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Heartburn drugs could raise risk of death
 Strengths and limitations of this study National large-scale data from a network of integrated health systems.

Employed a new user design and developed a number of analytical approaches where we consistently found a significant association between PPI exposure and risk of death.

Cohort included mostly older white male US veterans, which may limit the generalisability.

Did not include information on the cause of death.

Introduction Proton pump inhibitors (PPI) are widely prescribed and are also available for sale over the counter without prescription in several countries.1 2 Several observational studies suggest that PPI use is associated with increased risk of a number of adverse health outcomes.1 A number of studies have shown that PPI use is associated with significant risk of acute interstitial nephritis.3–5 Recent studies established an association between exposure to PPI and risk of chronic kidney disease (CKD), kidney disease progression and end-stage renal disease.2 6 7 Results from a large prospective observational German cohort suggest that patients receiving PPI had a higher risk of incident dementia.8 Several reports highlighted a rare but potentially fatal risk of hypomagnesemia among users of PPI.9–11 PPI use has been associated with increased risk of both incident and recurrent Clostridium difficile infections.12 Several observational analyses have shown that PPI use was also associated with increased risk of osteoporotic fractures, including hip and spine fractures.13 14 Less convincing—and to some extent inconsistent—evidence suggests a relationship between PPI use and risks of community-acquired pneumonia and cardiovascular events.15–17 Emerging—and far from conclusive—in vitro evidence suggests that PPI results in inhibition of lysosomal acidification and impairment of proteostasis, leading to increased oxidative stress, endothelial dysfunction, telomere shortening and accelerated senescence in human endothelial cells.18 The experimental work provides a putative mechanistic link to explain some of the adverse events associated with PPI use.18 The adverse outcomes associated with PPI use are serious, and each is independently associated with higher risk of mortality. Evidence from several small cohort studies of older adults who were recently discharged from the hospital or institutionalised in long-term care facilities suggests inconsistently that PPI use may be associated with increased risk of 1 year mortality.19–22 Whether PPI use is associated with excess risk of death is not known and has not been examined in large epidemiological studies spanning a sufficiently long duration of follow-up. We hypothesised that owing to the consistently observed associations between PPI use and risk of adverse health outcomes, PPI use is associated with excess risk of death, and that the risk of death would be more pronounced with increased duration of use. We therefore used the Department of Veterans Affairs national databases to build a longitudinal cohort of incident users of acid suppression therapy, including PPI and histamine H2 receptor antagonists (H2 blockers), to examine the association between PPI use and risk of all-cause mortality and to determine whether risk of death is increased with prolonged duration of use.

Methods Cohort participants Primary cohort Using administrative data from the US Department of Veterans Affairs, we identified patients who received an outpatient H2 blockers or PPI prescription between 1 October 2006 and 30 September 2008 (n=1 762 908). In order to select new users of acid suppression therapy (incident user design), we excluded 1 356 948 patients who received any outpatient H2 blockers or PPI prescriptions between 1 October 1998 and 30 September 2006. To account for patients’ kidney function, only patients with at least one outpatient serum creatinine value before the first acid suppression therapy prescription were selected in the cohort, yielding an analytic cohort of 349 312 patients. Patients whose first acid suppression therapy was PPI (n=275 977) were considered to be in the PPI group during follow-up. Patients who received H2 blockers as their first acid suppression therapy (n=73 335) served as the reference group before they received any PPI prescription (see online supplementary figure 1). Within the reference group, those who received a PPI prescription later (n=33 136) were considered to be in the PPI group from the date of their first PPI prescription until the end of follow-up.23 Time zero (T0) for primary cohort was defined as the first acid suppression therapy prescription date. Supplementary Material Supplementary data 1 [SP1.pptx] Secondary cohorts We additionally built two secondary cohorts to examine the association of PPI use and risk of death in (a) PPI versus no PPI users and (b) PPI versus non-users of acid suppression therapy. Patients with no PPI prescription between 1 October 1998 and 30 September 2006, and with at least one outpatient eGFR value before 1 October 2006, were selected to evaluate the risk of death associated with PPI use versus no PPI use (n=3 288 092) (see online supplementary figure 2a). Patients with no PPI prescription between 1 October 1998 and 30 September 2006, with no H2 blockers before the first PPI prescription and at least one outpatient eGFR value before 1 October 2006, were selected to evaluate the risk of death associated with PPI use versus no acid suppression therapy (n=2 887 030) (see online supplementary figure 2b). T0 for secondary cohorts was defined as 1 October 2006. Patients in both primary and secondary cohorts were followed until 30 September 2013 or death. The study was approved by the Institutional Review Board of the VA Saint Louis Health Care System, Saint Louis, Missouri.

Data sources We used the Department of Veterans Affairs databases, including inpatient and outpatient medical SAS data sets (that include utilisation of data related to all inpatient and outpatient encounters within the VA system), to ascertain detailed patient demographic characteristics and comorbidity information based on inpatient and outpatient encounters.2 24 The VA Managerial Cost Accounting System Laboratory Results (a comprehensive database that includes VA-wide results for selected laboratory tests obtained in the clinical setting) provided information on outpatient and inpatient laboratory results. The VA Corporate Data Warehouse Production Outpatient Pharmacy domain provided information on outpatient prescriptions. The VA Vital Status and Beneficiary Identification Records Locator Subsystem files provided demographic characteristics and death. Primary predictor variable PPI use was the primary predictor. Once cohort participants received PPI prescription, they were considered with the effect of PPI until the end of follow-up. Medications that contain esomeprazole, lansoprazole, omeprazole, pantoprazole or rabeprazole were counted as PPI. Medications including ranitidine, cimetidine and famotidine were counted as H2 blockers. Outcome The primary outcome in survival analyses was time to death. Death information is routinely collected by the Veterans Benefit Administration for all United States Veterans. Covariates Covariates included age, race, gender, eGFR, number of outpatient serum creatinine measurements, number of hospitalisations, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, cancer, hepatitis C, HIV, dementia and diseases associated with acid suppression therapy use such as gastro-oesophageal reflux disease (GERD), upper gastrointestinal (GI) tract bleeding, ulcer disease, Helicobacter pylori infection, Barrett's oesophagus, achalasia, stricture and oesophageal adenocarcinoma.25–28 eGFR was calculated using the abbreviated four-variable CKD epidemiology collaboration equation based on age, sex, race and outpatient serum creatinine.29 Race/ethnicity was categorised as white, black or other (Latino, Asian, Native American or other racial/ethnic minority groups). Comorbidities except for hepatitis C and HIV were assigned on the basis of relevant ICD-9-CM (the International Classification of Diseases, Ninth Revision, Clinical Modification) diagnostic and procedure codes and Current Procedural Terminology (CPT) codes in the VA Medical SAS data sets.2 30–33 Hepatitis C and HIV were assigned based on laboratory results. Baseline covariates were ascertained from 1 October 1998 till T0. All covariates except for age, race and gender covariates values were treated as time-varying covariates where they were additionally assessed until the date of the first PPI prescription in those patients who did not have PPI prescription at T0. Any comorbidity occurring during the assessment period was considered present during the remaining follow-up. eGFR was the outpatient eGFR value within and most proximate to the end of the assessment period. Number of outpatient serum creatinine measurements and number of hospitalisations were accumulated during the assessment period. Statistical analysis Means, SD and t-tests are presented for normally distributed continuous variables; medians, interquartile ranges and Wilcoxon-Mann-Whitney tests are presented for non-normally distributed continuous variables; and counts, percentages and χ2 tests are presented for categorical variables. Incident rates per 100 person-years were computed for death, and CIs were estimated based on the normal distribution. The Simon and Makuch method for survival curves was used for time-dependent covariates.34 Cox regression models with time-dependent covariates were used in the assessment of the association between PPI exposure and risk of death where patients could switch from H2 blockers to PPI in the models. In order to account for potential delayed effect of PPI, patients were considered to have the effect of PPI from the first PPI prescription till the end of follow-up. In addition, time-dependent Cox models were conducted in subgroups where patients had no GI conditions and where patients had no GI conditions except for GERD and in the secondary cohorts. Because exposure in this observational cohort is time dependent, we undertook 1:1 propensity score matching for the primary cohort where time-dependent propensity scores were calculated based on time-dependent Cox regression with all covariates35 (details are provided in online supplementary methods). After matching, all covariates except for age had an absolute standardised difference of less than 0.1, which indicated that all covariates except age were well balanced. Age had a standardised difference equal to 0.13. Doubly robust estimation was applied after matching, where all covariates were additionally controlled for in the model to obtain an unbiased effect estimator.36 Supplementary Material Supplementary data 3 [SP3.pdf] In order to optimise control of confounding, we additionally built high-dimensional propensity score-adjusted survival models following the multistep algorithm described by Schneeweiss et al 37 (details are provided in online supplementary methods). We also applied a two-stage residual inclusion estimation based on instrumental variable approach (see online supplementary methods)38 In addition, we evaluated the association between duration of PPI prescription and risk of death among new users of PPI. Duration was defined in cumulative days of use and categorised as ≤30, 31–90, 91–180, 181–360 and 361–720, where ≤30 days was considered as the reference group. To avoid immortal time bias (by definition, cohort participants must be alive to receive prescription hence introducing a bias commonly referred to as immortal time bias), time of cohort entry was defined as the date of last PPI prescription plus days’ supply.39 40 In order to ensure sufficient length of follow-up time following T0, we excluded cohort participants with cumulative duration of exposure exceeding 720 days (because of limited overall cohort timeline, and because T0 starts at the end of last prescription, those with long exposure will necessarily have limited follow-up time). In regression analyses, a 95% CI of an HR that does not include unity was considered statistically significant. All analyses were performed using SAS Enterprise Guide version 7.1. Sensitivity analyses In order to further evaluate the consistency and robustness of study findings, we examined the observed associations in a less contemporary cohort (dating back to an era where PPI prescription and use were far less frequent) of patients without acid suppression therapy prescriptions between 1 October 1998 and 30 September 2000 (washout period) and with acid suppression therapy prescription between 1 October 2000 and 30 September 2002 and at least one outpatient serum creatinine value before that. Patients in this cohort were followed till 30 September 2007 or death. To examine the impact of potential residual confounding on study results, we conducted additional sensitivity analyses as described by Schneeweiss41: (a) we used the rule-out approach to identify the strength of the residual confounding that could fully explain the association observed in primary analyses, and (b) we applied an external adjustment approach using external information (prevalence and risk estimates from published literature) to evaluate potential net confounding bias due to unmeasured confounders.2 41–44 Methods are described elegantly by Schneeweiss.41 In addition, to remove death events that were less likely to be related to PPI exposure, we excluded cohort participants who died within 90 days after the first PPI or H2 blocker prescription. We conducted analyses based on a three-level classification of exposure, where patient's status at time t could be current use (using PPI or finished last PPI prescription within 90 days before t), past use (used PPI after T 0 but finished more than 90 days before t) and never use. We conducted additional sensitivity analyses, which included haemoglobin as a covariate in cohort participants with available data. We also undertook analyses that stratified the cohort based on cardiovascular disease, history of pneumonia, CKD (eGFR <60 and ≥60 mL/min/1.73 m2) or age (<65 and ≥65 years old) at T 0 . Finally, and in order to ascertain the specificity of the findings, we examined the association between PPI exposure and the risk of a motor vehicle accident as a tracer outcome where a priori knowledge suggests an association is not likely to exist. Patient involvement No patients were involved in developing the hypothesis, the specific aims or the research questions, nor were they involved in developing plans for design or implementation of the study. No patients were involved in the interpretation of study results or write up of the manuscript. There are no plans to disseminate the results of the research to study participants or the relevant patient community.

