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Background Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss. Current approaches to control myopia progression are effective but have significant side effects. Therefore, identifying those at greatest risk who should undergo targeted therapy is of great clinical importance. The objective of this study was to apply big data and machine learning technology to develop an algorithm that can predict the onset of high myopia, at specific future time points, among Chinese school-aged children. Methods and findings Real-world clinical refraction data were derived from electronic medical record systems in 8 ophthalmic centres from January 1, 2005, to December 30, 2015. The variables of age, spherical equivalent (SE), and annual progression rate were used to develop an algorithm to predict SE and onset of high myopia (SE ≤ −6.0 dioptres) up to 10 years in the future. Random forest machine learning was used for algorithm training and validation. Electronic medical records from the Zhongshan Ophthalmic Centre (a major tertiary ophthalmic centre in China) were used as the training set. Ten-fold cross-validation and out-of-bag (OOB) methods were applied for internal validation. The remaining 7 independent datasets were used for external validation. Two population-based datasets, which had no participant overlap with the ophthalmic-centre-based datasets, were used for multi-resource validation testing. The main outcomes and measures were the area under the curve (AUC) values for predicting the onset of high myopia over 10 years and the presence of high myopia at 18 years of age. In total, 687,063 multiple visit records (≥3 records) of 129,242 individuals in the ophthalmic-centre-based electronic medical record databases and 17,113 follow-up records of 3,215 participants in population-based cohorts were included in the analysis. Our algorithm accurately predicted the presence of high myopia in internal validation (the AUC ranged from 0.903 to 0.986 for 3 years, 0.875 to 0.901 for 5 years, and 0.852 to 0.888 for 8 years), external validation (the AUC ranged from 0.874 to 0.976 for 3 years, 0.847 to 0.921 for 5 years, and 0.802 to 0.886 for 8 years), and multi-resource testing (the AUC ranged from 0.752 to 0.869 for 4 years). With respect to the prediction of high myopia development by 18 years of age, as a surrogate of high myopia in adulthood, the algorithm provided clinically acceptable accuracy over 3 years (the AUC ranged from 0.940 to 0.985), 5 years (the AUC ranged from 0.856 to 0.901), and even 8 years (the AUC ranged from 0.801 to 0.837). Meanwhile, our algorithm achieved clinically acceptable prediction of the actual refraction values at future time points, which is supported by the regressive performance and calibration curves. Although the algorithm achieved balanced and robust performance, concerns about the compromised quality of real-world clinical data and over-fitting issues should be cautiously considered. Conclusions To our knowledge, this study, for the first time, used large-scale data collected from electronic health records to demonstrate the contribution of big data and machine learning approaches to improved prediction of myopia prognosis in Chinese school-aged children. This work provides evidence for transforming clinical practice, health policy-making, and precise individualised interventions regarding the practical control of school-aged myopia., Therapies to control myopia progression confer significant side effects and should be targeted to those at highest risk. Here, Yizhi Liu and colleagues report a machine learning algorithm that predicts the progression of myopia, into early adulthood, among Chinese school-aged children., Author summary Why was this study done? Myopia has reached epidemic levels among young adults in East and Southeast Asia, affecting an estimated 80%–90% of high school graduates, with approximately 20% of them having high myopia. Various interventions, including atropine eyedrops and orthokeratology, have been proposed to control myopia progression; however, these approaches confer significant side effects. Identifying those at greatest risk who should undergo targeted therapy is the most important clinical challenge faced by ophthalmologists and optometrists. Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. Taking school-aged myopia, the most prevalent eye disease, as an example, it would be of great value to use ophthalmic-centre-based electronic medical records to develop a big-data-driven clinical prediction algorithm based on machine learning algorithms. What did the researchers do and find? This study analysed 687,063 longitudinal electronic medical records from the largest ophthalmic centres in China and developed and validated individualised prediction models for myopia prediction based on machine learning techniques. Our model predicted spherical equivalent and onset of high myopia at 18 years of age at a clinically acceptable accuracy and as early as 8 years in advance. What do these findings mean? The algorithm, which was trained and validated using a large real-world dataset, was able to predict the presence of high myopia with clinically acceptable accuracy among Chinese school-aged populations. Large-scale, long-term electronic medical records and machine learning algorithms provide unique opportunities for the development of prediction models for progressive diseases, such as myopia in school-aged children. Our findings have great potential to change current approaches used to manage school myopia by paediatric and general ophthalmologists as well as general practitioners and optometrists, who are often the first point of care.

