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3.3.3. Fruit, Vegetables, and Diet Quality | A clinically meaningful increase in the servings of fruit per day was observed in the txt4two cohort, compared with the PC cohort, 0.4 (±0.9) versus 0 (±0.9); however, this did not reach statistical significance ( | PMC9921852 | ||
3.3.4. Physical Activity | Non-significant increases in total physical activity were observed between groups over time (+45.8 min); the sample was not powered to detect statistical differences. Non-meaningful changes were observed in minutes of sedentary time and percentage of women meeting physical activity guidelines. | PMC9921852 | ||
4. Discussion | dietary behaviors | RECRUITMENT | This paper outlines the outcomes and key learnings from a pragmatic implementation of an adapted digital health program into the MMH antenatal service. The outcomes suggest that the program could feasibly be implemented with the considerable time and effort required to adapt and embed the program within the interdependent, but unaligned, hospital systems. While the recruited sample was underpowered, promisingly, clinically meaningful or statistically significant changes were observed in dietary behaviors (fruit and vegetables) and diet quality indices and overall physical activity. Greater proportions of women in the txt4two group gained within the IOM ranges for their ppBMIs. The numerous process negotiations and reflections on enablers provide guidance for future work, adapting and embedding evidence-based programs across different clinical settings. This research adapted an evidence-based intervention for a new implementation context. The use of adapted, previously tested interventions reduces the need to develop a new program and saves time and money, while expanding the availability of evidence-based treatments across clinical settings and demographically different populations [Hospitals are a series of complex administrative and clinical systems. Any intervention needs to operate through active contextual exchanges and influence, and be influenced by, system mechanisms [Despite the numerous barriers faced in integrating and adapting the txt4two program, as well as the lower recruitment and retention rate, it remained effective at changing the dietary behaviors and physical activity levels. The original txt4two program resulted in a lower reduction in physical activity (with over 80% of goals set relating to physical activity) [Future health services redesign projects that attempt to take findings from RCTs, especially related to digital health solutions, into the real world that have a number of considerations for a more streamlined approach. As new programs are embedded into services in response to health consumer needs, the enduring question of communication, recruitment, and continued engagement within education requires further refinement and research. This study showed that it took time to gain traction with recruitment and required additional, often novel (to research), avenues that aligned with usual hospital communication processes. An awareness of these avenues (by researchers and clinician–researchers), as well as a willingness to integrate programs (into hospital communication and data systems by those who manage them), is required to deeply and routinely embed interventions into business as usual for greater and more rapid impact, evaluation, and monitoring. | PMC9921852 |
Strengths and Limitations | The adaptation and testing of an effective and acceptable theoretically underpinned program that had robust formative concept testing and piloting phases was a strength of this study [ | PMC9921852 | ||
5. Conclusions | Adapting and implementing a previously tested digital intervention into a tertiary maternity hospital was feasible and elicited positive dietary quality and physical activity engagement changes. The barriers to this process included fragmented and unagile hospital and research governance and systems, while the enablers included a culture accepting of digital disruption and an embedded clinician–researcher able to navigate and overcome these complexities, while achieving diverse stakeholder engagement. As we move beyond pilots and embed research programs within health services or the community, we need to understand the facilitators and barriers to implementation and prepare implementation road maps that move beyond theory. In doing so, we may strengthen the evidence for the refinement of implementation plans. Further dialogue is also required to understand the implementation transformation of programs and the impact on program fidelity and quality and subsequent health outcomes. | PMC9921852 | ||
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC9921852 | ||
Author Contributions | Conceptualization, S.A.W. and J.C.W.; methodology, S.A.W., B.F. and J.C.W.; formal analysis, S.A.W.; investigation, S.A.W.; data curation, S.A.W.; writing—original draft preparation, S.A.W.; writing—review and editing, S.A.W., B.F. and J.C.W.; project administration, S.A.W.; funding acquisition, S.A.W. All authors have read and agreed to the published version of the manuscript. | PMC9921852 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Mater Misericordiae Ltd. Human Research Ethics Committee (HREC/MML/47416). | PMC9921852 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9921852 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available, due to privacy issues. | PMC9921852 | ||
Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC9921852 | ||
Introduction | Diabetes | VITREOUS HEMORRHAGE, PROLIFERATIVE DIABETIC RETINOPATHY (PDR), DIABETES | Edited by: Sobha Sivaprasad, NHS Foundation Trust, United KingdomReviewed by: Yong Tao, Beijing Chaoyang Hospital, Capital Medical University, China; Xiaodong Sun, Shanghai First People's Hospital, ChinaThis article was submitted to Clinical Diabetes, a section of the journal Frontiers in Public HealthThe aim of this study was to assess the effects of preoperative intravitreal aflibercept (IVA) injection on the incidence of postoperative vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy (PDR). | PMC9875129 |
Methods | PDR | This study involved a prospective, randomized clinical trial. One hundred twenty-eight eyes of 128 patients of PDR who underwent pars plana vitrectomy (PPV) were enrolled. Sixty-four eyes were assigned randomly to either the IVA group (IVA injection 1 to 5 days before PPV) or the control group (no IVA injection). The primary outcome was the incidence of VH at 1 month after PPV. Secondary outcome measures were best-corrected visual acuity (BCVA) changes from baseline to at 1 week, 1 month, 2 months, and 3 months after surgery. | PMC9875129 | |
Results | The VH incidences in the IVA group and the control group were 14.8 and 39.3% at week 1, 8.6 and 31.7% at month 1, 11.7 and 30.5% at month 2, and 8.6 and 30.5% at month 3, respectively. Intergroup differences showed a significantly decreased VH rate in the IVA group compared with that in the control group at week 1, month 1, and month 3 ( | PMC9875129 | ||
Conclusions | PDR | This study found that the adjunctive use of preoperative IVA reduces early and late postoperative VH in vitrectomy for PDR. | PMC9875129 | |
