Results from Expanded Access Programs: A Review of Academic Literature.

BACKGROUND: Although expanded access is an increasingly used pathway for patients to access investigational medicine, little is known on the magnitude and content of published scientific research collected via expanded access. METHODS: We performed a review of all peer-reviewed expanded access publications between January 1, 2000 and January 1, 2022. We analyzed the publications for drugs, diseases, disease area, patient numbers, time, geographical location, subject, and research methodology (single center/multicenter, international/national, prospective/retrospective). We additionally analyzed endpoints reported in all COVID-19-related expanded access publications. RESULTS: We screened 3810 articles and included 1231, describing 523 drugs for 354 diseases for 507,481 patients. The number of publications significantly increased over time ([Formula: see text]). Large geographical disparities existed as Europe and the Americas accounted for 87.4% of all publications, whereas Africa only accounted for 0.6%. Oncology and hematology accounted for 53% of all publications. Twenty-nine percent of all expanded access patients (N = 197,187) reported on in 2020 and 2021 were treated in the context of COVID-19. CONCLUSIONS: By summarizing characteristics of patients, diseases, and research methods described in all scientific literature published on expanded access, we provide a unique dataset for future research. We show that published scientific research on expanded access has surged over the past decades, partly due to COVID-19. However, international collaboration and equity in geographic access remain an issue of concern. Lastly, we stress the need for harmonization of research legislation and guidance on the value of expanded access data within real-world data frameworks to improve equity in patient access and streamline future expanded access research.

Green Synthesis, Characterizations of Zinc Oxide Nanoparticles from Aqueous Leaf Extract of Tridax procumbens Linn. and Assessment of their Anti-Hyperglycemic Activity in Streptozoticin-Induced Diabetic Rats.

Herein, zinc oxide nanoparticles (ZnO NPs) were greenly synthesized from Tridax procumbens aqueous leaf extract (TPE) and characterized physically (e.g., Fourier-transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM)) and biologically (test of their anti-diabetic activity). Anti-diabetic activities of TPE and TPE-derived ZnO NPs have been carried out in a streptozotocin (STZ)­induced diabetic rat model. Diabetes mellitus (DM) was induced with a single intraperitoneal dosage of the glucose analogue STZ (55 mg/Kg) known to be particularly toxic to pancreatic insulin-producing beta-cells. TPE and TPE-derived ZnO NPs were administered orally, once every day for 21 days in diabetic rats, at 100 and 200 mg/Kg, respectively. The standard antidiabetic medication, glibenclamide, was used as a control at a dose of 10 mg/Kg. Various parameters were investigated, including bodyweight (bw) variations, glycemia, lipidaemia, glycated hemoglobin (HbA1c), and histopathological alterations in the rat's liver and pancreas. The TPE-mediated NPs were small, spherical, stable, and uniform. Compared to TPE and, to a lesser extent, glibenclamide, TPE-derived ZnO NPs lowered blood glucose levels considerably (p < 0.05) and in a dose-dependent manner while preventing body weight loss. Further, positive benefits for both the lipid profile and glycated hemoglobin were also noticed with TPE-derived ZnO NPs. The histopathological assessment revealed that synthesized TPE-derived ZnO NPs are safe, non-toxic, and biocompatible. At 200 mg/Kg/day, TPE-derived ZnO NPs had a more substantial hypoglycemic response than at 100 mg/Kg/day. Thus, in this first reported experimental setting, ZnO NPs biosynthesized from the leaf extract of Tridax procumbens exert more potent anti-diabetic activity than TPE and glibenclamide. We conclude that such a greenly prepared nanomaterial may be a promising alternative or complementary (adjuvant) therapy, at least to the current Indian's traditional medicine system. Translational findings are prompted in human populations to determine the efficacy of these NPs.

Factors influencing the use of postoperative bilevel positive airway pressure (BiPAP) in patients undergoing adult cardiac surgery: A retrospective cohort study.