Background Secondhand smoke can cause adverse pregnancy outcomes, yet there is a lack of effective smoking cessation interventions targeted at expectant fathers. We examined the effectiveness of a video-based smoking cessation intervention focusing on maternal and child health in promoting quitting among expectant fathers. Methods and findings A single-blind, 3-arm, randomized controlled trial was conducted at the obstetrics registration centers of 3 tertiary public hospitals in 3 major cities (Guangzhou, Shenzhen, and Foshan) in China. Smoking expectant fathers who registered with their pregnant partners were invited to participate in this study. Between 14 August 2017 to 28 February 2018, 1,023 participants were randomized to a video (n = 333), text (n = 322), or control (n = 368) group. The video and text groups received videos or text messages on the risks of smoking for maternal and child health via instant messaging. The control group received a leaflet with information on smoking cessation. Follow-up visits were conducted at 1 week and at 1, 3, and 6 months. The primary outcome, by intention to treat (ITT), was validated abstinence from smoking at the 6-month follow-up. The secondary outcomes included 7-day point prevalence of abstinence (PPA) and level of readiness to quit at each follow-up. The mean age of participants was 32 years, and about half of them were first-time expectant fathers. About two-thirds of participants had completed tertiary education. The response rate was 79.7% (815 of 1,023) at 6 months. The video and text groups had higher rates of validated abstinence than the control group (video group: 22.5% [75 of 333], P < 0.001; text group: 14.9% [48 of 322], P = 0.02; control group: 9.2% [34 of 368]) with adjusted odds ratios (ORs) of 2.80 (95% confidence interval [CI]: 1.79–4.37, P < 0.001) in the video group and 1.70 (95% CI: 1.06–2.74, P = 0.03) in the text group. The video and text groups differed in the rates of validated abstinence (22.5% versus 14.9%, P = 0.008; adjusted OR: 1.64, 95% CI: 1.10–2.46, P = 0.02). The video and text groups had higher rates of 7-day PPA than the control group at 6 months (video group: 24.6% [82 of 333] versus 11.4% [42 of 368], P < 0.001; text group: 17.4% [56 of 333] versus 11.4% [42 of 368], P = 0.02). The video and text groups also differed in the rates of 7-day PPA (24.6% versus 17.4%, P = 0.02). Excluding the quitters, the video and text groups had higher levels of readiness to quit than the control group at 6 months (video group: 43.5% [109 of 251] versus 31.6% [103 of 326], P = 0.002; text group: 40.6% [108 of 266] versus 31.6% [103 of 326], P = 0.01), No such difference was detected between the video and text groups (43.5% versus 40.6%, P = 0.29). The study was limited in that the long-term effectiveness of the intervention is uncertain. Conclusions This smoking cessation intervention for expectant fathers that focused on explaining the ramifications of smoking on maternal and child health was effective and feasible in promoting quitting, and video messages were more effective than texts in delivering the information. Trial registration ClinicalTrials.gov: NCT03236025., Wei Xia and colleagues reveal the benefit of a video-based intervention to help expectant fathers quit smoking., Author summary Why was this study done? Exposure to secondhand smoke can cause adverse pregnancy and childbirth outcomes and negatively affect maternal and child health. Video has been used in multiple types of behavioral interventions, but there is a paucity of evidence on its effectiveness in changing addictive behaviors such as smoking. The aim of the study was to evaluate the effectiveness of a video-based smoking cessation intervention focusing on maternal and child health in promoting quitting among expectant fathers. What did the researchers do and find? A total of 1,023 smoking expectant fathers were randomly allocated to a video-based, text, or control group. Participants received four 1-minute videos (video group) or 4 text messages (text group) on the risks of smoking for maternal and child health via instant messaging every 2 weeks or a leaflet on smoking cessation (control group). At 6-month follow-up, participants who received the videos or texts had higher rates of validated abstinence than the controls. The video-based intervention was more effective than the text-based intervention. What do these findings mean? This trial provides evidence that videos incorporating information on the adverse effects of secondhand smoke on maternal and child health are effective in helping expectant fathers to quit smoking. Using instant messaging to deliver smoking cessation videos is feasible and acceptable to participants.

Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Using mendelian randomization approaches, Paul Brennan and colleagues reveal an association between 12 obesity-related factors, including insulin and the development of renal cell carcinoma., Author summary Why was this study done? Traditional observational studies wherein putative risk factors are measured directly have found several obesity-related factors associated with increased risk of renal cell carcinoma (RCC). Traditional observational studies are subject to confounding and reverse causation and have not been able to disentangle which obesity-related risk factors directly influence RCC risk. This study used an alternative methodology commonly referred to as mendelian randomization (MR). MR circumvents many of the inherent limitations of traditional observational study by use of genetic proxies of putative risk factors when evaluating their associations with disease risk, as they are not subject to reverse causation and are less likely to be confounded by other risk factors. What did the researchers do and find? First, we used large-scale genome-wide association studies (GWAS) to identify genetic variants associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose. Second, these genetic variants were used as proxies for the above-mentioned risk factors and evaluated in relation RCC risk using GWAS data from 10,000 RCC patients and 20,000 control participants. Based on these genetic data, we found that multiple measures of obesity, as well as diastolic blood pressure (DBP) and fasting insulin, are associated with RCC risk. In contrast, we found little evidence for an association with RCC risk for systolic blood pressure (SBP), circulating lipids, overall diabetes, or fasting glucose. What do these findings mean? This study provided robust and confirmatory evidence of an important role of obesity as an important risk factor of RCC. Further confirmatory evidence was found for elevated DBP as a risk factor of RCC, but it is not clear why DBP rather than SBP is important in RCC. The study, to our knowledge, provided novel evidence of an important role of circulating insulin in RCC etiology. This study provided some novel insights into the pathways involved in mediating the risk increase in RCC that is caused by obesity, most notably through insulin and DBP, but further research is needed to fully elucidate the important relationship between obesity and RCC.

Background Multistage stepwise HIV testing and treatment initiation procedures can result in lost opportunities to provide timely antiretroviral therapy (ART). Incomplete patient engagement along the continuum of HIV care translates into high levels of preventable mortality. We aimed to evaluate the ability of a simplified test and treat structural intervention to reduce mortality. Methods and Findings In the “pre-intervention 2010” (from January 2010 to December 2010) and “pre-intervention 2011” (from January 2011 to December 2011) phases, patients who screened HIV-positive at health care facilities in Zhongshan and Pubei counties in Guangxi, China, followed the standard-of-care process. In the “post-intervention 2012” (from July 2012 to June 2013) and “post-intervention 2013” (from July 2013 to June 2014) phases, patients who screened HIV-positive at the same facilities were offered a simplified test and treat intervention, i.e., concurrent HIV confirmatory and CD4 testing and immediate initiation of ART, irrespective of CD4 count. Participants were followed for 6–18 mo until the end of their study phase period. Mortality rates in the pre-intervention and post-intervention phases were compared for all HIV cases and for treatment-eligible HIV cases. A total of 1,034 HIV-positive participants (281 and 339 in the two pre-intervention phases respectively, and 215 and 199 in the two post-intervention phases respectively) were enrolled. Following the structural intervention, receipt of baseline CD4 testing within 30 d of HIV confirmation increased from 67%/61% (pre-intervention 2010/pre-intervention 2011) to 98%/97% (post-intervention 2012/post-intervention 2013) (all p < 0.001 [i.e., for all comparisons between a pre- and post-intervention phase]), and the time from HIV confirmation to ART initiation decreased from 53 d (interquartile range [IQR] 27–141)/43 d (IQR 15–113) to 5 d (IQR 2–12)/5 d (IQR 2–13) (all p < 0.001). Initiation of ART increased from 27%/49% to 91%/89% among all cases (all p < 0.001) and from 39%/62% to 94%/90% among individuals with CD4 count ≤ 350 cells/mm3 or AIDS (all p < 0.001). Mortality decreased from 27%/27% to 10%/10% for all cases (all p < 0.001) and from 40%/35% to 13%/13% for cases with CD4 count ≤ 350 cells/mm3 or AIDS (all p < 0.001). The simplified test and treat intervention was significantly associated with decreased mortality rates compared to pre-intervention 2011 (adjusted hazard ratio [aHR] 0.385 [95% CI 0.239–0.620] and 0.380 [95% CI 0.233–0.618] for the two post-intervention phases, respectively, for all newly diagnosed HIV cases [both p < 0.001], and aHR 0.369 [95% CI 0.226–0.603] and 0.361 [95% CI 0.221–0.590] for newly diagnosed treatment-eligible HIV cases [both p < 0.001]). The unit cost of an additional patient receiving ART attributable to the