The SECURE study:long-term safety of Ranibizumab 0.5 mg in neovascular age-related macular degeneration

Objective - To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). Design - Twenty-four–month, open-label, multicenter, phase IV extension study. Participants - Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. Methods - Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion). Main Outcome Measures - Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. Results - Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. Conclusions - The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment.

Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.

Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.

Countering the trend towards careerist orientation in the age of downsizing:test of a social exchange model

Predicated on the assumption that employee careerist orientation resulting from organizational actions to cut costs constitutes a potential threat to their long-term profitability and success, this study proposed and tested a social exchange model of careerist orientation in the People's Republic of China. Specifically, it was hypothesized that organizational justice and career growth opportunities will be related to careerist orientation, but the relationship will be mediated by trust in employer. Structural equation modeling results provided support for the model. Trust in organization fully mediated the relationship between careerist orientation and its antecedents.

Midterm to long-term longitudinal outcome of autologous chondrocyte implantation in the knee joint:a multilevel analysis

Background Autologous chondrocyte implantation is a cell therapeutic approach for the treatment of chondral and osteochondral defects in the knee joint. The authors previously reported on the histologic and radiologic outcome of autologous chondrocyte implantation in the short- to midterm, which yields mixed results. Purpose The objective is to report on the clinical outcome of autologous chondrocyte implantation for the knee in the midterm to long term. Study Design Cohort study; Level of evidence, 3. Methods Eighty patients who had undergone autologous chondrocyte implantation of the knee with mid- to long-term follow-up were analyzed. The mean patient age was 34.6 years (standard deviation, 9.1 years), with 63 men and 17 women. Seventy-one patients presented with a focal chondral defect, with a median defect area of 4.1 cm2 and a maximum defect area of 20 cm2. The modified Lysholm score was used as a self-reporting clinical outcome measure to determine the following: (1) What is the typical pattern over time of clinical outcome after autologous chondrocyte implantation; and (2) Which patient-related predictors for the clinical outcome pattern can be used to improve patient selection for autologous chondrocyte implantation? Results The average follow-up time was 5 years (range, 2.7–9.3). Improvement in clinical outcome was found in 65 patients (81%), while 15 patients (19%) showed a decline in outcome. The median preoperative Lysholm score of 54 increased to a median of 78 points. The most rapid improvement in Lysholm score was over the 15-month period after operation, after which the Lysholm score remained constant for up to 9 years. The authors were unable to identify any patient-specific factors (ie, age, gender, defect size, defect location, number of previous operations, preoperative Lysholm score) that could predict the change in clinical outcome in the first 15 months. Conclusion Autologous chondrocyte implantation seems to provide a durable clinical outcome in those patients demonstrating success at 15 months after operation. Comparisons between other outcome measures of autologous chondrocyte implantation should be focused on the clinical status at 15 months after surgery. The patient-reported clinical outcome at 15 months is a major predictor of the mid- to long-term success of autologous chondrocyte implantation.

A comparison of the vocational training system of Britain and West Germany as experienced by minimum-age school leavers.

