Observed fingerprint of a weakening Atlantic Ocean overturning circulation.

The Atlantic meridional overturning circulation (AMOC)-a system of ocean currents in the North Atlantic-has a major impact on climate, yet its evolution during the industrial era is poorly known owing to a lack of direct current measurements. Here we provide evidence for a weakening of the AMOC by about 3 ± 1 sverdrups (around 15 per cent) since the mid-twentieth century. This weakening is revealed by a characteristic spatial and seasonal sea-surface temperature 'fingerprint'-consisting of a pattern of cooling in the subpolar Atlantic Ocean and warming in the Gulf Stream region-and is calibrated through an ensemble of model simulations from the CMIP5 project. We find this fingerprint both in a high-resolution climate model in response to increasing atmospheric carbon dioxide concentrations, and in the temperature trends observed since the late nineteenth century. The pattern can be explained by a slowdown in the AMOC and reduced northward heat transport, as well as an associated northward shift of the Gulf Stream. Comparisons with recent direct measurements from the RAPID project and several other studies provide a consistent depiction of record-low AMOC values in recent years.

Scottish Firefighters Occupational Cancer and Disease Mortality Rates: 2000-2020.

BACKGROUND: Increased mortality from cancers and other diseases has been reported in USA, Canadian, and Nordic firefighters. However, UK firefighters are understudied. AIMS: To determine whether UK firefighters suffer increased mortality from cancers and other diseases when compared with the general population. METHODS: Mortality from cancer and other diseases in Scottish male firefighters between 2000 and 2020 was compared with the general Scottish male population and expressed as standardized mortality ratios (SMRs) (with 95% confidence intervals, CI). RESULTS: Significant overall excess cancer mortality was found for Scottish firefighters compared with the general population (SMR 1.61, CI 1.42-1.81). Scottish firefighters were nearly three times more likely to die of malignant neoplasms (unspecified sites) (SMR 2.71, CI 1.71-4.00). Excess cancer mortality was also found for several site-specific cancers, including prostate (SMR 3.80, CI 2.56-5.29), myeloid leukaemia (SMR 3.17, CI 1.44-5.58), oesophagus (SMR 2.42, CI 1.69-3.29) and urinary system (kidney and bladder) (SMR 1.94, CI 1.16-2.91). Mortality from neoplasms of unknown behaviour was over six times greater in Scottish firefighters (SMR 6.37, CI 2.29-12.49). Additionally, significantly higher mortality was found for: acute ischaemic heart diseases (SMR 5.27, CI 1.90-10.33), stroke (SMR 2.69, CI 1.46-4.28), interstitial pulmonary diseases (SMR 3.04, CI 1.45-5.22), renal failure (SMR 3.28, CI 1.18-6.44) and musculoskeletal system diseases (SMR 5.64, CI 1.06-13.83). CONCLUSIONS: UK firefighters suffer significant excess mortality from cancer and other diseases when compared with the general population. Preventative health monitoring and presumptive legislation are urgently required to protect UK firefighters' health.

OPTN/SRTR 2020 Annual Data Report: Kidney.

