The efficacy of a blended intervention to improve physical activity and protein intake for optimal physical recovery after oncological gastrointestinal and lung cancer surgery, the Optimal Physical Recovery After Hospitalization (OPRAH) trial: study protocol for a randomized controlled multicenter trial.

BACKGROUND: Improving physical activity, especially in combination with optimizing protein intake, after surgery has a potential positive effect on recovery of physical functioning in patients after gastrointestinal and lung cancer surgery. The aim of this randomized controlled trial is to evaluate the efficacy of a blended intervention to improve physical activity and protein intake after hospital discharge on recovery of physical functioning in these patients. METHODS: In this multicenter single-blinded randomized controlled trial, 161 adult patients scheduled for elective gastrointestinal or lung cancer surgery will be randomly assigned to the intervention or control group. The purpose of the Optimal Physical Recovery After Hospitalization (OPRAH) intervention is to encourage self-management of patients in their functional recovery, by using a smartphone application and corresponding accelerometer in combination with coaching by a physiotherapist and dietician during three months after hospital discharge. Study outcomes will be measured prior to surgery (baseline) and one, four, eight, and twelve weeks and six months after hospital discharge. The primary outcome is recovery in physical functioning six months after surgery, and the most important secondary outcome is physical activity. Other outcomes include lean body mass, muscle mass, protein intake, symptoms, physical performance, self-reported limitations in activities and participation, self-efficacy, hospital readmissions and adverse events. DISCUSSION: The results of this study will demonstrate whether a blended intervention to support patients increasing their level of physical activity and protein intake after hospital discharge improves recovery in physical functioning in patients after gastrointestinal and lung cancer surgery. TRIAL REGISTRATION: The trial has been registered at the International Clinical Trials Registry Platform at 14-10-2021 with registration number NL9793. Trial registration data are presented in Table 1.

Concordance between culture, Molecular Culture and Illumina 16S rRNA gene amplicon sequencing of bone and ulcer bed biopsies in people with diabetic foot osteomyelitis.

BACKGROUND: In clinical practice the diagnosis of diabetic foot osteomyelitis (DFO) relies on cultures of bone or ulcer bed (UB) biopsies, of which bone biopsy is reference standard. The slow growth or fastidious nature of some bacteria, hamper expeditious detection and identification. Rapid molecular techniques may solve both issues, but their additional value for everyday practice is unknown. We investigated the concordance between conventional culture, the molecular techniques Molecular Culture (MC), and illumina 16S rRNA gene amplicon (16S) sequencing in people with DFO. METHODS: In the BeBoP trial, bone and UB biopsies were obtained from people with DFO who visited Amsterdam UMC. These biopsies were analysed using 1) conventional culture, 2)MC, a rapid broad range PCR analysing the 16S-23S ribosomal-interspace-region, and 3) 16S sequencing, and evaluated concordance among these techniques. RESULTS: We analysed 20 samples (11 bone and 9 UB) of 18 people. A total of 84 infectious agents were identified, 45 (54%) by all techniques, an additional 22 (26.5%, overall 80.5%) by both MC and 16S, and the remaining 16 species by culture and MC or 16S, or by a single method only. MC and 16S identified anaerobes not detected by culturing in 5 samples, and the presence of bacteria in 7 of 8 culture-negative (6 bone, 2 UB) samples. CONCLUSION: The high level of concordance between MC and 16S and the additional ability of molecular techniques to detect various bacteria not detected by culturing opens up prospects for routine use of fast molecular techniques, in clinical settings including DFO. TRIAL REGISTRATION: The BeBoP trial is retrospectively registered on 05-03-2019 in Netherlands Trial Register: NL 7582.

Unique form of catheter malconnection following intrathecal baclofen surgery for spinal cord injury: a case report.

This case report concerns a patient suffering from traumatic spinal cord injury with severe spasticity treated with intrathecal baclofen therapy. After revision surgery for a confirmed catheter obstruction, progressive spasticity reappeared. Diagnostics demonstrated signs of catheter fracture or disconnection adjacent to the pump. During revision surgery, the silicone layer surrounding the sutureless pump connector was shown to be curled up, revealing the cause of dysfunction. As far as we know, this form of malconnection has not been reported before. Therefore, surgeons must be aware of this complication and additional inspection of the silicone connector prior to definite connection is advised.

The association between bacteria and outcome and the influence of sampling method, in people with a diabetic foot infection.

