Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics

The effectiveness and cost-effectiveness of strength and balance Exergames to reduce falls risk for people aged 55 years and older in UK assisted living facilities: A multi-centre, cluster randomised controlled trial

Background: Falls are the leading cause of fatal and non-fatal unintentional injuries in older people. The use of Exergames (active, gamified video-based exercises) is a possible innovative, community-based approach. This study aimed to determine the effectiveness of a tailored OTAGO/FaME based strength and balance Exergame programme for improving balance, maintaining function and reducing falls risk in older people. Methods: A two-arm cluster randomised controlled trial recruiting adults aged 55 years and older living in 18 assisted-living (sheltered housing) facilities (clusters) in the UK. Standard care (physiotherapy advice and leaflet) was compared to a tailored 12-week strength and balance Exergame programme, supported by physiotherapists or trained assistants. Complete-case analysis (intention to treat) was used to compare Berg Balance Scale (BBS) at baseline and at 12 weeks. Secondary outcomes included: fear of falling, mobility, falls risk, pain, mood, fatigue, cognition, healthcare utilisation and health-related quality of life; self-reported physical activity and falls. Results: Eighteen clusters were randomised (9 to each arm) with 56 participants allocated to the intervention and 50 to the control (78% female, mean age 78 years). Fourteen participants withdrew over the 12 weeks (both arms), mainly for ill health. There was an adjusted mean improvement in balance (BBS) of 6.2 (95% CI 2.4 to 10.0), reduced fear of falling (p=0.007) and pain (p=0.02) in Exergame group. Mean attendance at sessions was 69% (mean exercising time of 33 minutes/week). 24% of control group and 20% of Exergame group fell over trial period. The change in falls rates significantly favoured the intervention (incident rate ratio 0.31 (95% CI 0.16 to 0.62, p=0.001)). The point estimate of the incremental cost effectiveness ratio (ICER) was £15,209.80 per QALY. Using 10,000 bootstrap replications, at the lower bound of the NICE threshold of £20,000 per QALY, there was a 61% probability of Exergames being cost-effective, rising to 73% at the upper bound of £30,000 per QALY. Conclusions: Exergames, as delivered in this trial, improve balance, pain and fear of falling and are a cost-effective fall prevention strategy in assisted living facilities for people aged 55 years or older

Progress of Near-Infrared-Based Medical Imaging and Cancer Cell Suppressors

Diffuse optical tomography, an imaging modality that utilizes near-infrared light, is a new way to assess soft tissue. It provides a non-invasive screening of soft tissue, such as the breast in females and prostate in males, to inspect the existence of cancer. This new imaging method is considered cost-effective and preferred because the implementation is simply through the application of a laser or light-emitting diode as a light source. Near-infrared technology does not only offer cancer screening modality, but also acts as a cancer treatment method, called near-infrared photoimmunotherapy. Despite plentiful studies in the area of near-infrared technology for cancer imaging and cancer cell suppression, there is no consolidated review that provides an overview of near-infrared application in cancer cell imaging and therapy. The objective of this study is to review near-infrared-based medical imaging and novel approaches to eradicate cancer cells. Additionally, we have discussed prospective instrumentation to establish cancer therapeutics apparatuses based on near-infrared technology. This review is expected to guide researchers implementing near-infrared for a medical imaging modality and cancer suppression in vitro, in vivo, and in clinical settings

Laboratory exams in first programming courses

ABSTRAC

Laboratory Exams in First Programming

ABSTRAC

Estimating the cost-effectiveness of intermittently scanned continuous glucose monitoring in adults with type 1 diabetes in England.

