Measurement of feline-specific pancreatic lipase aids in the diagnosis of pancreatitis in cats.

OBJECTIVE: To establish a reference interval for a feline-specific pancreatic lipase assay (Spec fPL test; Idexx Laboratories Inc) in healthy cats and determine the sensitivity and specificity of the Spec fPL test in a large group of ill cats with and without pancreatitis. ANIMALS: 41 healthy cats, 141 cats with clinical signs consistent with pancreatitis, and 786 stored sera with known feline pancreatic lipase immunoreactivity (fPLI) concentrations. METHODS: This was a prospective, cross-sectional, nonrandomized study. Based on a detailed review of the medical history and results of physical examination, CBC, serum biochemical profile, urinalysis, abdominal ultrasonography, and clinical outcome, each cat was categorized by 2 board-certified internists masked to the fPLI test results into 1 of 6 categories from definitely pancreatitis to definitely not pancreatitis. RESULTS: The reference interval for the Spec fPL test, determined from the central 95th percentile of results from healthy cats, was fPLI of 0.7 to 3.5 µg/L. An fPLI concentration of ≥ 5.4 µg/L was determined to be consistent with pancreatitis. With an fPLI of 5.4 µg/L as the diagnostic cutoff, the sensitivity of the Spec fPL test for feline pancreatitis (definitely pancreatitis and probably pancreatitis) was 79.4%, the specificity for cats characterized as probably not pancreatitis and definitely not pancreatitis was 79.7%, and positive and negative predictive values were 69% and 87%, respectively. CLINICAL RELEVANCE: These findings support the use of the Spec fPL test as a valuable diagnostic test for feline pancreatitis.

Living with a diagnosis of frontotemporal dementia: An interpretative phenomenological analysis.

Frontotemporal dementia describes a spectrum of disorders which include behavioural changes, changes to affect, speech difficulties and physical issues. Although literature exists which identifies the need for the voices of people with dementia to be heard, there is a paucity of research which includes hearing the experiences of people diagnosed with FTD. The purpose of this research was to explore the lived experience of frontotemporal dementia from the persons' perspective using interpretative phenomenological analysis. The themes that emerged in the analysis were: the rocky road through assessment; the changing self; in touch with reality; and keeping going. Two overarching themes emerged which were: the need to hear the voice of people with frontotemporal dementia; and for people with frontotemporal dementia to exercise some control over the decision making process throughout their journey. Recommendations are presented for future practice and research.

Corrigendum: Variations in the Consumption of Antimicrobial Medicines in the European Region, 2014-2018: Findings and Implications From ESAC-Net and WHO Europe.

[This corrects the article DOI: 10.3389/fphar.2021.639207.].

Variations in the Consumption of Antimicrobial Medicines in the European Region, 2014-2018: Findings and Implications from ESAC-Net and WHO Europe.

Background: Surveillance of antimicrobial consumption (AMC) is important to address inappropriate use. AMC data for countries in the European Union (EU) and European Economic Area (EEA) and Eastern European and Central Asian countries were compared to provide future guidance. Methods: Analyses of 2014-2018 data from 30 EU/EEA countries of the European Surveillance of Antibiotic Consumption network (ESAC-Net) and 15 countries of the WHO Regional Office for Europe (WHO Europe) AMC Network were conducted using the Anatomical Therapeutic Chemical (ATC) classification and Defined Daily Dose (DDD) methodology. Total consumption (DDD per 1000 inhabitants per day) of antibacterials for systemic use (ATC group J01), relative use (percentages), trends over time, alignment with the WHO Access, Watch, Reserve (AWaRe) classification, concordance with the WHO global indicator (60% of total consumption should be Access agents), and composition of the drug utilization 75% (DU75%) were calculated. Findings: In 2018, total consumption of antibacterials for systemic use (ATC J01) ranged from 8.9 to 34.1 DDD per 1000 inhabitants per day (population-weighted mean for ESAC-Net 20.0, WHO Europe AMC Network 19.6, ESAC-Net Study Group, and WHO Europe AMC Network Study Group). ESAC-Net countries consumed more penicillins (J01C; 8.7 versus 6.3 DDD per 1000 inhabitants per day), more tetracyclines (J01A; 2.2 versus 1.2), less cephalosporins (J01D; 2.3 versus 3.8) and less quinolones (J01M; 1.7 versus 3.4) than WHO Europe AMC Network countries. Between 2014 and 2018, there were statistically significant reductions in total consumption in eight ESAC-Net countries. In 2018, the relative population-weighted mean consumption of Access agents was 57.9% for ESAC-Net and 47.4% for the WHO Europe AMC Network. For each year during 2014-2018, 14 ESAC-Net and one WHO Europe AMC Network countries met the WHO global monitoring target of 60% of total consumption being Access agents. DU75% analyses showed differences in the choices of agents in the two networks. Interpretation: Although total consumption of antibacterials for systemic use was similar in the two networks, the composition of agents varied substantially. The greater consumption of Watch group agents in WHO Europe AMC Network countries suggests opportunities for improved prescribing. Significant decreases in consumption in several ESAC-Net countries illustrate the value of sustained actions to address antimicrobial resistance.

