Applying Reflective Multicriteria Decision Analysis (MCDA) to Patient-Clinician Shared Decision-Making on the Management of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NET) in the Spanish Context.

INTRODUCTION: Unresectable, well-differentiated nonfunctioning gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be monitored (watchful waiting, WW) or treated with systemic therapy such as somatostatin analogues (SSAs) to delay progression. We applied a reflective multicriteria decision analysis (MCDA) shared-decision framework (previously developed for the USA) to explore what matters to Spanish patients and clinicians considering GEP-NET treatment options. METHODS: The EVIDEM-derived framework was updated and adapted to the Spanish context. During a Chatham House session, five patients and six physicians assigned criteria weights using hierarchical point allocation and direct rating scale (alternative analysis). Informed by synthesized evidence embedded in the framework, participants scored how each criterion favored SSA treatment (reference case lanreotide) or WW and shared insights and knowledge. Weights and scores were combined into value contributions (norm. weight × score/5), which were added across criteria to derive the relative benefit-risk balance (RBRB, scale - 1 to + 1). Exploratory comparisons to US study findings were performed. RESULTS: Focusing on intervention outcomes (effectiveness, patient-reported, and safety), the mean RBRB favored treatment over WW (+ 0.32 ± 0.24), with the largest contributions from progression-free survival (+ 0.11 ± SD 0.07), fatal adverse events (+ 0.06 ± SD 0.08), and impact on HRQoL (+ 0.04 ± SD 0.04). Consideration of modulating criteria (type of benefit, need, costs, evidence, and feasibility) increased the RBRB to + 0.50 ± 0.14, with type of therapeutic benefit (+ 0.10 ± SD 0.08) and quality of evidence (+ 0.08 ± SD 0.06) contributing most towards treatment. Alternative weighting yielded similar results. Results were broadly comparable to those derived from the US study. CONCLUSION: The multicriteria framework helped Spanish patients and clinicians identify and express what matters to them. The approach is transferable across decision-making contexts. FUNDING: IPSEN Pharma.

Pneumococcal serotype distribution: A snapshot of recent data in pediatric and adult populations around the world.

S. pneumoniae infection remains a serious public health concern despite the availability of vaccines covering up to 23 of more than 94 known serotypes. The purpose of the present study was to monitor recent serotype distribution data. PubMed, EMBASE, Cochrane Reviews and Ingenta databases were searched. Serotype data covering invasive pneumococcal disease (IPD) and non-IPD were extracted from articles published from March 2014 to March 2015. Fifty-nine studies presented pneumococcal serotype prevalence by specific age categories. Most prevalent serotypes not covered by pneumococcal conjugate vaccines (PCV) were as follows: 15B, 22F, 15A, 23A among children under the age of 7 y with IPD; among adults with IPD: 22F, 11A, 10A, 38 in the 65 y and older age group; 12F, 9N, 8 in the 50-64 year-old age group and 12F, 8, 6C, 16F in the 15-59 age group. Geographic variations in serotype distribution highlight the importance of monitoring evolving pneumococcal serotype prevalence after pneumococcal vaccine implementation.

Burden of Surgical Site Infections Associated with Select Spine Operations and Involvement of Staphylococcus aureus.

BACKGROUND: Spine operations may be indicated for treatment of diseases including vertebral injuries, degenerative spinal conditions, disk disease, spinal misalignments, or malformations. Surgical site infection (SSI) is a clinically important complication of spine surgery. Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), is a leading cause of post-spinal SSIs. METHODS: PubMed and applicable infectious disease conference proceedings were searched to identify relevant published studies. Overall, 343 full-text publications were screened for epidemiologic, mortality, health care resource utilization, and cost data on SSIs associated with specified spine operations. RESULTS: Surgical site infection rates were identified in 161 studies from North America, Europe, and Asia. Pooled average SSI and S. aureus SSI rates for spine surgery were 1.9% (median, 3.3%; range, 0.1%-22.6%) and 1.0% (median, 2.0%; range, 0.02%-10.0%). Pooled average contribution of S. aureus infections to spinal SSIs was 49.3% (median, 50.0%; range, 16.7%-100%). Pooled average proportion of S. aureus SSIs attributable to MRSA was 37.9% (median, 42.5%; range, 0%-100%). Instrumented spinal fusion had the highest pooled average SSI rate (3.8%), followed by spinal decompression (1.8%) and spinal fusion (1.6%). The SSI-related mortality rate among spine surgical patients ranged from 1.1%-2.3% (three studies). All studies comparing SSI and control cohorts reported longer hospital stays for patients with SSIs. Pooled average SSI-associated re-admission rate occurring within 30 d from discharge ranged from 20% to 100% (four studies). Pooled average SSI-related re-operation rate was 67.1% (median, 100%; range, 33.5%-100%). According to two studies reporting direct costs, spine surgical patients incur approximately double the health care costs when they develop an SSI. CONCLUSIONS: Available published studies demonstrate a clinically important burden of SSIs related to spine operations and the substantial contribution of S. aureus (including MRSA). Preventive strategies aimed specifically at S. aureus SSIs could reduce health care costs and improve patient outcomes for spine operations.

