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Background Severe acute respiratory syndrome coronavirus 2 is the virus that causes coronavirus disease 2019. Over six million deaths worldwide have been associated with coronavirus disease 2019. Objective To assess the cost-effectiveness of treatments used for the treatment of coronavirus disease 2019 in hospital or used in the community in patients with coronavirus disease 2019 at high risk of hospitalisation. Setting Treatments provided in United Kingdom hospital and community settings. Methods Clinical effectiveness estimates were taken from the coronavirus disease-network meta-analyses initiative and the metaEvidence initiative. A mathematical model was constructed to explore how the interventions impacted on patient health, measured in quality-adjusted life-years gained. The costs associated with treatment, including those of hospital care, were also estimated and used to form a cost per quality-adjusted life-year gained value which was compared with thresholds published by the National Institute for Health and Care Excellence. Estimates of cost-effectiveness compared against current standard of care were produced in both the hospital and community settings at three different levels of efficacy: mean, low and high. Public list prices were used for interventions with neither confidential patient access schemes nor confidential list prices considered. Results incorporating confidential pricing data were provided to the National Institute for Health and Care Excellence appraisal committee. Results The treatments were estimated to be clinically effective although not all reached statistical significance. All treatments in the hospital setting, or community, were estimated to plausibly have a cost per quality-adjusted life-year gained value below National Institute for Health and Care Excellence’s thresholds when compared with standard of care. However, almost all drugs could plausibly have cost per quality-adjusted life-years above National Institute for Health and Care Excellence’s thresholds. However, there is considerable uncertainty in the results as the prevalent severe acute respiratory syndrome coronavirus 2 variant, vaccination status, history of being infected with severe acute respiratory syndrome coronavirus 2 and standard of care have all evolved since the pivotal studies were conducted which could have significant impact on the efficacy of each drug. For drugs used in high-risk patients in the community setting, the proportion of people at high risk who need hospital admission was a large driver of the cost per quality-adjusted life-year. Limitations No studies were identified that were conducted in current conditions. This may be a large limitation as the severe acute respiratory syndrome coronavirus 2 variant changes. No head-to-head studies of interventions were identified. Conclusions The results produced could be informative to decision-makers, although conclusions regarding the most clinical – and cost-effectiveness of each intervention should be tentative due to the evolving nature of the decision problem and, in this report, the use of list prices only. Comparisons between interventions should also be treated with caution due to potentially large heterogeneity between studies. Future work Research assessing the relative clinical effectiveness of interventions within head-to-head studies in current conditions would be beneficial. Contemporary information related to the probability of hospital admission and death for patients at high risk in the community would improve the precision of the estimates generated. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information. Plain language summary Coronavirus disease 2019 is an infectious disease that can cause death and long-term ill-health. Treatments exist that can be provided in hospital to reduce the number of deaths from coronavirus disease 2019. Treatments also exist which can be provided in the community for people at high risk of needing to be admitted to hospital to reduce the number of admissions and to reduce the number of deaths from coronavirus disease 2019. However, the value for money of these treatments has not been estimated. We took the clinical effectiveness of nine treatments from published literature sources and built a model that estimated the value for money of six treatments compared with care without these treatments. Three treatments were excluded due to confidential prices. The results of the model showed that many treatments in a hospital setting had estimates of cost-effectiveness that would normally be seen to be good value for money using the thresholds published by the National Institute of Health and Care Excellence. The same was true for some treatments in a community setting. However, it is also possible that these treatments are not good value for money. The benefit of the drugs and value for money is highly uncertain as studies trying to estimate the gain have been done with (1) previous variants of the virus causing coronavirus disease 2019 being widespread, (2) where the proportion of people who have had vaccinations or who had previously had coronavirus disease 2019 is low and (3) where standard treatment was that when coronavirus disease 2019 was first identified, and not the drugs used now. Because of these differences, and the unknown price of some interventions, we cannot confidently say which (if any) treatments help patients the most, or which treatment represents the best value for money. Further research, in current conditions, would improve the accuracy of our answers. Scientific summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). At the time of writing (January 2023) there had been over 620 million confirmed cases and over six-and-a-half million deaths worldwide associated with COVID-19. For the UK, these values are more than 24 million cases and nearly 200,000 deaths. In addition to the widespread vaccination programme, treatments exist that can help people who have been hospitalised due to COVID-19 (casirivimab and imdevimab (henceforth casirivimab/imdevimab), tocilizumab, remdesivir, baricitinib, and baricitinib with remdesivir) or be used in patients who have COVID-19 and are at high risk of needing hospitalisation [casirivimab/imdevimab, molnupiravir, nirmatrelvir and ritonavir (henceforth nirmatrelvir/ritonavir), remdesivir, sotrovimab, and tixagevimab and cilgavimab (henceforth tixagevimab/cilgavimab)]. For reasons related to urgency, these treatments, unlike interventions in other disease areas, have not received positive guidance from the National Institute of Health and Care Excellence (NICE) before being routinely used. As the pandemic subsides there is more need for a formal evaluation of the clinical and cost-effectiveness of these treatments. Objectives The objective of this study is to summarise the current knowledge related to the clinical efficacy of the interventions and to conduct an economic evaluation that estimates the cost-effectiveness of each intervention against standard of care (SoC), as of January 2023. A full incremental analysis is performed while noting the caveats in the comparison of all interventions simultaneously. Methods Given the timescale of the project, where there were ˂ 3 months between the publication of the final scope and the deadline of a report for NICE and the consultation process, a literature review following best practice was not possible. Instead, a pragmatic, alternative approach was undertaken where evidence was taken from two living systematic reviews (supported by the COVID-network meta-analyses (NMA) initiative and the metaEvidence initiative) in line with current best practice guidelines. For interventions related to use in hospitals, data were extracted on time to death, clinical improvement and time to discharge. For interventions that are used in the community for patients at high risk of hospitalisation, data were extracted on the risks of hospitalisation or death, and the risks of death. These measures of efficacy were assumed generalisable to January 2023 despite changes in background conditions which include the SoC, the percentage of people who have been vaccinated and a change in the dominant SARS-CoV-2 variant. This is noted as a very large limitation as drugs that have looked effective in previous variants have not worked as well in later variants and sensitivity analysis on the efficacy of the interventions has been conducted. A mathematical model was constructed that used the data from the living systematic reviews to simulate the experiences of patients in hospital, and requirement for supplemental oxygen, until discharge or death in hospital. Due to the (conditional) marketing authorisations of the interventions, the model was developed such that results could be produced for the supplemental oxygen group and the non-supplemental oxygen group separately. The model structure used an eight-point ordinal scale that was used in clinical trials to categorise patients during their admissions. Outputs from this model included the costs associated with interventions and care, and the quality-adjusted life-years (QALYs) gained by the patient both within the hospital episode and after discharge, incorporating decrements in health-related quality of life associated with the lasting impact of COVID-19. For interventions used in the hospital, these values allowed a cost per QALY gained to be calculated for each treatment compared with SoC, and for completeness, a full incremental analysis to be conducted although