Introduction | diabetic retinopathy, TRD, PDR, Diabetic retinopathy, tractional retinal detachment, vitreous hemorrhage, vision loss, diabetes | DIABETIC RETINOPATHY, TRACTIONAL RETINAL DETACHMENT, DIABETIC RETINOPATHY, POSTOPERATIVE COMPLICATIONS, RETINA, PROLIFERATIVE DIABETIC RETINOPATHY (PDR), VITREOUS HEMORRHAGE, COMPLICATIONS, DIABETES | Patients with diabetic retinopathy (DR) are becoming more and more predominant in many countries with the increasing prevalence of diabetes worldwide. Diabetic retinopathy is the leading cause of vision loss in patients with diabetes. The standard and effective surgical treatment for vitreous hemorrhage (VH) and tractional retinal detachment (TRD) for proliferative diabetic retinopathy (PDR) is pars plana vitrectomy (PPV). Although the anatomical success rate of vitrectomy for PDR is good, it can have a few postoperative complications sometimes. Postvitrectomy VH is one of the most common complications after vitrectomy in PDR and has been reported with success rates ranging between 17 and 75% (The level of vascular endothelial growth factor (VEGF) is elevated in the retina of patients with diabetes (Aflibercept is a fully humanized recombinant fusion protein that has a molecular weight of 115 kDa and is made by fusing the fragment crystallizable (Fc) region of human immunoglobulin G (IgG) to the second domain of vascular endothelial growth factor receptor 1 (VEGFR-1) and the third domain of vascular endothelial growth factor receptor 2 (VEGFR-2). It can bind to not only all subtypes of VEGF but also placental growth factor (PlGF). The affinity of aflibercept for vascular endothelial growth factor-A165 (VEGF-A165) is 94 times greater than that of ranibizumab and approximately 120 times greater than that of bevacizumab. The intravitreal half-life of aflibercept is greater than those of ranibizumab and bevacizumab (4.7 vs 2.9 days and 4.3 days) ( | PMC9875129 |
Methods | PDR, myocardial infarction, liver or kidney dysfunction, diabetes mellitus, tractional retinal detachment, Diabetic Retinopathy, tamponade, postvitrectomy, choroidal or retinal disease, cerebrovascular accident, IOL, hypertension, T2DM, coagulation mechanism disorder | SYSTEMIC DISEASE, DIABETES MELLITUS, RETINAL TEAR, DIABETIC RETINOPATHY, EVENTS, INTRAOPERATIVE BLEEDING, POSTOPERATIVE COMPLICATIONS, PROLIFERATION, EYE, TRACTIONAL RETINAL DETACHMENT, IOL, LENS, TYPE 2 DIABETES MELLITUS, COMPLICATIONS, INTRAOCULAR PRESSURE, MYOCARDIAL INFARCTION, CEREBROVASCULAR ACCIDENT, NEOVASCULARIZATION, HYPERTENSION | This was a prospective, randomized clinical trial (NCT 05478967). The study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the Peking University People's Hospital. Written informed consent was signed by all participants before enrollment.The present study enrolled patients with PDR at the Department of Ophthalmology, Xiamen Eye Center of Xiamen University, between August 2019 and March 2021. The inclusion criteria were as follows: (1) patients with type 2 diabetes mellitus (T2DM), (2) patients aged between 35 and 65 years, and (3) patients with PDR who underwent primary pars plana vitrectomy (PPV) for VH. The following cases were excluded from analysis: (1) eyes with retinal tear, (2) eyes with iris or anterior angle neovascularization, (3) eyes with intraoperative use of silicone oil, (4) eyes with choroidal or retinal disease other than PDR or any inflammatory condition, (5) eyes that underwent any previous vitrectomy or scleral buckle surgery, (6) eyes that received intraocular triamcinolone acetonide (TA) injection within 90 days before screening, (7) eyes that received intraocular anti-VEGF treatment within 60 days before screening or contralateral eyes received intraocular anti-VEGF treatment during follow-up, (8) patients who had taken aspirin orally within 7 days before screening, (9) patients who had coagulation mechanism disorder or had taken any other medicine for anticoagulant treatment, (10) patients who had cerebrovascular accident and/or myocardial infarction occurring within 180 days before screening, (11) patients with uncontrolled blood pressure (sitting position > 160/100 mmHg), (12) patients with liver or kidney dysfunction or any severe systemic disease, and (13) patients who accepted any anti-VEGF therapy for the study eye during the follow-up. If both eyes of the same patients were eligible, the eye with worse vision was included in the study.The enrolled eyes were randomly assigned, according to the Central Randomization System, with a ratio of 1:1 to the IVA group and the control group. Patients in the IVA group received an IVA (0.5 mg/0.05 ml) injection before surgery (1 to 5 days before surgery); patients in the control group did not receive IVA injection before vitrectomy. The preoperative IVA injection was given following a standard protocol. All patients underwent 25-gauge transconjunctival sutureless vitrectomy using the 25-gauge trocar and cannula system under local anesthesia. Procedures, such as fibrovascular membrane dissection, endodiathermy, or endolaser photocoagulation, were performed with 25-gauge instruments, as required. Pan-retinal photocoagulation (PRP) was complicated as much as possible during the surgery. Intraoperative bleeding was controlled either by endodiathermy or by increasing the irrigation pressure.Patients were examined 1 week, 1 month, 2 months, and 3 months after surgery if there were no postoperative events. If postoperative complications, including VH, occurred, patients were instructed to visit the clinic, regardless of the visit schedule. At each visit, any events involving the study eye between the visit schedules were recorded accordingly. At each postoperative visit, slit-lamp biomicroscopy, indirect ophthalmoscopy, and fundus photography were performed.The primary outcome was the incidence of VH at 1 month after PPV. Secondary outcome measures were best-corrected visual acuity (BCVA) changes from baseline at 1 week, 1 month, 2 months, and 3 months after surgery. Preoperative, intraoperative, and postoperative data were collected for each patient. Preoperative data included age, sex, duration, and status of diabetes mellitus [hemoglobin A1c (HbA1c)]; the presence of other systemic diseases such as hypertension and renal function (serum creatinine); and ophthalmic parameters including best-corrected visual acuity (BCVA), intraocular pressure (IOP), lens status, previous PRP, and indication for surgery. Intraoperative data included phacoemulsification and intraocular lens (IOL) procedures, sulfur hexafluoride (SF6) or air tamponade, and the presence of fibrovascular proliferation and tractional retinal detachment. Postoperative data included BCVA at each visit and the number of episodes of complications. Postoperative VH was defined as a new episode of VH of grade 1 or above, occurring later than 3 days after the primary surgery and was evaluated according to the Diabetic Retinopathy Vitrectomy Study grading system. Incidences of VH at week 1, month 1, month 2, and month 3 were recorded. In the case of a gas-injected eye, complications were assessed in the region without the gas bubble. Outcome assessors were masked from the allocation of each study eye.The present study compared baseline clinical data and postvitrectomy complications between the IVA group and the control group in patients with PDR. The chi-square test and the Mann–Whitney test were used. A | PMC9875129 |
