Assessment of the Quality of the Clinical Evidence in Submissions to the Australian Pharmaceutical Benefits Advisory Committee: Fit for Purpose?

BackgroundAssessments of the comparative clinical (and cost) effectiveness of new medicines are increasingly being used to inform decisions on their reimbursement. Assessments of added clinical benefit are invariably based on evidence generated to support registration.ObjectiveOur objective was to identify and characterize significant problems relating to the quality of the clinical evidence in submissions to the Australian Pharmaceutical Benefits Advisory Committee (PBAC) seeking subsidy on the Pharmaceutical Benefits Scheme and thus determine whether the evidence presented to the committee was “fit for purpose.”MethodsWe conducted a retrospective analysis of submissions considered by the PBAC between 2005 and 2012 using a published evaluation framework. We developed an additional framework to categorize significant problems in more detail. Significant problems related to the choice of comparator, the unavailability of randomized clinical trial evidence, poor-quality data, a claim of clinical superiority, and a claim of clinical noninferiority.ResultsWe identified 261 significant problems in 479 major submissions. There was a significant problem with the sponsor’s choice of comparator in 11% of the submissions. The most common significant problem (29%) was the determination of a medicine’s comparative performance in the target patient population.ConclusionsThe supporting clinical evidence is the foundation of a PBAC submission. We found a poor fit for purpose; on average, one in every two major submissions had a significant problem with the supporting evidence. The findings from our study, if confirmed in other jurisdictions, raise important questions regarding what clinical evidence should be generated to support the reimbursement of new medicines.     

2016–2017 Arkansas mumps outbreak in a close-knit community: Assessment of the economic impact and response strategies

On August 8, 2016, a confirmed case of mumps was reported to the Arkansas Department of Health (ADH) in an adult resident of Springdale, Arkansas. By July 2017, nearly 3,000 cases of mumps were reported to ADH from 37 of the 75 counties in Arkansas. Over 50% of cases were in the Arkansas Marshallese community, a close-knit community characterized by large, and extended families sharing the same living space and communal activities. In a statewide effort, ADH collaborated with CDC, the Republic of the Marshall Island’s (RMI) Ministry of Health, and the Arkansas Department of Education (ADE) to rapidly respond to and contain the outbreak. We assessed the economic burden to ADH of the outbreak response in terms of containment and vaccination costs, as well as response costs incurred by CDC, RMI, and ADE. The 2016–2017 Arkansas mumps outbreak was the second largest US mumps outbreak in over 30 years and was unique in size, spread, and population affected. Total public health response costs as a result of the outbreak were over $2.1 million, approximately $725 per case. The costs incurred to control this outbreak reflect the response strategies tailored to the affected populations, including consideration of social, cultural, and political factors in controlling transmission and requirements of distinctive strategies for public health outreach. Aside from the burden these outbreaks have on the affected population, we demonstrate the potential for high economic burden of these outbreaks to public health.     

Induction of an effective anti-Amyloid-β humoral response in aged mice

Aging-related decline in immune functions, termed immunosenescence, is a primary cause of reduced protective responses to vaccines in the elderly, due to impaired induction of cellular and humoral responses to new antigens (Ag), especially if the response is T cell dependent. The result is a more severe morbidity following infections, more prolonged and frequent hospitalization, and a higher mortality rate than in the general population. Therefore, there is an increasing need to develop vaccination strategies that overcome immunosenescence, especially for aging-related diseases such as Alzheimer’s disease (AD). Here we report a new vaccination strategy harnessing memory-based immunity, which is less affected by aging. We found that aged C57BL/6 and 5xFAD mice exhibit a dramatic reduction in anti-Amyloid-β (Aβ) antibody (Ab) production. We aimed to reverse this process by inducing memory response at a young age. To this end, young mice were primed with the vaccine carrier Hepatitis B surface antigen (HBsAg). At an advanced age, these mice were immunized with an Aβ_1-11 fused to HBsAg. This vaccination scheme elicited a markedly higher Aβ-specific antibody titer than vaccinating aged unprimed mice with the same construct. Importantly, this vaccine strategy more efficiently reduced cerebral Aβ levels and altered microglial phenotype. Overall, we provide evidence that priming with an exogenous Ag carrier can overcome impaired humoral responses to self-antigens in the elderly, paving the route for a potent immunotherapy to AD.     

