Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Interactive pregnancy education on stress, cortisol, and epinephrine level in primigravida of trimester III pregnant: a quasi-experimental.

Infant mortality is caused by various health problems, especially since the gestation period, even starting before the gestation period. Stress during pregnancy affects the motor, cognitive, and emotional development of the baby. This study aims to determine the effect of interactive pregnancy education (IPE) on decreasing levels of cortisol, epinephrine, and its relationship with stress levels in third-trimester primigravida pregnant women. This research is a quasi-experimental study using a nonequivalent control group design, which has two groups, namely the experimental group and the control group. The authors compared the experimental group that was given the intervention with the control group that was not given any treatment. This research was conducted in the three Community Health Centers in Indonesia from June 2022 until December 2022. The samples were 30 third-trimester primigravida pregnant women for the intervention and control groups. Data were analyzed using the Mann-Whitney and Wilcoxon tests with SPSS 22 software. The results of this study indicate that IPE has a good impact on pregnant women, where there is a significant relationship in the post-test cortisol and epinephrine levels in the intervention group. This indicates that IPE contributed to the difference in post-test scores in the intervention group. The IPE method is effective in reducing stress levels and cortisol levels in pregnant women, especially in pregnant women with high levels of stress.

Quadriceps sparing total knee replacement. The initial experience with results at two to four years.

The aim of this study was to compare the results in patients having a quadriceps sparing total knee replacement (TKR) with those undergoing a standard TKR at a minimum follow-up of two years. All patients who had a TKR with a high-flex posterior-stabilised prosthesis prior to December 2002 were reviewed retrospectively. There were 57 patients available for follow-up. Those with a quadriceps sparing TKR had less pain peri-operatively with a greater degree of flexion at all the post-operative visits and at the final follow-up, but their operations took longer, with less accurate radiological alignment. There was no difference in the complications and in the Knee Society scores between the two groups at the final follow-up. Total knee replacement through a quadriceps sparing approach has some peri-operative advantages over the standard incision. At a minimum follow-up of two years the clinical results were similar to those with a standard incision, but the radiological outcomes of the quadriceps sparing group were inferior.

Comparative analytical characterization of two commercial human follicle-stimulating hormones extracted from human urine.

OBJECTIVE: Pharmaceutical preparations of human menopausal gonadotrophin (hMG), urine-derived follicle-stimulating hormone (u-FSH) and highly purified u-FSH (u-FSH-HP) have been available since the early 1960s and the mid 1980s and 1990s, respectively. Another commercial preparation of u-FSH-HP, Folyrmon P, was launched in Japan in 1999. The aim of this study is to assess the purity of Folyrmon P and to compare it with Fertinorm-P, another commercial preparation of u-FSH-HP that has been available since 1993. METHODS: Folyrmon P and Fertinorm-P were assessed for total protein content, biological activity, immunological activity, specific activity, purity and levels of protein contamination. RESULTS: Folyrmon P, which is extracted from the urine of post-menopausal women, has a specific activity of between 4000 and 5000 IU/mg, while Fertinorm-P, which is also manufactured from the urine of post-menopausal women, has a specific activity of at least 10,000 IU/mg. It has been well documented that commercially available hMG and u-FSH preparations can contain a number of urine-derived protein contaminants. This also proves to be the case for Folyrmon P, in which contaminant proteins other than FSH were shown to be present. It was also demonstrated that both preparations, Folyrmon P and Fertinorm-P, contained high levels of oxidized FSH. CONCLUSIONS: The low specific activity and high level of contaminants in Folyrmon P indicate that this u-FSH is not highly purified. Overall, Fertinorm-P, with higher specific activity and lower levels of contaminant proteins, appears to be of higher quality compared with Folyrmon P.

Viscoelastic behavior of osteoarthritic cartilage.

We have studied the incremental stress-strain behavior of human articular cartilage in tension in an attempt to understand the molecular basis for fibrillation and fissure formation in osteoarthritis. Our results indicate that the elastic spring constant for collagen in the direction per pendicular to the cleavage line pattern is about 1.6 GPa (2.3 GPa after correction for the collagen content) and the collagen fibril length is between 0.558 pm at low strains and 1.24 pm at high strains for normal cartilage. Values for the elastic spring constant and collagen fibril length were both found to decrease in OA. The value of the elastic spring constant for collagen perpendicular to the cleavage line pattern is similar to that calculated based on stress-strain curves reported by Kempson. Our results indicate that the elastic spring constant for collagen and the collagen fibril length decrease as the extent of fibrillation and fissure formation increase. Decreases in the elastic spring constant of collagen are consistent with loss of the superficial layer, degradation of proteoglycans and collagen, and subsequent mechanical fatigue. However, changes in the polymer volume fraction are consistent with enzymatic degradation preceding mechanical disruption. It is concluded that osteoarthritic changes to cartilage involve enzymatic degradation of matrix components and fibril fragmentation that is promoted by subsequent mechanical loading.