Results | vitreous hemorrhage, TRD, NVG, fifty-four | VITREOUS HEMORRHAGE, NEOVASCULAR GLAUCOMA, ENDOPHTHALMITIS, VITREOUS HEMORRHAGE, RESOLUTION | One hundred fifty-four eyes were enrolled in the study and allocated randomly into two groups: 78 eyes in the IVA group and 76 eyes in the control group. During follow-up, 26 eyes were excluded: 16 cases because of the loss of follow-up and 10 eyes because of the administration of intravitreal silicone oil injection. For the final data analysis, 64 eyes in each group were included.Patient demographics and preoperative clinical findings of the two groups are summarized in Patient demographics and preoperative clinical findings of the two groups.The VH incidences in the IVA group and the control group were 14.8 and 39.3% at week 1, 8.6 and 31.7% at month 1, 11.7 and 30.5% at month 2, and 8.6 and 30.5% at month 3, respectively. Intergroup differences showed a significantly decreased VH rate in the IVA group compared with that of the control group at week 1, month 1, and month 3 (Vitreous hemorrhage grading in the two groups. The number of patients with different categories of vitreous hemorrhage grading in the preoperative intravitreal aflibercept (IVA) injection group and control group (bar with dotted pattern) during follow-up.The mean BCVA changes in the logMAR scale were better in the IVA group than in the control group at week 1, month 1, month 2, and month 3 after surgery (0.70 vs. 0.81, 0.50 vs. 0.67, 0.51 vs. 0.66, and 0.46 vs. 0.65, respectively), but the difference between the two groups was not statistically significant at each visit point (The mean best-corrected visual acuity (BCVA) at each visit in the two groups. The mean BCVA in logMAR (Logarithm of the Minimum Angle of Resolution) scale at baseline, week 1, month 1, month 2, and month 3 after surgery in the preoperative intravitreal aflibercept (IVA) injection group and control group.The mean best-corrected visual acuity (BCVA) change comparing to baseline during follow-up in the two groups. The mean BCVA change in logMAR (Logarithm of the Minimum Angle of Resolution) scale at week 1, month 1, month 2, and month 3 after surgery comparing to baseline in the preoperative intravitreal aflibercept (IVA) injection group and control group.The number of patients with different categories of best-corrected visual acuity (BCVA) improvement in the two groups. The number of patients with different categories of BCVA improvement in logMAR (Logarithm of the Minimum Angle of Resolution) scale at week 1, month 1, month 2, and month 3 after surgery comparing to baseline in the preoperative intravitreal aflibercept (IVA) injection group and control group (bar with dotted pattern).There were no incidences of neovascular glaucoma (NVG), endophthalmitis, or TRD progression in the cases included for the final analysis. | PMC9875129 |
Discussion | PDR, TRD, Diabetic retinopathy, blindness, ischemia, tamponade | DIABETIC RETINOPATHY, BLINDNESS, ISCHEMIA, COMPLICATION, BLIND, NEOVASCULARIZATION, SCLERA, REGRESSION | Diabetic retinopathy (DR) is one of the leading causes of being legally blind in working-aged people and is responsible for up to 4.8% of blindness worldwide. Although PPV was the standard management for PDR with VH or TRD, they may suffer from postoperative VH. This complication will hinder fundus monitoring and/or additional retinal photocoagulation and delay their visual recovery.The incidence of postoperative VH in PDR had been reported to be around 75% in the 1980s (Vascular endothelial growth factor has been proven to play an important role in the development of neovascularization in DR (These controversies exist because there are numerous differences in the detail of each strategy, such as the time point for the injection of anti-VEGF, the trocar gauge, and the suture of sclera wound. Heterogeneity of baseline characteristics among different studies also made it difficult to compare their results directly. Wang et al. conducted a network meta-analysis including 26 randomized controlled trials (RCTs) and 1,806 patients with PDR to compare preoperative anti-VEGF to the sham group. They found that injection at 6 to 14 days before vitrectomy could significantly reduce the duration of surgery, improve postoperative BCVA, and decrease the incidence of postoperative VH (The ideal timing for pretreatment is controversial. Some authors suggested injecting more than 14 days before vitrectomy to make full use of anti-VEGF agents and induce the complete regression of neovascularization. However, Russo et al. studied the incidence of TRD following preoperative anti-VEGF injection and showed that the incidence of TRD after injection was 2.7% when the interval of injection and vitrectomy was less than 6 days, while it will be increased to 56% when the interval was prolonged to more than 10 days (Postoperative BCVA might be associated with numerous factors, such as the history of TRD, macular edema, macular ischemia, and ellipsoid zone (EZ) band integrity recurrent VH and gas or silicone oil tamponade (To our knowledge, this is the first RCT that compares the incidence of postoperative VH between the preoperative IVA and sham groups for PDR. However, it has the following limitations: (1) failure to compare the influence of different timings of preoperative anti-VEGF injection; (2) having a relatively shorter follow-up period; and (3) the lack of a group with different anti-VEGF agents.In conclusion, this RCT demonstrated that injective IVA at 1 to 5 days before vitrectomy for patients with PDR could reduce the incidence of early and late postoperative VH. | PMC9875129 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC9875129 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Institutional Review Board of People's Hospital of Peking University. The patients/participants provided their written informed consent to participate in this study. | PMC9875129 | ||
Author contributions | JQ and XL contributed to the interpretation of the data. The first draft of the manuscript was written by JQ and all authors commented on previous versions of the manuscript. All authors contributed to the study's conception and design. All authors read and approved the final manuscript. | PMC9875129 | ||
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC9875129 | ||
Publisher's note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC9875129 | ||
References | PMC9875129 | |||
Aims | cord injury | KCL‐286 is an orally available agonist that activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL‐286 in male healthy volunteers to establish dosing to be used in the SCI patient population. | PMC10835503 | |
Methods | BLIND | The design was a double blind, randomized, placebo‐controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells. | PMC10835503 | |
Results | rash | ADVERSE EVENTS, EYE DISORDERS | At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration–time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells. | PMC10835503 |
Conclusion | KCL‐286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL‐286 as a novel oral treatment for SCI.
