Interval Extension Research Articles

Factors Determining Retreatment Time Interval of Rituximab in Korean Patients With Rheumatoid Arthritis.

Unlike other biologic agents for rheumatoid arthritis (RA) that are administered at regular intervals even without flare, rituximab can be administered according to the timing of retreatment determined by the physician. Recently, there has been a tendency to prefer on-demand administration for disease flares rather than regular retreatment. We aimed to investigate the retreatment patterns of rituximab in patients with RA and to identify factors associated with extension of the time interval between retreatment courses. This study included RA patients on rituximab treatment who were enrolled in the Korean Rheumatology Biologics registry (KOBIO) or treated at Ajou University Hospital. Previous or current concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), corticosteroids, number of previous biologic agents, withdrawal, and time intervals of rituximab retreatment were collected. In case of treatment failure, the reasons such as lack of efficacy, adverse events, and others, were also identified. A total of 82 patients were enrolled. The mean follow-up period from the first cycle of rituximab was 46.1 months, and the mean interval between the retreatment courses was 16.3 months. The persistent rates of rituximab after 5 years was 72.4%. Concomitant use of at least two csDMARDs (β = 4.672; 95% CI: 0.089–9.255, p = 0.046) and concomitant use of corticosteroids (β = 7.602; 95% CI: 0.924–14.28, p = 0.026) were independent factors for extending the time interval between the retreatment courses. In conclusion, RA patients treated with rituximab in Korea show high persistence rates. Concomitant use of two or more csDMARDs and concomitant use of corticosteroids with rituximab are associating factors of extending the retreatment time interval. These findings should be considered when selecting rituximab as a treatment for patients with RA.

Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine

SummaryExtension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6–14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.

Extending INR testing intervals in warfarin patients at a multi-center anticoagulation clinic.

Warfarin has been used as an anticoagulant by millions of patients due to its effectiveness, availability, and low cost. Evidence on the safe extension of international normalized ratio (INR) testing frequency remains an area of interest, especially during the recent COVID-19 pandemic. The purpose of this study is to safely extend INR testing intervals in patients throughout a multisite, system-wide anticoagulation clinic. Updates were made to the pharmacist’s collaborative practice agreement (CPA) and nurse protocol to optimize practice and allow INR testing interval extension up to a maximum of 8-weeks. The primary outcome was the change in duration between INR tests (INR testing interval) measured before and after providing staff education on clinic updates. The mean duration between INR tests (SD) was 23.69 days (11.29) in the pre-intervention period and 25.58 days (13.91) in the post-intervention period. During the COVID-19 pandemic (post2), intervals were extended further to 27.81 days (14.96), demonstrating a statistically significant increase in INR testing interval from pre-intervention to post-intervention and to post2 (p < 0.001 and p < 0.001, respectively). A secondary outcome indicated the mean time in therapeutic range (SD) showed no significant difference in pre-intervention 70.11% (25.95) versus post-intervention of 69.76% (25.69) with a difference of − 0.35% (29.93) (p = 0.956) or versus the post2 of 68.82% (27.20) with a difference of − 1.29% (33.20) (p = 0.120). This study showed that changes to the CPA and protocol allowed for a significant increase in INR testing interval while simultaneously maintaining a mean time in therapeutic range > 60% for the clinic population.

Effectiveness of Canakinumab Treatment in Colchicine Resistant Familial Mediterranean Fever Cases.

