N = 20) with a sex- and age-matched group of healthy adolescents reared in families (N = 20) in China using a voxel-based morphometry analysis. First, we found that both total gray- and white-matter volumes did not differ between groups. Second, after correcting for age, sex, and total gray-matter volume, the AIDS orphan group demonstrated smaller hippocampal volumes, larger anterior cingulate cortex (ACC) volumes, and no differences in the amygdala. Third, a whole-brain analysis identified higher gray-matter volume of the ACC in the AIDS orphan group than in the control group. The preliminary findings of this study highlight the need for future research to confirm the sensitivity of the hippocampus and ACC to early adversity.Multiple studies have revealed that adolescent AIDS orphans have more psychosocial problems than healthy adolescents. However, little is known about whether and how the brain structures of adolescent AIDS orphans differ from those of healthy adolescents. Here, we used magnetic resonance imaging to compare adolescent AIDS orphans reared in institutions ( An estimated 17.8 million AIDS orphans < 18 years old have lost either or both parents to AIDS . AIDS orIn short, previous studies suggested that adolescent AIDS orphans, especially those reared in institutions, suffer more psychosocial and behavioral problems than healthy adolescents. However, very little is known about whether and how AIDS orphans differ from healthy adolescents at the neurobiological level. In particular, we aimed to identify the differences in neural structure between AIDS orphans and healthy children to determine how early adversity influences subsequent brain and behavioral development and develop effective intervention strategies to protect their health.Several decades of neuroimaging studies have indicated that total gray- and white-matter volumes, the structures of the prefrontal cortex (PFC), hippocampus, and amygdala are highly sensitive to early stressful events, such as poverty , maternaPrevious studies showed that gray- and white-matter volumes can be affected by institutional rearing experiences , 19, 20.Multiple studies have reported that the PFC, which is responsible for temporal sequencing of goal-directed behaviors, is highly sensitive to early adversity , 22. HowEarly adverse experiences are thought to influence the structure of the hippocampus and amygdala, two critical neural substrates that regulate stress responses, but the results are still mixed. For example, previous studies showed that poor children have smaller volumes of the hippocampus  and amygIn sum, previous studies showed that early adversity was associated with differences in the volumes of the white and gray matter, PFC, hippocampus, and amygdala . HoweverThe aim of the present study was to determine whether and how the brain structures of AIDS orphans differ from those of healthy adolescents. First, we investigated whether institutionally reared AIDS orphans had smaller cortical gray- and white-matter volumes relative to healthy adolescents. Second, regions of interest (ROI) analyses were performed to examine whether and how the gray-matter volumes of the PFC, hippocampus, and amygdala differ between AIDS orphans and healthy adolescents in. Third, a whole-brain analysis was performed to confirm the results of ROI analyses and determine which regions differed the most between the AIDS orphans and the controls.t = 0.13; p = 0.90) and gender . Signed informed consent was obtained from the AIDS orphans and their legal guardians (their teachers in the orphanage) before the data collection. Meanwhile, written informed consent was obtained from all healthy adolescents and their parents. The magnetic resonance imaging (MRI) protocol and consent procedure were approved by the Institutional Review Board of Beijing Normal University.Twenty AIDS orphans  were recruited from an orphanage located in Henan Province of China, an area with a high HIV/AIDS prevalence due to unsanitary commercial blood collections performed between the late 1980s and middle 1990s. They had lived in an orphanage a mean 5.08 ± 1.83, and 90% of them had been transferred from another orphanage  to their current orphanage . Another 20 school-aged adolescents  were recruited from Beijing as the control group. No significant group differences were identified on age  with a 12-channel phased-array head coil at the BNU Imaging Center for Brain Research, Beijing, China. The whole-brain structural images were acquired using a 3D magnetization prepared rapid gradient echo (MP-RAGE) T1-weighted sequence . One hundred and twenty-eight contiguous sagittal slices were acquired with 161-mm in-plane resolution and 1.33-mm slice thickness for whole-brain coverage.Voxel-based morphometry (VBM) is a fully automatic technique which allows an objective analysis of anatomical differences between groups across the entire brain, and it has been widely used to quantify structural brain changes associated with neuropsychiatric pathologies such as psychiatric disorders  and deprt-test to compare the differences in the total white- and gray-matter volumes. Mean total gray- and white-matter volume were extracted for each participant using FreeROI (http://freeroi.brainactivityatlas.org/).To fully investigate the neuroanatomical differences between the AIDS orphans and the control group, the current analysis started with an independent-sample http://www.fmrib.ox.a-c.uk/fsl) with the threshold set at 50%. Specifically, the PFC consisted of four subdivisions: middle frontal gyrus (MFG), inferior frontal gyrus (IFG), anterior cingulate cortex (ACC), and the orbital frontal cortex (OFC) [t-test was performed to identify differences in the gray-matter volumes of the PFC, amygdala, and hippocampus between AIDS orphans and healthy adolescents.Second, ROI analyses were conducted to examine whether and how AIDS orphans differed from healthy adolescents in the PFC, hippocampus, and amygdala, which were hypothesized to be sensitive to early adversity based on previous studies . All of the ROI masks were derived from Harvard-Oxford subcortical structural atlas available with FSL 4.1  . The totp < 0.005, uncorrected) and then tested these clusters using cluster-based correction in the entire brain. In the whole-brain correction, the minimum cluster size above which the probability of type I error was <0.05 was determined by the cluster program in FSL using the Gaussian Random Field theory. Local peak voxels were extracted using FreeROI.Third, to confirm the results of ROI analysis and determine which region differed the greatest between the AIDS orphans and controls, we further adopted a whole-brain VBM analysis. Total gray-matter volume, age, and sex were controlled for as confounding covariates. Through the analysis, we first identified clusters of contiguous voxels showing significant differences . After the addition of age and sex as confounding covariates, the two groups still showed no significant difference in total gray-matter volume .The independent-sample t = -0.49, p = 0.625). After the adjustment for age and sex, no significant group difference was identified .The total white-matter volume did not differ significantly between AIDS orphans and adolescents in the control group , as well as of all the sub-regions   and ACC , while a marginal difference was found in OFC . These findings indicated that AIDS orphans have larger gray-matter volume in PFC as well as its sub-regions like the ACC and OFC than adolescents in the control group  . When cool group .t = -2.06, p = 0.046; left hippocampus: t = -2.07, p = 0.047; right hippocampus: t = -2.00, p = 0.053) differed between the AIDS orphans and the control group  than adolescents in the control group  .No significant group difference was found in the volume of the amygdala  . After tp = 0.005, cluster-based correction)  , Fig 3. In this first volumetric study of the brain in AIDS orphans reared in institutions, we found substantial support for the hypothesis that institutionalized AIDS orphans have structural brain alternations in a previously predicted ROI (PFC and hippocampus) based on previous studies , 17, 22.Despite the obvious paucity of structural imaging studies of AIDS orphans reared in institutions, our findings are largely consistent with those of previous studies of individuals suffering from early adversity like poverty, maternal deprivation, and maltreatment, especially with respect to significant reductions in hippocampal volumes (adjusted and unadjusted) , 29, 37.Although our findings were inconsistent with those of previous MRI studies that showed reductions of PFC volumes in institutionalized children , we founIn contrast with two previous studies of institutionalized children , 49, we In summary, this study is the first to demonstrate that AIDS orphans reared in institutions developed smaller hippocampal volumes and larger ACC volumes than did healthy adolescents. We acknowledge several limitations of the current study that make its replication in a larger sample set desirable. Considering that the subjects of the orphan and control group were enrolled from different cities in China and had different socioeconomic backgrounds, socioeconomic status is a potential confounder in the current study. To confirm the current findings, it is better to compare AIDS orphans with healthy adolescents from the same area (such as Henan province) in future studies. Meanwhile, because of the current small sample of subjects and our inability to gather the participants’ histories of early stressful events, we cannot determine which adversity led to the neural differences between AIDS orphans and healthy adolescents. Therefore, a future strategy will explore whether specific brain changes in AIDS orphans are related to specific types of adversity. For example, whether the experience of being orphaned by AIDS or the institutional rearing led to differential brain alterations remained to be answered. Another limitation to the generalizability of our results is that our sample included only Chinese participants. Moreover, the sample contained very few subjects. The generalizability of our findings is limited until we learn whether these results are robust across samples with different races and ages. Moreover, fundamental questions regarding the effects of mediators or moderators on brain volume differences in AIDS orphans need to be addressed in future studies. There is also a need to study the differential roles of the hippocampus and PFC in predicting behavioral differences between AIDS orphans and healthy adolescents.Despite these shortcomings, the finding that AIDS orphanhood was related to a smaller hippocampus and a larger PFC has important research and clinical implications. First, structural changes in certain brain regions may be potential biomarkers for outlining the influence of AIDS orphanhood imposed on children, which reflects individuals’ vulnerability to early traumatic experiences. Second, if an intervention could normalize the brain anatomical differences found in AIDS orphans, it may provide valuable clues about how an individual responds to the intervention as well as future research on intervention targeting this population. Based on the current findings, interventions focused on promoting AIDS orphans’ resilience may be applicable to mitigate the impacts of early adversity on neurobehavioral development.S1 File(DOC)Click here for additional data file.S2 File(SAV)Click here for additional data file.