[Correction added on 17 August 2023, after first online publication: The joint authorship note has been removed in this version.] | PMC10835503 | ||
What is already known about this subject | injuries | SCAR |
Retinoic acid receptor (RAR) β signalling is involved in central nervous system (CNS) regeneration.RARβ is a neuronal transcription factor that regulates numerous pathways in CNS regeneration; these include, axonal outgrowth, synaptogenesis, modulation of the glial scar and axonal pathfinding.KCL‐286 is a preclinical RARβ agonist developed to treat CNS injuries. | PMC10835503 |
What this study adds | nerve injuries, cord injury |
KCL‐286 was tested in healthy male adults to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of this agent under investigation for the treatment of spinal cord injury.Safety and pharmacokinetic data indicate that KCL‐286 is well tolerated at a 100‐mg daily dose, which equates to a dose shown to elicit axonal regeneration in proof‐of‐concept models of spinal cord injury.KCL‐286 engages its receptor in white blood cells and maintains activation during dosing.KCL‐286, as far as we are aware, is the first orally available RARβ agonist drug for treatment of nerve injuries. | PMC10835503 | |
INTRODUCTION | RA, cord injury, road accidents | The reported global prevalence of spinal cord injury (SCI) is between 0.7 and 1.2 million incident cases per year with falls and road accidents being the major causes.The retinoic acid (RA) signalling pathway has been shown to be involved in axonal outgrowth. The pathway consists of the nuclear receptors, the RA receptors (RARs) and the retinoid x receptors (RXRs) of which there are 3 types—α, β and γ—and various subtypes. An RAR associates with an RXR and the heterodimer binds at RA response element (RARE) of target genes and transcription occurs once a retinoid binds (Figure KCL‐286 transcriptional neuronal signalling. KCL‐286 binds to a retinoic acid receptor (RAR)β2/retinoid x receptor (RXR) heterodimer located at a retinoic acid response element (RARE). This results in activation of transcriptional pathways required for axonal regeneration.KCL‐286, also known as C286, is an oral RARβ agonist with multifactorial reparative effects in the CNS.To determine the risk: benefit ratio of KCL‐286 it is necessary to establish the safety and pharmacokinetic (PK) profile in healthy volunteers and then progress to establish efficacy in SCI patients. Here we report a Phase I safety and PK study of KCL‐286 and show that it is a safe and well‐ tolerated drug with a satisfactory PK profile that engages with its receptor in white blood cells (WBCs), where RARβ2 is expressed, | PMC10835503 | |
MATERIAL AND METHODS | PMC10835503 | |||
Study oversight | PD, SAD | BLIND | The present study is a phase 1, first‐in‐human double blind, randomized, placebo‐controlled trial, in male healthy volunteers, consisting of a single ascending dose (SAD) adaptive design with a food interaction (FI) arm, and a multiple ascending dose (MAD) design, to evaluate the safety, tolerability, PK and pharmacodynamics (PD) of KCL‐286. (Trial ID: The trial, protocol amendments, informed consent forms, investigator's brochure and any other relevant information were reviewed and approved by the London‐Surrey Borders Research Ethics Committee. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.The trial was conducted from July 2018 to December 2021 at 2 sites in the UK. All participants provided written informed consent. | PMC10835503 |
Study design | SAD | SECONDARY, BLIND | This was a prospective, Phase I, double blind, randomized, placebo controlled, dose escalating study conducted at 2 sites. The study comprised 2 parts: Part A included SAD in 8 cohorts (S1 to S8) with a food interaction (FI) arm of 1 cohort and Part B MAD in 5 cohorts (M1 to M5) in which the volunteers were dosed once daily for 7 days after fasting overnight. For all cohorts, sentinel dosing was used, the first 2 participants, 1 active and 1 placebo in each cohort were first dosed and then the remainder of the cohort including 1 placebo were dosed up to 7 days later. Safety and interim plasma PK data were reviewed at safety review committee meetings prior to commencement of the next dose. There were at least 7 days between treatment periods.The primary objective was to determine the safety and tolerability of KCL‐286 administered to healthy adult male subjects in SAD and MAD cohorts, the secondary objective was to determine PK The exploratory objective was to show target engagement of KCL‐286 in MAD cohorts by assessment of RARβ2 expression in WBCs. These data were not used to inform dosing decisions as it was an exploratory biomarker. | PMC10835503 |
Study participants | Healthy adult males aged between 19 and 45 years were randomized into the trial. Female volunteers were excluded from this study as at that time reproductive toxicology data were not complete in female models. Participants had a body mass index ≥18 and ≤30 kg/m | PMC10835503 | ||
Sample collection and analysis | BLOOD | Blood and urine samples for PK analysis were collected from the individuals in all groups within 2 h before dosing and at 0.5, 1 1.25, 1.5, 2, 3, 5, 8, 12, 24, 36 and 48 h after dosing. Venous blood samples were collected in heparin treated tubes, and centrifuged within 30 min (400 × g, 4°C, 10 min). The upper plasma layer was collected, aliquoted and stored at −70 ± 10°C. Urine samples were aliquoted and stored at −70 ± 10°C. For RARβ2 expression in WBC from MAD cohorts, blood was collected before dosing and on Days 1, 2, 4, 7, 8, 9 and 14 and analysis carried out as described in | PMC10835503 | |
PK assessments | PMC10835503 | |||
Determination of drug concentrations and dose proportionality | Plasma and urine PK parameters of KCL‐286 were analysed using noncompartmental analysis. Actual dosing and PK sampling times were used for PK parameters. Linear log trapezoidal method (linear on ascending and log on descending concentrations) was used to integrate the plasma concentration time profiles out to the time that the last measurable concentration. Parameters included, AUC, area under the plasma concentration–time curve; AUC (Dose proportionality was assessed using a power model which was fitted by restricted maximum likelihood using SAS Proc Mixed. The intercept and slope were fitted as fixed effects based on the assumption of linearity. An estimate of the slope was obtained from the power model along with its 2‐sided 90 and 95% CI. Exposure was deemed dose‐proportional if it was within 2‐fold of the mean. | PMC10835503 | ||
Starting dose and escalation decisions | Safety results and limitations imposed by the protocol were the primary consideration when deciding on the starting dose and subsequent dose for the next cohort. To calculate the starting dose, the no‐observed‐adverse‐effect level from Day‐28 dog toxicokinetic study was used for planned ceiling exposure and dose level. The values were C | PMC10835503 | ||
Statistical methods | The data processing and statistical analysis of the results were performed by Richmond Pharmacology Limited. The PK parameters were computed using WinNonlin™ PK software (version 6.3 or higher Pharsight Corp, Sunnyvale, CA, USA). All other analyses were conducted using SAS PC Version 9.4 or later (SAS Institute, NC, USA). Quantitative data are expressed as the mean ± standard deviation. | PMC10835503 | ||
Nomenclature of targets and ligands | Key protein targets and ligands in this article are hyperlinked to corresponding entries in | PMC10835503 | ||
RESULTS | PMC10835503 | |||