The sectoral and occupational structure of Britain and West Germany has increasingly changed over the last fifty years from a manual manufacturing based to a non-manual service sector based one. There has been a trend towards more managerial and less menial type occupations. Britain employs a higher proportion of its population in the service sector than in manufacturing compared to West Germany, except in retailing, where West Germany employs twice as many people as Britain. This is a stable sector of the economy in terms of employment, but the requirements of the workforce have changed in line with changes in the industry in both countries. School leavers in the two countries, faced with the same options (FE, training schemes or employment) have opted for the various options in different proportions: young Germans are staying longer in education before embarking on training and young Britons are now less likely to go straight into employment than ten years ago. Training is becoming more accepted as the normal route into employment with government policy leading the way, but public opinion still slow to respond. This study investigates how vocational training has adapted to the changing requirements of industry, often determined by technological advancements. In some areas e.g. manufacturing industry the changes have been radical, in others such as retailing they have not, but skill requirements, not necessarily influenced by technology have changed. Social-communicative skills, frequently not even considered skills and therefore not included in training are coming to the forefront. Vocational training has adapted differently in the two countries: in West Germany on the basis of an established over-defined system and in Britain on the basis of an out-dated ill-defined and almost non-existent system. In retailing German school leavers opt for two or three year apprenticeships whereas British school leavers are offered employment with or without formalised training. The publicly held view of the occupation of sales assistant is one of low-level skill, low intellectual demands and a job anyone can do. The traditional skills - product knowledge, selling and social-communicative skills have steadily been eroded. In the last five years retailers have recognised that a return to customer service, utilising the traditional skills was going to be needed of their staff to remain competitive. This requires training. The German retail training system responded by adapting its training regulations in a long consultative process, whereas the British experimented with YTS, a formalised training scheme nationwide being a new departure. The thesis evaluates the changes in these regulations. The case studies in four retail outlets demonstrate that it is indeed product knowledge and selling and social-communicative skills which are fundamental to being a successful and content sales assistant in either country. When the skills are recognised and taught well and systematically the foundations for career development in retailing are laid in a labour market which is continually looking for better qualified workers. Training, when planned and conducted professionally is appreciated by staff and customers and of benefit to the company. In retailing not enough systematic training, to recognisable standards is carried out in Britain, whereas in West Germany the training system is nevertheless better prepared to show innovative potential as a structure and is in place on which to build. In Britain the reputation of the individual company has a greater role to play, not ensuring a national provision of good training in retailing.

Maternal periconceptional and gestational low protein diet affects mouse offspring growth, cardiovascular and adipose phenotype at 1 year of age

Human and animal studies have revealed a strong association between periconceptional environmental factors, such as poor maternal diet, and an increased propensity for cardiovascular and metabolic disease in adult offspring. Previously, we reported cardiovascular and physiological effects of maternal low protein diet (LPD) fed during discrete periods of periconceptional development on 6-month-old mouse offspring. Here, we extend the analysis in 1 year aging offspring, evaluating mechanisms regulating growth and adiposity. Isocaloric LPD (9% casein) or normal protein diet (18% casein; NPD) was fed to female MF-1 mice either exclusively during oocyte maturation (for 3.5 days prior to mating; Egg-LPD, Egg-NPD, respectively), throughout gestation (LPD, NPD) or exclusively during preimplantation development (for 3.5 days post mating; Emb-LPD). LPD and Emb-LPD female offspring were significantly lighter and heavier than NPD females respectively for up to 52 weeks. Egg-LPD, LPD and Emb-LPD offspring displayed significantly elevated systolic blood pressure at 52 weeks compared to respective controls (Egg-NPD, NPD). LPD females had significantly reduced inguinal and retroperitoneal fat pad: body weight ratios compared to NPD females. Expression of the insulin receptor (Insr) and insulin-like growth factor I receptor (Igf1r) in retroperitoneal fat was significantly elevated in Emb-LPD females (P&0.05), whilst Emb-LPD males displayed significantly decreased expression of the mitochondrial uncoupling protein 1 (Ucp1) gene compared to NPD offspring. LPD females displayed significantly increased expression of Ucp1 in interscapular brown adipose tissue when compared to NPD offspring. Our results demonstrate that aging offspring body weight, cardiovascular and adiposity homeostasis can be programmed by maternal periconceptional nutrition. These adverse outcomes further exemplify the criticality of dietary behaviour around the time of conception on long-term offspring health. © 2011 Watkins et al.