Have empirical early antibiotic prescribing patterns for premature infants changed over time?This multicenter cohort study of more than 40 000 premature infants found that most premature infants received early antibiotic administration and that rates of initiation of empirical early antibiotic therapy did not change from 2009 to 2015. Rates of prolonged antibiotic administration among very low-birth-weight infants decreased slightly, but did not change among extremely low-birth-weight infants.Despite concerns regarding the negative impact of early and prolonged empirical antibiotic use among premature newborns, neonatal clinicians across the United States continue to prescribe empirical antibiotics to the majority of very low-birth-weight infants in the first 3 days of age. This pharmacoepidemiology study assesses rates and duration of antibiotic use begun within the first 3 days of life in very low-birth-weight and extremely low-birth-weight infants using administrative database data of academic and community hospitals from 2009 to 2015. Premature infants are frequently administered empirical antibiotic therapy at birth. Early and prolonged antibiotic exposures among infants without culture-confirmed infection have been associated with increased risk of adverse outcomes.To examine early antibiotic use among premature infants over time and across hospitals in the United States.This retrospective cohort study used a comprehensive administrative database of inpatient encounters from 297 academic and community hospitals across the United States to examine data concerning very low-birth-weight (VLBW) infants (<1500 g), including extremely low-birth-weight (ELBW) infants (<1000 g), who were admitted to the neonatal intensive care unit and survived for at least 1 day. Data collection took place in November 2015 and analysis took place from February 2016 to November 2016.Antibiotic initiation within the first 3 days of age and subsequent antibiotic administration for more than 5 days.Temporal trends in early antibiotic initiation and duration from 2009 to 2015, and center variation in early antibiotic use from 2014 to 2015.P = .12 for VLBW and P = .52 for ELBW). The annual risk difference in the proportion of VLBW infants administered early antibiotic therapy ranged from −0.75%  to −0.87% ; in ELBW infants the annual risk difference ranged from −0.34%  to −0.38% . There was a small but significant decrease over time in the rate of prolonged antibiotic duration for VLBW infants (P = .02), but not for ELBW infants (P = .22). The annual risk difference in the proportion of VLBW infants with prolonged antibiotic duration ranged from −0.94%  to −1.08% ; in ELBW infants the annual risk difference ranged from −0.72%  to −0.75% . We also observed variation in early antibiotic exposures across centers. Sixty-nine of 113 centers (61.1%) started antibiotic therapy for more than 75% of VLBW infants, and 56 of 66 centers (84.8%) started antibiotic therapy for more than 75% of ELBW infants. The proportion of VLBW and ELBW infants administered prolonged antibiotics ranged from 0% to 80.4% and 0% to 92.0% across centers, respectively.We identified 40 364 VLBW infants  who survived for at least 1 day, including 12 947 ELBW infants, from 297 centers. The majority of premature infants had early antibiotic initiation (31 715 VLBW infants [78.6%] and 11 264 ELBW infants [87.0%]), and no differences were observed over time in temporal trend analyses (Most premature infants in this study received empirical early antibiotic therapy with little change over a recent 7-year period. The variability in exposure rates across centers, however, suggests that neonatal antimicrobial stewardship efforts are warranted to optimize antibiotic use for VLBW and ELBW infants. Infection is the cause of approximately one-third of cases of preterm labor and/or premature rupture of membranes,4 and approximately 1 in 90 VLBW infants is born with culture-confirmed early-onset bacterial infection.5 Infection-attributable mortality is 35% among VLBW infants with EOS and as high as 50% among the most premature infants, those born at 22 to 24 weeks’ gestation.6 The probability of EOS combined with the clinical instability characteristic of premature newborns leads to high rates of empirical antibiotic treatment: previous studies demonstrate that neonatal clinicians administer antibiotics from birth in 90% to 98% of VLBW and extremely low-birth-weight (ELBW) (birth weight <1000 g) infants.8Antibiotics are the most common class of medications used in the neonatal intensive care unit (NICU).18 Recent studies have identified declines in antibiotic use rates during hospitalization over time among premature infants in Canadian centers12 and variation in antibiotic use rates among all newborns in neonatal centers in California independent of infection burden.19 Such variation suggests that some proportion of antibiotic use may be unnecessary. Antimicrobial stewardship efforts have begun to focus on neonatal settings, and national quality improvement initiatives have targeted nonindicated early antibiotic use in VLBW infants.23 The impact of such efforts remains unclear. A detailed understanding of how antibiotics are used among specific categories of newborns may help optimize such efforts. The objective of this study was to specifically examine early antibiotic use among VLBW infants in a contemporary and nationally representative database to describe trends over time and across hospitals in the United States.Although antibiotics are administered to protect premature newborns, multiple recent studies suggest that antibiotics have potential risks as well as potential benefits for this population. Early and prolonged antibiotic exposure in premature infants without culture-confirmed infection has been associated with increased mortality as well as increased subsequent risks of necrotizing enterocolitis, invasive fungal infections, antibiotic-resistant infections, bronchopulmonary dysplasia, periventricular leukomalacia, and retinopathy of prematurity.28 The database includes both academic medical centers and community-based hospitals; contains diagnosis and procedure codes, demographic information, and billed services, including pharmacy charges; and is subject to routine validation and quality audits. Deidentified hospital-level information, including teaching status, hospital size, and geographic region, are available. Patient-level daily drug charge data, including drug name, class, dosage, and route, are also available. This study was not considered human subjects research given the fully deidentified nature of the data and was therefore exempted from institutional review board review and requirement for patient consent according to the policy of the Children’s Hospital of Philadelphia institutional review board. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline was used in the reporting of this study.We conducted a retrospective cohort study using the Premier Perspective Database (Premier Inc). Premier is a large, comprehensive administrative database of deidentified inpatient encounters from participating hospitals across the United States and has previously been used for research studies in both adult and pediatric populations.Data collection took place in November 2015 and analysis took place from February 2016 to November 2016. We identified patients in the Premier database between January 2009 and September 2015 with (1) a neonatal All Patient Refined Diagnosis Related Group (APR-DRG) code, (2) patient origin of “born inside this hospital,” (3) admission listed as “inpatient,” (4) NICU room and board charge on the first or second day of admission (to only include infants admitted to the NICU within 24 hours of birth), and (5) birth at a center that cared for more than 20 newborn patients per year . We excluded patients who survived for less than 1 day or had missing birth weight data. Using the APR-DRG codes, we identified VLBW infants and the subset of ELBW infants.8 For the analysis of prolonged antibiotic administration, we excluded infants admitted to the NICU for 5 or fewer days .We defined the day of birth as the day of hospital admission, given that we only included inborn infants and that VLBW infants are universally admitted to the NICU at birth in the United States. Early antibiotic initiation was defined as a billing charge for at least 1 parenteral antibiotic in the first 3 days of age. Prolonged antibiotic duration was defined as administration of parenteral antibiotics for more than 5 consecutive days after early initiation. This was chosen to align with the definition of prolonged antibiotic duration previously used by a large multicenter neonatal-specific database.We calculated the total duration (days) of early antibiotic therapy among all infants in the study sample, the proportions of VLBW and ELBW infants with early antibiotic initiation, and the proportions of VLBW and ELBW infants with prolonged antibiotic duration. To assess changes in antibiotic use over the study period, we fit a logistic regression with a linear time variable  for each outcome (early antibiotic initiation and prolonged duration). From the models, we obtained expected risk (interpreted as proportion) for each quarter, and described the annual change of the expected risk (risk difference over 4 quarters). Confidence intervals for risk differences were calculated by the delta method. Robust standard errors were calculated to account for clustering at the hospital level. Analyses were performed with the full VLBW infant cohort as well as the subcohort of ELBW infants. Because not every center contributed patients throughout the study period, we also performed sensitivity analyses including (1) only those hospitals that contributed VLBW infants in all years and (2) only those hospitals that contributed ELBW infants in all years for respective analyses, to confirm that observed trends were not due to the effect of hospitals entering or leaving the cohort.To describe variation of early antibiotic initiation and prolonged antibiotic duration by center, we used the most recent 12 months of the study period (October 2014 to September 2015). We chose this 12-month period to allow the most contemporary evaluation of variation, as well as to minimize the impact that changes in center-specific personnel and center-specific admission policies could have on antibiotic use. We excluded centers that admitted fewer than 10 VLBW or ELBW infants  during the 12-month period because such centers are not likely to have consistent policies for the care of infants they care for rarely, and such centers are more likely to transfer VLBW and ELBW infants to higher-acuity centers in the 24 to 48 hours after birth.P value) in the logistic regression models. P < .05 was considered statistically significant, and all reported P values are 2-sided. Statistical analyses were performed using Stata statistical software version 15.0 (StataCorp).A Wald test was used to determine the significance of the coefficient  and 11 264 ELBW infants (87.0%). Infants administered early antibiotic therapy had lower birth weights, were less likely to be cared for in teaching centers, and had longer lengths of stay compared with those not administered early antibiotic therapy . AmpicilP = .12 for VLBW; P = .52 for ELBW)  A. The anP = .02) but not for