the External Assessment Group (EAG) cautions against comparisons between treatments due to the heterogenous conditions when pivotal studies were undertaken. The costs of each intervention were taken from public sources where available. However, baricitinib, sotrovimab and tocilizumab have confidential patient access schemes agreed, which discount the price of the intervention, and are not considered in this document, but were provided to the NICE Appraisal Committee in a separate confidential appendix. The price of three treatments (casirivimab/imdevimab, molnupiravir and tixagevimab/cilgavimab) were not publicly available at the time of writing and the cost-effectiveness results for these three drugs are contained in a confidential appendix. For patients at high risk of hospitalisation treated in the community, a decision tree was put before the hospital model, which simulated the reduced need for hospitalisation associated with early treatment. The total costs and QALYs associated with treatment options were estimated to allow an evaluation of the cost per QALY of each treatment against SoC and for completeness, a full incremental analysis to be undertaken, noting the same caveat as for interventions used in hospital when comparing treatments. The modelling did not assess the logistical aspects of treatment in the community, but the EAG notes that this could be a large factor in deciding which treatments could be preferred, as oral treatments could be more acceptable to patients and healthcare systems than treatments that are given intravenously or subcutaneously. The costs of providing treatment within the community were provided by National Health Service (NHS) England. Three scenarios were run changing the efficacy of interventions. The ‘mean efficacy’ estimate used the mean of each distribution extracted from the living systematic reviews, the ‘high efficacy’ estimate used the most favourable limits of the 95% confidence intervals (CIs) and the ‘low efficacy’ estimate used the least favourable limits of the 95% CIs. The EAG has acknowledged a limitation that the CI is influenced by the number of observed events and the sample size, such that two identical treatments could have markedly different confident intervals purely due to the size of the pivotal study. Seven scenario analyses were performed, explored the impact of changing: (1) the duration of long COVID (ranging from half to double that of the base case); (2) changing the rate of hospital admission in the community with people being at ‘high risk’ of hospitalisation from a value of 2.79% to 1.00%, 5.00% and 10.00%; (3) changing the average age of patients at high risk of hospitalisation in the community from 55 years to 50 and 60 years; (4) using a hazard ratio (HR) of unity for all interventions in relation to time to hospital discharge and time to clinical improvement; (5) changing the baseline distribution of supplemental oxygen requirements from that associated with SoC (19% no supplemental oxygen, 55% high-flow oxygen, 16% non-invasive ventilation and 10% invasive ventilation) to an arbitrarily less severe baseline distribution (25% no supplemental oxygen, 60% high-flow oxygen, 10% non-invasive ventilation and 5% invasive ventilation) for patients who have received an intervention in the community; (6) assuming a utility decrement of 0.02 per day for patients receiving intravenous (i.v.) treatment in the community; and (7) changing the standardised mortality ratio for people during the period of long COVID from 7.7 to 5.0 and 10.0. Two scenario analyses were conducted that explored the use of different efficacy measures based on the Solidarity study for remdesivir and the ‘Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19’ (TACKLE) study for tixagevimab/cilgavimab. Results were presented in terms of incremental cost-effectiveness ratios (ICERs) measured in cost per QALYs gained and also using incremental net monetary benefit (NMB). An advantage of NMB is that interventions can be compared using different assumptions on efficacy for different interventions, and interventions can be omitted without the need to recalculate efficiency frontiers. Results Due to changes between the conditions when the pivotal studies were undertaken and the current conditions in terms of the SoC, the percentage of people who have been vaccinated and a change in the dominant SARS-CoV-2 variant all results should be treated with caution. Caution should also be applied when comparing between interventions. The results also do not incorporate confidential price discounts for baricitinib, sotrovimab and tocilizumab, nor were any cost-effectiveness results presented for casirivimab/imdevimab, molnupiravir and tixagevimab/cilgavimab which had confidential list prices. These analyses were seen by the NICE appraisal committee in a confidential appendix. All treatments used for hospitalised patients, had a median HR for death below one, indicating a benefit, although all CIs crossed unity apart from those for baricitinib, casirivimab/imdevimab and tocilizumab. The overlapping CIs and heterogeneous studies meant that no firm conclusions could be made regarding the relative efficacy of these treatments. There was less data relating to the relative risks (RRs) of clinical improvement at 28 days and the HRs for the time to discharge, although these were generally close to unity and had CIs that crossed unity. No clear conclusions could be made on the relative efficacy of treatments for these two measures compared with SoC. All treatments used in the community had favourable median RRs for hospitalisation and death at 28 days with the upper limit of the CI being below 1 for all drugs except molnupiravir. The median RRs associated with death at 28 days were favourable for all interventions, except for remdesivir where the median estimate was unity as no deaths were observed in the study within COVID-NMA. The CIs were wide and spanned one for all treatments except for molnupiravir and nirmatrelvir/ritonavir. For hospitalised patients requiring supplemental oxygen, all treatments had estimated ICERs compared with SoC below £12,000 in both the mean efficacy and high efficacy scenarios. However, in the low efficacy scenario only baricitinib and tocilizumab generated more QALYs than SoC. Baricitinib had an estimated ICER under £9000, while tocilizumab had an estimated ICER under £29,000. For hospitalised patients not requiring supplemental oxygen, all treatments had estimated ICERs compared with SoC below £12,000 in both the mean efficacy and high efficacy scenarios. However, in the low efficacy scenario, only baricitinib generated more QALYs than SoC with an estimated ICER below £6000. For interventions used in the community, the estimated ICERs compared with SoC were more varied. In the mean efficacy scenario, the estimated ICERs were below £7000 for nirmatrelvir/ritonavir, below £35,000 for sotrovimab and below £91,000 for remdesivir. In the high efficacy scenario, the estimated ICERs were below £5000 for nirmatrelvir/ritonavir, below £19,000 for sotrovimab and below £25,000 for remdesivir. In the low efficacy scenario, the estimated ICER was below £12,000 for nirmatrelvir/ritonavir, with remdesivir and sotrovimab having ICERs in excess of £10,000. Only one of the scenario analyses noticeably changed the ICERs for all interventions, which was changing the proportion of people with COVID-19 in the community at high risk of hospitalisation who are hospitalised when treated with SoC. Treatments became more cost-effective as the admission proportion increased at the mean and high efficacy scenarios. The ranges in the ICERs assuming mean efficacy for the drugs, when using 1%, 10% and 20%, rather than 2.82% as assumed in the base case, were: nirmatrelvir/ritonavir (£25,544, dominant and dominant), remdesivir (£280,819, £16,170 and £1512) and sotrovimab (£111,318, £4870 and dominant). If data from Solidarity are included, the low efficacy scenarios for remdesivir had a positive NMB regardless of the willingness-to-pay threshold and oxygen status assumed. For patients requiring supplemental oxygen the ICER was £25,903; the corresponding ICER was £34,550 for those not requiring supplementary oxygen. Conclusions There is considerable uncertainty in the efficacy of treatments compared to SoC observed in the studies due to the small number of events, which results in wide CIs for HRs and RRs. Some treatments (baricitinib and tocilizumab in the hospitalised setting and casirivimab/imdevimab, molnupiravir and nirmatrelvir/ritonavir in the community setting) were estimated to have a statistically significant benefit related to death due to COVID-19, however, this may also have been shown for other treatments if the pivotal studies had had larger sample sizes. However, the dominant SARS-CoV-2 variant, the SoC and the percentage of people who have had a vaccination, have all changed since the pivotal studies were undertaken meaning that the efficacies for treatments are highly uncertain. This is demonstrated by sotrovimab having favourable median and mean efficacies in prevention hospitalisation, but this drug is not authorised in the USA, as it is unlikely to be effective against the Omicron BA.2 subvariant. Further the World Health Organization has made strong recommendations against the use of sotrovimab. Given potential further changes in the variant, the results presented in this report, and within the confidential appendix, should be treated with caution. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information.

