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INTRODUCTION | rash, pain, Herpes zoster, HZ, PHN | POSTHERPETIC NEURALGIA, PHN, VIRUS INFECTION, DISEASE, HERPES ZOSTER, NEUROINFLAMMATORY RESPONSE, PATHOGENESIS, COMPLICATIONS | Herpes zoster (HZ) is a comment disease with distinctive clinical conditions, it is caused after varicella‐zoster virus infection. According to epidemiological investigation, one in four people might suffer from HZ during their lifetime, and for individuals aged over 50, the incidence for HZ increased to almost 50% (David, Postherpetic neuralgia (PHN) is one of the most common complications of HZ, PHN is defined as pain that persists for 3 months or more after the resolution of the initial rash. The risk of PHN is reported between 5% and 30% after the break out of HZ. Advanced age is one of the risk factors for developing PHN, as about 12.5% of HZ patients over 50 years old can develop PHN, and the increase in risk varies from 1.22 to 3.11 for every 10 years of age (Hadley et al., Numerous researchers have investigated the potential mechanism for the residual pain of PHN. Theories including peripheral sensitization, central sensitization and peripheral neuroinflammatory responses have been identified, yet the pathogenesis of PHN remains unclear (Hoon, One approach to prevent PHN could be autologous fat grafting, a widely used technique in cosmetic surgery and has proven to be a safe procedure in the past 30 years (Bucky & Percec, | PMC10097047 |
METHODS | PIAN | This open‐label pilot study was undertaken in the Pian Center of Shanghai Changhai Hospital, China, from February 1, 2020 to January 30, 2022. The protocol is in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement. This trial was prospectively registered at Chictr.org.cn with ID number ChiCTR1900025416. All participants provided written consent, and approval for the study was obtained from the Ethics Committee of Changhai Hospital (CHEC2019‐113). | PMC10097047 |
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Study design | PHN, herpetic neuralgia, rash, pain | PHN, HERPETIC NEURALGIA, SYNDROME | This is a prospective, single‐arm, and single‐center pilot study to investigate autologous fat grafting to the thoracic paravertebral space for elders with herpetic neuralgia in the rash phase, the main object of this trail is to investigate the feasibility and safety of this treatment in preventing PHN. Participants were all new diagnosed HZ patients visiting our outpatient department for significant pain syndrome. All procedures were performed at the Department of Plastic Surgery, Shanghai Changhai Hospital. The eligibility criteria including (1) age ranged from 50 to 80 years old; (2) BMI ranged from 18 to 28 kg/m | PMC10097047 |
Interventions | allodynia, Pain, hyperalgesia | All included patients were treated with autologous fat grafting to the thoracic paravertebral space with hyperalgesia and allodynia in related region. All procedures were performed by a skilled plastic surgeon. Before harvest, the region was injected by a tumescent solution (0.5% lidocaine + 0.0005% adrenaline). The fat was harvested by a syringe with low negative pressure (0.75–1.0 atmosphere) and blunt tip cannula (2.1–2.4 mm) through a stab incision on the abdomen or thigh. The harvested fat was sedimented for 10 min and then extra tumescent solution was decanted.After liposuction, patients were transited to the prone position. Then after sterilization, landmarks for HZ affected paravertebral space were identified under transversal ultrasound scanning. Using a 22‐G spinal needle, a total volume of 10–15 mL of harvested fat was injected at once. Epidural spread of the injection was certified by movement of the parietal pleura line under the ultrasound image.After the interventions, patients were monitored in the recovery room for 2 h. Pain score in 15 min and in next 3 days were assessed and recorded by an individual physician who was not aware of the study protocol. | PMC10097047 |
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Electoral pain threshold assessment | pain | In this trial, we assessed the pain threshold based on patients’ response to a gradual increased electrical stimulus (0.1 mA, pulse width 0.3 ms, impulse frequency 50 Hz) using a pain vision detection device (PS‐2100, Nipro Corporation, Osaka, Japan). During each assessment, a 1‐inch square electrode was placed either in the centered of the HZ skin or at the same area of contralateral skin. With the intensity of electrical stimulation increase, patients were asked to click a time‐count device. Three time point was measured based on previous studies (Shengai et al., | PMC10097047 |
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Data collection and outcomes | neuropathic pain, skin eruption, pain, PHN, herpetic pain, herpetic neuralgia | PHN, HERPETIC NEURALGIA, SKIN ERUPTION | Baseline data collected included demographic information; pain level (as perceived by the patient using visual analog scale, VAS, a 10‐cm unmarked line, with anchors: 0 = no pain and 10 cm = worst pain imaginable); current medications; smoking status; and pain threshold of the patient's affected dermal area as well as counterpart skin at healthy side.After intervention, in 1, 2, 4, 8, 12, 24 weeks after autologous fat injection, participants were asked to having the follow‐up visit at our department. At each visit, information were recorded including: the level of pain at the HZ site, the total analgesic consumption, the times of complete resolution of pain (from the date of paravertebral block until complete disappearance of herpetic pain) and skin eruption (identified by drop of last crust), and pain threshold. The quality of life was measured using the Short‐Form 36 (SF‐36) and the quality of neuropathic pain was recorded according to patients’ self‐report. A 5‐point Likert scale measuring treatment satisfaction (1 = very unsatisfied, 2 = unsatisfied, 3 = neither satisfied nor unsatisfied, 4 = satisfied and 5 = very satisfied) was also recorded. The primary outcome is the incidence of herpetic neuralgia in 3 months after this treatment, as this is determined according to the definition of PHN (Chan, All patients’ reported outcomes were collected based on standardized case report form filled out by patients at baseline and at follow‐ups. A pain physician who was blinded to the study protocol, was responsible for the follow‐up and the data collection. | PMC10097047 |
Sample size and statistical methods | This is a hypothesis‐generating feasibility study; the collected data and information are supposed to identify the safety and treatment responses, and to calculate a preliminary sample size for a randomized controlled trial. We chose to include a total of eight patients in this trial. Data were analyzed using the SPSS version 25 (IBM, Inc., Chicago, IL). One‐way ANOVA is used for analysis of VAS score in different time points, and a two‐way ANOVA is applied for analysis of VAS score with variables of time and skin position. A | PMC10097047 |