ELBW infants (P = .22)  B. The anP = .08); in ELBW infants the annual risk difference ranged from −0.68%  to −0.91%  (P = .35). The annual risk difference in the proportion of VLBW infants with prolonged antibiotic duration ranged from −1.14%  to −1.01%  (P = .01); in ELBW infants the annual risk difference ranged from −1.00%  to −0.95%  (P = .14).Sensitivity analyses including only those hospitals that contributed VLBW or ELBW infants in all years for respective analyses were consistent with the primary analyses. The annual risk difference in the proportion of VLBW infants administered early antibiotic therapy ranged from −1.00%  to −1.26%  (Sixty-nine of 113 centers (61.1%) started antibiotic therapy for more than 75% of VLBW infants, and 56 of 66 centers (84.8%) started antibiotic therapy for more than 75% of ELBW infants. Variation in antibiotic initiation was noted across centers A and B. 30 and little change in antibiotic use over a contemporary 7-year period. Most notably, we observed wide variation among centers in use of antibiotics for both VLBW and ELBW infants. These observations identify several issues that should be addressed to optimize antibiotic stewardship among VLBW infants.We examined early antibiotic administration among VLBW infants admitted to nearly 300 NICUs across the United States and observed high rates of antibiotic exposure during the first days after birth. Although VLBW premature infants are at higher risk of early-onset infection compared with term-born infants, we found an overall rate of antibiotic initiation that was an order of magnitude higher than the actual incidence of infection8 Another study included 790 ELBW infants born in 2000 at multiple centers within a university health care system in the United States; 94% were administered early empirical antibiotics, and 59% of those with negative blood cultures continued to receive antibiotics for 4 or more days.7 In a more recent analysis of antibiotic use rates among VLBW infants born from 2010 to 2014 in the Canadian Neonatal Network, 55% of 8414 VLBW infants without infection-related comorbidities received antibiotics for 4 or more days during their first 7 days after birth.12 The Centers for Disease Control and Prevention’s 12-Step Program to Prevent Antimicrobial Resistance in Health Care Settings was released in 2002.31 Patel and colleagues32 demonstrated that the antimicrobial stewardship elements of this campaign were relevant yet not frequently applied in their study of 4 tertiary care NICUs in 2005. A decade later, our study found overall lower rates of both antibiotic initiation and prolonged antibiotic administration among VLBW and ELBW infants compared with prior reports, potentially reflecting increased attention to indiscriminate antimicrobial use in the premature population. However, we found little change over the past 7 years, reflecting continued uncertainty among neonatal clinicians about the optimal application of antibiotic stewardship principles among very premature infants.This analysis represents the largest study to our knowledge of early antibiotic use among VLBW infants across the United States and included both academic and community hospitals. Smaller studies have addressed early antibiotic exposures among VLBW and/or ELBW infants in the United States, namely within academic centers, over the past 20 years. A study conducted among 4039 ELBW infants born in 19 Neonatal Research Network centers from 1998 to 2001 found that 96% were administered empirical antibiotics within 72 hours of birth, and 53% continued to receive these antibiotics for 5 or more days in the absence of culture-confirmed infection.33 and national guidance that has advocated the use of antibiotics for critical illness.34 The wide site variation in administration of prolonged antibiotics likely reflects clinical uncertainty more than variation in illness severity between sites, particularly among ELBW infants, who almost universally manifest some degree of cardiorespiratory instability. Significant site variation in antibiotic use rates was also noted in a study of 127 NICUs in California.19 This study analyzed infants of all gestational ages throughout their hospitalization and observed 40-fold variation independent of confirmed infection and infection-related morbidities and mortality. Little attention has been given to the identification of premature newborns who might be spared early antibiotic exposure. Two recent studies used delivery characteristics to identify VLBW and ELBW infants at lower risk of EOS.36 One study that analyzed all cases of EOS occurring among 5313 VLBW infants over a 25-year period at a single high-risk neonatal center found that 97% of the 109 identified cases occurred in infants born with some combination of premature rupture of membranes, preterm labor, or concern for intrauterine infection.35 In another study of 15 318 infants born at 22 to 28 weeks’ gestation at multiple centers within the Neonatal Research Network, those born by cesarean delivery with membrane rupture at delivery and without clinical chorioamnionitis were significantly less likely to have confirmed EOS.36 When placental pathology results were available, the additional absence of histologic chorioamnionitis defined ELBW infants at even lower risk of EOS. It is therefore possible that clinical strategies based on such delivery characteristics and/or placental pathologic findings might provide a framework for developing approaches to decreasing empirical antibiotic use among VLBW and ELBW infants.The substantial rates of antibiotic initiation observed in this study are not surprising given the frequency of clinical instability among VLBW and ELBW infantsOur study has several limitations. The Premier database does not contain information that allows for the calculation and comparison of scores for early illness severity, so we cannot directly address the role that local variation in patient acuity contributed to antibiotic use variation. In addition, neither microbiologic information nor other indications for antibiotic therapy were available, so we could not identify infants with culture-confirmed infections. While all regions of the country were represented in the center sample, the overrepresentation of centers located in the southern United States should be taken into consideration when interpreting these results. A small number of centers in the variation analysis have very low antibiotic use, which may be due to true differences in practice, patient population, or center-specific incidence of culture-confirmed infection or to errors in billing charge entry.Most VLBW and ELBW infants receive empirical early antibiotic therapy, and this has remained stable over time. There is discordance between rates of early antibiotic exposure and incidence of EOS in premature infants, and variation in exposure rates exists across centers. These findings suggest a continued need for neonatal antibiotic stewardship efforts designed to help clinicians identify premature infants at lowest risk of EOS to avoid nonindicated, and perhaps harmful, antibiotic exposure.


Antibiotic resistance has reached alarming proportions globally, prompting the World Health Organization to advise nations to take up antibiotic awareness campaigns. Several campaigns have been taken up worldwide, mostly by governments. The government of India asked manufacturers to append a ‘redline’ to packages of antibiotics as identification marks and conducted a campaign to inform the general public about it and appropriate antibiotic use. We investigated whether an antibiotic resistance awareness campaign could be organized voluntarily in India and determined the characteristics of the voluntarily organized campaign by administering a questionnaire to the coordinators, who participated in organizing the voluntary campaign India. The campaign characteristics were: multiple electro–physical pedagogical and participatory techniques were used, 49 physical events were organized in various parts of India that included lectures, posters, booklet/pamphlet distribution, audio and video messages, competitions, and mass contact rallies along with broadcast of messages in 11 local languages using community radio stations (CRS) spread all over India. The median values for campaign events were: expenditure—3000 Indian Rupees/day (US$~47), time for planning—1 day, program spread—4 days, program time—4 h, direct and indirect reach of the message—respectively 250 and 500 persons/event. A 2 min play entitled ‘Take antibiotics as prescribed by the doctor’ was broadcast 10 times/day for 5 days on CRS with listener reach of ~5 million persons. More than 85%ofcoordinators thought that the campaign created adequate awareness about appropriate antibiotic use and antibiotic resistance. The voluntary campaign has implications for resource limited settings/low and middle income countries. Antimicrobial resistance (AMR) is the ability of a microorganism  to stop an antimicrobial  from working against it and as a result, standard treatments become ineffective, infections persist, and may spread to others . ResistaIndia has a three-tier healthcare system , which has both public and private healthcare players, and is manned by allopathic as well as AYUSH  practitioners, with all of them potentially prescribing antibiotics. In addition, informal healthcare providers  and pharmacists may also prescribe/dispense antibiotics, with antibiotics likely to be also available ‘over the counter’ without prescription on demand by lay persons ,3,4. TheThe World Health Organization (WHO) published a global report on antimicrobial resistance surveillance in 2014 emphasizing that “resistance in common bacteria has reached alarming levels in many parts of the world and that in some settings, few treatment options remain effective for common infections” . It was This paper reports the results and characteristics of a campaign conducted in India on a voluntary initiative, entitled ‘Antibiotic Resistance Awareness Campaign (AMRAC-17)’ during 13–19 November 2017, and discusses future paths and pointers for resource-limited settings/low and middle income countries. In the article, the terms antimicrobial and antibiotic appear synonymously.2, population nearing 1.37 billion) [India is a country of sub-continental dimensions  , dividedA national level committee of Ashok J. Tamhankar (A.J.T.), National Coordinator of IIMAR, Ramesh Nachimuthu (R.N.), Joint Coordinator of IIMAR, and Ravikant Singh (R.S.), Chief Functionary of Doctors For You (DFY) coordinated the campaign. IIMAR and DFY are both non-governmental organizations (NGO) working in the field of public health. While IIMAR devotes itself mainly to management of antibiotic resistance, DFY works in the entire public health field, including disaster relief. Both have a wide network of non-healthcare and healthcare-related individuals interested in the objectives of these organizations throughout India. The potential campaigners, who were in these organization’s connectivity range–network and also some who became interested by reading the IIMAR blog and Facebook page, were invited to join the campaign through phone calls, emails, webpages, Facebook page, and ‘WhatsApp’ group (Antibiotic Resistance Ind) of IIMAR. Those who accepted the invite were sent a form to fill in with their details . Once reWe planned to