The year 2020 presented significant challenges to the field of kidney transplantation. After increasing each year since 2015 and reaching the highest annual count to date in 2019, the total number of kidney trans- plants decreased slightly, to 23642, in 2020. The decrease in total kidney transplants was due to a decrease in living donor transplants; the number of deceased donor transplants rose in 2020. The number of patients waiting for a kidney transplant in the United States declined slightly in 2020, driven by a slight drop in the number of new candidates added in 2020 and an increase in patients removed from the waiting list owing to death-important patterns that correlated with the COVID-19 pandemic. The complexities of the pandemic were accompanied by other ongoing challenges. Nationwide, only about a quarter of waitlisted patients receive a deceased donor kidney transplant within 5 years, a proportion that varies dramatically by donation service area, from 14.8% to 73.0%. The nonutilization (discard) rate of recovered organs rose to its highest value, at 21.3%, despite a dramatic decline in the discard of organs from hepatitis C-positive donors. Nonutilization rates remain particularly high for Kidney Donor Profile Index ≥85% kidneys and kidneys from which a biopsy specimen was obtained. Due to pandemic-related disruption of living donation in spring 2020, the number of living donor transplants in 2020 declined below annual counts over the last decade. In this context, only a small proportion of the waiting list receives living donor transplants each year, and racial disparities in living donor transplant access persist. As both graft and patient survival continue to improve incrementally, the total number of living kidney transplant recipients with a functioning graft exceeded 250,000 in 2020. Pediatric transplant numbers seem to have been impacted by the COVID-19 pandemic. The total number of pediatric kidney transplants performed decreased to 715 in 2020, from a peak of 872 in 2009. Despite numerous efforts, living donor kidney transplant remains low among pediatric recipients, with continued racial disparities among recipients. Of concern, the rate of deceased donor transplant among pediatric waitlisted candidates continued to decrease, reaching its lowest point in 2020. While this may be partly explained by the COVID-19 pandemic, close attention to this trend is critically important. Congenital anomalies of the kidney and urinary tract remain the leading cause of kidney disease in the pediatric population. While most pediatric de- ceased donor recipients receive a kidney from a donor with KDPI less than 35%, most pediatric deceased donor recipients had four or more HLA mis- matches. Graft survival continues to improve, with superior survival for living donor recipients versus deceased donor recipients.

OPTN/SRTR 2019 Annual Data Report: Kidney.

Despite the ongoing severe shortage of available kidney grafts relative to candidates in need, data from 2019 reveal some promising trends. After remaining relatively stagnant for many years, the number of kidney transplants has increased each year since 2015, reaching the highest annual count to date of 24,273 in 2019. The number of patients waiting for a kidney transplant in the United States was relatively stable, despite an increase in the number of new candidates added in 2019 and a decrease in patients removed from the waiting list owing to death or deteriorating medical condition. However, these encouraging trends are tempered by ongoing challenges. Nationwide, only a quarter of waitlisted patients receive a deceased-donor kidney transplant within 5 years, and this proportion varies dramatically by donation service area, from 15.5% to 67.8%. The non-utilization (discard) rate of recovered organs remains at 20.1%, despite adramatic decline in the discard of organs from hepatitis C-positive donors. Non-utilization rates remain particularly high for Kidney Donor Profile Index ≥85% kidneys and kidneys from which a biopsy specimen was obtained. While the number of living-donor transplants increased again in 2019, only a small proportion of the waiting list receives living-donor transplants each year, and racial disparities in living-donor transplant access persist. As both graft and patient survival continue to improve incrementally, the total number of living kidney transplant recipients with a functioning graft is anticipated to exceed 250,000 in the next 1-2 years. Over the past decade, the total number of pediatric kidney transplants performed has remained stable. Despite numerous efforts, living donor kidney transplant remains low among pediatric recipients with continued racial disparities among recipients. Congenital anomalies of the kidney and urinary tract remain the leading cause of kidney disease. While most deceased donor recipients receive a kidney from a donor with KDPI less than 35%, the majority of pediatric recipients had four or more HLA mismatches. Graft survival continues to improve with superior outcomes for living donor recipients.

'I just take them because I know the people that give them to me': A theory-informed interview study of community-dwelling people with dementia and carers' perspectives of medicines management.

OBJECTIVE: Identify facilitators and barriers to successful medicines management for people with dementia (PwD) in primary care from the perspectives of community-dwelling PwD and carers. METHODS: Semi-structured interviews conducted with PwD and carers in Northern Ireland. The 14-domain Theoretical Domains Framework guided data collection and analysis. Interviews explored participants' experiences and perceptions of medicines management. PwD also completed the Beliefs about Medicines Questionnaire indicating their level of agreement with statements about medicines. Qualitative data were analysed using the framework method and content analysis. Quantitative data were analysed descriptively. RESULTS: Eighteen PwD and 15 carers were interviewed. PwD believed they were competent with medicines management ('beliefs about capabilities'). Most PwD reported having strategies to prompt them to take their medicines ('memory, attention and decision processes'). Carers played an important role in supporting PwD with medicines management ('social influences') and monitoring adherence ('behavioural regulation') and anticipated having to take on a greater role as patients' cognitive impairment worsened ('beliefs about consequences'). Participants highlighted assistance provided by community pharmacies with medicines acquisition and delivery ('environmental context and resources') and placed great trust in primary healthcare professionals ('social influences'). PwD had positive attitudes towards medication and believed strongly in the necessity of their medicines. CONCLUSIONS: This is the first study to use a theoretical approach to explore medicines management for community-dwelling PwD. The findings provide new insights into the critical role of carers in facilitating optimal medicines management and will inform future intervention development, in which carers' needs assessment and involvement will be key.