Anti-interleukin 1 agents are used successfully in colchicine-resistant or intolerant Familial Mediterranean Fever (FMF) patients. Sixty-five patients with FMF who received canakinumab treatment for at least 6 months due to colchicine resistance or intolerance between 2016 and 2020 in our department were retrospectively analyzed. Canakinumab treatment was given subcutaneously every 4 weeks. After completing monthly canakinumab therapy over 12 months, in patients with complete remission, the dosing interval was extended to every 1.5 months for 6 months, then every 2 months for 6 months, and finally every 3 months for a year. In patients without disease activation, canakinumab treatment was discontinued at the end of 3 years and followed up with colchicine treatment. Patients who had a flare switched to the previous dosing interval. In patients with renal amyloidosis, monthly canakinumab treatment was continued without extending the dose intervals. The mean duration of canakinumab use in our patients was 31.4 ± 10.57 months (6–52 months). The mean age at onset of symptoms was 4.65 ± 3.84 (range, 1–18) years, and the mean age at diagnosis was 5.59 ± 3.9 (range, 4–19) years. Complete remission was achieved in 57 (87.6%) and partial remission in seven (10.7%) patients. One patient was unresponsive to treatment. Canakinumab treatment was discontinued in three patients with complete remission and one patient with drug resistance. Erythrocyte sedimentation rate (ESR) (51.85 ± 15.7 vs. 27.80 ± 13.73 mm/h) and C-reactive protein (CRP) [26 (3-73) vs. 5 (1–48) mg/L] values were compared before and after canakinumab treatment in attack-free periods, a significant decrease was found after canakinumab treatment (p < 0.001, p < 0.001, respectively). Bodyweight Z-scores (respectively −0.80 ± 0.86 vs. −0.49 ± 0.92) were compared, similarly, a statistically significant increase after canakinumab treatment (p < 0.001), but no significant increase in height Z scores (−1.00 ± 0.88 vs. −0.96 ± 0.94) (p = 0.445) was detected. Four patients had FMF-related renal amyloidosis. The decrease in proteinuria with canakinumab treatment was not statistically significant (p = 0.068). Cervical lymphadenitis developed in one and local reactions in two patients. No severe adverse effects requiring discontinuation of canakinumab treatment were observed. Our study showed that canakinumab treatment was highly effective, well-tolerated in pediatric FMF patients, and controlled extension of the canakinumab dose interval was safe.

Extension of the potential intervals of high redox activity and electronic conductivity of polypyrrole films on electrode surface via their electrochemical multi-cycle treatment in monomer-free solution

Thin polypyrrole films (thickness: about 30 nm) have been deposited at electrode surface via potentiostatic oxidation of dilute (1 mM) pyrrole solution in acetonitrile (AN). It has been shown that their subsequent treatment by means of multi-cycle voltammetry within a broad potential range (up to -2.0 V vs. Ag/Ag+ in AN) leads to their "activation", i.e. to a very strong extension of their redox response region in the negative direction as well as to almost uniform distribution of the redox activity within this potential range. Region of their high conductivity under in situ conditions has also extended significantly. Spectral and electrocatalytic properties of such PPy films before and after their "activation" have been analyzed. Two parameters for characterization of the variation of film's properties in the course of its "activation" (redox efficiency of polymerization and width of electroactivity region) have been proposed. Comparison of films deposited at different potentials (from 0.6 V to 0.8 V) has revealed that the effect of their "activation" increases for lower polymerization potential. Films deposited at 0.6 V possess after their "activation" a very broad electroactivity range (almost 2.5 V) and a record high redox charge per monomer unit (its oxidation degree) inside the film in contact with AN solution, 0.45. Such unusual properties of "activated" PPy films make them prospective materials for various applications.

Updated evidence-based recommendations for cervical cancer screening in France.

