Adverse events after a lower limb amputation (LLA) can negatively affect the rehabilitation process and may lead to emergency department (ED) visits. Earlier receipt of a prosthesis, as compared to delayed or not receiving a prosthesis, may decrease or moderate the risk of increased ED utilization. In addition, adverse events  may be associated with increased health care utilization as measured by ED use. The implication of the timing of prosthesis provision after amputation and reduced ED use is not well established. Obtaining data about ED utilization early post‐LLA could assist the rehabilitation team in ensuring timely and appropriate access to improve outcomes.To determine the role that timing of prosthesis receipt has in ED utilization and the association of fall/FRI with health care utilization.Retrospective observational cohort using commercial claims data. A logistic regression model was used to assess factors that influence ED utilization post‐LLA.Watson/Truven administrative database 2014 to 2016.The study sample consisted of 510 adults age 18 to 64 years with continuous enrollment for 3 years.Independent variables included age, sex, diabetes status, amputation level, fall diagnosis, and prosthesis receipt. Fall was defined as presence of a diagnosis code in any outpatient procedure after the amputation date.ED use after amputation was defined as the presence of procedure codes that billed for ED services (99281 to 99285).Individuals who receive a prosthesis early, within 0 to 3 months, post‐LLA were 48%  less likely to use the ED compared to those who did not receive a prosthesis. Individuals who experienced a fall/FRI had 2.8  times the odds of ED utilization.Receipt of a prosthesis reduces the risk of ED use. The current study underscores the value of prostheses during the rehabilitation process after LLA. The potentially preventable use of emergency departments (EDs) accounts for $38 billion dollars of spending waste within the health care industry in the United States.Lower limb amputation (LLA) is a life‐changing event that requires an increased use of health care services, encompassing the amputation surgery, immediate postoperative care, rehabilitation, fitting of a prosthesis, and follow‐ups with other services after discharge into the community. Previous studies report that a shorter time between amputation surgery and receipt of a prosthesis improves use of and satisfaction with the device.Individuals with LLA are at a high risk of falls and FRI, with more than half of individuals with LLA reporting a fall at least once per year.Earlier receipt of a prosthesis, as compared to delayed receipt or not receiving a prosthesis within 12 months after amputation surgery, may decrease the risk of future adverse events or increased health care utilization, and thereby contribute to improved patient outcomes and the value of having a prosthesis fit after amputation. The purpose of the present study was to determine the role that timing of prosthesis receipt has in ED utilization and the association of fall/FRI with health care utilization measured by ED use among adults who recently had a LLA in the United States. Two hypotheses were tested: (1) the receipt of a prosthesis and timing of intervention with a prosthesis reduces ED use and health care utilization, and (2) the receipt of a prosthesis and adverse events  may be factors associated with increased health care utilization among adults with LLA.This was a retrospective observational cohort analysis using data extracted from the International Business Machines (IBM) Corporation Watson/Truven administrative (Watson) database. The database is populated annually from approximately 350 payers providing commercial (private insurance) claims (billing data) for their members. Data contain de‐identified longitudinal, patient‐level records. Included within the data set are all fully adjudicated claims for approximately 230 million unique individual patients in the United States. This included any orthotic/prosthetic services as well as all other inpatient and outpatient claims. The subset of individuals extracted was limited to either persons who received an amputation or orthotic/prosthetic services enrolled from 1 January 2014 through 31 December 2016. The original database as maintained by IBM Watson is de‐identified in nature and complies with the Health Insurance Portability and Accountability Act (HIPAA). The subsequent analysis is not considered human subject research and therefore does not require institutional review board (IRB) review or approval.Enrollees in one of the commercial plans contained within the Watson database who were 18 years or older with continuous health coverage for the 3‐year period (n = 1100) were eligible for the study. Next, inclusion was based on amputation procedure codes using the International Classification of Diseases (ICD) and Current Procedural Terminology (CPT) codes (ICD‐9 and ICD‐10 used due to time period crossing 2015) to identify all cases of LLA surgery. The index event was amputation surgery during 2014 through 2015 while allowing for 3 months of data pre‐index to capture baseline characteristics and 12 months of data postamputation surgery Figure . Time waThe outcome variable, ED use, was defined as the presence of CPT codes billed for all‐cause ED services (99281 to 99285) on any claim that occurred after the amputation date up to 12 months postamputation. ED use was counted as a binary event, the first visit, or event occurrence postamputation was captured and counted based on procedure code. Fall/FRI was defined as the presence of diagnosis codes that met the criteria of fall (ICD‐9 and ICD‐10) in outpatient procedures that occurred after the amputation date up to 12 months postamputation (Appendix A). Fall/FRI was conceptualized as a proxy for functional limitation or reduced QoL for use in the second model as the fall required medical attention or health care utilization. Prosthesis receipt was determined by noting major lower limb prosthesis base codes billed after amputation surgery. Claims that included a prosthesis base code after amputation were flagged to have received a prosthesis and time elapsed postamputation noted. The prosthesis date of service is the date the prosthesis was delivered to the patient irrespective of the date billed. Presence of diabetes or vascular disease was identified based on ICD‐9 or ICD‐10 in claims any time after enrollees’ first admission, with the assumption that the disease persisted throughout the study period (Appendix A). Amputation level was determined based on diagnosis code. Amputation level was collapsed into two categories: above‐the‐knee (AKA) and below‐the‐knee (BKA). For example, amputations through the tibia  or distal to the knee were grouped as BKA. Amputation through‐the‐knee (knee disarticulation) and proximal, including at the level of the hip, were all grouped as AKA. Toe or partial‐foot amputations were excluded. There were no hemipelvectomy or further proximal levels of amputation.U‐tests were used to compare groups. Two‐tailed tests of significance with alpha levels set a priori at 0.05 were implemented in all statistical analyses. Next, bivariate logistic regression was used to model the crude association between outpatient fall/FRI and all‐cause ED use. Each independent variable was also analyzed in a bivariate model to measure the unadjusted association. Finally, multivariate logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).Summary and descriptive statistics were calculated among the sample population based on receipt of prosthesis for population subgroups Table . CharactIn the first model to address hypothesis 1, the influence of timing of prosthesis receipt on the likelihood of all‐cause ED use was analyzed while controlling for age, sex, diabetes status, and amputation level. Time in 3‐month‐based categories between amputation surgery and receipt of prosthesis was included as a primary independent variable of interest . Unadjusted ORs and 95% CIs were obtained using bivariate logistic regression to provide a crude association for each variable with ED use. A multivariate logistic regression was model conducted and then a post hoc pairwise multiple comparisons was applied to evaluate the difference between time categories .Among the patients in the sample, 13% (67/510) did not receive a prosthesis within 12 months postamputation surgery  by 10% or more. However, the decision was made to retain and control for the potential confounding variables in the final models based on strong previous literature identifying these variables as strong risk factors associated with falls/FRIs.The first model evaluated the impact of timing of prosthesis receipt against ED use while controlling for sex, age, diabetes/vascular status, and amputation level. Individuals who receive a prosthesis early, between 0 and 3 months, after LLA were 48%  less likely to use the ED compared to the referent group, those who did not receive a prosthesis during the 12‐month post‐amputation period  times increased odds of using the ED within the follow‐up period compared to those with no fall/FRI, while adjusting for covariates  adults with no