Advancing Subcutaneous Dosing Regimens for Biotherapeutics: Clinical Strategies for Expedited Market Access.

In recent years, subcutaneous administration of biotherapeutics has made significant progress. The self-administration market for rheumatoid arthritis has witnessed the introduction of additional follow-on biologics, while the first subcutaneous dosing options for monoclonal antibodies have become available for multiple sclerosis. Oncology has also seen advancements with the authorization of high-volume subcutaneous formulations, facilitated by the development of high-concentration formulations and innovative delivery systems. Regulatory and Health Technology Assessment bodies increasingly consider preference data in filing dossiers, particularly in evaluating novel drug delivery methods. The adoption of a pharmacokinetic-based clinical bridging approach has become standard for transitioning from intravenous to subcutaneous administration. Non-inferiority studies with pharmacokinetics as the only primary endpoint have started deviating from traditional randomization schemes, favoring the subcutaneous route and comparing with historical intravenous data. While nonclinical and computational models made progress in predicting safety and immunogenicity for subcutaneously dosed antibodies, clinical trial evidence remains essential due to inter-individual variations and the impact of formulation parameters on anti-drug antibody formation. Ongoing technological advancements and the expanding knowledge base on pharmacokinetic-pharmacodynamic correlation across specialty areas are expected to further accelerate clinical development of subcutaneous biologics.

Excess resource use and cost of drug-resistant infections for six key pathogens in Europe: a systematic review and Bayesian meta-analysis.

BACKGROUND: Quantifying the resource use and cost of antimicrobial resistance establishes the magnitude of the problem and drives action. OBJECTIVES: Assessment of resource use and cost associated with infections with six key drug-resistant pathogens in Europe. METHODS: A systematic review and Bayesian meta-analysis. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), Econlit databases, and grey literature for the period 1 January 1990, to 21 June 2022. STUDY ELIGIBILITY CRITERIA: Resource use and cost outcomes (including excess length of stay, overall costs, and other excess in or outpatient costs) were compared between patients with defined antibiotic-resistant infections caused by carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, CR or third-generation cephalosporin Escherichia coli (3GCREC) and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium, and patients with drug-susceptible or no infection. PARTICIPANTS: All patients diagnosed with drug-resistant bloodstream infections (BSIs). INTERVENTIONS: NA. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna Briggs Institute assessment tool, incorporating case-control, cohort, and economic assessment frameworks. METHODS OF DATA SYNTHESIS: Hierarchical Bayesian meta-analyses were used to assess pathogen-specific resource use estimates. RESULTS: Of 5969 screened publications, 37 were included in the review. Data were sparse and heterogeneous. Most studies estimated the attributable burden by, comparing resistant and susceptible pathogens (32/37). Four studies analysed the excess cost of hospitalization attributable to 3GCREC BSIs, ranging from -€ 2465.50 to € 6402.81. Eight studies presented adjusted excess length of hospital stay estimates for methicillin-resistant S. aureus and 3GCREC BSIs (4 each) allowing for Bayesian hierarchical analysis, estimating means of 1.26 (95% credible interval [CrI], -0.72 to 4.17) and 1.78 (95% CrI, -0.02 to 3.38) days, respectively. CONCLUSIONS: Evidence on most cost and resource use outcomes and across most pathogen-resistance combinations was severely lacking. Given the importance of this evidence for rational policymaking, further research is urgently needed.

Low cost, uncertain value: Why cheap PV may still not become UK's main power source.

We contrast a recent assessment by Mandys et al. that dropping PV LCOE in the UK will lead to photovoltaics becoming the most competitive renewable energy technology by 2030, by arguing that (1) strong seasonal variation, (2) too little demand correlation, and (3) highly concentrated production periods still lead to overall more competitiveness and less system cost of wind power production.

Rhodium-Catalyzed Cyclization of Terminal and Internal Allenols: An Atom Economic and Highly Stereoselective Access Towards Tetrahydropyrans.

A comprehensive study of a diastereoselective Rh-catalyzed cyclization of terminal and internal allenols is reported. The methodology allows the atom economic and highly syn-selective access to synthetically important 2,4-disubstituted and 2,4,6-trisubstituted tetrahydropyrans (THP). Furthermore, its utility and versatility are demonstrated by a great functional-group compatibility and the enantioselective total synthesis of (-)-centrolobine.

Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities.