BAckground and Aims: Respiratory complications are one of the biggest challenges following cardiac surgery, which can lead to hypoxia and acute respiratory failure (ARF). The aim of this study to identify the factors led to BiPAP application for postoperative respiratory complications and its effectiveness as the main outcome measures after cardiac surgery. Methods: It was a retrospective cohort study with consecutive sampling technique. A total of 335 postcardiac surgery patients medical record was reviewed who were underwent for surgery from November 1, 2018 to November 30, 2019. 265 patients were finalized for the recruitment, five patients were excluded before the final analysis. Data of 260 patients were analyzed for compiling of results. Results: The mean age was 59 years. 196 (75.4%) patients were males and females were 64 (24.6%). Mean weight was 72 kg and mean body mass index (BMI) 26.67 kg/m2 . BiPAP application was in 38 (14.6%) patients and significantly high in with high BMI, (p < 0.05). There are significant associations of BiPAP application patients with COPD (p < 0.05). Patients with positive fluid balance, cardiac dysfunction, and required inotropic support were significantly associated with BiPAP need (p < 0.05), respectively. Conclusion: BiPAP is effective to treat ARF and other respiratory complications after adult cardiac surgeries. High BMI, atelectasis, and pneumonia are also the independent factors causing ARF. BiPAP can be a successful tool for preventing the adverse effects of postoperative pulmonary complications after cardiac surgery.

Ramal Growth Assessment in Temporo-Mandibular Joint Ankylosis in Growing Patient Without Growth Centre Transplantation: Radiograph Based Study.

Introduction: The treatment of temporomandibular joint is mainly surgical and aims at restoring the function of joint and correcting the aesthetics deformity caused by ankylosis. Studies are available in the literature which showed that there is osteogenic potential in condylar stump remaining after gap arthroplasty, especially in children. Our objective was to assess the growth of ramus operated after surgery using orthopantomogram as the tool of assessment. Materials and method: Fifteen patients of prospective study design were selected for study. This study was undertaken to evaluate the mandibular ramal growth in TMJ ankylosis patients treated without growth center transplantation using orthopantomogram as a tool of assessment. Results: Mean ramal length of the operated right side was found to be 42.02 mm in immediate postoperative, 43.18 mm in sixth month postoperative and 44.57 mm in 1 year postoperative follow-up. Mean ramal length of the operated left side was found to be 40.15 mm in immediate postoperative, 42.10 mm in sixth month postoperative and 44.80 mm in 1 year postoperative follow-up. Conclusion: Our investigations showed that mandibular growth rate increases after successful treatment of ankylosis in children. One drawback of this treatment protocol that we observed was that the total growth deficit manifested in all our patients could not be made up.

Does Multimodal Therapy Influence Functional Outcome After Total Knee Arthroplasty?

Psychosocial health may influence the outcomes after total knee arthroplasty (TKA). We investigated the hypothesis that multimodal therapy influences the quality of life and function in patients diagnosed with osteoarthritis of the knee joint. Secondly, in patients who then proceed to have TKA post-multimodal therapy, does the response to the multimodal therapy influence the overall functional outcome of surgery? Patients diagnosed with osteoarthritis of the knee were enrolled in the study and prospectively followed-up. A total of 526 patients were enrolled and available for the study. All participants were enrolled for 12 classes of 60-minute duration over 6-weeks. Apart from an exercise program, the class also included physiotherapist-led education and a 'weight management' lecture by a dietitian. In summary, the multimodal therapy program improved the SF-12, OKS, pain scores (visual analogue scale) and WOMAC scores significantly. The multimodal therapy protocol can optimize patients' psychological scores prior to TKA and may enhance ultimate functional outcome.

Association of Biosecurity and Hygiene Practices with Environmental Contamination with Influenza A Viruses in Live Bird Markets, Bangladesh.

In Bangladesh, live bird market environments are frequently contaminated with avian influenza viruses. Shop-level biosecurity practices might increase risk for environmental contamination. We sought to determine which shop-level biosecurity practices were associated with environmental contamination. We surveyed 800 poultry shops to describe biosecurity practices and collect environmental samples. Samples from 205 (26%) shops were positive for influenza A viral RNA, 108 (14%) for H9, and 60 (8%) for H5. Shops that slaughtered poultry, kept poultry overnight, remained open without rest days, had uneven muddy floors, held poultry on the floor, and housed sick and healthy poultry together were more frequently positive for influenza A viruses. Reported monthly cleaning seemed protective, but disinfection practices were not otherwise associated with influenza A virus detection. Slaughtering, keeping poultry overnight, weekly rest days, infrastructure, and disinfection practices could be targets for interventions to reduce environmental contamination.

Robotic technology: current concepts, operative techniques and emerging uses in unicompartmental knee arthroplasty.

