The Societal Value of Vaccines: Expert-Based Conceptual Framework and Methods Using COVID-19 Vaccines as a Case Study.

Health technology assessments (HTAs) of vaccines typically focus on the direct health benefits to individuals and healthcare systems. COVID-19 highlighted the widespread societal impact of infectious diseases and the value of vaccines in averting adverse clinical consequences and in maintaining or resuming social and economic activities. Using COVID-19 as a case study, this research work aimed to set forth a conceptual framework capturing the broader value elements of vaccines and to identify appropriate methods to quantify value elements not routinely considered in HTAs. A two-step approach was adopted, combining a targeted literature review and three rounds of expert elicitation based on a modified Delphi method, leading to a conceptual framework of 30 value elements related to broader health effects, societal and economic impact, public finances, and uncertainty value. When applying the framework to COVID-19 vaccines in post-pandemic settings, 13 value elements were consensually rated highly important by the experts for consideration in HTAs. The experts reviewed over 10 methods that could be leveraged to quantify broader value elements and provided technical forward-looking recommendations. Limitations of the framework and the identified methods were discussed. This study supplements ongoing efforts aimed towards a broader recognition of the full societal value of vaccines.

NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

Pilot of a Charter to Improve Management of Medicines and Oral Care for Residents with Dysphagia in Care Homes.

Research in care homes has demonstrated that medication management practices in patients with dysphagia and those receiving medicines covertly may be inappropriate, illegal, and potentially cause harm. This paper presents the results of a feasibility study piloting a resident and healthcare professional best practice charter to improve such practices in care home residents with dysphagia. A charter was developed through a multi-professional expert panel, implemented in one care home, and then piloted in 22 homes in England, Wales, and Northern Ireland. A website was setup and developed iteratively to support the process. Care home staff and residents provided initial feedback on the implementation process and on perceived outcomes six months post implementation. A total of 16 (88.9%) out of 18 respondents from nine homes for six months reported a positive response to the charter. More than 80% of responses regarding the implementation process, impact on staff confidence, and perceived usefulness of the charter were positive. Perceived effectiveness and usefulness could, however, be further improved especially the perceived effect on frequency of medication review, which is reliant on external stakeholder involvement. The charter and supporting website were well received with respondents believing that it was useful, staff showing more confidence, and residents having enhanced care. Approaches to enhancing the charter's effectiveness were identified.

The first reported case of Burkholderia contaminans in patients with cystic fibrosis in Ireland: from the Sargasso Sea to Irish Children.

BACKGROUND: Burkholderia contaminans is an emerging pathogen in the cystic fibrosis (CF) setting. Included in the Burkholderia cepacia complex (Bcc), B. contaminans is a Gram negative, motile, obligate aerobe previously classified as a pseudomonad. Previous reports have described B. contaminans isolation from patients in Portugal, Switzerland, Spain, Argentina and the USA. This, however, is the first report relating to B. contaminans affecting Irish patients with CF, initially detected in a paediatric setting. CASE PRESENTATION: Burkholderia contaminans was identified in the routine analysis of sputum from a fourteen year old boy, at his annual review and subsequently from the sputum from his 19 year old brother. RecA gene sequencing and pulsed field gel electrophoresis (PFGE) were unable to distinguish between the isolates, which demonstrated with susceptibility to ciprofloxacin, cotrimoxazole, meropenem, pipercillin/tazobactam and ceftazidime. Both isolates were resistant to aztreonam, with reduced susceptibility to tobramycin. Following treatment with intravenous meropenem and ceftazidime, oral ciprofloxacin and nebulised tobramycin for 6 weeks, sputum specimens from both patients were negative for B. contaminans. No other member of the local CF cohort proved positive. CONCLUSIONS: Bcc bacteria are associated with poor prognosis in CF and decreased life expectancy, specifically leading to a more rapid decline in lung function and, in some cases, to a fatal necrotizing pneumonia known as the "cepacia syndrome". Some species exhibit innate resistance to multiple antimicrobial agents and their transmission rate can be high in susceptible patients. In that context, we describe the first incidence of CF-related B. contaminans in Ireland and its successful eradication from two patients, one paediatric, using an aggressive antimicrobial regimen.

Prolonged proteasome inhibition cyclically upregulates Oct3/4 and Nanog gene expression, but reduces induced pluripotent stem cell colony formation.