Subcutaneous delivery of biotherapeutics has become a valuable alternative to intravenous administration across many disease areas. Although the pharmacokinetic profiles of subcutaneous and intravenous formulations differ, subcutaneous administration has proven effective, safe, well-tolerated, generally preferred by patients and healthcare providers and to result in reduced drug delivery-related healthcare costs and resource use. The aim of this article is to discuss the differences between subcutaneous and intravenous dosing from both health-economic and scientific perspectives. The article covers different indications, treatment settings, administration volumes, and injection devices. We focus on biotherapeutics in rheumatoid arthritis (RA), immunoglobulin-replacement therapy in primary immunodeficiency (PI), beta interferons in multiple sclerosis (MS), and monoclonal antibodies (mAbs) in oncology. While most subcutaneous biotherapeutics in RA, PI, and MS are self-administered at home, mAbs for oncology are still only approved for administration in a healthcare setting. Beside concerns around the safety of biotherapeutics in oncology, a key challenge for self-administration in this area is that doses and dosing volumes can be comparatively large; however, this difficulty has recently been overcome to some extent by the development of high-concentration solutions, the use of infusion pumps, and the coadministration of the dispersion enhancer hyaluronidase. Furthermore, given the increasing number of biotherapeutics being considered for combination therapy and the high dosing complexity associated with these, especially when administered intravenously, subcutaneous delivery of fixed-dose combinations might be an alternative that will diminish these burdens on healthcare systems.

Industrial pollution load assessment in Phnom Penh, Cambodia using an industrial pollution projection system.

Approximately 56% out of the total 1302 Cambodian firms are operated in the Capital city of Cambodia. The necessary information on industrial pollution to set strategies, priorities and action plans on environmental protection issues is absent in Cambodia. In the absence of this data, effective environmental protection cannot be implemented. The objective of this study is to estimate industrial pollution load by employing the Industrial Pollution Projection System, a rapid environmental management tool for assessment of pollution load, to produce a scientific rational basis for preparing future policy direction to reduce industrial pollution in Phnom Penh city. Factory data between 1994 and 2014 obtained from the Ministry of Industry and Handicraft of Cambodia were used in our study. Due to the high number of employees, the total environmental load generated in Phnom Penh city was estimated to be 476,981Mg in 2014. Phnom Penh city generated 189,109Mg of VOC, 165,411Mg of toxic chemicals to air, 38,523Mg of toxic chemicals to land, and 28,968Mg of SO2 in 2014. The results of the estimation show that the Textiles and Apparel sector was the highest generators of toxic chemicals into land and air, and toxic metals into land, air and water, while the Basic Metal sector was the greatest contributor of toxic chemicals to water. The Textiles and Apparel sector alone emitted 436,016Mg of total pollution load. The results indicate that the Dangkao and Meanchey districts were the greatest emitters of all pollutants in Phnom Penh. The results suggest that reduction in industrial pollution could be achieved by focusing on the most polluting sectors and areas. Adopting waste minimization strategies, which include cleaner production processes, will not only reduce the cost of controlling pollution, it will also make manufacturing more efficient thereby increasing profits while reducing pollution load in the long run.

Incidence and economic burden of acute otitis media in children aged up to 5years in three Middle Eastern countries and Pakistan: A multinational, retrospective, observational study.

Epidemiological data on acute otitis media (AOM), an infectious disease frequently affecting children, are lacking in some countries. This study was undertaken to assess the incidence of AOM in children ≤5years in Saudi Arabia, Oman, Pakistan, and Turkey, as well as the economic burden from a parent/caregiver perspective. Medical records of 4043 children (Saudi Arabia=1023, Oman=998, Pakistan=1022, Turkey=1000) were retrospectively reviewed and the incidence of AOM episodes calculated from suspected and confirmed cases. Using a standardized Health Economics Questionnaire, parents recorded resource use and expenses incurred per AOM episode [in local currency and converted to US dollars (USD)]. The overall incidence of AOM episodes per 1000 person-years was: Saudi Arabia, 207 [95% confidence interval (CI): 178-238]; Oman, 105 (95% CI: 85-127); Pakistan, 138 (95% CI: 116-163); and Turkey, 99 (95% CI: 79-123). The mean total out-of-pocket healthcare expense incurred by parents/caregivers per episode was: Saudi Arabia USD67.1 [standard deviation (SD)=93.0], Oman USD16.1 (SD=16.4), Pakistan USD22.1 (SD=20.5), and Turkey USD33.6 (SD=44.9). The incidence of AOM episodes varied across all four countries, probably due to different diagnostic and management practices. Nevertheless, our results confirm that AOM causes a substantial burden to public health, reinforcing the need for cost-effective prevention strategies.

Microdialysis Sampling from Wound Fluids Enables Quantitative Assessment of Cytokines, Proteins, and Metabolites Reveals Bone Defect-Specific Molecular Profiles.