Unicompartmental knee arthroplasty (UKA) is associated with improved functional outcomes but reduced implant survivorship compared to total knee arthroplasty (TKA).Surgeon-controlled errors in component positioning are the most common reason for implant failure in UKA, and low UKA case-volume is associated with poor implant survivorship and earlier time to revision surgery.Robotic UKA is associated with improved accuracy of achieving the planned femoral and tibial component positioning compared to conventional manual UKA.Robotic UKA has a learning curve of six operative cases for achieving operative times and surgical team comfort levels comparable to conventional manual UKA, but there is no learning curve effect for accuracy of implant positioning or limb alignment.Robotic UKA is associated with reduced postoperative pain, decreased opiate analgesia requirements, faster inpatient rehabilitation, and earlier time to hospital discharge compared to conventional manual UKA.Limitations of robotic UKA include high installation costs, additional radiation exposure with image-based systems, and paucity of studies showing any long-term differences in functional outcomes or implant survivorship compared to conventional manual UKA.Further clinical studies are required to establish how statistical differences in accuracy of implant positioning between conventional manual UKA and robotic UKA translate to long-term differences in functional outcomes, implant survivorship, complications, and cost-effectiveness. Cite this article: EFORT Open Rev 2020;5:312-318. DOI: 10.1302/2058-5241.5.190089.

The effect of anterior cruciate ligament resection on knee biomechanics.

AIMS: The objectives of this study were to assess the effect of anterior cruciate ligament (ACL) resection on flexion-extension gaps, mediolateral soft tissue laxity, maximum knee extension, and limb alignment during primary total knee arthroplasty (TKA). METHODS: This prospective study included 140 patients with symptomatic knee osteoarthritis undergoing primary robotic-arm assisted TKA. All operative procedures were performed by a single surgeon using a standard medial parapatellar approach. Optical motion capture technology with fixed femoral and tibial registration pins was used to assess study outcomes pre- and post-ACL resection with knee extension and 90° knee flexion. This study included 76 males (54.3%) and 64 females (45.7%) with a mean age of 64.1 years (SD 6.8) at time of surgery. Mean preoperative hip-knee-ankle deformity was 6.1° varus (SD 4.6° varus). RESULTS: ACL resection increased the mean extension gap significantly more than the flexion gap in the medial (mean 1.2 mm (SD 1.0) versus mean 0.2 mm (SD 0.7) respectively; p < 0.001) and lateral (mean 1.1 mm (SD 0.9) versus mean 0.2 mm (SD 0.6) respectively; p < 0.001) compartments. The mean gap differences following ACL resection did not create any significant mediolateral soft tissue laxity in extension (gap difference: mean 0.1 mm (SD 2.4); p = 0.89) or flexion (gap difference: mean 0.2 mm (SD 3.1); p = 0.40). ACL resection did not significantly affect maximum knee extension (change in maximum knee extension = mean 0.2° (SD 0.7°); p = 0.23) or fixed flexion deformity (mean 4.2° (SD 3.2°) pre-ACL release versus mean 3.9° (SD 3.7°) post-ACL release; p = 0.61). ACL resection did not significantly affect overall limb alignment (change in alignment = mean 0.2° valgus (SD 1.0° valgus; p = 0.11). CONCLUSION: ACL resection creates flexion-extension mismatch by increasing the extension gap more than the flexion gap. However, gap differences following ACL resection do not create any mediolateral soft tissue laxity in extension or flexion. ACL resection does not affect maximum knee extension or overall limb alignment. Cite this article: Bone Joint J 2020;102-B(4):442-448.

The Changing Face of Infection, Diagnosis, and Management in the United Kingdom.

Prosthetic joint infection is still a rare but devastating complication following total hip and knee arthroplasty. The incidence of prosthetic joint infection ranges from 2% to 4% in primary procedures as opposed to nearly 20% in revisions. The challenges that arise here include mainly diagnostic uncertainty, management in immunocompromised patients, recurrent infection, infection around a well-fixed implant, and substantial bone loss, and require careful preoperative assessment and well-defined management plans. This article summarizes recent developments in the diagnosis and management of this increasingly prevalent issue specifically focusing on outcomes following debridement, antibiotics, and implants retention and one-stage revision procedures.

Risk factors, diagnosis and management of prosthetic joint infection after total hip arthroplasty.

