Antithrombotic therapy in patients with liver disease: population-based insights on variations in prescribing trends, adherence, persistence and impact on stroke and bleeding

Background: Patients with liver disease have complex haemostasis and due to such contraindications, landmark randomised controlled trials investigating antithrombotic medicines have often excluded these patients. As a result, there has been limited consensus on the safety, efficacy and monitoring practices of anticoagulant and antiplatelet therapy in patients with liver disease. This study aims to investigate prescribing prevalence, adherence, persistence and impact of adherence on bleeding and stroke risk in people with and without liver disease taking anticoagulants and antiplatelets. / Methods: We employed a population-based cohort consisting of person-level linked records from primary care, secondary care and the death registry. The cohort consisted of 3,929,596 adults aged ≥ 30 years during the study period of 1998 to 2020 and registered with an NHS general practitioner in England. The primary outcome was prescribing prevalence, adherence to and persistence with anticoagulant and antiplatelet therapy comparing patients with and without liver disease. Risk factors for non-adherence and non-persistence were analysed using multivariable logistic regression and Cox regression. Impact of adherence on bleeding and ischaemic stroke was assessed. / Findings: Among patients with any of the six liver diseases (ALD, autoimmune liver disease, cirrhosis, HBV, HCV and NAFLD), we identified 4,237 individuals with incident atrial fibrillation (indication for anticoagulants) and 4,929 individuals with incident myocardial infarction, transient ischaemic attack, unstable angina or peripheral arterial disease (indication for antiplatelets). Among patients without liver disease, 321,510 and 386,643 individuals were identified as having indications for anticoagulant and antiplatelet therapy, respectively. Among drug-naïve individuals, prescribing prevalence was lower in patients with liver disease compared with individuals without liver disease: anticoagulants (20.6% [806/3,921] vs. 33.5% [103,222/307,877]) and antiplatelets (56.2% [2,207/3,927] vs. 71.1% [249,258/350,803]). Primary non-adherence rates (stopping after one prescription) were higher in patients with liver disease, compared with those without liver disease: anticoagulants (7.9% [64/806] vs. 4.7% [4,841/103,222]) and antiplatelets (6.2% [137/2,207] vs. 4.4% [10,993/249,258]). Among individuals who were not primary non-adherent and had at least 12 months of follow-up, patients with liver disease however had a higher one-year adherence rate: anticoagulants (33.1% [208/628] vs. 29.4% [26,615/90,569]) and antiplatelets (40.9% [743/1,818] vs. 34.4% [76,834/223,154]). Likelihood of non-adherence was lower in apixaban and rivaroxaban (relative to warfarin) and lower in clopidogrel (relative to aspirin). Increased comorbidity burden (by CHA2DS2VASc score) was associated with decreased risk of non-adherence and non-persistence with anticoagulants. Overall rates of ‘non-adherent, non-persistent’ were highest in warfarin (compared with apixaban and rivaroxaban) and aspirin (compared with clopidogrel or dipyridamole) in patients with and without liver disease. Among patients without liver disease, not taking antithrombotic medications for >3 months was associated with a higher risk of stroke, however, adherence to these medications was also associated with a small increase in risk of bleeding. Patients with liver disease (when compared with those without liver disease) had higher risks of stroke, especially when they stopped taking antiplatelets for >3 months. Patients with liver disease who were adherent to antiplatelets, however, had a higher risk of bleeding compared with patients without liver disease. / Interpretation: Use of antithrombotic medicines in patients with and without liver disease is suboptimal with heterogeneity across medicines. As patients with liver disease are excluded from major randomised trials for these drugs, our results provide real-world evidence that may inform medicine optimisation strategies. We outline challenges and opportunities for tackling non-adherence, which begins with understanding patients’ views of medicines to help them make informed decisions about appropriate use. / Funding: AGL is supported by funding from the Wellcome Trust (204841/Z/16/Z), National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (BRC714/HI/RW/101440), NIHR Great Ormond Street Hospital Biomedical Research Centre (19RX02), the Health Data Research UK Better Care Catalyst Award (CFC0125) and the Academy of Medical Sciences (SBF006\1084). The funders have no role in the writing of the manuscript or the decision to submit it for publication