Subjects | SAD | A total of 109 healthy male participants took part in the study. The SAD substudy comprised 56 randomized participants: 42 participants across the single dose KCL‐286 treatment arms and 14 participants in the placebo arm. Across the cohorts, participants randomized to KCL‐286 included 3 to 1 mg, 4 to 2 mg, 5 to 48 mg and 6 participants each to 4, 8, 12, 24 and 100 mg. The 2‐mg cohort planned to include 3 participants treated with KCL‐286; however, 1 participant randomized to 2 mg KCL‐286 withdrew consent and was replaced. The 48‐mg cohort included 1 fewer participant randomized to KCL‐286 than planned (as agreed by the safety review committee). Therefore, 55 participants completed the SAD substudy.Part A: FI (single dose crossover with 7‐day washout). For the FI substudy, a dose of 6 mg KCL‐286 was selected based on the data from the SAD. The dose was chosen to ensure exposure did not exceed previous safe doses assuming a 2‐fold increase in bioavailability following food. The FI cohort comprised 8 randomized participants as planned, 4 to the fasted–fed crossover arm and 4 to fed–fasted crossover arm. One participant from each FI arm discontinued the study: 1 in the 6‐mg fasted–fed arm discontinued due to an AE and use of prohibited medication and 1 in the 6‐mg fed–fasted arm discontinued due to noncompliance and was lost to follow‐up. The remaining 6 participants in the FI cohort (3 participants in each arm) completed the study as planned.Part B: MAD (6 or 7 days of dosing once per day, fasted condition). This part of the study comprised 40 randomized participants: 30 across the multiple dose KCL‐286 treatment arms and 10 in the placebo arm. Across the cohorts, participants randomized to KCL‐286 included 6 each to the 6, 12, 24, 72 and 100‐mg multiple dose treatment arms. All 40 participants completed the MAD substudy as planned. The Surrey Clinical Research Centre had to close in December 2019; at this time, 6 SAD cohorts and the FI cohort were completed. Partially completed were SAD Cohort S7 (7 out of 8 participants dosed) and MAD Cohort M1 (5 out of 8 participants dosed). The trial was continued at Richmond Pharmacology, once covid restrictions allowed. The decision was taken to repeat MAD Cohort M1 in full (8 participants) to ensure that the full cohort was from the same study site. Furthermore, to reduce the potential for site bias in the analyses, 5 participants from the Surrey site randomized to Cohort M1 (4 randomized to active treatment and 1 randomized to placebo) were removed from the safety population.The demographics of the participants are summarized in Table Summary of participant demographics.Abbreviations: FI, food interaction; MAD, multiple ascending dose; SAD, single ascending dose; SD, standard deviation. | PMC10835503 | |
SAD | SAD | Plasma concentration–time profiles overlaid for each dose group in the SAD (linear) are in Figure Overlaid mean plasma KCL‐286 concentration Summary of pharmacokinetic parameters at Day 1 (PK set)—single ascending dose.Abbreviations: Ae, KCL‐286 excreted unchanged in a collection period; AeData show mean and standard deviation in brackets.In concentration–time data, there was a short lag time between dosing to appearance of KCL‐286 in plasma which became quantifiable at 0.25 h. Absorption was gradual. For the highest dose, 100 mg, the mean C | PMC10835503 | |
MAD | Plasma concentration–time profiles overlaid for each dose group of the MAD cohorts are in Figure Overlaid mean plasma KCL‐286 concentration Summary of pharmacokinetic parameters (PK set)—multiple ascending dose.Abbreviations: Ae, KCL‐286 excreted unchanged in a collection period; AeData show mean and standard deviation in brackets.Mean exposure for the highest dose 100 mg, on Day 1 (mean CThese reductions in exposure from Day 1 to Day 7 were observed at all doses. Variability in exposure between participants for the MAD cohorts on Day 1 was low‐moderate (CVs of 16.6–41.4% for CUrine PK concentration–time profiles are presented in Table | PMC10835503 | ||
Food effect | Plasma concentration–time profiles and plasma PK parameters following single oral doses of 6 mg KCL‐286 in fasted and fed participants are shown in Figure Summary of overall pharmacokinetic parameters (PK set)—food interaction.Abbreviations: Ae, KCL‐286 excreted unchanged in a collection period; AeData show mean and standard deviation in brackets. | PMC10835503 | ||
Assessment of dose proportionality | PMC10835503 | |||
SAD (includes 6‐mg dose from the food interaction substudy) | Increase in mean plasma exposure was between proportional and subproportional with dose in terms of mean CFor the 6‐mg fasted dose from the FI substudy, dose‐proportionality exposure increase was within 2‐fold of the nominal dose increment, and was considered to be effectively dose proportional and within normal variability (Table | PMC10835503 | ||
MAD | For the MAD cohorts, across the entire dose range steady‐state concentration was achieved from Day 3 or earlier at predose. Low concentrations of KCL‐286 were detected around 1 ng/mL from 36 or 48 h postdose through to the follow‐up time (nominally 168 h after dose 7). Over the entire dose range investigated there was a trend to subproportional exposure with increasing dose on Day 1 of the MAD being essentially similar to that observed from the SAD up to 100‐mg single dose. A similar relationship was apparent on Day 7 of the MAD, but at plasma exposures approximately half that found on Day 1 (Table | PMC10835503 | ||
Urine: All parts of the study | The amount of drug secreted in urine was proportional to the dose administered throughout all participants of the study (Tables | PMC10835503 | ||
PD results | PMC10835503 | |||
Exploratory biomarker for target engagement | RARβ2 was not detected in WBCs isolated from plasma from placebo samples or the 1‐ and 12‐mg dosed MAD cohorts. In the MAD cohorts of 24, 75 and 100 mg dosing, RARβ2 expression upon ligand binding becomes upregulated and measurable (Figure Expression of retinoic acid receptor (RAR)β2 in white blood cells in multiple ascending dose cohorts. With increasing dose of KCL‐286 there is a corresponding increase of RARβ2, which is maintained at least until Day 14, final day of blood collection. Error bars denote standard deviation. | PMC10835503 | ||
Safety evaluation | dry skin, epistaxis, stomatitis, abnormal dreams, TEAEs, pain, dizziness, nasal congestion, headache, paraesthesia, dysgeusia, TEAE, SAD | STOMATITIS, MEDICAL DEVICE SITE IRRITATION, EVENT, HYPERBILIRUBINAEMIA, DRY EYE, OCULAR HYPERAEMIA, PARAESTHESIA, EPISTAXIS, EVENTS, INJECTION SITE BRUISING, HYPERTRIGLYCERIDAEMIA | An overview of treatment‐emergent AEs (TEAEs) is provided for SAD in Table Across the SAD substudy, 56 TEAEs were reported by 31/56 (55.4%) participants. No dose relationship for any TEAE was evident. The most common TEAEs reported in the KCL‐286 treated participants included abnormal dreams (3 participants), skin exfoliation (3 participants), medical device site irritation (3 participants), headache (2 participants), dry eye (2 participants), dry skin (2 participants) and injection site bruising (2 participants). The most common TEAEs in placebo participants were abnormal dreams and headache (each in 2 participants). All other TEAEs were reported by no more than 1 participant. The events of medical device site irritation and injection site bruising resulted from study procedures (electrocardiogram electrodes and cannulation for blood draws). There was 1 clinically significant laboratory event of mild and reversible transaminase increase reported as a TEAE in a participant treated with a single 12‐mg dose.One participant in the 100‐mg cohort reported a mild unrelated TEAE of visual field defect on Day 2 that resolved within an hour. In the FI substudy, 8 TEAEs were reported by 6/7 (85.7%) participants during the fasted period and 2 TEAEs were reported by 2/7 (28.6%) participants during the fed period. In the