use multiple pedagogical and participatory physical and electronic techniques such as display of posters, distribution of pamphlets/booklets, audio and video messages, radio broadcast, lectures, slogan competition, rallies, etc., for the dissemination of the campaign message.The posters in English made available to coordinators were the ones advised by WHO . The posTo understand the characteristics of the campaign, after the campaign was over, the coordinators were asked to respond to a questionnaire  that eliIIMAR did not provide any funding or incentive to the coordinators and the volunteers. They were to fund their activity on their own.As a response to our call, 69 potential collaborators showed interest and were sent the form to register . To thisThe campaign message encompassed in a 2 min play entitled ‘Take antibiotics as prescribed by doctors’  was broaThe extent of the campaign’s geographical spread, inclusive of physical campaign places and CRS, can be visualized in The text of the invitation to potential collaborators for the nationwide campaign is available at the IIMAR webpage . Mass coAn example of an audio message in English entitled ‘Take antibiotics as prescribed by the doctor’ broadcasted on CRS and circulated among the public is presented in Among the coordinators, 48% were PhDs, 12% were doctors of medicine, 32% had Master’s degrees, 8% had Bachelor’s degrees. The male: female ratio among coordinators was 72:28. The coordinator’s specializations included medicine, public health, international/global health, pharmacy, disaster management, microbiology, biochemistry, biotechnology, dentistry, nursing, environmental health, limnology, and social work. The type of institutions/organizations they belonged to included: educational institutes-private—9, government—5, , NGO—2, private pathological laboratories—2. Some coordinators organized more than one distinct campaign event each: three organized 4 events, 5 organized 3 events, 3 organized 2 events, and the rest organized one event each . In BandThe distribution of the locations of the campaign was: city 46%, district place 27%, villages 27%. The campaign in Jammu and Kashmir covered several villages in the Bandipore district. CRS in India were distributed among educational institutes —57% and NGOs—43%. While the educational institute’s campuses were generally away from cities and were self contained, the NGO’s CRS generally focused on rural and remote areas.The campaign components preferred by the coordinators can be seen in The salient feature of our campaign was that the campaigners could choose from a catalogue of electro-physical  campaign materials, whatever was feasible for them to utilize. Lectures appeared to be the most preferred item. The campaigners and the organizations at which and through which the campaign was conducted, and the recipients of the campaign, included healthcare-related and non-healthcare-related stakeholders, students and non-students. The geographical spread of the campaign was throughout the country. More than 80% of coordinators perceived that the campaign delivered the targeted messages.A covariate analysis had earlier provided theoretical insight into the kind of groups to be targeted for antimicrobial awareness campaigns, namely, stewards, stockers, and demanders . The anaAnother suggested approach for a campaign is to adopt a social marketing approach to achieve sustainable behavior changes. Social marketing is a ‘process based on the application of marketing principles and techniques to create, communicate, and deliver social values designed to influence target audience behavior so that both society and the target audience benefit according to the ideological framework used’ . Since wThe approach is illustrated by taking an example of the audio and video messages that we created. The audio message, which was in 13 languages, ’ to spread the campaign message. Community radio has been defined as “one that is operated in the community, for the community, about the community and by the community-the community can be territorial, or geographical e.g., township, village, district, or island” . CRS areA campaign is a planned set of activities to achieve a certain objective . In the Antimicrobial/antimicrobial resistance awareness campaigns have been conducted earlier , general2, an estimated population of about 513 million, with several spoken languages and a variety of cultures [Considering the complexity and diversity of India, our campaign setting was somewhat comparable to the campaign setting in the European Union (EU) , althougcultures . Informacultures  and the cultures  put fortcultures , 16.0 DDcultures  and 11,5cultures ; howevercultures  and thusSince ours was a first attempt for a nationwide voluntary campaign in India, we compare here our campaign characteristics with the first EU campaign in 2008 . An analSome of the EU responses pointed out that the teams involved in the EU campaign were handling this campaign in addition to their regular work. This was true for us also. The respondents in the EU campaign indicated that their governments supported the campaign politically and financially. We did not have any support from government for our effort. Earlier information on budgets and funding reflected widely varying volume and intensity, from a budget of a few thousand USD, to expensive mass-media campaigns with budgets in the range of millions of USD . Ours waThe UK “Antibiotic Guardian Campaign” is an ‘always on’ campaign for AMR  The IIMAThis is probably the first and only antibiotic resistance awareness campaign conducted on such a wide scale  on a voluntary basis using electronic and physical campaign components in India and also probably, globally. We did not come across any reference in the literature for a comparable voluntary, non-centrally funded, wide scale campaign on antibiotic resistance awareness and so, our campaign becomes a significant achievement.Organizing public awareness campaigns in a multicultural, multilingual, and vast country like India on a voluntary basis is a challenge, particularly to take along a lot of un-acquainted, faceless, unknown people, bound only by a desire to reduce antibiotic resistance and promote appropriate antibiotic use. Absence of centralized funding was a great impediment. There was a general consensus among coordinators that if government or other funding was available, the campaign coverage would have been more extensive, geographically and impact-wise. Further, we would have been able to conduct an appropriate pre- and post-campaign evaluation of knowledge, attitudes, and practices regarding hygiene, infections, infection control, antibiotic use, antibiotic resistance, and behavior towards these among stakeholders. Public awareness campaigns must be repeated to achieve sustainability in behavioral change. IIMAR wanted to conduct a follow up campaign in 2018 with improvements, but in the absence of supply of funds, a majority of the coordinators expressed an inability to conduct a voluntary campaign once again. It is important to involve stakeholders in animal, agricultural, environmental sectors, etc., in such a campaign, which we could not do. It is not sure, whether this will be easier.For effective appropriate outcomes from such a campaign, rural areas must be covered, where the inappropriate use of antibiotics is rampant, both by healthcare providers and the population. Antibiotic use is strongly hammered by medical sales representatives causing an increase in its unnecessary use, therefore, these stakeholders must be targeted to reduce inappropriate antibiotic use. Governments have vast infrastructure and resources and also a responsibility for making antibiotic awareness programs successful, therefore government organizations should be instructed to come forward voluntarily to facilitate and support such vital campaigns taken up by non-governmental agencies voluntarily. It needs to be assessed whether bringing forth in campaigns, the harmful side effects of antibiotic misuse, playing on ‘fear for life’ psychological factor among stakeholders, could help in disrupting antibiotics overuse/misuse. Involvement of healthcare provider and patient associations and various types of social and specialist organizations should be explored to increase campaign outreach and effectiveness. Future campaigns also need to integrate and target all types of stakeholders in sectors such as animal, agriculture, environment, manufacturers, pharmaceutical companies, etc., and take up a ‘one health’ approach.2) and multi-lingual spread (11 languages) in a single country nationwide, that includes educational information on all aspects of the antibiotic resistance spectrum such as infection control, hand hygiene, appropriate antibiotic use, and antibiotic resistance awareness.This appears to be the first antibiotic resistance awareness campaign conducted voluntarily without political and financial support from government that encompasses a vast geographical , with the focus of the campaign components being to adopt the recommended social marketing approach so that the targeted audience owned up to the antibiotic resistance awareness message. In this context, inclusion of community radio stations owned by the community itself, to spread the antibiotic message, needs to be specially mentioned.As per the recommendations of a covariate analysis that provided theoretical insight into the kind of groups to be targeted for antimicrobial awareness campaigns, we included stewards, stockers, and demanders to achieve antimicrobial stewardship. To achieve this, our campaign covered all sections of society involved in antibiotic prescription, dissemination and use, such as physicians, pharmacists, nurses, hospitals, pathology laboratories, students of medical, pharmacy and nursing colleges, non-medical college students, school students, general public including office goers and small professionals like auto-riksha drivers, spread over cities, towns, district places, and villages.A successful campaign on antimicrobial/antimicrobial resistance awareness on voluntary basis is feasible and may have an impactful outreach and realistic outcomes as the campaign will be owned by the people doing it, and will not be a part of an imposed/assigned duty. Further, it will be a relatively low cost effort, also easing the burden on the exchequer of resource constrained settings/low and middle income countries.Lectures appear to be a better way of message spread compared to visuals as lectures are interactive and personal compared to visuals (posters etc.), which are impersonal and their message may not be understood in many places in low income countries where the lay public may not even understand what is an antimicrobial/antibiotic.A voluntary campaign involving lectures along with discussion will be low cost (US$~1.5). If it is also associated with poster/slogan- display/competition (USD~47), it will help with the understanding and ownership of the campaign message by stakeholders.Community radio networks are a powerful tool to reach local communities and its involvement will cost the state exchequer very little. Repeated message broadcast on CRS associated with lectures along with discussion and poster/slogan-display/competition during a campaign, appear to help in wide spread assimilation of the message in the public mind.