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RESULTS | PHN, pain, rash, abdominal pain | HERPES ZOSTER, PHN, EVENTS | Eight patients accept the intervention and complete all follow‐ups. All of them are female, with a mean age of 63.7 years (range from 50 to 76 years), while seven of them have a high school degree. All patients are suffered from chest, back or abdominal pain due to emerging herpes zoster, the mean duration for pain is 19.8 days (range from 10 to 27 days), with a rash appeared in about 1–5 days after pain. All patients have accepted or are accepting standard antivirus and analgesic medication. The affected spinal segment including T2–T12, demographic characters for all patients are presented in Table Demographic characteristics for all participantsFour patients have fat harvested from the lower abdomen, while remaining of them had fat harvested from the thighs. The amount of harvested fat ranges from 10–15 mL, according to patients’ physique. Liposuction and injection associated factors are presented in Table Treatment associated variablesFor primary outcome, no PHN events occurred, with all patients report pain intensity ≤3 in the VAS scale in 3 months after treatment. Our results also present a significant time‐dependent pain relief phenomenon (The degree of average pain after autologous fat grafting to the paravertebral space.The electrical pain threshold assessed at each follow‐up. The column factor refers to time after treatment; the row factor refers to the place of the measured skin.Secondary outcomesLikert scale: 1 = very unsatisfied, 2 = unsatisfied, 3 = neither satisfied nor unsatisfied, 4 = satisfied and 5 = very satisfied.* Heat map for the quality of life based on Short‐Form 36 scale. | PMC10097047 |
DISCUSSION | neuropathic pain, mood disorders, rash, pain, PHN | ADVERSE EVENTS, PHN, PATHOGENESIS, SYNDROME | In this trial, we identify that autologous fat grafting to the paravertebral space of the algogenic segment is a potentially valid method to prevent PHN. Among the eight patients accepted fat grafting, most of them have experienced immediate pain relief after the intervention, while eight of them have a lasting allogenic effect in all follow‐ups. No patients reported PHN in the 3‐month and longer follow‐ups, with a VAS score over 3 points. For other results, we identified that in accordance with the significant allogenic effect, autologous fat grafting also results in significant improvements in the mental state and the quality of life. Besides, for the eight patients with positive treatment response, the duration and consumption of analgesics is significantly reduced. In the assessment of pain thresholds, we identify that fat grafting differentially increases sensation and pain threshold in HZ area and healthy skin of patients. No serious adverse events occurred.Autologous fat grafting for HZ is a new clinical use for this proven technique, yet evidence is confined. Previously, Sollie et al. (At present, the pathogenesis of PHN is not completely understood. The principle of treatment is a long‐term control of pain syndrome, relief of accompanied sleep and mood disorders, as well as improvement of life quality (Schlereth et al., The main theory for fat grafting to treat neuropathic pain is that the harvested fat tissue contains abundant of adipose tissue‐derived stem cells (ADSC), growth factors and anti‐inflammatory molecules, which accelerate the repairing damaged nerves, and further reliefs pain syndrome (Dehdashtian et al., By review of literatures, we further proposed that the paravertebral space might be a better target location, as grafting fat directly affects the dorsal root ganglion. In animal studies, Shu‐Hung et al. (Several limitations should be mentioned. First, the small sample size and a single‐armed design limits the interpretation of our results. Besides, we only investigate this treatment for HZ patients with a rash in chest and back, application of fat grafting intrathecally or to the peripheral nerve may also works. What is more, in this pilot trail, all participants are female, which may limit the explanation of our conclusions. In the further randomized control study, more patients with both genders will be included to test the safety as well as the effectiveness of this novel treatment for PHN. | PMC10097047 |
CONCLUSION | PHN | ADVERSE EVENTS, PHN | In this prospective, single‐armed trial, we first report the feasibility and the safety of autologous fat transplantation to the paravertebral space in preventing PHN. More advantages of this technique including rich in fat content, easy to obtain, cost‐benefit as well as less adverse events makes it a promising treatment method in preventing PHN. The next step toward routine clinical translation is to perform a randomized, blinded, placebo‐controlled trial to investigate the actual long‐term benefice of autologous fat grafting to the paravertebral space in preventing PHN for early HZ. | PMC10097047 |
AUTHOR CONTRIBUTIONS | XJ Li designed the trial and conducted the experiments, R Tao conducted the experiments, XY meng analyzed the data and wrote the manuscript, H Wang revised the manuscript, HD Bi conceived the study and conducted the experiments, YC Xiong conceived the study. All authors read and approved the final version. | PMC10097047 |
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CONFLICT OF INTEREST STATEMENT | The authors declare that they have no competing interests. | PMC10097047 |
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PEER REVIEW | The peer review history for this article is available at | PMC10097047 |
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DATA AVAILABILITY STATEMENT | Data are available from the corresponding author with reasonable requesting. | PMC10097047 |
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REFERENCES | PMC10097047 |
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ABSTRACT | infusion-site, pain | RHD, SECONDARY, RHEUMATIC HEART DISEASE | The authors declare no conflict of interest.Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order ( | PMC10720493 |
KEYWORDS | PMC10720493 |
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INTRODUCTION | skin infections, throat, infections, ARF | ARF, AUTOIMMUNE RESPONSE, INFECTIONS, SKIN INFECTION, SECONDARY, ACUTE RHEUMATIC FEVER | Acute rheumatic fever (ARF) results from an abnormal autoimmune response to inadequately treated throat or skin infections with Group A Streptococcus (There is no specific treatment for ARF. However, the mainstay of current therapy, benzathine penicillin G (BPG), which is a long-acting formulation, is directed at preventing the colonization or infections with Although it has proven efficacy, adherence to secondary prophylaxis is low in many RHD-prevalent communities (Subcutaneous delivery of BPG is safe and potentially advantageous ( | PMC10720493 |
RESULTS | PMC10720493 |
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Participants | Seventy-seven adults were screened for eligibility, and 24 eligible participants were recruited; four were females. The median (range) screening age and body mass index (BMI) were 26.9 (18.0–54.1) years and 25.1 (21.9–34.0) kg/mConsort diagram for trial participants. | PMC10720493 |
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Study infusion | pain | Three participants did not receive the planned dose of BPG. The first two participants in cohort 1 received 3.1 MIU because ~1 mL infusate failed to progress through the flow control extension tubing, while one participant in cohort 3 received 8.2 MIU as the infusion after a period of cessation due to pain. All other participants received planned dosages of 3.6 MIU ( | PMC10720493 |
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Pain scores | NRS, pain | Reported numerical rating scale (NRS) pain scores ranged from 0 to 8 with the greatest intensity recorded during the infusion, but the median (range) pain scores were 2.5 (0–6), 3 (0–8), and 2.5 (0–6) for cohorts 1, 2, and 3, respectively. Moderate pain (NRS 4–7) was not experienced beyond 2 days, and no pain was reported beyond 7 days. The median (range) of pain scores for each cohort is shown (Median (range) reported numeric pain scores according to dosing cohort following subcutaneous infusion of benzathine penicillin G | PMC10720493 |
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Modified Skindex-16 scores | Normalized overall Skindex-17 scores ranged from 0 to 61 with the highest scores reported in the first 2 days after infusion. Scores decreased thereafter with only four participants reporting scores beyond Day 14. The highest normalized domain (symptoms) score was 75 reported by a cohort 2 participant on Day 2. The normalized domain and overall Skindex-16 scores for the first 7 days by cohort and all cohorts combined are provided (Table S2).For a between-cohort comparison of normalized overall Skindex scores by day, the only significant difference was noted on Day 3 between cohorts 1 and 2 ( | PMC10720493 |