Shortages and price variability of essential cytotoxic medicines for treating children with cancers.

INTRODUCTION: Low-income and middle-income countries (LMICs) face the largest burden of mortality from childhood cancers with limited access to curative therapies. Few comparative analyses across all income groups and world regions have examined the availability and acquisition costs of essential medicines for treating cancers in children. METHODS: A cross-sectional survey involved countries in five income groups-low-income (LIC), lower-middle-income (LMC), upper-middle-income (UMC), two high-income country groups (HIC1, HIC2). Physicians and pharmacists reported institutional use, availability, stock outs and prices (brand and generic products) of 34 essential medicines. Price comparisons used US$, applying foreign exchange rates (XR) and purchasing power parity (PPP) adjustments. Medicine costs for treating acute lymphoblastic leukaemia (ALL), Burkitt lymphoma (BL) and Wilms tumour (WT) were calculated (child 29 kg, body surface area 1 m2). Comparisons were conducted using non-parametric Kruskal-Wallis tests. RESULTS: Fifty-eight respondents (50 countries) provided information on medicine use, availability and stock outs, with usable price data from 42 facilities (37 countries). The extent of use of International Society of Paediatric Oncology core and ancillary medicines varied across income groups (p<0.0001 and p=0.0002 respectively). LMC and LIC facilities used fewer medicines than UMC and HIC facilities. UMC and LMC facilities were more likely to report medicines not available or stockouts.Medicine prices varied widely within and between income bands; generic products were not always cheaper than brand equivalents. PPP adjustment showed relatively higher prices in UMC and LMC facilities for some medicines. Medicine costs were highest in HICs for ALL (p=0.0075 XR; p=0.0178 PPP-adjusted analyses) and WT (p =<0.0001 XR; p=0.0007 PPP-adjusted). Medicine costs for BL were not significantly different. CONCLUSION: Problems with the availability of essential medicines, dependable supply chains, confidential medicine prices and wide variability in treatment costs contribute to persistent challenges in the care of children with treatable cancers, especially in LMICs.

AGILE-ACCORD: A Randomized, Multicentre, Seamless, Adaptive Phase I/II Platform Study to Determine the Optimal Dose, Safety and Efficacy of Multiple Candidate Agents for the Treatment of COVID-19: A structured summary of a study protocol for a randomised platform trial.