Rule-based Procedural Generation of Item in Role-playing Game

This paper demonstrates the significance of rule-based procedural generation of item in role-playing game. The main aims of this project are to: implement rule-based randomized algorithm and totally randomized algorithm in generating item procedurally in Role-Playing Game (RPG), and compare the advantage of rule-based randomized algorithm against totally randomized algorithm in item drop mechanism. Experimental results demonstrate success with all aims: rule-based randomized algorithm is proven to be a better game changing factor in procedural generation of item as it can control the prolific generation of strong items in the early stage of the game. This helps to balance the game and prevents any snow-balling effect as the game progresses

Late effects of cancer in children, teenagers and young adults: Population-based study on the burden of 183 conditions, in-patient and critical care admissions and years of life lost

Background: Children, teenagers and young adults who survived cancer are prone to developing late effects. The burden of late effects across a large number of conditions, in-patient hospitalisation and critical care admissions have not been described using a population-based dataset. We aim to systematically quantify the cumulative burden of late effects across all cancer subtypes, treatment modalities and chemotherapy drug classes. // Methods: We employed primary care records linked to hospitals, the death registry and cancer registry from 1998–2020. CTYA survivors were 25 years or younger at the time of cancer diagnosis had survived ≥5 years post-diagnosis. Year-of-birth and sex-matched community controls were used for comparison. We considered nine treatment types, nine chemotherapy classes and 183 physical and mental health late effects. Cumulative burden was estimated using mean cumulative count, which considers recurring events. Multivariable logistic regression was used to investigate the association between treatment exposures and late effects. Excess years of life lost (YLL) attributable to late effects were estimated. // Findings: Among 4,063 patients diagnosed with cancer, 3,466 survived ≥ 5 years (85%); 13,517 matched controls were identified. The cumulative burden of late effects at age 35 was the highest in survivors of leukaemia (23.52 per individual [95% CI:19.85–29.33]) and lowest in survivors of germ cell tumours (CI:6.04 [5.32–6.91]). In controls, the cumulative burden was 3.99 (CI:3.93–4.08) at age 35 years. When survivors reach age 45, the cumulative burden for immunological conditions and infections was the highest (3.27 [CI:3.01–3.58]), followed by cardiovascular conditions (3.08 [CI:1.98–3.29]). Survivors who received chemotherapy and radiotherapy had the highest disease burden compared to those who received surgery only. These patients also had the highest burden of hospitalisation (by age 45: 10.43 [CI:8.27–11.95]). Survivors who received antimetabolite chemotherapy had the highest disease and hospitalisation burden, while the lowest burden is observed in those receiving antitumour antibiotics. Regression analyses revealed that survivors who received only surgery had lower odds of developing cardiovascular (adjusted odds ratio 0.73 [CI:0.56–0.94]), haematological (aOR 0.51 [CI:0.37–0.70]), immunology and infection (aOR 0.84 [CI:0.71–0.99]) and renal (aOR 0.51 [CI:0.39–0.66]) late effects. By contrast, the opposite trend was observed in survivors who received chemo-radiotherapy. High antimetabolite chemotherapy cumulative dose was associated with increased risks of subsequent cancer (aOR 2.32 [CI:1.06–4.84]), metastatic cancer (aOR 4.44 [CI:1.29–11.66]) and renal (aOR 3.48 [CI:1.36–7.86]) conditions. Patients who received radiation dose of ≥50 Gy experienced higher risks of developing metastatic cancer (aOR 5.51 [CI:2.21–11.86]), cancer (aOR 3.77 [CI:2.22–6.34]), haematological (aOR 3.43 [CI:1.54–6.83]) and neurological (aOR 3.24 [CI:1.78–5.66]) conditions. Similar trends were observed in survivors who received more than three teletherapy fields. Cumulative burden analyses on 183 conditions separately revealed varying dominance of different late effects across cancer types, socioeconomic deprivation and treatment modalities. Late effects are associated with excess YLL (i.e., the difference in YLL between survivors with or without late effects), which was the most pronounced among survivors with haematological comorbidities. // Interpretation: To our knowledge, this is the first study to dissect and quantify the importance of late morbidities on subsequent survival using linked electronic health records from multiple settings. The burden of late effects is heterogeneous, as is the risk of premature mortality associated with late effects. We provide an extensive knowledgebase to help inform treatment decisions at the point of diagnosis, future interventional trials and late-effects screening centred on the holistic needs of this vulnerable population

Fistulotomy and drainage of deep postanal space abscess in the treatment of posterior horseshoe fistula