lower limb prosthesis within 12 months of amputation surgery are almost twice as likely to use the ED as compared to those who receive a prosthesis within 3 months, with the odds likely worsening with extended delays Table . This stOur descriptive analysis suggests that with further time delay from surgery to receipt of prosthesis, the use of the ED increases as seen in the percent of ED use comparison Figure . This isAs the findings from model 1 suggest, earlier receipt of a prosthesis decreases health care utilization as measured by ED use. Earlier intervention with physical rehabilitation and lower limb prostheses has been suggested to improve patient functional mobility and therefore reduce health care utilization due to adverse events reinforcing prosthetic value.The results of model 1 in this study did not indicate age, sex, and amputation level or diabetes/vascular disease status to be significant indicators for increased odds of ED use among people with LLA. The findings suggest that patient level factors such as age, sex, and cause of amputation should not create exemptions for certain patients to realize the benefits of early prosthesis fittings with regard to reduction in ED use. These findings are consistent with previous evidence that found that such factors were not necessarily restrictive to a patient's ability to achieve successful mobility with a prosthesis.The provision and access to a prosthesis is a critical component of a person's rehabilitation after an LLA, as it is associated with a person's ability to return to ADLs, safety, and reintegrate into social or work routines.The current findings from model 2 are consistent with recent literature suggesting that individuals having a LLA incur increased use of healthcare services due to adverse events such as falls and fractures.Individuals who experienced a fall/FRI after discharge from amputation were almost 3 times more likely to use the ED in the current study. Falls are common among those with amputation, including injurious falls that result in need for medical treatment, which has been demonstrated in a previous study among community dwelling adults with LLA.This study has several strengths, in particular the relatively large sample size for this specific population. In addition, findings are based on a nationally representative sample of commercial claims generalizable to the U.S. adult population with LLA who have commercial (private) health insurance. However, there are limitations of this study. Due to the nature of administrative data, it is not possible to differentiate the reasons some individuals took longer to receive a prosthesis or not at all. It is possible that a delayed fitting or functional limitations that contribute to falls may be associated with other health complications, lack of social support, certain payer policy restrictions, or another unseen complication that contributes to increased health care utilization. Future studies should attempt to determine such factors using clinical databases, or potentially registry data. However, understanding this should place greater emphasis on working to resolve issues seen to potentially delay provision of prosthetic rehabilitation so that patients are afforded the benefits of earlier receipt of their prosthesis.The current study did not assess the events prior to ED use. Unfortunately the nature of claims data makes it difficult to determine events that may have precipitated or caused increased health care utilization. This study did not assess the potential difference in severity or frequency of ED use. Further exploration on the association of adverse events, falls/FRIs, and the subsequent acute care utilization with respect to frequency remains needed. Such work, as well as the current study, would be enhanced, if possible, to ascertain the functional status of patients. There are other confounding variables that influence both the timing of prosthesis receipt and falls/FRIs, such as poor general health and functional mobility. The receipt of a prosthesis, as captured by date of service, does not guarantee use of the prosthesis. However, a strength of using claims data includes accurate reflection of dates, such as the date a prosthesis was received, as opposed to relying on patient recall.The current study findings have valuable implications for clinical care and potentially policy. Earlier receipt of a prosthesis is associated with a reduced marginal odds of ED use. This is valuable in further consideration of the current study results showing a strong association between falls/FRIs and ED use, indicating that a prosthesis plays an important role in individual mobility and the potential to reduce preventable health care utilization. In light of previous work, which has noted the negative impact of ED utilization on QoLIn below knee compared to above knee amputeesAssociated with falls within 12 months post amputationWhen prosthesis is received within 3 months of surgeryIn male versus female amputees of comparable ageThis retrospective study found that emergency department utilization after lower limb amputation was less likely:Answer online athttps://onlinelearning.aapmr.org/Appendix A: Amputation level determined by ICD‐9 or ICD‐10 procedure codesClick here for additional data file.


National averages obscure geographic variation in program performance. We determined Parliamentary Constituency (PC)‐wise estimates of TB notification to guide political engagement.We extracted district‐level TB notification data from the 2018 annual TB report. We derived PC‐level estimates by building a ‘cross‐walk’ between districts and PCs using boundary shapefiles. We described the spatial distribution of the PC‐wise estimates of Total Notification Rate and percentage of Private Sector Notification.The median PC‐wise Total Notification Rate was 126.24/100 000 . The median PC‐wise Percentage Private Sector Notification was 18.03% . Only 16 (2.94%) PCs met the target of 50% private sector notification. Most of high notification rates in PCs were driven by high notification in public sector. There was geographic – both interstate and within state inter‐PC – variation in the estimates of these indicators. The study identified some geographic patterns of notification – high positive outlier PCs with adjoining PCs in lower deciles of notification rates, intra‐state differences in PC performance, and similarities in notification rates of adjoining PCs in different states.In addition to regional inequality, the study identified geospatial patterns that can aid in the formulation of suitable interventions. These include decongestion of overburdened facilities by strengthening poorly performing units. The PCs with a high percentage Private Sector Notification can act as role models for neighbouring PCs to improve private sector engagement. MPs can play a crucial role in mobilising additional resources, creating awareness, and establishing inter‐PC and inter‐state collaboration to improve TB program performance. Political commitment to eliminate Tuberculosis (TB) is one of the fundamental pillars of the End TB Strategy of WHO . DiffereFirst, measuring TB burden using political units could help overcome the inadequacy of resource investment to TB programs. Notwithstanding verbal and symbolic commitment by political leaders to end TB, the current level of investment falls short of the estimated budget. In case of India, the country that bears over a quarter of TB burden in the world, it is reported that a gap of 16% existed between the approved and requested budget during 2017–20 period [Second, TB metrics of political units can guide policies to address regional inequality of TB. In most countries, TB burden is concentrated in poorer parts of the country, yet these regions also face competing development tasks. In India, the burden of TB is 8.7 times higher in Uttar Pradesh compared to Kerala . At the Lastly, focusing on private sector engagement could facilitate TB elimination in India where a majority of TB patients are seen in private sectors , 6. The We use Parliamentary Constituencies (PCs) of India as an example of a primary political unit for TB metrics. PCs are political units from which Members of Parliament (MPs) are elected to represent at Lok Sabha, the Lower House equivalent of India. The MPs hold the direct authority to lead policy actions at national and local levels. At the national level, MPs have an important role in mobilising national financial resources, as Financial Bills are often initiated and approved by the Lok Sabha. At the local level, MPs are authorised to support program implementation and mobilise additional resources for the National TB Elimination Program (NTEP). Therefore, aligning MPs interests to TB needs could be perhaps the most efficient way to fill the resource gap.Despite its potential to enhance political commitment, political geography has been underutilised as a monitoring and evaluation unit. Most nationally representative surveys, the ingredients for health and development metrics, only contain administrative unit identifiers such as states and districts. As political unit boundaries do not align with administrative unit