OBJECTIVES: Phase I - To determine the optimal dose of each candidate (or combination of candidates) entered into the platform. Phase II - To determine the efficacy and safety of each candidate entered into the platform, compared to the current Standard of Care (SoC), and recommend whether it should be evaluated further in a later phase II & III platforms. TRIAL DESIGN: AGILE-ACCORD is a Bayesian multicentre, multi-arm, multi-dose, multi-stage open-label, adaptive, seamless phase I/II randomised platform trial to determine the optimal dose, activity and safety of multiple candidate agents for the treatment of COVID-19. Designed as a master protocol with each candidate being evaluated within its own sub-protocol (Candidate Specific Trial (CST) protocol), randomising between candidate and SoC with 2:1 allocation in favour of the candidate (N.B the first candidate has gone through regulatory approval and is expected to open to recruitment early summer 2020). Each dose will be assessed for safety sequentially in cohorts of 6 patients. Once a phase II dose has been identified we will assess efficacy by seamlessly expanding into a larger cohort. PARTICIPANTS: Patient populations can vary between CSTs, but the main eligibility criteria include adult patients (≥18 years) who have laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We will include both severe and mild-moderate patients defined as follows: Group A (severe disease) - patients with WHO Working Group on the Clinical Characteristics of COVID-19 infection 9-point ordinal scale of Grades 4 (hospitalised, oxygen by mask or nasal prongs), 5 (hospitalised, non-invasive ventilation or high flow oxygen), 6 (hospitalised, intubation and mechanical ventilation) or 7 (hospitalised, ventilation and additional organ support); Group B (mild-moderate disease) - ambulant or hospitalised patients with peripheral capillary oxygen saturation (SpO2) >94% RA. If any CSTs are included in the community setting, the CST protocol will clarify whether patients with suspected SARS-CoV-2 infection are also eligible. Participants will be recruited from England, North Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is the current standard of care (SoC), in some CSTs plus placebo. Candidates that prevent uncontrolled cytokine release, prevention of viral replication, and other anti-viral treatment strategies are at various stages of development for inclusion into AGILE-ACCORD. Other CSTs will be added over time. There is not a set limit on the number of CSTs we can include within the AGILE-ACCORD Master protocol and we will upload each CST into this publication as each opens to recruitment. MAIN OUTCOMES: Phase I: Dose limiting toxicities using Common Terminology Criteria for Adverse Events v5 Grade ≥3 adverse events. Phase II: Agreed on a CST basis depending on mechanism of action of the candidate and patient population. But may include; time to clinical improvement of at least 2 points on the WHO 9-point category ordinal scale [measured up to 29 days from randomisation], progression of disease (oxygen saturation (SaO2) <92%) or hospitalization or death, or change in time-weighted viral load [measured up to 29 days from randomisation]. RANDOMISATION: Varies with CST, but default is 2:1 allocation in favour of the candidate to maximise early safety data. BLINDING (MASKING): For the safety phase open-label although for some CSTs may include placebo or SoC for the efficacy phase. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Varies between CSTs. However simulations have shown that around 16 participants are necessary to determine futility or promise of a candidate at a given dose (in efficacy evaluation alone) and between 32 and 40 participants are required across the dose-finding and efficacy evaluation when capping the maximum number of participants contributing to the evaluation of a treatment at 40. TRIAL STATUS: Master protocol version number v5 07 May 2020, trial is in setup with full regulatory approval and utilises several digital technology solutions, including Medidata's Rave EDC [electronic data capture], RTSM for randomisation and patient eConsent on iPads via Rave Patient Cloud. The recruitment dates will vary between CSTs but at the time of writing no CSTs are yet open for recruitment. TRIAL REGISTRATION: EudraCT 2020-001860-27 14th March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

A retrospective evaluation of the relationship between symmetric dimethylarginine, creatinine and body weight in hyperthyroid cats.

Hyperthyroidism in cats can mask changes in renal function, including chronic kidney disease (CKD), because of hyperfiltration and muscle loss. Symmetric dimethylarginine (SDMA) has been shown to increase earlier than creatinine in cats with renal dysfunction, and, unlike creatinine, SDMA is not impacted by lean muscle mass. The aim of this study was to describe the relationship between SDMA, creatinine, body weight and TT4 over time during treatment of hyperthyroidism. Cats were retrospectively identified from the US IDEXX Reference Laboratories database where TT4, SDMA and creatinine were measured on the same cat at multiple time points. A hyperthyroid treated group was identified (TT4 ≤ 4.7 µg/dL and decreased by a minimum of 2.5 µg/dL) that had body weight and laboratory results available from more than one visit, and was used to evaluate body weight, creatinine, SDMA and TT4 pre-treatment and at 1-30, 31-60, 61-90, 91-120 days post-treatment. Creatinine significantly decreased with increasing concentrations of TT4 (Spearman's ρ = -0.37, P < 0.001), whereas SDMA did not. Body weight, SDMA and creatinine concentrations significantly increased during the immediate 1-30 day post-treatment period (P < 0.012, P < 0.001, P < 0.001, respectively). During treatment creatinine continued to increase as cats gained weight. In contrast, SDMA remained stable during treatment and was comparable to age-matched control cats. Therefore, SDMA may be a more reliable biomarker of renal function than creatinine in hyperthyroid cats before and during treatment.

