The prognosis, specifically the case fatality and duration, of untreatedtuberculosis is important as many patients are not correctly diagnosed andtherefore receive inadequate or no treatment. Furthermore, duration and casefatality of tuberculosis are key parameters in interpreting epidemiologicaldata.To estimate the duration and case fatality of untreated pulmonarytuberculosis in HIV negative patients we reviewed studies from thepre-chemotherapy era. Untreated smear-positive tuberculosis among HIVnegative individuals has a 10-year case fatality variously reported between53% and 86%, with a weighted mean of 70%. Ten-year casefatality of culture-positive smear-negative tuberculosis was nowherereported directly but can be indirectly estimated to be approximately20%. The duration of tuberculosis from onset to cure or death isapproximately 3 years and appears to be similar for smear-positive andsmear-negative tuberculosis.Current models of untreated tuberculosis that assume a total duration of 2years until self-cure or death underestimate the duration of disease byabout one year, but their case fatality estimates of 70% forsmear-positive and 20% for culture-positive smear-negativetuberculosis appear to be satisfactory. Before the advent of chemotherapy, tuberculosis was one of the major causes of deathin both Western Mycobacteriumtuberculosis strains resistant to rifampicin and INH might be less fitthan drug susceptible strains and therefore lead to longer duration of disease withless mortality The prognosis of untreated tuberculosis is difficult to study these days as leavingpatients untreated, especially in a study setting, is unethical. As an alternative,one could consider, as an approximation, the prognosis of multi-drug resistant (MDR)tuberculosis treated with first line drugs. However, MDR-tuberculosis patients maybenefit to some extent from first line therapy To estimate the duration and case fatality of untreated pulmonary tuberculosis, wereviewed studies from the pre-chemotherapy era. For tuberculosis in HIV infectedpatients there are, of course, no data from the pre-chemotherapy era. Thus the onlydata that are potentially relevant are those on MDR-tuberculosis HIV positivepatients treated with (inadequate) first line tuberculosis drugs, as their prognosiswould probably be similar to that of untreated HIV positive tuberculosis. However,it is clearly important to distinguish patients by stage of HIV disease and bytreatment  with pulmonary tuberculosis, identifiable as either smear-positive orsmear-negative.Not a single study has measured the duration of disease directly, as this wouldrequire an exhaustive ascertainment of incident cases as well as a follow-up toeither death, which is easy to establish, or cure, which is more difficult toestablish, while withholding treatment, at least for some time. One thus has torely on indirect information to estimate duration of disease, on the assumptionthat duration of disease (D) and case fatality (CF) are related to incidence(I), prevalence (P) and mortality (M): D = P/I andCF = M/I We defined four types of data sources which may contribute information on thenatural duration and/or outcome of disease:Follow-up (cohort) studies. Diagnosed patients are individuallyfollowed–up over time and their mortality and morbidity experiencerecorded. Inevitably there is some kind of selection (bias) involved insuch studies as they exclude undiagnosed patients. Patients included maybe those identified through the health system, or those who attended aspecific institution (e.g. sanatorium), or patients may have beenidentified through a tuberculosis survey. These cohort studies providekey information on CF, but do not generally provide estimates ofduration of disease, as the start of the tuberculosis episode isnormally unknown and cure is usually not recorded.Prevalence and incidence studies. A comparison between prevalent andincident cases would yield the duration immediately if the population isstable, i.e. no migration. However, if incidence is measured throughrepeated waves of surveys (instead of recorded continuously), one has totake into account the fact that incident cases occurring in-betweensurveys, but who recovered or died before the next survey wave, will bemissed by the study. Although such studies are ideal for estimating theduration of disease they are less suitable for estimating the CF. Inorder to obtain an estimate of the CF one needs either follow-up ofincident cases or estimates of the frequency with which disease ends indeath among those patients for whom the end of disease is observed.Notification and mortality studies. Studies that relate notification tomortality are also relevant. While such studies may provide littleinformation on the duration of disease they do provide data on ultimateoutcome (cure versus death) as CF = M/I althoughone cannot be certain that all incident cases are notified nor that alldeaths occur among patients ever notified.Prevalence and mortality studies. These compare the prevalence oftuberculosis to its  mortality, but do not establish the fate ofindividual patients. To estimate the duration of disease, however,requires knowledge of the CF of  tuberculosis cases, as wellas an assumption of a stationary epidemiological situation. For then theratio of the mortality rate and the CF estimates the incidence rate, andone can use the fact that the prevalence equals the product of theincidence and the duration (P = I*D) to obtainthe duration. Conversely, estimating the CF would require knowledge ofthe duration of disease in addition to the prevalence and mortalityrate, as the incidence would then equal the prevalence divided by theduration, and the ratio of the mortality and incidence rate would yieldthe CF.th century up to 17 December 2010 and EMBASE, includingreferences from 1900 until 1966. The search strategy is summarized in We searched PubMed including OldMedline with publications from the early decadesof the 20All references were first screened independently by two authors (ET and NN) ontitle and, if no title was available, in the snowball sampling method, onreference in the text to assess whether they potentially assessed the prognosisof untreated pulmonary tuberculosis in representative adult populations. Ofpotentially eligible papers, if available, abstracts were subsequently assessedfor eligibility using the same strategy. If no abstract was available, paperswere accessed in full text. Among the identified sources we selected those thatwould potentially provide estimates of CF and/or duration of pulmonarytuberculosis in adults (≥15 years) by any of the four methods outlined above.Studies were included provided: a) their methodology was sound (e.g.(near-to-)complete follow-up or making use of actuarial methods), consideringpopulations that can be considered as more or less‘population-based’ (thus not including only specific populationsubgroups or pre-selecting certain categories of patients), b) they containedoriginal data , c) we could decidewhether patients included were smear-positive or smear-negative butculture-positive; in studies where patients were described as having“open” tuberculosis or “bacillary tuberculosis” before1930 (when culture became available) we assumed that these patients weresmear-positive, d) description of the available data was sufficient to enablecalculation 5- and/or 10-year survival probabilities or disease duration, and e)the study population was not treated with chemotherapy or was treated withprobably or proven ineffective therapy .Eligibility and data extracted from all eligible sources were checked anddiscussed by two authors (NN and ET) using the criteria described above. Thedata sources were reviewed and summarized with respect to their informationregarding the duration and outcome of untreated tuberculosis, and CF.Discrepancies between authors with respect to extracted data were resolved bydiscussing the differences and independently re-reviewing the data.There are some important limitations to studying the duration and CF of untreatedtuberculosis, since many of the included studies do not meet modern researchstandards. For example, the case definition, the onset of disease, or thebeginning of follow-up in cohort studies are often ill-defined or poorly described in older publications, and many casesincluded in those studies would not meet modern diagnostic standards.A large number of studies are based on passive case finding, which inevitablyentails some selection bias, as diagnosed cases may well differ from undiagnosedones. Some studies are limited to hospitalized (sanatoria) cases and thereforepresumably exclude both the mildest and the most severe cases, as some of thelatter probably died before they could have been hospitalized.M. tuberculosis in sputum.A comparison between sputum smear microscopy used in those days with thatcurrently in use is not available. Another methodological problem, alsoaffecting many modern studies on tuberculosis, is the implicit assumption thatpulmonary tuberculosis can reliably be classified as either smear-positive orsmear-negative and that no transitions between these categories take place. Thisis almost certainly untrue, if only because of the poor sensitivity of sputumsmear and its dependence on factors such as the number of repeat smears An additional methodological problem constitutes the way cases have beenclassified in old studies. Using the distinction of pulmonary tuberculosis intosputum smear-positive (smear-positive) and sputum smear-negative(smear-negative) cases, the most common classification used today, we mustassume  that the sensitivity and specificity of directsmear has not changed. Especially the diagnosis of smear-negative cases isproblematic as culture using the Löwenstein-Jensen (L-J) medium did notbecome available until the 1930s M. tuberculosis and progression totuberculosis disease is influenced by host factors and especially risk ofprogression depends on the hosts' immune status, which may be reduced dueto concomitant HIV infection, diabetes, and other underlying diseases A further methodological pitfall is that by combining different estimates onemakes the implicit, and untested, assumption that the natural history oftuberculosis does not differ significantly among countries and periods. However,the risk of infection with Data were extracted into Excel sheets and survival probabilities re-calculatedand provided with accompanying 95% Greenwood confidence intervals usingthe original paper's life table's information. Where insufficientdetails were available to recalculate survival probabilities, estimates ascalculated by the studies' authors were taken. Duration of active pulmonarytuberculosis disease from diagnosis till death or cure could be assessed fromtwo studies with a very different study design Because of the above-described methodological problems with combining the resultsof such diverse studies, we did not attempt to do a formal meta-analysishere.e.g., Using