Drought stress is considered one of the main factors that reduce plant growth, development and production. Therefore, studying plants during drought stress is highly useful to discover the newly gained characteristics of plants. The potato is considered one of the most important crop with economic value in Egypt and over the whole world. The main target is the proline-rich protein extracted from potato plants under drought stress. A stress experiment was applied to two potato (Solanum tuberosum L.) cultivars Desiree and Diamante. The stress experiment was conducted by poly-ethylene glycol (PEG) 4000; the used water potentials were: zero (control), (PEG 2%), (PEG 4%) and (PEG 8%), after drought stress, the solutes accumulation in the two potato cultivars were determined. Increasing drought stress through elevating PEG decreased leaf area as well as shoot and root lengths. Incontorary, the chlorophyll and proline contents increased with increasing PEG treatments. The proline-rich protein gene was cloned to the pGEM-T Easy vector and was submitted to the gene bank to be used later for enhancing drought resistance in other cultivars.

We describe a modification of a previously described measurement–analysis protocol to determine the intrinsic properties of triaxial accelerometers by using a measurement protocol based on angular stepwise rotation in the Earth’s gravitational field. This study was conducted with MEMS triaxial accelerometers that were co-integrated in four consumer-grade wireless microsensors. The measurements were carried out on low-cost rotation tables in different laboratories in different countries to simulate the reproducibility environment encountered in inter-comparisons of calibration capabilities. We used a previously described calibration–uncertainty metric to independently characterize the overall uncertainty of the calibration and analysis process. The intrinsic property analysis suggested, and the uncertainty metric confirmed, an unacceptably large error in one combination of microsystem and low-cost rotation table. A simple modification of the analysis protocol provided a substantial improvement in the reproducibility of the protocol with all combinations of microsystem and rotation table. Later, measurements with a high-performance triaxial accelerometer using a significantly more expensive rotation table carried out at one location further validated the usefulness of this modification. The results reported here also demonstrate the existence of unidentified defects in one microsystem and one low-cost rotation table that interact with each other in ways not currently understood to produce anomalously large errors with the old protocol but not with the new protocol.