BACKGROUND: Posterior horseshoe fistula with deep postanal space abscess is a complex disease. Most patients have a history of anorectal abscess drainage or surgery for fistula-in-ano. METHODS: Twenty-five patients who underwent surgery for posterior horseshoe fistula with deep postanal space abscess were analyzed retrospectively with respect to age, gender, previous surgery for fistula-in-ano, number of external openings, diagnostic studies, concordance between preoperative studies and operative findings for the extent of disease, operating time, healing time, complications, and recurrence. RESULTS: There were 22 (88%) men and 3 (12%) women with a median age of 37 (range, 25–58) years. The median duration of disease was 13 (range, 3–96) months. There was one external opening in 12 (48%) patients, 2 in 8 (32%), 3 in 4 (16%), and 4 in 1 (4%). Preoperative diagnosis of horseshoe fistula was made by contrast fistulography in 4 (16%) patients, by ultrasound in 3 (12%), by magnetic resonance imaging in 6 (24%), and by physical examination only in the remainder (48%). The mean ± SD operating time was 47 ± 10 min. The mean ± SD healing time was 12 ± 3 weeks. Three of the 25 patients (12%) had diabetes mellitus type II. Nineteen (76%) patients had undergone previous surgery for fistula-in-ano, while five (20%) had only perianal abscess drainage. Neither morbidity nor mortality developed. All patients were followed up for a median of 35 (range, 6–78) months and no recurrence was observed. CONCLUSIONS: Fistulotomy of the tracts along the arms of horseshoe fistula and drainage of the deep postanal space abscess with posterior midline incision that severs both the lower edge of the internal sphincter and the subcutaneous external sphincter and divides the superficial external sphincter into halves gives excellent results with no recurrence. When it is necessary, severing the halves of the superficial external sphincter unilaterally or even bilaterally in the same session does not result in anal incontinence. Close follow-up of patients until the wounds completely healed is essential in the prevention of premature wound closure and recurrence

The application of nitric oxide to control biofouling of membrane bioreactors

© 2015 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology. A novel strategy to control membrane bioreactor (MBR) biofouling using the nitric oxide (NO) donor compound PROLI NONOate was examined. When the biofilm was pre-established on membranes at transmembrane pressure (TMP) of 88-90kPa, backwashing of the membrane module with 80μM PROLI NONOate for 45min once daily for 37 days reduced the fouling resistance (Rf) by 56%. Similarly, a daily, 1h exposure of the membrane to 80μM PROLI NONOate from the commencement of MBR operation for 85 days resulted in reduction of the TMP and Rf by 32.3% and 28.2%. The microbial community in the control MBR was observed to change from days 71 to 85, which correlates with the rapid TMP increase. Interestingly, NO-treated biofilms at 85 days had a higher similarity with the control biofilms at 71 days relative to the control biofilms at 85 days, indicating that the NO treatment delayed the development of biofilm bacterial community. Despite this difference, sequence analysis indicated that NO treatment did not result in a significant shift in the dominant fouling species. Confocal microscopy revealed that the biomass of biopolymers and microorganisms in biofilms were all reduced on the PROLI NONOate-treated membranes, where there were reductions of 37.7% for proteins and 66.7% for microbial cells, which correlates with the reduction in TMP. These results suggest that NO treatment could be a promising strategy to control biofouling in MBRs

Pengaruh Pembangunan Penerapan Nilai dalam Pendidikan Abad Ke 21 Terhadap Pembentukan Sahsiah Murid Sekolah Kurang Murid (SKM) Luar Bandar di Sabah

Kajian ini dijalankan bagi mengkaji pengaruh pembangunan penerapan nilai dalam pendidikan abad ke-21 terhadap pembentukan sahsiah murid Sekolah Kurang Murid (SKM) luar bandar di Sabah. Selain itu, kajian ini mengkaji perbezaan skor min pembangunan penerapan nilai dalam pendidikan abad ke-21 dan pembentukan sahsiah murid Sekolah Kurang Murid (SKM) luar bandar di Sabah. Kajian ini menggunakan reka bentuk bukan eksperimen dan kaedah kuantitatif. Seramai 209 orang guru SKM telah dipilih untuk dijadikan sampel dalam kajian ini. Sampel ini ditentukan dengan menggunakan kaedah pensamplean rawak mudah. Instrumen soal selidik pula telah digunakan untuk memperoleh maklumat daripada sampel kajian. Data mentah yang diperoleh daripada sampel kajian dianalisis menggunakan perisian Statistical Package for Social Sciences (SPSS) dengan menggunakan analisis statistik inferensi yang melibatkan analisis Regresi Linear. Hasil analisis menunjukkan terdapat pengaruh signifikan yang positif dan kuat antara pembangunan penerapan nilai dalam pendidikan abad ke-21 terhadap pembentukan sahsiah murid Sekolah Kurang Murid (SKM) luar bandar di Sabah (Beta=0.88, t=27.65).  Hasil kajian ini diharap dapat memberikan input bermanfaat kepada pelbagai pihak khususnya Kementerian Pendidikan Malaysia dalam usaha meningkatkan kemampuan sekolah untuk melahirkan murid yang bersahsiah dan mampu memberi sumbangan kepada pembangunan negara