IntroductionA national organized cytology-based cervical cancer screening program was launched in 2018 and rollout is ongoing. Concomitantly, the High Authority for Health (HAS) recently assessed new evidence on primary HPV testing to update screening recommendations.MethodsThe HAS commissioned systematic reviews and meta-analyses to evaluate the effectiveness of primary HPV screening; accuracy of HPV testing on self-samples; effectiveness of self-sampling to reach underscreened women; and triage strategies to manage HPV-positive women. Recommendations developed by the HAS were reviewed by a multidisciplinary group.ResultsCompared with cytology screening, HPV screening is more sensitive to detect precancers but less specific. In women aged ≥30, if the test is negative, HPV screening greatly reduces the risk of developing precancer and cancer for at least 5 years. HPV testing, using validated PCR-based assays, is as sensitive and slightly less specific on self-samples than on clinician-taken samples. Self-sampling is more effective to reach underscreened women than sending invitations to have a specimen taken by a clinician. Two-time triage strategies ensure a sufficiently high risk if triage-positive to justify referral and low risk if triage-negative allowing release to routine screening.ConclusionsThe HAS recommends three-yearly cytology screening for women aged 25–29 and HPV screening for those aged 30–65 with an extension of the screening interval to 5 years if the HPV test is negative. Self-sampling should be offered to underscreened women aged ≥30. HPV-positive women should be triaged with cytology. Those with abnormal cytology should be referred for colposcopy and those with normal cytology re-tested for HPV 12 months later. Recommendations for implementation of HPV-based screening in the organized program are provided.

Impact of Preoperative Time Interval on Survival in Patients With Gastric Cancer.

A time interval between diagnosis and surgery for gastric cancer is necessary, although its impact on survival remains controversial. We evaluated the impact of preoperative time interval on survival in gastric cancer patients. We enrolled 332 patients who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. We separately analyzed early- (cStage I) and advanced-stage (cStages II and III) patients. Early-stage patients were divided according to preoperative time interval: short (≤ 42days) and long (> 42days) groups. Advanced-stage patients were also divided into short (≤ 21days) and long (> 21days) groups. We compared the survival between the short and long groups in early- and advanced-stage patients. The median preoperative time interval was 29days, and no significant differences were found in patient characteristics between the short and long groups in early- and advanced-stage patients. In early-stage patients, the 5-year survival rates of the short and long groups were 86.5% and 88.4%, respectively (P = 0.917). In advanced-stage patients, the 5-year survival rates were 72.1% and 70.0%, respectively (P = 0.552). In multivariate analysis, a longer time interval was not selected as an independent prognostic factor in early- and advanced-stage patients. In this study, survival difference was not found based upon preoperative time interval. The results do not affirm the delay of treatment without reason, however, imperative extension of preoperative time interval may be justified from the standpoint of long-term survival.

Vaccinations in Patients Receiving Systemic Drugs for Skin Disorders: What Can We Learn for SARS-Cov-2 Vaccination Strategies?

Large-scale vaccination strategies are currently being deployed against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2). Whether systemic medication for skin diseases affects the efficacy of vaccination and whether temporary interruption or extension of the dosing interval is necessary is under debate. Most immunomodulating/immunosuppressive drugs only affect vaccine-induced immune responses to a limited or moderate extent, preserving sufficient immunity in most patients. Mycophenolate mofetil, Janus kinase inhibitors, and rituximab require a more cautious approach, and judicious timing of vaccination might be appropriate in patients receiving these treatments. It should be noted that, for most drugs except methotrexate, data on the length of the interruption period to restore vaccine-induced immune responses to normal levels are either very limited or absent. In these cases, only the drug half-life can be used as a practical guideline. In most patients, systemic medication can be continued through the vaccination process, although case-by-case decisions can be considered.

Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit.

Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration <0.5 mg/L for at least 4 h) of the Hartford nomogram. A population pharmacokinetic model was built based on 307 measurements in 140 unique patients and externally validated by an independent study dataset. A two-compartment model was optimal for the structure model and creatinine clearance remained as the only covariate in the final model correlating to the clearance of tobramycin. Simulations indicated that the Hartford nomogram is effective for infections due to pathogens with an MIC of ≤1 mg/L, but not with an MIC of 2 mg/L. The percentage of patients who reached the non-toxicity target was quite low under the Hartford nomogram and a further extension of the dosing interval was necessary to minimize the toxicity. The Hartford nomogram was not suitable for critically ill patients with pathogen MICs of 2 mg/L and drug monitoring is required to manage efficacy and toxicity.