Results The demographic and health characteristics of the overall primary cohort of new users of acid suppression therapy (n=349 312), by type of acid suppressant drug at time of cohort entry (H2 blockers n=73 335; PPI n=275 977), and those who were ever exposed to PPI (n=309 113) are provided in table 1. There were significant baseline differences in that cohort participants who were treated with PPI were older and were more likely to have comorbid conditions, including diabetes, hypertension, cardiovascular disease and hyperlipidaemia. Cohort participants treated with PPI were also more likely to have upper GI tract bleeding, ulcer disease, H. pylori infection, Barrett's oesophagus, achalasia, stricture and oesophageal adenocarcinoma (table 1). Survival curves for PPI and H2 blockers are presented in figure 1. Figure 1 Survival curves for PPI and H2 blockers. PPI, proton pump inhibitor. Table 1 Baseline demographic and health characteristics of overall primary cohort of new users of acid suppression therapy, by type of acid suppressant at the time of cohort entry, and those who were ever exposed to PPI Association between PPI use and risk of death Among new users of acid suppression therapy (n=349 312), and over a median follow-up of 5.71 years (IQR 5.11–6.37), where exposure was treated as a time-dependent covariate, PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28) (table 2). Among new users of acid suppression therapy (n=3 49 312), in high-dimensional propensity score-adjusted models, new PPI users had increased risk of death compared with new users of H2 blockers (HR 1.16, CI 1.13 to 1.18); based on two-stage residual inclusion estimation, risk of death was higher in new PPI users when compared with new users of H2 blockers (HR 1.21, CI 1.16 to 1.26). In a 1:1 time-dependent propensity score-matched cohort of new users of PPI and H2 blockers (n=1 46 670), PPI users had significantly increased risk of death (HR 1.34, CI 1.29 to 1.39). Table 2 Association between PPI use and risk of death We examined the relationship of PPI and risk of death in secondary cohorts (as described in the Methods section) where we considered risk associated with PPI use versus no known exposure to PPI (no PPI use ±H2 blockers use) (n=3 288 092); the results suggest that PPI use was associated with increased risk of death (HR 1.15, CI 1.14 to 1.15) (table 2). Assessment of risk of death associated with PPI use versus no known exposure to any acid suppression therapy (no PPI use and no H2 blockers use) (n=2 887 070) suggests increased risk of death with PPI use (HR 1.23, CI 1.22 to 1.24). Association between PPI use and risk of death in those without GI conditions We then analysed the association between PPI use and risk of death in cohort where we excluded participants with documented medical conditions generally considered as indications for treatment with PPI, including GERD, upper GI tract bleeding, ulcer disease, H. pylori infection, Barrett's oesophagus, achalasia, stricture and oesophageal adenocarcinoma. The intent of this analysis was to examine the putative association of PPI use and risk of death in a lower risk cohort. Examination of risk of death associated with use of acid suppression therapy (PPI vs H2 blockers) suggests that risk of death was increased with PPI use (HR 1.24, CI 1.21 to 1.27) (table 2). Examination of the risk of death associated with PPI use versus no known exposure to PPI (no PPI use ±H2 blockers use) suggests a higher risk of death associated with PPI use (HR 1.19, CI 1.18 to 1.20). Results were consistent where we examined risk of death associated with PPI use versus no known exposure to any acid suppression therapy (no PPI use and no H2 blockers use) (HR 1.22, CI 1.21 to 1.23). Risk of death associated with PPI use in cohort participants without GI conditions but included participants with GERD yielded consistent results (PPI vs H2 blockers (HR 1.24, CI 1.21 to 1.27); PPI vs no PPI (HR 1.14, CI 1.13 to 1.14); PPI vs no PPI and no H2 blockers (HR 1.22, CI 1.21 to 1.22)) (table 2). Duration of exposure and excess risk of death We examined the association between duration of PPI exposure and risk of death among new users of PPI (n=166 098). Compared with those exposed for ≤30 days, there was a graded association between duration of exposure and risk of death among those exposed for 31–90, 91–180, 181–360 and 361–720 days (table 3, figure 2). Figure 2 Duration of PPI exposure and risk of death among new PPI users (n=166 098). PPI, proton pump inhibitor. Table 3 Duration of exposure to PPI and risk of death among new users of PPI (n=1 66 098)

Sensitivity analyses We tested the robustness of study results in sensitivity analyses where we built a less contemporary cohort as described in the Methods section; demographic and health characteristics of this cohort are provided in online supplementary table 1. Where exposure was treated as time dependent, PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.17, CI 1.15 to 1.19). In a 1:1 time-dependent propensity score-matched cohort of PPI and H2 blockers, PPI users had significantly increased risk of death HR 1.21 (CI 1.19 to 1.24). Furthermore, we also observed a graded association between cumulative duration of exposure to PPI and risk of death (see online supplementary table 2 and online supplementary figure 3). Supplementary Material Supplementary data 2 [SP2.pdf] To examine the potential impact of residual confounding on study results, we used rule-out and external adjustment approaches as described by Schneeweiss.41 Using the rule-out approach, we characterised a set of parameters (OR for relationship of PPI and confounder and HR for relationship of confounder and death) with sufficient strength to fully explain the association observed in primary analyses (see online supplementary figure 4). For example, if the confounder was two times as likely among PPI users (OR=2), and the HR of death associated with the uncontrolled confounder exceeded 4.0, then the uncontrolled confounder would fully explain the observed association between PPI and death (see online supplementary figure 4). Given that our analyses accounted for most known strong independent risk factors of death and employed an active comparator group, to cancel the results, any uncontrolled confounder of the required prevalence (OR 2 or more in the example above) and strength (HR 4 or more in the example above) would also have to be independent of the confounders already adjusted for and is unlikely to exist; thus, the results cannot be fully explained by this putative uncontrolled confounder. External adjustment to estimate the impact of three unmeasured confounders, including obesity, smoking and use of therapeutics including anticoagulants, antiplatelet agents and non-steroidal anti-inflammatory drugs, shows a net confounding bias of 9.66% (see online supplementary figure 5). The total bias could move a null association between PPI and death from HR 1.00 to HR 1.10 (reflecting the net positive bias of 9.66% rounded up to 10.0%). The association we observed between PPI and death was 1.25>1.10, which cannot be fully due to bias of unmeasured confounding. In analyses where time-dependent exposure was classified as current use (within 90 days), past use (use prior to 90 days) and never use of PPI, compared with use of H2 blockers and never use of PPI (the reference group), current use of PPI and past use of PPI were associated with increased in risk of death (HR 1.23, CI 1.21 to 1.26, and HR 1.53, CI 1.50 to 1.57, respectively). The association between PPI and death remained significant after excluding cohort participants who died within 90 days after the first PPI or H2 blocker prescription (HR 1.23, CI 1.20 to 1.26), or additionally controlling for haemoglobin levels (HR 1.25, CI 1.23 to 1.28). In models stratified for the presence of cardiovascular disease, history of pneumonia, CKD and age at T0, there was increased risk of death associated with PPI use in those with and without cardiovascular disease (HR 1.19, CI 1.15 to 1.23, and HR 1.30, CI 1.27 to 1.34, respectively), with and without history of pneumonia (HR 1.39, CI 1.32 to 1.45, and HR 1.21, CI 1.18 to 1.24, respectively), with and without CKD (HR 1.18, CI 1.14 to 1.22, and HR 1.29, CI 1.26 to 1.33, respectively) and above and below age 65 years (HR 1.17, CI 1.13 to 1.20, and HR 1.44, CI 1.39 to 1.50, respectively). As a test of specificity, among users of acid suppression therapy, PPI use was not associated with increased risk of the tracer outcome of a motor vehicle accident (HR 0.99, CI 0.89 to 1.10).