PURPOSE: Different bacteria lead to divers diabetic foot infections (DFIs), and some bacteria probably lead to higher amputation and mortality risks. We assessed mortality and amputation risk in relation to bacterial profiles in people DFI and investigated the role of sampling method. METHODS: We included people (> 18 years) with DFI in this retrospective study (2011-2020) at a Dutch tertiary care hospital. We retrieved cultures according to best sampling method: (1) bone biopsy; (2) ulcer bed biopsy; and (3) swab. We aggregated data into a composite determinant, consisting of unrepeated bacteria of one episode of infection, clustered into 5 profiles: (1) Streptococcus and Staphylococcus aureus; (2) coagulase-negative Staphylococcus, Cutibacterium, Corynebacterium and Enterococcus; (3) gram-negative; (4) Anaerobic; and (5) less common gram-positive bacteria. We calculated Hazard Ratio's (HR's) using time-dependent-Cox regression for the analyses and investigated effect modification by sampling method. RESULTS: We included 139 people, with 447 person-years follow-up and 459 episodes of infection. Sampling method modified the association between bacterial profiles and amputation for profile 2. HR's (95% CI's) for amputation for bacterial profiles 1-5: 0.7 (0.39-1.1); stratified analysis for profile 2: bone biopsy 0.84 (0.26-2.7), ulcer bed biopsy 0.89 (0.34-2.3), swab 5.9*(2.9-11.8); 1.3 (0.78-2.1); 1.6 (0.91-2.6); 1.6 (0.58-4.5). HR's (95% CI's) for mortality for bacterial profiles 1-5: 0.89 (0.49-1.6); 0.73 (0.38-1.4); 2.6*(1.4-4.8); 1.1(0.58-2.2); 0.80(0.19-3.3). CONCLUSIONS: In people with DFI, there was no association between bacterial profiles in ulcer bed and bone biopsies and amputation. Only in swab cultures, low-pathogenic bacteria (profile 2), were associated with a higher amputation risk. Infection with gram-negative bacteria was associated with a higher mortality risk. This study underlined the possible negative outcome of DFI treatment based on swabs cultures.

Self-monitoring of Physical Activity After Hospital Discharge in Patients Who Have Undergone Gastrointestinal or Lung Cancer Surgery: Mixed Methods Feasibility Study.

BACKGROUND: Self-monitoring of physical activity (PA) using an accelerometer is a promising intervention to stimulate PA after hospital discharge. OBJECTIVE: This study aimed to evaluate the feasibility of PA self-monitoring after discharge in patients who have undergone gastrointestinal or lung cancer surgery. METHODS: A mixed methods study was conducted in which 41 patients with cancer scheduled for lobectomy, esophageal resection, or hyperthermic intraperitoneal chemotherapy were included. Preoperatively, patients received an ankle-worn accelerometer and the corresponding mobile health app to familiarize themselves with its use. The use was continued for up to 6 weeks after surgery. Feasibility criteria related to the study procedures, the System Usability Scale, and user experiences were established. In addition, 6 patients were selected to participate in semistructured interviews. RESULTS: The percentage of patients willing to participate in the study (68/90, 76%) and the final participation rate (57/90, 63%) were considered good. The retention rate was acceptable (41/57, 72%), whereas the rate of missing accelerometer data was relatively high (31%). The mean System Usability Scale score was good (77.3). Interviewed patients mentioned that the accelerometer and app were easy to use, motivated them to be more physically active, and provided postdischarge support. The technical shortcomings and comfort of the ankle straps should be improved. CONCLUSIONS: Self-monitoring of PA after discharge appears to be feasible based on good system usability and predominantly positive user experiences in patients with cancer after lobectomy, esophageal resection, or hyperthermic intraperitoneal chemotherapy. Solving technical problems and improving the comfort of the ankle strap may reduce the number of dropouts and missing data in clinical use and follow-up studies.

The effectiveness of physical activity interventions using activity trackers during or after inpatient care: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Promoting physical activity (PA) in patients during and/or after an inpatient stay appears important but challenging. Interventions using activity trackers seem promising to increase PA and enhance recovery of physical functioning. OBJECTIVE: To review the effectiveness of physical activity interventions using activity trackers on improving PA and physical functioning, compared to usual care in patients during and/or after inpatient care. In addition, it was determined whether the following intervention characteristics increase the effectiveness of these interventions: the number of behaviour change techniques (BCTs) used, the use of a theoretical model or the addition of coaching by a health professional. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, EMBASE, Cinahl, SportDiscus and Web of Science databases were searched in March 2020 and updated in March 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized controlled trials (RCTs) including interventions using activity trackers and feedback on PA in adult patients during, or less than 3 months after, hospitalization or inpatient rehabilitation. METHODS: Following database search and title and abstract screening, articles were screened on full text for eligibility and then assessed for risk of bias by using the Physiotherapy Evidence Database (PEDro) scale. Meta-analyses, including subgroup analysis on intervention characteristics, were conducted for the outcomes PA and physical functioning. RESULTS: Overall, 21 RCTs totalling 2355 patients were included. The trials covered a variety of clinical areas. There was considerable heterogeneity between studies. For the 13 studies that measured PA as an outcome variable(N = 1435), a significant small positive effect in favour of the intervention was found (standardized mean difference (SMD) = 0.34; 95%CI 0.12-0.56). For the 13 studies that measured physical functioning as an outcome variable (N = 1415) no significant effect was found (SMD = 0.09; 95%CI -0.02 - 0.19). Effectiveness on PA seems to improve by providing the intervention both during and after the inpatient period and by using a theoretical model, multiple BCTs and coaching by a health professional. CONCLUSION: Interventions using activity trackers during and/or after inpatient care can be effective in increasing the level of PA. However, these improvements did not necessarily translate into improvements in physical functioning. Several intervention characteristics were found to increase the effectiveness of PA interventions. TRIAL REGISTRATION: Registered in PROSPERO ( CRD42020175977 ) on March 23th, 2020.

