Abstract Objective An overview of the economic consequences – overall costs as well as cost breakdown (direct and indirect) – of hip and knee osteoarthritis (OA) worldwide. Methods A systematic ...literature search of EMBASE, MEDLINE, Scopus and Cochrane databases for articles was performed independently by two rheumatologists who used the same predefined eligible criteria. Papers without abstracts and in languages other than English or French were excluded. Extracted costs were converted to an annual cost and to 2013 euros (€) by using the Consumer Price Index of the relevant countries and the 2013 Purchasing Power Parities between these countries and the European Union average. Results A total of 45 abstracts were selected, and 32 articles were considered for the review. The studied populations were heterogeneous: administrative, hospital and national health survey data. Annual total costs per patient ranged from 0.7 to 12 k€, direct costs per patient from 0.5 to 10.9 k€ and indirect costs per patient from 0.2 to 12.3 k€. The weighted average annual costs per patient living with knee and hip OA were 11.1, 9.5 and 4.4 k€ for total, direct and indirect costs, respectively. Conclusions This review highlights the heterogeneity of studies and lack of methodologic consensus to obtain reliable cost-of-illness estimates for lower-limb OA. However, costs induced by the disease seem substantial and deserve to be more extensively explored.
Advancing technologies of the corn dry-milling ethanol production process includes the mechanical separation of fiber containing particles from a portion of plant and yeast based nitrogenous ...particles. The resulting high protein processed corn coproduct (HPCoP) contains approximately 52% CP, 36% NDF, 6.4% total fatty acids. The objective of this experiment was to examine the effects of replacing non-enzymatically browned soybean meal with the HPCoP on DMI, energy and N utilization, and milk production of lactating Jersey cows. Twelve multiparous Jersey cows were utilized in a triplicated 4x4 Latin square design consisting of 4, 28 d periods. Cows were blocked by milk yield and assigned randomly to 1 of 4 treatment diets that contained HPCoP (DM basis) at (1) 0% (00CTRL); (2) 2.6% (2.6L); (3) 5.4% (5.4M); and (4) 8.0% (8.0H). Diets were formulated to be isonitrogenous and thus replace non-enzymatically browned soybean meal with HPCoP in the concentrate mix while forage inclusion remained the same across diets. Increasing the concentration of HPCoP had no effect on dry matter intake (averaging 19.9 ± 0.62 kg/d), but tended to linearly increase milk yield (27.8, 28.5, 29.8, and 29.0 ± 1.00 kg/d). While no difference was observed in the concentration of milk protein with increasing inclusion of HPCoP (3.40 ± 0.057%), the concentration of fat linearly increased with the inclusion of HPCoP (5.05, 5.19, 5.15, 5.47 ± 0.18%). No differences were observed in the digestibility of dry matter, neutral detergent fiber, crude protein, total fatty acids, and gross energy averaging 66.6 ± 0.68%, 49.0 ± 1.03%, 66.1 ± 0.82%, 73.6 ± 1.73%, 66.3 ± 0.72%, respectively with increasing HPCoP inclusion. The concentration of dietary gross energy linearly increased with increasing concentrations of HPCoP (4.25, 4.26, 4.28, and 4.31 ± 0.01 Mcal/kg), but no difference was observed in digestible energy and metabolizable energy (ME) across treatments averaging 2.83 ± 0.033 and 2.53 ± 0.043 Mcal/kg, respectively. Concentration of dietary net energy for lactation (NEL) tended to increase with increasing HPCoP (1.61, 1.72, 1.74, 1.72 ± 0.054 Mcal/kg) with the ratio of NEL:ME increasing linearly with increasing HPCoP inclusion (0.648, 0.676, 0.687, 0.677 ± 0.0124). Results of this study suggest that inclusion of the HPCoP can replace non-enzymatically browned soybean meal and support normal milk production.
To examine the maternal and foetal risks of adverse pregnancy outcome in relation to maternal obesity, expressed as body mass index (BMI, kg/m(2)) in a large unselected geographical population.
...Retrospective analysis of data from a validated maternity database system which includes all but one of the maternity units in the North West Thames Region. A comparison of pregnancy outcomes was made on the basis of maternal BMI at booking.
A total of 287,213 completed singleton pregnancies were studied including 176,923 (61.6%) normal weight (BMI 20--24.9), 79 014 (27.5%) moderately obese (BMI 25--29.9) and 31,276 (10.9%) very obese (BMI> or =30) women.
Ante-natal complications, intervention in labour, maternal morbidity and neonatal outcome were examined and data presented as raw frequencies and adjusted odds ratios with 99% confidence intervals following logistic regression analysis to account for confounding variables.