Output: Common medicines for heartburn and indigestion known as proton pump inhibitors (PPIs) could increase the risk of death, according to research. The drugs, for which over 50 million prescriptions are issued annually in the UK and which are also available without prescription, neutralise stomach acid. Researchers found that the risk of fatality was up to 25% higher for those taking PPIs compared to those taking another form of acid suppressant or none at all. Those taking the drugs without needing to were found to be most at risk. PPIs have previously been linked to hip fractures, kidney disease, pneumonia and sepsis.


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Heartburn drugs could raise risk of death
 Millions of people taking common heartburn and indigestion medications could be at an increased risk of death, research suggests.

The drugs, known as proton pump inhibitors (PPIs), neutralise the acid in the stomach and are widely prescribed, with low doses also available without prescription from pharmacies. In the UK, doctors issue more than 50m prescriptions for PPIs every year.

Now researchers say the drugs can increase risk of death, both compared with taking a different type of acid suppressant and not taking any at all.

“We saw a small excess risk of dying that could be attributed to the PPI drug, and the risk increased the longer they took them,” said Ziyad Al-Aly, an epidemiologist from the University of Washington and co-author of the study.

The team say the study suggests those who take the drugs without needing to could be most at risk. They urged people taking PPIs to check whether this was necessary.

Previous research has raised a range of concerns about PPIs, including links to kidney disease, pneumonia, more hip fractures and higher rates of infection with C difficile, a superbug that can cause life-threatening sepsis, particularly in elderly people in hospitals.

But the latest study is the first to show that PPIs can increase the chance of death. Published in the journal BMJ Open, it examined the medical records of 3.5 million middle-aged Americans covered by the US veterans healthcare system.

The researchers followed 350,000 participants for more than five years and compared those prescribed PPIs to a group receiving a different type of acid suppressant known as an H2 blocker. They also took into account factors such as the participants’ age, sex and conditions ranging from high blood pressure to HIV.

The results show that those who took PPIs could face a 25% higher risk of death than those who took the H2 blocker.

“In patients on [H2 blocker] tablets, there were 3.3 deaths per 100 people over one year. In the PPI group, this figure was higher at 4.7 per 100 people per year,” said Al-Aly.

The team also reported that the risk of death for those taking PPIs was 15% higher than those taking no PPIs, and 23% higher than for those taking no acid suppressants at all.

Similar levels of increased risk were seen among people who used PPIs but had no gastrointestinal conditions, a result which the authors speculated might be driving the higher risk seen overall.

Gareth Corbett, a gastroenterologist from Addenbrooke’s hospital in Cambridge who was not involved with the study, cautioned against panic, pointing out that in most cases the benefits of PPI far outweighed any risk. What was more, he said, while the increased risk sounded high, it was still very low for each person.

“PPIs are very effective medicines, proven to save lives and reduce the need for surgery in patients with bleeding gastric and duodenal ulcers and several other conditions,” he said.

The study’s authors said it was important that PPIs were used only when necessary and stopped when no longer needed.

Corbett agreed that many people take PPIs unnecessarily. “They could get rid of their heartburn by making lifestyle changes, such as losing weight and cutting back on alcohol, caffeine and spicy foods,” he said.

The authors said the study was observational, meaning it did not show that PPIs were the cause of the increased risk of death, and that it was unclear how the drugs would act to affect mortality. They said the drugs could affect components within cells, known as lysosomes, that help break down waste material, or shortening protective regions at the end of chromosomes, known as telomeres.

Aly said people on PPIs should check with their GP whether the drugs were still needed, adding: “In some cases we expect that PPIs can be safely stopped, particularly in patients who have been taking them for a long time.”

Output: Common medicines for heartburn and indigestion known as proton pump inhibitors (PPIs) could increase the risk of death, according to research. The drugs, for which over 50 million prescriptions are issued annually in the UK and which are also available without prescription, neutralise stomach acid. Researchers found that the risk of fatality was up to 25% higher for those taking PPIs compared to those taking another form of acid suppressant or none at all. Those taking the drugs without needing to were found to be most at risk. PPIs have previously been linked to hip fractures, kidney disease, pneumonia and sepsis.


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E. coli DNA feeds on xylose to boost biofuel yields 50%
 A team of scientists from Arizona State University are working to break through the innovation bottleneck for renewable bioproduction of fuels and chemicals, to create a renewable biofuel technology that would lead to a cheaper alternative to gasoline.

Reed Cartwright and Xuan Wang have focused on the manipulation of microbes as biocatalysts to convert biomass such as agricultural wastes and even carbon dioxide into bio-based products. In particular, they’re interested in “harnessing the trial and error power of evolution into revealing an answer.”

The scientists have grown generations of bacteria under special conditions in fermentation tanks, test tube evolving bacteria to better ferment sugars derived from biomass. Their results have appeared in the Proceedings of the National Academy of Sciences.

In particular, the scientists looked into non-food crop sources of biofuels, lignocellulosic biomasses like tall switchgrasses and the inedible parts of corn and sugarcane. Lignocellulosic biomasses are rich in xylose, a five-carbon, energy-rich sugar relative of glucose. Unfortunately, industrial E coli strains can’t use xylose because when glucose is available, it turns off the use of glucose. Consequently, it has typically been inefficient and expensive to fully harvest and convert xylose to biofuels.

Cartwright and Wang wanted to get more energy from xylose sugars. To do so, they challenged E coli that could thrive comfortably on glucose to grow solely on xylose, forcing the bacteria to adapt to the new food supply.

Faced with the challenge, the bacteria randomly mutated their DNA until it could adapt to the new conditions. The team set out to identify how the most beneficial mutations worked, and identified three single mutations that could enhance xylose fermentation by changing bacterial sugar metabolism.

"This suggests that there are potentially multiple evolutionary solutions for the same problem, and a bacterium's genetic background may predetermine its evolutionary trajectories," said Cartwright, a researcher at ASU's Biodesign Institute and assistant professor in the School of Life Sciences.

Focusing on a mutation in a regulatory protein called XyIR, where just two amino acid switches enhanced xylose utilisation and released the glucose repression, the team managed to achieve impressive increases in fermentation efficiency. When the XyIR mutant strain was placed in a “wild type” strain or an industrial E. coli biocatalyst, it massively improved the yield, by up to 50% over four days of fermentation, according to the team’s study.

"With these new results, I believe we've solved one big, persistent bottleneck in this field," concluded Wang. Arizona Technology Enterprises (AzTE) is now filling a non-provisional patent for their discovery.

Output: Researchers at Arizona State University working to harvest and convert the sugar xylose into biofuels have been able to mutate E. coli DNA to feed on xylose and improved yields of biofuels made from lignocellulosic feedstocks by up to 50%. Industrial E. coli strains cannot use xylose as a food and xylose has been typically an inefficient and expensive way in which to develop biofuels. However, the breakthrough may improve the viability of biofuels made from non-food crops such as switchgrass and corn and sugarcane waste.


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E. coli DNA feeds on xylose to boost biofuel yields 50%
 ASU scientists harness the trial-and-error power of evolution to coax nature into revealing answer to energy challenge

Whether or not society shakes its addiction to oil and gasoline will depend on a number of profound environmental, geopolitical and societal factors.

But with current oil prices hovering around $50 dollars a barrel, it won’t likely be anytime soon.

Despite several major national research initiatives, no one has been able to come up with the breakthrough renewable biofuel technology that would lead to a cheaper alternative to gasoline.

That research challenge led ASU scientists Reed Cartwright and Xuan Wang to enter the fray, teaming up to try to break through the innovation bottleneck for the renewable bioproduction of fuels and chemicals.

“My lab has been very interested in converting biomass such as agricultural wastes and even carbon dioxide into useful and renewable bio-based products,” said Wang

(pictured above, right), an assistant professor in the School of Life Sciences. “As a microbiologist, I’m interested in manipulating microbes as biocatalysts to do a better job.”

To do so, they’ve looked into a new approach: harnessing the trial-and-error power of evolution to coax nature into revealing the answer.

By growing bacteria over generations under specially controlled conditions in fermentation tanks, they have test-tube-evolved bacteria to better ferment sugars derived from biomass — a rich, potential renewable-energy source for the production of biofuels and chemicals. Their results appeared recently in the online edition of PNAS.

The research team includes postdoctoral scholar Christian Sievert, Lizbeth Nieves, Larry Panyon, Taylor Loeffler and Chandler Morris, and was led by Cartwright and Wang, in a collaboration between the ASU’s School of Life Sciences and the Biodesign Institute.

A sweet problem

The appeal of plants is ideal. Just add a little carbon dioxide, water and plentiful sunshine, and presto! Society has a rich new source of renewable carbons to use.

Corn ethanol (using starch from corn for alcohol production primarily in the U.S.) has been one major biofuel avenue, and sugarcane another alternative (abundant in Brazil) — but there is a big drawback. Turning the sugar-rich kernels of corn or sugarcane into ethanol competes with the food supply.