There is ample evidence that the ubiquitin-proteasome system is an important regulator of transcription and its activity is necessary for maintaining pluripotency and promoting cellular reprogramming. Moreover, proteasome activity contributes to maintaining the open chromatin structure found in pluripotent stem cells, acting as a transcriptional inhibitor at specific gene loci generally associated with differentiation. The current study was designed to understand further the role of proteasome inhibition in reprogramming and its ability to modulate endogenous expression of pluripotency-related genes and induced pluripotent stem cells (iPSCs) colony formation. Herein, we demonstrate that acute combinatorial treatment with the proteasome inhibitors MG101 or MG132 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) increases gene expression of the pluripotency marker Oct3/4, and that MG101 alone is as effective as VPA in the induction of Oct3/4 mRNA expression in fibroblasts. Prolonged proteasome inhibition cyclically upregulates gene expression of Oct3/4 and Nanog, but reduces colony formation in the presence of the iPSC induction cocktail. In conclusion, our results demonstrate that the 26S proteasome is an essential modulator in the reprogramming process. Its inhibition enhances expression of pluripotency-related genes; however, efficient colony formation requires proteasome activity. Therefore, discovery of small molecules that increase proteasome activity might lead to more efficient cell reprogramming and generation of pluripotent cells.

Silencing histone deacetylase-specific isoforms enhances expression of pluripotency genes in bovine fibroblasts.

Histone deacetylases (HDACs) catalyze deacetylation of histones that results in altered transcriptional activity. Inhibitors of HDACs have been shown to induce transcriptional changes that contribute positively to reprogramming somatic cells either by nuclear transfer or inducing a pluripotent state. However, the exact molecular mechanisms whereby HDAC inhibitors function and the specificity of the HDAC isoforms in cell reprogramming are not yet fully understood. Herein, we report the ability of individual isoform-specific HDACs to modulate endogenous expression of pluripotency-associated genes in bovine somatic cells. This in vitro study showed that a transient selective depletion of HDACs resulted in elevated mRNA levels of Oct-4, Sox2, and Nanog. In particular, we found that inhibition of specific HDAC isoforms using small interfering (si) RNA significantly increased expression of Nanog, a key factor required for totipotency induced by somatic cell nuclear transfer and for maintaining pluripotency in embryonic and induced pluripotent stem cells. Our study suggests that this gene might be the most susceptible to HDAC activity inhibition. Moreover, a regulatory role of the class III HDAC, SIRT3, on an Oct4-Sox2-Nanog transcriptional network was revealed. We observed the upregulation of pluripotency-related genes by depletion of SIRT3. SIRT3 is localized to mitochondria and is associated with energy metabolism processes, suggesting metabolic changes may be linked to reprogramming in bovine fibroblasts. In conclusion, we show that targeting selective HDACs can potentially be useful to enhance reprogramming and that sirtuins may play a pivotal role in somatic cell reprogramming by upregulating an Oct4-Sox2-Nanog transcriptional network. Dedifferentiating donor somatic cells by upregulating developmentally important genes through specific knockdown of epigenetic targets, in particular HDACs, may provide a path to improving livestock cloning and the in vitro production of pluripotent cells.

Modern antiplatelet agents in coronary artery disease.

Dual antiplatelet therapy is well recognized in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits of aspirin and clopidogrel therapy, a number of limitations curtail their efficacy: slow onset of action, variability in platelet inhibitory response and potential drug-drug interactions. Furthermore, the single platelet-activation pathway targeted by these agents allows continued platelet activation via other pathways, ensuring incomplete protection against ischemic events, thus, underscoring the need for alternate antiplatelet treatment strategies. A number of novel antiplatelet agents are currently in advance development and many have established superior effects on platelet inhibition, clinical outcomes and safety profile than clopidogrel in high-risk patients. The aim of this review is to provide an overview of the current status of P2Y12 receptor inhibition and PAR-1 antagonists in determining a future strategy for individualized antiplatelet therapy.

Screening for epigenetic target genes that enhance reprogramming using lentiviral-delivered shRNA.

Small molecules will need to be identified and/or developed that target protein classes limiting reprogramming efficiency. A specific class of proteins includes epigenetic regulators that silence, or minimize expression, of pluripotency genes in differentiated cells. To better understand the role of specific epigenetic modulators in reprogramming, we have used shRNA delivered by lentivirus to assess the significance of individual epi-proteins in reprogramming pluripotent gene expression.

