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2.4. General Procedure | During the 3 consecutive study days, participants were instructed to refrain from strenuous physical activity, to consume a standard dinner (100 g chicken, 50 g rice, 50 g white bread and one apple; 503 kcal, 7 g fat, 82 g carbohydrates, 30 g protein) the night before, to fast overnight and to eat a standard breakfast (200 mL coffee with semi-skimmed milk and a 50 g white bread sandwich with 30 g ham and 40 g cheese; 338 kcal, 11 g fat, 38 g carbohydrate, 24 g protein) 4 h before each study. After intubation per nose, the catheter (Flocare Bengmark NI Tube, Nutricia Medical, Hoofddorp, The Netherlands) was positioned into the duodenum under fluoroscopic control. Studies were conducted in a quiet, isolated room. Outcomes were measured 10 min before ingestion of the probe meal (pre-ingestion period), during the ingestion period and during the 60 min after ingestion (postprandial period) ( | PMC10221585 | ||
2.5. Interventions | PMC10221585 | |||
2.5.1. Probe Meal | hummus, digestive sensations | The probe meal consisted of 150 g low-fat hummus (219 Kcal; 12 g fat, 82 g carbohydrates, 13 g protein; Hummus Classic, Ametller Origen, Barcelona, Spain) served at a controlled temperature (20 °C), 20 g toasts (81 Kcal; 0.9 g fat, 15.2 g carbohydrates, 2.4 g protein; Mini Tostas, Bimbo, Barcelona, Spain) and 120 mL water. The probe meal was administered stepwise in 3 equal servings at a fixed rate: every 180 s one meal portion (50 g hummus plus a 6.6 g toast) was presented on a tray; after each serving, participants were allowed 60 s for evaluation of digestive sensations (see below); total ingestion time was 12 min, the water load (120 mL) was ingested ad libitum throughout the ingestion period. On the 1st study day, the original humus preparation (i.e., non-coloured) was served; on the 2nd and 3rd study days (conditioning and post-conditioning experiments, respectively), the humus was coloured by adding 1% fat-soluble, odourless and flavourless pink colourant (Decora, Karma, Salerno, Italy), to modify its appearance, but not its organoleptic characteristics or nutrient composition. The composition and meal load were established based on a series of preliminary feasibility studies. | PMC10221585 | |
2.5.2. Duodenal Infusion | bloating, nausea,, pain | Aversive conditioning (2nd study day in aversive conditioning group only) was produced by infusion of lipids (300 mg/mL purified soybean oil; Intralipid, Fresenius Kabi, Barcelona, Spain) into the duodenum via the nasoduodenal catheter. Lipids were continuously infused starting 3 min before, during and 60 min after ingestion of the probe meal (total infusion time = 75 min) using an infusion pump (Compat Ella Push, Nestle Health Science, Barcelona, Spain) at a rate of 150 mL/h during the first 15 min (3 min pre-ingestion period and 12 min ingestion period) and at 30 mL/h during the 60 min postprandial period (The aversive conditioning procedure (lipid load and delivery rate) was established by a series of preliminary studies in 3 additional participants so that the lipid infusion would induce a negative sensation of digestive well-being (below score −2 on a −5 to +5 scale, see below) without severe nausea, bloating or pain (score ≤ 2 on 0–10 scales; see below). | PMC10221585 | |
2.6. Outcomes | PMC10221585 | |||
2.6.1. Perception of Homeostatic and Hedonic Sensations | nausea, pain, fullness, abdominal bloating | Five 10-cm scales graded from −5 to +5 were used to measure: (a) meal wanting (impossible/eagerly), (b) meal liking (very disagreeable/very agreeable), (c) hunger/satiety (extremely hungry/completely satiated), (d) digestive well-being (extremely unpleasant sensation/extremely pleasant sensation) and (e) mood (negative/positive); three additional 10-cm scales graded from 0 (not at all) to 10 (very much) were used to measure (f) abdominal bloating–fullness, (g) discomfort–pain and (h) nausea. The wanting scale was scored at the presentation of each meal serving (how much would you like to eat this portion) and at the end of the meal (how much would you like to eat another portion). The liking scale was scored after each meal serving (how much did you like eating the previous portion). The rest of the scales were scored: (a) during the pre-ingestion period (10 min before the meal) at 5 min intervals, (b) during meal ingestion, after each meal serving, and (c) during the postprandial period at 5 min intervals during the first 20 min and at 10 min intervals up to 60 min after ingestion ( | PMC10221585 | |
2.6.2. Physiological Parameters | The following physiological parameters were measured at 4 time points: before meal ingestion (baseline) and at the beginning, mid and end of the postprandial observation period (0 min, 30 min and 60 min after ingestion) (Gastric emptying was measured by ultrasonography, as previously described [Changes in abdominal girth from pre-ingesta were measured by a tape measure placed over the umbilicus and the superior edge of the iliac crests [Changes in the position of the diaphragm from the pre-ingestion level were determined at each time point, as previously described [ | PMC10221585 | ||
2.7. Statistical Analysis | Calculations were performed using SPSS Statistics for Windows (Version 25.0, IBM Corp, Armonk, NY, USA). A significance level of 5% (two tails) was used for comparisons. In each group, the means and standard errors of the measured variables were calculated. In each experiment, the effects of the intervention on sensation scores were analysed, measuring the area under the curve normalised for baseline (except for the wanting and liking scores, which were not normalised) as follows: for each observation interval, the area was calculated as duration (min) of the observation interval × normalised score (absolute score—mean premeal score); the area under the curve during ingestion and the postprandial period (expressed as score × min) was calculated as the sum of the area of all observation intervals. In each participant, the effect of the aversive (or sham) stimulus was measured as the difference in the area under the curve on day 2 (duodenal lipids or sham infusion) minus day 1 (pre-conditioning); the effect of conditioning (previous exposure to aversive stimulus) was measured as the difference in day 3 (post-conditioning) minus day 1 (pre-conditioning). Mean values for the test group (lipid infusion) and control group (sham infusion) were calculated, and statistical analyses within groups and between groups were performed. The Shapiro–Wilk test was used to determine the normality of data distribution. Parametric normally distributed data were compared by Student’s All co-authors had access to the study data and reviewed and approved the final manuscript. | PMC10221585 | ||
3. Results | PMC10221585 | |||
3.1. Demographics | Participants were 30.9 ± 2.3 years of age (range 23–49 years), had a 21.3 ± 0.5 kg/m | PMC10221585 | ||
