An economic evaluation of highly purified HMG and recombinant FSH based on a large randomized trial

Public funding for IVF is increasingly being challenged by health authorities in an attempt to minimize health service costs. In light of treatment rationing, the need to consider costs in relation to outcomes is paramount. To assess the cost implications of gonadotrophin treatment options, an economic evaluation comparing highly purified human menopausal gonadotrophin (HP-HMG) and recombinant FSH (rFSH) has been conducted. The analysis is based on individual patient data from a large randomized controlled trial (n = 731) in a long agonist IVF protocol. The economic evaluation uses a discrete event simulation model to assess treatment costs in relation to live births for both treatments based on published UK costs. After one cycle the mean costs per IVF treatment for HP-HMG and rFSH were pound2396 (95% CI pound2383-2414) and pound2633 ( pound2615-2652), respectively. The average cost-saving of pound237 per IVF cycle using HP-HMG allows one additional cycle to be delivered for every 10 cycles. With maternal and neonatal costs applied, the median cost per IVF baby delivered with HP-HMG was pound8893 compared with pound11,741 for rFSH (P < 0.001). The cost-saving potential of HP-HMG in IVF was still apparent after varying critical cost parameters in the probabilistic sensitivity analysis.     

Epidermal growth factor receptor and human epidermal growth factor receptor 2 gene polymorphisms in endometrial cancer in a Japanese population

Endometrial cancer is associated with both EGFR and HER2 receptor activation. The EGFR and HER2 genes could be disease susceptibility candidate genes for this cancer. This study was conducted to investigate a possible association between EGFR and HER2 gene polymorphisms and endometrial cancer and the influence of these polymorphisms on the clinical outcome of endometrial cancer patients in a Japanese population. The authors compare the genotype distributions and allele frequencies of the EGFR +2073 A/T and HER2 +655 A/G polymorphisms in 116 endometrial cancer patients and 213 controls using polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis. RFLP results were confirmed by direct DNA sequencing. Of the 116 patients, 76 (65.5%) could be followed up. Disease-free survival estimates were computed using the Kaplan-Meier method, and differences between survival periods were assessed using the log-rank test. No significant differences were observed in either genotype distributions or allele frequencies in the EGFR +2073 A/T and HER2 +655 A/G polymorphisms between endometrial cancer patients and controls. The stratification by histological types and staging failed to identify significant differences between endometrial cancer patients and controls. No statistical differences were noted between these polymorphisms and disease-free survival (Kaplan-Meier log-rank test P = .55 and .66, for the EGFR +2073 A/T and HER2 +655 A/G, respectively). These results suggest that the EGFR +2073 A/T and HER2 +655 A/G polymorphisms are not associated with endometrial cancer in a Japanese population. These conclusions are based on relatively small numbers and will require verification from additional independent studies.     

Can bedside needle arthroscopy of the ankle be an accurate option for intra-articular delivery of injectable agents?

BACKGROUNDBedside needle arthroscopy of the ankle under local anesthesia has been proposed for intra-articular delivery of injectable agents. Accuracy and tolerability of this approach in the clinical setting–including patients with end-stage ankle pathology and/or a history of prior surgery–is not known.AIMTo assess clinical accuracy and tolerability of bedside needle arthroscopy as a delivery system for injectable agents into the tibiotalar joint.METHODSThis was a prospective study that included adult patients who were scheduled for an injection with hyaluronic acid to the tibiotalar joint. In our center, these injections are used as a last resort prior to extensive surgery. The primary outcome was injection accuracy, which was defined as injecting through the arthroscopic cannula with intra-articular positioning confirmed by a clear arthroscopic view of the joint space. Secondary outcome measures included a patient-reported numeric rating scale (NRS, 0-10) of pain during the procedure and willingness of patients to return for the same procedure. NRS of ankle pain at rest and during walking was collected at baseline and at 2-wk follow-up. Complications were monitored from inclusion up to a 2-wk control visit.RESULTSWe performed 24 inspection-injections. Eleven (46%) participants were male, and mean age was 46.8 ± 14.5 years. Osteoarthritis was the indication for injection in 20 (83%) cases, of which 8 (33%) patients suffered from osteoarthritis Kellgren-Lawrence grade IV, and 10 (42%) patients from Kellgren-Lawrence grade III. An osteochondral defect was the indication for injection in 4 (17%) cases. A history of ankle surgery was present in 14 (58%) participants and a history of multiple ankle surgeries in 11 (46%) participants. It was possible to confirm accuracy in 21 (88%) procedures. The 3 (12%) participants where needle arthroscopy did not reach a clear view of the joint space all suffered from Kellgren-Lawrence grade IV osteoarthritis. Pain during the procedure was reported with a median of 1 [interquartile ranges (IQR): 0–2]. Willingness to return was 100%. Pain in rest decreased from a median NRS of 4 (IQR: 2–7) at baseline to a median of 3 (IQR: 1–5) at follow-up (P < 0.01). Pain during walking decreased from a median NRS of 8 (IQR: 6–9) to a median of 7 (IQR: 4–8) (P < 0.01). Infections or other complications were not encountered.CONCLUSIONClinical accuracy and tolerability of bedside needle arthroscopy of the ankle as a delivery system for injectable agents are excellent. Accuracy was 100% in patients without total ventral joint obliteration.     

