Importance and vulnerability of the world's water towers.

Mountains are the water towers of the world, supplying a substantial part of both natural and anthropogenic water demands1,2. They are highly sensitive and prone to climate change3,4, yet their importance and vulnerability have not been quantified at the global scale. Here we present a global water tower index (WTI), which ranks all water towers in terms of their water-supplying role and the downstream dependence of ecosystems and society. For each water tower, we assess its vulnerability related to water stress, governance, hydropolitical tension and future climatic and socio-economic changes. We conclude that the most important (highest WTI) water towers are also among the most vulnerable, and that climatic and socio-economic changes will affect them profoundly. This could negatively impact 1.9 billion people living in (0.3 billion) or directly downstream of (1.6 billion) mountainous areas. Immediate action is required to safeguard the future of the world's most important and vulnerable water towers.

Graded Quasiperiodic Metamaterials Perform Fractal Rainbow Trapping.

The rainbow trapping phenomenon of graded metamaterials can be combined with the fractal spectra of quasiperiodic waveguides to give a metamaterial that performs fractal rainbow trapping. This is achieved through a graded cut-and-project algorithm that yields a geometry for which the effective projection angle is graded along its length. As a result, the fractal structure of local band gaps varies with position, leading to broadband "fractal" rainbow trapping. We demonstrate this principle by designing an acoustic waveguide, which is characterised using theory, simulation and experiments.

Antimicrobial use in animals: a journey towards integrated surveillance.

In 2015, the World Organisation for Animal Health (WOAH, founded as OIE) initiated the annual collection of data on antimicrobials intended for use in animals using a Microsoft Excel questionnaire. In 2022, WOAH initiated the migration to a customised interactive online system: ANIMUSE Global Database. This system enables national Veterinary Services not only to monitor and report data more easily and more accurately, but also to visualise, analyse and use data for surveillance purposes to their own benefit in the implementation of national action plans on antimicrobial resistance. This journey started seven years ago, with progressive improvements in the way data are collected, analysed and reported and continuous adaptations to overcome various challenges encountered (e.g. data confidentiality, training of civil servants, calculation of active ingredients, standardisation to enable fair comparisons and trend analyses, and data interoperability). Technical developments have been key in the success of this endeavour. However, it is important not to underestimate the importance of the human element: to listen to WOAH Members and their needs, and to exchange to solve issues, adapt tools, and gain and maintain trust. The journey is not over yet, and more developments are foreseen, such as to complement current data sources with data collected directly at the farm level; strengthen interoperability and integrated analysis with cross-sectoral databases; and facilitate institutionalisation of data collection and systematic use in monitoring, evaluation, lesson learning, reporting and, eventually, surveillance of antimicrobial use and antimicrobial resistance when implementing and updating national action plans. This paper describes how all these challenges were overcome and how future challenges will be addressed.

En 2015, l'Organisation mondiale de la santé animale (OMSA, fondée en tant qu'OIE) a démarré, au moyen d'un questionnaire Microsoft Excel, une collecte annuelle de données sur les agents antimicrobiens destinés à être utilisés chez les animaux. L'OMSA a engagé, en 2022, la migration de cette collecte vers un système interactif en ligne sur mesure : la base de données mondiale ANIMUSE. Grâce à ce système, les Services vétérinaires pourront non seulement suivre et faire remonter les données plus facilement et avec davantage de précision, mais ils pourront aussi visualiser, analyser et utiliser ces données à leurs propres fins de surveillance, dans le cadre de la mise en oeuvre de plans d'action nationaux sur la résistance aux antimicrobiens. Ce travail a commencé il y a sept ans et des progrès constants ont été enregistrés en termes de collecte, d'analyse et de notification des données ; des adaptations continues ont également permis de dépasser les différents défis rencontrés (par exemple, en termes de confidentialité des données, de formation des fonctionnaires, de calcul des ingrédients actifs, de normalisation permettant d'établir des comparaisons équitables et des analyses de tendances et d'interopérabilité des données). Les avancées techniques ont joué un rôle clé dans la réussite de cette initiative. Il est cependant essentiel de ne pas sous-estimer l'importance du facteur humain : écoute des Membres de l'OMSA et de leurs besoins, échanges afin de résoudre les problèmes, adaptation des outils et obtention et préservation de la confiance. Cette aventure n'est pas terminée et des évolutions sont à venir : ajout des données collectées directement au niveau des élevages parmi les sources de données actuelles ; renforcement de l'interopérabilité et de l'analyse intégrée en recourant aux bases de données intersectorielles ; et institutionnalisation de la collecte de données et de son usage systématique dans le suivi, l'évaluation, les enseignements, les notifications et, à terme, la surveillance de l'utilisation des agents antimicrobiens et de l'antibiorésistance lors du déploiement et de la mise à jour des plans d'action nationaux. Cet article décrit comment tous ces défis ont été surmontés, ainsi que la manière dont les futurs défis seront relevés.