3.2. Responses to the Probe Meal before Conditioning (Study Day 1) | nausea, discomfort/pain | Pre-ingestion. Before the probe meal (baseline fasting period), subjects reported hunger, neutral digestive well-being and positive mood without the sensations of abdominal fullness/bloating, discomfort/pain or nausea (Ingestion phase. All participants ingested the meal at a fixed rate (12 min). Participants found the meal attractive at the initial presentation and liked it (positive meal wanting and meal liking; Postprandial phase. During the postprandial phase, these sensations gradually decayed (No significant differences in the sensations measured before, during and after ingestion were detected between groups. | PMC10221585 | |
3.3. Effect of Aversive Stimulation (Study Day 2 vs. Day 1) | bloating, sensations, nausea, satiety | Pre-ingestion and ingestion phase. The sensations measured before and during meal ingestion on the second study day were not different from those on the first day in both groups (Postprandial phase. In the control group, sham infusion on the second study day did not modify the postprandial experience as compared to the first study day. By contrast, concomitant duodenal lipid infusion in the test group induced a marked change in postprandial sensations, with an increase in satiety and bloating, a decrease in digestive well-being and mood and some degree of abdominal discomfort and nausea ( | PMC10221585 | |
3.4. Effect of Conditioning (Study Day 3 vs. Day 1) | bloating, nausea | Pre-ingestion and ingestion phase. No significant differences were detected in the sensations measured before and during meal ingestion on the study day 3 as compared to day 1 in both groups (Postprandial phase. In the control group, sham conditioning (duodenal sham infusion on the previous day) did not modify the postprandial experience as compared to the first study day. By contrast, in the test group, aversive conditioning (duodenal lipid infusion on the previous day) significantly impaired postprandial well-being, and this was associated with a trend to increase in bloating and mild abdominal discomfort, without changes in satiety, nausea and mood ( | PMC10221585 | |
3.5. Physiological Parameters | PMC10221585 | |||
3.5.1. Responses to the Probe Meal before Conditioning (Study Day 1) | Ingestion of the probe meal was associated with gastric filling (increase in antral cross-sectional area) and abdominal accommodation (elevation of the diaphragm with limited increase in girth) ( | PMC10221585 | ||
3.5.2. Effect of Aversive Stimulation (Study Day 2 vs. Day 1) | gastric retention | GASTRIC RETENTION | In the control group, sham infusion on the second study day had no effects on any of the physiological parameters as compared to the first study day. By contrast, in the test group, lipid infusion (effect measured as the change in the area under the curve in day 2 minus day 1 vs. sham infusion) was associated with gastric retention (more sustained increase in the antral cross-sectional area; | PMC10221585 |
3.5.3. Effect of Conditioning (Study Day 3 vs. Day 1) | Neither aversive nor sham conditioning had consistent effects on the physiological response to meal ingestion ( | PMC10221585 | ||
4. Discussion | digestive dysfunction | Our study shows that pairing a pleasant meal with an experimentally-induced aversive sensation conditions the postprandial response to subsequent consumption of the same meal. Interestingly, aversive conditioning impaired the hedonic experience without significant impacts on homeostatic sensations or the physiological digestive response.The target for conditioning was a comfort probe meal [Aversive conditioning (i.e., previous pairing of the comfort meal with lipid-induced aversive sensation) conditioned the subsequent postprandial response to the same meal, particularly affecting the reward experience. Various mechanisms may be involved in the impairment of the postprandial experience by conditioning.In the first place, a satisfactory postprandial experience depends on a normal response of the digestive system, and conversely, digestive dysfunction deteriorates the postprandial experience [The conditioning paradigm used in the present experiments was analogous to that previously applied for conditioned taste aversion, pairing the rewarding meal with an aversive stimulus [Cognitive-emotive factors and expectations might be involved in conditioning the post-prandial experience. Indeed, a cognitive intervention (education) influenced the hedonic postprandial experience, without significant effects on homeostatic sensations [ | PMC10221585 | |
5. Limitations | Our conditioning paradigm introduced a colour clue (coloured meal during and after conditioning versus non-coloured meal pre-conditioning), but we do not know whether conditioned postprandial dissatisfaction was selective to the colour or if it would also affect the non-coloured meal; indeed, other forms of conditioning express generalisation and affect related stimuli [For this pilot study, a small sample size was included due to the complexity and invasiveness of the study; an interim sample size calculation justified no further inclusion for practical and ethical considerations, but once the concept is proven, a larger study with a less invasive methodology is indicated. Furthermore, only women were included and the effect of conditioning on men remains to be explored.This pilot study, proving a new concept, opens a series of questions, particularly in relation to the specificity versus generalisation of the conditioned response, extinction interval and the relation between aversive stimulus/conditioned response [ | PMC10221585 | ||
6. Conclusions and Inferences | obesity, dyspepsia, functional gut disorders, meal intolerance, diabetes | OBESITY, METABOLIC SYNDROME, HYPERCHOLESTEROLEMIA, DIABETES | Postprandial conditioning might have important implications and open relevant research avenues. Several conditions of great health impact, such as obesity, metabolic syndrome, diabetes or hypercholesterolemia, relate to consumption (or overconsumption) of specific foods, and in this context, aversive conditioning could be a tool to promote an avoidance behaviour.The proof of aversive conditioning sustains the hypothesis of reward conditioning. If feasible, reinforcement of the postprandial reward and food valence could be applied to counteract natural neophobia (i.e., rejection of new or unknown foods) in children [Patients with functional gut disorders, particularly with functional dyspepsia, complain of postprandial symptoms in the absence of a detectable cause and constitute about half of gastrointestinal consultations. Aversive food conditioning might be a mechanism of meal intolerance in these patients. Based on the present data, it could be speculated that an analogous technique could be applied to deconstruct aversive conditioning in these patients [ | PMC10221585 |
Author Contributions | A.N.: investigation, data curation, formal analysis, methodology, D.M.L.: conceptualisation (supporting), formal analysis (lead), investigation, methodology, visualisation, writing—draft preparation, F.A.: conceptualisation (lead), funding acquisition, methodology (lead), project administration, writing—review and editing. All authors have read and agreed to the published version of the manuscript. | PMC10221585 | ||