Introduction Traumatic brain injury (TBI) is a major cause of disability, with annual global incidence estimated as 69 million people. Survivors can experience long-term visual changes, altered mental state, neurological deficits and long-term effects that may be associated with mental illness. TBI is prevalent in military personnel due to gunshot wounds, and blast injury. This study aims to evaluate the relationship between evolving visual, biochemical and mental health changes in both military veterans and civilians, suffering from TBI, and detect preliminary indicators of prognosis for TBI recovery, and quality-of-life outcomes.Methods and analysis UNTANGLE is a 24-month prospective observational pilot study recruiting three patient groups: civilians with acute moderate-severe TBI, military veterans with diagnosis of a previous TBI and a control group of civilians or veterans with no history of a previous TBI. Patients will undergo visual, biochemical and mental health assessments, as well as patient-reported quality of life outcome measures over the course of a 1-year follow-up period.Ethics and dissemination Ethical approval has been obtained from the Health Research Authority and Health and Care Research Wales with a REC reference number of 23/NW/0203. The results of the study will be presented at scientific meetings and published in peer-reviewed journals, including both civilian and military-related publications. We will also present our findings at national and international meetings of learnt neuroscience and neuropsychiatry and military societies. We anticipate that our pilot study will inform a larger study on the long-term outcomes of TBI and quality of life, specific to military veterans, such that potential interventions may be accessed as quickly as possible.Trial registration number ISRCTN13276511.

No abstract

Potato tuber starch characteristic is influenced by the ratio of amylose to amylopectin, which is affected by the granule-bound starch synthase (GBSS) gene. GBSS gene expression was decreased in the leaves of the Desiree potato variety utilizing genome editing using CRISPR-Cas9. Constructs encoding Cas9 gene and sgRNAs targeting GBSS gene were inserted into plant leaves using Agrobacterium-mediated transformation delivery. The results obtained lines with mutations in GBSS genes accounting for 21% of regenerated shoots. The identification of mutations within one base pair of the used guide sequence provided further evidence of the considerable similarity between the target region around the protospacer adjacent motif (PAM) position and the used guide sequence. Transforming DNA into potato leaves produced mutants that lacked the Cas9 gene. Using microscopic inspection of iodine-stained starch granules, the increase of amylopectin in the starch granules of editing potato tubers was evaluated.