the methods described above we identified a wide range of studies on theprognosis of tuberculosis in the absence of chemotherapy . In totaThe sources we considered relevant to the natural (pre-chemotherapy) history oftuberculosis are listed in 1. Berg's study 2. Sinding-Larsen 3. Backer 4. Krebs 5. Tattersall 6. Magnusson 7. Rutledge and Crouch 8. Münchbach 9. Braeuning and Neisen 10. Griep 11. Baart de la Faille 12. Buhl and Nyboe 13. Lindhardt 14. Thompson The study of the National Tuberculosis Institute, Bangalore, India (NTI)Unfortunately, the reporting of both studies leaves much to be desired. Forexample, prognosis (death or cure) is not presented broken down by Z-Nstatus (i.e. for smear-positive and smear-negative separately). Moreover,Pamra and colleagues did not give any information about treatment oftuberculosis Drolet The Framingham Community Health and Demonstration project Direct estimates are available from cohort studies. In studies that reported on this  is much poorer (a 10-year CF of 70% or more) than5-year survival showing that tuberculosis can be a very long-lasting,chronic disease. Taking the crude unweighted average of all studies onearrives at a 5-year case fatality of 58% and a 10-year case fatalityof 73% for open (smear-positive) tuberculosis. Taking an averageweighted by sample size these numbers are 55% and 72%respectively. Of course, these mortality data are somewhat distorted bymortality from other causes, as most studies do not record cause of death,and all-cause mortality rates may have been somewhat higher in thepre-antibiotic era than they are now. On the basis of the above data,especially the studies by Berg A single, aggregate, CF for all smear positive patients is only justified ifin most studies the differences in mortality between the sexes and agegroups are rather small. This appears to be the case for sex, but higherages appear to have somewhat poorer prognosis. For example, in Berg'sstudy (providing the most detailed data), age- and sex specific 10-yearmortality rates were 66% for men aged 15–29 years, 70%for men aged between 30 and 49 years, and 94% for men of 50 andolder. For women, these rates were 70%, 69%, and 92%respectively Braeuning Drolet Fate ofcases discovered at the first survey and of patients still excretingbacilli when examined at subsequent surveys) with data on thefate of patients present at each survey  shows this. In Fig. 2 mortality of those discoveredat survey I, after 1.5 years is 30.2%, while in Fig. 3 it is24.7%. Another shortcoming of the paper is that patients withoutabnormalities on chest radiograph were not examined in this survey and thusnot identified. The percentage of pulmonary tuberculosis patients withoutchest radiograph abnormalities varies between 3 The CF of pulmonary tuberculosis, smear-positive and/or culture-positive, canalso be estimated from the NTI study There is a better approach to estimating the CF from the NTI data.Ultimately, all tuberculosis patients will either die or get cured. If theratio of the mortality rate to the cure rate is independent of diseaseduration, then one can simply look at the ratio of the number of deaths tonumber of patients cured over a fixed period of follow-up. This assumptionseems to be supported by their data , as the cured-to-deathratio among the cohort of tuberculosis patients discovered at survey 1 seemsto remain about equal at 27.8/30.2, to 23.6/20.0 to 17.2/15.0 in theintervals between survey 1 and 2, between survey 2 and 3, and between survey3 and 4 respectively. Thus, the prognosis (outcome) of theparticipants' disease (death or cure) did not seem to depend on thetime they had already suffered from tuberculosis. Nevertheless, an exceptionmay have to be made for incident tuberculosis patients who appear to faresomewhat better than prevalent cases, with a cured-to-death ratio of44/24.The study reports a total of 428 (often overlapping) individuals alive withtuberculosis at the beginning of any of the 1.5-year intervals. During thesubsequent 1.5 years, a total of 89 died and 132 were cured, suggesting an(ultimate) tuberculosis mortality of 40.2%. However, this is notentirely correct as the paper reports 7% mortality among “curedcases” (most presumably dying from tuberculosis) and a “relapserate” of 10%. We thus subtract 17% from 132 giving 109.5and add 7% of 132 to 89 giving 98. Thus if the fate of prevalentcases would equal that of incident cases, 47% would ultimatelydie.incident casesthere were almost twice as many cured cases (44) as deaths (24). Thisignores relapses. However, as the proportion dying (35%) among thosewho either die or get cured in these incident cases differs only marginally from the uncorrected (for relapse)mortality of prevalent cases (40.2% of those who either die or getcured), we seem to be justified assuming a constant death-to-cure rate. Thusour ‘best’ estimate of tuberculosis CF from this study is47%.The assumption, as stated above, that there is a constant death-to-cure ratiomay not be entirely true, as among follow-up prevalent cases,51% were smear-positive incident cases which are unidentifiable from theirdata, so this assumption is questionable) then (ultimate) mortality amongsmear-negative pulmonary patients would be 24%. Thus the 20%mortality for smear-negative pulmonary tuberculosis, as assumed by WHO andothers in their estimates of the burden of tuberculosis  then assuming that 50%of cases are smear-positive  and prevalent cases of cultureconfirmed tuberculosis are smear-positive. Overall this seems to support thenotion that the natural duration of smear-positive and smear-negativedisease are roughly similar.There is almost no reliable information regarding the relative duration ofsmear-positive and smear-negative tuberculosis disease. A study from SouthIndia In our study we combined available information on untreated tuberculosis toestimate its case fatality and duration of disease. We found only few studiesfrom the pre-chemotherapy era that allow for estimation of CFs and duration ofdisease of smear-positive tuberculosis. Given the limited information availableand assuming that a 10-year CF will closely approximate lifetime CF, we concludethat (lifetime) CF in untreated smear-positive tuberculosis among HIV negativeindividuals is approximately 70% and about the same for both sexes.Mortality seems to be approximately independent of age until the age of 50 yearsafter which it increases, perhaps due to concomitant complicating diseases suchas diabetes or cancer and a greater mortality from other causes. However, thisage effect would only be important in (patient) populations with a dramaticallydifferent age structure than the ones used in this review. For most high burdencountries this is not the case.For culture-positive smear-negative tuberculosis, lifetime CF is probablyslightly over 20%, although this could only be estimated indirectly andwith uncertain precision.The duration of tuberculosis from onset to cure or death is approximately 3 yearsand appears to be grossly similar for smear-positive and smear-negativetuberculosis.Because of the expected heterogeneity between studies with respect to studydesign and population, study period, duration and intensity of follow-up,definition of pulmonary tuberculosis , etc., we did not do aformal meta-analysis. Additional heterogeneity among studies may also exist inpatient selection and diagnostic procedures, for example the number of sputumsamples analyzed and how these were obtained (e.g. induced or spontaneous).However, these data were hardly ever reported in the included studies.Despite the fact that (HIV negative) tuberculosis has for centuries been a majorcause of mortality, the number of studies on its natural history is surprisinglylow.This contrasts sharply with, for example, HIV for which detailed information onits natural history became available within decades of the discovery of thevirus. Long term follow-up studies of HIV patients in carefully monitoredcohorts have generated this information. In contrast, follow-up of mosttuberculosis patients is nowadays usually limited to the duration of theirtreatment.Another limitation is our serious lack of knowledge on the prognosis ofextra-pulmonary and smear-negative pulmonary tuberculosis as most data on thenatural history are available for patients who tested sputum smear-positive. Noreliable prospective data on smear-negative culture-positive pulmonary patientsare available and their long term survival can only be estimated indirectly andthus with great uncertainty. These patients form currently the group most likelyto receive no or inadequate treatment, and may well account for large proportionof tuberculosis deaths. The prognosis of untreated extra-pulmonary patients - avery heterogeneous group that also includes most tuberculosis in children - iseven more uncertain, and insufficient data were identified to include it in ourreview.An important limitation of using electronic databases going back in time is thatthese do not include abstracts and searches therefore may miss potentiallyeligible papers. We have tried to obviate this by including quite general searchterms see .HoweverWe therefore supplemented our search strategy with snowball sampling. Alimitation of this approach is that it depends, perhaps heavily so, on itsstarting point. We choose dr. Rieder's book Quite some of the identified potentially eligible papers were not available tous. In theory, this may have influenced the outcome of our review. However, wewere able to identify papers appearing in a variety of journals, text books andpublished as reports (‘grey literature’) and did not find anyevidence for a correlation between the type of source and the quality of thedata. Therefore, we expect no important ‘availability bias’correlated with prognosis of untreated tuberculosis.Another limitation of our review is that most of the included studies on CF wereon predominantly Caucasian populations whereas most untreated patients currentlyare of different ethnicity. This is probably mainly due to the fact thatevaluating the natural history of tuberculosis requires long term follow-upwhich has proven to be difficult, especially in resource constrainedsettings.A key limitation is that we had to restrict our review to HIV-negative patients,as explained in the As regards the duration of disease, findings from these studies While pre-chemotherapy data appeared to be a useful source of data for theprognosis of untreated tuberculosis, inevitably questions remain. Particularly,the impact of risk factors other than (variably defined) smear status was hardto explore systematically. Perhaps, long-term follow-up of patients withinadequately treated MDR or XDR tuberculosis may fill some of the gaps in ourknowledge. Such follow-up may also fill other gaps in our knowledge such as thefrequency of transitions between smear-positive and smear-negative tuberculosisand the prognosis and duration of HIV-positive tuberculosis.