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Adverse events | swelling, erythema, pain, infusion-site, tenderness/pain | ADVERSE EVENTS, ERYTHEMA, HYPERPIGMENTATION | There were 101 adverse events reported during the study with no serious adverse events (Table S5). All participants experienced some infusion-site reaction including erythema, swelling, tenderness/pain, and pigmentation ranging in duration from less than 1 day (pain) to 217 days (hyperpigmentation). There were two off-study referrals for post-infusion hyperpigmentation, but no treatment was required, as they resolved spontaneously. Ultrasound changes were recorded in all participants post-infusion and were detectable between 4 and 9 months. Non-specific hyperechoic changes were noted in most participants, but two participants developed a loculated collection that resolved by 6.5 and 8.3 months. | PMC10720493 |
Pharmacokinetic modeling | From the 24 individuals, there were 400 samples included in the PK analysis. The fraction of samples below the limit of quantification (LOQ) (BLQ) was low (11%), those measured between the LOQ and limit of detection (LOD), Visual inspection of the population data demonstrated a change in the terminal phase occurring after 42 days, with a steeper decline in inter-individual variability (IIV) estimated after this point. Several models with zero-order absorption were assessed with the best model consisting of two absorption paths, one a bolus into the depot compartment and the other a zero-order process into the same depot modeled as the duration (DUR). Absorption from this depot compartment was through a transit compartment with corresponding transit half-life (Structure of the pharmacokinetic model. The best model consisted of two absorption paths, one a bolus into the depot compartment and the other a zero-order process into the same depot modeled as the duration. Absorption from this depot compartment was through a transit compartment with corresponding transit half-life (The IIV was estimated on volume (V/F) as well as separate IIV values for SC administration for DUR, The final model parameter estimates and the bootstrap results are presented (Final population pharmacokinetic estimates and bootstrap results following subcutaneous infusions of benzathine benzylpenicillin GCalculated from bootstrap.RSE, relative standard error; Prediction-corrected visual predictive checks for plasma benzylpenicillin G concentrations (ng/mL on log10 scale). Observed 50th (solid line) and 10th and 90th (dotted lines) percentiles within their simulated 95% CI (gray shaded areas) are shown with overlying data points (ο, The population estimate for RATIO corresponds to 28% of the dose passing through the zero-order absorption pathway; notably, this parameter had the highest IIV (88%). The average duration of this process was around 44 days with the effect of BMI resulting in a range of 38–63 days for the lowest (Simulations demonstrated a longer proportion of time between doses above the threshold of 20 ng/mL for the 13-weekly SCIP 10.8 MIU dose [median 63%, 90% simulation interval (SI) (51%–77%)] compared to standard 4-weekly IM 1.2 MIU doses [median 39% (27%–56%)] (Simulations of the pharmacokinetic model comparing high-dose subcutaneous infusions of benzathine penicillin G (10.8 MIU, dark gray) with intramuscular injection (1.2 MIU, light gray). The shaded region represents median with 90% simulation interval. | PMC10720493 |
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DISCUSSION | hyperpigmentation, Hyperpigmentation, erythema, pain, PD, bruising, infusion-site, NRS | HYPERPIGMENTATION, HYPERPIGMENTATION, ERYTHEMA, RHD, HYPERMELANOSIS | Subcutaneous infusion of high-dose BPG (SCIP) is tolerable and safe. Despite all participants experiencing some degree of infusion-site reaction, they all resolved spontaneously with no serious adverse outcomes. While pain is a subjective experience, the maximum reported pain at injection was severe (NRS 8), requiring analgesia, in only one participant; moderate pain (NRS 4–7) was experienced by another 11 participants in the first 2 days; nevertheless, the median cohort pain scores were all in the mild (1–3) category. Although we did not directly compare SCIP with intramuscular BPG, similar median or mean pain scores have been reported in other studies involving an intramuscular dose of 1.2 MIU of BPG in healthy adults (Participant experience of the infusion-site reaction indicated by modified Skindex-16 scores was variable, ranging from very little (zero) to fairly severe (75) “bother,” but severity categories have not been defined in literature. Nonetheless, the median scores all fall within the mild–moderate (0.8–12.5) categories, and the impact resolved within 3 days. Hyperpigmentation persisted beyond the first week and was reflected by scores in the emotional domain. As described in literature, hyperpigmentation was more common in darker-skinned participants in the study and carried some emotional stress, worsened by uncertainty and delayed resolution (Despite the high dose delivered in SCIP, the peak concentration was well below concentrations achieved with standard doses of intravenous penicillin G. Simulations from the PK model indicate that penicillin concentrations above the PK/pharmacodynamics (PD) target for While the participants found SCIP safe and tolerable, adults and children living with RHD will determine the acceptability of SCIP as they will have had experience with standard IM injections and an expectation of what is acceptable pain, erythema, or inconvenience related to function and emotional burden. Adolescents may experience difficulty with being unable to expose their abdomen for prolonged periods after SCIP and coping with the possible distress should hyperpigmentation develop. Less exposed sites for SCIP should be investigated along with the feasibility of earlier topical treatment for hypermelanosis.Younger patients with more pliant subcutaneous tissue may tolerate SCIP better than older patients, but this should be balanced with closer attention to the spring-loaded pump and flow control adjustment to prevent excessive pressure and bruising at the site.The limitations of this study include that the study was conducted in healthy adults without RHD, and women were under-represented. While we were able to deliver SCIP using the spring-loaded pump and a variable flow control device, there was limited scope for fine-controlling the flow of BPG because it only flowed with the highest settings. An improved flow control device is needed. While the sample size was adequate for PK modeling, it restricted subgroup analysis. Lastly, most people with RHD live in resource-constrained countries where pre-suspended BPG is not available and therefore will not have access to SCIP. There is an urgent need to explore SCIP using reconstituted powdered BPG formulations or improve access to pre-filled BPG preparations if SCIP is to be widely implemented. | PMC10720493 |
MATERIALS AND METHODS | PMC10720493 |
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Study design | SECONDARY | We conducted a phase 1 open-label study using three cohorts with increasing doses of BPG, with the primary objective of assessing the safety and tolerability of SCIP. The secondary objectives were to characterize the PK, including the time above the current accepted pharmacological surrogate for protection against | PMC10720493 |