Ovarian cysts in cattle

Ovarian cysts (OC) are among the major factors affecting dairy cattle fertility due to their impacts on reproductive performance. Extension of the calving-calving interval and the costs of treatmentassociated with this pathology are the main sources of economic losses for the dairy industry. This study involved conducting an epidemiological survey relating to ovarian cysts in cows based on the observations of veterinary practitioners in Algeria. This survey was performed using a questionnaire distributed to 103 practicing veterinarians in different regions of Algeria. According to the responses, OC dominated all ovarian diseases, followed by smooth ovaries and ovarian adhesions. Ovarian tumours were encountered very rarely. In general, veterinarians considered any follicular structure greater than 20 mm in diameter and persisting for at least 10 days to be cystic. The aetiology was multifactorial, and the following were cited: alimentation, high milk production, puerperal pathologies (metritis, retained placenta), postpartum, age, and winter season. Anoestrus was often the most observed behaviour in cystic cows, accompanied by changes in the genital tract, namely the cervix and uterus. As a consequence, in most cases, OC was associated with a delay of first insemination and conception. The use of hormones, especially PGF2α and GnRH, to treat OC was the most widely used method in the field. Clinical recovery was obtained approximately 11-15 days after the beginning of treatment, though the risk of recurrence was appreciable. The majority of vets interviewed promoted the preventionof OC. They advised breeders to improve feeding and hygiene conditions, especially during calving. Medical prevention was based on the use of hormones (PGF2α and GnRH). Though the survey showed varying results, they were generally consistent with the literature.

A high stem to leaf ratio reduced rainfall use efficiency under altered rainfall patterns in a semi-arid grassland in northeast China.

Rainfall use efficiency (RUE) is crucial for understanding the changes in grassland productivity due to variations in future rainfall patterns. Recently, numerous studies have been conducted on the relationship between RUE and the amount of rainfall, but there has been little research on the influence of rainfall distribution and the interactive effect of rainfall amounts and distribution on RUE. Here, a simulated rainfall experiment was conducted to evaluate the impacts of rainfall amount (average rainfall amount (R0), 334mm; decreased (R-) and increased (R+) rainfall amounts, 233mm and 434mm, respectively) and dry intervals (comprising 6-day, 9-day, 12-day, 15-day, 18-day and 21-day intervals between rainfall) on productivity and RUE in Leymus chinensis (Trin.) Tzvel., a dominant grass of the Eastern Eurasian Steppe. Our results showed that (1) for biomass production and RUE, moderate extension of dry intervals was conducive to enhancing total biomass production and RUE. The peak values of total biomass and RUE appeared during the 15-day interval for R-, and the 18-day interval for R0 and R+. (2) For biomass allocation, extension of dry intervals decreased the stem to leaf ratio (S/L) and the root to shoot ratio (R/S). (3) Further, the S/L ratio was significantly negatively correlated with RUE. These results suggest that variations in rainfall patterns can alter the RUE by changing the S/L ratio, and finally influence biomass production in L. chinensis. These findings have important implications for understanding and predicting the effect of future climate change on productivity in semi-arid grassland.

Lanadelumab Efficacy, Safety, and Injection Interval Extension in HAE: A Real-Life Study