boundaries, producing the PC‐wise estimates has been challenging. We aim to address the lack of TB information across political geography and share this conceptualisation to be widely adopted in other developing countries that experience low political priority to TB.While TB information is routinely collected at the district level in India, there have been no publicly available data at the Parliament Constituencies level. As the delimitation of PCs is carried out independently, a PC can span across multiple districts, and PC‐level estimates are not a direct aggregation of district‐level indicators. A cross‐walk derives PC‐level estimates from district‐level data by applying GIS‐based techniques , 9. The A cross‐walk assumes that TB distribution is unchanged within the district and is proportional to its population. If a PC comprises 40% of the population in district A and 60% of district B, the total notified patients in the PC are the summation of 40% patients in district A and 60% patients in district B. We generated a data set with each segment linked to unique PC and district, and calculated segment‐level population and notification, then aggregated by PC ID to derive PC‐level indicators.We extracted 2017 district‐wise TB data sets from the 2018 annual TB report . All 689Both PCs and districts shapefiles are downloaded from the Community Created Maps of India (CCMA) . The PC Georeferenced and edit functions in Arc GIS were used to draw new district boundaries at a scale smaller than 1:1 000 000. For districts without RNTCP units, we dissolved adjacent districts’ boundaries to create an accurate representation of the RNTCP unit border. In the final data set, 676 polygons were identified.While there is no official up‐to‐date district shapefile, we used the Census 2011 district shapefile as a base map and made edits on the borders to match with actual districts in 2017 in the RNTCP program. New district documentation from Reserved Bank of India, and Bharat Map, a multi‐layer GIS platform with latest administrative boundaries, served as two critical references , 15. GeoWorldPop2015 provides a granular level of population distribution estimates in 2015 . It estiintersect to create a new shapefile based on the PC and district shapefile, identifying 3828 segments linked with PC and district ID. Next, we performed Zonal Statistics using WorldPop as the underlying data raster to derive the segment and district‐level population estimates in 2015. Finally, we calculated the percentage of the population by dividing the segment population by the district population.First, we used ArcGIS Pro Assuming population distribution unchanged between 2015 and 2017, segment population in 2017 was calculated by percentage of the population multiplying district population in 2017. TB notification at segment level was calculated by percentage of the population multiplying district notification. The final PC‐level population and notification were aggregated by segment population and segment TB notification. A flow chart detailing the steps to derive the total notification rate per 100,000 population at PC level is shown in Figure The Harvard T.H. Chan School of Public Health Institutional Review Board reviewed this study and considered it exempt from full review because it utilises an anonymous public use data set.We estimated TB notification rate (per 100 000 population) and percentage of private sector notification for each PC. These indicators have been recommended for monitoring the program implementation at the subnational level . We usedFrom the analysis, we were able to identify TB notification indicators for all 543 PCs of India. Figure We found a large variation in PC‐wise total notification rates between states and PCs. Figure . The staConsidering the geographical distribution of PC‐wise estimates, we identified some pertinent patterns in Total Notification Rates Figure . There wOnly 16 PCs 2.94%) met the target of 50% private sector notification and there was a wide variation of PC‐wise percentage of private‐sector notification Figure . Bihar, .94% met P‐value less than 0.001; the Spearman's correlation coefficient was 0.19, with a P‐value less than 0.001. Most high notification rates in PCs were driven by high notification in public sector, but there were a few PCs (in lower right corner) with low public notification and high private notification (Figure There was a significant but weak positive correlation between the public and private sector TB notification rates. The Pearson's correlation coefficient was 0.20, with a n Figure . PCs in This is the first study to estimate the burden of TB at the PC level. PC‐level data of TB program indicators will be crucial in sensitising the MPs to TB scenarios and program performance in their PCs. The Central TB Division publishes annual reports with aggregate data at the district level. However, the administrative districts and parliamentary constituencies are not coterminous. We have overcome this problem by deriving PC‐wise estimates for notification rates using the available district‐level program data by applying a cross‐walk between districts and PCs. The distribution and geospatial comparison of the estimates of PC‐wise TB notification rates have identified patterns that can lead to effective policy action.The public health sector is the primary component of TB notification. For PCs in the bottom decile of notification rates, the strategy should be to review and strengthen the performance of the public sector, improve community awareness, followed by enhanced private sector engagement. India accounts for 26% of the total estimated global gap between incidence and notifications . This stThe distribution and comparison of PC‐wise total notification rates highlight the inter‐state and inter‐PC inequalities and bring up different patterns. We noted high total notification rates and high percentage of private‐sector notification in Gujarat and a pattern of high total notification rate with a low percentage private sector notification in Delhi, Chandigarh and Himachal Pradesh. The latter indicates an overburdened public sector and the need to prioritise private sector involvement in the program. PCs with high notification rates adjoining PCs in low notification categories could indicate cross‐district health service utilisation, thereby burdening a district’s diagnosis and reporting system. For example, all the PCs in Bihar had low notification rates except for the state capital. There are temporary movements of patients from rural areas and towns into the city for diagnostic evaluation. The high TB notification in Delhi ad Chandigarh has been attributed to the state providing diagnostic care for populations beyond their boundaries . In a stWhile PCs in Tripura and Lakshadweep have low estimates of both indicators, PCs in Kerala and Bihar are in lower deciles of TNR and higher deciles of percentage private sector notification. However, the performances of these two states in TB programs have been documented to be different. Kerala has achieved good integration of TB services with primary healthcare services, good private sector engagement and local self‐government stewardship. It has resulted in Kerala's multi‐layered and sustained TB control model . The shoIn addition to the critical role of public health systems in TB control, the contribution of the private sector in service provision has been acknowledged since the 1990s. Improving private sector notification offers an entry point for public‐private partnerships, ensures the rational use of drugs and linkages with public health action for patients in the private sector, prevents out‐of‐pocket expenditure and improves treatment outcomes. The proportion of private sector notification indicates private sector engagement in the program. The target set for the proportion of TB patients notified by the private sector is 50% for the year 2025 . In thisA careful interpretation of the study results is needed as the estimates of notification are influenced by multiple factors. High case notification rates may suggest a higher TB burden or better access to diagnosis and care and vice‐versa . It indiExperience with smallpox and polio eradication has shown that achieving such ambitious goals is more than a technical mission. They are social and political phenomena requiring careful negotiations with local public health workers, political and community leaders, and members of the general population , 31. In The variation in TB notification along with regional diversity in program performance indicates that straight‐jacket solutions may not be an effective strategy to achieve the goal of TB elimination in India. Policy and program initiatives need be tailored to meet location‐specific needs. The MPs have a sustained interface with the community with the authority to voice the concerns of their constituents. Their active involvement will give the much‐needed acceleration to the program. The study results will help align the interest of policymakers in mobilising finances, correcting regional inequality and ensuring private sector engagement. It can be a step towards the data‐driven engagement of elected representatives in NTEP.