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Participants | Twenty-four healthy participants were recruited into the study from eligible adults aged 18–65 years, without significant co-morbidities. Full eligibility/exclusion criteria are provided (Table S6). To explore the effect of body composition, 12 participants with an ideal BMI (20–24.9 kg/m | PMC10720493 |
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Study intervention | ADVERSE EVENTS, RECRUITMENT, SKIN NECROSIS | Participants received a single SC infusion of 3.6 (2,700 mg, 9 mL), 7.2 (5,400 mg, 13.8 mL), or 10.8 MIU (8,100 mg, 20.7 mL) of BPG (Bicillin L-A, Pfizer, Sydney, Australia) delivered under ultrasound guidance. To achieve sustained plasma penicillin concentrations of 73% and 99% for a 3-month period above target concentrations of 20 ng/mL and 10 ng/mL, respectively, we chose a maximal dose of 10.8 MIU BPG (nine vials) (Assignment to treatment was by recruitment order and BMI group ensuring equal BMI representation in each cohort. An independent SMC was appointed to review the safety of study procedures and all adverse events 72 hours after dosing, to approve progression to the next cohort. In particular, skin necrosis at the injection site, which has been reported following SC infusion of other antibiotics ( | PMC10720493 |
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Study infusion | Prior to infusion, participants underwent an ultrasound examination (Acuson S3000 and Acuson 18L6 probe, Siemens Medical Solutions, Malvern, USA) to assess SC fat using a validated protocol (The prescribed BPG dose was transferred to a 30 mL syringe (JMS Co. Ltd, Hiroshima, Japan) and delivered into a single injection site on the lower anterior abdomen over a period of up to 30 minutes using a spring-driven syringe infusion pump (Springfusor30, Go Medical Industries Pty Ltd., Subiaco, Australia), a variable flow control device (VersaRate Plus, EMED Technologies, El Dorado Hills, California, USA) and a 22 G SC catheter (BD Saf-T-Intima, BD Medical, Mississauga, ON, Canada). Two milliliters of 1% lignocaine was used to prime the system and provide local anesthesia prior to commencing the infusion. | PMC10720493 |
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Pharmacokinetic samples | Pharmacokinetic samples consisted of serial dried blood spots and venous samples. DBSs were collected 2, 6, 12, 24, 48, and 72 hours pre-dose and 5, 7, 14, 21, 28, 42, 56, 70, 84, 98, and 112 days post-dose, and two venous blood samples were collected at 12 hours and 14 days post-dose. Three to five drops of mixed capillary blood from a fingerprick were individually spotted directly on filter paper cards (Whatman 903 Protein Saver Cards, GE Healthcare, Parramatta, NSW, Australia) to allow the blood to be drawn by capillary action and distributed evenly on the DBS card. The card was air-dried at room temperature for 1.5 hours and stored at <12°C for at least 3 hours to dry, placed in an airtight foil envelope with a single desiccant sachet, and stored at −80 | PMC10720493 |
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Safety monitoring | NRS, pain | Safety and tolerability were assessed using the numerical rating scale for pain (The NRS with scores from 0 to 10 was used for its ease of application and validity in assessing acute and change in pain over time, with 0 and 10 representing “no pain” and “worst pain imaginable,” respectively. The minimally clinically important differences (MCIDs) for moderate pain (NRS 4–7) and severe pain (NRS 8–10) are 1.3 and 1.8, respectively, but there is no MCID for mild pain (NRS 1–3) (Semi-structured qualitative interviews were conducted just prior to and during the infusion process and repeated at 2 hours and 7 days post-infusion to better understand the SCIP experience. Interviews were recorded, transcribed verbatim, and analyzed using thematic analysis. The qualitative assessment of the volunteer experience of SCIP has been reported separately (We used a modified Skindex-16 questionnaire ( | PMC10720493 |
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Population pharmacokinetic analysis | LogThe principal structure of the pharmacokinetic modeling was based on our previous published population of PK models (Inter-individual variability as well as correlations between IIV terms was then evaluated for each parameter. The IIV was exponentially modeled for all parameters. Given the wide range of participant sizes, the most appropriate measure for allometric scaling (affecting volume and clearance terms) was selected from WT, fat free mass (FFM), ideal body weight (IBW), ABW, and a more complex model based on FFM with an additional parameter estimating the relative contribution of fat weight (WT-FFM) on each PK parameter (The model evaluation started with the inspection of goodness-of-fit plots including observed versus individual- and population-predicted values, and time versus CWRES. Bootstrapping was performed using Perl-speaks-NONMEM (PSN) with 1,000 samples to obtain 95% empirical confidence intervals for model parameters. Simulation-based model evaluation utilized prediction-corrected visual predictive checks using 1,000 data sets simulated from the final models. To assess the predictive performance of the model and to evaluate any major bias, the observed 10th, 50th, and 90th percentiles and the fraction of samples below the limit of quantification data observed were plotted with their respective simulated 90% | PMC10720493 |
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Simulations | Once a final population pharmacokinetic model was established, simulations were performed based on weight and BMI data from the CDC for 20-year-olds (Penicillin concentrations were determined every 6 hours for all simulations. Four-weekly doses of 1.2 MIU of BPG given IM at steady state ( | PMC10720493 |
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ACKNOWLEDGMENTS | INFECTIOUS DISEASES, STREP | We gratefully acknowledge the assistance of Elizabeth Eadie-Mirams, Renae Barr, Christine Everest, Rebecca Trowman, Jana Ilievski, David Pham, and Evelyn Carapetis in the planning, administration, and conduct of the study. We also acknowledge Lara Hatchuel, Nicola Norton, and the Linear Clinical Research team for their support in conducting the study. We thank the MAPI Research Trust and Professor Margaret Chren for the use of the Skindex-16 instruments.This research was funded by Cure Kids NZ (Grant number 7012). The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication. J.K. is supported by a Strep A PhD Scholarship and a Scholarship for International Research Fees at the University of Western Australia (UWA). T.K.H. is supported by a Post Graduate Research Scholarship at the University of Western Australia, partly funded by the Athelstan Saw Bequest Fund. S.E. is supported by a Research Program Training scholarship at UWA and a Wesfarmers Centre of Vaccines and Infectious Diseases Top Up scholarship. L.M. and J.C. are supported by NHMRC Investigator Awards (GNT1197177 and GNT 1173874, respectively). | PMC10720493 |
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SUPPLEMENTAL MATERIAL | The following material is available online at | PMC10720493 |
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aac.00962-23-s0001.docx | Supplemental material.Click here for additional data file.ASM does not own the copyrights to Supplemental Material that may be linked to, or accessed through, an article. The authors have granted ASM a non-exclusive, world-wide license to publish the Supplemental Material files. Please contact the corresponding author directly for reuse. | PMC10720493 |
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REFERENCES | PMC10720493 |