Worldwide, potato (Solanum tuberosum L.) is one of the most essential agro-economically food crops. To ensure its presence throughout the year for food processors and to extend its shelf life, it should be stored in cold temperatures. Despite the benefits of storage at low temperatures, it causes undesirable phenomena; one of them is cold-induced sweetening, which reduces the quality and the commercial value of the potato tubers. In this study, the CRISPR technology ″Clustered Regularly Interspaced Short Palindromic Repeats″ has been used in potato cultivar Desiree via Agrobacterium mediated transformation to edit starch phosphorylase gene that is responsible for starch degradation in cold temperature storage, after regeneration steps. The regenerated plants were used in the screening of genome editing by Sanger sequencing and the ICE program. Screening results showed that Desiree 2 (DE2), Desiree 7 (DE7) and Desiree 27 (DE27) lines have mutations in sgRNA sequence that indicated a significant reduction in reduced sugar contents of tubers after cold storage for 90 and 120 days. The reduction mean values were 29.224, 35.078 and 35.862 in DE2, DE7 and DE27 respectively after 90 days and 83.212, 56.674 and 34.109 after 120 days without visible differences in plant morphology and tubers

Abstract The Wim Hof method (WHM) is a multi-disciplinary approach to physical and mental well-being combining cold exposure, breathing exercises, and meditation. This study evaluated the effects of a 15 days WHM intervention on cardiovascular parameters at rest and during a cold pressor test (CPT), as well as on various psychological parameters. Forty two participants were randomized into an intervention (IG) and a control group. Throughout the 15 days intervention, the IG performed the WHM daily. Before and after the intervention, systolic (SBP) and diastolic blood pressure (DBP), pulse wave velocity (PWV), heart rate (HR), root mean sum of squared distance (RMSSD), and standard deviation of RR-intervals (SDNN) were assessed at rest and during a CPT. Furthermore, perceived stress (PSS), positive affect (PANAS+), negative affect (PANAS−), and subjective vitality (trait (SVSt) and state (SVSs)) was determined. No significant time × group interactions could be detected in HR (p = 0.709); RMSSD (p = 0.820), SDNN (p = 0.186), SBP (p = 0.839), DBP (p = 0.318), PWV (p = 0.983), PANAS+ (p = 0.427), PANAS− (p = 0.614), SVSt (p = 0.760), SVSs (p = 0.366), and PSS (p = 0.364). No significant time × group effects could be detected during the CPT (ΔHR: p = 0.596; ΔSBP: p = 0.366; ΔDBP: p = 0.999; ΔPWV: p = 0.635; perceived pain: p = 0.231). Performing the WHM daily did not exert positive effects on cardiovascular and psychological parameters.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition characterized by the growth of multiple bilateral cysts in the kidneys. We describe the case of a 35-year-old male with combined ADPKD and type 1 diabetes mellitus with a strong family history of both. At the age of 32, he developed end-stage kidney disease for which he underwent preemptive simultaneous pancreatic and kidney transplant, which in turn led to multiple perioperative complications. Evaluation of familial clustering of genetic disease is critical in genetic epidemiology and precision medicine as it enables estimation of lifetime disease risk and early assessment as well as detection of the disease among one’s siblings.

Objectives: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease of chronic uncontrolled complement pathway activation that leads to thrombotic-microangiopathy, along with severe organ damage, including end-stage kidney disease. This study aimed to evaluate the epidemiology, management, and outcome of aHUS in an Omani population. Methods: This retrospective descriptive cohort study assessed all cases of aHUS diagnosed and followed up at two tertiary care centers in Oman from January 2008 to December 2019, based on clinical features, complement pathway assays, histopathological, and genetic testing. Results: The study accrued 19 patients who fulfilled the inclusion criteria, of whom 11 (57.9%) were male. The participants’ median age was 25.0 years (range = 0.1–69.0). Most (15; 78.9%) patients presented in the acute phase of the disease. The triad of hemolytic anemia, acute kidney injury, and thrombocytopenia was present in all patients. A trigger factor (e.g., infection) was identified in 68.4% of cases. Of the 14 (73.7%) patients who underwent kidney biopsy, 10 (71.4%) were found to have aHUS in native kidneys and three in grafted kidneys. Of the 11 (57.9%) patients who underwent genetic analysis, five (45.5%) were found to have a known pathogenic variant in their aHUS susceptibility genes. Plasma exchange followed by eculizumab was the treatment method in 11 (57.9%) cases. Complete renal recovery was achieved in seven (36.8%) patients, while four (21.1%) passed away during the study period. Conclusions: The wide spectrum and multiple expressions of aHUS make it a challenge to diagnose and consequently may delay the commencement of the targeted treatment. Eculizumab is considered the first-line therapy and should be commenced as early as possible.