Institutional Review Board Statement | The clinical study was conducted according to the Declaration of Helsinki. The study protocol had previously been approved by the Institutional Review Board of the University Hospital Vall d’Hebron (Comitè d’Ètica d’Investigació Clinica, Vall d’Hebron Institut de Recerca; protocol number PR(AG)338/2016M approved 28 October 2016, revised 11 December 2020) and all participants provided written informed consent. The study protocol was registered with | PMC10221585 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10221585 | ||
Data Availability Statement | The data presented in this study will be shared upon reasonable request from the corresponding author. | PMC10221585 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10221585 | ||
References | DAY 3).Homeostatic sensations, nausea | BLIND, DELAYED GASTRIC EMPTYING | Experimental design and procedure. In a sham-controlled, parallel, randomised, blind study, a comfort meal was paired with duodenal lipid infusion to induce aversive conditioning (DAY 2) and the responses to the meal were compared before (DAY 1) and after conditioning (DAY 3).Homeostatic sensations. Concomitant duodenal lipid infusion on day 2 impaired the postprandial response and the effect was significant for abdominal discomfort and nausea (effect measured as the change in the area under the curve on day 2 minus day 1; * Hedonic sensations. Concomitant duodenal lipid infusion on day 2 impaired the postprandial response and the effect was significant for digestive well-being (effect measured as the change in the area under the curve on day 2 minus day 1; * Reward value during meal ingestion. The comfort meal was served in 3 portions; meal wanting was measured before each serving and at the end of ingestion; meal liking was measured after each serving. On day 2, concomitant duodenal lipid infusion impaired the ingestive response (effect measured as the change in the area under the curve on day 2 minus day 1 vs. sham infusion; * Digestive response to meal ingestion. On day 2, duodenal lipid infusion in the test group was associated with a sustained increase in antral cross-sectional area (delayed gastric emptying; * | PMC10221585 |
Introduction and hypothesis | SUI | STRESS URINARY INCONTINENCE | The purpose was to investigate the safety and feasibility of transurethral injections of autologous muscle precursor cells (MPCs) into the external urinary sphincter (EUS) to treat stress urinary incontinence (SUI) in female patients. | PMC10506953 |
Methods | ADVERSE EVENTS, PAD, INCONTINENCE | Prospective and randomised phase I clinical trial. Standardised 1-h pad test, International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF), urodynamic study, and MRI of the pelvis were performed at baseline and 6 months after treatment. MPCs gained through open muscle biopsy were transported to a GMP facility for processing and cell expansion. The final product was injected into the EUS via a transurethral ultrasound-guided route. Primary outcomes were defined as any adverse events (AEs) during follow-up. Secondary outcomes were functional, questionnaire, and radiological results. | PMC10506953 | |
Results | SUI, dysuria | URINARY TRACT INFECTION | Ten female patients with SUI grades I–II were included in the study and 9 received treatment. Out of 8 AEs, 3 (37.5%) were potentially related to treatment and treated conservatively: 1 urinary tract infection healed with antibiotics treatment, 1 dysuria and 1 discomfort at biopsy site. Functional urethral length under stress was 25 mm at baseline compared with 30 mm at 6 months’ follow-up ( | PMC10506953 |
Conclusion | Transurethral injections of autologous MPCs into the EUS for treatment of SUI in female patients can be regarded as safe and feasible. Only a minimal number of expected and easily treatable AEs were documented. | PMC10506953 | ||
Keywords | Open access funding provided by University of Zurich | PMC10506953 | ||
Introduction | urinary incontinence | URINARY INCONTINENCE | More than 400 million people worldwide suffer from urinary incontinence (UI), whereas the ratio between women and men is three to one [ | PMC10506953 |
Patients and methods | PB_2017-00621) and Swissmedic (Ref. | We conducted a prospective and randomised phase I clinical trial using ultrasound-guided injections of autologous MPCs into the EUS. The aim of the study was to assess the safety and feasibility of this autologous cell therapy for the treatment of SUI in female patients. The local ethics committee (KEK-ZH-Nr. 2014-0547, BASEC Nr. PB_2017-00621) and Swissmedic (Ref. Nr. 2014TpP1009) both approved the phase I study, and the trial was registered on | PMC10506953 | |
Patient recruitment | RECRUITMENT | Initial recruitment was accomplished by specialist referral, online advertisements (study website | PMC10506953 | |
Inclusion and exclusion criteria | neurological disease, incontinence, cystocele, prolapse, enuresis, DSD, fistula, urogenital cancer, acontractile detrusor, hypersensitivity, congenital abnormality | NEUROLOGICAL DISEASE, INCONTINENCE, URETHRAL STENOSIS, URINARY TRACT DISEASES, CYSTOCELE, PROLAPSE, ENURESIS, INCONTINENCE, PAD, MUSCULAR DISEASE, HYPERSENSITIVITY, DETRUSOR INSTABILITY | The main inclusion criteria were: female gender; age 20–60 years; a clinical diagnosis of SUI grade ≥I according to the Stamey classification for at least 6 months; and post-void residual (PVR) <100 ml.The main exclusion criteria were: a history of anti-incontinence or prolapse surgery; a previous diagnosis of urinary tract diseases (cystocele, fistula, congenital abnormality or interstitial cystitis); UUI; adult enuresis; urodynamically proven detrusor instability or detrusor–sphincter–dyssynergia (DSD); hyposensitive and/or acontractile detrusor; urethral stenosis; a history of urogenital cancer or pelvic radiotherapy; pregnancy or <12 months postpartum; and unstable systemic, neurological disease or genetically determined muscular disease.Objective and subjective assessments were performed during the screening (baseline) visit to guarantee that the female patients met the strict inclusion and exclusion criteria. The screening visit included the acquisition of personal medical history, physical examination, vital signs, blood tests, pregnancy test, hypersensitivity test to the injection solution (subcutaneous injection), uroflowmetry, ultrasound of the bladder (including measurement of the PVR) and the kidneys, 1-h pad test, incontinence questionnaire (International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form [ICIQ-UI-SF]), urodynamic study and magnetic resonance imaging (MRI) of the pelvis. | PMC10506953 |
One-hour pad test | Continence | PAD | The testing protocol was accomplished according to the standardised International Continence Society 1-h pad test [ | PMC10506953 |
Urodynamic study | Continence | URETHRA | The urodynamic study was performed according to the International Continence Society (ICS) standards. To conduct urodynamic investigations, a multichannel urodynamic system (Laborie Medical Technologies Corp., Toronto, Canada) was used. Patients were assessed in a sitting position. UDI comprised same-session repeat filling cystometry, pressure flow study and a resting as well as a stress urethra pressure profile. The bladder was filled with a body-temperature (36°C) 0.9% sodium chloride solution at a speed of 20–30 ml per minute. For simultaneous measurements of vesical and abdominal pressure a 7-French transurethral and rectal latex-free, single-use catheter (T-DOC®, Air-Charged Dual and Abdominal catheter, Laborie Medical Technologies Corp., Toronto, Canada) was used. For the UPP measurement the bladder was prefilled with 150 ml and the catheter was withdrawn by a mechanical device at a rate of 1 mm/s. The urethral closure pressure (UCP) profile, the maximum urethral pressure (MUP), the maximum urethral closure pressure (MUCP) and the functional urethra length (FUL) were obtained from the UPP. | PMC10506953 |