Poor availability of essential medicines for women and children threatens progress towards Sustainable Development Goal 3 in Africa.

BACKGROUND: Most maternal and child deaths are preventable or treatable with proven, cost-effective interventions for infectious diseases and maternal and neonatal complications. In 2015 sub-Saharan Africa accounted for up to 66% of global maternal deaths and half of the under-five deaths. Access to essential medicines and commodities and trained healthcare workers to provide life-saving maternal, newborn and post-natal care are central to further reductions in maternal and child mortality. METHODS: Available data for 24 priority medicines for women and children were extracted from WHO service availability and readiness assessments conducted between 2012 and 2015 for eight countries in sub-Saharan Africa. The mean availability of medicines in facilities stating they provide services for women or children and differences by facility type, ownership and location are reported. RESULTS: The mean availability of 12 priority essential medicines for women ranged from 22% to 40% (median 33%; IQR 12%) and 12 priority medicines for children ranged from 28% to 57% (median 50%; IQR 14%). Few facilities (<1%) had all nominated medicines available. There was higher availability of priority medicines for women in hospitals than in primary care facilities: range 32%-80% (median 61%) versus 20%-39% (median 23%) and for children's medicines 31%-71% (median 58%) versus 27%-57% (median 48%). Availability was higher in public than private facilities: for women's medicines, range 21%-41% (median 34%) versus 4%-36% (median 27%) and for children's medicines 28%-58% (median 51%) versus 5%-58% (median 46%). Patterns were mixed for rural and urban location for the priority medicines for women, but similar for children's medicines. CONCLUSIONS: The survey results show unacceptably low availability of priority medicines for women and children in the eight countries. Governments should ensure the availability of medicines for mothers and children if they are to achieve the health sustainable development goals.

Noncommunicable diseases, access to essential medicines and universal health coverage.

Universal Health Coverage is key to reach the overall health-related Sustainable Development Goal, and within this, access to safe, effective, quality, and affordable essential medicines is critical. Currently, medicines for noncommunicable diseases in many countries are not available when needed and if they are present, are unaffordable. Countries face the challenges of rising prevalence of noncommunicable diseases due to increasing risk factors and ageing populations, along with under-diagnosis and under-treatment. Providing noncommunicable disease medicines is only one piece of a complex picture of providing care within Universal Health Coverage that requires strengthening health-care systems, as well as financial resources, priority setting, and monitoring and evaluation systems. Financing for Universal Health Coverage needs to enable adequate resources to be allocated for medicines with a focus on equity as well as priority setting for noncommunicable diseases medicines for reimbursement in benefits packages, efficient procurement and distribution of these medicines, supported by price regulation. These processes need to be evidence-based, transparent and grounded on national values and priorities. Monitoring and evaluation of availability and affordability are key components of sustainable reimbursement systems. With the current Universal Health Coverage agenda, the World Health Organization and countries can no longer ignore the issue of access to medicines for noncommunicable disease and need to develop the appropriate responses in order to guarantee equitable access.

Assessing the impact of law enforcement to reduce over-the-counter (OTC) sales of antibiotics in low- and middle-income countries; a systematic literature review.