Development of Rule-based Procedural Content Generation for 2-Dimensional RPG

This paper demonstrates the capabilities of developing a 2-dimensional role-playing game from scratch using only VB.net without other additional extension. Although VB.net which is usually not preferred by game developers, it has the potential to create a simple game prototype. The main aims of this project are to: test the feasibility of VB.net in developing a 2-dimensional role-playing game from scratch, and create a functional game prototype that can be used for future researches which are on procedural generation of item and users’ preference of item. This game prototype is essential to the listed researches as direct implementation of item drop mechanism is easier. Experimental results demonstrate success with all aims: VB.net is capable in developing 2-dimensional role-playing game, and a functional game prototype has been created which can be used for future researches

A Comparison of BPNN, RBF, and ENN in Number Plate Recognition

In this paper, we discuss a research project that related to autonomous recognition of Malaysia car plates using neural network approaches. This research aims to compare the proposed conventional Back propagation Feed Forward Neural Network (BPNN), Radial Basis Function Network (RBF), and Ensemble Neural Network (ENN). There are numerous research articles discussed the performances of BPNN and RFB in various applications. Interestingly, there is lack of discussion and application of ENN approach as the idea of ENN is still very young. Furthermore, this paper also discusses a novel technique used to localize car plate automatically without labelling them or matching their positions with template. The proposed method could solve most of the localization challenges. The experimental results show the proposed technique could automatically localize most of the car plate. The testing results show that the proposed ENN performed better than the BPNN and RBF. Furthermore, the proposed RBF performed better than BPNN

A Review of Computer Vision Methods for Fruit Recognition.

This paper reviews the use of computer vision methodology in the field of fruit recognition. A fruit recognition process usually consists of three steps which are image acquisition, pre-processing, and image analysis. Various approaches are employed in the pre-processing and image analysis stages and some of these are presented in this paper. This review is conducted in order to understand the current state of the art of these approaches and to study the improvements and the advances in this area. A comparison between these methods will also be discussed

Hubungan antara Pembangunan Penerapan Nilai dalam Pendidikan Abad Ke-21 dengan Pembentukan Sahsiah Murid Sekolah Kurang Murid (SKM) Luar Bandar di Sabah

Penerapan nilai dalam pendidikan abad ke-21 amat penting bagi membentuk sahsiah murid yang mapan dalam pelbagai aspek seperti yang digariskan dalam Falsafah pendidikan Kebangsaan (FPK). Kajian korelasi ini dijalankan bagi mengkaji hubungan pembangunan penerapan nilai dalam pendidikan abad ke-21 dengan pembentukan sahsiah murid Sekolah Kurang Murid (SKM) luar bandar di Sabah. Kajian ini menggunakan reka bentuk bukan eksperimen dan kaedah kuantitatif. Seramai 209 orang guru SKM dijadikan sampel dalam kajian ini yang dipilih menggunakan kaedah pensamplean rawak mudah. Instrumen soal selidik pula digunakan bagi mengukur variabel-variabel kajian. Data mentah dianalisis menggunakan perisian Statistical Package for Social Sciences (SPSS) dengan menggunakan analisis statistik inferensi yang melibatkan ujian Korelasi Pearson. Hasil analisis menunjukkan terdapat hubungan positif signifikan yang kuat antara pembangunan penerapan nilai dalam pendidikan abad ke-21 dengan pembentukan sahsiah murid Sekolah Kurang Murid (SKM) luar bandar di Sabah (r=0.88, P<0.05). Dapatan kajian ini memberi maklumat berguna berkaitan dengan penerapan nilai dalam pendidikan abad ke-21 dan pembentukan sahsiah murid yang diharap dapat memberikan sumbangan ke arah memperkasakan sistem pendidikan kebangsaan