In reinforced concrete (RC) structures, the compressive strength of concrete can play a crucial role in seismic performance and is usually difficult to estimate. Major seismic codes prescribe that concrete strength must be determined essentially from in situ and laboratory tests. Mean values obtained from such tests are the reference design values when assessing existing structures under seismic actions. The variability of concrete strength can also play an important role, generally requiring that various homogeneous domains are identified in a single structure, in each of which a specific mean value should be assumed as representative. This study analyzes the inter- and intra-variability of the concrete strength of existing buildings using a very large database made up of approximately 1600 core tests extracted from RC buildings located in the Basilicata region . The analysis highlighted that concrete strength variability was dependent on the structures’ dimensions as well as on the number of storeys. Moreover, the concrete strength of cores extracted from columns was found to be, on average, lower than that from beams, thus justifying the usual practice to extract cores mainly from columns, which results in a conservative approach as well as a more feasible one. Finally, some case studies were analyzed, specifically focusing on the effects of the within-storey variability. Conservative strength values, to be used especially in the case of vertical members subjected to high axial loads, are suggested. In order to more effectively face natural risks, civil protection activities should be devoted to post-earthquake emergency, and above all, to prevention through a wide range of risk mitigation programs. Focusing in particular on the seismic risk reduction of buildings, vulnerability assessment is of fundamental importance for several reasons, among which: (i) to evaluate current safety conditions in view of possible urgent decisions; (ii) to define priorities and timescales in carrying out extensive strengthening programs; and (iii) to drive towards strengthening interventions that are highly effective in terms of the benefit–cost ratio.The knowledge of concrete strength is essential to perform seismic and gravity load assessments of older reinforced concrete (RC) buildings. Reinforced concrete buildings, in fact, are frequently not provided with proper reinforcement detailing, thus brittle crises can occur in beam and column  members, and most importantly, in beam–column joints equipped with either deep beams  or wide Reliable seismic and gravity load assessments are also important in defining intervention priority, although it should be recognized that these decisions are based also on other socio-political demands and criteria. Further, the knowledge of seismic vulnerability at the territorial scale can allow the elaboration of seismic scenarios for the most probable seismic events which can occur in a given area. Regarding this issue, some procedures aimed at large-scale vulnerability assessment of buildings  based oIn a similar context, other studies  evaluatFor this reason, it appears appropriate to refer to the results of compression tests on concrete cores extracted from RC buildings at the time the seismic assessment is being carried out. Indeed, in Italy, starting from 2004, a huge (and still ongoing) assessment program was started to draw a picture of public buildings’ vulnerability in order to allow owners and political authorities to make decisions and time scaling in view of an extensive strengthening plan. In fact, once the results of the seismic assessment are available, decisions specifically applicable to single buildings can be taken. First of all, the convenience of strengthening (either retrofitting or upgrading) with respect to replacing should be evaluated, and secondly, a comparison with other buildings should be made in order to establish priorities .As a result of more than ten years of seismic assessments of public buildings, a large amount of data on concrete strength values obtained from a laboratory compression test on cores extracted from these buildings are available. As an example, Ferrini et al.  obtainedA similar database on concrete core tests (approximately 1600 specimens) is described and analysed in the present paper. They were collected as a result of the seismic assessments conducted in the Basilicata region on RC buildings whose construction period ranges between 1940 and 1990. Therefore, concrete strength distribution depending on the construction period can be determined. First, this can provide a useful tool for seismic vulnerability assessments at the regional level . SecondlIn Reference , the higAccounting for the frequent large variability of concrete strength within a single building, a procedure for identifying homogenous areas is proposed in Reference , based oIn the present paper, an updated version of the database reported in Reference  is studiData analyzed in this study were collected within a large program of seismic vulnerability assessments of public buildings located in the Basilicata region , which was managed by the local regional authorities , as prescribed by the national law OPCM 3274/2003 [core were converted into the corresponding in situ strength fc through the Relationship (1) reported in Reference [H/D is the correction coefficient for the height/diameter ratio H/D different from 2.0; Cdia is the correction coefficient for the diameter of the core; Cst is the correction coefficient for the presence of reinforcing bars; and Cd is the correction coefficient for damage due to the drilling. Regarding this latter factor Cd, FEMA 274 [d = 1.06, while other researchers [core < 20 MPa, and 1.10 for fcore > 20 MPa, considering that the lower the strength, the higher the expected drilling damage. Following this approach, in the present paper, the values reported in Reference [d = 1.30 for fcore ≤ 10 MPa;Cd = 1.20 if 10 < fcore ≤ 20 MPa;Cd = 1.10 if 20 < fcore ≤ 30 MPa;Cd = 1.00 if fcore > 30 MPa.CIn order to correct the strength values directly achieved on core specimens, possibly different from in situ strength, thus obtaining comparable results, the core strength values feference .(1)fc= there was a significant quota of buildings with very low concrete strength (<10 MPa). Moreover, the last two periods did not show an improvement in terms of concrete homogeneity, as could be expected after the enforcement of a new code on RC constructions.In When planning a destructive tests campaign, a crucial issue relates to the choice of the sampling points. Current seismic codes on the evaluation of RC buildings provide rules forcing the extraction of cores from both column and beam members. However, due to the practical constraints, difficulties in extracting cores from beams are well known among structural engineers, and more importantly, in some cases, extraction can be almost impossible . Moreover, even in the case of deep beams, firmly fixing the drilling machine could be rather difficult. As a result, in most cases, core drilling is carried out on vertical members , and only in a few cases on beams.This is clearly revealed by the database under study, where most cores were extracted from columns, that is approximately 1400 out of a total of ~1600 cores.In order to understand if/how the strength of the cores drilled from columns can be assumed as representative also of beams and then used to determine the design value to be used in safety verifications, the database was analyzed to highlight possible differences between column and beam cores . The comAs displayed in t-tests were performed on the two strength value sets (columns versus beams). The tests can be applied in two different ways:In order to evaluate whether the observed differences were significant, Students’ - two-tailed test: to know whether the mean values are equal;- one-tailed test: to know whether a mean is higher than the other.If one cannot exclude that a mean value is higher than the other, the two-tailed test is preferable. t-test assumes a null hypothesis (H0), meaning that the mean related to the two sets values  belong to the same population, the differences being due to the random variations, and the alternative hypothesis (H1) that the two mean values belong to different populations, that is:The The test was carried out referring to two significance levels: α = 0.05 and α = 0.01.t-test for each construction period is reported, where OK means that the hypothesis H0 cannot be rejected.t-test yielded a positive result for two out of the three construction periods, while for a significance level α = 0.01, a positive result was found for all the construction periods. Therefore, the differences between the two populations were negligible, and consequently, the strength values of columns and beams can be considered as belonging to the same population. For a significance level α = 0.05, the Further, there were two additional aspects to be addressed in order to perform core drilling on column members: i) core drilling from columns is generally less expensive and time-consuming; ii) columns play a more important role in the load-bearing structural system under both vertical and seismic loads.In sum, although the above findings should be considered valid with respect to the database under study, they are nevertheless important as performing core drilling only on columns appears to be on the safe side, with their concrete strength being, on average, lower than that of beams, although they belong to the same population. Therefore, the strength values found on columns’ cores can also be representative of beams’ strength. This remark is consistent with the work in progress to update the Eurocode 8 (EC8)-Part 3: Assessment and retrofitting of buildings and bridges , where tPrevious analyses were devoted to outlining the general features of the whole database under consideration. However, the concrete strength properties can show high variability in the same building, between different storeys, and even at the same storey, although it can be assumed that the concrete used at different storeys has the same mix design, as it is in usual construction practice.In order to analyze the within-building variability, further analyses were performed only on buildings where a large number of cores were available. Assuming that this number is not less than 5, the new database includes 100 buildings and 802 cores . Relating the coefficient of variation to the mean value of the concrete strength in each building , no corrThe estimation of concrete strength for design and assessment purposes is related to the choice of the knowledge level (KL) of the structure under study. Three KLs are defined  in order to choose the appropriate confidence factor (CF) value to be adopted to reduce the concrete strength in the evaluation process. Once a knowledge level is assumed , the current European and Italian seismic codes define the number of cores to be extracted depending on the total storey area, implicitly assuming that a single storey can be considered a homogeneous area. This assumption appears justifiable given that, except in the case of a very large floor area, the members of a single storey are generally cast almost simultaneously, thus similar concrete properties should be expected. On the other hand, different storeys can be cast after a period of time, leading to possible differences, for example, due to the modified environmental curing conditions . This supports the preliminary assumption that different storeys might represent different homogeneous areas. On the basis of the above remarks, it is expected that the global dispersion within a whole building should increase with the number of storeys. In fact, Further, the analysis of data showed that the average floor area did not vary significantly with the number of storeys, so the variation of CV values, shown in This result confirms that considering a whole building as a single homogenous domain can be inappropriate in most cases, as the assumed mean strength value would be associated with an unacceptable high variability.As can be seen in Looking at the