So scientists over the past few decades have migrated to research on conversion of non-food-based plant materials into biofuels and chemicals. These so-called lignocellulosic biomasses, like tall switchgrasses and the inedible parts of corn and sugarcane (stovers, husks, bagasses, etc.) are rich in xylose, a five-carbon, energy-rich sugar relative of glucose.

Lignocellulosic biomass has an abundance of glucose and xylose, but industrial E. coli strains can’t use xylose because when glucose is available, it turns off the use of xylose. And so, to date, it has been an inefficient and costly to fully harvest and convert the xylose to biofuels.

Benchtop evolution

Wang and Cartwright wanted to squeeze out more energy from xylose sugars. To do so, they challenged E. coli bacteria that could thrive comfortably on glucose — and switch out the growth medium broth to grow solely on xylose.

The bacteria would be forced to adapt to the new food supply or lose the growth competition.

They started with a single colony of bacteria that were genetically identical and ran three separate evolution experiments with xylose. At first, the bacteria grew very slowly. But remarkable, in no more than 150 generations, the bacteria adapted and, eventually, learned to thrive in the xylose broth.

Next, they isolated the DNA from the bacteria and used next-generation DNA sequencing technology to examine the changes within the bacteria genomes. When they read out the DNA data, they could identify the telltale signs of evolution in action, mutations.

Nature finds a way

The bacteria, when challenged, randomly mutated their DNA until it could adapt to the new conditions. They held on to the fittest mutations over generations until they became fixed beneficial mutations.

And in each case, when challenged with xylose, the bacteria could grow well. Their next task was to find out what these beneficial mutations were and how did they work. To grow better on xylose, the three bacterial E. coli lines had “discovered” a different set of mutations to the same genes. The single mutations the research team identified all could enhance xylose fermentation by changing bacterial sugar metabolism.

“This suggests that there are potentially multiple evolutionary solutions for the same problem, and a bacterium’s genetic background may predetermine its evolutionary trajectories,” said Cartwright, a researcher at ASU’s Biodesign Institute and assistant professor in the School of Life Sciences.

The most interesting mutation happened in a regulatory protein called XylR whose normal function is to control xylose utilization. Just two amino acid switches in the XylR could enhance xylose utilization and release the glucose repression, even in the non-mutated original hosts.

Through some clever genetic tricks, when the XlyR mutant was placed back in a normal “wild-type” strain or an industrial E. coli biocatalyst, it could also now grow on xylose and glucose, vastly improving the yield. Wang’s team saw up to a 50 percent increase in the product after four days of fermentation.

Together, Wang and Cartwright’s invention has now significantly boosted the potential of industrial E. coli to be used for biofuel production from lignocellulosic materials. In addition, they could use this same genetic approach for other E. coli strains for different products.

Arizona Technology Enterprises (AzTE) is filing a non-provisional patent for their discovery. Wang hopes they can partner with industry to scale up their technology and see if this invention will increase economic viability for bioproduction.

“With these new results, I believe we’ve solved one big, persistent bottleneck in this field,” Wang said.

Output: Researchers at Arizona State University working to harvest and convert the sugar xylose into biofuels have been able to mutate E. coli DNA to feed on xylose and improved yields of biofuels made from lignocellulosic feedstocks by up to 50%. Industrial E. coli strains cannot use xylose as a food and xylose has been typically an inefficient and expensive way in which to develop biofuels. However, the breakthrough may improve the viability of biofuels made from non-food crops such as switchgrass and corn and sugarcane waste.


Instruction: create a high quality summary of the given input

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Bee colonies threatened by pesticides: Syngenta study
 Widely used insecticides damage the survival of honeybee colonies, the world’s largest ever field trial has shown for the first time, as well as harming wild bees.

The farm-based research, along with a second new study, also suggests widespread contamination of entire landscapes and a toxic “cocktail effect” from multiple pesticides.

The landmark work provides the most important evidence yet for regulators around the world considering action against neonicotinoids, including in the EU where a total ban is poised to be implemented this autumn. The insecticides are currently banned on flowering crops in the EU.

The negative impacts found varied across different countries, leading the pesticide manufacturers to question whether the results of the research, which they funded, were real. The new research is published in the prestigious peer-review journal Science.

Neonicotinoids represent a quarter of the multi-billion dollar pesticide market but have been repeatedly linked to serious harm in bees in lab-based studies. Bees and other pollinators are vital to food production but are in decline, in part due to loss of habitats and disease. But there had been few realistic field studies to date to address the role of the insecticides and only occasional evidence for colony-level harm in wild bees.

The new research took place at 33 large farmland sites spread across the UK, Germany and Hungary. Honeybees, bumblebees and solitary bees living by insecticide-treated fields of oil seed rape were compared with those in fields where insecticides were not used in the year of the study.

The survival of honeybee colonies was reduced by exposure to the insecticides in the UK and Hungary, but not in Germany, where the bees foraged far less on oil seed rape and had lower levels of disease. The reproductive success of the wild bees was cut as the insecticide exposure increased in all three countries.

“We showed significant negative effects at critical life cycle stages,” said Prof Richard Pywell, from the UK’s Centre for Ecology and Hydrology (CEH), and part of the research team. “If the bees are foraging a lot on oil seed rape, they are clearly at risk. This is a large and important piece of evidence, but it is not the only evidence regulators will look at.”

Bees and other pollinators are vital to food production but are in decline. Photograph: Jeremy T Kerr/Science

Scientists not involved in the research backed the conclusions. “Together, the two studies make strong contributions to the growing scientific consensus about the harms of neonicotinoid pesticides to bees,” said Prof James Nieh, at the University of California San Diego. Addressing the differences between countries, Prof Jeremy Kerr, at the University of Ottawa in Canada, said: “Neonicotinoid applications are a kind of reproductive roulette for bees. Depending on local environmental characteristics, they can materially reduce survival prospects.”

The $3m cost of the research was met by Syngenta and Bayer, the companies that sell the two neonicotinoids tested, as part of a voluntary commitment to increase the available field data. But the companies were not involved in the designing, conducting or reporting of the study.

It found that the bees in Germany got just 15% of their food from the oil seed rape fields, compared to 40-50% in the UK and Hungary. “Clearly the bees in Germany are feeding on other flower resources in the landscape and are less exposed to neonics,” said Pywell.

The scientists also discovered that the wild bees were exposed to a neonicotinoid that was not even used in the trial and concluded the harm caused may result from “persistent residues in arable systems due to their widespread and often very frequent use”.

However, both Bayer and Syngenta expressed doubt about the “simplistic” interpretation of complex and “inconsistent” results. “We do not share CEH’s interpretation and remain confident that neonicotinoids are safe when used responsibly” said Richard Schmuck, director of environmental safety at Bayer CropScience.

Peter Campbell, from Syngenta, said: “The negative and positive results reported by CEH could easily be random, ie not real.” He said even taking the results at face value “demonstrates that neonics can be used safely or even with benefit to bees under certain circumstances, such as reported in Germany.”

But CEH’s Pywell said: “We stand by our peer-reviewed paper. We undertook the statistical analysis and reported the findings as we saw them and those are underpinned by the data. We are absolutely independent.”

A honeybee worker has a radio-frequency identification tag attached to its back that allows researchers to monitor when it leaves and returns to the colony, as well as when it is no longer active and presumed dead. Photograph: Amro Zayed/York University/Science

The second new study published in Science, carried out on corn farms in Canada, also found crops were not the main source of neonicotinoids to which bees were exposed. Instead, the contaminated pollen came from wildflowers, as has been shown recently in the UK.

“This indicates that neonicotinoids, which are water soluble, spill over from fields into the surrounding environment, where they are taken up by other plants that are very attractive to bees,” said Nadia Tsvetkov, at York University in Canada and who led the research.

“The detection of the potential long-term persistence of neonicotinoids in the soil by both studies raises the spectre of a reprise of Rachel Carson’s Silent Spring,” said Prof Robert Paxton at Martin-Luther-University Halle-Wittenberg in Germany.

The Canadian research also found that the presence of realistic levels of a fungicide made the neonicotinoids twice as toxic to bees. “The effect of neonicotinoids on honey bees quickly turns from bad to worse when you add the fungicide boscalid to the mix,” said Prof Valérie Fournier, at Laval University in Canada and also part of the team. Pesticides are not tested in combination by regulators and Kerr said: “This study shows that mixtures matter.”

Environmental campaigners said the new research exposed the full impact of neonicotinoids. “The horror story is clear: we have contaminated our land and water with persistent neonicotinoid pesticides,” said Matt Shardlow, CEO of the charity Buglife.

A tractor sprays pesticide onto a field of wheat near Kleptow, Germany. Neonicotinoids, which are water soluble, spill over from fields into the surrounding environment. Photograph: Sean Gallup/Getty Images

“This major study marks a watershed moment in the fight to protect our bees [and] fills a crucial gap in our scientific understanding,” said Greenpeace UK’s chief scientist Doug Parr. “The case for a permanent ban on these pesticides is now unassailable, and our politicians will have to take action.”

But Guy Smith, from the National Farmers Union in Britain said neonicotinoids were important in protecting crops and producing food: “We strongly believe that policy decisions – such as restricting the use of neonicotinoids – must be based on sound science which gives strong evidence. And while this CEH study provides more useful information, we still don’t have that definitive evidence for the impact of neonicotinoids.”