Compared to women with normal BMI, the following outcomes were significantly more common in obese pregnant women (odds ratio (99% confidence interval) for BMI 25--30 and BMI> or =30 respectively): gestational diabetes mellitus (1.68 (1.53--1.84), 3.6 (3.25--3.98)); proteinuric pre-eclampsia (1.44 (1.28--1.62), 2.14 (1.85--2.47)); induction of labour (2.14 (1.85--2.47), 1.70 (1.64--1.76)); delivery by emergency caesarian section (1.30 (1.25--1.34), 1.83 (1.74--1.93)); postpartum haemorrhage (1.16 (1.12--1.21), 1.39 (1.32--1.46)); genital tract infection (1.24 (1.09--1.41), 1.30 (1.07--1.56)); urinary tract infection (1.17 (1.04-1.33), 1.39 (1.18--1.63)); wound infection (1.27 (1.09--1.48), 2.24 (1.91--2.64)); birthweight above the 90th centile (1.57 (1.50--1.64), 2.36 (2.23--2.50)), and intrauterine death (1.10 (0.94--1.28), 1.40 (1.14--1.71)). However, delivery before 32 weeks' gestation (0.73 (0.65--0.82), 0.81 (0.69--0.95)) and breastfeeding at discharge (0.86 (0.84--0.88), 0.58 (0.56--0.60)) were significantly less likely in the overweight groups. In all cases, increasing maternal BMI was associated with increased magnitude of risk.
Maternal obesity carries significant risks for the mother and foetus. The risk increases with the degree of obesity and persists after accounting for other confounding demographic factors. The basis of many of the complications is likely to be related to the altered metabolic state associated with morbid obesity.
Many people do not meet the recommended health guidance of participation in a minimum of 150-300 min of moderate intensity physical activity per week, often promoted as at least 30 min of physical ...activity on 5 days of the week. This is concerning and highlights the importance of finding innovative ways to help people to be physically active each day. Snacktivity™ is a novel approach that aims to encourage people to do small, 2-5 min bouts of physical activity 'snacks' throughout the whole day, such that they achieve at least 150 min of moderate intensity activity per week. However, before it can be recommended, there is a need to explore whether the concept is acceptable to the public.
A survey to assess the views of the public about Snacktivity™ was distributed to adult patients registered at six general practices in the West Midlands, UK and to health care employees in the same region.
A total of 5989 surveys were sent to patients, of which 558 were returned (9.3%). A further 166 surveys were completed by health care employees. A total of 85% of respondents liked the Snacktivity™ concept. The flexibility of the approach was highly rated. A high proportion of participants (61%) reported that the ability to self-monitor their behaviour would help them to do Snacktivity™ throughout their day. Physically inactive participants perceived that Snacktivity™ would help to increase their physical activity, more than those who were physically active (OR = 0.41, 95% CI: 0.25-0.67). Approximately 90% of respondents perceived that Snacktivity™ was easy to do on a non-working day compared to 60% on a working day. Aerobic activity 'snacks' were preferred to those which were strength based.
The Snacktivity™ approach to promoting physical activity was viewed positively by the public and interventions to test the merits of such an approach now need to be developed and tested in a variety of everyday contexts.
The contribution of thrombosis to the aetiology of perioperative myocardial infarction (MI) is uncertain. We used optical coherence tomography (OCT) to determine the presence of thrombus and plaque ...morphology in patients experiencing a perioperative MI and matched patients experiencing a non-operative MI using OCT.
We conducted a single-centre, prospective, cohort study. Thirty patients experiencing a perioperative MI and 30 matched patients experiencing a non-operative MI, without ST elevation, underwent OCT to determine the presence of thrombus and culprit lesion plaque morphology. Angiography and OCT were performed a mean of 1.93(1.09) days and 1.53(0.68) days after the onset of perioperative and non-operative MI, respectively. OCT images were evaluated by an independent core laboratory without knowledge of whether the patient had suffered a perioperative or non-operative MI.
We identified thrombus at the culprit lesion in four of 30 patients (13.3%) who experienced a perioperative MI and in 20 of 30 patients (66.7%) who experienced a non-operative MI, P<0.01. The only non-culprit lesion with thrombus was in a perioperative MI patient who also had a culprit lesion thrombus. Perioperative and non-operative MI culprit lesions demonstrated fibroatheroma in 18 patients (60.0%) us 20 patients (66.7%), respectively (P=0.52) and thin cap fibroatheroma in one patient (3.3%) us five patients (16.7%), respectively (P=0.11). One perioperative MI patient (3.3%) suffered a cardiac death and no non-operative MI patient died during the 30-day follow-up.
Thrombosis was less common in perioperative than non-operative MI, despite similar underlying plaque morphology.
This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day ...class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication.
•Compound-specific toxicology limits were developed for common potential impurities in drug substances.•A class-specific limit of 15 μg/day was developed for monofunctional alkyl bromides.•All compound-specific toxicology limits were based on existing data, current regulatory guidance, and scientific knowledge.