graph in R = 0.91) was found using the following logarithmic regression relationship:p is the number of storeys.The mean CV value correlates well with the number of storeys, as can be seen in This finding confirms the importance of appropriately identifying the different homogeneous areas in each building accounting for the fact that, in general, the variability of concrete properties increases with the building dimensions, especially with the number of storeys. Further, this finding suggests taking into account the average expected dispersion of concrete strength as a function of the number of storeys when making vulnerability assessments at the territorial scale .To further develop the analyses carried out in the previous sections by examining also the within-storey variability, five buildings with a number of storeys ranging from 3 to 7 and with at least 4 cores per storey, were selected .Previous analyses demonstrated the high variability of concrete strength in a single building and even within a single storey, in most cases, is due to the intrinsic variability of the material properties. Increasing the number of cores did not reduce the dispersion of strength values. This latter result was evidenced by the high number of buildings having a CV larger than 0.15. One should derive that a single strength value cannot be representative of more than one storey, which represents the maximum extent of the so-called homogenous areas. Indeed, in some cases, more homogenous areas should be set for a single storey, so that any possible irregularity in the plan due to the concrete strength variability ,29 is nos1 = 450 mm2 for column n.1 (four 12 mm diameter bars) and As2 = 900 mm2 for column 2 (six 14 mm diameter bars). The storey height was set to h = 3000 mm.A lower strength value on the larger structural members  can lead to remarkable negative effects on the total structural capacity. This is especially true for frame structures with high axial load values on the columns. In order to clarify this aspect, a simple example was considered: a shear-type portal frame made up of two columns with dimensions of 300 × 300 mm for column n.1 and 300 × 600 for column n.2 see , providemed = 19.53 MPa and minimum strength fmin =10.68 MPa. The steel yielding stress was assumed as fy = 320 MPa.As for concrete strength, the characteristics of the 2nd storey of building no.1  were conu = Ac·fmin. This means that the axial load value on column 1 was about N1 = 360 kN, while that on column 2 was N2 = 720 kN.Axial load values proportional to the columns’ gross area were assumed , i.e., equal to 40% of the ultimate axial load determined as NBased on the assumption of shear type, a double plastic hinge is expected to develop at column ends in a storey failure mechanism due to the horizontal actions. So, the frame base shear is directly proportional to the yielding moments developed at column ends. The total horizontal strength capacity of the structure is then:med (case “a”) or fmin (case “b”) can be computed:(a)y1a = 60.0 kNm, My2a = 238.2 kNmM(b)y1b = 50.6 kNm, My2b = 185.6 kNmMYielding moment values for the two columns using either fmed and column 2 fminColumn 1 having concrete strength fmin and column 2 fmedColumn 1 having concrete strength fNow, two scenarios are assumed:In scenario 1, the total strength capacity is:While in scenario 2:As can be seen, scenario 1 results in a total base shear 15% lower than scenario 2.This means that assuming a strength value equal to the mean concrete strength can lead to overestimation of the storey shear capacity due to the possible presence of low strength values on structural members such as larger columns or walls. This happens even for ductile mechanisms such as flexure for columns, for which the concrete strength plays an important role in the presence of significant axial load values. In order to visualize this situation, the base shear values of the example portal frame in scenarios 1 and 2 were plotted as a function of the axial load. As can be seen from Therefore, for storeys with high concrete strength variability (CV > 0.15), it is advisable to use the mean value minus one standard deviation, as proposed by FEMA 356 , in ordeTherefore, it is strongly suggested to integrate destructive tests with non-destructive tests in order to obtain a sufficient number of strength values . Howevermed, the minimum fmin, and fmed–σ are displayed.In order to derive some indication, the distributions of concrete strength along the height of the five selected buildings are plotted in med–σ is generally very close to fmin. For example, in buildings no. 1, 2, and 4, the two strength values had almost the same trend, except for the 1st storey of buildings no. 2 and 4 and the 2nd storey of building no. 1. Buildings no. 3 and 5 showed larger differences at the first storeys, although a good correspondence between fmin and fmed–σ was generally found.As can be seen from med–σ, that is, a more conservative strength value is suggested by FEMA356 [Based on the above considerations, in the case of seismic assessment where concrete strength was based on few cores per floor, and high scatter was observed among related strength values; it seems advisable to use the minimum concrete strength value of each floor in place of the mean. In fact, the results showed that the minimum value was somehow representative of f FEMA356  when disThe availability of a large database of seismic assessments of RC buildings located in Basilicata  allowed the analysis of concrete strength properties , in terms of mean values and variability, across different construction periods. First, the analyses showed that the concrete strength in column members was, on average, lower than that in beams. This outcome has important implications in practical seismic assessments of existing RC buildings, justifying the extraction of concrete cores only from columns, being both on the safe side and more feasible. Further, determining the concrete strength directly on columns appears still more remarkable accounting for their crucial role in carrying gravity loads.After these preliminary analyses, the within-building variability of concrete strength was investigated. It was found that the coefficient of variation of concrete strength was mostly higher than the limit value provided by structural codes , and was almost independent of the number of cores extracted from each storey. Looking at large-scale vulnerability assessments, where mean values as well as variability of concrete strength are required, a logarithmic relationship between CV and the number of storeys was found. The variability of concrete strength was specifically analyzed in five buildings where a large number of cores was available . The results showed that the variability across the whole building was comparable to that relevant to each single storey. Analyzing the within-storey variability of concrete strength, it was found that using the mean value in the presence of a high dispersion of strength values can lead to an overestimation of the storey capacity, especially when lower strength values were related to the larger structural member such as large columns or shear walls. The influence of axial load values in this regard was also examined, underlining that this also happens in the presence of ductile mechanisms, such as flexure in column members. In order to overcome this, it is suggested to assume as a design value the mean value minus one standard deviation, provided that a sufficient number of test values are available for each floor. Taking into account that in usual practice, due to the costs and occupancy disruption constraints, the number of in situ tests at each storey is generally less than three, and it is not possible to calculate dispersion parameters (CV and standard deviation). In these cases, particularly in the case of significant differences among the available strength values, it is suggested to assume the minimum value from tests as the design value.


The number of scholarly publications on the topic of biosensors has increased rapidly; as a result, it is no longer easy to build an informed overview of the developments solely by manual means. Furthermore, with many new research results being continually published, it is useful to form an up-to-date understanding of the recent trends or emergent directions in the field. This paper utilizes bibliometric methods to provide an overview of the developments in the topic based on scholarly publications. The results indicate an increasing interest in the topic of biosensor(s) with newly emerging sub-topics. The US is identified as the country with highest total contribution to this area, but as a collective, EU countries top the list of total contributions. An examination of trends over the years indicates that in recent years, China-based authors have been more productive in this area. If research contribution per capita is considered, Singapore takes the top position, followed by Sweden, Switzerland and Denmark. While the number of publications on biosensors seems to have declined in recent years in the PubMed database, this is not the case in the Web of Science database. However, there remains an indication that the rate of growth in the more recent years is slowing. This paper also presents a comparison of the developments in publications on biosensors with the full set of publications in two of the main journals in the field. In more recent publications, synthetic biology, smartphone, fluorescent biosensor, and point-of-care testing are among the terms that have received more attention. The study also identifies the top authors and journals in the field, and concludes with a summary and suggestions for follow up research. With advances in biosensor technologies, we have witnessed rapid growth in related research, publications, use domains, and application areas in multiple fields including drug discovery and biomedicine. It is difficult to stay abreast of developments in biosensors or to build an informed, up-to-date overview of related research due to the complexity of the topic and the growing numbers of publications, sources, and research areas. In this paper, we utilize various bibliometric analyses in order to provide an overview of the trends in scholarly publications related to biosensors.Biosensors are described as “analytical devices that use a biological or biologically derived material immobilized at a physicochemical transducer to measure one or more analytes”  , we have identified over 700 overview articles by experts in the field, which are based on sub-selections of publications. Those overviews provide rich discussions of narrower sub-areas, for example on s , imp, impgraps , surface e.g., ,15), che, chegrapg e.g., ,17) and  and grapHow has the number of publications on the topic of biosensors evolved over time? Which authors and countries are most active in producing publications on the topic and in which journals are most publications found? What are the core keywords in biosensor publications? Are there any identifiable sub-domains in the research related to biosensors, and if so, which? What can be said about the trends in biosensor research? This study came about due to an expressed need for an overview of the developments in biosensors-related publications based on consistent terms that would allow logical comparisons of the topical growth over the years to be made. With that as a starting point, this paper aims to identify and map potential patterns in the production of scholarly publications on biosensors and to offer insights into the subdomains of biosensors research. Accordingly, bibliometric methods are used to investigate the following research questions:Measuring objects and events around us is said to be a scientific necessity and a means to making sense of “the complexity of natural phenomena” . BibliomThrough an extensive search for earlier, related bibliometric studies, only half a dozen articles were identified, and none had the same focus or was based on a similarly full range of data as this study. For example, with an interest in the use of biosensors in medical diagnostics, Sheikh