Magnetic resonance imaging of the pelvis | tumour, necrosis | TUMOUR, NECROSIS | Magnetic resonance imaging of the pelvis was performed at a field strength of 3 Tesla (Siemens MAGNETOM Skyra, Siemens Healthineers, Erlangen, Germany) using standard high-resolution T2-weighted turbo spin echo sequences with and without fat suppression and T1-weighted turbo spin echo sequences. An 18 Ch body coil was used for signal reception. The longest diameter of the sphincter muscle was measured on pre- and post-therapeutic examinations and all examinations were screened for possible areas of necrosis or tumour. | PMC10506953 |
Muscle biopsy | To obtain an appropriate muscle specimen for MPC isolation and expansion, an open surgical biopsy coming from a striated skeletal muscle was performed in analgosedation on either the left or the right lower leg in each of the patients. After weighing the muscle biopsy in a cooled Falcon tube containing biopsy medium, it was sent to the good manufacturing practice (GMP) facility. | PMC10506953 | ||
Cell isolation, expansion and final product | Manufacturing of the MPCs was performed according to GMP standards in the clean room facility of the Wyss Translational Center Zurich (manufacturer authorisation number 512701-102673231). The manufacturing process consisted of MPC isolation, MPC expansion and final product preparation, including strict in-process and product release controls. With confirmed compliance, 80–100 × 10 | PMC10506953 | ||
Injection of MPCs | URETHRA | The injection was performed according to a standardised procedure under general anaesthesia and in full lithotomy position. Before starting the operation, the batch number from the GMP facility was double-checked with the patient’s study ID. After insertion of a vaginal ultrasound probe (BK Medical®, Endocavity 3D 8838) the anatomy was assessed, and the EUS identified. Then, a transurethral catheter (Rüsch®, SupraCath Silicone Ch10) was inserted. The implantation of the cooled final product (autologous MPCs) was performed through transurethral injections under ultrasound guidance into the horseshoe-configured anterior and anterolateral muscle tissue of the EUS, surrounding the proximal part of the urethra. At the end of the procedure, all devices were removed except for the indwelling catheter. | PMC10506953 | |
Follow-up visits | The first follow-up visit was on the first postoperative day. After removal of the catheter in the morning, patients were seen for a physical examination, uroflowmetry and ultrasound including PVR measurement. Further visits in the ambulatory setting were arranged 1, 3 and 6 months after the intervention. The follow-up visit at 6 months was composed of an additional urodynamic study and MRI of the pelvis as a comparison with the baseline visit. | PMC10506953 | ||
Neuromuscular electromagnetic stimulation | SUI, pain | After the injection, the study nurse unveiled the 1:1 randomisation to the two treatment groups of either MPC vs MPC + NMES. NMES included two sessions per week for 20 min for 6 weeks with a total of 12 sessions on a BioCon-2000W™ chair (Marly Products®, Germany). Patients used its predefined program for SUI and the percentage of intensity was individually ramped up to the subjective pain threshold as instructed by the study doctors. | PMC10506953 | |
Primary and secondary outcomes | incontinence, necrosis | NECROSIS, INCONTINENCE, ABERRANT TISSUE, PAD, ADVERSE EVENT, LEAKAGE, URETHRA | To analyse the safety and feasibility of our therapy, primary outcomes were defined as any adverse event (AE) during the follow-up period. AEs were classified according to Clavien–Dindo grade I–V. Secondary outcomes were chosen as objective and subjective outcome parameters. Objective parameters were uroflowmetry, PVR and the 1-h pad test. Further, the results from the urodynamic study included maximal bladder capacity, bladder compliance, presence and amount of leakage, maximal urethral closure pressure (MUCP) and functional urethra length (FUL) at rest and under stress (continuous coughing). Subjective parameters were patient-reported outcomes (PROMs) as in the evaluation of the filled-in questionnaires (ICIQ-UI-SF [0–21 points] including amount of pad usage per day, Visual Analogue Scale [VAS 0–10 points] for degree of suffering and quality of life) and necessity of subsequent incontinence surgery during follow-up. Anatomical aspects (aberrant tissue or necrosis formation) and the diameter of the EUS were measured before treatment and at EOS on the MRI of the pelvis in every patient. | PMC10506953 |
Statistical analysis | The statistical analysis was outsourced to an independent company (Hemex AG, Liestal, Switzerland) and performed using | PMC10506953 | ||
Results | STERILITY | Ten female patients were included in the study, 9 of whom received treatment and completed all follow-up visits during the study period between January 2020 and September 2021. One patient had to be excluded in between muscle biopsy and injection owing to an erroneous interpretation of a supposedly contaminated sterility test of the cell product by an external laboratory. The test was later repeated, and the sterility of the cell product was confirmed retrospectively. | PMC10506953 | |
Functional outcome parameters | No relevant PVR (<50ml) was documented with sonography at baseline and follow-up visits in all patients. Median MUCP at rest decreased from 91 cmHBaseline and follow-up visits compared. | PMC10506953 | ||
Pad use | PAD | At baseline, 2 patients reported using no pads during daily routine, whereas 6 patients reported using 1 pad/day, and 1 patient using 2 pads/day. At the 6-month follow-up, 1 out of the 6 patients who needed 1 pad/day reported no longer needing any pads, 5 patients still used 1 pad/day, and the patient who needed 2 pads/day had reduced to 1 pad/day 6 months after MPC treatment. Three patients had a positive 1-h pad test and lost urine at baseline visit (range: +1 to +6 g, median: +3 g), whereas pads stayed dry in all other patients. At follow-up, the 1-h pad test was positive in 1 patient (+3 g at baseline and +1 g at follow-up), whereas no increase in pad weight was found in the rest of the cohort. | PMC10506953 | |
ICIQ-UI-SF questionnaires | The ICIQ-UI-SF questionnaires showed a statistically significant improvement in scores from a median of 7 points at baseline to a median of 4 points at 6 months’ follow-up (difference: −3 points, 95% CI: −7 to −2.5, | PMC10506953 | ||