Bone healing involves a variety of different cell types and biological processes. Although certain key molecules have been identified, the molecular interactions of the healing progress are not completely understood. Moreover, a clinical routine for predicting the quality of bone healing after a fracture in an early phase is missing. This is mainly due to a lack of techniques to comprehensively screen for cytokines, growth factors and metabolites at their local site of action. Since all soluble molecules of interest are present in the fracture hematoma, its in-depth assessment could reveal potential markers for the monitoring of bone healing. Here, we describe an approach for sampling and quantification of cytokines and metabolites by using microdialysis, combined with solid phase extractions of proteins from wound fluids. By using a control group with an isolated soft tissue wound, we could reveal several bone defect-specific molecular features. In bone defect dialysates the neutrophil chemoattractants CXCL1, CXCL2 and CXCL3 were quantified with either a higher or earlier response compared to dialysate from soft tissue wound. Moreover, by analyzing downstream adaptions of the cells on protein level and focusing on early immune response, several proteins involved in the immune cell migration and activity could be identified to be specific for the bone defect group, e.g. immune modulators, proteases and their corresponding inhibitors. Additionally, the metabolite screening revealed different profiles between the bone defect group and the control group. In summary, we identified potential biomarkers to indicate imbalanced healing progress on all levels of analysis.

Epidemiology of community-acquired pneumonia and implications for vaccination of children living in developing and newly industrialized countries: A systematic literature review.

This systematic review evaluated the epidemiology of community-acquired pneumonia in children <6 y of age within 90 developing and newly industrialized countries. Literature searches (1990-2011), based on MEDLINE, EMBASE, Cochrane, CAB Global Health, WHO, UNICEF, country-specific websites, conferences, health-technology-assessment agencies, and the reference lists of included studies, yielded 8,734 records; 62 of 340 studies were included in this review. The highest incidence rate among included studies was 0.51 episodes/child-year, for children <5 y of age in Bangladesh. The highest prevalence was in Chinese children <6 months of age (37.88%). The main bacterial pathogens were Streptococcus pneumoniae, Haemophilus influenzae and Mycoplasma pneumoniae and the main viral pathogens were respiratory syncytial virus, adenovirus and rhinovirus. Community-acquired pneumonia remains associated with high rates of morbidity and mortality. Improved and efficient surveillance and documentation of the epidemiology and burden of community-acquired pneumonia across various geographical regions is warranted.

Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies.

Safety monitoring following new vaccine introduction includes assessment of potential new onset autoimmune diseases (AID). As knowledge regarding AID background rates is limited, we evaluated the incidence of 11 AID in Northern California Kaiser Permanente. AID cases were identified using electronic records of members aged 10-62 years from 1998 to 2004, excluding those with AID diagnoses from 1996 to 1997. Using prespecified criteria, all identified cases of rare diseases were verified by medical record review, while a sample of cases was reviewed for common diseases; incidence rates were calculated based on the proportion of confirmed cases. Overall, the incidence of AID varied from 0.8/100,000 person-years (PY) for autoimmune hemolytic anemia (AIHA) to 54.1/100,000 PY for thyroiditis. Incidence rates in increasing order were AIHA, juvenile rheumatoid arthritis, Guillain-Barre Syndrome, idiopathic thromobocytopenia purpura, transverse myelitis, systemic lupus erythematosus, uveitis, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes mellitus and thyroiditis; incidence rates also varied according to age and gender. These background incidence rates should prove useful for future observational vaccine safety studies and will help guide evaluation of potential vaccine AID events following introduction of new vaccines.

Delay in treatment of colorectal cancer: multifactorial problem.

The stage of a colorectal carcinoma represents the most important prognostic factor regarding the probability of survival. The primary objective of this study was to document the management of patients with colorectal carcinoma after onset of symptoms. Factors influencing the delay in definitive therapy should thus be determined. Anthropometric, social, and operative data were obtained by standardized questionnaires from 40 patients with colonic cancer and 30 patients with rectal cancer. The influence of delayed treatment on outcome was analyzed. A significant correlation was found for the time between onset of first symptoms and definitive surgical therapy with tumor stage (colon cancer: r = 0.52, p < 0.05; colorectal cancer: r = 0.62, p < 0.05). The time delay in rectal carcinoma patients averaged 224 days and in patients with colonic carcinoma 149 days. Social influences such as profession, type of education, marital status, and quality of health insurance had a significant influence on treatment delay, as did the clinical experience of the physician first contacted. The leading symptom in patients with rectal cancer was peranal hemorrhage, and in patients with colonic cancer it was abdominal pain. The main causes of iatrogenic delay were insufficient clinical investigation and a lack of awareness when typical first symptoms were present. Delayed treatment of colorectal cancer seems to be a multifactorial problem. Causes for such delay are found not only in the patients and their social environments but also in the type and quality of their medical care systems. Intensified education and earlier prevention are the major aims for patients and their physicians.