Relationship among biomechanical, biochemical, and cellular changes associated with osteoarthritis.

Articular cartilage that lines the surface of long bones is a multilayered material. The superficial layer consists of collagen fibrils and chondrocytes that run parallel to the joint surface. In the deeper layers, the collagen fibrils are more randomly arranged and support vertical units termed chondrons containing rows of chondrocytes. In the deepest layers, the collagen fibrils run almost vertically and ultimately insert into the underlying subchondral bone. Osteoarthritis (OA) is a disease that affects articular cartilage and is characterized by enzymatic and mechanical breakdown of the extracellular matrix, leading to cartilage degeneration, exposure of subchondral bone, pain, and limited joint motion. Changes in mechanical properties of articular cartilage associated with OA include decreases in modulus and ultimate tensile strength. These changes parallel the changes observed after enzymatic degradation of either collagen or proteoglycans in cartilage. Results of recent viscoelastic studies on articular cartilage suggest that the elastic modulus of collagen and fibril lengths decrease in OA and are associated with a loss of the superficial zone and a decreased ability of articular cartilage to store elastic energy during locomotion. It is suggested that osteoarthritic changes to cartilage involve enzymatic degradation of matrix components and fibril fragmentation that is promoted by subsequent mechanical loading.

Patellar fractures in posterior stabilized knee arthroplasties.

In the present study, a significantly higher rate of lateral release was demonstrated in the patients with patellar fractures despite the relative high overall lateral release rate (82%). Although the complication of patellar fractures in total knee arthroplasty has a multifactorial etiology, these findings implicate lateral retinacular release as a significant factor. It is unclear whether the lateral retinacular release was a direct result of the surgical technique or whether it was necessitated by the anatomy of the patellofemoral articulation in this component system. Lateral release may continue to be performed as needed during total knee arthroplasty to maintain optimal patellofemoral mechanics. However, if it is performed, an attempt should be made to preserve the lateral superior genicular artery.

Patella baja in anterior cruciate ligament reconstruction of the knee.

Twenty-nine consecutive arthroscopic assisted anterior cruciate ligament (ACL) reconstructions of the knee were retrospectively studied to evaluate the incidence of patella baja and the correlation of the finding with patellofemoral pain after the ligament surgery. The central one third of the patellar ligament was used and positioned isometrically. The patellar ligament defect was sutured closed. The incidence of patellar chondromalacia at the time of surgery was 24%. The incidence of medial femoral condyle chondromalacia was 59%. The incidence of symptoms of patellofemoral pain after surgery was 14%. Patella baja occurred in 76% of the ligament reconstructions. Two knees showed unexplained patellar tendon lengthening. There was no statistical difference in the results between the knees with and without baja. Postoperative symptoms of patellofemoral pain correlated best with chondromalacia of the patella or the medial femoral condyle at the time of the surgical procedure. Use of the central one third of the patellar tendon with closure of the defect does lead to baja; however, the presence of this radiographic finding does not correlate with patellofemoral pain.

Conservative care for patellofemoral pain.

Patellofemoral pain is the most common presenting complaint about the knee joint. The explanation for this pain is not entirely clear. The four schools of thought concerning the etiology are divided among explanations based on anatomy, biomechanics, and biochemistry. The treatment for the disease is compromised by the lack of a clear causative agent. Exercises, braces, activity modification, and some medications form the basic protocol for treatment. Until the etiology becomes clear, these approaches represent the only reasonable therapy.

Anterior cruciate ligament reconstruction using a composite collagenous prosthesis. A biomechanical and histologic study in rabbits.