MRI of the pelvis | tumour, necrosis | ABERRANT TISSUE, TUMOUR, NECROSIS | The evaluation of MRI of the pelvis revealed no evidence of aberrant tissue formation (i.e. tumour) or necrosis. The diameter of the EUS was measured with a statistically significantly larger median of 1.8 mm at baseline and 1.9 mm at follow-up (difference: +0.1 mm, 95% CI: 0.10 to 0.25, MRI of the pelvis with a T2-weighted sequence in axial and sagittal orientation for the anatomical analysis of the external urinary sphincter ( | PMC10506953 |
Discussion | tumour, necrosis | PAD, TUMOUR, COMPLICATIONS, NECROSIS | Our phase I clinical trial demonstrates that the implantation of autologous MPCs in combination with or without NMES for the treatment of SUI grade ≥I in women is safe and feasible. Therapy was well tolerated by patients and no relevant or unexpected AEs and no need for consecutive surgical or interventional treatments were documented (all complications Clavien–Dindo grade ≤II). Further, our analysis demonstrated an objective improvement of the median FUL under stress in the urodynamic study 6 months after injection of autologous MPCs into the EUS. In addition, PROMs evaluated by questionnaires improved with a lower median ICIQ-UI-SF score at 6 months after the intervention, suggesting a better quality of life in these patients. All patients with a positive 1-h pad test at baseline improved at follow-up with 2 out of 3 patients being completely dry. Finally, the analysis of the MRI of the pelvis revealed an increase in EUS diameter. Most importantly, no evidence of cell transformation (i.e. tumour tissue or necrosis) at the end of follow-up was found radiologically. The decrease in MUCP and FUL values at rest comparing from before with after treatment was not statistically significant. However, all results need to be further elucidated in larger patient cohorts during prospective phase II and III trials. To investigate the overall regenerative potential of this approach, patients are further included in a long-term follow-up study for the analysis of safety and efficacy up to 5 years after treatment.For more than two decades, there has been an immense research effort to ameliorate the treatment of SUI with a regenerative approach [Results from studies investigating other therapy approaches with transurethral injections of autologous MDSCs have shown them to be safe and feasible without any relevant AEs or SAEs. Dose-ranging studies using MDSCs (1–200 million cells) by Chancellor and his group [It is worth mentioning that different muscle-derived cell populations have shown a potentially different impact on functional regeneration and their modes of action—some through paracrine effects, others through direct integration into the damaged tissue. Importantly, the main therapeutic effect in our patient population is achieved by MPC-induced muscle regeneration of the EUS. The additional usage of NMES may be a potential advantage for an ameliorated functional outcome owing to additional growth stimulation through training of the pelvic musculature. However, a subgroup analysis to investigate the therapeutic effect of MPC + NMES vs MPC alone was not feasible in the underlying study owing to limited patient numbers. Altogether, all these results underline the potential of a regenerative therapy approach to the treatment of SUI in women.Our functional results need to be interpreted with caution as this was a phase I trial investigating solely safety and feasibility. Owing to the limited number of patients and the associated lack of statistical power, no subgroup analysis regarding the randomisation into MPC vs MPC + NMES was performed. Further, only 3 out of 9 patients had a positive 1-h pad test at baseline. Therefore, the efficacy and durability of the treatment need to be confirmed with larger patient cohorts and longer follow-up periods in specifically designed, accordingly powered and prospectively performed phase II and III trials. | PMC10506953 |
Conclusion | SEQUELAE | The transurethral ultrasound-guided injection of autologous MPCs into the EUS for the treatment of SUI in female patients can be regarded as safe and feasible. Only a minimal number of expected AEs were documented, and all AEs were easily treatable and healed without sequelae. No severe or unexpected AEs were diagnosed. At the same time, promising overall functional and anatomical outcomes, as well as quality of life measurements, were found. | PMC10506953 | |
Acknowledgements | We thank Prof. Dr. K. Schallmoser (Paracelsus Medical University, Salzburg, Austria) and Prof. Dr. W. Aicher (University of Tübingen, Germany) for material supply and monitoring during the study. We thank the Wyss Translation Center Zurich for the usage of their clean rooms and their support while conducting the trial. | PMC10506953 | ||
Authors’ contributions | protocol/project | F.A.S.: protocol/project development, data collection and management, data analysis, manuscript writing and editing; J.A.P: protocol/project development, data collection and management, data analysis, manuscript writing and editing; M.K.: data collection, data analysis, manuscript editing; C.B.: data collection, manuscript editing; R.A.S: data collection; N.S.: data collection; M.H.: data collection; F.L.: data collection; M.V.: data management, data analysis, manuscript editing; R.G.: protocol development, manuscript editing; A.L.: data collection and management, data analysis, manuscript writing; A.M.H.: data collection, data analysis, manuscript editing; A.B.: project development, data analysis, manuscript editing; D.M.H.: protocol/project development, data analysis, manuscript editing; D.E.: protocol/project development, data collection, data analysis, manuscript editing. | PMC10506953 | |
Funding | Open access funding provided by University of Zurich This project has received funding from the European Union‘s Horizon 2020 research and innovation program under grant agreement No. 731377. | PMC10506953 | ||
Declarations | PMC10506953 | |||
Conflicts of interest | F.A.S., M.K., C.B., R.A.S., N.S., M.H., F.L., M.V., R.G., A.L., A.M.H., A.B.: none. The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: J.A.P., D.M.H. and D.E. own stocks in the company MUVON Therapeutics AG, aimed at further developing MPC therapy towards a commercial product. No company employees were involved in conducting the study or analysis of the presented study. Besides that, no other relation, benefit, potential conflict must be reported in the context of this study. All other authors declare that the research presented in this study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10506953 | ||
References | PMC10506953 | |||
Methods | NAFLD, liver stiffness, cirrhosis, virologically-suppressed HIV-1 | LIVER FIBROSIS, CIRRHOSIS, RECRUITMENT | We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores. | PMC10348519 |
Results | ADVERSE REACTION, TYPE 2 DIABETES MELLITUS | Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6–7.8) kPa, 325 (IQR 279–351) dB/m and 9.1 (IQR 8.6–9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores | PMC10348519 | |
Conclusions | hepatic steatosis, fibrosis | RECRUITMENT, HEPATIC STEATOSIS, FIBROSIS | This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis. | PMC10348519 |
Data Availability | Data are available within the publicly accessible University of Sussex Figshare DOI | PMC10348519 | ||