intervention was US$83.80. The unit cost of a death prevented because of the intervention was US$234.52. Conclusions Our results demonstrate that the simplified HIV test and treat intervention promoted successful engagement in care and was associated with a 62% reduction in mortality. Our findings support the implementation of integrated HIV testing and immediate access to ART irrespective of CD4 count, in order to optimize the impact of ART., In a before and after analysis, Zunyou Wu and colleagues assess the impact on mortality of an HIV test and treat intervention in two counties in Guangxi, China., Editors' Summary Background Every year, about 2.1 million people (mostly living in resource-limited countries) are newly infected with HIV, the virus that causes AIDS and that has killed 39 million people over the past three decades. HIV, which is usually transmitted through unprotected sex with an infected individual, gradually destroys CD4 lymphocytes and other immune system cells, leaving HIV-positive individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) became available, and, for people living in high-income countries, HIV became a chronic condition. But ART was expensive, so HIV/AIDS remained largely untreated and fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal ART coverage. By 2013, about 12.9 million people living with HIV (a third of all HIV-positive people) had access to ART, and the rate of AIDS-related deaths had fallen by a third from its 2005 peak. Why Was This Study Done? Unfortunately, in many countries, late diagnosis of HIV infection, incomplete linkage to care after diagnosis, and high rates of loss to follow-up before and after ART initiation remain major barriers to effective HIV/AIDS treatment and to maximization of the preventative benefits of ART: as well as keeping HIV-positive people healthy, ART also reduces their chances of transmitting HIV to a sexual partner. Here, the researchers investigate whether a simplified “test and treat” intervention can reduce HIV/AIDS mortality (death) rates in China by reducing these barriers. Currently, CD4 testing is offered to people in China only after an initial HIV diagnosis has been confirmed using a second type of test. This standard-of-care policy introduces a delay into ART initiation because a CD4 count below 350 cells/μl blood is the primary determinant of eligibility for treatment through the Chinese national free ART program. By contrast, the simplified test and treat intervention, which is designed to be completed within a week of the patient’s first positive HIV test result, incorporates immediate HIV confirmatory testing, pre-ART CD4 testing, pre-treatment counseling, and ART initiation regardless of CD4 count. What Did the Researchers Do and Find? The researchers followed about 1,000 patients who tested positive for HIV at health care facilities in two counties in Guangxi (one of the Chinese provinces most heavily affected by HIV/AIDS) in two 12-month pre-intervention phases, during which patients followed the standard-of-care process, and two 12-month post-intervention phases, during which patients were offered the simplified test and treat intervention. About 65% and 97% of the patients received baseline CD4 testing during the pre-intervention and post-intervention phases, respectively. Following the structural intervention, the time from HIV confirmation to ART initiation decreased from around 50 days to five days, and the proportion of individuals who initiated ART increased from below 36% to above 90% among all the patients and from below 47% to above 93% among patients eligible for treatment under the standard-of-care policy. Notably, the mortality rate decreased from about 26% to about 10% among all the study participants following the intervention, and from about 37% to about 13% among the participants eligible for ART under the standard-of-care policy. Finally, the researchers estimated that the cost of each death prevented by the intervention was about US$234.52 over the study period; importantly, most of this cost was accrued during the initial year of the intervention. What Do These Findings Mean? These findings indicate that, in the two Chinese counties involved in this study, the simplified test and treat intervention—which incorporated a streamlined, standardized time frame for HIV diagnosis and expanded access to ART—promoted successful engagement in care among HIV-positive individuals and was associated with a 62% reduction in mortality. Moreover, the intervention required very little further investment once it had been set up and should, therefore, be sustainable. Because the design of the simplified test and treat intervention took into account the characteristics of the HIV epidemic and the health care structure in China, these findings may not be fully generalizable to other countries. In addition, reliance on a pre-intervention/post-intervention study design, rather than a controlled trial, may limit the accuracy of these findings. Nevertheless, these results suggest that the implementation of integrated HIV testing and immediate access to ART regardless of CD4 count has the potential to optimize the individual and public health impacts of ART by ensuring that fewer patients are lost along the multistage continuum of HIV testing and treatment. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001874. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART and on HIV/AIDS in China; Avert also provides personal stories about living with HIV/AIDS The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its Consolidated Guidelines on the Use of Antiretroviral Therapy for Treating and Preventing HIV Infection, its recently released consolidated guidelines on HIV testing, and information on the WHO/UNAIDS Treatment 2.0 strategy, an initiative to expand access to HIV testing and ART The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it, including progress towards universal access to antiretroviral therapy