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1. Introduction | HS.Hidradenitis suppurativa, TNF-α, psoriasis | DISEASE, PATHOPHYSIOLOGY, PSORIASIS, SKIN CONDITION, ABSCESSES, HIDRADENITIS SUPPURATIVA, SCARRING, PATHOLOGY, PATHOGENESIS | Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS.Hidradenitis suppurativa (HS) is an autoinflammatory skin condition that causes recurrent painful nodules, abscesses, and tunnel formation, leading to chronic non-healing wounds and scarring [Proteomic analysis in a limited number of samples showed that patients with HS had a greater dysregulation of circulating proteins compared to patients with psoriasis, demonstrating a larger systemic burden [Previous transcriptomic analyses of HS lesional skin have identified several inflammatory pathways that may be implicated in disease pathogenesis [Several differentially expressed genes (DEGs) identified in the prior analyses are regulated to some extent by the activation of Janus kinases (JAKs) and subsequent induction of signal transducer and activator of transcription (STAT) activity. Targeting the JAK pathway in HS was investigated because the JAK/STAT signal transduction pathways are responsible for the production of numerous pro-inflammatory mediators thought to contribute to the pathology of HS [ | PMC10139090 |
2. Results | PMC10139090 |
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2.1. Transcriptomics | Lesional skin punch biopsies from 12 sample pairs taken from the edge of an active HS lesion [In the pathway enrichment analysis, a number of inflammatory pathways were found to be enriched in the Week 8 DEGs from the 30 mg povorcitinib QD group (We previously reported on a 128-gene signature of HS [Treatment-related changes with 30 mg povorcitinib QD were also assessed on two previously published gene sets from HS lesional (vs non-lesional) and wounded (vs non-wounded) skin. The overlap of DEGs in HS lesions with genes expressed during wound healing was previously reported [ | PMC10139090 |
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2.2. Proteomics | Based on paired comparisons and the significance cutoff, a total of 33 differentially expressed proteins (DEPs) of interest were selected (6 upregulated and 27 downregulated proteins), representing the union of statistically significant upregulated and downregulated proteins for each treatment at Weeks 4 and 8 (FDR < 0.05 and absolute fold change [|FCH|] > 1.5). Modulation of these DEPs appeared to be dose dependent both at Week 4 ( | PMC10139090 |
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3. Discussion | Hidradenitis suppurativa, tissue damage | HIDRADENITIS SUPPURATIVA, DISEASE, SCARRING | Hidradenitis suppurativa is a chronic, painful disease that can lead to permanent tissue damage and scarring, and it has a significant negative impact on quality of life [Treatment with povorcitinib QD over 8 weeks was associated with a dose-dependent modulation of several proteins of interest, some of which have been previously reported to be differentially expressed in serum samples from patients with moderate-to-severe HS versus those from healthy controls [These findings may also have implications for the identification of predictive biomarkers in HS. Few studies have investigated the role of biomarkers in predicting HS treatment response, and there are currently no validated clinical biomarkers for this purpose [The study described herein was limited by the small sample size and unavailability of paired biopsies for all patients, which may affect the interpretability of our findings. Transcriptomic data were not available for time points between baseline and Week 8, nor from the 60 and 90 mg povorcitinib QD dose groups, which limits the detection of time- and dose-dependent effects of povorcitinib on DEGs. In addition, patients in the study were not stratified by disease severity, and this study had a short treatment duration (8 weeks) compared with previously reported HS clinical trials. In contrast, proteomic data were available for all dose groups and for both Week 4 and Week 8 timepoints. These data show that proteomic changes appeared to already plateau by 4 weeks, suggesting a rapid onset of action. | PMC10139090 |
4. Materials and Methods | PMC10139090 |
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4.1. Study Design and Patients | Clinical samples were collected from two phase 2 studies of patients with moderate-to-severe HS [Serum was collected from all participants at baseline and Weeks 4 and 8 for proteomic analysis. Availability of skin biopsy samples for transcriptomic analysis was limited to 12 sample pairs (15 mg povorcitinib once daily [QD], | PMC10139090 |
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4.2. Transcriptomic Analyses | RNA sequencing was conducted on frozen samples at the Beijing Genomics Institute using the Illumina HiSeq 4000 system (Illumina, Inc., San Diego, CA, USA), and sequences were aligned by using the Human Genome B38 library (National Center for Biotechnology Information) and the Gencode.V29 gene model (Gencode Project, EMBL-EBI). The fragments per kilobase of transcript per million mapped reads were generated, normalized, log2 transformed, and used for all downstream analyses.Pathway enrichment was performed using Hallmark gene sets from the Molecular Signatures Database (MSigDB v7.2), which were generated using computational methodology and show coherent expression in well-defined biological states [ | PMC10139090 |
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4.3. Proteomic Analyses | BLOOD | Blood samples were obtained at baseline, Week 4, and Week 8 from multiple dose groups (15 mg povorcitinib QD, | PMC10139090 |
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4.4. Statistical Analyses | For transcriptomic analyses, a paired | PMC10139090 |
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5. Conclusions | DISEASE, PATHOLOGY | In conclusion, based on findings observed in skin biopsies and blood of patients with moderate-to-severe HS, 8 weeks of treatment with the JAK1 inhibitor povorcitinib was associated with the reversal of a previously identified HS transcriptomic signature, as well as dose-dependent changes in a number of circulating proteins that may contribute to disease pathology. In agreement with the mechanism of action of povorcitinib, many observed changes involved pathways modulated by JAK/STAT signaling. Other biomarker changes seemed to reflect the clinical efficacy findings and therefore highlight the potential of JAK1 inhibition to modulate the underlying disease pathology in HS. | PMC10139090 |
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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10139090 |
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Author Contributions | Conceptualization: H.L., L.L.S. and S.H.S.; Data curation: H.L., L.L.S. and S.H.S.; Formal analysis: H.L., L.L.S. and S.H.S.; Resources: H.L., L.L.S. and S.H.S.; Software: H.L.; Visualization: H.L., L.L.S. and S.H.S.; Writing—reviewing & editing: H.L., L.L.S. and S.H.S. All authors have read and agreed to the published version of the manuscript. | PMC10139090 |
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Institutional Review Board Statement | Ethikkommission der Universität zu Lübeck, Ethik-Kommission der Medizinischen | The clinical studies were conducted in accordance with the Declaration of Helsinki and approved by the institutional review board (IRB) or institutional ethics committee (IEC) at each participating site (United States and Canada central IRB/IEC: Advarra; United States local IRBs/IECs: Penn State College of Medicine IRB, The Rockefeller University IRB; Canada local IRB/IEC: Biomedical Research Ethics Board; Denmark central IRB/IEC: Den Regionale Videnskabsetiske Komité; Germany central IRB/IEC: Ethik-Kommission der Medizinischen Fakultätder Ruhr-Universität Bochum; Germany local IRBs/IECs: Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität Münster, Ethikkommission der Universität zu Lübeck). | PMC10139090 |