BACKGROUND: Many low- and middle-income countries (LMIC) are moving towards enforcing prescription-only access to antibiotics. This systematic literature review aims to assess the interventions used to enforce existing legislation prohibiting over-the-counter (OTC) sales of antibiotics in LMICs, their impact and examine the methods chosen for impact measurement including their strengths and weaknesses. METHODS: Both PubMed and Embase were systematically searched for studies reporting on impact measurement in moving towards prescription only access to antibiotics in LMICs. The PRISMA methodological review framework was used to ensure systematic data collection and analysis of literature. Narrative data synthesis was used due to heterogeneity of study designs. RESULTS: In total, 15 studies were included that assessed policy impact in 10 different countries. Strategies employed to enforce regulations prohibiting OTC sales of systemic antibiotics included retention of prescriptions for antibiotics by pharmacies, government inspections, engaging pharmacists in the design of interventions, media campaigns for the general public and educational activities for health care workers. A variety of outcomes was used to assess the policy impact; changes in antimicrobial resistance rates, changes in levels of antibiotic use, changes in trends of antibiotic use, changes in OTC supply of antibiotics, and changes in reported practices and knowledge of pharmacists, medicine sellers and the general public. Differences in methodological approaches and outcome assessment made it difficult to compare the effectiveness of law enforcement activities. Most effective appeared to be multifaceted approaches that involved all stakeholders. Monitoring of the impact on total sales of antibiotics by means of an interrupted time series (ITS) analysis and analysis of pharmacies selling antibiotics OTC using mystery clients were the methodologically strongest designs used. CONCLUSIONS: The published literature describing activities to enforce prescription-only access to antibiotics in LMICs is sparse and offers limited guidance. Most likely to be effective are comprehensive multifaceted interventions targeting all stakeholders with regular reinforcement of messages. Policy evaluation should be planned as part of implementation to assess the impact and effectiveness of intervention strategies and to identify targets for further activities. Robust study designs such as ITS analyses and mystery client surveys should be used to monitor policy impact.

The role of evidence in consumer choice of non-prescription medicines.

OBJECTIVES: To identify factors influencing Australian consumer decision-making and attitudes towards non-prescription medicine (NPM) purchases, pharmacy's role in providing these medications and views around sources of evidence for effectiveness of these products. METHODS: Cross-sectional survey of a general population sample of 1731 adults using an Australian online consumer panel stratified by gender, age and location (State/Territory). Beliefs about NPM purchases and evidence of their efficacy were assessed using a 5-point Likert scale (strongly disagree-strongly agree). Non-parametric measures (Ridit analysis and Mann-Whitney U-test) were used to explore associations between responses and previous experience with medicines. KEY FINDINGS: The most important factors when purchasing NPMs were effectiveness and safety. However, personal experience was the most common method of determining effectiveness. Most respondents believed buying NPMs in pharmacies gave access to advice, but were less likely to agree that pharmacies were associated with safe and effective treatments. Around half the respondents agreed that it is wrong to sell treatments lacking scientific evidence; many also agreed that it is up to consumers to decide what they want even without scientific evidence. Individuals experiencing an ineffective NPM were less likely to trust scientific evidence of efficacy as the sole source of effectiveness information; regular prescription medicine users often agreed that scientific evidence is needed to support effectiveness. CONCLUSIONS: Consumers have conflicting views regarding the need for scientific evidence and the desire for patient autonomy in NPM purchases. This presents a challenge for pharmacists wishing to maintain professional obligations to provide evidence-based treatments to consumers.

Cross-programmatic consultation on the role of primary care in the responsible use of medicines and the reduction of antimicrobial resistance.

This meeting was held from the 30 October to the 1 November 2018 in Almaty, Kazakhstan. The meeting brought together participants from 16 countries of central Asia, Caucasus, eastern Europe and expert speakers from western Europe and India. Participants discussed the analysis and use of data on antimicrobial medicines consumption, country experiences in enforcing legislation for prescription-only access to antibiotics, the role of primary health care (PHC) in tackling antimicrobial resistance (AMR), strategies to improving competencies of practitioners using evidence-based clinical protocols and public engagement in the responsible use of medicines. Moving toward prescription-only access to antibiotics requires that government involve, from the onset, different stakeholders, e.g. public, patients, practitioners, pharmacists and pharmaceutical industry in designing and applying policies that ensure access to antibiotics accompanied by measures that promote responsible use and limit excessive use.

Day Care for People with Dementia: A Qualitative Study Comparing Experiences from Norway and Scotland.