Rabies recently hit the national headlines when a Wisconsin teenager survived after showing full-blown symptoms. Even more remarkable, the girl—who was bitten by a bat—recovered after receiving a novel therapy, since doctors felt her case was too advanced for the standard rabies inoculations to work. Rabies is nearly always fatal if not treated immediately, and continues to pose a serious public health threat. Though most rabies fatalities in the United States stem from bat bites, far more people are treated for raccoon rabies.A new strain of raccoon rabies started spreading throughout the eastern United States in the mid-1970s, after raccoons caught in Florida were released along the West Virginia–Virginia border to replenish hunting stocks. Some of the imports carried a rabies variant that caused an outbreak in local populations and has been steadily expanding ever since. In 1990, raccoons topped the list of most often reported rabid mammal.PLoS Biology, Real and colleagues apply their model to the likely spread of rabies in Ohio—a potential gateway for spread throughout the Midwest—and find that raccoon rabies could spread throughout the state in just three years.Controlling this re-emerging public health threat depends on predicting the spatial dynamics of the disease—where new outbreaks might occur and how the virus might spread. Toward this end, Leslie Real and colleagues work on probabilistic simulation models that calculate the effects of various factors, such as local transmission rates between townships, ecological barriers to transmission, and long-distance “translocation” rates between townships.  As reported elsewhere, these models previously accurately reflected rabies spread in both Connecticut and New York. In a new study reported in cordon sanitaire strategy limited rabies in Ohio to sporadic cases from 1997 until 2004, when a rabid animal was detected—11 kilometers beyond the buffer zone—in northeastern Ohio. The authors had previously shown that local transmission was significantly reduced when townships were separated by geographical barriers—the Connecticut River in Connecticut and the Adirondack Mountains in New York. In modeling the likely transmission path in Ohio, the authors incorporated the likely effect of Ohio's five major rivers on transmission from local points along the Pennsylvania or West Virginia border.One strategy for limiting rabies spread is to establish vaccine corridors by distributing vaccine baits—vaccine doses hidden in fishmeal—to wild raccoons. This Given Ohio's topography  and a single point of emergence in the northeast, the authors adjusted their simulations to estimate the potential impact of translocations. Even without the occasional garbage truck ride, because of the lack of ecological barriers in central Ohio, the simulations predict that rabies will spread far faster in Ohio than in New York and Connecticut.Factoring in those garbage truck rides, the scenario is considerably bleaker: rabies would take just 33 months to spread across central Ohio—compared to 48 months to cross the much smaller state of Connecticut—and cover the state in 41 months. This transmission rate—100 kilometers/year—significantly surpasses previous estimates, which range from 30 to 60 kilometers/year. The potential for such rapid spread, if unchecked, “is quite alarming,” the authors warn. But they also point out that the path of a real epidemic would likely fall somewhere between these two scenarios, given the unpredictable nature of translocations. The authors also simulated potential breech points in the vaccine corridor and found that the Ohio and Muskingum rivers halted viral advance initially. But a raccoon can certainly cross a bridge when the opportunity arises, so any delays would likely be temporary.Given the unpredictable nature of rabies transmission—challenging efforts to identify potential leaks in vaccine corridors and sites of dispersal—the authors' simulations provide a valuable resource for anticipating alternate outbreak scenarios and preparing multiple game plans to prevent or contain them. They also indicate the best sites for establishing a new vaccine barrier. And given how fast raccoon rabies could spread, Real and colleagues make a strong case that halting its western march depends on a strategy based on early detection and high-powered intervention programs—a sensible approach for any infectious disease.


It is readily understandable that Dutton of the International Nickel Company (INCO) would like to separate the nickel emissions from the 381-m INCO smelter stack from the highly statistically significant Ni-associated effects on heart rate and heart rate variability that we observed on 14 of 103 consecutive weekdays of exposure in our laboratory (located within the Sterling Forest State Park) in a mouse model of atherosclerosis . Indeed,We commend Dutton on identifying a mislabeled key in Figure 4 of our article  that occ1 mice were exposed in this study, and that healthy B6 mice had much greater survival times than seven other inbred mice strains when exposed to nickel sulfate by Dutton provided no supporting reference for his comment that “2-year inhalation exposures of rodents to nickel sulfate at levels 600 times higher than those used by 10 (particulate matter < 10 μm in aerodynamic diameter) NMMAPS mortality coefficients for 60 NMMAPS cities were significantly associated with annual average ambient Ni and V concentrations in those same cities.Dutton also states that “there is no statistical relationship between NMMAPS [National Mortality and Morbidity Air Pollution Study] CVR [cardiovascular risk] mortality rates and Ni emission rates.” Again, no reference was cited. Even if his statement was supported by a negative study, it relates to emissions and not concentrations. In our article , we showFinally, we take exception to Dutton’s comment that implies that we lack sufficient expertise in atmospheric science. The only issue in our article that relates to atmospheric science is our use of HYSPLIT back trajectories, and we fail to see how we misused them.


Auvert and colleagues present preliminary evidence for the protective effect of male circumcision on HIV acquisition . Their rWe are baffled that the factor most strongly associated with incident HIV infection—attendance at “a clinic for a health problem related to the genitals” —is neither highlighted nor specifically discussed. Given evidence for increased risk of acquiring HIV from treatment for sexually transmitted diseases (STDs) in sub-Saharan Africa (relative to untreated STDs) , such a Regrettably, the authors did not control for blood exposures . Nor did they assess anal intercourse, the variable most strongly associated with sexual transmission of HIV. Anal intercourse is not uncommon in sub-Saharan Africa . The autFurthermore, the authors did not report the relationship between level of condom use and HIV incidence. The need for more detailed investigation of sexual exposures is underlined by the negligible associations between such traditional measures of sexual risk—any type of unprotected sex, the number of sexual exposures (“contacts”), and the number of nonspousal partners—and HIV incidence . Indeed,Until all modes of HIV transmission—by sex and by puncturing—are comprehensively investigated ,6, the


Consumer Reports (CR).Ionizing air cleaners—those staples of infomercials and splashy magazine ads—are not only ineffective at removing contaminants from indoor air, but also may emit enough ozone to be a health concern. The effects may be even greater in people with respiratory problems, who make up 80% of the buyers of such devices. Those are the conclusions reached in tests of the units described in the May 2005 CR tested five units (including the top-selling Ionic Breeze from The Sharper Image) and confirmed results reported in October 2003 rating most of the air cleaners “poor” at removing dust and tobacco smoke from the indoor environment. This time around, pollen was added as well, with similarly disappointing results. The cleaners were also tested for generation of ozone, a respiratory irritant. The results showed that some of the least effective models also emitted potentially harmful ozone levels.CR.“We felt that it was particularly important to notify our subscribers that these air cleaners not only don’t remove particulates from the air, but they also put ozone into it,” says Jeff Asher, vice president and technical director of Consumers Union, the publisher of CR used Underwriters Laboratories Standard 867 to measure the units’ ozone levels from 2 inches away in a sealed polyethylene room. All five machines failed that test.There is no regulatory standard for ozone emission by air cleaners; manufacturers claim to adhere to a voluntary standard of 50 parts per billion (ppb), a limit established by the Food and Drug Administration for medical devices. CR also tested the devices in an open laboratory, from distances of 2 inches and 3 feet. Two units failed this this test; the other three (including the Ionic Breeze) produced levels of 26–48 ppb at 2 inches and 2–18 ppb at 3 feet—still high enough by CR’s estimation to be of concern. “The levels were not what I would call of great imminent risk,” says Asher, “but it was of significant risk in the sense of being in an indoor environment, where we just don’t need more ozone.”To more accurately reflect actual use conditions, CR over its 2003 report, has fired back, assailing the magazine’s credibility. In a 6 April 2005 press statement, CEO Richard Thalheimer called the article “irresponsible in the way it casually and unscientifically speculates about public health and safety. . . . We continue to emphatically disagree with Consumer Union’s methods in evaluating the Ionic Breeze.”The Sharper Image, which unsuccessfully sued CR results troubling. “These levels make these devices inappropriate to use for asthmatic patients and for patients with respiratory disease,” says Peyton Eggleston, interim director of the Johns Hopkins Children’s Center.But health and engineering experts find the Richard Shaughnessy, an environmental engineer at the University of Tulsa who has researched air cleaners for many years, concurs, pointing out that “not only are people with respiratory illnesses and asthma the population targeted by most of these air cleaners, they’re also the ones who are most likely to be adversely affected in terms of exposure to small amounts of ozone.”