Return to Play After Distal Biceps Tendon Repair

Purpose of ReviewDistal biceps tendon ruptures (DBTR) are uncommon injuries in 40- to 50-year-old men but occur at a younger age in the athlete population. The distal biceps tendon is an important supinator of the forearm and flexor of the elbow. A complete injury results in limiting function in the upper extremity. The current review evaluates the different options in management and the current literature on return to play in athletes.Recent FindingsThe distal biceps tendon inserts on the posterior aspect of the radial tuberosity as two independent heads. The long head footprint is more proximal and posterior giving it a better lever arm for supination. The short head footprint is more distal and anterior giving it a better lever arm for flexion. Surgical anatomic repair is highly recommended among the athlete population, to restore proper function of the upper extremity. There is scarce literature on return to play among athletes. The most recent studies on high-performance athletes are on National Football League (NFL) players. These studies showed that 84–94% of NFL players returned to play at least one game after distal biceps repair. Compared to matched control groups, there was no difference in the player’s performance after surgery.SummaryAnatomic repair of DBTR results in excellent outcomes, high return to work, and high rate of return to play among athletes. When compared to matched control groups, NFL players have the performance score and play the same number of games after surgery.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12178-022-09742-x.     

Sclerostin Antibody Treatment Increases Bone Formation,Bone Mass,and Bone Strength in a Rat Model of Postmenopausal Osteoporosis

The development of bone‐rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long‐standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl‐AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six‐month‐old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency‐induced bone loss, at which point Scl‐AbII was administered for 5 wk. Scl‐AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency‐induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non‐ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody‐mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone‐related disorders, such as postmenopausal osteoporosis.     

Tim-3 mediates T cell trogocytosis to limit antitumor immunity

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1–positive (PD-1⁺) Tim-3⁺CD8⁺ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3⁺ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen–specific CD8⁺ T cells and PD-1⁺Tim-3⁺ CD8⁺ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8⁺ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8⁺ T cells impeded the trogocytosis of CD8⁺ TILs in vivo. Trogocytosed CD8⁺ T cells presented tumor peptide–major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.     

The Role of Streptococcal Cell-Envelope Proteases in Bacterial Evasion of the Innate Immune System

Bacteria possess the ability to evolve varied and ingenious strategies to outwit the host immune system, instigating an evolutionary arms race. Proteases are amongst the many weapons employed by bacteria, which specifically cleave and neutralize key signalling molecules required for a coordinated immune response. In this article, we focus on a family of S8 subtilisin-like serine proteases expressed as cell-envelope proteases (CEPs) by group A and group B streptococci. Two of these proteases known as Streptococcus pyogenes CEP (SpyCEP) and C5a peptidase cleave the chemokine CXCL8 and the complement fragment C5a, respectively. Both CXCL8 and C5a are potent neutrophil-recruiting chemokines, and by neutralizing their activity, streptococci evade a key defence mechanism of innate immunity. We review the mechanisms by which CXCL8 and C5a recruit neutrophils and the characterization of SpyCEP and C5a peptidase, including both in vitro and in vivo studies. Recently described structural insights into the function of this CEP family are also discussed. We conclude by examining the progress of prototypic vaccines incorporating SpyCEP and C5a peptidase in their preparation. Since streptococci-producing SpyCEP and C5a peptidase are responsible for a considerable global disease burden, targeting these proteases by vaccination strategies or by small-molecule antagonists should provide protection from and promote the resolution of streptococcal infections.