Potential benefits from day care attendance are reported in the literature for both people with dementia and caregivers, although the evidence-base is limited. The study aimed to explore and compare experiences of day care services for people with dementia as described by day care attendees and their caregivers in Norway and Scotland. Whereas day care receives prominence in Norway's national dementia plan, Scotland does not highlight day care in its national dementia strategy. A qualitative cross-national comparative study was undertaken. Semi-structured interviews were conducted with 17 people with dementia and 17 caregivers in Norway, and 19 people with dementia and 15 caregivers in Scotland. Data were analyzed thematically and comparatively to explore the experiences and outcomes of the participants. Findings indicate positive outcomes from day care for both people with dementia and caregivers. Satisfaction with services related to meaningful activities, getting out of the home, strengthening social connections and careful staff facilitation to create a positive and welcoming atmosphere. There were strong similarities in the content of services and experiences reported in the two countries. Some minor differences were noted, with caregiver support being an area of notable divergence in experiences. Specialist day care for people with dementia seems to provide important support and positive outcomes for people with dementia, and respite and reassurance for their caregivers. More research is needed to further explore the effect of day care designed for people with dementia both on the attendees and their caregivers.

Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non-small cell lung cancer.

Immune checkpoint blockade has significantly improved clinical outcomes for patients with non-small cell lung cancer (NSCLC) and other solid tumours, but many patients do not respond and acquired resistance is common. Aspects of the tumour microenvironment linked to clinical outcomes include the proportion of tumour-infiltrating lymphocytes (TIL), tumour programmed death ligand 1 ( PD-L1) score and tumour mutation burden. Adoptive cell therapy (ACT), a technique that works by infusing ex vivo expanded T lymphocytes to increase the effector cell pool in tumours, is anticipated to become a viable therapeutic option for patients with solid tumours, akin to chimeric antigen receptor T cell (CAR-T) therapy in haematological malignancies. TIL therapy has shown durable clinical responses in heavily pre-treated patients with melanoma and other solid tumours. We review the experience of ACT with TILs and the recent evidence that clonal neoantigens might be the most relevant immunotherapeutic targets in heterogeneous solid tumours such as NSCLC. Clonal (or truncal) neoantigens arise from the earliest mutagenic events in tumour evolution, and are retained over time in all tumour cells within a patient, making them the ideal target for T cell therapy. NSCLC has one of the highest clonal mutation burdens of all cancers through exposure to carcinogens in tobacco smoke, providing a strong rationale to develop clonal neoantigen reactive T cells (cNeT) for this indication. The first treatment modality to test this concept clinically is ATL001, a cNeT product that is derived from autologous TILs and enriched for T cells specifically recognizing clonal neoantigenic epitopes by selective expansion. Clinical studies of ATL001 will commence in 2019.

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.

BACKGROUND: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours. METHODS: Tumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. RESULTS: Patients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients. CONCLUSIONS: Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm.

PTEN Deficiency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells.

We report that PTEN-deficient prostate cancer cells use macropinocytosis to survive and proliferate under nutrient stress. PTEN loss increased macropinocytosis only in the context of AMPK activation, revealing a general requirement for AMPK in macropinocytosis and a novel mechanism by which AMPK promotes survival under stress. In prostate cancer cells, albumin uptake did not require macropinocytosis, but necrotic cell debris proved a specific macropinocytic cargo. Isotopic labeling confirmed that macropinocytosed necrotic cell proteins fueled new protein synthesis in prostate cancer cells. Supplementation with necrotic debris, but not albumin, also maintained lipid stores, suggesting that macropinocytosis can supply nutrients other than amino acids. Nontransformed prostatic epithelial cells were not macropinocytic, but patient-derived prostate cancer organoids and xenografts and autochthonous prostate tumors all exhibited constitutive macropinocytosis, and blocking macropinocytosis limited prostate tumor growth. Macropinocytosis of extracellular material by prostate cancer cells is a previously unappreciated tumor-microenvironment interaction that could be targeted therapeutically.Significance: As PTEN-deficient prostate cancer cells proliferate in low-nutrient environments by scavenging necrotic debris and extracellular protein via macropinocytosis, blocking macropinocytosis by inhibiting AMPK, RAC1, or PI3K may have therapeutic value, particularly in necrotic tumors and in combination with therapies that cause nutrient stress. Cancer Discov; 8(7); 866-83. ©2018 AACR.See related commentary by Commisso and Debnath, p. 800This article is highlighted in the In This Issue feature, p. 781.

