homes: formal caregivers in the 'need-based care' group (intervention; n = 195) spent time twice a week with residents who had behavioral and psychological symptoms according to the principles of need-based care while formal caregivers in the 'time' group (n = 257) filled in the way they spent time twice a week; a third group delivered standard care (n = 299). An implementation strategy was built upon the Implementation Quality Framework and used in the 'need-based care group'. A total of 741 formal caregivers completed the digital questionnaire at one or more of the five time points (every nine weeks) between November 2021 and July 2022; they rated their sense of competence in dementia care, level of burnout, and, level of engagement. Moments of time were registered in a printed registration book. RESULTS: Only formal caregivers from the 'need-based care' group experienced a higher sense of competence in dementia care at time points three (p = 0.010) and four (p = 0.001) compared with baseline with an increase of respectively 1.5 (95 % confidence interval [0.25, 2.84]) and 2.4 (95 % confidence interval [0.77, 4.04]) points. No differences in scores on burnout and engagement were found. CONCLUSION: Despite challenging workforce circumstances in nursing homes, caregivers in the need-based care group as well as in the time group were able to spend time twice a week with residents with behavioral and psychological symptoms. No negative effects were found on formal caregivers' wellbeing after the implementation of need-based care in nursing homes. However, it requires strong leadership and the use of well-considered implementation strategies including reflective practice. TRIAL REGISTRY: Trial registration number ISRCTN56768265 (10/08/2023).

Evaluating the Predictive Value of a Short Preoperative Holistic Risk Factor Screening Questionnaire in Preventing Persistent Pain in Elective Adult Surgery: Study Protocol for a Prospective Observational Pragmatic Trial [PERISCOPE].

Background: The global incidence of persistent pain after surgery is approximately 10%, with considerable clinical and socioeconomic impacts. Despite identifying many risk factors in its development and the challenging management of the often neuropathic pain complaints, preoperative recognition of high-risk patients in various surgical populations using a standardized risk factor assessment questionnaire is lacking. This study evaluates the predictive value of a short holistic risk factor screening questionnaire as a first step in preventing and treating persistent pain in adults undergoing elective surgery. Methods: This prospective observational pragmatic trial will include 560 adults undergoing elective surgery. The primary endpoint is the evaluation of the predictive value of the screening questionnaire, including the optimal cut-off determination in terms of sensitivity and specificity for inclusion in a perioperative high-vigilance program. Secondary endpoints are postoperative pain (intensity and characterization using the NRS and DN4), postoperative analgesic usage, and well-being using the EQ-5D-5 L. To assess the performance of the designed screening questionnaire in the identification of psychosocial pain aspects, HADs, and STAI-trait are being surveyed. Additionally, the multidimensional pain inventory (MPI, part 1) is being used to assess the impact of pain on daily life in patients. Discussion: This pragmatic clinical trial will evaluate a short preoperative screening questionnaire to predict persistent postoperative pain after elective surgery in adults. Suppose high-risk patients could be identified earlier using this short preoperative holistic screening questionnaire. In that case, it might contribute to a more widespread implementation of standardized preoperative assessment and awareness for preventing persistent postoperative pain. Trial Registration: Local ethics committee: B3002022000112. ClinicalTrials.gov identifier: NCT05526976. Registered on: 02 September 2022. Start of recruitment: 22 December 2022. Trial Status: This paper is based on protocol version 4.0. The first patient was assigned to the research project on the 22 of December 2022. We anticipate including the last patient in October 2023 and plan to finalize the study by January 2024.

Fatigue and Physical Activity Patterns in Children With Inflammatory Bowel Disease.