Cebus apella) acquire a same/different concept in a matching-to-sample task on the basis of relational similarity among multi-item stimuli. We evaluated (i) the ability of five capuchin monkeys to learn the same/different concept on the basis of the number of items composing the stimuli and (ii) the ability to match novel stimuli after training with both several small stimulus sets and a large stimulus set. We found the first evidence of same/different relational matching-to-sample abilities in a New World monkey and demonstrated that the ability to match novel stimuli is within the capacity of this species. Therefore, analogical reasoning can emerge in monkeys under specific training conditions.The ability to understand similarities and analogies is a fundamental aspect of human advanced cognition. Although subject of considerable research in comparative cognition, the extent to which nonhuman species are capable of analogical reasoning is still debated. This study examined the conditions under which tufted capuchin monkeys ( The use of abstract concepts improves the ability to sort objects, events, and relations into common classes on the basis of shared perceptual, associative, and relational properties and to transfer knowledge to new stimuli or contexts. In humans, these capabilities underpin advanced cognitive skills such as analogical reasoning. This type of reasoning is often considered the highest form of conceptually mediated behaviour because it involves the ability to judge relations-between-relations, or second order relations same condition) the other one with the presence of non-identical figures (different condition). Another paradigm used to assess same/different concept acquisition is the Matching-to-Sample (MTS) task, which allows the use of multiple levels of abstraction varying in relational complexity. On the one hand, the identity MTS (IDMTS) involves solving first-order relations by choosing which of two (or more) comparison stimuli is perceptually equivalent to the sample stimulus. On the other hand, the analogical or relational MTS (RMTS) involves second-order relations, i.e. relations-between-relations, regardless of perceptual similarity among objects composing different sets In comparative research, abstract concept learning has been mostly investigated by using same/different discrimination tasks, in which subjects had to judge whether two items are physically the same or different Individuals may learn to solve the tasks reported above in a way that applies only to familiar stimuli , or in a way that goes beyond the training stimuli and applies to novel stimuli . Only in the latter case it is possible to infer that abstract concepts have been acquired Previous experience improves animals' ability to use same/different concept in order to judge relations-between-relations. Acculturation has been considered one of the most relevant factors and it has been argued that only apes that have been language trained same and 16 different stimulus arrays. In addition, baboons' performance dramatically decreases and reaches the level of chance with 2-icon stimuli when the number of items composing the stimuli is gradually reduced. Fagot et al. entropy, i.e. the amount of perceptual variation within a display. In fact, the amount of variance between same and different displays is more evident when the stimuli contain more items and facilitate solution. Finally, high spatial proximity between parts composing the stimuli  improves the accuracy of baboons in a same/different RMTS task Perceptual constraints also affect relational learning abilities. Great apes are able to solve RMTS tasks using stimuli made of only two objects or figures Cebus apella) to learn same and different abstract concepts and to use them to solve a relational matching task that mirrored the tasks presented to apes The current study evaluates the ability of the New World tufted capuchin monkeys  if capuchin monkeys previously trained to solve MTS tasks on the basis of perceptual similarity . Housing conditions and experimental procedures were performed in full accordance with the European law on humane care and use of laboratory animals and complied with the recommendations of the Weatherall report (The use of non-human primates in research). To increase three-dimensional space available to the animals, indoor enclosures were furnished with perches and ropes and outdoor enclosures were furnished with logs, branches and ropes. Moreover, the presence of natural substrates, including woodchips on the ground, served to promote monkeys' exploratory behaviours. All subjects were habituated to the experimental cage, the experimental routine and the experimenters.Cebus apella), two males (Robot and Sandokan) and three females . All subjects were adults (8–27 years old) born in captivity and hosted at the Primate Center of the Institute of Cognitive Sciences and Technologies, CNR, Rome, Italy. They lived in three groups, each housed in an indoor-outdoor enclosure . Capuchins were individually tested in an adjacent experimental cage (0.76 m long × 1.70 m wide × 0.73 m high), that they could access through a sliding door. Each subject was separated from the group just before the daily testing session solely for the purpose of testing. The testing occurred between 10:30 a.m. and 4:00 p.m. Water was freely available at all times. Fresh fruit, vegetables and monkey chow were provided in the afternoon after testing.The subjects were five tufted capuchin monkeys  connected to a 19” touchscreen  and an automatic food dispenser  . E-PrimeA wooden frame (48 cm wide × 64 cm high × 30 cm deep) with a central aperture (36 cm wide × 26 cm high) surrounded the touchscreen. The food dispenser was placed behind the wooden frame, out of sight of the subject. Moreover, an additional LCD monitor was placed at the back of the touchscreen to allow the experimenter to see the progress of the session so as to remove the apparatus at the end of the session. The touchscreen, food dispenser and additional LCD monitor were mounted on the top shelf of a trolley (81 cm long × 45 cm wide × 80 cm high), whereas the PC was on the bottom shelf.The apparatus was placed approximately 15 cm from the grid of the experimental cage within the arm's reach of the subject. The grid was made of horizontal metal bars (0.5 cm thick) that were separated by 4.5 cm.Each stimulus consisted of a black frame with two, four or sixteen icons inside . Twelve A simultaneous Matching-to-Sample (MTS) procedure was adopted, in which three stimuli, the sample (SS) and the two comparison stimuli, the matching stimulus (S+) and the non-matching stimulus (S−), were presented on the computer screen. At the beginning of each trial, the sample stimulus appeared in the centre of the upper half of the screen. The sample consisted of identical or non-identical icons. Then, immediately after the subject touched the sample stimulus, the two comparison stimuli were simultaneously displayed on the lower part of the screen 5 cm apart from one another, and 4 cm below the sample . The possame stimuli including two identical icons and two different stimuli including two non-identical icons). A novel set was presented only after the monkey reached the learning criterion on the previous set. We hypothesised that the monkeys would require fewer trials to reach the learning criterion after the first set of stimuli. Moreover, on the basis of a previous study on identity concept acquisition In Experiment 1, the subjects had to solve a same/different relational matching-to-sample task on the basis of the relation between the two icons composing each stimulus (same shape or different shape). Step-by-step we presented a total of seven small stimulus sets (Sets I-VII), each involving four 2-icon stimuli .same and 24 different) out of 60 consecutive trials (corresponding to 80% correct responses), non-correction sessions were administered.At first, a correction procedure in which an incorrect trial was repeated until the subject made the correct response was adopted. Each session lasted until at least 48 correct responses were collected in which the four stimuli appeared as the sample an equal number of times. When the subject completed at least 48 correct responses , a new transfer test was presented. Otherwise, the 96-trial sessions were repeated until the subject reached the criterion. This procedure was repeated for a total of six new sets of stimuli. Each transfer included a new set of stimuli and