Burden of Surgical Site Infections Associated with Arthroplasty and the Contribution of Staphylococcus aureus.

BACKGROUND: Patients undergoing arthroplasty are at considerable risk of experiencing post-operative complications, including surgical site infections (SSIs). In addition to potential economic consequences, SSIs can have a negative impact on patient outcomes and may potentially be life-threatening. Staphylococcus aureus has been consistently shown as the leading cause of SSIs associated with orthopedic surgery, with an important contribution from methicillin-resistant S. aureus (MRSA). This study evaluated the global burden of SSIs among patients undergoing orthopedic surgical procedures, and specifically those undergoing knee and hip arthroplasties. METHODS: An extensive search of PubMed and recent conference proceedings was conducted. English articles published between 2003 and 2013 pertaining to SSI epidemiology, patient outcomes, and healthcare resource utilization and costs were reviewed. RESULTS: Overall, 81 studies were included, mainly from North America and Europe. Median SSI and S. aureus SSI rates, calculated as percentage of all arthroplasty procedures, were 1.7% (range: 0.25%-4.4%; 15 studies) and 0.6% (range: 0.1%-23%), respectively. Median SSI rates were 1.3% (range: 0.05%-19%; 22 studies) after knee arthroplasty, and 2.1% (range: 0.05%-28%; 24 studies) after hip arthroplasty. S. aureus SSI rates ranged from 0.2%-2.4% and 0.18%-3.8% for patients undergoing knee and hip arthroplasty, respectively. The percentage of S. aureus SSIs because of MRSA varied widely within each patient category. SSI-related mortality data (14 studies) showed that in-hospital mortality rates were low (1.2%-2.5%), but increased with time after index arthroplasty procedure (up to 56% over 1 y). Studies assessing healthcare resource utilization (n = 21) revealed that developing post-orthopedic SSIs resulted in a two- to three-fold increase in length of hospital stay (LOS) compared with non-infected patients (median LOS: 18.9 d vs. 6 d for non-SSI patients). Patients with SSIs because of methicillin-resistant staphylococci incurred greater mean LOS compared with SSIs because of methicillin-sensitive organisms. Readmission rates reported in 11 studies indicate a greater likelihood in the presence of SSIs; comparison across studies was not feasible because of differences in data reporting. Consistent with increased healthcare resource utilization (LOS and readmission) associated with SSIs, cost studies (n = 23) revealed that the presence of SSIs was associated with up to three-fold cost increase compared with the absence of SSI across all orthopedic patient categories assessed. CONCLUSIONS: SSIs are associated with increased morbidity, mortality rates, healthcare resource utilization, and costs. Despite the relatively low SSI incidence following orthopedic surgery and specifically arthroplasty, preventive methods, specifically those targeting S. aureus, would serve to minimize costs and improve patient outcomes.

Global availability of data on HPV genotype-distribution in cervical, vulvar and vaginal disease and genotype-specific prevalence and incidence of HPV infection in females.