OBJECTIVES: Fatigue is a common symptom in children with inflammatory bowel disease (IBD). Diagnostic tests to evaluate biological causes of fatigue commonly include markers of inflammation and hemoglobin (Hb), yet functional parameters have been inadequately studied in pediatric IBD. In this study, we compared fatigued and non-fatigued children with IBD from both a biological and functional point of view. METHODS: A cross-sectional study of 104 pediatric IBD patients with mild to moderately active IBD was conducted. Fatigued children were defined as those with a Pediatric Quality of Life Inventory Multidimensional Fatigue Scale z score <-2.0. Non-fatigued children had a z score ≥-2.0. Disease-specific quality of life (measured with IMPACT-III score), C-reactive protein (CRP), fecal calprotectin (FC), hemoglobin z score (Hb z score), and physical activity tests including 6-minute walking distance z score (6MWD z score) and triaxial accelerometry (TA) were evaluated. RESULTS: Fatigued children (n = 24) had a significant lower IMPACT-III score than non-fatigued children (n = 80). Hb z scores, CRP, FC, and 6MWD z scores were not significantly different between groups. TA was performed in 71 patients. Wear time validation requirements were met in only 31 patients. Fatigued patients spent significant shorter median time in moderate-to-vigorous activity than non-fatigued patients (18.3 vs 37.3 minutes per day, P = 0.008). CONCLUSION: Biological parameters did not discriminate fatigued from non-fatigued patients. TA possibly distinguishes fatigued from non-fatigued patients; the potential association may provide a target for interventions to combat fatigue and improve quality of life.

Effect of need-based care on behavioural and psychological symptoms in residents with dementia and formal caregivers' distress in nursing homes: a three-arm cluster randomized controlled trial.

PURPOSE: To evaluate to what extent the standardized concept of need-based care on Behavioural and Psychological Symptoms of Dementia (BPSD), and formal caregiver distress, is superior when compared to spending more time or standard care with residents with BPSD. METHODS: A longitudinal cluster randomized controlled study in 23 nursing homes in Belgium with 3 parallel groups was set up. A total of 481 residents with dementia participated. Formal caregivers in the need-based care group treated residents who displayed agitated or aggressive behaviour with a non-pharmacological intervention, tailored to unmet needs, twice a week with re-evaluation every 8 weeks. In the time group, formal caregivers spent 'extra time'. In the standard care group, it was 'care as usual'. Outcomes were measured at four different time points with the Doloplus-2 (to assess pain behaviour), Cohen-Mansfield Agitation Inventory (CMAI) for agitation, the Neuropsychiatric Inventory (NPI-NH) for BPSD and formal caregivers' distress. RESULTS: Need-based interventions had a significant effect on residents' levels of pain behaviour. In the need-based care group, scores on overall BPSD (agitation and aggression, depression, euphoria, irritability, sleep and night-time behaviour) improved significantly from baseline when compared to other timepoints. No significant different interactions over time were found between all three groups for categorized versions of NPI scores (ever versus never). CONCLUSION: Need-based care reduced the level of BPSD in residents with dementia as well as formal caregivers' distress. The study supports the importance of tailored non-pharmacological interventions in the residential care for people with dementia. TRIAL REGISTRY: Trial registration number B300201942084 (18/11/2019).

Randomised, controlled, open-label pragmatic trial evaluating changes in functional exercise capacity after primary care PUlmonary REhabilitation in patients with long COVID: protocol of the PuRe-COVID trial in Belgium.