Introduction: Although a relatively rare complication, the incidence and prevalence of prosthetic joint infection (PJI) is certainly rising. This is mainly due to the number of arthroplasties performed each year and our ability to capture more cases. There is currently no consensus in the optimal diagnosis and management of the infected total hip arthroplasty. Various management techniques have been described in literature.Areas covered: We discuss and summarize the literature in diagnosing prosthetic joint infection (PJI) including next-generation sequencing. An in-depth critical analysis of the biomarkers and the novel tests available in the market is reviewed including the evolving nature of the diagnostic criteria for PJI. The key issues in managing infected THA are identified.Expert commentary: The senior authors' expert opinion on diagnostic criteria is discussed. We also stress the importance of tissue/fluid analysis of microbiology and histology being key to diagnosis of PJI. The indications of one-stage versus two-stage revision arthroplasty is examined, including techniques for successful one-stage revision.

Novel Bat Alphacoronaviruses in Southern China Support Chinese Horseshoe Bats as an Important Reservoir for Potential Novel Coronaviruses.

While bats are increasingly recognized as a source of coronavirus epidemics, the diversity and emergence potential of bat coronaviruses remains to be fully understood. Among 1779 bat samples collected in China, diverse coronaviruses were detected in 32 samples from five different bat species by RT-PCR. Two novel alphacoronaviruses, Rhinolophus sinicus bat coronavirus HKU32 (Rs-BatCoV HKU32) and Tylonycteris robustula bat coronavirus HKU33 (Tr-BatCoV HKU33), were discovered from Chinese horseshoe bats in Hong Kong and greater bamboo bats in Guizhou Province, respectively. Genome analyses showed that Rs-BatCoV HKU32 is closely related to BatCoV HKU10 and related viruses from diverse bat families, whereas Tr-BatCoV HKU33 is closely related to BtNv-AlphaCoV and similar viruses exclusively from bats of Vespertilionidae family. The close relatedness of Rs-BatCoV HKU32 to BatCoV HKU10 which was also detected in Pomona roundleaf bats from the same country park suggests that these viruses may have the tendency of infecting genetically distant bat populations of close geographical proximity with subsequent genetic divergence. Moreover, the presence of SARSr-CoV ORF7a-like protein in Rs-BatCoV HKU32 suggests a common evolutionary origin of this accessory protein with SARS-CoV, also from Chinese horseshoe bats, an apparent reservoir for coronavirus epidemics. The emergence potential of Rs-BatCoV HKU32 should be explored.

National surveillance and control costs for highly pathogenic avian influenza H5N1 in poultry: A benefit-cost assessment for a developing economy, Nigeria.

We conducted benefit-cost analysis of outbreak and surveillance costs for HPAI H5N1in poultry in Nigeria. Poultry's death directly cost US$ 939,734.0 due to outbreaks. The integrated disease surveillance and response originally created for comprehensive surveillance and laboratory investigation of human diseases was adapted for HPAI H5N1 in poultry. Input data were obtained from the field, government documents and repositories and peer-reviewed publications. Actual/forecasted bird numbers lost were integrated into a financial model and estimates of losses were calculated. Costs of surveillance as alternative intervention were determined based on previous outbreak control costs and outputs were generated in SurvCost® with sensitivity analyses for different scenarios. Uncontrolled outbreaks will lead to loss of over US$ 2.2 billion annually in Nigeria with 47.8% of the losses coming from eggs. The annual cost of all animal related health activities was

Redox imbalance correlates with high Nugent score in bacterial vaginosis.

AIM: The main goal of this work was to highlight the significance of redox imbalance in the pathophysiology of bacterial vaginosis (BV). We studied the pro-oxidant (malondialdehyde) and antioxidants (glutathione, total antioxidant capacity) in the vaginal fluids of women and compared them on the basis of their Nugent score (NS). METHODS: Women were clinically screened using Amsel criteria (≥2 were regarded as positive) and were further screened for NS on the basis of microscopic examination. Subjects were classified into one of three groups - healthy controls, intermediate, and BV - on the basis of NS (0-3, 4-6, and 7-10, respectively). High vaginal swabs were collected from the study participants in order to estimate the levels of pro and antioxidants in the vaginal fluids. RESULTS: Our results indicated that levels of both pro- and antioxidants were elevated in high vaginal swabs of women in the intermediate (NS: 4-6) and BV (NS: 7-10) groups as compared to those of healthy control women. The difference in mean values for total antioxidant capacity and glutathione was found to be statistically significant. Furthermore, in the BV group (NS: ≥7) both antioxidants (glutathione and total antioxidant capacity) and the pro-oxidant, malondialdehyde, were found to be negatively correlated to NS. Interestingly, the correlation between NS and malondialdehyde was statistically significant. CONCLUSION: Our results suggest a significant correlation between redox imbalance and NS, which signifies changes in vaginal ecology from normal flora (Lactobacillus spp.) towards a more mixed bacterial population representing BV.