DNA barcodes for species identification and the analysis of human mitochondrial variation have developed as independent fields even though both are based on sequences from animal mitochondria. This study finds questions within each field that can be addressed by reference to the other. DNA barcodes are based on a 648‐bp segment of the mitochondrially encoded cytochrome oxidase I. From most species, this segment is the only sequence available. It is impossible to know whether it fairly represents overall mitochondrial variation. For modern humans, the entire mitochondrial genome is available from thousands of healthy individuals. SNPs in the human mitochondrial genome are evenly distributed across all protein‐encoding regions arguing that COI DNA barcode is representative. Barcode variation among related species is largely based on synonymous codons. Data on human mitochondrial variation support the interpretation that most – possibly all – synonymous substitutions in mitochondria are selectively neutral. DNA barcodes confirm reports of a low variance in modern humans compared to nonhuman primates. In addition, DNA barcodes allow the comparison of modern human variance to many other extant animal species. Birds are a well‐curated group in which DNA barcodes are coupled with census and geographic data. Putting modern human variation in the context of intraspecies variation among birds shows humans to be a single breeding population of average variance. Science develops as isolated and compact “pebbles,” or islands, of understanding in a vast and unknown sea Newton . OccasioTwo isolated islands of the literature concern themselves with the analysis of mitochondrial DNA sequence: (1) human mitochondrial variation; and (2) DNA barcode analysis. After a brief indication of each subfield, or island of scholarly information, three questions are framed that can be better addressed via their intersection.The study of human mitochondrial sequence variation informs two subfields: (1) human migration . Taxonomic domain experts and algorithmic application of the barcode sequence agree for approximately 95% or more of the species in most groups. Controversial or borderline cases that were more closely analyzed turned out to be mostly due to introgression, hybridization, incorrect labeling, or sequence errors  is usually <1%, whereas the distance between even the most closely related animal species is typically 2% or more  segment of the mitochondrial COI gene has proven effective and has become the dominant standard for the genetic identification of animal species. The sequence of this region is often referred to as a “DNA barcode” , bonobos (Pan paniscus), Homo neanderthalensis, and H. sapiens Denisova. Sequences obtained by focused PCR or bioinformatics extraction from whole genomes are seamlessly compatible. In this way, barcodes and variance of barcode sequences within and across animal species can be aligned and compared.DNA barcodes for modern humans were extracted from human mitogenome sequences that together represent the major mitochondrial haplogroups. Mitogenome datasets in PhyloTree , bonobos (n = 55), H. sapiens Denisova (n = 2), and H. neanderthalensis (n = 4), all mitogenomes available at the time of analysis were included. It is impractical in this format to include all 9413 modern human barcodes because the modern human square would dwarf the others. The 53 modern human sequences utilized in this analysis represent the extremes of known modern human diversity, including African, European, Asian, Polynesian, and New World lineages  and taxonomically broadest sampling of species‐level differences currently available. DNA barcodes are the only sequence information available for multiple individuals in tens of thousands of species. In principle, there are potential pitfalls to using only a short sequence. However, this study showed that human DNA barcode variation is representative of the coding mitogenome as a whole Fig. . Entire Mitochondrial and nuclear genomes are subject to a Venn diagram of selective forces, that is, some overlap and others do not, such that variance in the two genomes is not always the same. Mitochondrial inheritance is uniparental and the entire mitochondrial genome forms a single “take it or leave it” linkage group Neher . In contDespite advances in sequencing and data analysis, nuclear genomes from multiple individuals of multiple species may never approach the millions of mitochondrial COI DNA barcode sequences that are already available and continuing to increase with valuable contributions from citizen science (Geiger et al. The foremost genetic characteristic of modern humans seen through a comparison of DNA barcode variation with other animal species is that of modest mitochondrial sequence variation made remarkable in light of relatively large population size and wide dispersion. By “zooming out” to examine modern humans as one star in the galaxy of the animal kingdom, our species is seen to have the low variance that is absolutely typical for an animal species with a single breeding population.None declared.


EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting.Epithelial/mesenchymal transition ( CFPcyan fluorescent proteinCRCcolorectal cancerCTCcirculating tumor celleDTCsearly disseminated tumor cellsEMTepithelial/mesenchymal transitionEMT‐TFepithelial/mesenchymal transition transcription factorEpCAMepithelial cell adhesion moleculeFSP1fibroblast‐specific protein 1GFPgreen fluorescent proteinHCChepatocellular carcinomaHER2/Neu/ERBB2ERBB2 receptor tyrosine kinase 2HNSCChead and neck squamous cell carcinomaILKintegrin‐linked kinaseMETmesenchymal/epithelial transitionMMPmetalloproteinaseNCIDNotch intracellular cytoplasmic domainNSCLCnon‐small‐cell lung cancerPCaprostate cancerPDACpancreatic ductal adenocarcinomaRFPred fluorescent proteinSCCsquamous cell carcinomaTCGAThe Cancer Genome AtlasTGF‐βtumor growth factor betaWNTwinglessYFPyellow fluorescent protein11.1in vitro studies have firmly established that activation of the EMT program promotes tumor cell invasion and metastasis and have defined the molecular players, environmental cues, and signaling pathways implicated in EMT induction  and that intermediate EMT states coexist in most tumors, with cells acquiring some mesenchymal properties without undergoing a full EMT  the actual relevance of EMT in the clinical practice. In the following sections, we provide an update of the evidence on the first issue and discuss recent insights into EMT translational opportunities presently and in the near future.Despite the overwhelming information accumulated on EMT and cell plasticity in tumor biology, at least two key questions are still unresolved: (a) the requirement of EMT/MET processes for metastasis to occur 2in vivo functional contribution of EMT/MET processes to cancer progression, we will discuss the recent, and sometimes controversial, evidences obtained using genetically engineered mouse cancer models. Most of the current genetic models are based on the manipulation to knock‐out/knock‐in key regulators of EMT  and/or in EMT lineage tracing models  cancer models, respectively  were detected already in initial premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, presenting features of undergoing EMT (E‐cadherin‐/N‐cadherin+) and, noticeably, showing high ZEB1 expression and being able to disseminate in the bloodstream  tracer  and inactivating p53 within the intestine Fig. B  and a constitutive Cre‐switchable fluorescent marker (lox‐RFP‐STOP‐lox‐GFP). Thus, RFP+ (red fluorescent protein+) epithelial tumor cells undergoing a full EMT permanently convert into GFP+ cells  promoter to mesenchymal cells  (E‐cadherin‐CFP+)‐expressing cells . Importantly, the Ecadlo population had the abilities to invade, migrate, intravasate, and extravasate besides reaching metastatic organs such as the liver. Rapid conversion of Ecadlo cells to Ecadhi  occurred at metastatic sites as early as upon two cell divisions  was recently reported using the MMTV‐Her2 breast cancer mouse model  suffering a partial EMT , generalizations cannot be made. Indeed, some studies support that both plasticity‐dependent and plasticity‐independent mechanisms can operate in different cancer contexts  locus occurs , currently being characterized and emerging as a new promising prognostic factor in different types of tumors  might be independent of epithelial plasticity  phenotype  in which one of the main selection criteria is the expression of specific EMT markers and the final aim is the direct or indirect EMT inhibition using novel molecular‐based personalized therapies  using hormonotherapy (androgen receptor inhibition) with and without chemotherapy against SRC or MEK  in terms of EMT inhibition (Table 990196 uset al., et al., Already finalized clinical trials have provided valuable data confirming the potential benefit of the treatments aimed at targeting EMT. This is the case of the phase I trial performed in advanced solid tumor patients that demonstrated the effectiveness of MRX34 (Beg Despite the advances in the molecular understanding of EMT and cell plasticity processes, not only regarding invasiveness and metastasis but also in association with therapy response and stem cell‐like properties, further experimental work is necessary to render EMT knowledge beneficial for clinical standard of care. An important word of caution toward therapeutic approaches aimed at blocking EMT relates to the inherent plasticity of the EMT process during tumor progression and metastasis. While some therapies could help halt tumor cell invasion and dissemination, they might be highly deleterious for metastasis outgrowth by favoring the MET program. In addition, they may not be exploited for targeting early disseminated tumor cells believed to shred from primary tumors before diagnosis. From the present knowledge, targeting the hybrid E/M phenotype Fig.  seems th5in vivo and highlighted the nonredundant and complementary functions of EMT‐TFs and their specificity in distinct tumors. All these recent studies have contributed to clarify the key in vivo role of epithelial plasticity processes at different metastasis steps. Despite all this progress, EMT clinical translation is still very limited. Nevertheless, support for using EMT markers and/or EMT signatures as predictor or prognosis factors is continuously increasing. This is particularly relevant in relation to acquired resistance for which further improvements in CTC detection methods aimed at capturing different plastic E/M states are envisioned for the near future. In addition, better understanding of the contribution of the stromal component, in particular activated fibroblast and immune components, to modulate epithelial plasticity processes, will undoubtedly contribute to improve its translation potential.The EMT field has experienced an enormous progress in the last years leading to a comprehensive understanding of the molecular pathways and regulators of the process. In the context of metastasis, the demonstration of the transient and reversible nature of EMT process, the requirement of MET for metastasis outgrowth along with the report of hybrid E/M states during the metastatic cascade have been key advances. Preclinical genetic mouse models and innovative intravital imaging have also helped to demonstrate the plasticity of the process It is anticipated that the continuous development of highly sophisticated preclinical models and novel imaging techniques, together with innovative high‐throughput screening platforms to target hybrid E/M phenotypes, will provide new avenues to explore the clinical potential of epithelial plasticity in the near future.