En 2015, la Organización Mundial de Sanidad Animal (OMSA, fundada como OIE) implantó un sistema de obtención anual de datos sobre los productos antimicrobianos destinados a los animales, empleando para ello un cuestionario en forma de hoja de cálculo Excel. En 2022, la OMSA inició la migración de este dispositivo a un sistema interactivo en línea especialmente adaptado al efecto: la base de datos mundial ANIMUSE. Este sistema permite a los Servicios Veterinarios nacionales no solo obtener y notificar datos con más facilidad y exactitud, sino también visualizar, analizar y aprovechar esta información con fines de vigilancia en la aplicación de planes nacionales de acción sobre la resistencia a antimicrobianos. Este viaje, que empezó hace siete años, ha supuesto una progresiva mejora de los métodos de obtención, análisis y notificación de los datos y continuas adaptaciones para superar las diversas dificultades que iban surgiendo (p.ej. en cuanto a confidencialidad de los datos, formación de funcionarios, cálculo de las cantidades de principio activo, normalización con fines de comparación y de análisis de tendencias, o compatibilidad de los datos). Aunque los avances técnicos han sido fundamentales para el éxito de la empresa, no cabe subestimar la importancia del factor humano, ese empeño de escuchar a los Miembros de la OMSA y tener en cuenta sus necesidades, favorecer el intercambio para resolver problemas, adaptar las herramientas y forjar y mantener relaciones de confianza. El viaje aún no ha terminado. Previsiblemente habrá nuevos avances que permitan, por ejemplo, complementar las actuales fuentes de información con datos obtenidos directamente en la explotación, mejorar la compatibilidad y los análisis integrados con bases de datos intersectoriales, o institucionalizar en mayor medida la obtención de datos y su uso sistemático con fines de seguimiento, evaluación, aprendizaje, notificación y a la postre vigilancia del uso de antimicrobianos y de eventuales resistencias a la hora de aplicar o actualizar planes nacionales de acción. Los autores explican cómo se fueron superando todas esas dificultades y cómo se abordarán los problemas que puedan ir surgiendo en el futuro.

Chronic subdural haematoma: the role of peri-operative medicine in a common form of reversible brain injury.

Epidemiological studies project a significant rise in cases of chronic subdural haematoma over the next 20 years. Patients with this condition are frequently older and medically complex, with baseline characteristics that may increase peri-operative risk. The intra-operative period is only a small portion of a patient's total hospital stay, with a majority of patients in the United Kingdom transferred between institutions for their surgical and rehabilitative care. Definitive management remains surgical, but peri-operative challenges exist which resonate with other surgical cohorts where multidisciplinary working has become the gold standard. These include shared decision-making, medical optimisation, the management of peri-operative anticoagulation and the identification of key points of equipoise for examination in the future trials. In this narrative review, we use a stereotyped patient journey to provide context to the recent literature, highlighting where multidisciplinary expertise may be required to optimise patient care and maximise the benefits of surgical management. We discuss the triage, pre-operative optimisation, intra-operative management and immediate postoperative care of patients undergoing surgery for a chronic subdural haematoma. We also discuss where adjunctive medical management may be indicated. In so doing, we present the current and emerging evidence base for the role of an integrated peri-operative medicine team in the care of patients with a chronic subdural haematoma.

Incidence of chronic subdural haematoma: a single-centre exploration of the effects of an ageing population with a review of the literature.