Hazelnut and neuroprotection: Improved memory and hindered anxiety in response to intra-hippocampal Aβ injection

Objectives: Corylus avellana L. (hazelnut) is known to be a delicious and nutritious food. This study was carried out to evaluate the use of hazelnut as a therapy for memory impairment because in Iranian traditional medicine, it is recommended for those suffering from a particular type of dementia, with symptoms of Alzheimer's disease.

Methods: In this study, rats were fed with hazelnut kernel [(without skin) 800?mg/kg/day] during 1 week before stereotaxic surgery to 24?hours before behavioral testing (in general, for 16 consecutive days) and the effect of hazelnut eating on memory, anxiety, neuroinflammation and apoptosis was assessed in the amyloid beta-injected rat.

Results: The results of this study showed that feeding with hazelnut improved memory, (which was examined by using Y-maze test and shuttle box apparatus), and reduced anxiety-related behavior, that was evaluated using elevated plus maze. Also, western blotting analysis of cyclooxygenase-2, interleukin-1β, tumor necrosis factor-α, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, and caspase-3 showed that hazelnut has an ameliorating effect on the neuroinflammation and apoptosis caused by Aβ.

Discussion: These ?ndings suggest that hazelnut, as a dietary supplement, improves healthy aging and could be a beneficial diet for the treatment of AD.     

Enhanced protective immune response to PCV2 subunit vaccine by co-administration of recombinant porcine IFN-γ in mice

The capsid (Cap) protein of PCV2 is the major immunogenic protein that is crucial to induce PCV2-specific neutralizing antibodies and protective immunity; thus, it is a suitable target antigen for the research and development of genetically engineered vaccines against PCV2 infection. IFN-γ has exhibited potential efficacy as an immune adjuvant that enhances the immunogenicity of certain vaccines in experimental animal models. In this study, three recombinant proteins: PCV2-Cap protein, porcine IFN-γ (PoIFN-γ), and the fusion protein (Cap-PoIFN-γ) of PCV2-Cap protein and PoIFN-γ were respectively expressed in the baculovirus system, and analyzed by Western blot and indirect ELISA. Additionally, we evaluated the enhancement of the protective immune response to the Cap protein-based PCV2 subunit vaccine elicited by co-administration of PoIFN-γ in mice. Vaccination of mice with the PCV2-Cap + PoIFN-γ vaccine elicited significantly higher levels of PCV2-specific IPMA antibodies, neutralizing antibodies, and lymphocyte proliferative responses compared to the Cap-PoIFN-γ vaccine, the PCV2-Cap vaccine, and LG-strain. Following virulent PCV2 challenge, no viraemia was detected in all immunized groups, and the viral loads in lungs of the PCV2-Cap + PoIFN-γ group were significantly lower compared to the Cap-PoIFN-γ group, the LG-strain group, and the mock group, but slightly lower compared to the PCV2-Cap group. These findings suggested that PoIFN-γ substantially enhanced the protective immune response to the Cap protein-based PCV2 subunit vaccine, and that the PCV2-Cap + PoIFN-γ subunit vaccine potentially serves as an attractive candidate vaccine for the prevention and control of PCV2-associated diseases.     

Chemical composition of surgical smoke formed in the abdominal cavity during laparoscopic cholecystectomy – Assessment of the risk to the patient

Objectives

The aim of this study was to assess the exposure of patients to organic substances produced and identified in surgical smoke formed in the abdominal cavity during laparoscopic cholecystectomy.

Material and Methods

Identification of these substances in surgical smoke was performed by the use of gas chromatography-mass spectrometry (GC-MS) with selective ion monitoring (SIM). The selected biomarkers of exposure to surgical smoke included benzene, toluene, ethylbenzene and xylene. Their concentrations in the urine samples collected from each patient before and after the surgery were determined by SPME-GC/MS.

Results

Qualitative analysis of the smoke produced during laparoscopic procedures revealed the presence of a wide variety of potentially toxic chemicals such as benzene, toluene, xylene, dioxins and other substances. The average concentrations of benzene and toluene in the urine of the patients who underwent laparoscopic cholecystectomy, in contrast to the other determined compounds, were significantly higher after the surgery than before it, which indicates that they were absorbed.