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Informed Consent Statement | All patients provided written informed consent. | PMC10139090 |
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Data Availability Statement | Access to individual patient-level data is not available for this study. Information on Incyte’s clinical trial data sharing policy and instructions for submitting clinical trial data requests are available at: | PMC10139090 |
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Conflicts of Interest | H.L., L.L.S. and S.H.S. are employees and shareholders of Incyte Research Institute/Incyte Corporation. Incyte was involved in the design of the study; the collection, analysis, and interpretation of data; and in writing the manuscript. | PMC10139090 |
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Methods | MINOR | We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor ( | PMC10645316 |
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Results | muscle mass | Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% p | PMC10645316 |
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Conclusion | These data suggest that polymorphic variation in the | PMC10645316 |
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Data Availability | The data are provided in the attached Excel file. | PMC10645316 |
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Introduction | muscle mass, sarcopenia, Sarcopenia, sarcopenic | SARCOPENIA, ATROPHIC, SARCOPENIA | The maintenance of a healthy muscle mass is important in giving individuals the strength to perform the tasks of daily living. Muscle protein is continually turned over such that muscle mass is maintained by balancing the rates of protein synthesis and degradation within relatively tight windows [Sarcopenia, is defined by the European Working Group on Sarcopenia in Older People (EWGSOP) as the loss of both muscle mass and strength, leading to low muscle mass together with a walking speed less than 0.8m/s or a reduced grip strength [Myostatin, perhaps the best-known atrophic signalling protein, signals through a complex of the activin type II B receptor (ACVR2B) and activin type I receptors to initiate a SMAD2/3-dependent signalling cascade. In muscle, this activation increases the expression of the muscle-specific ubiquitin ligases, MuRF and atrogin-1, to promote muscle protein catabolism [Consistent with a role in the development and maintenance of muscle, polymorphic variation in the activin receptors has been associated with muscle mass and strength. One polymorphism in the first intron of Myostatin is expressed in other tissues including adipose tissue where it has been suggested to contribute to the differentiation of adipocytes [The above studies suggest that variation in activin receptor function may contribute to body composition in individuals with sarcopenia but a search for studies exploring these polymorphisms in the sarcopenic population did not yield any results. We therefore determined the frequency of the activin type I receptor polymorphisms rs2854464 and rs10783486 in individuals with sarcopenia in the LACE trial and compared these with body mass determined by DXA scans and grip and quadriceps strength at enrolment to determine whether these polymorphisms associated with body composition or strength in individuals with sarcopenia. | PMC10645316 |
Materials and methods | PMC10645316 |
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Participants and physiological analysis | sarcopenia | SARCOPENIA | Participants aged 70 years and over with sarcopenia, according to the EWGSOP definition (2010) [ | PMC10645316 |
DNA analysis | Whole blood samples were taken at the first study visit and frozen. DNA was extracted from the first 110 whole blood samples received using the QIAamp DNA blood mini kit according to the manufacturer’s instructions. This set of samples were the first batches received from the various trial sites by the laboratory, and analysis was restricted to this group for purely logistical reasons relating to the COVID pandemic and subsequent funding. DNA genotyping was performed by Taqman qPCR using assays C2022135-10 and C15826314-10 on an ABI 7500 fast thermocycler according to the manufacturer’s instructions. Two samples did not amplify for rs2854464 and 3 samples did not amplify for rs10783486. Data from these individuals were not included in the analysis. | PMC10645316 |
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Statistical analysis | All of the data used in this analysis is available in Whether the alleles were in Hardy-Weinberg equilibrium was determined by Chi squared test using allele frequencies published for the European Caucasian population (rs10783486, MAF = 0.26 and rs2854464, MAF = 0.26) [The threshold for statistical significance (alpha) was taken as 0.05. All available data were used for each comparison and no manipulations were performed to include missing values for individual tests. As this analysis is exploratory no adjustments were made for multiple testing. | PMC10645316 |
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GTEX data | NINDS | The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the GTEx analyses described in this manuscript were obtained from: the GTEx Portal ( | PMC10645316 |
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Results | The demographics of participants included in this analysis are given in | PMC10645316 |
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Baseline demographics of the study population. | CONTRACTION | BMI: body mass index, cv: coefficient of variation, SARC-F: Strength, assistance with walking, rising from a chair, climbing stairs, and falls questionnaire score, SPPB: Short Physical Performance Battery score: QMVC: Quadriceps Maximal Voluntary contraction. For normally distributed data values are given as mean ± SD and for data that did not show a normal distribution are median (interquartile range).Body composition measurements were not available for 1 male. QMVC measurements were not available for 1 female and 6 males. | PMC10645316 |
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rs10783486 | muscle mass | Given population differences in body composition and strength between males and females, the sexes were analysed separately. There were no associations of genotype with strength, total body muscle mass (quantified by bioimpedance) or limb muscle mass (quantified by DXA) in either sex ( | PMC10645316 |
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Associations of rs10783846 with height and limb fat mass in individuals in the LACE study. | MINOR | Height and limb fat were compared in males and females possessing the minor allele for rs10783846 with those homozygous for the major allele. Median height (A, p = 0.023), arm fat mass (B, p = 0.008) and leg fat mass (C, p = 0.046) were higher in males with the minor allele than their counterparts homozygous for the major allele. However, in females there were no differences. | PMC10645316 |
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Effect of the minor allele of rs10783846 on body composition and strength in females and males at baseline. | CONTRACTION | BMI: body mass index, SARC-F: Strength, assistance with walking, rising from a chair, climbing stairs, and falls questionnaire score, SPPB: Short Physical Performance Battery score: QMVC: Quadriceps Maximal Voluntary contraction. For normally distributed data values are given as mean ± SD and for data that did not show a normal distribution values are median (interquartile range). Body composition measurements were not available for 1 male. QMVC measurements were not available for 1 female and 6 males. 6MW distance was not available for 1 male.Given the difference in height between the genotypes, we investigated the associations of limb muscle and fat mass with height. In males, leg and limb fat mass were weakly associated with height (r = 0.31, p = 0.025 and r = 0.30, p = 0.032 respectively) but there was no significant association between arm fat mass and height (r = 0.21, p = 0.145) nor were leg or arm fat associated with height in females ( | PMC10645316 |