BACKGROUND: Chronic subdural haematoma (cSDH) is a common neurosurgical pathology frequently occurring in older patients. The impact of population ageing on cSDH caseload has not been examined, despite relevance for health system planning. METHODS: This is a single-centre study from the UK. Operated cases of cSDH (n = 446) for 2015-2018 were identified. Crude and directly standardised incidence rates were calculated. Medline and EMBASE were systematically searched to identify studies reporting on the incidence of cSDH by year, so an estimate of rate of incidence change could be determined. Local incidence rates were then applied to population projections for local catchment area to estimate operated cSDH numbers at 5 yearly intervals due to shifting demographics. RESULTS: We identified nine studies presenting incidence estimates. Crude estimates for operative cases ranged from 1.3/100,000/year (1.4-2.2) to 5.3/100,000/year (4.3-6.6). When non-operated cases were included, incidence was higher: 8.2/100,000/year (6.0-11.2) to 48/100,000/year (37.7-61.1). Four pairs of studies demonstrated incidence rate increases of 200-600% over the last 50 years, but data was deemed too heterogeneous to generate formal estimate of incidence change. Local crude incidence of operated cSDH was 3.50/100,000/year (3.19-3.85). Directly standardised incidence was 1.58/100,000/year (1.26-1.90). After applying local incidence rates to population projections, case numbers were predicted to increase by 53% over the next 20 years. CONCLUSIONS: The incidence of cSDH is increasing. We project a 53% increase in operative caseload within our region by 2040. These are important findings for guiding future healthcare planning.

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Bespoke video vignettes - an approach to enhancing reflective learning developed by dental undergraduates and their clinical teachers.

This study explores the selective use of video as a medium to support reflective processes as related to dental undergraduate learning. With the objective of developing and enhancing high-quality adult dental care, the use of compiled video materials created in an undergraduate clinical setting was investigated. Video cameras were used to capture elements of reflection-in-action and reflection-on-action typically found during everyday clinical practice. 'Gold standard' or 'textbook outcomes' are rarely, if ever, fully achieved in dental practice. Real-life clinical experiences offer challenges and opportunities for both teachers and students to engage with reflective learning processes. The materials generated allowed for an experience of individual reflective learning and the creation of a data bank or archive with potential use for the benefit of a wider student cohort. Various aspects of the students' views and comments on the process of reflection were reported and explored by means of a semi-structured focus group moderated by a linked educational advisor.

Qualitative grading of disc degeneration by magnetic resonance in the lumbar and cervical spine: lack of correlation with histology in surgical cases.

BACKGROUND: Clinically, magnetic resonance (MR) imaging is the most effective non-invasive tool for assessing IVD degeneration. Histological examination of the IVD provides a more detailed assessment of the pathological changes at a tissue level. However, very few reports have studied the relationship between these techniques. Identifying a relationship may allow more detailed staging of IVD degeneration, of importance in targeting future regenerative therapies. OBJECTIVES: To investigate the relationship between MR and histological grading of IVD degeneration in the cervical and lumbar spine in patients undergoing discectomy. METHODS: Lumbar (N = 99) and cervical (N = 106) IVD samples were obtained from adult patients undergoing discectomy surgery for symptomatic IVD herniation and graded to ascertain a histological grade of degeneration. The pre-operative MR images from these patients were graded for the degree of IVD (MR grade) and vertebral end-plate degeneration (Modic Changes, MC). The relationship between histological and MR grades of degeneration were studied. RESULTS: In lumbar and cervical IVD the majority of samples (93%) exhibited moderate levels of degeneration (ie MR grades 3-4) on pre-operative MR scans. Histologically, most specimens displayed moderate to severe grades of degeneration in lumbar (99%) and cervical spine (93%). MR grade was weakly correlated with patient age in lumbar and cervical study groups. MR and histological grades of IVD degeneration did not correlate in lumbar or cervical study groups. MC were more common in the lumbar than cervical spine (e.g. 39 versus 20% grade 2 changes; p < 0.05), but failed to correlate with MR or histological grades for degeneration. CONCLUSIONS: In this surgical series, the resected IVD tissue displayed moderate to severe degeneration, but there is no correlation between MR and histological grades using a qualitative classification system. There remains a need for a quantitative, non-invasive, pre-clinical measure of IVD degeneration that correlates with histological changes seen in the IVD.

Annual review of children with neurofibromatosis type 1.

We aim to provide a concise, evidence-based framework to assist secondary level, community and acute paediatricians during a 20-60 min annual review of children with neurofibromatosis type 1. This review does not cover all aspects of the disorder. We recognise the importance of an overview of the pathogenesis, molecular genetic testing, clinical manifestations and management; we shall cover some of this briefly, but this is not our focus here. We focus instead on the following areas: (A) what questions should be asked during annual review, (B) what should be included in a focused examination, (C) when to request further investigations and (D) when should a referral be made to tertiary specialists and other members of the multidisciplinary team. Ongoing debates regarding screening remain in certain areas, particularly regarding imaging and ophthalmology follow-up; here we summarise the differing opinions and make a recommendation based on the currently available evidence.