The association between body mass index (BMI) and major clinical events after acute coronary syndrome (ACS) remains controversial. We investigated the impact of BMI on major clinical events after ACS ...in a large individual patient data meta-analysis. Data on 81,553 patients from 45 different countries with ACS enrolled in 8 large randomized clinical trials were included, followed up for a median of 171 days. The mean age was 63.4 ± 11.7, 70% were male, and the mean BMI was 27.3 ± 4.7 kg/m2. Compared with upper–normal-weight participants (BMI 21.75 to 24.9 kg/m2, reference category), underweight participants (<18.5 kg/m2) had an increased risk of death (hazard ratio HR 1.35, 95% confidence interval CI 1.10 to 1.66, p = 0.004). Both overweight subcategories, BMI 25 to 27.5 kg/m2 (HR 0.81, 95% CI 0.75 to 0.89, p <0.001) and BMI 27.5 to 29.9 kg/m2 (HR 0.84, 95% CI 0.76 to 0.92, p <0.001), and type I obesity (30 to 34.9, HR 0.81, 95% CI 0.73 to 0.89, p <0.001) had a significantly lower mortality. Type II and III obesities were not significantly associated with mortality. Mortality was lowest at a BMI of 30.9 kg/m2. Compared with normal-weight patients, overweight and obese categories were related with a significantly lower risk of bleeding and refractory ischemia. Overweight patients had a lower risk of myocardial infarction, heart failure hospitalizations, and heart failure-related deaths. There were no associations between BMI and revascularization rates or stroke. In conclusion, underweight and normal-weight patients were associated with an increased mortality risk, bleeding, ischemia, and heart failure compared with those with higher BMI after ACS.
The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one ...generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dnCNV on human diseases.
Chromosomal microarray analysis (CMA), array-based comparative genomic hybridization, short- and long-read genome sequencing (GS) were performed on the newly identified MdnCNV family to identify de novo mutations including dnCNVs, de novo single-nucleotide variants (dnSNVs), and indels. Short-read GS was performed on four previously published MdnCNV families for dnSNV analysis. Trio-based rare variant analysis was performed on the newly identified individual and four previously published MdnCNV families to identify potential genetic etiologies contributing to the peri-zygotic genomic instability. Lin semantic similarity scores informed quantitative human phenotype ontology analysis on three MdnCNV families to identify gene(s) driving or contributing to the clinical phenotype.
In the newly identified MdnCNV case, we revealed eight de novo tandem duplications, each ~ 1 Mb, with microhomology at 6/8 breakpoint junctions. Enrichment of de novo single-nucleotide variants (SNV; 6/79) and de novo indels (1/12) was found within 4 Mb of the dnCNV genomic regions. An elevated post-zygotic SNV mutation rate was observed in MdnCNV families. Maternal rare variant analyses identified three genes in distinct families that may contribute to the MdnCNV phenomenon. Phenotype analysis suggests that gene(s) within dnCNV regions contribute to the observed proband phenotype in 3/3 cases. CNVs in two cases, a contiguous gene duplication encompassing PMP22 and RAI1 and another duplication affecting NSD1 and SMARCC2, contribute to the clinically observed phenotypic manifestations.
Characteristic features of dnCNVs reported here are consistent with a microhomology-mediated break-induced replication (MMBIR)-driven mechanism during the peri-zygotic period. Maternal genetic variants in DNA repair genes potentially contribute to peri-zygotic genomic instability. Variable phenotypic features were observed across a cohort of three MdnCNV probands, and computational quantitative phenotyping revealed that two out of three had evidence for the contribution of more than one genetic locus to the proband's phenotype supporting the hypothesis of de novo multilocus pathogenic variation (MPV) in those families.
Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with ...low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.
The increasing incidence of resistance to current HIV-1 therapy underscores the need to develop antiretroviral agents with new mechanisms of action. Integrase, one of three viral enzymes essential ...for HIV-1 replication, presents an important yet unexploited opportunity for drug development. We describe here the identification and characterization of L-870,810, a small-molecule inhibitor of HIV-1 integrase with potent antiviral activity in cell culture and good pharmacokinetic properties. L-870,810 is an inhibitor with an 8-hydroxy-(1,6)-naphthyridine-7-carboxamide pharmacophore. The compound inhibits HIV-1 integrase-mediated strand transfer, and its antiviral activity in vitro is a direct consequence of this ascribed effect on integration. L-870,810 is mechanistically identical to previously described inhibitors from the diketo acid series; however, viruses selected for resistance to L-870,810 contain mutations (integrase residues 72, 121, and 125) that uniquely confer resistance to the naphthyridine. Conversely, mutations associated with resistance to the diketo acid do not engender naphthyridine resistance. Importantly, the mutations associated with resistance to each of these inhibitors map to distinct regions within the integrase active site. Therefore, we propose a model of the two inhibitors that is consistent with this observation and suggests specific interactions with discrete binding sites for each ligand. These studies provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and nonoverlapping resistance profiles.
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