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Association of height with limb fat mass in individuals in the LACE study. | Height was compared with limb fat mass in males and females from the LACE study. In males there was a weak association of leg fat mass with height (r = 0.31, p = 0.025) but not in females. Arm fat mass was not associated with height in males or females. | PMC10645316 |
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Association of height with limb muscle mass in individuals in the LACE study. | muscle mass | Height was compared with limb muscle mass in males and females from the LACE study. In both males (r = 0.57 p<0.001) and females (r = 0.61, p<0.001) there was a strong association of leg muscle mass with height. Arm muscle mass was also associated with height in both males (r = 0.51, p<0.001) and females (r = 0.52, p<0.001).After correction for height, arm fat mass remained significantly higher in AA/AG males than in GG males (mean | PMC10645316 |
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Arm and leg fat mass in LACE males adjusted for height. | Limb fat mass was log | PMC10645316 |
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rs2854464 | muscle mass or limb muscle mass | Analysis of the rs2854464 allele showed a similar pattern to that described for rs10783486 both with no associations with total muscle mass or limb muscle mass ( | PMC10645316 |
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Associations of rs2854464 with height and limb fat mass in males and females in the LACE study. | MINOR | Height and limb fat were compared in males and females possessing the minor allele for rs2854464 with those homozygous for the major allele. Median height (A, p = 0.023), arm fat mass (B, p = 0.008) and leg fat mass (C, p = 0.046) were higher in males with the minor allele than their counterparts homozygous for the major allele. However, in females there were no differences. | PMC10645316 |
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Effect of the minor allele of rs2854464 on body composition and strength in females and males at baseline. | CONTRACTION | BMI: body mass index, SARC-F: Strength, assistance with walking, rising from a chair, climbing stairs, and falls questionnaire score, SPPB: Short Physical Performance Battery score: QMVC: Quadriceps Maximal Voluntary contraction. For normally distributed data values are given as mean ± SD and for data that did not show a normal distribution values are median (interquartile range). Body composition measurements were not available for 1 male. QMVC measurements were not available for 1 female and 6 males. 6MW distance was not available for 1 male.In the UK biobank neither polymorphism associated with height or with arm fat mass at a significance that exceeded p = 10 | PMC10645316 |
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Expression of different alleles in skeletal muscle | MINOR | Previous data have suggested that the rs2854464 polymorphism is located in a miR-24 binding site and that the major A allele has greater affinity for miR-24 leading to a reduction in ACVR1B mRNA. If this hypothesis was correct, it might be expected that there would be differential expression of the two ACVR1B alleles with the minor allele being expressed at higher levels. We therefore examined the GTEx dataset for single tissue eQTLs for rs2854464. Consistent with the hypothesis the expression of the minor allele was higher in skeletal muscle than expression of the major allele ( | PMC10645316 |
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Discussion | PROLIFERATION, GIANT, MINOR | These data show that males in the LACE cohort with at least one minor allele for either rs10783486 or rs2854464 were taller than those homozygous for the major allele and had more arm fat but we did not see any associations of these alleles with body composition in females. Previous studies have shown that polymorphisms in Previous studies have shown that muscle strength measured as grip strength or leg strength are proportional to height [The associations that we identify with height were not identified in the previous studies of these alleles and are not apparent in the GIANT consortium at p<10Although our data cannot demonstrate causality, they raise the possibility that the accumulation of extramuscular limb fat may be influenced by activin receptor signalling—a hypothesis consistent with known effects of both myostatin and activin. Previous studies have shown that activin A signalling increases the proliferation of adipocyte progenitors but reduces adipocyte differentiation [Small numbers in our analysis limit our ability to draw strong conclusions about differences between males and females, but it is possible that the difference in fat accumulation may be either more detectable in males due to differences in relative fat proportions, or may be larger in males than in females. It is possible that the increase in fat is a consequence of reduced relative strength and activity, or is due to a difference in muscle metabolism that contributes to the difference in strength but leads to a greater resistance to insulin over time and therefore an increase in the accumulation of fat that accompanies this. However, even though the median strength of the rs10783486 GG individuals was higher than that of the AA/AG individuals, consistent with the known associations of this polymorphism [The greater height in those carrying the minor allele is more difficult to rationalise if the minor alleles are associated with higher ACVR1B protein levels as both activin and myostatin inhibit bone growth [ | PMC10645316 |
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Limitations of the study | muscle mass, sarcopenia, appendicular muscle mass | RECRUITMENT, SARCOPENIA | This analysis is limited by the size of the study populations and by the lack of a control group of individuals of similar age who did not have sarcopenia. Both these limitations arise from the samples coming from the LACE clinical trial. Firstly, the trial was placebo-controlled trial within the sarcopenia population, as a result there was no recruitment of individuals without sarcopenia. Secondly, recruitment of individuals to the trial proved difficult [Our analysis of total muscle mass is limited by being derived from bioimpedance rather than DXA. The bioimpedance was conducted as a screening tool to limit the number of DXA scans and the analysis of the DXA data was carried out to identify changes in appendicular muscle mass specifically. However, within our data set the bioimpedance measurements of total muscle mass are tightly correlated with the limb muscle measurements [(r = 0.815, p<0.001 arm and r = 0.830, p<0.001 leg muscle), associations that are similar to the association between arm and leg muscle measurements, both by DXA (r = 0.864, p<0.001 arm vs leg muscle)]. As we did not see any differences in muscle mass based on DXA measurements, it is unlikely that the lower reliability of the bioimpedance measurements affected the outcome.A further limitation is that, as a cross-sectional observational study, data demonstrate association only, and not causation. Indeed, it is not currently clear whether the changes in receptor mRNA observed in the GTEx are present in all tissues and are sufficient to significantly modify activin receptor signalling. | PMC10645316 |