INTRODUCTION: Long COVID is a prevalent condition with many multisystemic symptoms, such as fatigue, dyspnoea, muscle weakness, anxiety, depression and sleep difficulties, impacting daily life and (social and physical) functioning. Pulmonary rehabilitation (PR) may improve physical status and symptoms of patients with long COVID, yet the evidence is limited. Therefore, this trial aims to study the effect of primary care PR on exercise capacity, symptoms, physical activity and sleep in patients with long COVID. METHODS AND ANALYSIS: PuRe-COVID is a prospective, pragmatic, open-label, randomised controlled trial. A sample of 134 adult patients with long COVID will be randomised to a 12 week PR programme in primary care, supervised by a physiotherapist or to a control group, following no PR. A 3 month and 6 month follow-up period is foreseen. The primary endpoint will be the change in exercise capacity measured by 6-minute walk distance (6MWD) at 12 weeks, hypothesising a more significant improvement in the PR group. Other parameters, such as pulmonary function tests (including maximal inspiratory pressure/maximal expiratory pressure), patient-reported outcomes (COPD Assessment Test, modified Medical Research Council Dyspnoea Scale, Checklist Individual Strength, post-COVID-19 Functional Status, Nijmegen questionnaire, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment Questionnaire and EuroQol-5D-5L), physical activity measured by an activity tracker, hand grip strength and sleep efficiency, are secondary and exploratory outcomes.The recruitment started on 19 April 2022, and 52 patients were included as of 14 December 2022. ETHICS AND DISSEMINATION: Ethical approval was obtained in Belgium from the relevant institutional review boards on 21 February 2022 (Antwerp University Hospital, approval number 2022-3067) and on 1 April 2022 (Ziekenhuis Oost-Limburg in Genk, approval number Z-2022-01). Findings from this randomised controlled trial will be disseminated in peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT05244044.

Regional Citrate Anticoagulation in Continuous Renal Replacement Therapy: Is Metabolic Fear the Enemy of Logic? A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Anticoagulation is recommended to maintain the patency of the circuit in continuous renal replacement therapy (CRRT). However, anticoagulation-associated complications can occur. We performed a systematic review and meta-analysis to compare the efficacy and safety of citrate anticoagulation to heparin anticoagulation in critically ill patients treated with CRRT. METHODS: Randomised controlled trials (RCTs) evaluating the safety and efficacy of citrate anticoagulation and heparin in CRRT were included. Articles not describing the incidence of metabolic and/or electrolyte disturbances induced by the anticoagulation strategy were excluded. The PubMed, Embase, and MEDLINE electronic databases were searched. The last search was performed on 18 February 2022. RESULTS: Twelve articles comprising 1592 patients met the inclusion criteria. There was no significant difference between the groups in the development of metabolic alkalosis (RR = 1.46; (95% CI (0.52-4.11); p = 0.470)) or metabolic acidosis (RR = 1.71, (95% CI (0.99-2.93); p = 0.054)). Patients in the citrate group developed hypocalcaemia more frequently (RR = 3.81; 95% CI (1.67-8.66); p = 0.001). Bleeding complications in patients randomised to the citrate group were significantly lower than those in the heparin group (RR 0.32 (95% CI (0.22-0.47); p < 0.0001)). Citrate showed a significantly longer filter lifespan of 14.52 h (95% CI (7.22-21.83); p < 0.0001), compared to heparin. There was no significant difference between the groups for 28-day mortality (RR = 1.08 (95% CI (0.89-1.31); p = 0.424) or 90-day mortality (RR 0.9 (95% CI (0.8-1.02); p = 0.110). CONCLUSION: regional citrate anticoagulation is a safe anticoagulant for critically ill patients who require CRRT, as no significant differences were found in metabolic complications between the groups. Additionally, citrate has a lower risk of bleeding and circuit loss than heparin.

Considerations on the Obstacles That Lead to Slow Recruitment in a Pain Management Clinical Trial: Experiences from the Belgian PELICAN (PrEgabalin Lidocaine Capsaicin Neuropathic Pain) Pragmatic Study.