Influence of light exposure during early life on the age of onset of bipolar disorder

Background: Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association. Methods: Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4N and 70.7N, and 1.2S and 41.3S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation. Results: More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model. Conclusions: Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration

Background: The aim of this study was to describe bilateral visual outcomes and the effect of incomplete follow-up after 3 years of ranibizumab therapy for neovascular age-related macular degeneration. Secondarily, the demands on service provision over a 3-year period were described. Methods: Data on visual acuity, hospital visits, and injections were collected over 36 months on consecutive patients commencing treatment over a 9-month period. Visual outcome was determined for 1) all patients, using last observation carried forward for missed visits due to early discontinuation and 2) only those patients completing full 36-month follow-up. Results: Over 3 years, 120 patients cumulatively attended hospital for 1,823 noninjection visits and 1,365 injection visits. A visual acuity loss of <15 letters (L) was experienced by 78.2% of patients. For all patients (n=120), there was a mean loss of 1.68 L using last observation carried forward for missing values. Excluding five patients who died and 30 who discontinued follow-up, mean gain was 1.47 L. In bilateral cases, final acuity was on average 9 L better in second eyes compared to first eyes. Also, 91% of better-seeing eyes continued to be the better-seeing eye. Conclusion: We have demonstrated our approach to describing the long-term service provision and visual outcomes of ranibizumab therapy for neovascular age-related macular degeneration in a consecutive cohort of patients. Although there was a heavy burden with very frequent injections and clinic visits, patients can expect a good level of visual stability and a very high chance of maintaining their better-seeing eye for up to 3 years. © 2014 Chavan et al. This work is published by Dove Medical Press Limited.

Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis:an observational, cross-sectional study

Introduction: Methotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM. Methods: Data were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy. Results: Wide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively). Conclusions: Nonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated. Trial registration: ISRCTN Registry identifier: ISRCTN93945409. Registered 2 December 2011.

Short- and long-term changes in corneal aberrations and axial length induced by orthokeratology in children are not correlated

PURPOSE: To assess the correlation between changes in corneal aberrations and the 2-year change in axial length in children fitted with orthokeratology (OK) contact lenses. METHODS: Thirty-one subjects 6 to 12 years of age and with myopia −0.75 to −4.00DS and astigmatism ≤1.00DC were fitted with OK. Measurements of axial length and corneal topography were taken at regular intervals over a 2-year period. Corneal topography at baseline and after 3 and 24 months of OK lens wear was used to derive higher-order corneal aberrations (HOA) that were correlated with OK-induced axial length changes at 2 years. RESULTS: Significant changes in C3, C4, C4, root mean square (RMS) secondary astigmatism and fourth and total HOA were found with both 3 and 24 months of OK lens wear in comparison with baseline (all P0.05). Coma angle of orientation changed significantly pre-OK in comparison with 3 and 24 months post-OK as well as secondary astigmatism angle of orientation pre-OK in comparison with 24 months post-OK (all P0.05). DISCUSSION: Short-term and long-term OK lens wear induces significant changes in corneal aberrations that are not significantly correlated with changes in axial elongation after 2-years.

Medication review of children on long term medications:a review of the literature