Conclusions

The source of the compounds produced in the abdominal cavity during the surgery is tissue pyrolysis in the presence of carbon dioxide atmosphere. All patients undergoing laparoscopic procedures are at risk of absorbing and excreting smoke by-products. Exposure of the patient to emerging chemical compounds is usually a one-time and short-term incident, yet concentrations of benzene and toluene found in the urine were significantly higher after the surgery than before it.     

Blood, sweat and semen: the economy of axé and the response of Afro-Brazilian religions to HIV and AIDS in Recife

This article provides an ethnographic analysis of Afro-Brazilian religious responses to the HIV epidemic in Recife. Drawing on participant observation and in-depth interviews conducted with Afro-Brazilian religious leaders and public health officials, it highlights the importance of the axé--a mystical energy manipulated in religious rituals that is symbolically associated with blood, sweat and semen. In an analysis of the relationship formed between the state AIDS programme and Afro-Brazilian religious centres, we conclude that the recognition of native categories and their meanings is one of the key elements to a fruitful dialogue between public health programmes and religious leaders that in the case studied, resulted in the re-signification of cultural practices to prevent HIV. Although the Afro-Brazilian religious leaders interviewed tended to be more open about sexuality and condom promotion, stigma towards people living with HIV (PLHIV) was still present within the religious temples, yet appeared to be more centred upon the perception of HIV as negatively affecting followers' axé than judgement related to how one may have contracted the virus. We discuss the tensions between taking a more liberal and open stance on prevention, while also fostering attitudes that may stigmatise PLHIV, and make suggestions for improving the current Afro-Brazilian response to the epidemic.     

Use of the Spanish Version of the Rapid Geriatric Assessment in Mexican Patients in Long-Term Care

We report our experience with the use of a Spanish version of the rapid geriatric assessment of 30 patients in 2 long-term care institutions in Mexico City by a group of healthcare students without prior experience in geriatric medicine. The Spanish version of the rapid geriatric assessment is a very easy tool to administer that can provide overall good results for identifying frailty, sarcopenia, anorexia, weight loss, and cognitive impairment.     

Local and Remote Sequel? of Infection in the Parodontal Sulcus: (Section of Odontology)

(1) It is shown in this paper that the infecting organisms in the parodontal sulcus are confined to the surface, but may be forced into the blood and lymph stream by traumatic interference.2. Local and general disturbances may therefore arise both as a result of the absorption of soluble toxic matter from the pocket into the tissues and also as a result of this traumatic introduction of organisms into the blood-stream.3. The effect of toxic absorption on the local tissues is destruction of the attachment of the tooth-pyorrhœa.4. The remote effects of toxic absorption may be a similar destruction of the connective tissue generally-arthritis and fibrositis. The liver and kidney may suffer since they excrete the toxic matter, and other susceptible tissues may also be involved.5. Traumatic bacteræmia may produce local bone necrosis or “dry” socket. Acute suppurative lymphangitis produces the “pyorrhœtic abscess”.6. The remote effect of bacteræmia may be to produce osteomyelitis (e.g. of the tibia) or to convert a simple endocarditis into the bacterial type.7. The mechanism of bone absorption and deposition in response to irritation is discussed.8. Methods of eliminating parodontal infection are referred to and the importance of complete elimination is stressed. It is shown to be not incompatible with the conservation of the teeth.     

Assessment of global cardiovascular risk and risk factors in Portugal according to the SCORE® model

Background/objective

Cardiovascular diseases (CVD) are the leading cause of mortality in European countries. This study aimed at estimating the 10-year risk of fatal CVD in Portuguese adults and to assess the prevalence of major cardiovascular risk factors, according to the SCORE® risk prediction system.

Subjects and methods

A cross-sectional survey was carried out in 60 community pharmacies (CP) from October 2005 to January 2006 in a sample of CP users (≥40 and ≤65 years). Data were collected by patient interviews using a structured questionnaire applied by a trained pharmacist.

Results

A total of 1,043 individuals were enrolled in the study (participation rate: 91%). The mean age was 53.7 years (SD: 7.1) with a ratio men/women of 0.68. The average risk in the sample was 1.94 (minimum 0, maximum 28, SD?=2.69). About 20% of the studied adults were at high risk, of which 39.4% were asymptomatic. CV risk was significantly higher in the oldest age group and in men (p?2): 28.0?±?4.5.

Conclusions

According to SCORE®, about one-fifth of the individuals was classified as high risk, and 7.7% was asymptomatic. CV risk was significantly higher in the oldest age group (55–65 years old) and in men (p?