all subjects received the different sets in the same order. During transfer tests subjects received 1–2 sessions per day on 5 days per week.As in Experiment 1, the subjects had to solve a relational matching-to-sample task based on the relation (same shape or different shape) between/among the icons composing each stimulus. Furthermore, in Experiment 2, we used large sets of stimuli (Sets VIII-XI) including either 2 or 4 icons. On the basis of previous studies, we hypothesised that concept acquisition would benefit from the use of large sets of stimuli same and in the different trials in the previous set, or when the subject performed 100 96-trial sessions without reaching criterion. Both in the training and transfer each session consisted of 96 trials . Within each session the positive comparison stimulus (S+) appeared on the left and on the right with equal frequency. During training subjects received 1-2 training session for 5 days per week. Transfer tests consisted of one 96-trial session.Each new set of stimuli was introduced either when the subject performed significantly above chance  in the z scores were used to assess whether or not the individual number of correct responses was significantly above chance (50%). The significance level was set at p<0.01 with small stimulus sets because in these sets the same stimuli were frequently repeated within a session increasing the probability of solutions due to item specific learning processes. In contrast, the significance level was set at p<0.05 with large stimulus sets because in these sets stimuli were never repeated within a session. Since the Kolmogorov-Smirnov test showed that the group data were normally distributed, parametric statistics were used to compare the accuracy scores across conditions.The binomial Roberta, Sandokan and Robot completed both training with and without correction procedure, whereas Pippi and Carlotta completed only the correction sessions. Roberta and Sandokan received six sets of novel stimuli (Sets II-VII), whereas Robot received only one transfer test (Set II). After a total of 14,764 and 16,316 trials for Carlotta and Pippi, respectively, we interrupted their training because they never approached the learning criterion during training.same  =  75.0%, different  =  70.8%); this performance would have been above chance with an alpha level of 0.05.None of the subjects immediately transferred to the new sets of stimuli since they did not reach criterion within the first 192 trials. However, Roberta in the first session of Set VII was close to criterion. Her mean percentage of correct responses with the novel stimuli was 72.7  than in the different trials (59.2%) . And the same holds true for the three subjects that proceeded to the following sets, with the exception of Sandokan (Set IV) and Roberta .In the first training (Set I), there was a general advantage for the same and different trials (p<0.05). All subjects did not perform higher than chance . The percentage of correct responses was higher in the same trials  than in the different trials ,  for all subjects except Sandokan.All the five subjects completed the first 100 96-trial training sessions without reaching the criterion of 64.6% both in the same trials  compared with the different trials , . After 77 96-trial sessions  Roberta shifted from a pattern featured by high performance in the same trials and low accuracy in the different trials to a pattern with opposite trends. Hence, we kept her training during which she recombined the knowledge previously acquired and reached criterion in both types of trials  familiar 4-icon stimuli presented upside down, (b) novel 4-icon stimuli . As in the 2-icon condition, Carlotta, Pippi, Roberta, and Robot showed a percentage of correct responses significantly higher in the f trials . She too stimuli , (c) 2-i stimuli , and (d) stimuli . The perThe current study demonstrates the acquisition of abstract concepts based on second-order relations by one capuchin monkey, Roberta. She was first successful with four-item stimuli and then with two-item stimuli, the latter being the most difficult condition previously thought to be mastered only by apes In Experiment 1, one capuchin lost interest in the task and received only two sets of stimuli and the other two capuchins failed to immediately transfer to novel stimuli after being presented with seven sets of stimuli, each including only four stimuli. Despite this poor performance, we cannot rule out the possibility that further reiteration of such a step-by-step procedure with small stimulus sets could eventually promote subjects' transfer ability and allow an immediate transfer to novel stimuli. However, our results seemed to be not promising in that sense. In fact, after the sharpest decrease occurring between the first and second sets, probably due to a ‘learning set’ phenomenon same compared with the different trials. Similarly baboons tested with stimuli containing 2 or 4 icons, when a different sample stimulus is presented exhibit a strong tendency to choose the same comparison stimulus same with 2- and 4-icon different sample displays different displays makes them similar to the same displays, thus increasing the percentage of same responses.In Experiment 2, using a large number of either 2- or 4-icon stimuli none of the five capuchins succeeded in reaching the learning criterion within 100 sessions . Furthermore, four out of five subjects performed significantly better in the One capuchin (Roberta), after 228 sessions , succeeded in solving the 4-icon stimuli condition of Experiment 2 and in transfer to: (a) familiar 4-icon stimuli presented upside down, (b) novel 4-icon stimuli, (c) 2-icon stimuli, and (d) 16-icon stimuli. To our knowledge, this is the first New World monkey to solve the 2-icon condition in a same/different RMTS task. This result is consistent with recent findings demonstrating that one species of Old World monkeys, the Guinea baboons, solve the RMTS task when they judge stimuli made of pairs of colour patches Inter-individual differences are common in very cognitively demanding tasks. In a previous study, only one out of four capuchins solved a relational matching task based on the relative size of 3-dimensional objects same trials and then she reached criterion on the different trials. Her success in the different condition co-occurred with a worsening of performance on the same condition. Eventually, in the last part of the learning process, she recombined the knowledge previously acquired separately becoming concurrently successful in both conditions. On this basis we argue that a very demanding aspect, in terms of attentive resources and/or working memory load, of the same/different relational matching is to learn two concepts (sameness and difference) “at once”, that is when trials presenting same or different conditions are randomly alternated. If this were the case, presenting the same trials and the different trials separately should make the RMTS task less demanding than when the same and different trials are presented together. In this case, the solution of the RMTS task will require less parallel processing of information.Our detailed analysis of the complete sequence of Roberta's training sessions highlighted a very distinctive learning trend. Initially, she seemed to spontaneously decompose the task in two sub-problems. Her learning pattern reveals that first she reached criterion on the Roberta outperformed other capuchins also in other previous studies. In an IDMTS task Costello and Truppa The study of relational matching-to-sample across different animal species may prove to be a crucial step toward the comprehension of both abstract concept acquisition and the precursors of analogical reasoning. Our study indicates that same/different relational matching-to-sample abilities are within the ken of capuchin monkeys. Furthermore, it suggests that manipulating the number of figures composing the stimuli could facilitate the comprehension of second-order relations in capuchins, as argued for baboons Video S1Roberta, a female capuchin, carrying out the relational matching-to-sample task with 4-icon stimuli.(MPG)Click here for additional data file.Video S2Roberta, a female capuchin, carrying out the relational matching-to-sample task with 2-icon stimuli.(MPG)Click here for additional data file.Video S3Roberta, a female capuchin, carrying out the relational matching-to-sample task with 16-icon stimuli.(MPG)Click here for additional data file.