Introduction | NAFLD, inflammation, MVC, fibrosis | INFLAMMATION, SECONDARY, FIBROSIS, NON-ALCOHOLIC FATTY LIVER DISEASE | Non-alcoholic fatty liver disease (NAFLD), defined as fat accumulation in ≥5% of hepatocytes without a secondary cause, [Lifestyle changes, including physical activity and dietary modification, are the mainstay of therapy [Chemokine (C-C motif) ligand 5 (CCL5)/ Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES), the ligand for C-C chemokine receptor type 5 (CCR5), plays a key role in hepatic inflammation. CCR5 mediates intrahepatic immune cell interactions which promote activation and migration of Kupffer cells and hepatic stellate cells; these in turn promote inflammation and fibrosis [The CCR5 receptor antagonist, maraviroc (MVC), is licensed for HIV-1 treatment as part of combination antiretroviral therapy (cART) in therapy-naïve and -experienced individuals, where the infecting strain is CCR5 tropic [MVC therefore represents a potential treatment for HIV-NAFLD. However, dosing is usually twice daily, unlike currently recommended antiretrovirals. We therefore aimed to conduct a RCT to evaluate the safety, acceptability and feasibility of MVC add-on therapy to cART in HIV-NAFLD in preparation for conducting a larger RCT in the future. The RCT was successfully completed and findings are presented below. | PMC10348519 |
Materials and methods | PMC10348519 | |||
Study design and participants | WEST | This was a phase IV, open-label, dual, parallel arm, randomised, multi-centre, feasibility trial comparing MVC plus optimised background therapy (MVC+OBT) versus OBT alone in HIV-NAFLD over 96 weeks. The sites were hospitals in London (Barts, Chelsea and Westminster), the Midlands (Nottingham), North (Liverpool, South Tees), South (Brighton) and West (Bristol) of England.Potentially eligible individuals were identified by members of the direct care team through review of clinic databases, pre-identification of those attending routine consultations and review of medical notes during follow-up. Anonymised information collected on individuals contacted but not randomised were age, gender, ethnicity, reason for lack of eligibility or if they were potentially eligible but declined.Detailed methodology has been presented previously [ | PMC10348519 | |
Randomisation | Participants were randomised 1:1 in accordance with a computer-generated randomization schedule using Sealed Envelope [ | PMC10348519 | ||
Procedures | NAFLD, AIDS toxicity | INFECTIOUS DISEASES, ADVERSE EVENT, ALLERGY, LIVER FIBROSIS, CHRONIC LIVER DISEASE | MVC was prescribed twice daily at the licensed dose for HIV-1 therapy, adjusted according to co-medications according to the Summary of Product Characteristics. Participants attended every 24 weeks for 96 weeks plus a week 4 safety visit for those receiving maraviroc. All participants received advice on lifestyle and dietary modifications as standard of care interventions for HIV-NAFLD. Supplementary Table S1 in In brief, the screening visit included history-taking, physical examination, height and weight measurement, laboratory investigations for eligibility, ECG, LSM and Controlled Attenuation Parameter (CAP) score measured by Fibroscan, and hepatic ultrasound scan. Fibroscan readings, HbA1c, CD4 T-lymphocyte count, and VL from screening were used as the baseline measures. This visit was performed by the site investigator or sub-investigator, who also confirmed eligibility. The baseline assessment included diet and exercise history, fasting bloods for glucose and lipids, Enhanced Liver Fibrosis (ELF) score and proviral DNA co-receptor tropism. There was an optional CT scan liver and spleen, and this was only offered at one site. Participants additionally completed questionnaires to evaluate quality of life (QoL): chronic liver disease questionnaire for NAFLD (CLDQ-NAFLD) [Assessments performed each 24 weeks were review of symptoms and Adverse Events (AE), examination, weight, VL, full blood count, routine serum chemistries and urinalysis. Additional assessments performed every 48 weeks were diet and exercise history, questionnaire completion, CD4 count, fasting glucose and lipids, HbA1c, ELF score, Fibroscan. An optional CT scan of liver and spleen was performed at 96 weeks. Self-reported adherence noted on diary cards and pill counts by the pharmacist of returned MVC doses were recorded every visit. AE severity and laboratory abnormalities was assessed using the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity grading scale [The first participant was enrolled on 24/07/18 and the final participant completed the last study assessment on 08/11/21. | PMC10348519 |
Outcome measures | ADVERSE REACTION, RECRUITMENT | The primary objective was to assess the safety, feasibility and acceptability of adding MVC to OBT in HIV-NAFLD. This was assessed through the following outcome measures and minimum target values to indicate feasibility: (1) proportion of eligible individuals who were recruited [target >50%] (2) monthly recruitment rate [>2 individuals per month] (3) retention rate [>65%] (4) proportion of participants with missing data [<80%] (5) proportion of participants with Adverse Reactions (AR) [<10%], which represents the rate observed for a potential alternative agent for treatment of HIV-NAFLD [Secondary outcome measures were: (1) ELF score (2) LSM (3) CAP (4) fasting lipids (5) fasting glucose (6) HbA1c (7) ALT (8) BMI (9) waist circumference (10) CD4 count (11) VL (12) change in the % with a CT liver: spleen attenuation ratio of <1.0 (13) questionnaire-assessed QoL. | PMC10348519 | |
Analyses | PMC10348519 | |||
Sample size | fibrosis | EVENT, FIBROSIS, CHRONIC LIVER DISEASE | This was a pilot study evaluating feasibility, with the intention that results would be used to estimate the variability of the treatment effect of MVC on the ELF score. This in turn would inform the sample size calculation for an RCT to evaluate drug efficacy. We based our sample size justification for this pilot study on change in ELF score. In a previous longitudinal study in people with chronic liver disease, a unit increase of 1 in the ELF score was associated with a 2.5-fold increased risk of a liver-related event, adjusted for age and stage of fibrosis. A unit increase of 1 was therefore considered a clinically important entity [ | PMC10348519 |
Statistical analyses | SECONDARY, RECRUITMENT | Reasons for screen failures are summarised in the CONSORT flowchart, according to the 2010 Statement extension to pilot and feasibility studies [Primary outcome measures are presented with 95% CI for the following measures, at 48 and 96 weeks: participant retention, the proportion of individuals for whom data are missing, the proportion of individuals with ARs and the level of self-reported adherence to MVC. The latter was calculated by (a) the proportion of study medication dispensed that was returned at the final study visit (b) the mean number of doses taken that were prescribed. The proportion of eligible individuals approached who were successfully recruited with 95% CI, and the monthly recruitment rate, are also presented.For each secondary outcome, we estimated the difference in means between groups from baseline to 48 and to 96 weeks and the 95% CI around these differences [ | PMC10348519 | |