Strain-dependent variations in the response of cancellous bone to ovariectomy in mice.

UNLABELLED: The goal of this study was to characterize the skeletal response to ovariectomy in mice (129P3, C57BL/6, and B6129PF2) commonly used in gene manipulation studies to evaluate their potential as preclinical models of postmenopausal osteoporosis. The magnitude of cancellous bone loss and cellular indices of increased bone turnover in response to ovariectomy varied with mouse type and skeletal site, but in general, were less pronounced and less consistent than in Sprague-Dawley rats, the established preclinical model for postmenopausal bone loss. INTRODUCTION: The ovariectomized (OVX) rat is the most widely used preclinical rodent model for postmenopausal osteoporosis. However, the underlying mechanisms of bone disorders, including osteoporosis, have been explored predominantly in the mouse. The purpose of this study was to evaluate mice (129P3 and C57BL/6 inbred strains and their F2 hybrid offspring, B6129PF2), commonly used for gene knockout and overexpression studies, for their potential as preclinical models of postmenopausal bone loss. MATERIALS AND METHODS: The mice were OVX or sham-operated at 4 months of age and killed at 1 or 3 months after surgery. Lumbar vertebrae and distal femora were subjected to histomorphometric assessment. RESULTS: Mice in the two strains and the F2 hybrids (will be referred to as strain for the remainder of the abstract) lost vertebral cancellous bone after OVX; bone volume (BV/TV) was 20% and 27% lower at 1 and 3 months after surgery, respectively. The decreased cancellous BV/TV was associated with an increase in osteoclast surface at 1 month after OVX in the 129P3 strain only. Osteoblast surface was increased by 20% with OVX at both 1 and 3 months after surgery, irrespective of mouse strain. However, bone formation rate was not altered by OVX in any of the mouse strains. In contrast to the lumbar vertebrae, cancellous bone loss in response to OVX differed in the distal femur among the three mouse strains. OVX had no significant effect on distal femur BV/TV in the B6129PF2 mouse strain. In the C57BL/6 strain, cancellous BV/TV was reduced by OVX at 1 month after surgery but not at 3 months after surgery, whereas distal femur BV/TV in 129P3 mice was reduced at 3 months after surgery. Osteoclast surface was not affected by OVX at either time-point in the C57BL/6 strain, but was increased by 116% at 1 month after surgery in the 129P3 strain. Osteoblast surface was increased with OVX at 1 month after surgery, irrespective of strain, whereas bone formation rate was not altered by OVX at either time-point in any of the strains. CONCLUSIONS: The magnitude of cancellous bone loss and cellular indices of increased bone turnover in response to OVX varied with mouse strain and skeletal site, but in general, were less pronounced and less consistent than in the Sprague-Dawley rat. Although mouse models will continue to provide insights into genetic influences on bone mass and turnover, caution should be exercised when using 129P3 and C57BL/6 mice, and their F2 hybrids, as models for postmenopausal bone loss and preclinical testing of potential therapies for osteoporosis.

Patterns of marijuana use among patients with HIV/AIDS followed in a public health care setting.

OBJECTIVES: To examine prevalence and patterns of smoked marijuana and perceived benefit and to assess demographic and clinical factors associated with marijuana use among HIV patients in a public health care setting. METHODS: Participants (n = 252) were recruited via consecutive sampling in public health care clinics. Structured interviews assessed patterns of recent marijuana use, including its perceived benefit for symptom relief. Associations between marijuana use and demographic and clinical variables were examined using univariate and multivariate regression analyses. RESULTS: Overall prevalence of smoked marijuana in the previous month was 23%. Reported benefits included relief of anxiety and/or depression (57%), improved appetite (53%), increased pleasure (33%), and relief of pain (28%). Recent use of marijuana was positively associated with severe nausea (odds ratio [OR] = 4.0, P = 0.004) and recent use of alcohol (OR = 7.5, P < 0.001) and negatively associated with being Latino (OR = 0.07, P < 0.001). No associations between marijuana use and pain symptoms were observed. CONCLUSIONS: The findings suggest that providers be advised to assess routinely and better understand patients' "indications" for self-administration of cannabis. Given the estimated prevalence, more formal characterization of the patterns and impact of cannabis use to alleviate HIV-associated symptoms is warranted. Clinical trials of smoked and noncombustible marijuana are needed to determine the role of cannabinoids as a class of agents with potential to improve quality of life and health care outcomes among patients with HIV/AIDS.