OBJECTIVE: We previously showed that intermittently scanned continuous glucose monitoring (isCGM) reduces HbA1c at 24 weeks compared with self-monitoring of blood glucose with finger pricking (SMBG) in adults with type 1 diabetes and high HbA1c levels (58-97 mmol/mol [7.5%-11%]). We aim to assess the economic impact of isCGM compared with SMBG. METHODS: Participant-level baseline and follow-up health status (EQ-5D-5L) and within-trial healthcare resource-use data were collected. Quality-adjusted life-years (QALYs) were derived at 24 weeks, adjusting for baseline EQ-5D-5L. Participant-level costs were generated. Using the IQVIA CORE Diabetes Model, economic analysis was performed from the National Health Service perspective over a lifetime horizon, discounted at 3.5%. RESULTS: Within-trial EQ-5D-5L showed non-significant adjusted incremental QALY gain of 0.006 (95% CI: -0.007 to 0.019) for isCGM compared with SMBG and an adjusted cost increase of £548 (95% CI: 381-714) per participant. The lifetime projected incremental cost (95% CI) of isCGM was £1954 (-5108 to 8904) with an incremental QALY (95% CI) gain of 0.436 (0.195-0.652) resulting in an incremental cost-per-QALY of £4477. In all subgroups, isCGM had an incremental cost-per-QALY better than £20,000 compared with SMBG; for people with baseline HbA1c >75 mmol/mol (9.0%), it was cost-saving. Sensitivity analysis suggested that isCGM remains cost-effective if its effectiveness lasts for at least 7 years. CONCLUSION: While isCGM is associated with increased short-term costs, compared with SMBG, its benefits in lowering HbA1c will lead to sufficient long-term health-gains and cost-savings to justify costs, so long as the effect lasts into the medium term.This work was supported by Diabetes UK grant number 18/0005836. The device manufacturer played no part in design, conduct or any other aspects of the study. The study devices were paid by the National Health Service (NHS) UK. Work was supported by the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support for MLE from the National Health Service in the East of England through the Clinical Academic Reserve

Estimating the cost‐effectiveness of intermittently scanned continuous glucose monitoring in adults with type 1 diabetes in England

Funder: Diabetes UK; doi: http://dx.doi.org/10.13039/501100000361Objective: We previously showed that intermittently scanned continuous glucose monitoring (isCGM) reduces HbA1c at 24 weeks compared with self‐monitoring of blood glucose with finger pricking (SMBG) in adults with type 1 diabetes and high HbA1c levels (58–97 mmol/mol [7.5%–11%]). We aim to assess the economic impact of isCGM compared with SMBG. Methods: Participant‐level baseline and follow‐up health status (EQ‐5D‐5L) and within‐trial healthcare resource‐use data were collected. Quality‐adjusted life‐years (QALYs) were derived at 24 weeks, adjusting for baseline EQ‐5D‐5L. Participant‐level costs were generated. Using the IQVIA CORE Diabetes Model, economic analysis was performed from the National Health Service perspective over a lifetime horizon, discounted at 3.5%. Results: Within‐trial EQ‐5D‐5L showed non‐significant adjusted incremental QALY gain of 0.006 (95% CI: −0.007 to 0.019) for isCGM compared with SMBG and an adjusted cost increase of £548 (95% CI: 381–714) per participant. The lifetime projected incremental cost (95% CI) of isCGM was £1954 (−5108 to 8904) with an incremental QALY (95% CI) gain of 0.436 (0.195–0.652) resulting in an incremental cost‐per‐QALY of £4477. In all subgroups, isCGM had an incremental cost‐per‐QALY better than £20,000 compared with SMBG; for people with baseline HbA1c >75 mmol/mol (9.0%), it was cost‐saving. Sensitivity analysis suggested that isCGM remains cost‐effective if its effectiveness lasts for at least 7 years. Conclusion: While isCGM is associated with increased short‐term costs, compared with SMBG, its benefits in lowering HbA1c will lead to sufficient long‐term health‐gains and cost‐savings to justify costs, so long as the effect lasts into the medium term

Intermittently scanned continuous glucose monitoring in adults with type 1 diabetes: A subgroup analysis from the FLASH-UK study.