INTRODUCTION: Children on long term medication may be under the care of more than one medical team including the patients GP. Children on chronic medication should be supported and their medications reviewed, especially in cases of polypharmacy. Medicines Use Reviews (MURs) were introduced into the pharmacy contract in 2005. The service was designed for community pharmacists to review patients on long term medication. The service specified that MURs were done on patients who can give consent and cannot be conducted with a parent or carer. Hence the service may be inaccessible to paediatric patients. This review aims to find studies that identify medication review services in primary care that cater for children on long term medication. METHODS: A literature search was conducted on 6th June 2015 using the keywords, ("Medication" or "review" or "Medication Review" or "Medicines use review" or "Medication use review" or "New Medicine Service") AND ("community pharmacy" OR "community pharmacist" OR "primary care" OR "General practice" OR "GP" OR "community paediatrician" OR "community pediatrician" OR "community nurse"). Bibliographic databases used were AMED, British Nursing Index, CINAHL, EMBASE, HMIC, MEDLINE, PsycINFO and Health Business Elite. Inclusion criteria were: paediatric specific medication review in primary care, for example by either a GP, community paediatrician, community nurse or community pharmacist. Exclusion criteria were studies of medication review in adults/unclear patient age and secondary care medication reviews. RESULTS: From the 417 articles, 6 relevant articles were found after abstract and full text review. 235 articles were excluded after title and abstract review (11 did not have full text in English); 96 were adult or non-age specified medication review/MUR/New Medicine Service studies; 63 referred to observational, evaluative studies of interventions in adults; 6 were non-paediatric specific systematic reviews and 17 were protocols, commentaries, news, and letters.The 6 relevant articles consisted of 1 literature review (published 2004), 3 research articles and 1 published protocol. The literature review[1] recommended that children's long term medication should be reviewed. The published protocol stated that the NMS minimum age for inclusion in the trial was for children aged over 13 years of age. The four studies were related to psychiatrists reviewing paediatric mental health patients in the USA, a pharmacist using Drug Related Problem to review patients in GP practices in Australia, a UK study based on an information prescription concept by providing children dispensed medications in community pharmacy with signposting them to health information and one GP practice based study observing pharmaceutical care issues in children and adults. CONCLUSION: The results show that there are currently no known studies on medication use reviews specific to children, whereas in adults, published evaluations are available. The terms of the MUR policy restrict children's access to the service and so more studies are necessary to determine whether children could benefit from such access.

Long-term efficacy of orthokeratology contact lens wear in controlling the progression of childhood myopia

Purpose: The primary outcome of this study is to compare the axial length growth of white European myopic children wearing orthokeratology contact lenses (OK) to a control group (CT) over a 7-year period. Methods: Subjects 6–12 years of age with myopia −0.75 to −4.00DS and astigmatism ≤1.00DC were prospectively allocated OK or distance single-vision spectacles (SV) correction. Measurements of axial length (Zeiss IOLMaster), corneal topography, and cycloplegic refraction were taken at 6-month intervals over a 2-year period. Subjects were invited to return to the clinic approximately 5 years later (i.e., 7 years after the beginning of the study) for assessment of their ocular refractive and biometric components. The CT consisted of 4 SV and 12 subjects who switched from SV to soft contact lens wear after the initial 2 years of SV lens wear. Changes in axial length relative to baseline over a 7-year period were compared between groups. Results: Fourteen and 16 subjects from the OK and CT groups, respectively, were examined 6.7 ± 0.5 years after the beginning of the study. Statistically significant changes in the axial length were found over time and between groups (both p <0.001), but not for the time*group interaction (p = 0.125). The change in the axial length for the OK group was 22% (p = 0.328), 42% (p = 0.007), 40% (p = 0.020), 41% (p = 0.013), and 33% (p = 0.062) lower than the CT group following 6, 12, 18, 24, and 84 months of lens wear, respectively. Conclusion: A trend toward a reduction in the rate of axial elongation of the order of 33% was found in the OK group in comparison to the CT group following 7 years of lens wear.

Short-term and long-term changes in corneal power are not correlated with axial elongation of the eye induced by orthokeratology in children

PURPOSE: To assess the relationship between short-term and long-term changes in power at different corneal locations relative to the change in central corneal power and the 2-year change in axial elongation relative to baseline in children fitted with orthokeratology contact lenses (OK). METHODS: Thirty-one white European subjects 6 to 12 years of age and with myopia −0.75 to −4.00 DS and astigmatism ≤1.00 DC were fitted with OK. Differences in refractive power 3 and 24 months post-OK in comparison with baseline and relative to the change in central corneal power were determined from corneal topography data in eight different corneal regions (i.e., N[nasal]1, N2, T[temporal]1, T2, I[inferior]1, I2, S[superior]1, S2), and correlated with OK-induced axial length changes at two years relative to baseline. RESULTS: After 2 years of OK lens wear, axial length increased by 0.48±0.18 mm (P0.05). CONCLUSION: The reduction in central corneal power and relative increase in paracentral and pericentral power induced by OK over 2 years were not significantly correlated with concurrent changes in axial length of white European children.