We describe a modification of a previously described measurement–analysis protocol to determine the intrinsic properties of triaxial accelerometers by using a measurement protocol based on angular stepwise rotation in the Earth's gravitational field. This study was conducted with MEMS triaxial accelerometers that were co-integrated in four consumer-grade wireless microsensors. The measurements were carried out on low-cost rotation tables in different laboratories in different countries to simulate the reproducibility environment encountered in inter-comparisons of calibration capabilities. We used a previously described calibration–uncertainty metric to independently characterize the overall uncertainty of the calibration and analysis process. The intrinsic property analysis suggested, and the uncertainty metric confirmed, an unacceptably large error in one combination of microsystem and low-cost rotation table. A simple modification of the analysis protocol provided a substantial improvement in the reproducibility of the protocol with all combinations of microsystem and rotation table. Later, measurements with a high-performance triaxial accelerometer using a significantly more expensive rotation table carried out at one location further validated the usefulness of this modification. The results reported here also demonstrate the existence of unidentified defects in one microsystem and one low-cost rotation table that interact with each other in ways not currently understood to produce anomalously large errors with the old protocol but not with the new protocol. [ABSTRACT FROM AUTHOR]

Plain English summary Decision aids are paper or electronic tools that help people make medical decisions. They have been shown to help with shared decision making between patients, their loved ones, and a health professional. When we create decision aids, we try to involve patients at each step, traditionally using focus groups. However, new approaches are needed because focus groups take a lot of time and money. We developed a new method of involving people eligible for cancer screening and used this method during the development of four decision aids at two centers for research in primary care. Two of the decision aids were for colorectal cancer screening (one in French, one in German), and one each for prostate and lung cancer screening. We recruited people aged 50 to 75 interested in improving health information materials from community organizations and among standardized patients from local medical schools to form citizen advisory groups. Standardized patients act as patients during teaching sessions and exams. Some people took part in face-to-face meetings to give us feedback on the materials, while others responded to questionnaires and gave feedback by mail. The same participants gave feedback multiple times as we made improvements to the decision aids. The citizen advisory groups provided us with repeated, meaningful input during the development of decision aids. We think they allowed us to create better, more patient-centered decision aids, while using fewer resources than traditional focus groups. Other researchers who develop decision aids may want to use a similar approach.

Author(s): Elisabeth L. Metry [sup.1] , Liza M. M. van Dijk [sup.1] , Hessel Peters-Sengers [sup.2] , Michiel J.S. Oosterveld [sup.1] , Jaap W. Groothoff [sup.1] , Rutger J. Ploeg [...], Background Primary hyperoxaluria type 1 (PH1) is characterized by hepatic overproduction of oxalate and often results in kidney failure. Liver-kidney transplantation is recommended, either combined (CLKT) or sequentially performed (SLKT). The merits of SLKT and the place of an isolated kidney transplant (KT) in selected patients are unsettled. We systematically reviewed the literature focusing on patient and graft survival rates in relation to the chosen transplant strategy. Methods We searched MEDLINE and Embase using a broad search string, consisting of the terms 'transplantation' and 'hyperoxaluria'. Studies reporting on at least four transplanted patients were selected for quality assessment and data extraction. Results We found 51 observational studies from 1975 to 2020, covering 756 CLKT, 405 KT and 89 SLKT, and 51 pre-emptive liver transplantations (PLT). Meta-analysis was impossible due to reported survival probabilities with varying follow-up. Two individual high-quality studies showed an evident kidney graft survival advantage for CLKT versus KT (87% vs. 14% at 15 years, p Conclusions Our study suggests that CLKT leads to superior kidney graft survival compared to KT. However, evidence for merits of SLKT or for KT in pyridoxine-responsive patients was scarce, which warrants further studies, ideally using data from a large international registry.

This study tested the hypothesis that the relationship between faith in God and poor mental health (depression, stress, and anxiety), in higher education students, is mediated by the constructs of hope, meaning of life and resilience. A sample of 527 Australian tertiary students from across the country completed an online survey. Path analysis was used to test the hypothesis. The results supported the proposed model. These findings provide preliminary support for a model that, with further testing through longitudinal data, may guide the development of faith-based interventions for university students with depression, anxiety, and stress. [ABSTRACT FROM AUTHOR]

This study evaluates the cost‐effectiveness of the geko device a neuromuscular electro‐stimulator technology with standard of care (SoC) versus SoC alone for venous leg ulcer (VLU) treatment, from the UK National Health Service (NHS) perspective over 12 months. Research was conducted across NHS UK facilities, primarily within community services and outpatient leg ulcer clinics, encompassing a total of 51 patients. A partitioned survival model, based on a two‐arm randomised controlled trial, assessed wound healing rates using Kaplan–Meier curves and parametric extrapolations over a 12‐month time horizon. Costs were derived from UK reference costs the British National Formulary, and the Personal Social Services Research Unit (2021/22). The primary outcome measured was the incremental cost per quality‐adjusted life‐year gained. The geko device provides additional benefits by stimulating the lateral popliteal nerve, augmenting venous, arterial, and microvascular flow. The addition of the geko device to SoC significantly enhanced outcomes, increasing healing probability by 68% compared to SoC. This integration would result in a cost saving of £774.14 per patient when compared to the SoC alone across the NHS. Economic analyses indicate that integrating the geko device into SoC protocols would reduce the overall NHS expenditure on VLU wound management by as much as 15%. The approach also positively impacted health‐related quality of life. The geko™ device when used adjunctively with SoC would be a cost‐effective method for managing chronic VLUs within the NHS, improving healing rates and offering economic benefits. [ABSTRACT FROM AUTHOR]