Background Industrialization and demographic transition generate nonstationary dynamics in human populations that can affect the transmission and persistence of infectious diseases. Decades of increasing vaccination and development have led to dramatic declines in the global burden of measles, but the virus remains persistent in much of the world. Here we show that a combination of demographic transition, as a result of declining birth rates, and reduced measles prevalence, due to improved vaccination, has shifted the age distribution of susceptibility to measles throughout China. Methods and findings We fit a novel time-varying catalytic model to three decades of age-specific measles case reporting in six provinces in China to quantify the change in the age-specific force of infection for measles virus over time. We further quantified the impact of supplemental vaccination campaigns on the reduction of susceptible individuals. The force of infection of measles has declined dramatically (90%–97% reduction in transmission rate) in three industrialized eastern provinces during the last decade, driving a concomitant increase in both the relative proportion and absolute number of adult cases, while three central and western provinces exhibited dynamics consistent with endemic persistence (24%–73% reduction in transmission rate). The reduction in susceptible individuals due to supplemental vaccination campaigns is frequently below the nominal campaign coverage, likely because campaigns necessarily vaccinate those who may already be immune. The impact of these campaigns has significantly improved over time: campaigns prior to 2005 were estimated to have achieved less than 50% reductions in the proportion susceptible in the target age classes, but campaigns from 2005 onwards reduced the susceptible proportion by 32%–87%. A limitation of this study is that it relies on case surveillance, and thus inference may be biased by age-specific variation in measles reporting. Conclusions The age distribution of measles cases changes in response to both demographic and vaccination processes. Combining both processes in a novel catalytic model, we illustrate that age-specific incidence patterns reveal regional differences in the progress to measles elimination and the impact of vaccination controls in China. The shift in the age distribution of measles susceptibility in response to demographic and vaccination processes emphasizes the importance of progressive control strategies and measures to evaluate program success that anticipate and react to this transition in observed incidence., Matthew Ferrari and colleagues use a mathematical modelling approach to explore the contribution of both demographic forces and immunization programs to the changing age-distribution of measles cases in China., Author summary Why was this study done? Though the incidence of measles has been greatly reduced, achieving elimination remains a significant public health challenge. The epidemiology of measles, in particular the age-specific patterns of incidence, is strongly influenced by both demographic rates and vaccination and control efforts. China has observed an increase in the number and proportion of measles cases in adults in recent years, a pattern that has been seen in many other countries with successful vaccination programs. Our study was designed to quantify the contribution of both demographic forces and immunization programs to the changing age distribution of measles cases in China. What did the researchers do and find? We analyzed 30 years of age-specific measles case reports from six provinces in China using a novel model that accounts for the impact of demographic change and age-targeted vaccination campaigns. We found that the increase in adult cases in China is more pronounced in eastern provinces and is consistent with indirect protection from exposure to measles infection in childhood due to herd immunity, but age incidence patterns in the central and western provinces are consistent with continued endemic measles transmission. We estimate that while historical supplemental vaccination campaigns resulted in lower immunity than expected based on coverage, recent campaigns have resulted in substantial improvements in population immunity. What do these findings mean? Progress towards measles elimination at the national level is often heterogeneous in space. Demographic and age-specific case surveillance data, linked via epidemiological models, can be integrated to provide evaluation of vaccine program performance.

Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker., Background Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer. Methods and Findings Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis. Conclusions Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease., Editors' Summary Background Each year, more than one million women discover that they have breast cancer. This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy. These “adjuvant” therapies are designed to kill any remaining cancer cells but can make patients very ill. Generally speaking, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis. Why Was This Study Done? Although breast cancer is usually diagnosed in women in their 50s or 60s, some women develop breast cancer much earlier. In these women, the disease is often very aggressive. Compared to older women, young women with breast cancer have a lower overall survival rate and their cancer is more likely to recur locally or to metastasize. It would be useful to be able to recognize those younger women at the greatest risk of cancer recurrence so that they could be offered intensive surveillance and adjuvant therapy; those women at a lower risk could have gentler treatments. To achieve this type of “stratification,” the genetic changes that underlie breast cancer in young women need to be identified. In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease. What Did the Researchers Do and Find? The researchers used “suppression subtractive hybridization” to identify a new gene in a region of human Chromosome 1 where loss of heterozygosity (LOH; a genetic alteration associated with cancer development) frequently occurs. They called the gene DEAR1 (ductal epithelium-associated RING Chromosome 1) to indicate that it is expressed in ductal and glandular epithelial cells and encodes a “RING finger” protein (specifically, a subtype called a TRIM protein; RING finger proteins such as BRCA1 and BRCA2 have been implicated in early cancer development and in a large fraction of inherited breast cancers). DEAR1 expression was reduced or lost in several ductal carcinomas in situ (a local abnormality that can develop into breast cancer) and advanced breast cancers, the researchers report. Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes). To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1. They then examined the growth of these genetically manipulated cells in special three-dimensional cultures. The breast cancer cells without DEAR1 grew rapidly without an organized structure while the breast cancer cells containing the introduced copy of DEAR1 formed structures that resembled normal breast acini (sac-like structures that secrete milk). In normal human mammary epithelial cells, the researchers silenced DEAR1 expression and also showed that without DEAR1, the normal mammary cells lost their ability to form proper acini. Finally, the researchers report that DEAR1 expression (detected “immunohistochemically”) was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome. What Do These Findings Mean? These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer. Although laboratory experiments may not necessarily reflect what happens in people, the results from the three-dimensional culture of breast epithelial cells suggest that DEAR1 may regulate the normal acinar structure of the breast. Consequently, loss of DEAR1 expression could be an early event in breast cancer development. Most importantly, the correlation between DEAR1 expression and both local recurrence in early-onset breast cancer and a breast cancer subtype with a poor outcome suggests that it might be possible to use DEAR1 expression to identify women with early-onset breast cancer who have an increased risk of local recurrence so that they get the most appropriate treatment for their cancer. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000068. This study is further discussed in a PLoS Medicine Perspective by Senthil Muthuswamy The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on genetic alterations in breast cancer (in English and Spanish) The MedlinePlus Encyclopedia provides information for patients about breast cancer; MedlinePlus also provides links to many other breast cancer resources (in English and Spanish) The UK charities Cancerbackup (now merged with MacMillan Cancer Support) and Cancer Research UK also provide detailed information about breast cancer

Pixin Ran, Nanshan Zhong, and colleagues report that cleaner cooking fuels and improved ventilation were associated with better lung function and reduced COPD among a cohort of villagers in Southern China. Please see later in the article for the Editors' Summary, Background Biomass smoke is associated with the risk of chronic obstructive pulmonary disease (COPD), but few studies have elaborated approaches to reduce the risk of COPD from biomass burning. The purpose of this study was to determine whether improved cooking fuels and ventilation have effects on pulmonary function and the incidence of COPD. Methods and Findings A 9-y prospective cohort study was conducted among 996 eligible participants aged at least 40 y from November 1, 2002, through November 30, 2011, in 12 villages in southern China. Interventions were implemented starting in 2002 to improve kitchen ventilation (by providing support and instruction for improving biomass stoves or installing exhaust fans) and to promote the use of clean fuels (i.e., biogas) instead of biomass for cooking (by providing support and instruction for installing household biogas digesters); questionnaire interviews and spirometry tests were performed in 2005, 2008, and 2011. That the interventions improved air quality was confirmed via measurements of indoor air pollutants (i.e., SO2, CO, CO2, NO2, and particulate matter with an aerodynamic diameter of 10 µm or less) in a randomly selected subset of the participants' homes. Annual declines in lung function and COPD incidence were compared between those who took up one, both, or neither of the interventions. Use of clean fuels and improved ventilation were associated