fasted period, TEAEs reported were headache (2 participants), dizziness, dysgeusia, epistaxis, nasal congestion, pain in extremity and skin exfoliation (each in 1 participant). In the fed period, TEAEs reported were dizziness and dry skin (each in 1 participant).Across the MAD part of the study, 27 TEAEs were reported by 20/40 (50.0%) participants. The most common TEAEs reported in the KCL‐286 treated participants included dry skin (4 participants) and stomatitis (2 participants). The events of dry skin were reported in the 72‐ and 100‐mg multiple dosing groups and started within 6 days of dosing and resolved after 6–8 days. The events of stomatitis were reported in the 72‐mg multiple dosing group and started within 2 days of dosing and resolved after 11–12 days following nonpharmacological treatment. The most common TEAEs in placebo participants was dry skin (2 participants) that started on Day 2 and Day 10 and latest for 10–11 days. All other TEAEs were reported by no more than 1 participant. In the placebo group, there were 2 mild TEAEs reported for clinically significant laboratory events; these were mild hyperbilirubinaemia, which started on Day 3 and was still ongoing at follow‐up and was considered unrelated to IMP, and mild hypertriglyceridaemia, which started on Day 3 and resolved after 8 days and was considered possibly related to IMP.TEAEs reported in participants excluded from the safety analyses were reported in 3/5 participants in the MAD substudy. Two TEAEs of dry skin were reported in 1 participant in the 6‐mg MAD group; 1 event started on Day 2 and the second event on Day 3; both were considered mild and possibly related to treatment and resolved after 9 and 12 days, respectively. One TEAE of ocular hyperaemia was reported in 1 participant in the 6 mg MAD group; the event started on Day 3 and lasted for 7 days. The TEAE of ocular hyperaemia was considered mild and possibly related to treatment. One TEAE of paraesthesia was reported in the same participant; the event started on Day 1 and lasted for 20 min. The TEAE of paraesthesia was considered mild and unrelated to treatment. | PMC10835503 |
DISCUSSION | nerve injuries, dry irritated, axonal regenerationThe TEAEs, SAD | MINOR | The treatment of nerve injuries including SCI is a major unmet clinical need as there are no therapies that can lead to axonal regeneration and functional recovery. RARβ2 activation is an attractive target to treat an SCI, as it is a neuronal located transcription factor that has multiple effects on pathways involved in axonal regenerationThe TEAEs observed are consistent with the known clinical safety of oral retinoids, such as bexarotene, acitretin, isotretinoin and alitretinoin, where it has been shown that they cause dry irritated and peeling skin, which once drug administration is stopped is fully reversible.The highest dose achieved in both the SAD and MAD cohorts was 100 mg, which surpasses the anticipated desired pharmacological exposures in the rat efficacy model.Concentrations of KCL‐286 were not measured in cerebrospinal fluid in this trial as concentrations in cerebrospinal fluid are a poor indicator of CNS penetranceRenal clearance of unchanged KCL‐286 is a minor elimination process. This may be due to a formation of other metabolites although in our preclinical studies of the potential for KCL‐286 (2 μM, 0.669 μg/mL) to be metabolized by a wide range of recombinant human cytochrome and UDP glucuronosyltransferases only CYP1A2 and UGT1A1 were found to metabolize KCL‐286 to an appreciable extent. Nevertheless, as KCL‐286 development advances in the clinic the identification of KCL 286 metabolites will be determined to confirm these findings.Given that healthy volunteers were assessed in this study, CNS tissue could not be obtained to assess RARβ2 expression, so WBCs were used instead. The increase in RARβ2 expression does show that the drug engages its receptor. How much activation is required to elicit an effect in the injured nerve tissue is not known, but exposure has been achieved in the human healthy participants, which exceeds exposure in the injured rat to give a pharmacological response, suggesting that a clinical effect can be achieved in nerve injured patients. In addition, since a ceiling of RARβ2 expression was not achieved, it is possible that higher exposure may give a better therapeutic outcome.The accumulation of the retinoid within the cell | PMC10835503 |
CONCLUSIONS | PD, injuries, SCIs | This study has demonstrated that KCL‐286 an orally available RARβ agonist, engages its receptor, and the safety, tolerability, PK and PD data support the use of up to 100 mg daily in fed conditions for future clinical studies in SCIs and other CNS injuries where axonal regeneration is required. | PMC10835503 | |
AUTHOR CONTRIBUTIONS | P. | Jonathan P. T. Corcoran, Maria B. Goncalves, Adrian P. Mander, Tim Mant, Jane Holmes, Daryl Bendel, Jörg Täubel, John Posner, Henry Fok and Hana Hassanin made substantial contributions to the conception and design of the work and the analysis and interpretation of the data as well as drafting and revising the work. E.C. performed the reverse transcription–polymerase chain reaction. Tim Mant was the study sponsor chief investigator, Jörg Täubel was the principal investigator at Richmond pharmacology Ltd, and Daryl Bendel was the principal investigator at the University of Surrey. All authors have revised the work critically for important intellectual content and have provided final approval of the version to be published. | PMC10835503 | |
CONFLICT OF INTEREST STATEMENT | The authors declare no competing financial interests. MBG and J.P.T.C have a matter of composition patent for KCL‐286. | PMC10835503 | ||
Supporting information |
Click here for additional data file. | PMC10835503 | ||
ACKNOWLEDGMENTS | We thank the NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, for their support. | PMC10835503 | ||
DATA AVAILABILITY STATEMENT | The data in this article belong to the sponsor. The data may be made available to readers with permission from the corresponding author and sponsor. | PMC10835503 | ||
REFERENCES | PMC10835503 | |||
Background | hepatitis B | HEPATITIS B, VIRUS, CHRONIC HEPATITIS, HEPATITIS D | The geographical distribution of hepatitis B virus (HBV) and hepatitis D virus (HDV) genotypes is uneven and has its own clinical and organizational implications for health systems. Despite the introduction of vaccination and successful antiviral therapy the prevalence of chronic hepatitis B (with or without delta agent) increased over the past 5 years. This study aimed for the first time to investigate the molecular epidemiology of HBV and HDV in Kazakhstan. | PMC10426108 |
Methods | CHRONIC HEPATITIS | Total 834 chronic hepatitis B (with or without delta agent) patients were included to the study from November 2017 to June 2019. The material was collected from the regional hepatological сenters from 13 cities of Kazakhstan. Genotyping of HBV/HDV isolates was carried out using phylogenetic analysis of null-binary sequences of Kazakhstani isolates, in comparison with the reference sequences. Nucleotide sequence alignment was performed using the ClustalW algorithm, the “neighbor-joining” method was used for the construction of phylogenetic trees and subsequent analysis. | PMC10426108 | |
Results | Overall 341 samples were PCR-positive and genotyped for HBV. Comparison and phylogenetic analysis of nucleotide sequences of HBV isolates showed that they were represented by genotypes HBV-D (95.9%), HBV-A (3.5%) and HBV-C (0.6%). At the same time, the identity of the nucleotide sequences of Kazakhstani isolates were: HBV-D (95–100%); HBV-A (97.2–100%) and HBV-C (99%). 256 samples were PCR positive and genotyped for HDV, all of them belonged to genotype 1. | PMC10426108 | ||