While ulceration is one of the most common infantile hemangioma (IH) complications, severe bleeding is a rare consequence, with a paucity of patients reported. We report a 5‐month‐old girl with a very large, mixed, partial segmental IH of the upper chest wall who, despite medical intervention, developed severe ulceration and multiple episodes of life‐threatening bleeding that ultimately led to hemorrhagic shock. Experience in our patient and a review of six previous reports shows that severe bleeding is a risk when ulceration extends directly into an arterial feeding vessel that is often visible clinically. Other potential predictors for severe bleeding include large to very large IH size with extension of the tumor into underlying structures, segmental or partial segmental patterning, mixed and bulky morphology, and white discoloration as a sign of impending or worsening ulceration. [ABSTRACT FROM AUTHOR]

Plants are severely affected by many biotic stresses, which cause a reduction in crop quality and quantity. One of the strategies to manage biotic stresses is the generation of transgenic plant lines that can be used as biosensors. These biosensor plants can trigger an early warning upon any pathogen infection. Two promoters with β-glucuronidase reporter gene fusions were constructed. The first contained the flagellin sensing 2 gene promoter, whereas the second contained synthetic promoter containing four repeats of cis-acting elements from the pathogen-related protein 1 gene and two transcription enhancers from the 35S promoter. Transformed leaves were treated with a phytohormone salicylic acid to mimic the occurrence of biotic stress. Validation of reporter gene expression induced from both constructs in transformed potato leaves displayed an increase upon salicylic acid treatment. The results reflect that both constructs could serve in the production of potato biotic stress biosensors.

Finite control set model predictive control (MPC) is a model-based control method that can include multi-objective optimization, constrained control, adaptive control, and online auto-tuning of weighting factors all in a single controller that exhibits fast dynamic tracking. This paper utilizes the model-based framework of MPC to develop a sensorless current maximum power point tracking (MPPT) algorithm. Eliminating the current sensor can reduce the cost and improve the reliability of the photovoltaic system. This paper also utilizes constrained control and online auto-tuning of MPC to develop an adaptive perturbation MPPT to reduce steady-state oscillation and improve dynamic performance. This paper builds in a single framework the different layers of the MPPT problem: control, estimation, and MPPT. The proposed adaptive perturbation sensorless current mode MPPT (ASC-MPPT) technique performance is compared to the well-known incremental conductance (InCon) MPPT technique. The EN50530 European industrial test standards were used to demonstrate performance.

We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella coined recurrent constellations of embryonic malformations (RCEMs). The RCEMs represent a phenotypically overlapping spectrum of rare disorders of caudal dysgenesis with unknown cause but likely shared pathogenesis. It has recently been proposed that LUMBAR be considered an RCEM. This report of infants with combined features of OEIS and LUMBAR is the first to demonstrate an overlap between LUMBAR and another RCEM, which supports LUMBAR's inclusion within the RCEM spectrum. [ABSTRACT FROM AUTHOR]

Drought stress is considered one of the main factors that reduce plant growth, development and production. Therefore, studying plants during drought stress is highly useful to discover the newly gained characteristics of plants. The potato is considered one of the most important crop with economic value in Egypt and over the whole world. The main target is the proline-rich protein extracted from potato plants under drought stress. A stress experiment was applied to two potato (Solanum tuberosum L.) cultivars Desiree and Diamante. The stress experiment was conducted by polyethylene glycol (PEG) 4000; the used water potentials were: zero (control), (PEG 2%), (PEG 4%) and (PEG 8%), after drought stress, the solutes accumulation in the two potato cultivars were determined. Increasing drought stress through elevating PEG decreased leaf area as well as shoot and root lengths. Incontorary, the chlorophyll and proline contents increased with increasing PEG treatments. The proline-rich protein gene was cloned to the pGEM-T Easy vector and was submitted to the gene bank to be used later for enhancing drought resistence in other cultivars. [ABSTRACT FROM AUTHOR]

Seventeen bacterial isolates have been successfully isolated and purified from soil rhizosphere samples collected from different agricultural areas Buhayra, Sharqia and Alqilyubia of Egypt, and screened for production of chitinase enzymes had the highest chitinolytic activities amongst those investigated. Isolate S3-C and S1-C were Identified by biochemical, physiological tests and 16s rRNA gene primer as Bacillus cereus S3C, Gene Bank NCBI accession MK185696 and Bacillus cereus S1C accession MK185697. The production of chitinase by B.cereus S3C and Bacillus cereus S1C was optimized using colloidal chitin medium amended with 1% colloidal chitin at 30°C after five days of incubation. B.cereus S3C had potential for cell wall lysis of many phytopathogenic fungi tested such as Fusarium oxysporum and Rhizoctonia solani Potato phytopathogenic fungi by in vitro antagonistic test. The addition of B. cereus S3C chitinase was more effective than that of B.cereus S1C in increasing the resistance of Potato plants infected with various Soil- borne phytopathogenic fungi.