Husbandry, handling, and nutrition for marmosets.

Marmosets, especially Callithrix jacchus, have become an established part of the laboratory animal community. Information on marmoset life history, behavior, and diet acquired from experience with natural and captive habitats has increased, but the early information from workers with colonies, principally those of tamarins, has led to some common perceptions about how to house, handle, and especially, feed callitrichids that may not apply to marmoset requirements. The availability of commercially produced, almost-complete base diet components and a wider variety of cage construction materials, combined with the recent emphasis on the integration of engineering and performance standards for housing, have made captive life and the implementation of research requirements better for the animals and the people that work with them. We will review some of the routine aspects of husbandry, handling, and nutrition for marmoset monkeys maintained in a research setting.

Social support, substance use, and denial in relationship to antiretroviral treatment adherence among HIV-infected persons.

This study examined the relationship of adherence to antiretroviral treatment with three types of social support (partner, friends, and family) and use of two coping strategies (denial and substance use). Participants were 73 men and women with HIV infection drawn from a larger sample of 186 clinical trial patients. Based on inclusion criteria, parent trial participants taking antiretroviral therapies, and those with complete data on self-reported measures of adherence were considered eligible for the present study. Overall, 26% of participants were found to be nonadherent, which was defined as one or more missed doses of treatment in the prior 4-day period. Logistic regression analysis was conducted to determine associations of sociodemographic and psychosocial variables with adherence to antiretroviral regimen. Results indicated that heterosexual participants (p < 0.01) and participants of Latino ethnicity (p < 0.05) were significantly more likely to report missed medications. Perceived satisfaction with support from a partner was associated with taking antiretroviral therapy as prescribed, whereas satisfaction with support from friends and from family was not significantly related to adherence. Examination of coping strategies showed that participants reporting drug and alcohol use (p <.05) to cope with HIV-related stress were more likely to be nonadherent. These findings call for adherence interventions designed to address barriers and strengths, such as community norms or traditional cultural values, specific to certain populations. Furthermore, couple-based approaches enlisting partner support may help persons living with HIV to adhere to antiretroviral regimens.

Alternative therapies: a common practice among men and women living with HIV.

This study examined the prevalence and factors associated with alternative therapy use in an ethnically diverse, gender-balanced sample of persons living with HIV/AIDS. More than two thirds (67%) of the participants who were taking HIV-related medications were also taking an alternative supplement. Half of the sample (50%) reported that they took one or more multivitamins, 17% reported using mineral supplements, 12% reported using Chinese herbs, and 12% reported using botanicals. Substantial proportions of the sample also reported using acupuncture (31%), massage (23%), and meditation (28%) to specifically treat HIV-related symptoms. Women were four times more likely to use alternative therapies than men. Also, Caucasians were nearly four times more likely to use alternative treatments compared to other ethnic groups. The results of this study indicate a strong need to assess individual patients' use of alternative treatment approaches as well as to further investigate their efficacy among HIV-positive patients.

Resting energy metabolism of Goeldi's monkey (Callimico goeldii) is similar to that of other callitrichids.

The resting metabolic rates (RMRs) of six adult Goeldi's monkeys (Callimico goeldii) were measured using standard methods of open circuit respirometry during both the active (daytime) and inactive (nighttime) circadian phases for this species. One subject was measured both while she was pregnant and after she delivered a full-term, stillborn infant. Inactive-phase RMR within thermal neutrality (above 27.5 degrees C) averaged 288.5 +/- 30.8 ml O2/hr; active-phase RMR within thermal neutrality averaged 416.3 +/- 60.9 ml O2/hr. These values are 74.6% and 107.6%, respectively, of the mammalian expected for animals of this body mass. During the inactive phase, metabolic rate increased an estimated 4.3% for every degree decline in temperature below 27.5 degrees C. The RMR in Goeldi's monkey is similar quantitatively and qualitatively to those of other captive callitrichids that have been studied, with active-phase RMR being at or slightly above the mammalian expected, and inactive-phase RMR being significantly reduced. We propose that this circadian pattern of RMR is a consequence of small body size, and is not a specific metabolic adaptation within the Callitrichidae. Thus we predict that metabolic studies measuring both circadian phases in other small primates will also find this pattern of reduced RMR during the inactive phase. The inactive-phase RMR within thermal neutrality of the pregnant female was not different from that measured after the stillbirth, despite an almost 15% difference in body mass. During pregnancy, however, the female was more metabolically responsive to temperature below thermal neutrality, and had a lower upper critical temperature (i.e., was less tolerant of heat).