Background: A qualitative evaluation study of the prematurely terminated PrEgabalin Lidocaine Capsaicin Neuropathic Pain (PELICAN) study was performed. The PELICAN study aimed to examine pain management for localized neuropathic pain (LNP), as epidemiological figures have shown a high percentage of LNP patients in Belgium. The study compared systemic and topical medications according to pain relief, adverse effects, and several measures of quality of life. Objective: Achieving better study patient recruitment through qualitative research. To investigate and determine the causes of the observed recruitment problems in the PELICAN study, pain centers involved in the study as well as nonrecruiting pain centers were included. Furthermore, it aimed to highlight the positive and negative lessons learned from the conducted study and the number of obstacles the team had to overcome. Methods: A qualitative study, using a mixed methods approach, was performed. Multiple pain centers in Belgium completed an online survey, after which a structured interview was conducted to elaborate the responses in more detail. The broad topics of these meetings were feedback about the study, reviewing survey answers, and actions undertaken to enhance recruitment. Results: Different factors contributed to the low recruitment rate in the PELICAN study, such as limited and late referral from the general practitioners to the Belgian pain centers, insufficient internal referrals from nonpain specialists, lack of specific expertise on LNP in some centers, scarcity of staff, limited reimbursement to administer complex analgesic schemes, overestimation of the patient population, and the reluctance of patients to participate in pain research. Additionally, shortcomings in the implemented study design and the need for more logistical investments were identified. Conclusion: The findings of the qualitative study demonstrate the need for further, more varied LNP research in Belgium, not limited to pharmacological studies. It also sheds important light on the recruitment obstacles that may be faced during these studies. Future studies could support this research by offering better proposals for feasibility and recruitment, for instance, by designing and conducting a compelling pilot study or applying social media during the recruitment phase. Clinical Trials. This trial is registered with NCT03348735. EUDRACT number 2018-003617-17.

Audit of a computerized version of the Manchester triage system and a SIRS-based system for the detection of sepsis at triage in the emergency department.

BACKGROUND AND IMPORTANCE: Different triage systems can be used to screen for sepsis and are often incorporated into local electronic health records. Often the design and interface of these digitalizations are not audited, possibly leading to deleterious effects on screening test performance. OBJECTIVE: To audit a digital version of the MTS for detection of sepsis during triage in the ED. DESIGN: A single-center retrospective study SETTINGS AND PARTICIPANTS: Patients (n=29766) presenting to an ED of a tertiary-care center who received formal triage were included. OUTCOME MEASURES AND ANALYSIS: Calculated performance measures included sensitivity, specificity, likelihood ratios, and AUC for the detection of sepsis. Errors in the application of the specific sepsis discriminator of the MTS were recorded. MAIN RESULTS: A total of 189 (0.7%) subjects met the Sepsis-3 criteria, with 47 cases meeting the criteria for septic shock. The MTS had a low sensitivity of 47.6% (95% CI 40.3 to 55.0) for allocating sepsis patients to the correct triage category. However, specificity was high at 99.4% (95% CI 99.3 to 99.5).

Variability in Sperm DNA Fragmentation in Men with Mild/Unexplained Subfertility in a Prospective Longitudinal Intrauterine Insemination Trial.

The biological variability of semen and sperm DNA fragmentation (SDF) parameters in a longitudinal intrauterine insemination (IUI) trial over multiple IUI cycles was investigated. A TUNEL assay was used for SDF testing, both before and after density gradient centrifugation. A significant age effect was observed: while semen parameters deteriorated with advancing age, on average, higher SDF values were observed for older males. There was quite some variability observed for both semen and SDF variables. Using fertile threshold values, three patient categories were distinguished: those with a high SDF in all samples, those with low SDF in all samples and those who fluctuated between high and low during the whole IUI trial. Density gradient centrifugation increases SDF. However, the three patient categories react differently after semen processing. A large percentage of those with high SDF retain their high SDF even after gradient centrifugation. The SDF fluctuaters react with a high SDF after gradient centrifugation. The low SDF category, on the contrary, distributes itself evenly between the three categories after gradient centrifugation. SDF testing after semen processing might be indispensable for therapeutic purposes, probably influencing medical decision-making. In order to isolate fluctuaters, a second SDF testing might be advocated in certain cases. SDF after semen processing is indispensable for therapeutic management.

The LH endocrine profile in gonadotropin-releasing hormone analogue cycles.