Background: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. Objective: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. Design: This was a three-arm, double-masked, randomised controlled non-inferiority trial. Setting: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. Participants: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. Interventions: The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). Main outcome measures: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of –5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. Results: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows – ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval –2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference –1.73 letters, 95% confidence interval –6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was –3.96 letters, 95% confidence interval –8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means –1.8, 95% confidence interval –2.9 to –0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000–30,000 per quality-adjusted life-year. Limitations: The comparison of aflibercept and bevacizumab was a post hoc analysis. Conclusion: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. Future work: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. Trial registration: Current Controlled Trials ISRCTN13623634. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019. At the time of writing (October 2020), the number of cases of COVID-19 had been approaching 38 million and more than 1 million deaths were attributable to it. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in hospital wards. Objective: The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests. A further objective was to assess occupancy levels in hospital areas, such as waiting bays, before allocation to an appropriate bay. Perspective/setting: The perspective was that of the UK NHS in 2020. The setting was a hypothetical hospital with an accident and emergency department. Methods: An individual patient model was constructed that simulated the spread of disease and mortality within the hospital and recorded occupancy levels. Thirty-two strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests were modelled. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits, and key patient outcomes, such as death and intensive care unit care, caused directly by COVID-19 were recorded. Results: A SARS-CoV-2 point-of-care test with a desirable target product profile appears to have a relatively small number of infections, a low occupancy level within the waiting bays, and a high net monetary benefit. However, if hospital laboratory testing can produce results in 6 hours, then the benefits of point-of-care tests may be reduced. The acceptable target product profiles performed less well and had lower net monetary benefits than both a laboratory-based test with a 24-hour turnaround time and strategies using data from currently available SARS-CoV-2 point-of-care tests. The desirable and acceptable point-of-care test target product profiles had lower requirement for patients to be in waiting bays before being allocated to an appropriate bay than laboratory-based tests, which may be of high importance in some hospitals. Tests that appeared more cost-effective also had better patient outcomes. Limitations: There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. The example hospital simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain. Conclusions: Should a SARS-CoV-2 point-of-care test with a desirable target product profile become available, this appears promising, particularly when the reduction on the requirements for waiting bays before allocation to a SARS-CoV-2-infected bay, or a non-SARS-CoV-2-infected bay, is considered. The results produced should be informative to decision-makers who can identify the results most pertinent to their specific circumstances. Future work: More accurate results could be obtained when there is more certainty on the diagnostic accuracy of, and the reduction in time to test result associated with, SARS-CoV-2 point-of-care tests, and on the impact of these tests on occupancy of waiting bays and isolation bays. These parameters are currently uncertain. Funding: This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 21. See the NIHR Journals Library website for further project information.

A defining feature of sea urchins is their extreme fecundity. Urchins produce millions of transparent, synchronously developing embryos, ideal for spatial and temporal analysis of development. This biological feature has been effectively utilized for ensemble measurement of biochemical changes. However, it has been underutilized in imaging studies, where single embryo measurements are used. Here we present an example of how stable genetics and high content imaging, along with machine learning‐based image analysis, can be used to exploit the fecundity and synchrony of sea urchins in imaging‐based drug screens. Building upon our recently created sea urchin ABCB1 knockout line, we developed a high‐throughput assay to probe the role of this drug transporter in embryos. We used high content imaging to compare accumulation and toxicity of canonical substrates and inhibitors of the transporter, including fluorescent molecules and antimitotic cancer drugs, in homozygous knockout and wildtype embryos. To measure responses from the resulting image data, we used a nested convolutional neural network, which rapidly classified embryos according to fluorescence or cell division. This approach identified sea urchin embryos with 99.8% accuracy and determined two‐cell and aberrant embryos with 96.3% and 89.1% accuracy, respectively. The results revealed that ABCB1 knockout embryos accumulated the transporter substrate calcein 3.09 times faster than wildtypes. Similarly, knockouts were 4.71 and 3.07 times more sensitive to the mitotic poisons vinblastine and taxol. This study paves the way for large scale pharmacological screens in the sea urchin embryo. Research Highlights: Sea urchin embryos are widely used to study development and toxicology. Here we describe a screening platform for evaluating drug sensitivity in urchin embryos, using drug transporter (ABCB1) knockout lines of Lytechinus pictus. We utilized semi‐automated liquid handling, high content imaging, and machine learning to dramatically increase throughput. The results demonstrate chemosensitivity of drug transporter knockouts, and establish a powerful platform for drug screening in sea urchin lines. [ABSTRACT FROM AUTHOR]