A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for cross-sectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers.Performance of testing algorithms was evaluated using 2,282 samples from individuals in the United States collected 1 month to >8 years after HIV seroconversion. The capacity of selected testing algorithms to accurately estimate incidence was evaluated in three longitudinal cohorts. When used in a single-assay format, the LAg-Avidity assay classified some individuals infected >5 years as assay positive and failed to provide reliable incidence estimates in cohorts that included individuals with long-term infections. We evaluated >500,000 testing algorithms, that included the LAg-Avidity assay alone and MAAs with other biomarkers , varying the assays and assay cutoffs. We identified an optimized 2-assay MAA that included the LAg-Avidity and BioRad-Avidity assays, and an optimized 4-assay MAA that included those assays, as well as HIV viral load and CD4 cell count. The two optimized MAAs classified all 845 samples from individuals infected >5 years as MAA negative and estimated incidence within a year of sample collection. These two MAAs produced incidence estimates that were consistent with those from longitudinal follow-up of cohorts. A comparison of the laboratory assay costs of the MAAs was also performed, and we found that the costs associated with the optimal two assay MAA were substantially less than with the four assay MAA.The LAg-Avidity assay did not perform well in a single-assay format, regardless of the assay cutoff. MAAs that include the LAg-Avidity and BioRad-Avidity assays, with or without viral load and CD4 cell count, provide accurate incidence estimates. HIV incidence measures the rate of new HIV infections in a population 3), elite controllers, and individuals on antiretroviral therapy from incidence surveys The United States (US) Centers for Disease Control recently developed a limiting antigen avidity enzyme immunoassay (LAg-Avidity assay) for cross-sectional HIV incidence estimation In this report, we evaluated the performance of the LAg-Avidity assay alone and in MAAs that included other serologic and non-serologic biomarkers. We evaluated the probability that samples were classified as assay positive or MAA positive over time (using tabulated classification frequencies and fitted smoothed spline curves). We also compared the mean window periods and shadows of the different testing approaches, as well as the relative sample sizes needed for incidence surveys, and relative costs. Finally, we evaluated the ability of the different testing approaches to produce incidence estimates in three cohorts with low, medium, and high incidence that were consistent with those obtained by direct longitudinal follow-up.Written informed consent was obtained from study participants and all studies were reviewed and approved by relevant institutional review boards. Only stored samples from individuals who consented to have their samples could be used for future research were used in this investigation. No new samples were obtained specifically for this study. The study for cross sectional incidence testing on stored study samples was approved by the institutional review board of the Johns Hopkins University. The research was conducted according to the principles expressed in the Declaration of Helsinki.The performance of the LAg-Avidity assay and MAAs that include the LAg-Avidity assay was evaluated using 1,782 plasma and serum samples from three cohort studies in the US (duration of infection from 1 month to >8 years): the Multicenter AIDS Cohort Study The LAg-Avidity assay  was performed according to the manufacturer's instructions. The results are reported as OD-n. Samples with an initial result <2.0 OD-n were retested in triplicate for confirmation and the median confirmation value was used for analysis. Most of the data for the BED-CEIA, the BioRad-Avidity assay, and HIV viral load were generated in previous studies. The BED-CEIA  was performed according to the manufacturer's instructions Samples analyzed using the LAg-Avidity assay alone were classified as assay positive (below the assay cutoff) or assay negative (above the assay cutoff); similarly, samples analyzed using MAAs were classified as MAA positive  or MAA negative (failing to meet the criteria of one or more of the component assays). Samples classified as assay positive or MAA positive are counted as incident infections in incidence estimates.3), and (3) 2-assay MAAs that included the LAg-Avidity assay (assay cutoffs of 1.0 or 1.5 OD-n) and viral load  without CD4 cell count. For these analyses, duration of infection was classified into time intervals by midpoint imputation.In the first phase of the analysis, we calculated the number of samples classified as assay positive or MAA positive by duration of infection (years after HIV seroconversion). For individuals who had acute or early HIV infection at the time of sample collection ; viral load: 10 cutoffs ranging from 400–10,000 copies/mL; CD4 cell count: 12 cutoffs ranging from 50–1,000 cells/mmIn the third phase of the analysis, we compared the number of samples needed in cross-sectional surveys to obtain the same precision in incidence estimates using two optimized MAAs . We also compared the relative cost of the two MAAs, optimizing the order of the component assays. For this analysis, the relative costs of the LAg-Avidity assay, BioRad-Avidity assay, CD4 cell count, and viral load were considered to be r, r, 2.5r, and 5r, respectively, where r is the unit cost of the LAg-Avidity assay. For the cost analysis, CD4 cell count was listed first when used in a MAA, since CD4 cell count must be performed at the time of sample collection. In addition, costs were adjusted by multiplying the relative costs by the relative sample sizes that are needed to account for differences in mean window periods. These analyses considered only the cost of sample testing.3, respectively), and (3) two optimized MAAs. These analyses were performed for the following three cohorts: HIVNET 001 (see above), HPTN 061 (a cohort of black MSM) In the last phase of the analysis, we compared cross-sectional incidence estimates obtained using the LAg-Avidity assay and MAAs to longitudinal incidence estimates previously reported for three cohort studies from the US with varying HIV incidence. Cross-sectional incidence estimates were calculated for: (1) the LAg-Avidity assay alone (using assay cutoffs of 1.0 or 1.5 OD-n), (2) the LAg-Avidity assay with viral load and CD4 cell count , elite controllers, and individuals on antiretroviral therapy. To address this, we evaluated the performance of the LAg-Avidity assay in a 3-assay MAA that included viral load and CD4 cell count , and viral load (assay cutoff: 400 copies/mL); this MAA is identical to MAA #2 , viral load  and CD4 cell count  in this MAA are recommended by the manufacturer Acceptable incidence estimates were also obtained using a 3-assay MAA that included the LAg-Avidity assay, CD4 cell count, and viral load. The cutoffs used for the LAg-Avidity assay (1.5 OD-n) and CD4 cell count  are larger than those obtained by longitudinal follow-up of cohorts. Additional studies that improve the precision of the mean window period would reduce the width of these confidence intervals. The width of the confidence intervals could also be reduced with larger cross-sectional surveys. Furthermore, even with larger cross-sectional surveys, it may be less expensive to estimate incidence using a MAA than a cohort study because no longitudinal follow-up is required.Our identification of an optimized 2-assay MAA that does not require CD4 cell count or HIV viral load has major implications for global HIV surveillance. The optimized 2-assay MAA identified in this report, which includes the LAg-Avidity and BioRad-Avidity assays without CD4 or viral load, has lower testing costs than the optimized 4-assay MAA, even after accounting for the larger sample sizes that would be needed with the 2-assay MAA because of its shorter mean window period. Note that this cost comparison only included costs for laboratory testing; costs associated with obtaining samples for analysis were not included in this analysis. Because the 2-assay MAA does not require CD4 cell count data, it can be performed entirely using stored plasma or serum samples, which would be an advantage in some studies. We previously described an optimized 3-assay MAA that included the BED-CEIA, the BioRad-Avidity assay, and viral load (without CD4 cell count) The samples used in this report were obtained from diverse cohorts that included men and women of different ethnicities and ages; and individuals infected through heterosexual, homosexual and parenteral routes. All of these samples were from the US where the most prevalent HIV-1 subtype is B. Serologic assays developed for cross-sectional incidence estimation have been shown to perform differently depending on the infecting subtype


Quantitative analysis of craniofacial morphology is of interest to scholarsworking in a wide variety of disciplines, such as anthropology, developmentalbiology, and medicine. T1-weighted  magnetic resonance images (MRI)provide excellent contrast between soft tissues. Given its three-dimensionalnature, MRI represents an ideal imaging modality for the analysis ofcraniofacial structure in living individuals. Here we describe how T1-weightedMR images, acquired to examine brain anatomy, can also be used to analyze facialfeatures. Using a sample of typically developing adolescents from the SaguenayYouth Study , we quantified inter-individual variations in craniofacial structure intwo ways. First, we adapted existing nonlinear registration-based morphologicaltechniques to generate iteratively a group-wise population average ofcraniofacial features. The nonlinear transformations were used to map thecraniofacial structure of each individual to the population average. Usingvoxel-wise measures of expansion and contraction, we then examined the effectsof sex and age on inter-individual variations in facial features. Second, weemployed a landmark-based approach to quantify variations in face surfaces. Thisapproach involves: (a) placing 56 landmarks  on a surface representation of the MRI-based groupaverage; (b) warping the landmarks to the individual faces using the inversenonlinear transformation estimated for each person; and (3) using a principalcomponents analysis (PCA) of the warped landmarks to identify facial features(i.e. clusters of landmarks) that vary in our sample in a correlated fashion. Aswith the voxel-wise analysis of the deformation fields, we examined the effectsof sex and age on the PCA-derived spatial relationships between facial features.Both methods demonstrated significant sexual dimorphism in craniofacialstructure in areas such as the chin, mandible, lips, and nose. Anthropologists have long analyzed craniofacial features on skull remains obtainedfrom hominids, Neanderthals, apes and modern humans to study differences betweenspecies, early migration patterns, and phenotypic differences within Neanderthals.For example, analyses of mandibular et al. etal. Biomedical research has recently started using craniofacial structure to examinespecific phenotypes in the context of brain dysfunction, hormonal environments, andsexual dimorphism. For example, Cohen Procrustes superposition of all landmarks, such that alllandmark positions are transformed to a common coordinate space and reflect theremaining nonlinear differences in the population Morphometry-based classification of skull remains is generally performed using thevariability in the position of landmarks and semi-landmarks, the latter beinglandmarks defined in relation to precise craniofacial features The current work is motivated by the availability of MR images collected in a numberof large