A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer.

BACKGROUND: The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. PATIENTS AND METHODS: In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. RESULTS: Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was -1.52% [95% confidence interval (CI): -3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: -1.05 to 1.27) while for treatment-related hospitalisations it was -1.68% (95% CI: -2.73% to -0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: -3.17%, 95% CI: -9.51% to 3.18%). CONCLUSION: Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. CLINICALTRIALS. GOV REGISTRATION: NCT02428114 and NCT02816164.

Improving medicines management for people with dementia in primary care: a qualitative study of healthcare professionals to develop a theory-informed intervention.

BACKGROUND: People with dementia (PwD) face unique challenges with medicines management, yet little is known about these challenges from the perspectives of primary healthcare professionals, particularly general practitioners (GPs) and community pharmacists. Few medicines management interventions have been developed which are aimed at community-dwelling PwD. This study sought to develop an intervention to improve medicines management for PwD in primary care using a theory-informed approach. METHODS: Semi-structured interviews were conducted with GPs (n = 15) and community pharmacists (n = 15) to explore participants' views and experiences of medicines management for PwD, and their perceptions of barriers and facilitators to successful medicines management for PwD. The 14-domain Theoretical Domains Framework was the underpinning theoretical guide, allowing key theoretical domains to be identified and mapped to behaviour change techniques (BCTs) which are considered the 'active ingredients' of an intervention. Draft interventions were developed to operationalise selected BCTs and were presented to GPs and community pharmacists during task groups. Final selection of an intervention for feasibility testing was guided by feedback provided during these task groups and through application of the APEASE (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety, Equity) criteria. RESULTS: Participants expressed a number of concerns about medicines management for PwD, particularly monitoring adherence to medication regimens and conducting medication review. Two draft interventions comprising selected BCTs ('Modelling or demonstration of behaviour'; 'Salience of consequences'; 'Health consequences'; 'Social and environmental consequences'; 'Action planning'; Social support or encouragement', 'Self-monitoring of behaviour') were developed, each targeting GPs and community pharmacists. Following the task groups and discussions within the research team, the community pharmacy-based intervention was selected for future feasibility testing. The intervention will target community pharmacists to conduct a medication review (incorporating an adherence check) with a PwD, delivered as an online video demonstrating key behaviours. The video will include feedback emphasising positive outcomes of performing the behaviours. Action planning and a quick reference guide will be used as complementary intervention components. CONCLUSIONS: A community pharmacist-based intervention has been developed targeting medicines management for PwD in primary care using a systematic, theory-informed approach. Future work will determine the usability and acceptability of implementing this intervention in clinical practice.

OPTN/SRTR 2017 Annual Data Report: Lung.

Each year since 2012, the number of lung transplants has increased, reflecting an increase in the number of donors, improved use of recovered organs, and more candidates being listed for transplant. However, the need for organs continues to outpace available donors. Despite an increase of 126 donors in 2017, 1360 candidates remained on the waiting list at the end of the year, and 326 patients died or became too sick to undergo transplant. Approximately 14,000 individuals were living with a lung transplant in 2017; 9492 were aged 50 years or older, 4075 were aged 18-49 years, and 408 were aged younger than 18 years.

OPTN/SRTR 2017 Annual Data Report: Kidney.

Many positive trends in kidney transplantation were notable in 2017. Deceased donor kidney transplant rates and counts continued to rise, the kidney transplant waiting list declined for the third year in a row after decades of growth, and both short- and long-term allograft survival continued to improve year over year. In total, more than 220,000 patients were living in the United States with a functioning allograft. With 3 years of data available since implementation of the new kidney allocation system, better prediction of longer-term results of the allocation policy changes became possible. The data also reveal several areas in need of improvement and attention. Overall, the challenge of providing adequate access to kidney transplant persisted nationally, with additional dramatic regional variation. The proportion of living donor kidney transplants in both adults and children continued to fall, and racial disparities in living donor kidney transplant grew in the past decade.