Sepsis‐induced acute kidney injury (SI‐AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI‐AKI is unknown, and no curative treatment exists. Toll‐like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram‐negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI‐AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI‐AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI‐AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI‐AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies. Toll‐like receptors (TLRs) are crucial for sensing invading microorganisms like bacteria, virus and fungi. As a first line of defence, they initiate an innate immune response that includes activation of polymorphonuclear leucocytes (PMN), monocytes and macrophages    and RANTES when exposed to synthetic lipid A and released CXCL1 and CXCL2 in response to LPS  and mammalian target of rapamycin (mTOR) respectively  has traditionally been viewed as a result of hypoperfusion due to distributional hypovolemia and shock  and the risk of progression of AKI  during sepsis where renal hypoperfusion in a global sense reasonably cannot explain the reduction in GFR  occurs  and Resatorvid ; however, none have focused specifically on SI‐AKI. Eritoran is a synthetically produced lipopolysaccharide that binds to cell‐surface TLR4‐MD2 receptor without activating it and thereby blocks the effects of bacterial LPS. Resatorvid attaches to the intracellular domain of TLR4 and inhibits the signal transduction leading to NFκB activation. A randomized, double‐blind, placebo‐controlled trial of TAK‐242 showed a trend towards a reduced 28‐day mortality in patients with both septic shock and respiratory failure in the treatment group, but the result was not significant  plays a role in diminishing GFR. TLR4‐mediated mitochondrial dysfunction and an adaptive reduction in bicarbonate reabsorption further compromises tubular function. In human sepsis, the mechanisms underlying renal dysfunction remain unknown, and so is the exact role of LPS mediated TLR4‐activation. For completely blocking the detrimental effects of the immune system in SI‐AKI, it appears likely that further signalling pathways other than those elicited via TLR4 require targeting.Today, plenty pre‐clinical data support targeting TLR4 for preventing or treating AKI in human gram‐negative sepsis. Strict selection of patients with gram‐negative infections and assessment of circulating LPS is recommended at this stage.The authors report no conflicting interests.We would like to thank the Stiftelsen Nordisk Fysiologi (SNF) and the German Research Foundation  for their generous support for the AP Symposium on ‘RENOPROTECTION’. RF was supported by funds from the Swedish Research Council (grant 523‐2014‐2569).


UK (CCUK) study. We also wanted to explore centre‐level variation in child outcomes and investigate individual predictors of such outcomes.The aims of this study were to describe child behavioural and psychosocial outcomes associated with appearance and speech in the Cleft Care UCLP) recruited to CCUK.Two hundred and sixty‐eight five‐year‐old children with non‐syndromic unilateral cleft lip and palate (SDQ) and reported their own perceptions of the child's self‐confidence. Child facial appearance and symmetry were assessed using photographs, and intelligibility of speech was derived from audio‐visual speech recordings. Centre‐level variation in behavioural and psychosocial outcomes was examined using hierarchical models, and associations with clinical outcomes were examined using logit regression models.Parents completed the Strengths and Difficulties questionnaire , and for girls, the average score was 3.8 vs 3.1 (P=.008). There was no evidence of centre‐level variation for behaviour or parental perceptions of the child's self‐confidence. There is no evidence of associations between self‐confidence and SDQ scores and either facial appearance or behaviour.Children with UCLP have higher levels of behaviour problems than the general population.Children born with  They may be more or less well behaved and they are likely to fall in and out of friendships but for the majority, such issues resolve over time.While there is some evidence that children with chronic health conditions,It is unclear whether reported behavioural problems are a consequence of the condition of CLP or due to differences in key clinical outcomes such as facial appearance and speech.Despite evidence that childhood behavioural problems may be a characteristic of children born with CLP,The aims of this study are to extend analysis of the CCUK data to describe psychosocial and behavioural outcomes in more detail, explore variation in outcomes as a function of treatment centre and investigate individual predictors of these outcomes.22.1We used data from the CCUK study. This is a UK‐wide cross‐sectional study of 5‐year‐old children born between April 2005 and March 2007 with UCLP. A full description of recruitment procedures and eligibility criteria can be found elsewhere.2.2Two questionnaires were used to collect behavioural and psychosocial data, one concerned with the psychosocial assessment of the child .2.4The SDQ comprises 25 parent‐completed items relating to five different domains: emotional (anxiety and depression), conduct, hyperactive and peer‐related behaviour problems as well as prosocial behaviour. Parents were asked to respond to each item using a three‐point response scale from 0 (not true) to 2 (certainly true). Each domain is assessed by five items giving an overall domain scale ranging between 0 and 10. Anchor points for each item in each domain except the prosocial were reversed as appropriate so that high scores represent higher levels of behavioural difficulties. High scores for the prosocial domain represent fewer behavioural difficulties. Individual SDQ domains can also be aggregated to produce an internalizing score (anxiety and depression scores combined), an externalizing score (hyperactive and conduct scores combined) and a total difficulty score which combines all domains except the prosocial domain.2.5Full details of the methodology have been reported previously elsewhere.2.6The data collection methods for speech have been described previously.2.7Centre‐level variation in self‐confidence and SDQ scores at age 5 was examined using hierarchical regression. Based on these models, we estimated the variance partition coefficient (VPC)—a measure of the proportion of total variation in outcomes that can be attributed to centre and used estimates from the model to predict the mean outcomes in each centre. Likelihood ratio tests were performed to assess whether any observed variation between centres could be attributed to chance. All results are adjusted for differences in age and gender. Full details of the method for examining centre‐level variation are described elsewhere in this supplement.2.8We have reported mean scores and standard deviations (SD) for SDQ scores by age and gender and have compared these with population averages.2.9P values. Facial appearance and speech were dichotomized because some of the descriptive categories had relatively few children in them. Children were therefore categorized as having either a “good appearance”  or “poor appearance”  and “good” (excellent or good) or “poor” intelligibility.Associations between parent‐reported self‐confidence, SDQ scores and