neuroimaging initiatives First, we demonstrate the methods for the development of a population-based modelusing nonlinear registration and the voxel-by-voxel analyses of the deformationdata. In a second analysis, we use the model and nonlinear transformations toanalyze facial shape using landmark-based data.etal. All participants are white Caucasians recruited from a population with a knowngenetic founder effect living in the Saguenay Lac Saint-Jean (SLSJ) region ofQuebec, Canada. The MR images have been acquired in the context of the SaguenayYouth Study (SYS), which is described in detail in Pausova Ethics approval for data collection from the adolescents who participated in thisstudy was provided by the research ethics committee from the Centre desanté et de services sociaux de Chicoutimi. All participants in the studyprovided informed written assent for this study and their parents providedinformed written consent for the inclusion of their child in this study.For each participant, T1-weighted MR images of the brain were acquired on aPhilips 1.0-T superconducting magnet using the following parameters:three-dimensional (3D) radio frequency (RF)- spoiled gradient-echo scan with 140–160 slices, an isotropic resolution of 1 mm, a repetition time (TR) of 25ms, an echo time (TE) of 5 ms, and flip angle of 30°.http://packages.bic.mni.mcgill.ca/). Nonlineartransformations were estimated using the previously optimized version of theANIMAL algorithm In order to estimate differences in shape between faces within thepopulation, a group-wise nonlinear average of the craniofacial features wasestimated using methods similar to those used in the deformation-basedanalysis of brain anatomy in humans fmristat (http://www.math.mcgill.ca/keith/fmristat/) software packagesand multiple comparisons were corrected using Gaussian Random Field Theory.Voxel-wise analysis of deformation fields. Shape differences were analyzedover the entire extent of the craniofacial region but excluding the parts ofthe head posterior to the top of the forehead, thus limiting the analysis tovariations in facial morphometry. The Jacobian determinants The voxel-wise analyses were carried out to examine the effect of sex whilecovarying for age and overall head size . To analyze the effectof age, we carried out separate analyses in male and female adolescentswhile covarying for overall headsize.et al. While the above deformation-based analysis gives a measure of local expansionsand contractions, it does not provide an intuitive representation of the actualfacial features and their shape. To analyze these relationships, we draw fromprevious work in our group on morphing body-images In order to create a point distribution, we use methods employed previouslyin model-based segmentation techniques in neuroimaging studies. In thesetypes of methodologies semi-landmark around the jaw was defined as thepoint located half the distance between the inferior tip of the chin and themaxillary process along the convexity of the jaw line. See Here we placed, on the average non-linear model, 56 landmarks similar tothose employed by Fink et al. http://www.bic.mni.mcgill.ca/ServicesSoftwareVisualization/HomePage).Only full landmarks were chosen for this purpose. Accuracy and precision ofthe nonlinear transformations were evaluated by calculating the Euclideandistance between the homologous automatically and manually derivedlandmarks.Accuracy of group-wise nonlinear registration. To evaluate the accuracy ofthe group-wise nonlinear registration strategy, we warped the landmarksdefined using the inverse of the transformation that maps their craniofacialfeatures to the model. A co-author on this paper (RA) manually identified 17of the craniofacial landmarks on 10 randomly-selected subjects see . All lanAs is often done in classical anthropometric studies, we also analyzeddistances between landmarks. Here we chose a number of absolute distances,including the width and height of the left and right eyes, mouth width, thedistance between the ears and the zygomatic arches, nose width, filtrumlength (bottom of the nose to top of the lip), nose-to-chin length, andlip-to-chin length. See R software package (http://www.r-project.org/). To quantify variability withrespect to the original landmark locations, original x, y and z positionsfrom the landmarked model were first subtracted from each coordinate pointand the PCA was performed on the normalized coordinates.To characterize the shape of the face, and to reduce the dimensionality ofour landmark-based data, we developed a point-distribution model (PDM) Principal component (PC) scores were estimated for each individual and usedto evaluate the effect of sex, age, and interactions of age and sex (4degrees of freedom) for each of the first five PCs. All statistical analyseswere performed in JMP8.For visualization of the relationship between facial features captured in asingle PC, we performed simulations for the first 5 PCs. Original landmarkssee  were disThe results of the population-based model-building process demonstrate excellentalignment of the craniofacial structures. ×10−7,cluster volume [v] = 6.80×1053mm, peak t-value  = 16.2).Females, as compared with males, show a far more localized expansion in theregion of the lips, in the region between the lips and the nose, around thebridge of the nose, and near the left temple. These sex differences are demonstrated in two different clusters; the first is acontinuous cluster showing expansion of the lips, upper lip, and the bridge ofthe nose area  andthe second is a smaller region in the left temple.A voxel-wise analysis of sex differences (age removed) in the deformation fieldsdemonstrates “expansion” of the mandible, chin, forehead, andzygomatic area in males in comparison with females. As seen in the middle row of×10−7,v = 1.95×1073mm, peak t-value  = 13.0).Age-related decreases in the local volume are localized (in a single cluster)around the nose, lips, forehead, region of the eyebrow, bottom of the chin andin the temples, lateral to the forehead .Voxel-wise analysis of age-related changes in the deformation fields, carried outseparately for male and female adolescents, yielded the following observations.In male adolescents see , there i×10−7,v = 1.7×1063mm, peak t-value  = 7.0).Similarly, local expansions in the mandible and temple are also observed. Age-related decreases in localvolumes were found in the region of the scalp directly above the forehead. Other age-related decreases are alsoobserved above the eyebrow ridge , left zygomatic arch, right zygomatic arch, and mandible.In female adolescents, there is very focal evidence of age-related changes in thefacial structure see . Large aThe evaluation of the warped landmarks against the landmarks that were manuallyplaced on 10 individual faces demonstrates great precision in the anatomicallocalization of specific craniofacial features see . For allThe anthropometric indices see  estimateThe first 10 PCs in this analysis account for 75.3% of the variability inthe distribution of landmark position see . PC1 andResults of the simulation are shown in In this paper we have presented a novel methodology for the analysis of craniofacialstructure using structural MR images. We demonstrate how techniques originallydeveloped for the image processing and statistical analysis of structural andfunctional neuroimaging data can be adapted for this purpose. A population-basedaverage of craniofacial structure was estimated using a hierarchical and iterativeanatomical matching technique using the head MRI (after removing the brain). Theresulting nonlinear transformation matches the craniofacial structure of eachsubject to the average of the population. Fifty-six landmarks were placed on theaverage model and warped back to fit each subject using this nonlineartransformation. Voxel-wise analysis shows sexual dimorphism and age-related changesin craniofacial structure. The PDM derived from the landmark-based analysisdemonstrates several modes of variation that describe the difference between malesand females, and age-related changes during male adolescence. To the best of ourknowledge, this is the first demonstration of a fully automated three-dimensionalanalysis of craniofacial structure using MRI data.Our voxel-wise deformation analysis shows clear differences between male andfemale adolescents .The broThe anthropometric results demonstrate similar changes in the size and shape ofthe eyes, size of the chin, and mouth. These results do not, however, capturethe relationship between any different facial features. On the other hand, theresults from the PCA analysis from PDM allow us to understand better suchspatial relationships. Our results from PC1 and PC3 demonstrate broadening ofsimilar areas of the jaw, zygomatic arch, and browline. Age-related changes insubject-wise loadings on PC1 and PC3 in male adolescents are going in theopposite directions: negative for PC1 and positive for PC3. Clearly, twodifferent biological processes are at play here; future studies may help usunderstand whether, for example, “masculinization” (PC1) and“demasculinization” (PC3) of the facial features could be related tothe balance of male and female sex hormones. PC5 clearly demonstrates highervalues in females. This PC mimics the results in shape regression against the2D:4D ratio Most biomedical research of craniofacial morphology has used photographs andadvanced laser-scanning techniques to image the exterior of the face. Since wehave used MR images here, we are able to take into account three-dimensionalrepresentations of the face. Like previous studies, however, the analysispresented does not dissociate soft tissues (fat and skin) from the skull. Thus,all measures provided are a composite of measures of the skull and soft tissuesand the actual source of craniofacial features detected here cannot beidentified. This could be addressed in analyses where the skull is segmentedfrom the MRI data In light of these limitations and to test the robustness of our findings, weperformed a second analysis where percent body-fat was accounted for using theresidual error after regression of each PC score against total body-fat assessedwith bioimpedance, a standard measurement in the SYS data acquisition protocolAnthropological work on the evolutionary changes of the cranium has usedthree-dimensional PDMs Deformation-based analyses have created some controversy in the neuroimagingliterature due to their inability to match differing gyrification patternsbetween individuals The atlas-building strategy may also require further investigation. A large fieldof research suggests that there are optimal methods for the creation of an atlasthat best represents the group being studied. Some of these methods involve thesimultaneous estimation of transformations that warp all subjects to a groupaverage in an iterative unbiased fashion While our PDM uses 56 landmarks, the number of landmarks can be increased bycreating an equally spaced grid over the entire craniofacial structure, similarto the work done in the analysis of the hominoid cranium Unlike previous methodologies, our method can analyze the entire ensemble offacial features using voxel-wise analyses and simulations are only limited tothe number of landmarks chosen. Further, more sophisticated models of shapeanalysis could be used to analyze the modes of variance directly from thedeformation fields, such as an active appearance model Figure S1Population distribution for subjects used in this study for (A) malesand (B) females.(PNG)Click here for additional data file.Table S1Full description of all landmarks used for analysis of facialmorphometry.(DOC)Click here for additional data file.Table S2Analysis of subject-wise loading from PCA from the PDM of facialfeatures on the residuals from regression of PCs against percent bodyfat.(DOC)Click here for additional data file.