Publication status: PublishedFunder: Diabetes UK; doi: http://dx.doi.org/10.13039/501100000361AIMS: The FLASH-UK trial showed lower HbA1c with intermittently scanned continuous glucose monitoring (isCGM), as compared with self monitoring of blood glucose (SMBG), in adults with type 1 diabetes and HbA1c ≥58 mmol/mol (≥7.5%). Here, we present results from the pre-specified subgroup analysis for the 24-week HbA1c (primary outcome) and selected sensor-based secondary outcomes. METHODS: This was a multi-centre, parallel-design, randomised controlled trial. The difference in treatment effect between subgroups (baseline HbA1c [≤75 vs. >75 mmol/mol] [≤9.0 vs >9.0%], treatment modality [pump vs injections], prior participation in structured education, age, educational level, impaired awareness of hypoglycaemia, deprivation index quintile sex, ethnic group and Patient Health Questionnaire-9 [PHQ-9] detected depression category) were evaluated. RESULTS: One hundred fifty-six participants (females 44%, mean [SD] baseline HbA1c 71 [9] mmol/mol 8.6 [0.8%], age 44 [15]) were randomly assigned, in a 1:1 ratio to isCGM (n = 78) or SMBG (n = 78). The mean (SD) baseline HbA1c (%) was 8.7 (0.9) in the isCGM group and 8.5 (0.8) in the SMBG group, lowering to 7.9 (0.8) versus 8.3 (0.9), respectively, at 24 weeks (adjusted mean difference -0.5, 95% confidence interval [CI] -0.7 to -0.3; p 9.0%-11.0%) had a marginally non-significant higher reduction in HbA1c of 8.4 mmol/mol (3.3-13.5) compared to 3.1 (0.3-6.0) in those with HbA1c 58-75 mmol/mol (p = 0.08). For 'Time in range' (% 3.9-10 mmol/L), the difference was larger for those with at least a bachelor's degree. For 'Time below range' (% <3.9 mmol/L), the difference was larger for those using injections, older people and those with less than bachelor's degree. CONCLUSIONS: Intermittently scanned continuous glucose monitoring is generally effective across a range of baseline characteristics.This work was supported by Diabetes UK grant number 18/0005836. The device manufacturer played no part in design, conduct or any other aspects of the study. The study devices were funded by the National Health Service (NHS) UK. Work was supported by the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support for MLE from the National Health Service in the East of England through the Clinical Academic Reserve

Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study

Background: Although most patients with hereditary haemochromatosis have HFE C282Y mutations, the lifetime risk to HFE C282Y homozygotes of developing fatal diseases such as hepatocellular carcinoma is uncertain. We have carried out a cross-sectional study to determine the proportion of diagnosed hepatocellular carcinoma patients who are homozygous for the HFE C282Y mutation; and to estimate the penetrance of this genotype with respect to hepatocellular carcinoma in East Anglia. Methods: Tissue biopsies were analysed from 144 cases of hepatocellular carcinoma for HFE C282Y mutations; the data produced were compared with the frequency of HFE mutations in a large sample of the local population. Data were also retrieved from the East Anglian Cancer Intelligence Unit to determine the annual incidence of hepatocellular carcinoma; and from appropriate life tables. Results: Eight out of 144 of the cases were homozygous for the HFE C282Y mutation, all 8 cases were male. 6 of these 8 cases had a previous diagnosis of hereditary haemochromatosis. Male HFE C282Y homozygotes were more likely to be diagnosed with hepatocellular carcinoma (odds ratio [OR] = 14, 95% confidence interval [CI] = 5–37). For this population, we estimate that the penetrance of the HFE C282Y homozygous genotype, with respect to hepatocellular carcinoma, was between 1.31 % and 2.1% for males and was zero for females. Conclusion: In this population, we found that only a very small proportion of homozygotes for the HFE C282Y mutation developed hepatocellular carcinoma. However, individuals with this genotype have a significantly increased risk of this rare disease relative to those who do not carry the mutations