We evaluated a prototype composite collagenous anterior cruciate ligament replacement device designed to possess the advantages of biological grafts and synthetic materials. Collagenous anterior cruciate ligament prostheses were made by embedding 225 reconstituted type I collagen fibers in a type I collagen matrix, and placing polymethylmethacrylate bone fixation plugs on the ends. The collagenous prosthesis was used to replace the anterior cruciate ligament of 31 mature rabbits. At 4 and 20 weeks postimplantation, histologic and mechanical studies were performed on the developing neoligament tissue, and compared to values for the contralateral sham-operated control. At 4 weeks, neoligament tissue infiltrated the collagen fibers of the prostheses. The tibial bone tunnel attachment site contained new bone approaching the fibrous neoligament. The glutaraldehyde-treated prosthetic fibers appeared intact, while the carbodiimide-treated prosthetic fibers began to resorb. The ultimate load and ultimate tensile strength of femur-neoligament-tibia complexes had decreased. At 20 weeks, glutaraldehyde-treated fibers appeared partially intact; in contrast, the carbodiimide-treated prostheses appeared to be completely degraded, and were replaced by organized, crimped neoligament tissue. The ultimate tensile strength and ultimate load increased substantially due to deposition and remodeling of neoligament tissue. The neoligament ultimate load was 2 to 4 times the initial load value of the prosthesis. Implantation of a resorbable, composite collagenous anterior cruciate ligament prosthesis encourages the development of functional neoligament tissue. Studies are underway to optimize the mechanical and biological properties of the prostheses.

Regeneration of Achilles tendon with a collagen tendon prosthesis. Results of a one-year implantation study.

We previously reported on the short-term biocompatibility of a reconstituted type-I collagen prosthesis that had been tested in the Achilles tendons of rabbits. Preliminary results indicated that, by ten weeks after implantation, carbodiimide-cross-linked implants had been replaced by neotendon in a manner that was similar to that of autogenous tendon grafts that had been used as controls. Also by ten weeks after implantation, glutaraldehyde-cross-linked collagen implants were encapsulated and appeared to have caused an acute inflammatory response. In the present study, carbodiimide and glutaraldehyde-cross-linked collagen implants and autogenous grafts that served as controls were implanted for fifty-two weeks as a replacement for a three-centimeter section of the Achilles tendon of rabbits. The absence of a crimp in a cross-linked implant and the presence of a crimp in normal tendon and in tendon that formed after an implant had been resorbed made it possible to distinguish between a cross-linked implant and new host tendon that had replaced the implant after it was resorbed. New collagen that had replaced the implant and autogenous (control) tendon graft were compared with normal Achilles tendon with respect to the angle and length of the crimp. The autogenous grafts and the carbodiimide-cross-linked collagen implants had been completely resorbed and replaced by neotendon. The neotendon that was present fifty-two weeks after implantation was similar, but not identical, to normal tendon. In contrast, the glutaraldehyde-cross-linked implant was essentially inert, had not been resorbed, and was surrounded by a capsule of collagenous connective tissue. The neotendon in the capsule was also similar, but not identical, to normal tendon. There were more cells in the capsule than in the autogenous grafts or in the carbodiimide-cross-linked implants. The results of the present study indicate that rapid repair is achieved with a carbodiimide-cross-linked collagenous implant that has a structure and mechanical properties that are similar to those of an autogenous tendon graft and that biodegrades at a similar rate. Prolonged biodegradation of a glutaraldehyde-cross-linked collagenous implant results in formation of a capsule and only limited formation of neotendon.

Anterior cruciate ligament replacement: a review.

The anterior cruciate ligament (ACL) is the major intra-articular mechanical element that limits motion of the tibia with respect to the femur. It is a multi-fasciculated structure composed of crimped aligned collagen fibers. The purpose of this paper is to review the literature on ACL structure and mechanical properties in an effort to stimulate the development of a new generation of more effective replacement devices. Replacement of the ACL is achieved using biologic and synthetic grafts. Biologic grafts include illiotibial band, semitendinosus and gracilis tendons, patellar tendon, and meniscus. Bone-patellar-bone complexes used to replace the ACL are revascularized and ultimately replaced by neo-ligament. Synthetic implants including the Integraft, Leads-Keio ligament, Gore-Tex¿ ligament and Kennedy Ligament Augmentation Device (LAD) have either not been approved or approved by the FDA for limited use as a replacement for the ACL. The Kennedy LAD has been found to increase the strength of autogenous tissue during revascularization. Based on the success of autografts and the Kennedy LAD, we conclude that the next generation of ACL replacement devices will consist of a scaffold and a biodegradable augmentation device. The scaffold will have a structure that mimics the normal ACL as well as stimulates revascularization and healing. A biodegradable augmentation device will be employed to mechanically reinforce the scaffold without stress shielding the neo-ligament. By combining the advantages of autografts and a biodegradable augmentation device, a new generation of ACL replacements will be achieved.

Development of a reconstituted collagen tendon prosthesis. A preliminary implantation study.