Ethics | This study was approved by the London Dulwich Research Ethics Committee (Reference 17/LO/2093). The authors did not have access to information that could identify individual participants during or after data collection. Study data will be made available on reasonable request to the Brighton & Sussex Clinical Trials Unit. The trial was registered on the ISRCTN Registry, registration number 31461655 | PMC10348519 | ||
Results | PMC10348519 | |||
Participant flow | Eighty individuals were referred for screening, 21 (26%) and 6 (8%) of whom were excluded prior to and following attendance at the formal eligibility assessment, respectively. The remaining 53 (66%) individuals entered the randomized treatment portion of the trial and were included in analyses; 23 (43%) and 30 (57%) were allocated to MVC+OBT and OBT, respectively. The flowchart and reasons for participant exclusion are shown in | PMC10348519 | ||
CONSORT flow diagram. | PMC10348519 | |||
Baseline characteristics | Baseline demographic and clinical characteristics were broadly similar across groups ( | PMC10348519 | ||
Participant baseline characteristics. | liver stiffness | *Tropism testing from HIV proviral DNA sequencing was successful for 39/53 (74%)cART combination antiretroviral therapy, CAP controlled attenuation parameter, INSTI integrase strand transfer inhibitor, LS liver stiffness, MVC maraviroc, NNRTI Non-nucleoside reverse transcriptase inhibitor, OBT optimised background therapy, PI protease inhibitor, TAF tenofovir alafenamide | PMC10348519 | |
Completion of assessments | All mandatory 48 and 96 week clinical assessments were completed by 41 (77%) and 39 (74%) participants, respectively. At 48 / 96 weeks, CLDQ-NAFLD, SF36 and WPAI: SHIP questionnaires were completed by 45 (85%) / 44 (83%), 43 (81%) / 43 (81%) and 25 (47%) / 25 (47%) participants, respectively. The incompletely answered questions for WPAI: SHIP were related to work productivity. For optional CT scans, only seven (13%) participants, all in one site, undertook paired scans. Therefore, this analysis was excluded from the main results and is presented in Supplementary Table S2 ( | PMC10348519 | ||
Primary outcome measures–assessment of progression criteria against predefined targets | ADVERSE REACTION, RECRUITMENT | All individuals considered eligible after screening consented to participate, exceeding the target of 50%. The average recruitment rate was 2.9 per month over 18 months, exceeding the target of 2 per month. Participant retention was 45/53 (85%, 95% CI (72%, 93%)) and 44/53 (83%, 95%CI (70%, 92%)) by weeks 48 and 96, respectively, exceeding the target of 65%. At weeks 48 / 96, data completeness was 94% / 96% respectively, exceeding the target of 80%. There were no Serious Adverse Reactions, with 5/23 (22%, 95% CI (5%, 49%)) participants reporting AR by week 48 and no new AR by week 96 ( | PMC10348519 | |
Adverse Reactions (AR) to maraviroc. | ADVERSE REACTION | AR Adverse Reaction, BL baseline visit, MVC maraviroc | PMC10348519 | |
Adverse events | ideation, vomiting, SAEs, gastro-oesophageal reflux disease, urinary retention | GASTRO-OESOPHAGEAL REFLUX DISEASE, BENIGN PROSTATIC HYPERPLASIA, COVID-19 PNEUMONIA, DEGENERATIVE, COMMUNITY ACQUIRED PNEUMONIA, LISTERIA MENINGITIS | Two SAEs were observed in the MVC+OBT group (community acquired pneumonia and gastro-oesophageal reflux disease with vomiting) and four in the OBT group (fatal COVID-19 pneumonia, urinary retention from benign prostatic hyperplasia, suicidal ideation, listeria meningitis). One SAE was observed in a participant prior to randomisation (spinal degenerative disease)There were 71 AEs (3.1 per participant) and 62 AEs (2.1 per participant) in the MVC+OBT and OBT groups, respectively (Supplementary Table S3 in | PMC10348519 |
Difference in change from baseline in metabolic and liver parameters for the maraviroc + OBT versus OBT group with bootstrapped 95% confidence intervals. | LCL, lower confidence limit; UCL upper confidence limitSupplementary Table S4 in For QoL outcomes, comparing change from baseline through weeks 48 and 96 between treatment groups, 95% CI were wide indicating imprecise estimation of between-group differences. In all cases, 95% CI included zero, consistent with there being no detectable between-group differences ( | PMC10348519 | ||
Difference in change from baseline in quality of life outcomes for the maraviroc + OBT versus OBT group with bootstrapped 95% confidence intervals. | NAFLD | CHRONIC LIVER DISEASE | LCL, lower confidence interval, UCL upper confidence intervalCLDQ-NAFLD Chronic Liver Disease Questionnaire for NAFLD, SF36 36-item Short Form Survey, WPAI:SHP Work Productivity and Activity Impairment: Specific Health Problem | PMC10348519 |
Protocol deviations | There were 263 protocol deviations due to missing a study assessment (96, 37%); COVID-19 pandemic related factors resulting in assessments out of window (67, 25%); assessment out of window for other reasons (46, 17%); scheduling of the whole visit out of window (36, 14%); other reason (wrong stratification, incorrect randomisation number, missing data, IMP dispensing, incorrect eligibility assessment) (18, 7%). | PMC10348519 | ||
Discussion | NAFLD, non-AIDS-defining disease, PWH, inflammation, cirrhosis, fibrosis, TG | ADVERSE REACTIONS, INFLAMMATION, CIRRHOSIS, FIBROSIS, ADVERSE REACTION | These data provide preliminary evidence that add-on maraviroc as therapy for NAFLD without cirrhosis in PWH on effective cART may be safe, acceptable and feasible. We recruited ~90% of our target of 60 individuals, and, of those referred for possible participation, 66% were randomised, including all who met eligibility criteria at screen. Participant retention until week 96 was acceptable, achieving ~80%, despite the unprecedented circumstances of the SARS-CoV-2 pandemic. Adherence to maraviroc, taken twice daily by almost all participants, was high (>90%). The adverse reaction rate of 22% was numerically greater than the 10% pre-selected target; however, this figure fell within the 95% CI around 22% of 5%-49% indicating the uncertainty as to whether or not there was an increase in AR compared to the target. Taken in conjunction with findings that all adverse reactions resolved, including in the 9% who discontinued maraviroc, and that there were no serious adverse reactions, no clear evidence of a significant safety concern was identified It was notable that blip rates were numerically greater in the MVC+OBT versus OBT arms (22% versus 10%), but if baseline visit blips were excluded, these became 13% and 7% respectively. Although this remained higher in the MVC+OBT group, both rates are comparable to that seen in the clinic population for one of the participating sites with available published data (~10%) [We observed differences in the changes of two participant characteristics during follow up between the two treatment groups. ALT and LSM scores improved in the MVC+OBT but worsened in the OBT group over 96 weeks. CAP scores declined in both groups but by a numerically greater level in the MVC+OBT group. These findings raise the possibility of an improvement in liver fat and fibrosis. However, the 95% CI for the differences contained zero so were consistent with there being no detectable