BACKGROUND: Country-level HPV genotyping data may be sought by decision-makers to gauge the genotype-specific burden of HPV-related diseases in their jurisdiction and assess the potential impact of HPV vaccines. We investigated, by country, the availability of published literature on HPV genotypes in cervical, vaginal and vulvar cancers and intraepithelial neoplasms (CINs, VaINs and VINs) and on prevalence and incidence of genital HPV infections among women without clinically manifest disease. FINDINGS: Primary sources of publications were the PubMed/Medline and EMBASE databases. Original studies or meta-analyses published from 2000, covering genotypes 16 and 18 and at least one of genotypes 31/33/45/52/58, were included. Key exclusion criteria were language not English, cervical lesions not histologically confirmed (cytology only), special populations (e.g., immunocompromised) and, for cervical studies, small population (<50). A total of 727 studies reporting HPV genotype-specific data were identified: 366 for cervical cancers and CINs, 43 for vulvar or vaginal cancers and VINs/VaINs, and 395 and 21 for infection prevalence and incidence, respectively, in general female population samples. A large proportion of studies originated from a small set of countries. Cervical cancer/CIN typing data was scarce for several regions with the highest cervical cancer burden, including Eastern, Middle and Western Africa, Central America, South-East Asia, South Asia, and Eastern Europe. Data for vulvar/vaginal disease was limited outside of Europe and North America. CONCLUSIONS: Although a large body of published HPV genotype-specific data is currently available, data gaps exist for genotype-specific infection incidence and several world regions with the highest cervical cancer burden.

Systematic review of the incidence and prevalence of genital warts.

BACKGROUND: Anogenital warts (AGWs) are a common, highly infectious disease caused by the human papillomavirus (HPV), whose high recurrence rates contribute to direct medical costs, productivity loss and increased psychosocial impact. Because of the lack of a systematic review of the epidemiology of AGWs in the literature, this study reviewed the published medical literature on the incidence and prevalence of AGWs. METHODS: A comprehensive literature search was performed on the worldwide incidence and prevalence of AGWs between 2001 and 2012 using the PubMed and EMBASE databases. An additional screening of abstracts from relevant sexual health and infectious disease conferences from 2009 to 2011 was also conducted. Only original studies with general adult populations (i.e., at least including ages 20 through 40 years) were included. RESULTS: The overall (females and males combined) reported annual incidence of any AGWs (including new and recurrent) ranged from 160 to 289 per 100,000, with a median of 194.5 per 100,000. New AGW incidence rates among males ranged from 103 to 168 per 100,000, with a median of 137 per 100,000 and among females from 76 to 191 per 100,000, with a median of 120.5 per 100,000 per annum. The reported incidence of recurrent AGWs was as high as 110 per 100,000 among females and 163 per 100,000 among males. Incidence peaked before 24 years of age in females and between 25 and 29 years of age among males. The overall prevalence of AGWs based on retrospective administrative databases or medical chart reviews or prospectively collected physician reports ranged from 0.13% to 0.56%, whereas it ranged from 0.2% to 5.1% based on genital examinations. CONCLUSIONS: The literature suggests that AGWs are widespread and the prevalence depends on study methodology as suggested by higher rates reported from routine genital examinations versus those from treatment records. However, there remains a need for more population-based studies from certain regions including Africa, Latin America and Southern Asia to further elucidate the global epidemiology of this disease.

Antagonistic effects of Grg6 and Groucho/TLE on the transcription repression activity of brain factor 1/FoxG1 and cortical neuron differentiation.

Groucho (Gro)/TLE transcriptional corepressors are involved in a variety of developmental mechanisms, including neuronal differentiation. They contain a conserved C-terminal WD40 repeat domain that mediates interactions with several DNA-binding proteins. In particular, Gro/TLE1 interacts with forkhead transcription factor brain factor 1 (BF-1; also termed FoxG1). BF-1 is an essential regulator of neuronal differentiation during cerebral cortex development and represses transcription together with Gro/TLE1. Gro/TLE-related gene product 6 (Grg6) shares with Gro/TLEs a conserved WD40 repeat domain but is more distantly related at its N-terminal half. We demonstrate that Grg6 is expressed in cortical neural progenitor cells and interacts with BF-1. In contrast to Gro/TLE1, however, Grg6 does not promote, but rather suppresses, BF-1-mediated transcriptional repression. Consistent with these observations, Grg6 interferes with the binding of Gro/TLE1 to BF-1 and does not repress transcription when targeted to DNA. Moreover, coexpression of Grg6 and BF-1 in cortical progenitor cells leads to a decrease in the number of proliferating cells and increased neuronal differentiation. Conversely, Grg6 knockdown by RNA interference causes decreased neurogenesis. These results identify a new role for Grg6 in cortical neuron development and establish a functional link between Grg6 and BF-1.

NAD- and NADP-dependent mitochondrially targeted methylenetetrahydrofolate dehydrogenase-cyclohydrolases can rescue mthfd2 null fibroblasts.