Nonlinear optical response of low loss silicon germanium waveguides in the mid-infrared.

We have investigated the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared wavelength range from 3.25- 4.75µm using picosecond optical pulses. We observed and measured the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index. The dynamics of the spectral broadening suggests that, in addition to multiphoton absorption, the corresponding higher order nonlinear refractive phenomena also needs to be included when high optical pulse intensities are used at mid-infrared wavelengths in this material.

Mid-infrared nonlinear optical response of Si-Ge waveguides with ultra-short optical pulses.

We characterize the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared between 3.3 µm and 4 µm using femtosecond optical pulses. We estimate the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index from the experimental measurements. The effect of multiphoton absorption on the optical nonlinear Kerr response is evaluated and the nonlinear figure of merit estimated providing some guidelines for designing nonlinear optical devices in the mid-IR. Finally, we compare the impact of free-carrier absorption at mid-infrared wavelengths versus near-infrared wavelengths for these ultra-short pulses.

Should an increase in cerebral neurochemicals following head kicks in full contact karate influence return to play?

BACKGROUND: Cerebral neurochemicals are markers of traumatic brain injury (TBI). OBJECTIVES: The aim of the study was to determine whether kicks to the head (KTH) in full contact karate significantly increased serum concentrations of protein S-100B, and neurone specific enolase (NSE). Kicks to the body (KTB) were also quantified to asses muscle tissue injury. Muscle damage was assessed by analysis of serum total creatine kinase (CK). METHODS: Twenty-four full contact karate practitioners were observed and filmed during actual competition and divided into two main groups post event: (1) Kicks to the head and body group (KTH): n = 12; mean ± SD; age, 30.4 ± 6.7 years; height, 1.74 ± 0.1 m; weight, 79.1 ± 2.1 kg; and (2): Kicks to the body group (KTB): n = 12; mean ± SD; age, 28.2 ± 6.5 years; height, 1.75 ± 0.1 m; weight, 79.2 ± 1.7 kg. The KTH group received direct kicks to the head, while group KTB received kicks and punches to the body. Blood samples were taken before and immediately post-combat for analysis of serum S-100B, NSE, CK and cardiac troponin. RESULTS: Significant increases in serum concentrations of S-100B (0.12 ± 0.17 vs. 0.37 ± 0.26, µg.L(-1)) and NSE (11.8 ± 4.1 vs. 20.2 ± 9.1 ng.mL(-1)) were encountered after combat in the KTH group and CK (123 ± 53 vs. 184 ± 103 U.L(-1)) in the KTB group (all P <0.05). CONCLUSIONS: Head kicks in full contact karate cause elevation of neurochemical markers associated with damaged brain tissue. The severity of injury is related to the early post-traumatic release of protein S-100B and NSE. The early kinetics and appearance post injury can reflect intracranial pathology, and suggest S-100B and NSE are extremely sensitive prognostic markers of TBI.

A study examining the relationship between alexithymia and challenging behaviour in adults with intellectual disability.

BACKGROUND: Research suggesting that people with intellectual disabilities (ID) have difficulties in recognising emotions provides a rationale for studying alexithymia in this population. A number of studies have found a relationship between alexithymia and challenging behaviours in various populations and this study aims to discover if this is the case for people with ID. METHOD: Cross-sectional data were collected from 96 participants with ID and 95 of their carers. The service user participants completed an alexithymia questionnaire for children while carers completed the checklist for challenging behaviour and the observer alexithymia scale. Correlational analyses were employed to explore relationships between the variables. RESULTS: The relationship between service user and carer-rated alexithymia was very weak. The analysis did show significant associations between observer-rated alexithymia and challenging behaviour frequency, management difficulty and severity, but there was no significant relationship between challenging behaviour and alexithymia as rated by service users themselves. CONCLUSIONS: This study suggests that observer-rated alexithymia is important in understanding challenging behaviour presented by people with ID. Service user-rated alexithymia had no association with challenging behaviour, in contrast to the results from similar research with other challenging populations.