and Sheikh  use biblIn another paper , the treWe did find one paper with the focus on biosensor-related publications ; howeverDe Bellis  relates 2 of those making one [contribution]” )bution]”  p. 323)32 of thobution]” ) and is In other words, these laws state that by identifying the core authors or by accessing the material in the core journals, one should be able to form a reasonable sense of the field. Bibliometric methods offer quantitative measures to identify such indicators.biosensors as a main topic in their papers. Therefore, an early decision in the study became to analyze trends based on a uniform set of keywords. That, in combination with other criteria , defined the choice of database to become PubMed due to the presence of its MeSH terms.To form an understanding of the topical discussions in a field, a study of keywords can be useful. The starting point for this study was to form an overview of the developments in publications on biosensors based on uniform and consistent keywords to provide a level of stability in the comparisons over time. While author keywords are very useful and insightful, the choice of terms by individuals can vary from paper to paper and author to author. For example, different authors can use different keywords to indicate https://www.ncbi.nlm.nih.gov/pubmed/). PubMed allows easy downloading of large sets of bibliographic records in one go, a function that is often restricted in other databases. More importantly, the PubMed database provides a uniform indexing of biomedical literature. The Medical Subject Headings, or MeSH terms, form a controlled vocabulary or a specific set of terms that describe the topic of a paper in a consistent and uniform fashion. In PubMed, even author keywords are also available (since 2013–in the field Other Terms). The main advantages of using PubMed for this study were the presence of uniform MeSH terms and ease of access to, and retrieval of large sets of data. The disadvantages of using PubMed include: (a) the lack of citation information, (b) a somewhat skewed topical presence, where biomedical applied biosensors publications are privileged; hence, as a result the number of items included in this database are limited as compared with other databases such as Web of Science or Scopus and (c) at times, a lesser complete metadata for some items  as compared with the information available in other databases.PubMed is a free resource offered by the National Centre for Biotechnology Information (NCBI). It comprises over 28 million bibliographic records for biomedical literature from MEDLINE, and other life science journals, as well as online books ((((biosensor) OR biosensors) OR bio-sensor) OR bio-sensorsWith that said, the dataset that forms the empirical basis for this paper comprises of bibliometric data related to 55,971 publications on biosensors. The data set was retrieved from PubMed on 2 March 2018, based on the following search terms:.(((“biosensing techniques”[MeSH Terms] OR (“biosensing”[All Fields] AND “techniques”[All Fields]) OR “biosensing techniques”[All Fields] OR “biosensor”[All Fields]) OR (“biosensing techniques”[MeSH Terms] OR (“biosensing”[All Fields] AND “techniques”[All Fields]) OR “biosensing techniques”[All Fields] OR “biosensors”[All Fields])) OR bio-sensor[All Fields]) OR bio-sensors[All Fields]This search string in turn was expanded by PubMed to become:Timespan: All years. Indexes: SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI. The three instances of retrieval were as follows: 2 March 2018 (to see if there is support for the declining numbers even in WoS), 18 January 2019 , and 8 May 2019 (for most recent updates of the publication trends up to the date of submission). The searches conducted in January 2019 involved cross referencing those items in the PubMed dataset that lacked affiliation or country data, with items in WoS using available fields such as title, author, doi and more and even by manual means. With these efforts, the number of items with no author country information was reduced from 1989 to 650. The searches in WoS, in May 2019 were multiple as listed in However, considering the issues mentioned above, additional information was gathered to allow for the inclusion of some missing data and comparison between the findings from this dataset and other sources. The additional data was captured on three different occasions from the database Web of Science (WoS), Core Collection, with these specification in all three instances: Typical bibliometric analyses include publication counts, co-citation analysis, co-word analysis and so on . Lack oPublication counts indicate “the volume of scientific and technical output” and provide a descriptive measure of levels of activity and productivity in a given field )However, it should be noted that there is typically a time lapse in registration and inclusion of recent publications in databases. Furthermore, the speed of registration may differ from database to database. To examine this decline in numbers further, additional data was captured at the same time (March 2018) from the WoS database for the sake of comparison. The data from WoS did not support the above findings and recent decline, but rather indicated continued growth even in the more recent years. There may be several explanations for this discrepancy. There may be a slower rate of inclusion of new items in the PubMed database as compared to WoS. An alternative explanation could be that although the total number of publications on biosensor(s) is on the rise, the number of publications that correspond to the interest areas of PubMed may be declining. This issue needs further investigation.Meanwhile, although this study is mainly based on data retrieved from the PubMed database in 2018, for an up-to-date overview of the trends, additional new data (8 May 2019) was captured from the WoS database. Biosensors & bioelectronics and Sensors. The findings are collated in Biosensors & bioelectronics  or Sensors . The publications on biosensors  have increased on an even pace. As shown, the growth rate of publications in the journal Sensors follows a steeper slope while the number of publications in the journal Biosensors and bioelectronics has fluctuated over the years.It may also be of interest to see how the publications on biosensors compare, in relative terms, with other trends. For this, further data (8 May 2019) was captured from WoS on publications on biosensors and all the publications on any subject in the two journals of Another topic with close affinity with biosensor(s) is that of sensor(s). Further new data (from WoS on 8 May 2019) was captured regarding the number of publications on the topic of sensor(s) which resulted to 1,039,670 items. The growth of the number of publications on both topics is illustrated in While publications on both topics are on the rise, there are some fluctuation, most noticeably in the number of publications on the topic of sensor(s). To get a sense of the growth in an area, some scholars have examined the trends of cumulative number of publications (c.f. ), howeveWhen it comes to analyses of publication numbers as a measure of scientific output, a few issues should be observed. For one thing, the research output cannot solely be measured by the number of items found in traditional databases. Presence of open access repositories, online publication practices, and more, have changed the traditional publication methods and have added to the complexity of the matter. Furthermore, number counts assume an equal value for all publications, which is not always the case. Regardless, analyses similar to what is presented above are still seen as valuable and informative and do provide some indications about the research output trends in specified areas.Book Chapter, Journal Article, etc.), others are terms that are more descriptive of the contents,  or research support types, . Many of the items are given multiple publication types, although the orders vary from item to item .The field ‘publication type’, contains 54 unique values; some of the terms are those typically used to describe the forms of publications , whether in the first or in alternative positions. In the remaining 12,849 items, the top five publication types are Review (4382 items), Evaluation studies (4311 items), Comparative study (1771 items), Validation studies (532 items), and English abstract (523 items), with the remaining 40 types each occurring in smaller numbers.We separated any types of research support , from our main findings and examined separately. Since a publication can be assigned multiple types, all publication types besides research support were identified and their trends illustrated in Journal Article) and the top research support type .As can be expected of this dataset, publications in English dominate by far (98.7%), followed by Chinese (0.41%), Russian (0.38%), and Japanese (0.23%). The numbers of publications in other languages were minimal.place of publication. This provides information about the countries in which different papers are published. If one is interested in the countries in which the research has been conducted, the situation becomes more complex. Should one examine the nationality of the authors, the country of the funding organization, or the country of author affiliation? It is most common to go by the latter. However, some complications remain since at times an author may have multiple affiliations, (raising the question about which country to include) or in some cases, the affiliation information is fully or partially missing, for one or more of the authors. Furthermore, when a paper is co-authored some choose to look at the first author, while others choose to use a fractionalized counting where the credit is subdivided equally among all the countries involved. That is, for a paper that has five authors from five different countries, the country of each author would be assigned a value of 1/5th. Even this is problematic, since this treatment assumes equal contribution by all authors which is not always the case. We chose to examine the countries in two ways: the country information extracted from (a) the fields PL—Place of Publication , and (b) AD—Affiliation , however, only the country of the first author. The reason behind this choice was two folded. The first authors typically act as the driver of the publication. More importantly, we made this choice in order to be consistent in the application of the chosen method for the whole period included in the dataset. In PubMed, only the affiliation of the first author is included prior to 2014 .For a study of the countries, one can extract country information from the field Place of Publication data, we find that the US and the UK are the dominant countries, indicating that most of the related journals and publication sources (in this dataset) are located in these two countries.Based on the publication sources are situated mainly in the US and the UK, this analysis indicates a strong presence of authors from other countries. Researchers located in China, especially, become noticeable in the second position in total . By this grouping, we find that the EU becomes dominant with the majority of publications , followed by the US, China, and Asian countries other than China. America-others include Canada, central, and southern American countries and Oceania include Australia and New Zealand. Based on this dataset, the publications by both the EU- and US-based first authors have slowed down from 2014 , but pubIndeed, consideration of the size of countries or regions and associated population provides further insights. That is, if we divide the number of contributions by the size of population in each country, the level of contributions by each country becomes rather different to the order presented in journal article and hence published in a journal. The journal of Biosensors & bioelectronics (ISSN: 0956-5663|1873-4235 (Electronic)) is the dominant source of publications followed by Analytical chemistry, Optics express and Sensors. Biosensors & bioelectronics, Analytical chemistry, The Analysts, and Sensors has been