differences, and the trial was not powered to evaluate for differences in these characteristics. A future RCT of add-on maraviroc with a larger sample size should assess for any differences in these outcomes.There was a high level (>80%) of completion of questionnaires to assess QoL outcomes for CLDQ-NAFLD and SF36, but <50% completion for WPAI:SHIP. This was related to lack of responses to work productivity questions only, likely due to a combination of some participants being unemployed plus missing data. CLDQ-NAFLD and SF36 would therefore be more suitable for inclusion in a larger trial. Regarding QoL outcomes, 95% CI for differences between groups contained zero which was consistent with there being no detectable difference. Few individuals undertook optional CTs, either as this was not offered by sites or participant choice. This may be because CT is less acceptable than ultrasound for NAFLD follow up due to the increased radiation exposure and should not be included in a future RCT. The alternative imaging modality of Magnetic resonance imaging (MRI)–estimated proton density fat fraction (PDFF) is expensive and not routinely available.Limited data on the potential efficacy of maraviroc as a treatment for NAFLD are available from previous studies. In a retrospective cohort in PWH, 74 individuals receiving maraviroc were compared to 312 who had never been exposed to maraviroc, matched for age, sex and CD4 count nadir. In the non-maraviroc group, a significant association was found between a marker of inflammation (hsCRP) and lipoprotein levels (LDL, TG, TC) at baseline and after 3 years. By contrast, in the maraviroc group, this relationship was observed at baseline but lost after 3 years. The incidence of non-AIDS-defining disease was lower in the maraviroc group but this was not statistically significant. The authors speculated that CCR5 inhibition may offer protection against a lipid-dependent inflammatory process [In a phase III trial, PWH -NAFLD were randomised into four groups: OBT (n = 24), ± maraviroc (n = 23), metformin (n = 21) or maraviroc with metformin (n = 22). Hepatic fat scores were measured at baseline and week 48 using MRI-PDFF. Maraviroc ± metformin was found to be safe with acceptable tolerability but did not reduce liver fat scores compared to no adjunctive treatment, and LSM scores were not presented [We instituted a number of measures in response to the COVID-19 pandemic. First, time windows for visits were lengthened from ±1 to ±8 weeks to provide flexibility for staff redeployed to COVID-19 responsive work and for participants experiencing difficulty in accessing clinical sites. Second, virtual visits were permitted for follow up visits, excluding week 48 and 96. This was to provide focus on high completeness of the final dataset whilst enabling participants to avoid travel and clinical contact while self-isolating. Third, we regularly sought feedback from sites to identify problems early and work towards finding local solutions for keeping participants engaged, for example, mailing out IMP. | PMC10348519 |
Limitations | NAFLD, PWH, hepatic steatosis, fibrosis | DISEASE, HEPATIC STEATOSIS, FIBROSIS | We used non-invasive assessment methods for hepatic steatosis and fibrosis, whilst the gold standard, liver biopsy, would have permitted more accurate classification of disease. However, recruiting a sufficient sample of PWH and mild NAFLD to a randomised study requiring consecutive liver biopsies presents feasibility challenges. We did not control for all ART classes, and emerging data have highlighted the possible association of INSTI and TAF with NAFLD progression, as well as a possible protective role for tenofovir disoproxil, although data are conflicting [ | PMC10348519 |
Considerations for an efficacy RCT of add-on MVC in HIV-NAFLD | NAFLD | Given conflicting data for associations between NAFLD development and different ART classes [ | PMC10348519 | |
Conclusions | NAFLD, PWH, fibrosis | HEPATIC STEATOSIS, FIBROSIS | This study provides preliminary evidence that add-on maraviroc as therapy for HIV-NAFLD may be safe, feasible and acceptable. Although there were differences in the trend for ALT and LSM scores, with improvement in the MVC+OBT versus OBT group, the 95% CI contained zero, which was consistent with there being no detectable differences, and the study was not powered to evaluate changes in these characteristics. Overall, these data support a larger RCT assessing efficacy of add-on maraviroc on hepatic steatosis and fibrosis in PWH and NAFLD. | PMC10348519 |
Supporting information | PMC10348519 | |||
CONSORT 2010 checklist of information to include when reporting a pilot or feasibility trial. | (DOC)Click here for additional data file. | PMC10348519 | ||
This file contains all supporting tables (S1-S4 Tables). | (DOCX)Click here for additional data file. | PMC10348519 | ||
Trial protocol. | (PDF)Click here for additional data file.The authors wish to acknowledge the participants who generously participated in this trial. | PMC10348519 | ||
References | PMC10348519 | |||
Abstract | PMC10512773 | |||
Introduction | AKI, sepsis, dysbiosis, acute kidney injury | SEPSIS | During acute kidney injury (AKI) due to sepsis, the intestinal microbiota changes to dysbiosis, which affects the kidney function recovery (KFR) and amplifies the injury. Therefore, the administration of probiotics could improve dysbiosis and thereby increase the probability of KFR. | PMC10512773 |
Methods | AKI, sepsis | ADVERSE EVENTS, SEPSIS, KIDNEY REPLACEMENT | In this double-blind clinical trial, patients with AKI associated with sepsis were randomized (1:1) to receive probiotics or placebo for 7 consecutive days, with the objectives of evaluate the effect on KFR, mortality, kidney replacement therapy (KRT), urea, urine volume, serum electrolytes and adverse events at day 7. | PMC10512773 |
Results | From February 2019 to March 2022, a total of 92 patients were randomized, 48 to the Probiotic and 44 to Placebo group. When comparing with placebo, those in the Probiotics did not observe a higher KFR (HR 0.93, 0.52–1.68, | PMC10512773 | ||
Conclusion | AKI, sepsis | SEPSIS | In AKI related to sepsis, probiotics for 7 consecutive days did not increase the probability of KFR, nor did other variables related to clinical improvement, although they were safe. | PMC10512773 |
Keywords | PMC10512773 | |||
Introduction | AKI, inflammation, endotoxemia | ENDOTOXEMIA, PROLIFERATION, INFLAMMATION, DISEASE, SYNDROME, IMMUNODEFICIENCY | The intestinal microbiota comprises 100 trillion microorganisms, such as bacteria, viruses, fungi, and protozoa, that interact with the human host during health and disease processes [During disease and inflammation, the intestinal microbiome undergoes changes in its composition, causing the proliferation of pathogenic bacteria, which in turn promotes more local and systemic inflammation, elevated concentrations of uremic toxins, increased intestinal permeability, endotoxemia, and immunodeficiency [AKI occurs in one out of every four hospitalized patients, and 22.8% of these patients die during hospitalization [Since AKI is a syndrome that generates intense systemic inflammation [ | PMC10512773 |
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