Lanadelumab has been available in Germany for the prophylactic treatment of hereditary angioedema since February2019. To investigate real-life treatment outcome of lanadelumab and gain practical experience in adapting the therapy to individual patients. The study included 34 patients. In 24 patients with hereditary angioedema and 4 patients with angioedema due to acquired C1-inhibitor deficiency, the previous treatment was switched to lanadelumab. In 6 patients with hereditary angioedema, lanadelumab from the open-label Hereditary Angioedema Long-term Prophylaxis study was continued in regular care. During the transition, patients were monitored using the angioedema control test and the angioedema quality of life questionnaire. At the time at which patients became symptom-free, the dosage interval was increased gradually (+3 days). On average, the angioedema control test values improved from 7.5 (poorly controlled disease) to 14.9 (well-controlled disease), and all patients showed adequate disease control. All treated patients, except 1 outlier, scored angioedema quality of life questionnaire values representing only a slight reduction in quality of life (mean, 14 points). At the time point of data collection, 9 patients used an average fixed injection interval of 30 days. Twenty-two patients were symptom-free from the beginning of the treatment phase and intended to extend their injection interval from 30 to 32.5 days (median). We recommended reducing the initial dosing interval from 24 to 21 days (median) to 3 patients because of intermediately occurring symptoms. Gradual extension of injection intervals of lanadelumab presented in this study can minimize the burden oftherapy without losing efficacy.

Sa001 OPTIMAL USE OF LIMITED COLONOSCOPY CAPACITY IN A FIT-BASED CRC SCREENING PROGRAM DURING COVID-19 PANDEMIC

Aims A second wave of the COVID-19 pandemic may force many health care providers to downscale their services again,including colonoscopies which may impact capacity for colorectal cancer (CRC) screening. This study aimed to determinethe optimal measure to handle these temporary shortages in colonoscopy capacity in the Dutch national CRC screeningprogram to retain as much of the preventive effect of the screening program as possible. Methods We used the MISCAN-Colon model to simulate the Dutch national CRC screening program, providing biennial FITto individuals aged 55-75, under three different scenarios to temporarily reduce required colonoscopy capacity in thesecond half of 2020 and 2021: increase in FIT cut-off value exclusion of specific age-groups, and extension of the screening interval For each scenario, we estimated the impact on required colonoscopy capacity in 2020-2021, long-term CRC incidence,mortality and life years (LYs) lost. Outcomes were compared to a reference scenario without colonoscopy restrictions. Results In 2020 and 2021, the required colonoscopy capacity without any restrictions was 100,300 colonoscopies.Increasing the cut-off, excluding age-groups and extending the screening interval resulted in a reduction of 11,600-27,000,10,800-17,500, and 16,100-49,500 colonoscopies, respectively (Table 1). Increasing the cut-off resulted in 400-900 excessCRC cases and 200-500 excess CRC-related deaths from 2020-2050, while excluding age-groups resulted in 200-600excess CRC cases and 200-500 excess CRC-related deaths. Unexpectedly, extending the screening interval up to 34 months prevented 200-300 more CRC cases and 200-600 more CRC-related deaths, because screening occurred until slightlyhigher ages due to the initial delay. All measures resulted in LYs lost, but extending the screening interval up to 34 monthshad the smallest impact. Abbreviations: CRC, colorectal cancer;LYs, Life Years;μg Hb/g feces, microgram Hemoglobin per gram feces.∗Number between brackets are negative numbers. Conclusions A temporary extension of the screening interval to accommodate reduction in available colonoscopy capacityresults in the smallest impact on the CRC incidence, mortality and LYs lost. (Table Presented).

How air pollution lowers the domestic value-added ratio in exports: an empirical study of China.

This paper analyzes the theoretical mechanism and transmission channel for the impact of air pollution on firms' domestic value-added ratio (DVAR) in exports. Based on the matched Chinese Industrial Enterprises Database and China Customs Enterprise Database, the DVAR in exports is measured, and this mechanism is empirically tested with standard measurement methods. The study concludes that air pollution is not conducive to raising the DVAR during the sample period. This conclusion remains robust to many issues, such as endogeneity, measurement error, extension of the sample interval, substitution of the air pollution index, and policy changes. The impact of air pollution on the DVAR varies by the type of firm ownership, size, and age, as well as the size and location of the city. In addition, the negative impact of air pollution on the DVAR grows with increases in the PM2.5 concentration. The growing factor prices of domestic intermediate goods and the falling productivity due to air pollution are important transmission channels for the negative impact of air pollution on the DVAR. In order for firms to open up on all fronts through quality trade development, we recommend the prevention and control of air pollution, fueling internal driving forces for firms' independent innovation, and encouraging firms to target the medium- and high-end markets.