Role of 1.5 mm microplates in treatment of symphyseal fracture of mandible: A stress analysis based comparative study.

AIMS AND OBJECTIVES: To perform comparative finite element analysis (FEA)for 2.0 mm standard miniplate and 1.5 mm microplate in isolated symphyseal mandibular fractures. MATERIAL AND METHOD: Two FE models of mandible were developed and symphyseal fracture was created in both of them. Each fractured model was reduced and fixed using two mini plates and two microplates, respectively according Champ's principle. Stresses thus developed in the plates after application of masticatory load were observed in the models. RESULTS: Results of the study indicated there was no significant difference in the stresses developed in either of the bone plating system. CONCLUSION: 1.5 mm Microplates can be used in place of 2.0 mm miniplates in isolated symphyseal fractures of the mandible.

Visible and Sub-visible Particle Formation for a Model Bioconjugate.

The time-course and extent of visible particle (VP) and sub-visible particle (SVP) formation was monitored as a function of interfacial area (IA) for a model bioconjugate. To facilitate particle formation, the bioconjugate was agitated in a glass vial and exposed to IAs up to 478 mm2. Since vials had equal fill and headspace volumes, the area of the air-water interface was varied by placing vials on angled blocks at 0°, 30°, 60°, or 90° from the horizontal. A significant increase in visible and sub-visible particle formation was observed with increasing air-water IA. Exposure to IAs below ∼305 mm2 resulted in the formation of very few particles, while IAs > ∼305 mm2 resulted in substantial particle formation. Visible and sub-visible particle morphology varied with interfacial area and time. The sub-visible particles initially increased with time but did not reach steady state; instead the initial increase was followed by complete depletion. These phenomena indicate that visible particle formation likely increased at the expense of the sub-visible particle population and demonstrate a potential link between the two particle populations for this model bioconjugate. Initiation of particle formation did not result in corresponding decreases in protein concentration or increases in soluble aggregates. However, extended agitation time resulted in a significant decrease in protein concentration.

High Diversity of Genogroup I Picobirnaviruses in Mammals.

In a molecular epidemiology study using 791 fecal samples collected from different terrestrial and marine mammals in Hong Kong, genogroup I picobirnaviruses (PBVs) were positive by RT-PCR targeting the partial RdRp gene in specimens from five cattle, six monkeys, 17 horses, nine pigs, one rabbit, one dog, and 12 California sea lions, with 11, 9, 23, 17, 1, 1, and 15 sequence types in the positive specimens from the corresponding animals, respectively. Phylogenetic analysis showed that the PBV sequences from each kind of animal were widely distributed in the whole tree with high diversity, sharing 47.4-89.0% nucleotide identities with other genogroup I PBV strains based on the partial RdRp gene. Nine complete segment 1 (viral loads 1.7 × 104 to 5.9 × 106/ml) and 15 segment 2 (viral loads 4.1 × 103 to 1.3 × 106/ml) of otarine PBVs from fecal samples serially collected from California sea lions were sequenced. In the two phylogenetic trees constructed using ORF2 and ORF3 of segment 1, the nine segment 1 sequences were clustered into four distinct clades (C1-C4). In the tree constructed using RdRp gene of segment 2, the 15 segment 2 sequences were clustered into nine distinct clades (R1-R9). In four sea lions, PBVs were detected in two different years, with the same segment 1 clade (C3) present in two consecutive years from one sea lion and different clades present in different years from three sea lions. A high diversity of PBVs was observed in a variety of terrestrial and marine mammals. Multiple sequence types with significant differences, representing multiple strains of PBV, were present in the majority of PBV-positive samples from different kinds of animals.

Forehead flap in maxillofacial surgery: Our experiences.

The forehead flap is a commonly used technique to reconstruct the deep and large nasal defects. It can be conveniently performed under local or general anesthesia and provides a very good color and texture matching to the nasal skin, which makes it a suitable graft harvesting site for nasal reconstruction. It has only single disadvantage disadvantagethat it is a two-stage procedure and "finishing" surgeries are needed occasionally for best surgical and cosmetic outcome. In this paper, we describe three different applications of forehead flaps.