The UK geochemical environment and cardiovascular diseases: magnesium in food and water.

Cardiovascular diseases (CVDs) contribute approximately one-third to noncommunicable diseases in the UK. The central role of magnesium in CVDs (enzyme activity, cardiac signalling, etc.) is well established. Mortality and morbidity rates for CVDs may be inversely related to water hardness, suggesting a role for environmental magnesium. Published official and quasi-official data sources were evaluated to establish a model magnesium intake for a representative adult: standardised reference individual (SRI), standardised reference male (SRM) or standardised reference female (SRF). For typical dietary constituents, only tap water is probably locally derived and bottled water may not be. Fruits and vegetables are imported from many countries, while meat, dairy and cereal products represent a composite of UK source areas. Alcoholic beverages provide magnesium, there is doubt about its absorptive efficiency, and they are not locally derived. A simple model was devised to examine the effect of varying dietary contributions to total daily intake of magnesium. Omitting tap or bottled water, the combined intake, solid food plus alcoholic beverages, is 10.57 mmol Mg (84.5 % RNI) for the SRM and for the SRF, 8.10 mmol Mg (71.7 % RNI). Consumers drinking water derived from reservoirs or rivers, or supplementing it with the purest bottled water, improve their magnesium intake only slightly compared with water containing no magnesium. Choosing bottled water with high magnesium content when the public supply derives from rivers or reservoirs partially satisfies magnesium needs. Real improvement in SRI magnesium nutrition is seen only where water is hard. However, this conclusion cannot be validated until new measurement technologies for body magnesium become available.

A consideration of the paradigm of exercise physiology.

Exercise physiology, in terms of the history of biological sciences, is quite young and has a rather tumultuous history - as it spans physical education, health & medicine, sport science, and biology. This has led to the development of differing definitions, research approaches, practices and goals. This is easily seen in the presence of competing and non-universally adopted definitions of fitness. Such internal inconsistencies portray to the outside world a discipline experiencing the problems associated with a changing paradigm. Every science requires the presence of a paradigm that both describes and guides the evolution of thinking, experimentation, and the application of such. It is argued here that exercise physiology has been operating without benefit of a satisfactory and relevant paradigm. A further proposition is that the required disciplinary definitions derived from an articulated paradigm are also absent. A paradigmatic scheme based on biological dogma is presented along with proposed definitions.

Low loss coupling to sub-micron thick rib and nanowire waveguides by vertical tapering.

Highly nonlinear planar glass waveguides have been shown to be useful for all optical signal processing. However, the typical SMF-28 fiber to waveguide coupling loss of ~5dB/end remains a barrier to practical implementation. Low loss coupling to a fiber using vertical tapering of the waveguide film is analyzed for rib and nanowire waveguides and experimentally demonstrated for ribs showing polarization and wavelength independence over >300nm bandwidth. Tapers with essentially zero excess loss led to total losses from the waveguide to fiber core of 1.1dB per facet comprising only material absorption (0.75dB) and mode overlap loss (0.36dB), both of which can be eliminated with improvements to processing and materials.

Evaluation of a collaborative chronic care approach to improve outcomes in kidney transplant recipients.

Several studies found that renal transplant recipients with chronic kidney disease have untreated complications and do not attain recommended clinical targets. Using a before/after design with propensity score-matched controls, we evaluated whether an advanced practice nurse-led interprofessional collaborative chronic care approach could improve clinical outcomes for CKD transplant patients compared with a traditional physician-led model. The intervention included strategies for disease self-management, shared decision making, and healthcare system reorganization. The primary outcome was the proportion of patients attaining at least seven of nine targets as per published guidelines. A greater proportion of intervention patients achieved the outcome (68% vs. 10%; p = 0.0001) and had discussions about end-stage treatment options (88% vs. 13%; p = 0.0001) compared with controls. The intervention patients had significantly fewer emergency room visits (incidence rate ratio [IRR] 0.53; 95% CI 0.29-0.91; p = 0.02) and hospital admissions (IRR 0.34; 95% CI 0.16-0.68; p = 0.001) compared with the control patients. There were no significant differences found between the groups in systolic/diastolic blood pressure, carbon dioxide, hemoglobin, or phosphate parameters. An advanced practice nurse-led approach, based on the chronic care model, has the potential to improve clinical outcomes for renal transplant recipients and needs to be tested in a multicenter randomized controlled trial.