Extension of lubricant drain interval by modified pure biomass oil filter

AbstractWith the extensive use of internal combustion engines, the large volume of lubricant consumption has become an urgent problem. In this study, a new adsorbent of modified sawdust (MS) was used to clean the waste diesel engine lubricant and prepared into a pure biomass oil filter (PBF) for the actual operation of buses. The characterization results of sawdust showed that the crystallinity index of MS enhanced 19.26%, and MS had smoother morphology, obvious pores than raw sawdust (RS). In on‐road tests, both total acid number (1 mg KOH·g−1) and total base number (9 mg KOH·g−1) were within the permitted range of the standard, and the kinematic viscosity showed a decreasing trend. In addition, the concentration of metals and insoluble colloids (&lt;0.2%) in the lubricant was far below the oil change limit, which made the oil drain interval of the two vehicles extended from 15 000 km (recommended by manufacture) to 60 500 and 71 500 km, respectively. Conclusively, it is believed that PBF is efficient to alleviate lubricant deterioration and prolong the oil drain interval.

Conversion from Aranesp® to NESP® in dialysis patients-Exploration of dosing strategies and the feasibility of extending the dosing interval.

Darbepoetin alpha is available as Aranesp® and NESP®, which differ in the inactive component and maximum dose-strength of prefilled syringes. We conducted an observational cohort study to investigate optimal conversion strategies and the feasibility of extending dosing intervals with higher-dose preparations in dialysis patients converting from Aranesp® to NESP®. Adult dialysis patients on Aranesp® with stable haemoglobin of 9-12 g/dL were converted to NESP® at the same monthly total dose according to one of three conversion regimens. Group A included patients on ≤80 mcg/month of Aranesp® who converted with dosing regimen unchanged. Group B patients converted to NESP® with extended dosing intervals using higher individual dose preparations. Group C were patients on 100 mcg Aranesp® who converted to NESP® 120 mcg with extended dosing intervals. Patients were observed for 6months. Fifty patients were included. All 24 Group A patients maintained stable haemoglobin. In Group B, 10 patients (50%) maintained stable haemoglobin with extension of dosing interval from 1.04 ± 0.14 to 3.03 ± 1.28 weeks. Factors associated with success in extending dosing interval included a lower prevalence of cardiovascular disease and a higher Kt/Vurea in peritoneal dialysis patients. Four patients (80%) in Group C maintained stable haemoglobin after conversion to NESP® 120 mcg with extended dosing interval. The use of NESP® 120 mcg was well tolerated, and was associated with reduced patient-reported pain score and 38% reduction of drug cost. Dialysis patients on Aranesp® can be successfully converted to NESP® and the dosing interval can be extended successfully in a significant proportion of patients, which could reduce discomfort and drug cost.

Tolerance analysis of the volumetric error of heavy-duty machine tool based on interval uncertainty

Tolerance design is one of the main stages in the robust design process of machine tool. For heavy-duty machine tools, traditional tolerance analyses based on probabilistic methods may not be suitable because it is generally difficult and costly to obtain the accurate probability distribution of error by the limited geometric error measurements in large dimension. In this paper, a new tolerance analysis method for heavy-duty machine tools is proposed based on the interval uncertainty. Considering independent geometric error components have certain bounds but accurate distributions are unknown, the interval theory is introduced to the kinematic modeling of the static volumetric error of heavy-duty machine tools based on the multi body system (MBS) and homogeneous transformation matrix (HTM). Geometric error components are described in forms of interval numbers to extend the error model to the interval number system. The interval extension of the volumetric error function is further modified so that the variation interval of the volumetric error is thus accurately evaluated by the interval arithmetic. Comparative studies on tolerance analyses of different typical probabilistic/non-probabilistic methods are conducted through numerical simulations. It is found that under the given computational condition, the tolerance analysis based on the interval uncertainty can accurately evaluate the variation range of the volumetric error.