the child's appearance and speech were investigated with cumulative logit regression models, adjusted for gender, age and social deprivation. They were reported using odds ratios, 95% confidence intervals and Wald test 33.1Data on self‐confidence and strengths and difficulties were available on 243 and 205 children, respectively. Average SDQ scores and standard deviations (SD) are shown in Table 3.2P=.03 and .008 for boys and girls, respectively). Boys born with CLP had higher overall externalizing difficulties scores than girls. In Table Table 3.3Results of the centre variation analysis are shown in Table 3.4Tables 4In our study, 5‐year‐old children with UCLP have higher levels of parentally reported behavioural difficulties than the general population as measured by the SDQ. We found no evidence of centre‐level variation in either behavioural problems or self‐confidence within the UK centralized multidisciplinary service. There is also no evidence of any association between child appearance, self‐confidence and behaviour or the intelligibility of their speech, self‐confidence and behaviour.4.1Our results are consistent with other research reporting higher levels of behavioural difficulties in children born with CLP.4.2This study was large  and nationwide with a good response rate, limited age range, a series of validated key outcomes measured with enough precision to demonstrate improvements over time. However, our work does have a number of limitations. First, the data are cross‐sectional meaning that caution is required when making assumptions about causality. Second, we only recruited families with a child born with UCLP to the study meaning that we cannot generalize to other phenotypic subgroups. Third, although the majority of eligible families consented to participate in the study, there is a relatively large amount of missing data. This is especially true for those items comprising the self‐report questionnaire to be completed at home. Fourth, this study has limited power to detect modest centre‐level variation in treatment and outcome and other effects. Finally, there is the possibility that observed associations reflect confounding that we have not accounted for—for example, as noted above, the parent‐child relationship is likely to influence both speech and child behaviour.4.3Our findings have implications for policy and practice. More children in this cohort have higher than average levels of poor behaviour than are found in the general population. Other papers in this supplement4.4To our knowledge, this is the first study of this size to report on these associations and these findings require replication. If our findings are confirmed, and given the potentially lifelong adverse outcomes associated with behavioural difficulties in childhood (for example reduced social, academic and activity competencies5Our study showed that children born with UCLP have higher levels of behaviour problems compared to those in the general population. There is no centre variation in these behavioural outcomes and no associations between facial appearance, intelligibility and self‐confidence or behaviour. Further studies are required to replicate and extend these analyses. Given the relatively high levels of behavioural problems in this cohort, children with CLP should have access to psychological support within the current multidisciplinary centralized service, and this support should be provided in conjunction with appropriate speech and language and audiology support.


TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology. This article presents the quality control guideline accelerator‐integrated cone‐beam systems for verification imaging that has resulted from this process.The Canadian Organization of Medical Physicists, in close partnership with the Canadian Partnership for Quality Radiotherapy has developed a series of Technical Quality Control ( Financial and strategic backing is provided by the federal government through the Canadian Partnership Against Cancer, a national resource for advancing cancer prevention and treatment. The mandate of the CPQR is to support the universal availability of high quality and safe radiotherapy for all Canadians through system performance improvement and the development of consensus‐based guidelines and indicators to aid in radiation treatment program development and evaluation. The development of the individual Technical Quality Control (TQC) guidelines is spearheaded by expert reviewers and involves broad stakeholder input from the medical physics and radiation oncology community.Accelerator‐Integrated Cone‐Beam Systems for Verification Imaging. Please refer to the overarching document Technical Quality Control Guidelines for Canadian Radiation Treatment CentresThis document contains detailed performance objectives and safety criteria for All information contained in this document is intended to be used at the discretion of each individual center to help guide quality and safety program improvement. There are no legal standards supporting this document; specific federal or provincial regulations and license conditions take precedence over the content of this document.2In this report, a linac integrated cone‐beam CT (CBCT) imaging system is defined as a kV source and a flat panel x‐ray detector that are attached orthogonally to a linear accelerator (kV‐CBCT). Unlike conventional CT, kV‐CBCT uses a cone shaped x‐ray beam and acquires an entire volume (14–26 cm in length) in a single gantry rotation lasting approximately 2 min. To acquire the kV‐CBCT projection data, flat‐panel detectors are used in fluoroscopy mode, obtaining multiple projections per second; these projections are used to reconstruct the CBCT volumetric images. The imaging system is capable of providing radiographic, fluoroscopic, and CBCT imaging capabilities for image‐guided radiation therapy, and possibly simulation. kV‐CBCT produces a full CT dataset that, although below diagnostic quality, is generally adequate for directly targeting bone and, in some sites, soft tissue. At this writing, two commercial systems are available in Canada: the On‐Board Imager™ (OBI) by Varian Medical Systems, Inc. , and the Elekta XVI system by Elekta Oncology Systems .A variant commercial offering from Siemens uses similar principles, but uses the linear accelerator as the imaging x‐ray source and an optimized portal imaging system for CBCT image acquisition and reconstruction.All systems can produce two‐dimensional (2D) images that can be registered with reference digitally reconstructed radiographs generated by treatment planning systems and three‐dimensional (3D) datasets that can be aligned with the planning CT. Both the 2D and 3D approaches allow verification and correction of patient positioning prior to delivery of the therapeutic dose.Various attempts to recommend quality control guidelines for accelerator‐integrated cone‐beam systems have been reported in the literature and have been considered in developing the current guidelines shown in Tables 3In order to comprehensively assess accelerator‐integrated cone‐beam systems performance, additional guideline tests, as outlined in related CPQR TQC guidelines must also be completed and documented, as applicable:Safety systemsMedical linear accelerators and multileaf collimatorsMajor dosimetry equipment4The author has no conflict of interest to declare.