Facilitators and barriers for the implementation of exercise are medicine in routine clinical care in Dutch university medical centres: a mixed methodology study on clinicians' perceptions.

OBJECTIVES: Despite the many proven advantages of a physically active lifestyle in patient populations, prescription of exercise is currently not widely implemented in routine clinical practice. The aims of this study were twofold: (1) to assess perceptions of clinicians on the current practice of exercise is medicine (E=M) prescription in two Dutch university medical centres and (2) to determine their perceived barriers and facilitators for the implementation of E=M in routine clinical care in Dutch university medical centres. DESIGN: A mixed methodologies study, using both online questionnaires and semi-structured interviews. SETTING: Dutch university medical centres. PARTICIPANTS: Clinicians working within the departments of medical oncology, orthopaedics and rehabilitation medicine of two university medical centres. RESULTS: Forty-five clinicians (response rate of 51%) completed the questionnaire, and 19 clinicians were interviewed. The results showed that even though clinicians had a positive attitude towards prescribing E=M, only a few reported to regularly prescribe E=M to their patients. The 52 identified facilitators and barriers for implementation of E=M were categorised into four main themes: (1) beliefs toward the implementation of E=M (eg, clinicians knowledge and skills, and social support), (2) factors related to the patient perspective (eg, patient priorities or motivation), (3) factors related to the referral options (eg, knowledge of and trust in local referral options) and (4) practical considerations when implementing E=M (eg, time constraints). CONCLUSIONS: Our study showed that even though many clinicians have a positive attitude toward an active lifestyle, many are not prescribing E=M on a regular basis. In order for clinicians to effectively implement E=M, strategies should focus on increasing clinicians E=M referral skills, improving clinicians knowledge of E=M referral options and develop a support system to ensure that E=M is high on the priority list of clinicians.

Using a BonE BiOPsy (BeBoP) to determine the causative agent in persons with diabetes and foot osteomyelitis: study protocol for a multicentre, randomised controlled trial.

BACKGROUND: Diabetic foot osteomyelitis (DFO) poses a major disease burden. It can generally be treated with long-term antibacterial therapy. International guidelines recommend to base antibacterial therapy choices on percutaneous bone biopsy culture, while in practice, therapy is frequently based on (less invasive) ulcer bed cultures. It is currently unknown if treatment outcomes of DFO differ depending on the chosen diagnostic strategy. METHODS: The BeBoP trial is a multicentre; randomised controlled; physician-, researcher- and subject-blinded; clinical trial comparing two diagnostic strategies in persons with DFO. Culture-directed antibacterial therapy will be based on either percutaneous bone biopsy culture results (intervention group) or ulcer bed biopsy culture results (comparison group). We will enrol 80 subjects with diabetes mellitus (≥ 18 years) and DFO, and we will use block randomisation stratified per centre to randomise them in a 1:1 allocation. The primary outcome is remission of DFO 12 months after enrolment. The secondary outcomes are the time to remission, signs of inflammation or ulceration at the primary location of infection at 6 and 12 months, microbiological and molecular profiles of culture outcomes, surgical interventions including amputation, total antibacterial therapy duration, infection-free survival days, adverse events, quality of life and survival. We will compare the outcomes by intention-to-treat and per-protocol analysis. DISCUSSION: We aim to compare clinical remission in persons with DFO treated with antibacterial therapy based on either percutaneous bone biopsy culture results or ulcer bed biopsy culture results. TRIAL REGISTRATION: Netherlands Trial Register NL 7582 . Registered on 05 March 2019.

Fatigue in patients with multiple sclerosis: is it related to pro- and anti-inflammatory cytokines?

OBJECTIVE: To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue. METHODS: Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. RESULTS: Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. CONCLUSION: The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS. TRIAL REGISTRATIONS: ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.

Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform.

A linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody-drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2-expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. The ADC is stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2-positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology.

Polypropylene ankle foot orthoses to overcome drop-foot gait in central neurological patients: a mechanical and functional evaluation.

The aim of this study was to assess the functional effects and mechanical contribution of Ankle Foot Orthoses (AFO) prescribed to overcome drop-foot gait. We hypothesized that poor functional effects of the AFO relate to insufficient mechanical contribution of the AFO during the swing phase, or unwanted constraining of the ankle during the stance phase. In seven patients with Stroke or Multiple Sclerosis, we determined changes in energy cost of walking resulting from wearing an AFO, as a measure of the functional effects. In addition, an instrumented gait analysis was performed, and the mechanical AFO properties were measured, to calculate the mechanical contribution of the AFO. The AFO was sufficiently stiff to effectively support the foot in swing, without hampering the ankle during stance. For the whole group, there was a significant improvement in walking speed and energy cost (12%). However, the AFO had no functional benefit in terms of a reduced energy cost of walking for three patients, who coherently demonstrated no pathological plantar flexion during swing without their AFO. We conclude that functional benefit from the AFO was only found when the mechanical AFO characteristics met the need to support the patients' mechanical deficiencies.