Prof David Goulson, a bee expert at the University of Sussex, UK, said: “In the light of these new studies, continuing to claim that use of neonicotinoids in farming does not harm bees is no longer a tenable position. In my view we should also consider the bigger picture; the current model of farming based on huge monocultures treated with dozens of pesticides is causing devastating environmental harm, undermining vital ecosystem services that keep us all alive.”

Output: A study funded by two of the world's largest pesticide manufacturers has shown that neonicotinoids, which constitute 25% of the multi-billion-dollar pesticide industry, damage honeybee colonies as well as wild bees. The study, conducted at 33 sites in Germany, Hungary and the UK by the Centre for Ecology and Hydrology, supports the findings of lab-based research and reinforces previous evidence for colony-level harm. The $3m research project was financed by Syngenta and Bayer, which produce two of the pesticides tested. Both companies said they don't believe the research proves that the pesticides can't be used safely.


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Kangaroo hop confuses semi-autonomous driving systems
 Kangaroos are involved in an estimated 15,000 collisions with cars in Australia each year, according to the country’s largest car insurance company. Kangaroos account for about 80 per cent of all collisions with animals.

With the enormous advances in assisted driving technologies over the past few years, you’d logically assume that number would soon start to decline as detection systems make their way into new cars.

However, Sweden-based Volvo recently discovered a kangaroo’s hop presents a unique problem for defence driver assist systems, because when the animals are in the air they appear to move further away, when they really are staying the same distance away.

“This totally confuses the systems,” said Ken Kroeger, chairman of Seeing Machines (pictured), a provider of intelligent sensing technology to the automotive, aviation, medical and other industries.

The car maker’s animal detection systems have no problem identifying animals that walk and run, such as deer, elk, cows and household pets. According to Volvo’s website, if a large animal appears in front of a car, the system can warn the driver about the animal and provide brake assistance in certain situations.

New obstacles

Kroeger, who spoke during the Industry & the Human Element keynote at Mobile World Congress Shanghai last Friday (30 June), said kangaroos are just one of the many problems facing companies developing the technology for semi-autonomous cars.

He noted the ‘handover’ from machine back to human is still a big unknown: “Nobody knows whether the average driver will be able to manage this process on his own, or whether the industry will have to provide technology to help manage it.”

The first level 4 cars, where the driver doesn’t have to think about driving, he reckons are still five to ten years away and will first be used in more controlled highway scenarios. Analysts forecast fully autonomous cars (level 5) will come to market in volume after 2035, with some predicting they’ll have less than a 3 per cent market share in 2050.

Long before reaching those milestones, the kangaroo detection problem illustrates the importance of verifying systems across all possible environments. Volvo first tested its detection system in Sweden in areas populated with moose, then found during trials in Australia it couldn’t recognise marsupials.

In another example Robert Bosch, an automotive parts supplier, had to adapt its braking systems after black swans caused interference, The Guardian reported (every car sold globally features an average of nine chips made by Bosch).

No doubt the self-driving industry, which is at the intersection of the fast-growing telematics and artificial intelligence (AI) sectors, will stumble on additional obstacles such as ‘hopping’ as it moves towards truly autonomous vehicles. As it overcomes them, insurance companies and animal lovers will certainly celebrate.

The editorial views expressed in this article are solely those of the author and will not necessarily reflect the views of the GSMA, its Members or Associate Members.

Output: Volvo has discovered that a kangaroo's hop generates confusion for defence driver assist technology. The Sweden-based carmaker's animal detection system fails to recognise that when kangaroos are in the air they only seem to travel further away, when in fact they remain in close proximity to the vehicle. Since the kangaroo is not registered as being directly in front of the car, the vehicle's warning and brake assist mechanisms are not activated. The manner in which kangaroos appear to move could partly explain why they account for the vast majority of all animal-vehicle collisions in Australia.


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Battery range deters more than half of potential EV buyers
 A study by Venson Automotive Solutions has revealed that 61% of motorists are deterred by an EV switch due to worries over limited battery range.

To support the launch of its guide to electric vehicles, Venson carried out the research to tackle 'range anxiety’.

It found that the main concern for motorists is a lack of charging points.

“The UK is the largest market in Europe for zero emissions capable cars, accounting for almost a quarter (23.8%) of registrations in the EU, in 2016,” said Venson Automotive Solutions’ marketing director Alison Bell.

“However, limited battery range remains one of the biggest concerns associated with electric vehicles with many citing this as a reason why they are reluctant to buy.”

According to Go Ultra Low figures, the average commute in the UK is less than 10 miles, which could be covered by most plug-in vehicles after a home or work charge. Go Ultra Low claims more than a third of UK motorists never travel more than 80 miles in a single trip.

The Nissan Leaf offers a range of 155 miles and technology is improving all the time, with the Tesla Model S offering a published range of 265 miles.

Currently, there are three different levels of charging points, offering different recharge times. The higher the kilowatts (kW), the faster the battery will charge.

Most networks offer a mix of ‘rapid’ (43kW-50kW), ‘fast’ (7kW-22kW) and ‘standard’ (up to 3kW) charging options. The standard service station is rapid and will charge a battery from flat to 80% in under 30 minutes.

Fast points are installed in public locations and will recharge some batteries in two to four hours. The standard, home charging point generally takes around six hours to fully charge a battery. The only key is for owners to know which type of connector their vehicle needs.

“Charging an electric vehicle sounds complicated, but once drivers get to know their vehicle, it’s no more complicated than charging a smartphone,” said Bell.

“In addition, the Electric Vehicle Homecharge Scheme offers grant funding of up to 75% of the cost of installing electric vehicle chargepoints at home, up to £500. Charging at home costs about £3 for a full charge or 2 pence per mile, offering clear savings for motorists, which could outweigh the worries for many.”

Venson's tips :

Output: A study by Venson Automotive Solutions has found that 61% of motorists are discouraged from switching to an EV due to anxiety over limited battery range. This is despite figures published by Go Ultra Low indicating that the average commute of UK car owners is below 10 miles, a distance easily achieved by most plug-in vehicles following a charge at home or work.


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Apple to block ad tracking while Google targets quality
 Both Apple and Google are introducing new ad blocking tech, but it is Apple’s focus on retargeting and making an ad-free experience part of its premium positioning that should concern marketers.

Advertisers were met with a double whammy at the beginning of the month when both Google and Apply outlined new plans to block ads.

The changes at Apple take effect in its Safari browser. They mean pre-roll ads on videos will no longer auto-play and that tracking will be automatically disabled so advertisers can no longer use cookies to track them across different websites.

Meanwhile, at Google, its Chrome browser is getting a built-in ad blocker that will block all ads on a site (including its own) if they don’t meet the standards set out by the Coalition for Better Advertising.

READ MORE: Auto-play video and pop-ups named among the most ‘annoying’ ad formats

The issues with autoplay

Auto-play video with sound has been at issue for some time, with many consumers finding the ads invasive and irrelevant. According to the Coalition, consumers rate auto-play video ads as among the most annoying on desktop and mobile.

And the IAB says its welcomes the moves and any changes that promote better digital advertising.

“Google’s move quickly puts weight behind the stance set by the Coalition for Better Ads following the release of their better ads standards,” a spokesperson for the IAB tells Marketing Week.

The changes will mean marketers will have to find new ways to grab their audience’s attention. However, Alessandra Di Lorenzo, chief commercial officer of media and partnerships at Lastminute.com, believes this offers a better experience for consumers and an opportunity for marketers to “up their game”

“While people are happy to engage with content that is relevant and useful to them, serving ads that don’t tick these boxes can be ineffective at best, and reputation-damaging at worst,” Di Lorenzo says.

’Stick with us’, Apple is saying, ‘and we’ll make sure nobody can poke their nose into your internet experience’ Phil Dyte, iProspect

“There’s no need for marketers to be concerned about these latest changes from Apple and Google. Instead, they should focus on upping their relevance game, using a combination of data and creativity to ensure they are delivering the right content to the right people at the right time – and in the right format.”

Di Lorenzo says marketers should focus on the use of data to do this and should continue to move in the direction of native, which she says offers a more seamless user experience by blending advertising and content with data.

Why Apple is the bigger concern

However, not all are convinced by Google and Apple’s approach. Phil Dyte, strategy director at digital agency iProspect, highlights how the two approaches are very different, with Google focusing on format, while Apple goes after targeting. He says in theory Google should only worry “unscrupulous” ad tech companies who are building “bad, disruptive ad experiences” and that the industry will welcome this.

However, he says Apple’s efforts are more concerning as it isn’t promoting ad blocking as a user benefit but as a marketing business tool, by making privacy part of its premium image.

“’Stick with us’, they’re saying, ‘and we’ll make sure nobody can poke their nose into your internet experience’,” Dyte says.

“This is all well and good – but users will still see ads, just less appropriate ones, so I’m not sure it helps anyone outside the minority of super-privacy types.”

Apple’s move is also problematic because it has the potential to affect all players in the digital ecosystem, apart from Apple itself. This will make it more difficult for its rivals, including Google, that rely on advertising for their business models and retargeting to drive revenues.

“This probably won’t impact Apple too much. Nobody is going to not buy an iPhone because they might get worse ads. But if it works it will have an impact on everyone, except of course Apple,” Dyte adds.

Output: Apple has disabled auto-play on pre-roll video ads and cookie tracking on its Safari web browser, meaning advertisers can no longer use cookies to track campaigns across websites. Google has started blocking ads on the Chrome web browser that do not meet the Coalition for Better Advertising's standards. While Google's move has been welcomed by marketers who expect to see fewer poor-quality ads, Apple's move will mean ads are less relevant to users, in exchange for greater privacy that is only coveted by a small number of users.