A reconstituted collagen tendon prosthesis was developed and implanted in rabbit Achilles tendons. The prosthesis was prepared by extruding type-I collagen into fibers and crosslinking it either with glutaraldehyde or with dehydrothermal treatment followed by exposure to carbodiimide. A tendon prosthesis was assembled by coating a longitudinal array of the fibers with uncrosslinked collagen. In one leg of the rabbit, the Achilles tendon was replaced with the synthetic tendon; in the contralateral leg of the animal, the tendon was excised, devascularized, and anastomosed as an autogenous graft. The autogenous tendon grafts were seen to be infiltrated centrally by fibroblasts and capillaries ten weeks postoperatively and to have been partially replaced by repair tissue twenty weeks postoperatively. Three weeks after implantation, all collagen implants were noted to have been infiltrated with fibrous tissue. At ten weeks, reorganization of collagenous tissue was observed in and around the prostheses, and the carbodiimide-crosslinked implants had been resorbed and replaced by normal-appearing neotendon. The implants that had been treated with glutaraldehyde were resorbed more slowly and were surrounded by more inflammatory cells, compared with the prostheses that had been treated with carbodiimide. Neotendon in the glutaraldehyde-treated prostheses matured more slowly. When the implants were examined at intervals after the operation, their mechanical properties approached those of fresh tendon. The initial strength of the carbodiimide-treated implants was lower than that of the fresh autogenous grafts. Twenty weeks after implantation, the strength and modulus of the carbodiimide-treated implants approached those of fresh tendon.(ABSTRACT TRUNCATED AT 250 WORDS)

The popliteus tendon.

The posterior aspect of forty cadaver knees was dissected to determine the proximal insertion of the popliteus tendon, particularly its relationship to the lateral meniscus. Thirty-three (82.5 per cent) of the specimens demonstrated no major attachment of the popliteus tendon to the lateral meniscus. Eight specimens were from bilateral dissections and revealed no major asymmetry. On the basis of these dissections, we found no evidence that the popliteus tendon has a role in the retraction and protection of the lateral meniscus.

Laminectomy with and without spinal fusion.

This retrospective study evaluates two groups of patients surgically treated for a symptomatic, myelographically proven, herniated nucleus pulposus with a follow-up period from 3.5 to 16 years. One hundred thirty-four patients were treated with laminectomy, discectomy, and fusion (LDF) between the years 1972 and 1978; 49 returned for follow-up examination. Two hundred patients had laminectomies and discectomies between the years 1968 and 1981; 40 returned for follow-up evaluation. Two of the disc patients had a repeat laminectomy for recurrent disc herniation, thus totaling 42 laminectomies. Each patient was scored on a scale from zero to 100. The LDF cases had an average score of 70 points. The disc cases had an average score of 69 points. Three of the LDF cases (6%) and eight of the disc cases (19%) had had a second operation. Laminectomy patients have a significantly higher reoperation rate than patients who have had spinal fusion along with laminectomy; however, the authors were unable to evaluate the results in the two groups by the overall score.

Patellar pain and incongruence. II: Clinical application.

Proximal realignment was performed in 75 knees due to patellar pain or instability. With a follow-up period of from two to ten years, the result was excellent or good in 68 knees (91%) and fair or poor in seven knees (9%). Postoperative Merchant views were obtained in 57 knees. In the 52 knees rated good and excellent, the average congruence angle was -11 degrees. Five knees were rated fair or poor, with an average congruence angle of 0 degree. Clinical results seemed to correlate more with correction of patellar congruence than with the severity of chondromalacia found at operation.

Principles of surgical technique in knee arthroplasty.

Surgical technique in knee arthroplasty is quite demanding, requiring an understanding of arthritic deformities and meticulous attention to the principles of component insertion. Increasing clinical success in knee arthroplasty can be attributed to better designs, materials, and, most significantly, surgical technique. Although the "new generation" of instruments enhances the likelihood of a reproducible technique, anatomic variation precludes precise application of any instrumentation to all knees. The surgeon must recognize the weakness of the selected system while understanding the principles of conformity, alignment, and rotation to insure technical accuracy.

Resurfacing of the patella.

The results of use of twenty-nine patellar resurfacing prostheses in twenty-eight patients were studied. The diagnosis was osteoarthritis in twenty-two knees, chondromalacia in five knees, and habitual dislocation with severe osteoarthritis in two. The follow-up time was from three to six years. A cemented chromium-cobalt prosthesis was used. Of the twenty-nine knees studied, two were rated excellent; fourteen, good; three, fair; and ten, poor. Failure was always due to unrelieved pain.