Bronchoperitoneal fistulas are extremely rare. We present a case where retained surgical drains from a previous surgery resulted in erosion and fistula formation. This condition required an extensive surgical procedure and advanced ventilator techniques.A 24-year-old African-American man presented to our Emergency Department with a one-week history of fever, dyspnea, cough, and abdominal pain. A computed tomography scan of his chest and abdomen revealed bilateral lower lobe pneumonia and two retained Jackson-Pratt drains in the right upper quadrant. He was taken to the operating room for drain removal, a right hemicolectomy, debridement of a duodenal injury, a Roux-en-y duodenojejunostomy, and an end ileostomy. He subsequently became increasing hypoxemic in the intensive care unit and a bronchoperitoneal fistula was diagnosed. He required high-frequency oscillatory ventilation followed by lung isolation, and was successfully resuscitated using these techniques.To the best of our knowledge, this is the first known case report of a bronchoperitoneal fistula caused by retained surgical drains. This is also the first known report that details successful management of this condition with advanced ventilatory techniques. This case highlights the importance of follow-up for trauma patients since retained surgical drains have the potential to cause life-threatening complications. When faced with this condition, clinicians should be aware of advanced ventilatory methods that can be employed in the intensive care unit. In this case, these techniques proved to be life-saving. The formation of a fistula between the bronchus and peritoneal cavity is exceedingly rare. Most causes are due to subphrenic abscess or iatrogenic biliary procedures causing diaphragmatic rupture -4. We prA 24-year-old African-American man presented to our Emergency Department with a one-week history of fever, dyspnea, cough with brownish phlegm, and abdominal pain. A computed tomography (CT) scan of the chest and abdomen revealed bilateral lower lobe pneumonia and two retained Jackson-Pratt drains in the right upper quadrant with a small amount of subcutaneous emphysema and stranding adjacent to one of the drain tips Figure . In addiHis history was significant for an exploratory laparotomy, right nephrectomy, and diaphragm repair for a gunshot wound sustained to the right lower back and abdomen eight years previously. The entrance wound was via the diaphragm into the abdomen, with the bullet traversing segments eight and five of the liver and then into the retroperitoneum. There was no significant bleeding from the right lobe liver wound, but there was a large zone 2 retroperitoneal hematoma on the right. The mid-portion of the parenchyma of the right kidney had been essentially obliterated, and the pelvis of the right kidney was involved; the right kidney was therefore resected. The diaphragm injury was repaired with a running #0 Prolene suture and then two separate 3/16 inch round silastic drains were placed, one over the dome of the liver, the second into the subhepatic pararenal space. Our patient was discharged home with the drains left in place for large output drainage. He stated that a non-medically trained acquaintance cut the surgical drains at the skin several months after he had been sent home. He was taken to the operating room for drain removal, right hemicolectomy, debridement of duodenal injury, Roux-en-y duodenojejunostomy, and end ileostomy. On exploration, one drain was found eroding into the duodenum causing a chronic duodenotomy that had previously communicated with the sinus tract on our patient's anterior abdominal wall. The defect was in the lateral wall on the anti-mesenteric side of the c-loop of the duodenum. The duodenum was inspected carefully intra-luminally and the ampulla was identified clearly. It was therefore felt safe to debride the edges and perform a side-to-side duodenojejunostomy with a Roux-en-y limb. A 10-mm Jackson-Pratt drain was left near the anastomosis. There were no signs of anastomotic leakage post-operatively. During the case, bubbling of air was noticed near the dome of the liver, and while under anesthesia, our patient sporadically became hypoxemic despite ventilation with 100% oxygen. However, no obvious diaphragmatic injury could be identified intra-operatively. He was admitted to the surgical ICU for further post-operative care.2O) and plateau pressures (36 to 38 cm H2O) remained elevated and the chest radiograph showed bilateral patchy infiltrates consistent with acute respiratory distress syndrome (ARDS), and no pneumothorax. Multiple ventilation modes were attempted, including all available pressure-limiting modes as well as bi-level ventilation and airways pressure release ventilation (APRV) to improve oxygenation and attenuate the high airways pressures. During conventional ventilation, approximately 60 mL per breath of air leak was observed in a right upper quadrant Jackson-Pratt drain, and a persistent air leak of greater than 100 mL/mL breath was found in the right-sided thoracostomy tube that had been placed intra-operatively. A total of four thoracostomy tubes were eventually placed: two at each apex and two at each base. Brochoalveolar lavage (BAL) specimens recovered from the right middle and right lower lobes grew pan-sensitive Escherichia coli. During serial bronchoscopies, no laceration or evidence of fistula could be identified. A CT scan was obtained which showed a large volume pneumoperitoneum, and an old drain exit site near the right upper quadrant was leaking air  of 54 on 100% fraction of inspired oxygen (FiO2)), he was sedated, paralyzed, and high-frequency oscillatory ventilation (HFOV) was initiated with a frequency of 5 Hz, FiO2 of 100%, mean airway pressure (mPaw) of 44 cm H2O, and oscillation pressure amplitude (ΔP) of 90 cm H2O. Over the course of four days, the frequency was gradually increased to 10 Hz, the FiO2 was weaned to 0.4, the mPaw was decreased to 26 cm H2O, and the ΔP was decreased to 30 cm H2O. As his oxygenation and hemodynamic status improved, he was removed from HFOV and a left-sided double-lumen tube was inserted to provide differential lung ventilation. After two days of differential ventilation with the right lung receiving a tidal volume of 150 mL, FiO2 of 40%, PEEP of 0 cm H2O, with peak inspiratory pressures of 14 to 18 cm H2O, the air leaks from both the abdominal drain and chest tubes were found to have stopped completely. Our patient received a tracheostomy, mechanical ventilation was eventually discontinued, and the chest tubes were removed. He was discharged home and had a documented full functional recovery with an osteomy takedown completed one year later.Over the course of the next 48 hours, he remained hypotensive, hypoxemic, acidotic, and increasingly dys-synchronous with the ventilator. Both peak airway pressures 38 to 42 cm H cm H2O aBronchoperiotoneal fistulas are rare phenomena . The conTo the best of our knowledge, this is the first report of retained drains causing diaphragm erosion and fistula formation. The fistula was recognized in the post-operative period when our patient became increasingly septic with increasing oxygen and vasopressor requirements. The combination of larger-than-expected post-surgical pneumoperitoneum on abdominal CT, and an air leak from an old site, ultimately led to the diagnosis.In our patient, healing of the fistula was accomplished by employing the same strategy used to treat bronchopleural fistulas. Both HFOV and differential ventilation have been used as novel methods for managing ventilation in patients with bronchopleural fistulas -10. In tBronchoperitoneal fistulas, while rare, can be life-threatening. This case highlights the importance of patient education and follow-up for traumatically injured patients. Bronchoperitoneal fistulas may also be difficult to diagnose, and when identified, the patient may present in extremis. We describe the use of advanced ventilatory techniques that may be employed to allow the fistula to heal.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.CP and SG analyzed and interpreted the data from our patient regarding the surgical procedure, history, and intensive care unit course. All authors read and approved the final manuscript.