Conclusions | muscle mass, obesity, sarcopenic, sarcopenia, sarcopenic obesity | OBESITY, OBESE, SARCOPENIA | Our data suggest that polymorphisms in the activin I B receptor locus are associated with height and limb fat mass rather than muscle mass and strength in older men with sarcopenia. These findings are potentially of clinical significance; interventions that target the activin/myostatin pathway could potentially exert beneficial effects on extramuscular fat, at least in the limbs, with consequent amelioration of the deleterious effects of such fat on skeletal muscle physiology. Such mechanisms may be of particular interest in improving muscle function in individuals who have both obesity and sarcopenia (‘sarcopenic obesity’). If functional studies validate our findings, the obese and sarcopenic population would be a key target for future intervention studies using myostatin/activin pathway modulators. | PMC10645316 |
Supporting information | PMC10645316 |
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All data used. | (XLSX)Click here for additional data file. | PMC10645316 |
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SPSS statistics output from ANCOV analysis. | (XLSX)Click here for additional data file. | PMC10645316 |
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Genotype frequencies in sarcopenia. | (DOCX)Click here for additional data file. | PMC10645316 |
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Associations of rs10783846 with limb muscle mass in individuals in the LACE study. | MINOR | Arm and leg muscle masses were compared in males and females possessing the minor allele for rs10783846 with those homozygous for the major allele. Median arm muscle mass and leg muscle mass did not differ based on possession of the minor allele of rs10783846 in either gender.(TIF)Click here for additional data file. | PMC10645316 |
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Associations of rs2854464 with limb muscle mass in individuals in the LACE study. | MINOR | Arm and leg muscle masses were compared in males and females possessing the minor allele for rs2854464 with those homozygous for the major allele. Median arm muscle mass and leg muscle mass did not differ based on possession of the minor allele of rs2854464in either gender.(TIF)Click here for additional data file. | PMC10645316 |
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Association of polymorphisms in the ACVR1B locus with height and arm fat in the UK biobank study. | The UK biobank data set ((TIF)Click here for additional data file. | PMC10645316 |
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eQTL analysis of rs2854464 and rs10783846 in skeletal muscle. | MINOR | The GTEx data set was analysed to determine whether either polymorphism showed differential expression. In skeletal muscle both minor alleles of rs2854464 and rs10783846 were more highly expressed than the major alleles. The data are shown in violin plot form taken from the GTEx portal.(TIF)Click here for additional data file. | PMC10645316 |
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Tissue eQTL analysis of rs2854464. | The GTEx data set was analysed for eQTL associations with rs2854464. The strongest effects of the polymorphism on expression were observed in the lung and in skeletal muscle.(TIF)Click here for additional data file. | PMC10645316 |
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STROBE statement—Checklist of items that should be included in reports of observational studies. | (DOCX)Click here for additional data file.(DOCX)Click here for additional data file.AAS, TA, and MDW acknowledge support from the NIHR Newcastle Biomedical Research Centre. AA acknowledges support from the Health Services Research Unit, which is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate. The authors acknowledge support from the NIHR Ageing Clinical Research Network and the NHS Scotland Support for Science programme. The authors would also thank the efforts of all the research nurses and other site research staff who recruited participants to the trial, all the participants, and all the staff of the Tayside Clinical Trials Unit for their support of the trial. | PMC10645316 |
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References | PMC10645316 |
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Subject terms | knee osteoarthritis, human abuse, KOA | CHRONIC PAIN, KNEE OSTEOARTHRITIS | The potential synergistic effects of combining cannabinoids and opioids for analgesia has received considerable attention. No studies to date have evaluated this combination in patients with chronic pain. The present study aimed to evaluate the combined analgesic and drug effects of oral opioid (hydromorphone) and delta-9-tetrahydrocannabinol (dronabinol), as well as their effects on physical and cognitive functioning, and human abuse potential (HAP) outcomes among individuals with knee osteoarthritis (KOA). This was a within-subject, double-blind, randomized, placebo-controlled study. Participants ( | PMC10516978 |
Introduction | chronic pain, pain | ADVERSE EVENTS, ADVERSE EFFECTS, CHRONIC PAIN, DRUG EFFECT | The potential synergistic effects of combining cannabinoids and opioids for analgesia have drawn significant attention following preclinical evidence that cannabinoids and opioid combinations have additive nociceptive benefit with limited adverse effects [Evidence for the cannabinoid-opioid synergistic effects in human laboratory studies remains tenuous, however [The present study rigorously evaluated the combined effects of Using a within-subject, double-blinded, randomized, and placebo-controlled design, the present study examined the independent and combined effects of dronabinol and hydromorphone on experimentally-induced acute and chronic pain models, clinical pain, physical and cognitive functioning, HAP ratings, and adverse events. A subset of participants provided blood samples that were analyzed for pharmacokinetic profiles, and the potential moderating effects of sex across outcomes were explored. To our knowledge, this is the first behavioral pharmacology study to examine the drug effect profile and analgesic response, as well as physical and cognitive functioning following co-administration of oral THC with an opioid in a clinical chronic pain sample. | PMC10516978 |
Materials and methods | PMC10516978 |
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Participants | KOA | Individuals with KOA were recruited between 11/2017 and 12/2020 using locally posted and online flyers and print/radio advertisements. A CONSORT flow diagram is depicted in Fig. | PMC10516978 |
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Study consort diagram. | A/E | ADVERSE EVENT | A/E adverse event. | PMC10516978 |
Study design and procedure | This Phase II study used a randomized, double-blind, placebo-controlled, within-subject study design. Potential participants completed a phone and in-person screening, during which they provided a urine sample that was tested for recent drug exposure and pregnancy (for premenopausal females) and were excluded if they reported past month opioid exposure. Eligibility was determined based on medical history and physical including ECG, hepatic, hematologic, and chemistry functioning (see Online Supplement Table | PMC10516978 |
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Experimental study sessions | Eligible participants completed four experimental study sessions scheduled ≥7 days apart. All sessions started around 0800. Participants were asked to refrain from over-the-counter medications on session days and maintain steady doses of prescribed and non-contraindicated medications throughout participation. After providing a urine sample testing negative for drugs and pregnancy (as applicable), participants received a calorie and fat-controlled (~10 g) breakfast. Participants ( | PMC10516978 |
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Measures | PMC10516978 |
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