Conclusion | CHRONIC HEPATITIS | This study describes for the first time the molecular epidemiology of HBV and HDV in Kazakhstan. The data obtained expand the knowledge of the global epidemiology of viruses; have potential implications for public health policy and for further clinical research on chronic hepatitis in Kazakhstan. | PMC10426108 | |
Trial registration | ClinicalTrials.gov NCT05095181 (registered on 27/10/2021). | PMC10426108 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12879-023-08524-1. | PMC10426108 | ||
Keywords | PMC10426108 | |||
Introduction | hepatitis B infection, cirrhosis, Cirrhosis, HBV infection | CIRRHOSIS, INFECTION, HEPATITIS B INFECTION, CIRRHOSIS, SUPERINFECTION, DISEASES | The burden of hepatitis B infection is highest in the WHO Western Pacific Region and the WHO African Region, where 116 million and 81 million people, respectively, are chronically infected. Sixty million people are infected in the WHO Eastern Mediterranean Region, 18 million in the WHO South-East Asia Region, 14 million in the WHO European Region and 5 million in the WHO Region of the America [Superinfection of HDV in individuals with HBV infection leads to progressive diseases and cirrhosis in approximately 80% of cases. Cirrhosis develops at a younger age than in patients with chronic HBV infection only [The course of HBV infection and progression of chronic HDV infection may depend on host and viral factors [ | PMC10426108 |
Materials and methods | PMC10426108 | |||
Study population | chronic hepatitis B | The study involved 834 adults with chronic hepatitis B (the presence of HBsAg in the blood or serum for more than 6 months), who were treated in regional hepatological centers during the November 2017 to June 2019 in 13 cities of Kazakhstan. | PMC10426108 | |
Ethics statement | Study was approved by the institutional review board of Local Ethical Committee of the National Scientific Center of Surgery named after A.N. Syzganov (Almaty, Kazakhstan) on 14 September 2017. Informed written consent was obtained after detailed explanation of the study at the time of sampling from all participants. | PMC10426108 | ||
Serological analysis | HbsAg (Abbott ARCHITECT | PMC10426108 | ||
DNA isolation | -20 | Venous blood from HBV and HDV positive patients were used for studies. HBV DNA and HDV RNA were isolated using the GeneJET Viral DNA/RNA Purification Kit (Thermo Fisher Scientific™, USA) according to the manufacturer’s instructions. 200 µl of venous blood with EDTA was used for isolation. cDNA from RNA was obtained using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems™, USA) according to the manufacturer’s instructions. DNA/cDNA was stored at -20 | PMC10426108 | |
PCR for DNA amplification | SEPARATION, AMPLIFICATION, POSITIVE | PCR was performed using a set of specific primers proposed by Sitnik et al. (2004) for HBV and Shahinsaz et al. (Shahinsaz et al., 2006) for HDV, the characteristics of which presented in Tables S1 and S2 [In the absence of a PCR product of a given size, a second round of PCR was performed with nested primers and under the same conditions, instead of DNA, PCR products of the first round were used. Positive and negative control samples were used during PCR. Both rounds of PCR were carried out with a total volume of the reaction mixture of 50 µl.Amplification of PCR products was carried out on a GeneAmp® PCR System 9700 thermal cycler (Applied Biosystems™, USA). Detection and separation of PCR products was carried out in 2% agarose gel, on TAE buffer, using GeneRuler 100 bps DNA Ladder (Thermo Fisher Scientific™, USA). Gels were stained using UltraPure™ Ethidium Bromide (Invitrogen™, USA). Samples with specific PCR products were further used for purification and subsequent sequencing. | PMC10426108 | |
Sequencing of PCR products and nucleotide sequence analysis of HBV and HDV | SEPARATION | Before sequencing, PCR products of HBV/HDV were purified from primer and nucleotide residues using ExoSAP-IT™ PCR Product Cleanup Reagent (Applied Biosystems™, USA) according to the manufacturer’s instructions. The purified PCR products were sequenced in two directions, using a forward and reverse FHBS1-RHBS1 or FHBS2-RHBS2 primers for HBV and HD-1,2 or HD-3,4 primers for HDV (developed by ThermoFisher ScientificTM, USA), in accordance with the manufacturer’s instructions for BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems™, USA).Electrophoresis and separation of labeled fragments were performed on a 3130 Genetic Analyzer (Applied Biosystems™, USA). Before electrophoresis, the PCR mixtures were cleaned of terminator residues using BigDye XTerminator (Applied Biosystems™, USA), in accordance with the manufacturer’s instructions. The analysis of the primary data was carried out using the Sequencing Analysis Software program (Applied Biosystems™, USA). The alignment and assembly of HBV and HDV nucleotide sequences was performed using the DNA Baser Sequence Assembly Software program. | PMC10426108 | |
Genotyping and HBV/HDV reference sequences | Verification of HBV DNA and HDV RNA sequences was carried out using the Nucleotide BLAST application as well as using the Genotyping (HBV) application [Genotyping of HBV/HDV isolates was carried out using phylogenetic analysis of null-binary sequences of Kazakhstani isolates, in comparison with the reference sequences indicated above and the data obtained during Nucleotide BLAST. Nucleotide sequence alignment was performed using the ClustalW algorithm of the Molecular Evolutionary Genetic Analysis (MEGA) version 7, and for the construction of phylogenetic trees and subsequent analysis, the method “neighbor-joining (NJ)” was used [ | PMC10426108 | ||
Results | Among 834 patients registered in hepatological centers of the Republic of Kazakhstan, 487 samples were positive for HBsAg at the time of the study, among which 341 were PCR-positive for HBV and genotyped. Among 487 HBsAg-positive samples, 261 samples were also positive for HDAg, while 256 were PCR-positive for HDV and genotyped. | PMC10426108 | ||
Hepatitis B virus genotyping results | hepatitis B, ’ blood | HEPATITIS B, VIRUS | Patients’ blood (487 samples in total) positive for HBsAg were obtained from the following regions of the Republic of Kazakhstan: Aktau, Atyrau, Oskemen, Turkestan, Taraz, Chimkent, Almaty, Astana, Kyzylorda, Pavlodar, Aktobe, Kostanay and Karaganda.In total, out of 487 samples, 341 samples were positive for PCR and genotyped (70% of the total number of submitted samples). Comparison and phylogenetic analysis of nucleotide sequences of PCR products of HBV isolates showed that they (n = 341) are represented by genotypes HBV-D (95.9%; n = 327), HBV-A (3.5%; n = 12) and HBV-C (0.6%; n = 2). At the same time, the identity of the nucleotide sequences of Kazakhstani isolates was: HBV-D (95–100%; n = 327); HBV-A (97.2–100%; n = 12) and HBV-C (99%; n = 2) (Table
Data on genotyping of HBV isolates isolated in the territory of the Republic of Kazakhstan, by regionThe most common HBV genotype in Kazakhstan was the D genotype with a frequency of 95.9% of the total number of sequenced samples. This genotype met and prevailed in all the studied regions. Genotype A was found in 3.5% of cases, and was found in the following regions of the Republic of Kazakhstan: Turkestan, Taraz, Chimkent, Almaty, Kyzylorda and Pavlodar, mostly in the southern regions RK. Genotype C was found only in two cases, and these were samples from Almaty. Previously, the presence of this genotype in the territory of the Republic of Kazakhstan was not reported in the literature. In 21 patients with positive PCR of HBV DNA and HDV RNA, hepatitis B virus genotype D was detected.In current study the most common subgenotype was D1–61.5% (Fig.