Investigating blood alcohol concentrations in injury- related deaths before and during the COVID-19 national lockdown in Western Cape Province, South Africa: A cross-sectional retrospective review.

BACKGROUND: Alcohol is a significant contributor to injury-related morbidity and mortality in South Africa (SA). During the COVID-19global pandemic, restrictions to movement and to legal access to alcohol (i.e. ethanol) were introduced in SA. OBJECTIVES: To investigate the effect of alcohol bans during the COVID-19 lockdown periods on injury-related mortality and blood alcoholconcentrations (BACs) in these deaths. METHODS: A retrospective, cross-sectional analysis of injury-related deaths in Western Cape Province (WC), SA, between 1 January 2019 and31 December 2020 was conducted. Cases where BAC testing was performed were further examined according to the periods of lockdownand alcohol restrictions. RESULTS: A total of 16 027 injury-related cases were admitted to Forensic Pathology Service mortuaries in the WC over the 2-year period. Anaverage decrease of 15.7% injury-related deaths in 2020 compared with 2019 was noted, as well as a 47.7% decrease in injury-related deathsduring hard lockdown (April - May 2020) compared with the same period in 2019. In the injury-related deaths, 12 077 (75.4%) had bloodspecimens collected for BAC testing. In 5 078 (42.0%) of submitted cases, a positive BAC (≥0.01 g/100 mL) was reported. No significantdifference was observed in the mean positive BAC between 2019 and 2020. However, in April and May 2020, the mean BAC observed(0.13 g/100 mL) was less than that in 2019 (0.18 g/100 mL). A high number of positive BACs in the 12- 17-year age group (23.4%) was observed. CONCLUSION: There was a clear decrease in injury-related deaths in the WC during the COVID-19-related lockdown periods, whichcoincided with the alcohol ban and restriction of movement, and an increase following relaxation of restrictions on alcohol sales andmovement. The data illustrate that mean BACs were similar between all periods of alcohol restriction compared with 2019, apart from hardlockdown in April - May 2020. This coincided with a smaller mortuary intake during the level 5 and 4 lockdown periods.

Investigating blood alcohol concentrations in injury-related deaths before and during the COVID-19 National lockdown in Western Cape, South Africa: A cross-sectional retrospective review.

BACKGROUND: Alcohol is a significant contributor to injury-related morbidity and mortality in South Africa (SA).  During the COVID-19 global pandemic, restrictions to movement and to the legal access of alcohol* were introduced in SA.  This study aimed to investigate the effect of alcohol bans during the COVID-19 lockdown periods on injury-related mortality and the blood alcohol concentrations (BAC) in these deaths. METHODS: A retrospective, cross-sectional analysis of injury-related deaths in Western Cape (WC) province, SA, between 1 January 2019 to 31 December 2020 was conducted. Cases where BAC testing was performed were further examined according to the periods of lockdown (AL5-1) and alcohol restrictions. RESULTS: A total of 16,027 injury-related cases were admitted to Forensic Pathology Service mortuaries in the WC over the two-year period.  An average decrease of 15.7% injury-related deaths in 2020 compared to 2019 was noted, as well as a 47.7% decrease in injury-related deaths during hard lockdown (April -May 2020) compared to the same period in 2019. In the injury-related deaths, 12,077 (75.4%) had blood specimens collected for BAC testing. In 5,078 (42.0%) of submitted cases, a positive BAC (≥0.01g/100 mL) was reported. No significant difference was observed in the mean positive BAC between 2019 and 2020, however in April and May 2020, the mean BACs observed (0.13 g/100 mL) was less than that in 2019 (0.18 g/100 mL). A high number of positive BACs in the 12-17-year age group (±23.4%) was observed. CONCLUSION: There was a clear decrease in injury-related deaths in the WC during the COVID-19-related lockdown periods that coincided with the alcohol ban and restriction of movement and an increase following relaxation of restrictions on alcohol sales and movement. The data illustrated that mean BACs were similar between all periods of alcohol restriction compared to 2019, apart from hard lockdown in April-May, 2020.  This coincided with a smaller mortuary intake during the level 5 and 4 lockdown periods.   Keywords: Alcohol; blood alcohol concentration; COVID-19; injury; lockdown; South Africa; violent death; Western Cape   * Alcohol refers to ethanol.

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.

BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy. METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations. RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib. CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.