HIV‐positive vs. HIV‐negative women and changes as antiretroviral treatment (ART) is scaled up, to improve estimates of predicted need for and coverage of prevention of mother‐to‐child transmission services at national and subnational levels.To describe regional differences in the relative fertility of HIV‐positive and HIV‐negative women by age using exponential regression and test for regional and urban/rural differences. We estimated the association between national ART coverage and the relationship between HIV and fertility.We analysed 49 nationally representative household surveys in sub‐Saharan Africa between 2003 and 2016 to estimate fertility rate ratios of HIV and fertility relationships, with less HIV‐associated subfertility in Southern Africa. Age patterns of relative fertility are similar. HIV impact on fertility is weaker in urban than rural areas. For women below age 30, regional and urban/rural differences are largely explained by differences in age at sexual debut. Higher levels of national ART coverage were associated with slight attenuation of the relationship between HIV and fertility.Significant regional differences exist in HIV‐associated subfertility and urban–rural differences in age patterns of relative fertility should be accounted for when predicting need for and coverage of PMTCT services at national and subnational level. Although HIV impacts on fertility are somewhat reduced at higher levels of national ART coverage, differences in fertility between HIV positive and negative remain, and fertility of women on ART should not be assumed to be the same as HIV‐negative women. There were few data in recent years, when ART has reached high levels, and this relationship should continue to be assessed as further evidence becomes available.Regional differences in  Elimination of mother‐to‐child transmission of HIV (MTCT) through provision of antiretroviral treatment (ART) to all HIV‐positive pregnant women is a major policy objective for national HIV programmes: The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the US President's Emergency Plan for AIDS Relief (PEPFAR) Coverage and unmet need for PMTCT services are estimated by dividing number of pregnant women receiving PMTCT services from routine programmatic data (the numerator) by a modelled estimate of the number of HIV‐positive pregnant women (the denominator). Estimating the number of HIV‐positive pregnant women, and hence need for PMTCT services, relies on information about (i) age‐ and sex‐specific HIV prevalence in the population, (ii) age‐specific fertility rates and (iii) the fertility of HIV‐positive women relative to HIV‐negative women. Existing literature about the effects of HIV status on fertility emphasises a changing relationship with age et al. It is widely anticipated that ART scale‐up will ameliorate the subfertility of HIV‐positive women, which would affect the number of HIV‐positive pregnant women, although evidence of this is limited This study aimed to improve the characterisation of the relative fertility of HIV‐positive women to HIV‐negative women by region and place of residence and update widely used estimates with data from the ART era.We used data from 49 Demographic and Health Surveys (DHS) and AIDS indicator surveys (AIS) conducted in 27 sub‐Saharan African countries between 2003 and 2016 in which both full birth histories and HIV testing outcomes were available DHS and AIS are nationally representative household surveys Each woman respondent was asked birth history questions for up to 20 births, beginning with the most recent. Dates of birth of the women and children are given in months and years, we assigned the day of birth to be the mid‐point of the month.We initially analysed fertility rates by HIV status during the three years prior to the interview. This cut‐off was used in previous studies We used the standard demographic definition of age‐specific fertility rates (ASFR):We then estimated the fertility rate ratios in the general population. Subsequently, we restricted the analysis to person years after first sex to assess the extent to which variation in age at first sex explains fertility differences among HIV‐positive women and HIV‐negative women in the younger age groups. We assumed sexual debut occurred on the date corresponding to the mid‐point of the reported age at first sex (which is reported as an integer age). Age at first sex was changed to nine months before the reported date of first birth if this was earlier than the mid‐point of reported age at first sex.Other variables included women's HIV status at the time of the survey, calendar year, ART coverage, region and place of residence . Those infected with HIV‐2 and those whose HIV test was indeterminate were excluded from the analysis (0.04%).Countries were grouped into regions as follows: Southern , East and mid‐Africa  and West and central Africa with Ethiopia Table . HIV epiART coverage estimates, taken from UNAIDS estimates We used exponential regression to investigate the interaction between HIV status and five‐year age group, place of residence, region and ART coverage with respect to their impacts on fertility. Each analysis was adjusted for country and survey year. The analysis was repeated excluding person time prior to first sex. The multivariate Wald test was used to assess significance of interaction terms. The first model includes only the interaction between age and HIV status controlled for country and year of survey. Subsequent models include the effect of place of residence, region and national ART coverage and the interactions between them and age and HIV status.All models included the three‐way interaction between year before the survey, five‐year age group and HIV status. Results are reported for the first year before the interview date. Analyses were conducted using Stata version 14.1Model 1 estimated the crude fertility rate ratio (FRR) for HIV‐positive women relative to HIV‐negative women by five‐year age group across all countries and surveys, adjusted only for calendar year and country. In the 15‐ to 19‐year age group, fertility was 1.38 (95% CI 1.19–1.61) times higher in HIV‐positive women than HIV‐negative women, consistent with the fact that for younger ages many women have not yet been exposed to sex and therefore neither to HIV. Thereafter, fertility of HIV‐positive relative to HIV‐negative women decreased with age from an FRR of 0.93 (95% CI 0.85–1.03) in 20‐ to 24‐year‐olds to 0.29 (95% CI 0.13–0.66) in 45‐ to 49‐year‐olds , indicating lack of evidence of regional difference in the relative age pattern of HIV subfertility.There was a significant interaction between HIV status and region Table , Model 2F = 2.80, P = 0.010), with a steeper gradient in urban areas than in rural areas .The fertility differences between HIV‐positive and HIV‐negative women slightly reduced as ART coverage increased. With ART coverage at over 50%, the fertility rate ratio was 1.09 times higher (95% CI 1.01–1.18), compared to when ART coverage was below 20%. However, overall the fertility of HIV‐positive women remained significantly lower than that of HIV‐negative women in recent surveys with high ART coverage. For example, in urban Southern Africa, the fertility rate ratio increased from 0.70 (95% CI 0.59–0.82) in 30‐ to 34‐year‐olds in a time with <20% national ART coverage to 0.76 (95% CI 0.64–0.91) when there was 50% ART coverage  when restricted to sexually active women (Figure Across surveys, we observed consistently higher median age at first sex among young women in urban areas compared to rural areas and in southern African countries compared to east Africa and west and central Africa Table . This suThis analysis has shown that overall subfertility attributable to HIV is slightly less pronounced than previously thought, and we find that it varies across settings. Consistent regional and urban/rural differences have been found, which are largely explained by variation in age at first sex. The fertility differential between HIV‐positive and HIV‐negative women appears to have narrowed in recent years as ART coverage has increased; however, caution is required in attributing this directly to ART.vs. 18–19 years in the southern African countries (Table We corroborated patterns found in previous studies showing increasing HIV‐associated subfertility with age This analysis suggests that the relationship between HIV and fertility has attenuated slightly as the introduction of ART, but overall fertility remains significantly lower among HIV‐positive women than HIV‐negative women. These reductions are somewhat less dramatic than predicted by current estimates of PMTCT need published by UNAIDS using the Spectrum model, which assumes that women on ART for more than six months have the same fertility as HIV‐negative women of the same age. For example, under this assumption, a 50% increase in ART coverage would attenuate the overall FRR of HIV‐positive women from 0.7 times that of HIV‐negative women to 0.85. This is an increase of 1.21 times, somewhat greater than the 1.11 times increase that we estimated for survey periods with ART coverage >50% compared to those <20%. There was no evidence that the effect of ART coverage on HIV subfertility varied by age. As the differences in HIV‐associated subfertility by national ART coverage are small, it is possible that we did not have the power to detect any further differences by age. National ART coverage is an ecological variable. It does not measure individual exposure to treatment, and hence, we are cautious about attributing causality, for example countries with better roll out of ART may also have other things in common such as good health systems, with better provision of family planning services.We find substantially less HIV‐associated subfertility than Chen and Walker A number of recommendations arise from these analyses for improving estimates and predictions of need for PMTCT services. We found evidence for variation across regions, with less HIV‐associated subfertility in Southern Africa, but no evidence of differences by age pattern. This suggests that scaling the estimated age pattern of relative fertility of HIV‐positive women to reflect overall prevalence among pregnant women observed through routine HIV testing may be a reasonable approach to calibrating and reflecting variation across countries and settings. There are significant differences in the pattern of relative fertility by urban/rural residency, which appeared to be largely explained by older sexual debut in urban areas. This should be accounted for in planning and allocating resources for PMTCT at the subnational level and evaluating local progress towards MTCT elimination. Finally, the relationship between HIV and fertility has attenuated slightly as ART has been introduced, supporting the current practice to account for ART coverage when predicting fertility of HIV‐positive women and need for PMTCT. However, overall the reductions are somewhat less dramatic than predicted by current Spectrum assumptions, and fertility remains lower among HIV‐positive women than HIV‐negative women at older ages. Overall, we have characterised the fertility patterns of HIV‐positive women over time and across regions in sub‐Saharan Africa as ART scaled up from the mid‐2000s through 2015. However, they could continue to evolve rapidly as HIV treatment and prevention programmes enter a new era. Improving timely data about the fertility patterns of HIV‐positive women and deeper understanding of the mechanisms underlying changes will be important to plan and evaluate PMTCT policy and monitor epidemic trends.Supplementary Digital Content 1.Click here for additional data file.Supplementary Digital Content 2.Click here for additional data file.