Mouse fibroblasts in which the mthfd2 gene encoding mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase (NMDMC) was previously inactivated were infected with retroviral expression constructs of dehydrogenase/cyclohydrolase cDNA. Cellular fractionation confirmed that the expressed proteins were properly targeted to the mitochondria. Expression of the NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase enzyme in mitochondria corrected the glycine auxotrophy of the null mutant cells. A construct in which the cyclohydrolase activity of NMDMC was inactivated by point mutation also rescued the glycine auxotrophy, although poorly. This suggests that the cyclohydrolase activity is also required to ensure optimal production of 10-formyltetrahydrofolate. The expression of the NADP-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase in the mitochondria also reversed the glycine requirement of the null cells demonstrating that the use of the NAD cofactor is not absolutely essential to maintain the flux of one-carbon metabolites. All rescued cells demonstrated a decrease in the ratio of incorporation of exogenous formate to serine in standardized radiolabeling studies. This ratio, which is approximately 2.5 for nmdmc(-/-) cells and 0.3 for the wild type cells under the conditions used, is a qualitative indicator of the ability of the mitochondria of the cells to generate formate.

Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria.

The Mthfd1 gene encoding the cytoplasmic methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase enzyme (DCS) was inactivated in embryonic stem cells. The null embryonic stem cells were used to generate spontaneously immortalized fibroblast cell lines that exhibit the expected purine auxotrophy. Elimination of these cytoplasmic activities allowed for the accurate assessment of similar activities encoded by other genes in these cells. A low level of 10-formyltetrahydrofolate synthetase was detected and was shown to be localized to mitochondria. However, NADP-dependent methylenetetrahydrofolate dehydrogenase activity was not detected. Northern blot analysis suggests that a recently identified mitochondrial DCS (Prasannan, P., Pike, S., Peng, K., Shane, B., and Appling, D. R. (2003) J. Biol. Chem. 278, 43178-43187) is responsible for the synthetase activity. The lack of NADP-dependent dehydrogenase activity suggests that this RNA may encode a monofunctional synthetase. Moreover, examination of the primary structure of this novel protein revealed mutations in key residues required for dehydrogenase and cyclohydrolase activities. This monofunctional synthetase completes the pathway for the production of formate from formyltetrahydrofolate in the mitochondria in our model of mammalian one-carbon folate metabolism in embryonic and transformed cells.

Mammalian fibroblasts lacking mitochondrial NAD+-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase are glycine auxotrophs.

Primary fibroblasts established from embryos of NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (NMDMC) knockout mice were spontaneously immortalized or transformed with SV40 Large T antigen. Mitotracker Red CMXRos staining of the cells indicates the presence of intact mitochondria with a membrane potential. The nmdmc(-/-) cells are auxotrophic for glycine, demonstrating that NMDMC is the only methylenetetrahydrofolate dehydrogenase normally expressed in the mitochondria of these cell lines. Growth of null mutant but not wild type cells on complete medium with dialyzed serum is stimulated about 2-fold by added formate or hypoxanthine. Radiolabeling experiments demonstrated a 3-10 x enhanced incorporation of radioactivity into DNA from formate relative to serine by nmdmc(-/-) cells. The generation of one-carbon units by mitochondria in nmdmc(-/-) cells is completely blocked, and the cytoplasmic folate pathways alone are insufficient for optimal purine synthesis. The results demonstrate a metabolic role for NMDMC in supporting purine biosynthesis. Despite the recognition of these metabolic defects in the mutant cell lines, the phenotype of nmdmc(-/-) embryos that begin to die at E13.5 is not improved when pregnant dams are given a glycine-rich diet or daily injections of sodium formate.

Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase.

We have isolated the cDNA and the gene encoding the murine cytoplasmic methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (DCS). Comparison of these sequences with the 3'-untranslated region of the mitochondrial NAD(+)-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase (mt-DC) revealed areas of significant homology. Both exon and intron sequences of the synthetase domain of DCS are homologous to sequences in the untranslated region of mt-DC. A similar comparison between the mt-DC and the DCS sequences of humans as well as Drosophila supports the conclusion that in higher eukaryotes the bifunctional mt-DC replaced a trifunctional precursor through inactivation of the synthetase domain. The mt-DC should be considered in models of one-carbon folate fluxes in mammals.