OPTN/SRTR 2017 Annual Data Report: Heart.

In 2017, 3273 heart transplants were performed in the United States. New listings continued to increase, and 3769 new adults were listed for heart transplant in 2017. Over the past decade, posttransplant mortality has declined. The number of new pediatric listings increased over the past decade, as did the number of pediatric heart transplants, although some fluctuation has occurred more recently. New listings for pediatric heart transplants increased from 481 in 2007 to 623 in 2017. The number of pediatric heart transplants performed each year increased from 330 in 2007 to 432 in 2017, slightly fewer than in 2016. Short-term and long-term mortality improved. Among pediatric patients who underwent transplant between 2015-2016, 4.8% had died by 6 months and 6.2% by 1 year.

OPTN/SRTR 2017 Annual Data Report: Liver.

Data on adult liver transplants performed in the US in 2017 are notable for (1) continued growth in numbers of new waitlist registrants (11,514) and of transplants performed (8,082); (2) continued increase in the transplant rate (51.5 per 100 waitlist-years); (3) a precipitous decrease in waitlist registrations and transplants for hepatitis C-related indications; (4) reciprocal increases in waitlist registrants and recipients with alcoholic liver disease and with clinical profiles consistent with non-alcoholic fatty liver disease; and (5) continued improvement in graft survival despite changing recipient characteristics such as older age and higher rates of obesity. Variability in transplant rates remained by candidate race, presence of hepatocellular carcinoma, urgency status (status 1A versus model for end-stage liver disease (MELD) score >35), and geography. More than half of all children listed for liver transplant in 2017 were aged younger than 5 years in 2017, and the highest rate of pretransplant mortality persisted for children aged younger than 1 year. Children underwent transplant at higher acuity than the past, as evidenced by higher MELD/pediatric end-stage liver disease scores and listings at status 1A and 1B. Higher acuity at transplant is likely due to lack of access to suitable donor organs, which has been compensated for by persistent trends toward use of partial or split liver grafts and ABO-incompatible grafts. Despite higher illness severity scores at transplant, pediatric graft and patient survival posttransplant have improved over time.

Correction: Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.

The role of lysosomes and autophagosomes in frontotemporal lobar degeneration.

INTRODUCTION: Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD). METHODS: We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal-associated membrane proteins 1 (LAMP-1) and 2 (LAMP-2), cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx). RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in the DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD-TDP and FTLD-tau. CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.

Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens.

Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2) (cohort 1) or pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC. Patients enrolled on cohort 2 had non-squamous histology. Dose escalation of selumetinib proceeded using a 3 + 3 design: 50 mg b.i.d. days 2-19 (dose level 1); 75 mg b.i.d. days 2-19 (dose level 2); and 75 mg b.i.d. continuously. Adverse events were evaluated using CTC AE v4 and response by RECIST 1.1. Results Thirty-nine patients were enrolled (cohort 1 n = 16; cohort 2, n = 23). There were no dose limiting toxicities in either cohort and the recommended phase II dose for both regimens was standard doses of carboplatin, paclitaxel or pemetrexed and cisplatin with continuous selumetinib at a dose of 75 mg b.i.d. Most adverse events were grade 1 or 2 and were predominantly diarrhea, nausea, stomatitis, peripheral edema, neutropenia, and skin rash. Response rate was 37.5% for cohort 1 and 30.4% for cohort 2. Conclusion Selumetinib at a dose of 75 mg b.i.d continuously can be safely combined with paclitaxel and carboplatin or pemetrexed and cisplatin in patients with advanced or metastatic NSCLC. This trial provided the dose for the regimens used in a randomized phase II trial in NSCLC (CCTG IND.219).

Dynamics of the Electromagnetic Fields Induced by Fast Electron Propagation in Near-Solid-Density Media.