HIV: effectiveness of complementary and alternative medicine.

Outcome studies examining the efficacy of CAM among people living with HIV-AIDS are often conducted among small sample sizes with very little follow-up data or time points. Generalizability of many of the study findings is further limited by participant attrition. It is difficult to conduct clinical studies on chronically ill patients without participants dropping out, typically because the study demands coupled with their illness become too burdensome. Several studies have been conducted that include control groups, double-blind designs, and randomization. These scientifically sound studies have demonstrated promising results that strongly indicate a need for further research with larger samples in a prospective research design so that safety and efficacy can be determined over time. Many of the studies with small sample sizes reported trends, but did not find statistical significance. Increasing sample sizes in future studies is necessary to evaluate the scientific merit of these trends. Moreover, researchers need to evaluate the clinical and statistical significance in CAM use. The psychologic benefits of taking CAM should not be underestimated. For the purposes of this article, the authors did not include psychologic outcomes; however, there is evidence suggesting that decreasing depression can decrease HIV-related somatic complaints [69]. Studies need also to examine the effectiveness of CAM on psychologic outcomes and physical outcomes. This article and the authors' own research (Gore-Felton C et al, unpublished data) have revealed a high prevalence of alternative supplement use in conjunction with HIV medication, indicating an urgent need to understand the health benefits and the health risks of alternative supplements among patients with HIV and AIDS. Patients and physicians need more empirically based research to examine the toxicities, interactions, and health benefits of CAM. Many patients do not report the use of CAM to their physicians and very few physicians record treatments in the clinical record [70]. This will likely change as CAM becomes more widely recognized as a legitimate medical intervention; however, controlled outcome studies among large, diverse samples of people living with HIV-AIDS are needed. Health care providers need to assess the use of herbal and alternative therapy practices by their patients. Some patients may not be aware that they are taking a supplement or plant-based herb. Furthermore, some patients may believe that they are using something innocuous and even healthy simply because it came from a health food store. Understanding the contraindications of alternative therapies is necessary to prevent deleterious outcomes and to facilitate the safe and efficacious use of CAM in the management of HIV disease and related symptoms. As the epidemic in the United States continues to rise among women and minority populations, clinical research trials must include ethnically diverse patient populations that are gender balanced. Current available studies indicate that many CAM interventions may improve the quality of life of people living with HIV-AIDS; however, further studies using longitudinal, controlled designs are needed to accurately assess the safety of such interventions.

Acute stress reactions to recent life events among women and men living with HIV/AIDS.

OBJECTIVE: This study examined the prevalence of acute stress reactions to recent life events among persons living with HIV/AIDS. A second aim was to investigate the relationship of acute stress reactions among HIV-infected men and women to posttraumatic stress disorder (PTSD) symptoms to previous traumatic life events. METHOD: Participants included 64 HIV-seropositive persons (33 men and 31 women) drawn from a larger study examining the effects of group therapy on quality of life and health behavior. These individuals were assessed at baseline on demographic and medical status characteristics and (PTSD) symptoms andthen randomly assigned to either receive group therapy plus education or education alone. Three months later they were assessed for acute stress reactions to recent life events. RESULTS: Nearly a third (31.3 percent) of the participants reported levels of acute stress reactions to recent life events that met all symptom criteria for the diagnosis of acute stress disorder. However, only 9.4 percent of the respondents described a recent stressful life event that was threatening to the life or physical integrity of themselves or others. Acute stress reactions to recent life events were significantly and positively related to experiencing PTSD symptoms to prior traumatic life events. Acute stress did not differ significantly by gender, AIDS status, or whether or not participants had received 12 weeks of group therapy. CONCLUSIONS: A subset of individuals with HIV/AIDS experience high levels of acute stress reactivity to life events considered non-traumatic. HIV-infected individuals who react strongly to ongoing life stressors are more likely to have developed PTSD symptoms in response to previous traumatic life events.