with a reduced decline in forced expiratory volume in 1 s (FEV1): decline in FEV1 was reduced by 12 ml/y (95% CI, 4 to 20 ml/y) and 13 ml/y (95% CI, 4 to 23 ml/y) in those who used clean fuels and improved ventilation, respectively, compared to those who took up neither intervention, after adjustment for confounders. The combined improvements of use of clean fuels and improved ventilation had the greatest favorable effects on the decline in FEV1, with a slowing of 16 ml/y (95% CI, 9 to 23 ml/y). The longer the duration of improved fuel use and ventilation, the greater the benefits in slowing the decline of FEV1 (p, Editors' Summary Background Nearly 3 billion people in developing countries heat their homes and cook by burning biomass—wood, crop waste, and animal dung—in open fires and leaky stoves. Burning biomass this way releases pollutants into the home that impair lung function and that are responsible for more than a million deaths from chronic obstructive pulmonary disease (COPD) every year. COPD is a group of diseases that interfere with breathing. Normally, air is breathed in through the nose or mouth and travels down the windpipe into two bronchial tubes (airways) in the lungs. These tubes branch into smaller tubes (bronchioles) that end in bunches of tiny air sacs (alveoli). Oxygen in the air passes through the thin walls of these sacs into small blood vessels and is taken to the heart for circulation round the body. The two main types of COPD—chronic bronchitis (long-term irritation and swelling of the bronchial tubes) and emphysema (damage to the walls of the alveoli)—make it hard for people to breathe. Most people with COPD have both chronic bronchitis and emphysema, both of which are caused by long-term exposure to cigarette smoke, indoor air pollution, and other lung irritants. Symptoms of COPD include breathlessness during exercise and a persistent cough that produces large amounts of phlegm (mucus). There is no cure for COPD, but drugs and oxygen therapy can relieve its symptoms, and avoiding lung irritants can slow disease progression. Why Was This Study Done? Exposure to indoor air pollution has been associated with impaired lung function and COPD in several studies. However, few studies have assessed the long-term effects on lung function and on the incidence of COPD (the proportion of a population that develops COPD each year) of replacing biomass with biogas (a clean fuel produced by bacterial digestion of biodegradable materials) for cooking and heating, or of improving kitchen ventilation during cooking. Here, the researchers undertook a nine-year prospective cohort study in rural southern China to investigate whether these interventions are associated with any effects on lung function and on the incidence of COPD. A prospective cohort study enrolls a group of people, determines their characteristics at baseline, and follows them over time to see whether specific characteristic are associated with specific outcomes. What Did the Researchers Do and Find? The researchers offered nearly 1,000 people living in 12 villages in southern China access to biogas and to improved kitchen ventilation. All the participants, who adopted these interventions according to personal preferences, completed a questionnaire about their smoking habits and occupational exposure to pollutants and had their lung function measured using a spirometry test at the start and end of the study. Some participants also completed a questionnaire and had their lung function measured three and six years into the study. Finally, the researchers measured levels of indoor air pollution in a randomly selected subset of homes at the end of the study to confirm that the interventions had reduced indoor air pollution. Compared with non-use, the use of clean fuels and of improved ventilation were both associated with a reduction in the decline in lung function over time after adjusting for known characteristics that affect lung function, such as smoking. The use of both interventions reduced the decline in lung function more markedly than either intervention alone, and the benefits of using the interventions increased with length of use. Notably, the combined use of both interventions reduced the risk of COPD occurrence among the study participants. What Do These Findings Mean? These findings suggest that, among people living in rural southern China, the combined interventions of use of biogas instead of biomass and improved kitchen ventilation were associated with a reduced decline in lung function over time and with a reduced risk of COPD. Because participants were not randomly allocated to intervention groups, the people who adopted the interventions may have shared other unknown characteristics (confounders) that affected their lung function (for example, having a healthier lifestyle). Thus, it is not possible to conclude that either intervention actually caused a reduction in the decline in lung function. Nevertheless, these findings suggest that the use of biogas as a substitute for biomass for cooking and heating and improvements in kitchen ventilation might lead to a reduction in the global burden of COPD associated with biomass smoke. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001621. The US National Heart, Lung, and Blood Institute provides detailed information for the public about COPD The US Centers for Disease Control and Prevention provides information about COPD and links to other resources (in English and Spanish) The UK National Health Service Choices website provides information for patients and carers about COPD, personal stories, and links to other resources The British Lung Foundation, a not-for-profit organization, provides information about COPD in several languages The Global Initiative for Chronic Obstructive Lung Disease works to improve prevention and treatment of COPD around the world The World Health Organization provides information about all aspects of indoor air pollution and health (in English, French, and Spanish) MedlinePlus provides links to other information about COPD (in English and Spanish)