The contribution of the English NHS Diabetic Eye Screening Programme to reductions in diabetes-related blindness, comparisons within Europe, and future challenges

The aim of the English NHS Diabetic Eye Screening Programme (DESP) is to reduce the risk of sight loss amongst people with diabetes by the prompt identification and effective treatment if necessary of sight-threatening diabetic retinopathy, at the appropriate stage during the disease process, with a long-term aim of preventing blindness in people with diabetes.For the year 2009–2010, diabetic retinopathy (DR) was no longer the leading cause of blindness in the working age group. There have been further reductions in DR certifications for WHO severe vision impairment and blindness from 1,334 (5.5% of all certifications) in 2009/2010 to 840 (3.5% of all certifications) in 2018/2019. NHS DESP is a major contributor to this further reduction, but one must also take into account improvements in glycaemic and blood pressure control, timely laser treatment and vitrectomy surgery, improved monitoring techniques for glycaemic control, and vascular endothelial growth factor inhibitor injections for control of diabetic macular oedema. The latter have had a particular impact since first introduced in the UK in 2013.Current plans for NHS DESP include extension of screening intervals in low-risk groups and the introduction of optical coherence tomography as a second line of screening for those with screen positive maculopathy with two dimensional markers. Future challenges include the introduction of automated analysis for grading and new camera technologies.

The Hukuhara difference, gH-difference and gH-division are not inclusion isotonic

This paper shows that the Hukuhara difference and generalized gH-difference, as well as the gH-division, are not inclusion-isotonic interval extensions of the difference and division of real numbers, respectively, and discusses how this fact may affect the reliability of some results in specific epistemic mathematical models with respect to the semantics being considered.

Very-low-dose aspirin and surveillance colonoscopy is cost-effective in secondary prevention of colorectal cancer in individuals with advanced adenomas: network meta-analysis and cost-effectiveness analysis

BackgroundIndividuals with advanced colorectal adenomas (ACAs) are at high risk for colorectal cancer (CRC), and it is unclear which chemopreventive agent (CPA) is safe and cost-effective for secondary prevention. We aimed to determine, firstly, the most suitable CPA using network meta-analysis (NMA) and secondly, cost-effectiveness of CPA with or without surveillance colonoscopy (SC).MethodsSystematic review and NMA of randomised controlled trials were performed, and the most suitable CPA was chosen based on efficacy and the most favourable risk–benefit profile. The economic benefits of CPA alone, 3 yearly SC alone, and a combination of CPA and SC were determined using the cost-effectiveness analysis (CEA) in the Malaysian health-care perspective. Outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2018 US Dollars ($) per quality-adjusted life-year (QALY), and life-years (LYs) gained.ResultsAccording to NMA, the risk–benefit profile favours the use of aspirin at very-low-dose (ASAVLD, ≤ 100 mg/day) for secondary prevention in individuals with previous ACAs. Celecoxib is the most effective CPA but the cardiovascular adverse events are of concern. According to CEA, the combination strategy (ASAVLD with 3-yearly SC) was cost-saving and dominates its competitors as the best buy option. The probability of being cost-effective for ASAVLD alone, 3-yearly SC alone, and combination strategy were 22%, 26%, and 53%, respectively. Extending the SC interval to five years in combination strategy was more cost-effective when compared to 3-yearly SC alone (ICER of $484/LY gain and $1875/QALY). However, extending to ten years in combination strategy was not cost-effective.ConclusionASAVLD combined with 3-yearly SC in individuals with ACAs may be a cost-effective strategy for CRC prevention. An extension of SC intervals to five years can be considered in resource-limited countries.