The propagation of fast electron currents in near solid-density media was investigated via proton probing. Fast currents were generated inside dielectric foams via irradiation with a short (∼0.6 ps) laser pulse focused at relativistic intensities (Iλ^{2}∼4×10^{19} W cm^{-2} µm^{2}). Proton probing provided a spatially and temporally resolved characterization of the evolution of the electromagnetic fields and of the associated net currents directly inside the target. The progressive growth of beam filamentation was temporally resolved and information on the divergence of the fast electron beam was obtained. Hybrid simulations of electron propagation in dense media indicate that resistive effects provide a major contribution to field generation and explain well the topology, magnitude, and temporal growth of the fields observed in the experiment. Estimations of the growth rates for different types of instabilities pinpoints the resistive instability as the most likely dominant mechanism of beam filamentation.

Cerebral-placental-uterine ratio as novel predictor of late fetal growth restriction: prospective cohort study.

OBJECTIVE: Fetal growth restriction (FGR) is a major risk factor for stillbirth and most commonly arises from uteroplacental insufficiency. Despite clinical examination and third-trimester fetal biometry, cases of FGR often remain undetected antenatally. Placental insufficiency is known to be associated with altered blood flow resistance in maternal, placental and fetal vessels. The aim of this study was to evaluate the performance of individual and combined Doppler blood flow resistance measurements in the prediction of term small-for-gestational age and FGR. METHODS: This was a prospective study of 347 nulliparous women with a singleton pregnancy at 36 weeks' gestation in which fetal growth and Doppler measurements were obtained. Pulsatility indices (PI) of the uterine arteries (UtA), umbilical artery (UA) and fetal vessels were analyzed, individually and in combination, for prediction of birth weight < 10th , < 5th and < 3rd centiles. Doppler values were converted into centiles or multiples of the median (MoM) for gestational age. The sensitivities, positive and negative predictive values and odds ratios (OR) of the Doppler parameters for these birth weights at ∼ 90% specificity were assessed. Additionally, the correlations between Doppler measurements and other measures of placental insufficiency, namely fetal growth velocity and neonatal body fat measures, were analyzed. RESULTS: The Doppler combination most strongly associated with placental insufficiency was a newly generated parameter, which we have named the cerebral-placental-uterine ratio (CPUR). CPUR is the cerebroplacental ratio (CPR) (middle cerebral artery PI/UA-PI) divided by mean UtA-PI. CPUR MoM detected FGR better than did mean UtA-PI MoM or CPR MoM alone. At ∼ 90% specificity, low CPUR MoM had sensitivities of 50% for birth weight < 10th centile, 68% for < 5th centile and 89% for < 3rd centile. The respective sensitivities of low CPR MoM were 26%, 37% and 44% and those of high UtA-PI MoM were 34%, 47% and 67%. Low CPUR MoM was associated with birth weight < 10th centile with an OR of 9.1, < 5th centile with an OR of 17.3 and < 3rd centile with an OR of 57.0 (P < 0.0001 for all). CPUR MoM was also correlated most strongly with fetal growth velocity and neonatal body fat measures, as compared with CPR MoM or UtA-PI MoM alone. CONCLUSIONS: In this cohort, a novel Doppler variable combination, the CPUR (CPR/UtA-PI), had the strongest association with indicators of placental insufficiency. CPUR detected more cases of FGR than did any other Doppler parameter measured. If these results are replicated independently, this new parameter may lead to better identification of fetuses at increased risk of stillbirth that may benefit from obstetric intervention. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

The development of a Core Outcome Set for medicines management interventions for people with dementia in primary care.

BACKGROUND: people with dementia (PWD), and their carers, face challenges with medicines management activities. As interventions to support medicines management for PWD are developed, consideration must be given to the outcomes chosen to measure their effectiveness. A Core Outcome Set (COS) is a minimum set of outcomes to be measured in all trials in a particular clinical area, which seeks to reduce heterogeneity of outcome reporting across trials. OBJECTIVE: to develop a COS for trials assessing the effectiveness of medicines management interventions for PWD in primary care. METHODS: a comprehensive list of outcomes was compiled through a systematic review and semi-structured interviews with PWD (n = 18), their carers (n = 15), community pharmacists (n = 15) and general practitioners (n = 15). These outcomes were rated by a Delphi panel (n = 52) on a nine-point Likert scale from 1 (limited importance) to 9 (critical) during three sequential rounds of questionnaire distribution. The Delphi panel comprised participants with expertise in dementia and medicines management, including academics and healthcare professionals. An outcome was eligible for inclusion in the COS if ≥70% of participants rated it critical and <15% of participants rated it of limited importance. RESULTS: twenty-nine outcomes identified from the systematic review and stakeholder interviews were presented to the Delphi panel. Consensus was reached on 21 outcomes, of which the 7 most highly rated were recommended for inclusion in the COS. CONCLUSION: this study used robust methodology to develop a COS for medicines management interventions for PWD. Future work should identify the most appropriate tools to measure these outcomes.