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Online real estate broker Redfin submits IPO proposal
 Online real estate broker Redfin is preparing to sell shares to the public, filing on Friday to raise up to $100 million.

Goldman Sachs is leading the IPO for Seattle-based Redfin, which specializes in buying and selling homes and uses a mobile app to do tasks like schedule home tours and suggest listings.

Revenue in 2016 jumped 43 percent to $267.2 million from $187.3 million a year earlier. The company's net loss narrowed to $22.5 million from $30.2 million. Redfin calls itself a "technology-powered real estate broker." It's the human element that leads to a gross margin of 31 percent, much lower than most big internet companies.

In its prospectus, Redfin differentiates itself from other tech companies that use only the internet and mobile apps to connect consumers with businesses.

"In an age when the technology economy is increasingly divided from the rest of the world," the filing says, "we have hired our own real estate agents, not as a disposable labor force, but as partners in this business, with a salary, health-care benefits and the opportunity to earn stock options."

Technology investors like Madrona Ventures, Greylock Partners, Draper Fisher Jurvetson and T. Rowe Price backed Redfin, which was created in 2004.

Redfin CEO Glenn Kelman, who joined in 2006, told CNBC in May that the company's sales were being limited by historically low inventories of homes.

"We're going to be fine in terms of market share, but I think the overall industry for the first time is seeing sales volume really limited by the inventory crunch," Kelman said.

Zillow , another major player in online real estate, is located just up the road in Seattle. Zillow is more than three times the size of Redfin by revenue and is valued at about $9 billion.

— CNBC's Diana Olick contributed to this report.

Output: Seattle-based online real estate broker Redfin has been preparing for an initial public share offering in which it hopes to raise $100m, according to recently filed documents. The firm's revenue in 2016 rose 43% to $267.2m, compared to $187.3m the previous year, while net loss was down to $22.5m from $30.2m. Redfin is a specialist home buyer and seller, and uses a mobile app to offer users scheduled tours and suggest listings.


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Patient data transfer to Google DeepMind by NHS trust was illegal
 The transfer of 1.6 million NHS patients' personally identifying data to Google was illegal, according to the UK's data watchdog.

The Royal Free NHS Trust gave the data to Google DeepMind, the artificial intelligence arm of Google, for the purpose of testing a smartphone app called Streams - and did so without requesting the patients' permission.

In doing so it "failed to comply with the Data Protection Act" the Information Commissioner's Office (ICO) ruled today, following the conclusion of a long investigation into the deal.

Data belonging to a 1.6 million patients, some of whom had simply attended A&E within the last five years, was given to Google to test a smartphone app which could detect acute kidney injuries (AKIs).

The watchdog stated that those patients did not consent to the transfer, and that the justification offered by Royal Free and DeepMind was unlawful.

Although the regulator has the power to issue monetary penalties of hundreds of thousands of pounds, it chose to recognise a dearth of guidance from the Department of Health in demanding that Royal Free commit to make changes to address its shortcomings.

Elizabeth Denham, the information commissioner, said that while there was "huge potential" in the use of patient data to deliver clinical improvements, "the price of innovation does not need to be the erosion of fundamental privacy rights".

The ruling follows a Sky News investigation in May which revealed that the most senior data protection adviser to the NHS, Dame Fiona Caldicott, had warned the ICO that patients' data had been transferred to Google on an "inappropriate legal basis".

Please use Chrome browser for a more accessible video player 0:38 Royal Free's Professor Stephen Powis said the Trust was 'committed' to protecting patient data

At the time of the Sky News investigation, Royal Free's Professor Stephen Powis said: "We have been very grateful to Dame Fiona for her support (and) advice during this process and we would absolutely welcome further guidance on this issue."

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Royal Free Hospital said it would "consider" the ICO's findings when they were released. In a statement today, the Trust said: "We accept the ICO's findings and have already made good progress to address the areas where they have concerns."

DeepMind, originally a British business that was acquired by Google in 2014, received the data to test a smartphone app called Streams which could detect if patients were suffering from AKIs and then rapidly inform clinicians so that those patients' could receive potentially life-saving treatment.

The testing for the Streams app has now concluded and the app itself is being used at the Royal Free Hospital under a second agreement which is not being investigated by the ICO.

In a statement released on its site, DeepMind said it welcomed "the ICO's thoughtful resolution of this case, which we hope will guarantee the ongoing safe and legal handling of patient data for Streams".

Please use Chrome browser for a more accessible video player 0:48 DeepMind: Patient data not shared with Google

"Although today's findings are about the Royal Free, we need to reflect on our own actions too," the company stated.

"In our determination to achieve quick impact when this work started in 2015, we underestimated the complexity of the NHS and of the rules around patient data, as well as the potential fears about a well-known tech company working in health."

In response to critics alleging that it had not sought NHS patients' permission to receive their data, DeepMind appointed nine "Independent Reviewers" to judge its handling of patients' data.

DeepMind claims it appointed the independent reviewers "long before any regulatory or media criticism". A spokesperson told Sky News that the reviewers have been in place since February 2016.

Those independent reviewers' report on the company's use of patient data is now due to be released on Wednesday.

On seeing the ICO's ruling, Phil Booth, coordinator of medConfidential - an organisation which campaigns in support of the privacy of patients' data within the NHS - said: "We look forward to Google DeepMind's Independent Reviewers' report on Wednesday.

"Google DeepMind has shown that it is content to break the law in order to get copies of people's medical records. That being the case, how can the public trust Google's ongoing exploitation of their healthcare data?"

Output: The sharing of patient data with Google's DeepMind by an NHS trust has been ruled illegal by the UK's Information Commissioner's Office (ICO). The watchdog ruled that the Royal Free NHS Trust failed to comply with the Data Protection Act when it transferred 1.6 million NHS patient records to DeepMind so it could test a smartphone app called Streams, without requesting patients' permission. The app was devised to detect kidney injuries. The ICO can issue fines but acknowledged a dearth of guidance from the Department of Health and instead called on the Royal Free to make changes to address its shortcomings.


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Chan-Zuckerberg to back 'whole child personalised learning' plan
 Pediatrician Priscilla Chan and Facebook founder and CEO Mark Zuckerberg are gearing up to invest hundreds of millions of dollars a year in a new vision of “whole-child personalized learning,” with the aim of dramatically expanding the scope and scale of efforts to provide every student with a customized education.

The emerging strategy represents a high-stakes effort to bridge longstanding divides between competing visions for improving the nation’s schools. Through their recently established Chan Zuckerberg Initiative, the billionaire couple intends to support the development of software that might help teachers better recognize and respond to each student’s academic needs—while also supporting a holistic approach to nurturing children’s social, emotional, and physical development.

The man charged with marrying those two philosophies is former Deputy U.S. Secretary of Education James H. Shelton, now the initiative’s president of education.

“We’ve got to dispel this notion that personalized learning is just about technology,” Shelton said in an exclusive interview with Education Week. “In fact, it is about understanding students, giving them agency, and letting them do work that is engaging and exciting.”

Vast Resources, Many Levers

To advance that vision, Shelton has at his disposal a massive fortune and a wide array of levers to pull.

Chan and Zuckerberg created CZI as a vehicle for directing 99 percent of their Facebook shares—worth an estimated $45 billion—to causes related to education and science, through a combination of charitable giving and investment.

The initiative is structured as a limited-liability corporation, rather than a traditional foundation. That means CZI will be able to make philanthropic donations, invest in for-profit companies, lobby for favored policies and legislation, and directly support candidates for elected office—all with minimal public-reporting requirements.

For now, Shelton said, CZI is “one of the best-resourced startups in the world, but still a startup,” with fewer than 20 people on its education team.

In the near future, though, he expects the initiative to give out “hundreds of millions of dollars per year” for education-related causes. Such a figure would place the Chan Zuckerberg Initiative among the highest-giving education-focused philanthropies in the country.

Within five years, Shelton said in the June 22 interview, CZI’s work should have helped launch a “meaningful number” of schools and learning environments “where kids are performing dramatically better, and feel more engaged, and teachers feel more engaged in the work that they’re doing.”

Chan, 32, and Zuckerberg, 33, also have embraced the idea of a long horizon for the initiative’s work, saying their support for personalized learning will extend over decades.

From the outset, however, the couple’s attempt to engineer big changes in the U.S. education system faces significant obstacles.

“Personalized learning” was an amorphous concept even before this new attempt to integrate it with equally hard-to-define “whole child” strategies. It remains unclear how Chan, Zuckerberg, and Shelton intend to balance the organization’s support for research and development with their desire to quickly bring to scale new products and approaches, many of which have limited or no evidence to support their effectiveness.

And CZI won’t commit to publicly disclosing all of its financial and political activity or to making the source code for its software open and accessible to the larger education community. That stance has stirred complaints about a lack of transparency.

Other large-scale philanthropic attempts at improving education have run aground on similar barriers.

It can be hard for smart people with a fortune at their fingertips to remain patient, said Frederick M. Hess, the director of education policy studies at the American Enterprise Institute.

But the Chan Zuckerberg Initiative would be wise to avoid trying to go too far, too fast in its support for personalized learning, Hess said.

“This isn’t engineering a new ride-sharing app,” he said. “It’s how do we influence the learning of millions of children, day after day, for years to come.”

’Whole Child’ Personalization

Chan and Zuckerberg officially announced the creation of CZI in December 2015, shortly after the birth of their first child.