increasing steadily, while Optics express shows a peak and then falls in year 2013. The strong fluctuations for some journals  are somewhat puzzling  have contributed with only one publication; at the other end of the scale a few authors  (18) have contributed to more than 100 publications each. In some disciplines, the main author is listed first, with the rest of authors appearing in descending order based on the level of their contributions. In other disciplines, the last position in the list of authors is just as important as the first position, and is typically assigned to the most senior researcher in the group. Regardless of discipline or level of seniority, the first authors typically play a central, or driving role in the production of the articles. To get a sense of the most frequently occurring authors in this dataset, we examined several core papers by Yuan, Ruo e.g., ,45,46) t,46 t45,4http://www.vosviewer.com/documentation/Manual_VOSviewer_1.6.11.pdf) for the first five clusters.To get a sense of collaborations between different authors, a co-authorship analysis was conducted using VOSviewer. VOSviewer tool creates maps and visualization of network data based on sophisticated clustering and analysis algorithms ,50,51. WPubMed includes two types of keywords, MeSH Terms and Other Terms (which consist mainly of author keywords from 2013 onwards). The advantage of MeSH terms is their uniformity; however, the author-defined terms provide a level of flexibility and make possible the introduction of terms that have not yet been included in MeSH terms. This paper includes an examination of both MeSH and Other Terms.Humans, Biosensing Techniques, Animals, Biosensing Techniques/methods, and Surface Plasmon Resonance. As indicated in Humans, have increased steadily over the years. The number of publications with the term Humans exceeds by far, the number of publications with other terms in year 2015. Indeed, the number of publications related to the term Humans in year 2015 is by far more than the number of publications related to any other term in any year. The trends indicate a rather steady rise of publications associated to the MeSH terms Humans, Biosensing Techniques and Animals. Even publications associated with other terms such as Biosensing Techniques/methods have risen, although with some fluctuation. The fluctuations and sharp peaks become more noticeable in publications associated with terms such as Equipment Design, Sensitivity and Specificity, and Equipment Failure Analysis.We performed some pre-processing before analyzing the trends of the MeSH terms. For this, we removed the attached symbol of asterisk (*), which is used as an indicator of the centrality of the term in the given publications. If this was not done, the same term with and without the asterisk would have been recognized as two different terms. Following that, the numbers of occurrences of different terms were analyzed. The top 20 MeSH terms are displayed in descending order in MeSH Terms  in this data set was less than the total number of unique Other Terms . At the same time, many papers did not include Other Terms and hence as a result, the total number of occurrences of MeSH Terms  was by far more than the total number of occurrences of Other Terms .A study of keyword co-occurrences is a useful means of forming a sense of the core topics of discussions and network of conceptual relations. Both MeSH and Other terms were extracted and their occurrences were analyzed. Since MeSH Terms are controlled, the total number of unique MeSH keywords, i.e., MeSH Terms, (b) Author keywords, i.e., Other Terms, and (c) All keywords (which is a combination of the former two keyword types).For a sense of the overall use of keywords, co-occurrence analyses were conducted using the VOSviewer tool , which aword to “word(s)”, or the conversion of different versions of the same term, e.g., hyphenated, non-hyphenated and abbreviated forms, to one of the forms.To begin with, some pre-processing and data clean-up was performed using the thesaurus option provided by the tool. This pre-processing included, for example, a conversion of both the plural and singular forms of a surface plasmon resonance, dna, and electrochemistry). The information in For the analyses, the minimum number of occurrences of keywords was set up to be “5”, the tool then calculated the total strength of co-occurrence links with other keywords. Based on this, the top 500 keywords were then selected to be included in the analyses and visualizations. Notably, the top ranked word in Other Terms, i.e., “biosensor(s)” takes the position 27 in the list of All Keywords and hence does not appear in the list of top 20 below. It should, however, be noted that some of the terms that are ranked lower than “biosensor(s)” in the list of Other Terms, for example “dna”, do appear in the list of top 20 terms in All Keywords. This is because they are also included in the MeSH Terms and therefore the summation of their occurrences both as MeSH and Other terms leads to their higher placement in the All Keywords list.In the following three subsections, findings are presented, first on the collective of all keywords and then with a focus on each of the MeSH Terms and Other Terms.biosensing techniques and biosensor(s) respectively. An analysis of All Keywords provides a sense of the level of use of different terms in the dataset. The keywords, with most frequent co-occurrences in MeSH and Other Terms are When conducting a co-occurrences analysis, by setting the minimum number of occurrences of a keyword to 5, of 12,546 terms, 5686 keywords meet the threshold and of these the top 500 with the greatest link strength are selected and depicted in humans, animals, mice, and rats; the term dna is rather frequent in the items in cluster four, and demographic variables seem to be of interest in cluster six.By examining this network visualization more closely, some common denominators among the items in each cluster become evident. For example, the publications in cluster one often relate to subjects such as Typically, new terms emerge at different times and then referred to in varying degrees over the years. Some are used continually, some become dominant in periods, while others die away. It is difficult to form an understanding of the temporal trends in a field simply from a general overview of the co-occurrences of terms. To get a sense of the recent developments, blood glucose, adult, middle aged. A longer list of older keywords is shown in The basis for this image is the average publication year. As shown, keywords colored in darker blue and purple denote keywords whose average year of publication goes back to the mid-2000s. Among the older keywords clearly visible in the diagram are for example biosensing techniques, human, electrodes) indicates that those terms have been continually used. Keywords marked in light green or yellow, however, have a more recent average year of appearance. Among these, as listed in optical imaging, limit of detection, and electrochemical techniques.An examination of the terms in green . The same procedure is followed. By setting the threshold of minimum number of occurrences to 5; of 32,087 keywords, 1689 met the threshold and top 500 terms with greatest total link strength were selected. When clustering is done, the landscape looks somewhat different. Here, the terms “biosensor(s)” is the main keyword used by authors rather than “biosensing techniques”. There are now nine clusters formed as presented in As mentioned earlier, Author keywords are only indexed since 2013 and, hence, they are not present in all items of the dataset affecting the average publication years. With that in mind, a temporal dimension is overlaid, by changing the color scheme . A list In addition to co-occurrence analyses, it would also be informative to identify the new keywords that emerge each year as assigned by the authors. This study has provided an overview of the patterns of scholarly publications on the topic of biosensor(s). The study indicates a steady growth in related publications, with a lower rate of growth in recent years which needs to be investigated further at a later date to allow for potential time lapse in registration. When analyzing total numbers per country, contributions by authors from the US, China, followed by Japan, Germany, UK, and South Korea are dominant in the field. A breakdown of the analysis by countries over time shows a slowdown of publications on the topic in the US, while publications by China-based authors have continued to evolve with upward trends, holding the top position since 2013. The decline in the number of publications by US-based authors in recent years raises questions requiring further investigation. Have new concepts or subdomains evolved that are being written about instead? The recent dominance of publications by Chinese authors is in line with studies  that haBiosensors & bioelectronics, Analytical chemistry, Optics express and Sensors. In analyses of publication types, the data even provided an initial indication of different support forms, . A question that arises for future studies is an examination of the support provided by public funding in each country in comparison with the level of publications by scholars in those countries.The data in this study indicates that the majority of publications on the topic are of type ‘journal articles’ and the top journals in which these articles are published are Top authors in the field have also been examined and presented. A finding was that some of the authors with most publications appeared less as the first author, while some of the authors with high but slightly fewer number of publications had a significant presence both as first and last authors. The position in author lists varies from discipline to discipline. With large number of authors in some papers (the highest number being over 150 authors in one of the papers), it would be interesting to examine the role and the level of contributions of the authors to the contents of the publications in general and in connection to their position in author lists in particular.In examining the number of publications related to authors, journals, countries and regions, a distribution with a long tail has been the norm, where the top few have been related to a large number of publications. Moreover, a large number have collectively been associated with a smaller number of publications, as indicated by the core distribution laws of bibliometrics.biosensing techniques, humans, surface plasmon resonance, animals, and equipment design. In a similar analysis of Other Terms, the top five keywords were identified to be biosensor(s), surface plasmon resonance, aptamer(s), gold nanoparticle(s), and fluorescence. Moreover, we identified various clusters or grouping of different topics within the publications and by overlaying a time dimension on the findings, a temporal sense of emerging topics over the years has been presented.The study has also examined in some detail the keywords associated with the publications. Due to the choice of database, MeSH terms have a larger presence in this dataset. In a co-occurrence analysis, the top five MeSH terms were identified as These findings are indicative of developments in the field. We hope that these findings may be of use to scholars in the biosensors field. Due to the interest in MeSH Terms and other considerations, the main dataset used for this study was extracted from the PubMed database which includes publications on biosensor with some bias privileging biomedicine and biomedical applied biosensors. Furthermore, the dataset did not include citation information. It would be of interest to conduct a similar study based on the data extracted from other sources, including both indexed citation databases and web-based unstructured data to provide further insights as to the impact of the publications in terms of reach and citations. Moreover, further studies could provide access to more recent developments based on web-based discussions, other discourse, and conference presentations that have not yet been formally published.