Vitrification of in vitro-derived bovine embryos: targeting enhancement of quality by refining technology and standardising procedures.

Bovine invitro fertilisation technology has been widely exploited in commercial settings. The majority of invitro-derived cattle embryos are transferred into recipient cows as recently collected (i.e. 'fresh') embryos due to the lack of a reliable cryopreservation method that results in favourable pregnancy rates following transfer of thawed embryos. This is a primary reason for the poor industry uptake of this extreme temperature freezing process. Numerous investigations into vitrification have revealed the importance of rapid cooling and warming rates, enhancing embryo viability after cryopreservation compared with conventional slow freezing. Those studies spawned a considerable assortment of cryovessels and diversity of procedures, delivering variable rates of success, which makes performing vitrification consistently a practical challenge. Hence, further research is required in order to both optimise and standardise vitrification methodology and to design a cryovessel that enables direct transfer of vitrified embryos to recipients after warming. In parallel with improvements in vitrification, it is important to continue to raise the quality of invitro-derived cattle embryos through modifications in laboratory culture techniques. The twin goals of methodology refinement and standardisation, leading to embryo quality enhancement, are each imperative if invitro fertilisation technology is to be adopted in the field.

Measuring and monitoring equity in access to deceased donor kidney transplantation.

The Organ Procurement and Transplantation Network monitors progress toward strategic goals such as increasing the number of transplants and improving waitlisted patient, living donor, and transplant recipient outcomes. However, a methodology for assessing system performance in providing equity in access to transplants was lacking. We present a novel approach for quantifying the degree of disparity in access to deceased donor kidney transplants among waitlisted patients and determine which factors are most associated with disparities. A Poisson rate regression model was built for each of 29 quarterly, period-prevalent cohorts (January 1, 2010-March 31, 2017; 5 years pre-kidney allocation system [KAS], 2 years post-KAS) of active kidney waiting list registrations. Inequity was quantified as the outlier-robust standard deviation (SDw ) of predicted transplant rates (log scale) among registrations, after "discounting" for intentional, policy-induced disparities (eg, pediatric priority) by holding such factors constant. The overall SDw declined by 40% after KAS implementation, suggesting substantially increased equity. Risk-adjusted, factor-specific disparities were measured with the SDw after holding all other factors constant. Disparities associated with calculated panel-reactive antibodies decreased sharply. Donor service area was the factor most associated with access disparities post-KAS. This methodology will help the transplant community evaluate tradeoffs between equity and utility-centric goals when considering new policies and help monitor equity in access as policies change.

OPTN/SRTR 2016 Annual Data Report: Lung.

In 2016, 2692 candidates aged 12 years or older were added to the lung transplant waiting list; 2345 transplants were performed, the largest number of any prior year. The median waiting time for listed candidates in 2016 was 2.5 months, and waiting times were shortest for group D candidates. The transplant rate increased to 191.9 transplants per 100 waitlist years in 2016, with a slight decrease in waitlist mortality to 15.1 deaths per 100 waitlist years. Short-term survival continued to improve, with a 6-month death rate of 6.6% and a 1-year death rate of 10.8% among recipients in 2015 compared with 8.0% and 13.3%, respectively, among recipients in 2014. Long-term survival rates remained unchanged; 55.6% of recipients were alive at 5 years. In 2016, 23 new candidates aged 0-11 years were added to the waiting list and 16 lung transplants were performed. Incidence of posttransplant mortality for lung transplant recipients aged 0-11 years who underwent transplant in 2014-2015 was 13.8% at 6 months and 19.6% at 1 year. Changes in waitlist and transplant demographic features continued to evolve following implementation of the revised lung allocation score in 2015. Some early trends that may be attributable to the revised LAS are shorter waiting times, stabilization of the number of group D candidates listed for transplant, and convergence of LAS with lower prevalence of extremely high scores.