The couple’s commitment to personalized learning was a major boost for a trend with strong winds already at its back. Over the past several years, other philanthropists, venture capitalists, and advocates, along with the ed-tech industry, have pushed the notion hard. Many district and school leaders have responded favorably.

Now, Chan and Zuckerberg have a second child on the way. Facebook has its hands full with its network of nearly 2 billion social-media users, a new mission, and public concerns over its role in the spread of “fake news.” And Zuckerberg has been meeting with Iowa truckers and Ohio families on a 50-state tour, which many observers have speculated may be a precursor to a run for public office, although he has denied any such plans.

Still, the couple is finding time to play a hands-on role in shaping CZI’s educational strategy. Chan, a former classroom teacher, is at the initiative’s Palo Alto, Calif., offices as often as four days a week, Shelton said. Zuckerberg is there at least once every other week.

Each brings different priorities to the table, according to Shelton.

“Priscilla and I come into this work from similar perspectives,” he said. “She saw firsthand the impact that things outside the classroom had on students, and the range of needs that young people have.”

Zuckerberg, meanwhile, brings an engineering and design perspective to education problems, Shelton said. His focus: “how you get to everyone in the world.”

Both points of view are reflected in the Chan Zuckerberg Initiative’s early efforts on education.

To date, CZI has hired both its own engineers and its own learning scientist.

On the technology side, the initiative has invested in BYJU’S, an India-based startup behind a popular online-learning app, and Enlearn, a Seattle-based nonprofit that has developed a new adaptive-learning platform. The organization has also partnered with the Bill & Melinda Gates Foundation on a $12 million “venture philanthropy” grant award. (The Gates Foundation has also provided grant support for Education Week.)

At the same time, Shelton has overseen a number of grants to groups without a technology focus. Among them:

• Vision to Learn, a Los Angeles-based nonprofit that has provided free eye exams and prescription glasses to tens of thousands of students;

• The Center on the Developing Child, a Harvard University research center focused on using science to improve social policy and care for low-income children and families; and

• SAGA Innovations, a Newtown, Mass.-based nonprofit that provides struggling students with intensive face-to-face help from human tutors.

“Many people have a preconceived notion that ‘personalized learning’ is a kid in the corner alone with a computer,” Shelton said. “Forget about that.”

It’s a welcome message for a field that has long been split into opposing camps, said Robert Schwartz, a professor emeritus of education policy at Harvard and a former director of education grantmaking at the Pew Charitable Trusts.

“Saying we have to focus either on what happens inside schools, or on underlying issues around poverty and communities and families, is a false choice,” Schwartz said. “This is an important signal that CZI is sending.”

The initiative’s whole-child focus is also a smart tactical play, said David DeSchryver, a senior vice president at Whiteboard Advisors, an education policy research firm.

One big reason: the newest version of the main federal K-12 education law, the Every Student Succeeds Act, which is already pushing states and schools to think about more than standardized-test scores when determining what it means to help students thrive.

“It makes complete sense [for CZI] to push out [its] strategy in the context of what current administrators and leaders are already discussing,” DeSchryver said.

Personalized Learning Ready to Scale?

Still, some observers worry that the Chan Zuckerberg Initiative’s broad approach will further muddy two concepts—“personalized learning” and “whole child”—that already mean different things to different people.

The lack of clarity has made the personalized-learning movement hard to evaluate. Research so far is mixed, yielding some promising early findings around specific instructional practices and schools, but limited evidence to back up the transformative potential that proponents describe. The research has also sent strong signals that implementing personalized models is a huge challenge for many schools.

Those dynamics create a dilemma for the CZI. The resulting tension has shown up in Zuckerberg’s public remarks.

In a March 2016 interview with Education Week, for example, the Facebook CEO said many versions of personalized learning needed to be tested in the real world before any conclusions could be drawn, suggesting a focus on R&D.

But nine months later, Zuckerberg talked during a speech in Peru about “bringing personalized learning to all children” and helping “upgrade a majority of schools to personalized learning,” suggesting a Silicon Valley-style focus on rapid growth.

In the interview with Education Week, Shelton sought to straddle that divide. The Chan Zuckerberg Initiative, he said, will first aim to bring small advances to large numbers of students. As an example, he cited a recent grant to the College Board, aimed at expanding access to the organization’s personalized online SAT preparation and college-planning resources, which have shown early promise.

“You can bring those incremental improvements to people and improve their lives on a daily basis, even as you figure out how to get better,” Shelton said. “One small breakthrough leads to another breakthrough leads to another breakthrough, [and] pretty quickly they start adding up.”

But some skeptics say that if Chan, Zuckerberg, and Shelton were truly interested in seeing a thousand flowers bloom, they would pledge to making the software tools that CZI is developing and supporting open-source. That way, the underlying code would be available to others to use and adapt in ways that their original creators may not have foreseen.

Shelton avoided such a commitment. Any such decision would be made “over time,” he said.

Bill Fitzgerald, an open-source proponent and the director of the privacy-evaluation initiative at Common Sense Media, a San Francisco-based nonprofit and advocacy group, is among those who find that stance less than satisfying.

“If you’re serious about allowing people to learn in the ways that make the most sense to them, you have to give them more choices than just using your software, under your rules,” Fitzgerald said.

And Stanford University emeritus education professor Larry Cuban described an even more fundamental challenge in bringing personalized learning to scale.

Innovations in public education are more about people than technology, Cuban said. As a result, even the best-funded improvement efforts are often stymied by institutional barriers to changing how teachers teach and children learn.

“What they have run up against in public schools are the structures of the age-graded school, the demand of standards, and the responsibility for doing well on standardized tests,” Cuban said.

“If the Chan Zuckerberg Initiative thinks it will be easy to scale up within those structures, they’re in for a massive disappointment.”

Transparency Concerns

That’s a reality that Shelton has been wrestling with for a long time.

Before joining CZI, the 49-year-old Washington, D.C., native worked as a program officer at the Bill & Melinda Gates Foundation. As a top official in President Barack Obama’s Department of Education, he oversaw the Investing in Innovation program, which awarded $1.3 billion in federal grants to create a “pipeline” of research-based interventions.

Neither the foundation nor the department found clear success in bringing educational innovations to scale.

Now, though, Shelton said the Chan Zuckerberg Initiative is “trying to do something that’s never been done before, in a way that has never been done.”

One big difference is the many levers the organization will be able to pull.

One example: Traditional nonprofit philanthropies, such as the Gates Foundation, are generally prohibited from lobbying for specific legislation or participating directly in political campaigns. As a limited-liability corporation, CZI is not bound by such rules.

For now, at least, Shelton said CZI is “just figuring out how to use” the policy-advocacy tools at its disposal. The organization does not currently have a specific education policy agenda it is seeking to advance, he said.

But CZI won’t rule out the possibility that it might engage in a host of political activities in the future, including giving to candidates and establishing its own 501(c)4 organization or political action committee.

Nor would the initiative commit to publicly disclosing such activity if it occurs.

Despite professing a “commitment philosophically to transparency,” Shelton declined to commit to letting the public know of all the initiative’s philanthropic grants and for-profit investments.

And CZI has clearly signaled its intent to try to shape policy debates in education and to exert different kinds of influence in complementary ways. An online job description for the position of “director of innovative schools and tools,” for example, called for someone who can “ensure our nonprofits and for-profit investments are coordinated for maximum impact.”

Those emphases create the real potential for hidden conflicts, said Sarah Reckhow, an assistant professor of political science at Michigan State University who tracks philanthropic giving in education.

It’s not hard to imagine a CZI grant award predicated on schools using CZI’s favored software, Reckhow said, or a lobbying campaign to push for a charter school authorizer to approve new schools that use CZI’s favored personalized-learning approach.

So what is the Chan Zuckerberg Initiative doing to mitigate the potential for problematic overlap in its spheres of influence?

“We’re paying really close attention,” said Shelton. He added that forcing grantees to adopt specific tools is “not how we want to operate.”

Whether that’s enough to assuage critics who have already begun to mobilize against the personalized-learning movement—and who have voiced concern at the prospect of another billionaire seeking to push the educational system in his preferred direction—remains to be seen.

Ultimately, Shelton said, the Chan Zuckerberg Initiative feels as though it’s responsible primarily to the people the organization is hoping to serve.

“What we hope to do is understand how we can create the environments, tools, and resources that let all teachers do their best work and all students benefit from their teacher’s best teaching,” he said.

“I know many people will be watching.”

Output: The Chan-Zuckerberg Initiative (CZI), run by Facebook CEO Mark Zuckerberg and his wife, Priscilla Chan, is set to invest in a decades-long strategy of "whole child personalised learning". The initiative's head, former deputy US Secretary of Education James Shelton, said the concept was about "understanding students, giving them agency, and letting them do work that is engaging and exciting". CZI's limited liability status means it can lobby for specific legislation as it "tries to do something that’s never been done before, in a way that has never been done". Critics have challenged CZI's apparent lack of transparency.


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LeEco assets worth $180m frozen by Chinese court over arrears
 Chinese firm LeEco's downward spiral continues after unpaid debts lead a Shanghai court to freeze 1.2 billion yuan ($180 million) in assets owned by its subsidiaries, chairman and CEO Jia Yueting and his wife, according to various local media reports citing court documents.

The assets were originally pledged as collateral in 2015 for a 2.4 billion yuan loan, and cover bank deposits and other assets owned by subsidiaries including LeEco's main listed unit, LeShi Internet Information & Technology, LeShi Mobile Intelligence and LeView Mobile.