Research question: What does the evolution of serum luteinizing hormone (LH) levels look like throughout the follicular phase of cycles in which gonadotrophins and gonadotropin-releasing hormone (GnRH) analogues in the context of ovarian stimulation for assisted reproduction technologies (ART) were used?Design: This was a retrospective, observational cohort study in a tertiary infertility clinic. 1303 patients aged between 18 and 43 years of age were included with a total of 2200 cycles for ART, using GnRH-analogues for pituitary down-regulation stimulated with human menopausal gonadotropin (hMG) or recombinant follicle stimulating hormone (rec-FSH). Follicular evolution of LH during ovarian stimulation in different treatment protocols was modeled as repeated measures.Results: LH evolution showed a significant decrease in antagonist/hMG cycles of 0.17 IU/L per day (95% CI [-0.20, -0.12]) and 0.26 IU/L per day in rec-FSH cycles (95% CI [-0.29, -0.22]). This decrease was significantly stronger in rec-FSH cycles than in hMG cycles (estimated difference of 0.09 IU/L per day, 95% CI [0.04, 0.15]). Short agonist/hMG cycles showed a significant increase in LH of 0.04 IU/L per day (95% CI [0.01, 0.08]), while the increase of 0.01 IU/L per day in cycles with rec-FSH was not significant (95% CI [-0.08, 0.10]).Conclusion: Follicular evolution of LH during controlled ovarian stimulation differs between different GnRH analogue cycles. A statistically significant decrease in LH was shown in GnRH antagonist cycles being more pronounced with rec-FSH compared to hMG. This decrease in LH in antagonist cycles and the potential impact on estradiol levels and follicle growth needs further examination.

SHIFTPLAN: a randomized controlled trial investigating the effects of a multimodal shift-work intervention on drivers' fatigue, sleep, health, and performance parameters.

BACKGROUND: Shift work is commonly associated with health problems resulting from circadian misalignment and sleep restriction. About one in three shift workers is affected by insomnia and up to 90% report regular fatigue and/or sleepiness at the workplace. Epidemiological data shows that shift workers are at increased risk of cardiovascular disease, diabetes, obesity, breast cancer, mental-health problems, and shift-work disorder, which conditions typically lead to reduced work performance, processing errors, accidents at work, absenteeism, and reduced quality of life. Given these widespread and debilitating consequences, there is an urgent need for treatments that help improve the sleep, health, and functional performance of the shift-working population. The most common non-pharmacological recommendations are improved scheduling, bright-light exposure, napping, psychoeducation promoting sleep hygiene, and cognitive-behavioral techniques. The objectives of the present study are to investigate the effects of a multimodal shift-work intervention on perceived fatigue, sleepiness, physical and mental health, sleep parameters, and absenteeism. METHODS: A randomized controlled interventional study comparing the two groups each comprising at least 80 drivers of a public transport company, using self-report questionnaires and health checks completed at intake and after 3 and 6 months following the start of the intervention or waiting-list period. The intervention consists of (a) healthy scheduling taking into account shift-rotation direction and speed, chronotype, resting time, and napping; (b) an education program specifically developed for shift workers; and (c) a dedicated information campaign for shift planners. The primary outcome is symptomatic burden in terms of sleepiness, and the key secondary outcome is symptomatic burden in terms of fatigue. Supplementary secondary outcomes are sleep parameters, absenteeism, general and clinical health, changes in mood, and anxiety. DISCUSSION: Expected outcomes are significant improvements on all primary and secondary outcome parameters in the intervention group. To our knowledge, ours is the first randomized controlled study to systematically investigate the effects of a multimodal program on multiple health, sleep, and performance parameters in shift workers. Our research also aims at providing evidence-based practice guidelines for healthy scheduling in general and thus contribute to diminishing the serious health and economic burdens associated with shift work overall. TRIAL REGISTRATION: EDGE registration number: 000339. CLINICALTRIALS: gov NCT05452096.