The prevalence of hepatitis B virus subgenotypes in the regions of Kazakhstan | PMC10426108 |
The result of a study of hepatitis D virus genotypes | VIRUS | Patient blood (261 samples) positive for HBsAg and anti-HDVAg ELISA were received from the following regions: Taraz, Chimkent, Almaty and Almaty region, Kyzyl-Orda, Pavlodar, Aktobe, Oskemen, Aktau, Atyrau, South Kazakhstan region.In total, out of 261 samples, 256 samples (98%) were PCR positive and genotyped. Comparison and phylogenetic analysis of the nucleotide sequences of PCR products of HDV isolates showed that they all belonged to genotype 1 (Fig.
Phylogenetic tree for HBV in Kazakhstan
Phylogenetic analysis of HDV isolates from the Republic of Kazakhstan, together with isolates and strains of the virus, presented in the international GenBank database. All Kazakhstani isolates are included in one common HDV-1 cluster | PMC10426108 | |
Discussion | HDV | This study described for the first time the molecular (genetic) epidemiology of hepatitis B and hepatitis Delta viruses in Kazakhstan. A total sample of 341 people with HBV and 256 people with HDV were genotyped.The most common HBV genotype was the D genotype (95.9%), specifically subgenotype D1 (61.5%) in Kazakhstan. However, genotype D is prevalent in Africa, Europe, the Mediterranean region and India, and genotypes B and C are common in Asia [In addition to genotype D of the HBV, genotype A (7.7%) and Genotype C (1.0%) were detected. In some regions of Kazakhstan (Pavlodar, Almaty, Zhambyl and Kyzylorda), HBV genotype A were identified, which has better clinical outcomes and a higher response to interferon alpha [Genotyping of the HDV revealed the presence of only genotype HDV-1 in the population of Kazakhstan. Genotype HDV-1 is the most common and it is present worldwide [ | PMC10426108 | |
Conclusion | Current study was the first to describe the molecular epidemiology of HBV and HDV in Kazakhstan. The genotype D (namely, the D1 subgenotype) of the HBV was predominant, and in all cases, the genotype 1 of the HDV was identified. The data obtained expand the knowledge of the global epidemiology of HBV and HDV and have clinical and organizational implications for the healthcare system in Kazakhstan. | PMC10426108 | ||
Acknowledgements | The authors thank the administration of the regional hepatological centers of Kazakhstan for their support in conducting the study. | PMC10426108 | ||
Author contributions | Conceptualization and Methodology: B.I.; Investigation and Data curation: B.A., K.Sh., G.A., and G.I.; Genetic testing: V.B., M.S., D.M., J.G., and I.S.; Formal analysis: D.S.; Writing - original draft preparation: B.I., B.A., and B.B.; Writing - review and editing: B.I. and A.B.; Funding acquisition: B.I.; Supervision: B.I. and S.K. | PMC10426108 | ||
Funding | This research was funded by the Ministry of Healthcare of the Republic of Kazakhstan, grant number OR12165486 “National Programme for the Introduction of Personalized and Preventive Medicine in The Republic of Kazakhstan (2021–2023)” (Grant number OR12165486, registration number 0119РКИ0356). | PMC10426108 | ||
Data Availability | All data available by request to corresponding author. | PMC10426108 | ||
Declarations | PMC10426108 | |||
Ethics approval and consent to participate | This study is being carried out in accordance with relevant guidelines and regulations. All participants had given written informed consent to one of the study investigators in accordance with the Declaration of Helsinki. Study was approved by the institutional review board of Local Ethical Committee of the National Scientific Center of Surgery named after A.N.Syzganov (Almaty, Kazakhstan) on 14 September 2017. | PMC10426108 | ||
Consent for publication | Not applicable. | PMC10426108 | ||
Clinical trial registration | ClinicalTrials.gov NCT05095181 (registered on 27/10/2021). | PMC10426108 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10426108 | ||
List of abbreviations | hepatitis B, Hepatitis B virusHepatitis D | HEPATITIS B | Hepatitis B virusHepatitis D virusWorld Health OrganizationChronic hepatitis B | PMC10426108 |
References | PMC10426108 | |||
Objectives | SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) | To explore the feasibility and effectiveness of telehealth-supervised exercise for adults with Systemic lupus erythematosus (SLE). | PMC9944478 | |
Methods | fatigue, pain | This was a non-randomised controlled pilot trial comparing telehealth-supervised exercise (8 weeks, 2 days/week, 45 min, moderate intensity) plus usual care with usual care alone. Mixed methods were used to assess change in fatigue (FACIT-fatigue), quality of life (SF36), resting fatigue and pain (11-point scale), lower body strength (five-time sit-to-stand) and endurance (30 s sit-to-stand), upper body endurance (30 s arm curl), aerobic capacity (2 min step test), and experience (survey and interviews). Group comparison was performed statistically using a two-sample T-test or Mann–Whitney U-test. Where known, we used MCID or MCII, or assumed a change of 10%, to determine clinically meaningful change within groups over time. Interviews were analysed using reflexive thematic analysis. | PMC9944478 | |
Results | Fifteen female adults with SLE were included (control group | PMC9944478 | ||
Conclusion | Key findings from this mixed-method investigation suggest that telehealth-supervised exercise was feasible for, and well-accepted by, adults with SLE and resulted in some modest health improvements. We recommend a follow-up RCT with more SLE participants. | PMC9944478 | ||
Introduction | chronic, multisystem, autoimmune disease | CARDIOPULMONARY DISEASES, AUTOIMMUNE DISEASE, SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) | Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease characterised by an immune response to self-antigens.Telehealth is a possible strategy for delivering exercise interventions for people with SLE that may alleviate some of the reported barriers (i.e. exercise performed in the comfort of the participants’ home, requiring no additional travel time and energy, and supervised to ensure safety, and increase motivation). Telehealth exercise interventions targeting fitness have proved effective and safe in other populations, including cardiopulmonary diseases | PMC9944478 |
Methods | PMC9944478 |
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