This is the latest blow to LeEco — once a tech darling success story in China, the firm's fortunes seem to be reversing almost as quickly as they rose. The company, founded by Jia, originally started as an online streaming site before quickly expanding its business into everything from smartphones to electric vehicles. The company even jumped overseas, launching in the U.S. and India.

Output: Assets worth $180m owned by LeEco's billionaire co-founder, Jia Yueting, his wife and three affiliates have been frozen by a Shanghai court after the company failed to pay interest due on bank loans taken out to fund its smartphone business, according to court documents. LeEco was once a tech success story in China, however, as the company branched out beyond smartphones, it spent far beyond its means and failed to sustain its revenues.


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Japanese bitcoin exchange bitFlyer offers transaction insurance
 Bitcoin has gained the status of a mainstream currency in Japan. The growth in adoption of a new mode of payment comes with its own set of challenges due to the decentralized nature of the cryptocurrency. Merchants including Bitcoin as a method of payment are a bit apprehensive about possible failed transactions which might force them to incur losses.

The leading Japanese Bitcoin exchange platform, bitFlyer has come up with a solution for merchants and businesses in the country. The company has partnered with one of the leading Japanese insurance firms, Mitsui Sumitomo Insurance to provide retailers with a unique Bitcoin insurance. The new insurance is custom made to address the merchants’ apprehensions about failed cryptocurrency transactions.

The first of its kind insurance product was released on Friday, and more similar policies are expected to enter the Japanese market soon. The new insurance will cover merchants of damages incurred during the occasions when the customers’ payment doesn’t go through correctly due to system problems or other issues.

A leading financial magazine also provides information about another upcoming insurance offering in the making, created by CoinCheck and Tokio Marine & Nichido Fire Insurance.

The insurance sector has so far been quite apprehensive about the cryptocurrency sector. There have been many instances where similar ideas were shot down before giving it serious consideration. With increasing popularity of Bitcoin, the insurance providers have evolved to meet the changing needs.

Even blockchain technology has gained inroads into the insurance industry. Various companies are currently working on creating distributed ledger based solutions that make use of smart contract to automate the issuance of policies and claim processing. The segment of the industry has already gained a name for itself, “Insurtech”.

As insurance companies increasingly opt a friendly stance towards cryptocurrencies, more crypto-businesses will opt for the services.

Ref: Nikkei | Image: NewsBTC

Output: Japanese bitcoin exchange bitFlyer has partnered with Mitsui Sumitomo Insurance to provide retail merchants with coverage for failed cryptocurrency transactions. In what is said to be the first product of its kind, the offering covers losses by merchants when customers opting to use a cryptocurrency fail to pay. Another similar offering is reportedly in the works between CoinCheck and Tokio Marine & Nichido Fire Insurance.


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NHS chief says precision medicine calls for routine DNA testing
 Genomic testing should become a normal part of NHS care, beginning with cancer patients and those with rare diseases, says the chief medical officer, Dame Sally Davies.

In her annual report, Davies stresses her enthusiasm for the genomic revolution which could transform the treatment that NHS patients receive. Drugs can be matched to the disease and to the patient to maximise the benefit and reduce side-effects.

The genome is the collection of 20,000 genes, including 3.2 billion letters of DNA, that make up any individual. We all share about 99.8% of the genome. The secrets of our individuality – and also of the diseases we are prone to – lie in the other 0.2%, which is about 3 or 4 million letters of DNA.

Davies says that individual patients have everything to gain from the pooling of data which allows scientists to compare hundreds of thousands of genomes, to find out why some have small mutations or errors in the code that lead to illness. She talked of a new “social contract”, in which the public recognises that they and everybody else will benefit if they allow data about their own genome to be studied.

“The age of precision medicine is now and the NHS must act fast to keep its place at the forefront of global science,” said Davies. “This technology has the potential to change medicine forever – but we need all NHS staff, patients and the public to recognise and embrace its huge potential. Genomic medicine has huge implications for the understanding and treatment of rare diseases, cancer and infections.”

Cancer and rare diseases are the first targets for genomic medicine. More than 30,000 people have had their genomes sequenced so far. Within five years, she would like to see genomic testing to be as normal as blood tests and biopsies for cancer patients, leading to the most appropriate treatment for the individual. Davies said she wanted to “democratise” genomics medicine so that it would be available to every patient for whom it was appropriate.

“That means we have got to change the NHS system,” she said. Genomics is at present “a cottage industry” which needed to be centralised and extended across the country. “We need to take the science to the patients and not the patients to the science,” she said.

There are great potential benefits for patients with rare diseases, defined as those affecting fewer than one in 2,000 patients. But there are at least 6,000 rare diseases worldwide and at least three million people – often children – in the UK suffer from them. Genome sequencing is also very useful in infectious diseases, allowing doctors to find out whether antibiotic and antiviral drugs will work in a patient.

Amongst her recommendations, Davies calls for a National Genomics Board to be set up, chaired by a government minister. All genomic laboratories should be centralised and a national network established to provide equal access across the country, she says.

Output: The UK National Health Service should perform genomic testing to better match patients' diseases to treatment as part of a standard care package, according to chief medical officer Dame Sally Davies in her annual report. She also called for the centralisation of all genomic laboratories, and the creation of a National Genomics Board, headed by a government minister. "Genomic medicine has huge implications for the understanding and treatment of rare diseases, cancer and infections," said Davies.


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Judge dismisses lawsuit against Facebook tracking logged out users
 A judge has dismissed a lawsuit brought by Facebook users aggrieved at being tracked by the social networking giant even after they’d logged out – by pinning responsibility on plaintiffs to keep their own browsing history private.

Judge rules in favour of Facebook tracking logged-out users

The court case was brought by users concerned that by clicking ‘like’ buttons on other websites the Silicon Valley firm would be able to build a picture of an individual’s browsing habits, amounting to a possible infringement of privacy.

Output: A US District Court judge has thrown out a lawsuit against social media giant Facebook, in which the plaintiffs argued their privacy had been infringed by clicking 'like' buttons on other websites. The claimants also said Facebook could use their browsing behaviour to build up a picture of users' habits. However, Edward Davila ruled the perceived intrusion could be easily blocked using Facebook's own tools. He said: "The fact that a user’s web browser automatically sends the same information to both parties does not establish that one party intercepted the user’s communication with the other."


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Facebook mobile app will roll out WiFi finder feature
 Facebook is rolling out a new feature within its mobile app that will help you find the nearest public Wi-Fi networks anywhere in the world. Originally spotted last November as part of a limited test, the feature is now launching for everyone under the Find WiFi section within the 'More' tab.

You might be prompted to turn it on first since it's not on by default. Once that's done you will be able to see a list of the closest public Wi-Fi hotspots or browse them on a map, then after clicking on one of them you'll see more information on the businesses hosting it, like open hours, what kind of place it is (restaurant, library, etc.), and the name of their network.

Find WiFi could be useful for people in emerging markets where mobile data is slow or expensive, as well as people who don't want to incur heavy roaming charges when traveling internationally, and otherwise pretty much anyone that doesn't want to eat up their data allowance while using data intensive features like broadcasting through Facebook Live.

This isn't the first time Facebook tries to facilitate Wi-Fi access. Two years ago, the company partnered with Cisco in a pilot program that offered free internet access in participating businesses in exchange for a check in. It also launched the controversial 'Free Basics' service, which offered free but limited internet access to people who don't have it.

In this case Facebook isn't providing Wi-Fi hotspots itself, nor it is compiling its own map of businesses offering them. Instead it's simply letting businesses register their hotspots, so they appear under the new Find WiFi menu in the Facebook mobile app.

The new feature is beginning to roll out on iPhone and Android. Keep in mind that enabling Find WiFi also turns on Facebook's Location History feature which the social network uses to gather data it can then use to sell targeted ads.

Output: Facebook is rolling out a tool across iPhone and Android, enabling users to find their nearest public WiFi hotspots. Located under the 'More' tab, the Find WiFi feature needs to be turned on to function, although activating it also turns on Facebook's Location History feature, which allows brands to send targeted ads. Find WiFi is Facebook's third foray into facilitating WiFi access and could help international travellers avoid heavy roaming costs, or help people living in areas with slow or costly mobile data.


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Tencent limits amount of time children can spend on game app
 Generally, the aim for most apps is to increase user engagement time – but Chinese internet giant Tencent has put restrictions on one of its most popular mobile games, in an attempt to address concerns about children's gaming habits.

Honour of Kings, which is the world's highest-grossing mobile game with over 200m users, is introducing daily time limits for younger players. Users under 12 years of age will be limited to an hour of play each day, and 12-18 year olds will be limited to two hours.

It is also restricting under-12s from logging into the game after 9pm, and will be putting limits on the amount of money younger users can spend in-app.

The game's 200m-strong audience is primarily Chinese and young – over a quarter are under 19, according to data firm Jiguang, putting them in the age range for these new measures.

Don’t forget to enter the Effective Mobile Marketing Awards. The Early Bird deadline for submissions is 22 July. More details here.

Output: Up to a quarter of the 200 million Chinese gamers playing Honour of Kings, the world's highest-grossing mobile game, could be affected by Tencent's decision to bring in daily time limits for players aged up to 18 years. The tech giant, responding to concerns about children's gaming habits, has said users below the age of 12 will be limited to an hour's daily play, while user aged between 12 and 18 will have two hours.