Antimicrobial Medicines Consumption in Eastern Europeand Central Asia - An Updated Cross-National Study and Assessment of QuantitativeMetrics for Policy Action.

Introduction: Surveillance of antimicrobial medicines consumption is central to improving their use and reducing resistance rates. There are few published data on antibiotic consumption in Eastern Europe and Central Asia. To address this, 18 non-European Union (EU) countries and territories contribute to the WHO Regional Office for Europe (WHO Europe) Antimicrobial Medicines Consumption (AMC) Network. Objectives: (i) Analyze 2015 consumption of J01 class antibacterials for systemic use from 16 AMC Network members; (ii) compare results with 2011 data and 2015 ESAC-Net estimates; (iii) assess consumption against suggested indicators; (iv) evaluate the impact of planned changes to defined daily doses (DDDs) in 2019 for some commonly used antibiotics; and (v) consider the utility of quantitative metrics of consumption for policy action. Methods: Analysis methods are similar to ESAC-Net for EU countries. The Anatomical Therapeutic Chemical (ATC) classification and DDD methodology were used to calculate total consumption (DDD/1000 inhabitants/day [DID]), relative use measures (percentages), extent of use of WHO Watch and Reserve group antibiotics and impact of DDD changes. Findings: Total J01 consumption in 2015 ranged 8.0-41.5 DID (mean 21.2 DID), generally lower than in 2011 (6.4-42.3 DID, mean 23.6 DID). Beta-lactam penicillins, cephalosporins, and quinolones represented 16.2-56.6, 9.4-28.8, and 7.5-24.6% of total J01 consumption, respectively. Third-generation cephalosporins comprised up to 90% of total cephalosporin consumption in some countries. Consumption of WHO Reserve antibiotics was very low; Watch antibiotics comprised 17.3-49.5% of total consumption (mean 30.9%). Variability was similar to 2015 ESAC-Net data (11.7-38.3 DID; mean 22.6 DID). DDD changes in 2019 impact both total and relative consumption estimates: total DIDs reduced on average by 12.0% (7.3-35.5 DID), mostly due to reduced total DDDs for commonly used penicillins; impact on rankings and relative use estimates were modest. Discussion: Quantitative metrics of antibiotic consumption have value. Improvements over time reflect national activities, however, changes in total volumes may conceal shifts to less desirable choices. Relative use measures targeting antibiotics of concern may be more informative. Some, including WHO Watch and Reserve classifications, lend themselves to prescribing targets supported by guidelines and treatment protocols.

Scaffolding and working together: a qualitative exploration of strategies for everyday life with dementia.

Background: living with dementia has been described as a process of continual change and adjustment, with people with dementia and their families adopting informal strategies to help manage everyday life. As dementia progresses, families increasingly rely on help from the wider community and formal support. Methods: this article reports on a secondary analysis of qualitative data from focus groups and individual interviews with people with dementia and their carers in the North of England. In total, 65 people with dementia and 82 carers took part in the research: 26 in interviews and 121 in focus groups. Focus group and interview audio recordings were transcribed verbatim. A qualitative, inductive, thematic approach was taken for data analysis. Findings: the article applies the metaphor of scaffolding to deepen understanding of the strategies used by families. Processes of scaffolding were evident across the data where families, communities, professionals and services worked together to support everyday life for people with dementia. Within this broad theme of scaffolding were three sub-themes characterising the experiences of families living with dementia: doing things together; evolving strategies; and fragility and fear of the future. Conclusions: families with dementia are resourceful but do need increasing support (scaffolding) to continue to live as well as possible as dementia progresses. More integrated, proactive work is required from services that recognises existing scaffolds and provides appropriate support before informal strategies become unsustainable; thus enabling people with dementia to live well for longer.

Medication reconciliation at two teaching hospitals in Australia: a missed opportunity?

Medication reconciliation prevents medication related harm at patient hospitalisation. This cross-sectional study demonstrated that the Hunter New England Health Admission Medication History Form that supports the two processes is underutilised in two hospitals in New South Wales with many doctors unaware of the form and pharmacists facing understaffing and time constraints for completing it. Triaging of patients and, more collaboration between doctors and pharmacists are required for efficient in-hospital medication reconciliation.