Despite the large number of adolescents and young adults in employment training programs, a population that has poorer health and greater health risk than similarly aged in-school peers, we are unaware of any health interventions that have been evaluated in this setting. The primary objective of our study was to evaluate changes in depressive symptoms, coping strategies, and receipt of mental health services among low-income African American adolescents and young adults receiving a mental health intervention integrated into an employment training program.The intervention consisted of an on-site mental health clinician, a peer-led depression prevention intervention, and training sessions for employment training staff. A pretest-posttest design assessed depressive symptoms, coping strategies, and receipt of mental health services at baseline and 12-month follow-up. Complete baseline and follow-up data were available for 136 of 218 eligible participants. Most study participants were African American (98%); average age was 18.8 years.The intervention had no effect on depressive symptoms or coping strategies. The percentage of participants who used mental health services at follow-up increased, but not significantly. Age was associated with use of active and support-seeking coping strategies, whereas use of mental health services before program enrollment was associated with use of mental health services at follow-up.Alternative intervention strategies may be needed to decrease the severity of depressive symptoms and increase use of coping strategies among adolescents and young adults in employment training programs. Future research evaluating such interventions should use quasi-experimental or experimental designs to provide evidence of intervention effect. National community studies have found that 25% of adolescents and young adults aged 16 to 24 years will experience a depressive episode by age 24 — the highest incidence of any age group .Sixty-five percent of African Americans aged 16 to 24 who have dropped out of school are unemployed . Many ofThe primary objective of our study was to evaluate changes in depressive symptoms, coping strategies, and receipt of mental health services among low-income African American adolescents and young adults receiving a mental health intervention integrated into an employment training program. The secondary objective was to examine individual and environmental variables associated with changes in study outcomes.In 2000, the US Department of Labor awarded Youth Opportunity (YO) grants to 36 high-poverty areas  characteWe used a pretest-posttest design to assess 3 outcomes: depressive symptoms, coping strategies, and receipt of mental health services. Study participants completed a baseline audio computer-assisted self-interview (ACASI) and a follow-up ACASI 12 months later.Between May 2007 and February 2008, 390 adolescents and young adults who were not in foster care enrolled at the Eastside YO Center. Of the 390 newly enrolling YO members, 323 (83%) completed a baseline ACASI designed to assess depressive symptoms, the use of coping strategies, and the use of mental health services and address other mental health and health topics. An ACASI allows a person to sit at a computer, hear questions on headphones while they appear on a screen, and use simple keyboard commands to respond. We used ACASIs to minimize concerns about participants' reading comprehension. In addition, ACASIs more accurately assess such stigmatizing behaviors as drug use and violence perpetration than paper-and-pencil self-administered surveys .A research assistant obtained informed consent for participants aged 18 or older and youth assent and parental consent for younger participants. All procedures were approved by Johns Hopkins Bloomberg School of Public Health's Committee on Human Subjects Research.We found no significant differences in race, sex, or age between participants completing baseline ACASIs and those enrolling in YO but not completing the ACASI. Of the 323 YO members completing the baseline ACASIs, 218 were eligible for the 12-month follow-up. The remaining 105 YO members were ineligible for the following reasons: incarceration at follow-up (n = 38), death (n = 1), moving out of state (n = 1), and never receiving services at YO (n = 65). Of the 218 eligible for follow-up, 136 (62%) completed 12-month ACASIs; these follow-up ACASIs also asked YO members about depressive symptoms, coping, and use of mental health services. We found no significant differences in race, sex, or age between the 136 YO members completing 12-month ACASIs and the 82 noncompleters.The mental health intervention consisted of 3 components.Referral to onsite mental health clinician. After all baseline ACASIs were completed, a research assistant generated a short report on each participant's ACASI responses, and each participant was referred to the onsite clinical social worker. The short report was designed to provide the clinician with preliminary mental health information and help guide the first visit. The purpose of the referral was to familiarize the participant with the clinician; the referral process was hypothesized to facilitate subsequent receipt of mental health services. After assessment by the clinician, some participants were referred to an offsite mental health provider for additional services, including medication management.Depression prevention curriculum (SOS Club). YO members who had a score of 10 to 26 on the Center for Epidemiologic Studies Depression Scale (CES-D) ( (CES-D) ,14 were  (CES-D) ,16. EachTraining for YO staff. We provided 2-day training sessions to all YO staff to help them better understand the mental health issues of YO members, understand the role mental health plays in healthy adolescent development, engage in conversations about mental health with YO members, understand the range of mental health services available to YO members, and encourage YO members to obtain mental health services when appropriate. YO staff are employment and training specialists but have no formal education in mental health. The training sessions were led by several mental health researchers and practitioners. We provided these sessions to all YO staff and expected this component to have an effect on all YO members.Depressive symptoms. We used the CES-D . We used χ2 tests to compare the percentage of participants at baseline and follow-up with a mean CES-D score of 16 or more who reported receiving mental health services in the previous 12 months. Multivariate linear regression assessed individual and social environmental variables associated with changes in depressive symptoms and coping strategies between baseline and follow-up, and multivariate logistic regression assessed variables associated with receipt of mental health services at follow-up. We controlled for the baseline score for each outcome variable when we modeled that variable. We used splines for some independent variables based on the distribution of LOWESS  plots of the independent and dependent variables. We checked collinearity for all models and chose the most parsimonious model based on Akaike information criteria. We used a 2-tailed α of .05 to define statistical significance. We analyzed data using STATA version 10 .We summarized the sociodemographic characteristics of the sample. We calculated the mean CES-D score and mean coping strategies score for the sample at baseline and follow-up and conducted paired Nearly all (98%) study participants were African American; 45% were male; the average age was 18.8 . Only 14The mean CES-D score of 15.0 at baseline increased to 16.5 at 12-month follow-up . Fifty-oP = .047) for every year increase in age, but after age 21, the active coping score increased by 4.17  for every year increase in age. After age 18, the support-seeking coping score decreased by 0.92  for every year increase; the support-seeking coping score decreased by 0.11  for participants who had a baseline social support score higher than 25, after adjusting for other factors. Participants who received mental health services in the 12 months before baseline were almost 7 times as likely to receive services between baseline and follow-up.A 1-point increase in the baseline stress score did not change the CES-D score significantly . Age wasOur intervention did not have an overall effect on reducing the severity of depressive symptoms or increasing the use of coping strategies. Among the 51 participants who entered the study with clinically meaningful depressive symptoms, 22 did not have such symptoms at follow-up. A decrease in symptomatology reduces the likelihood of substance abuse, interpersonal problems, and other behavioral concerns  to provide emotional, tangible, and informational support .Some research suggests that adolescents and young adults use more support-seeking coping in school and peer contexts . The parOur study had several limitations. We had a small sample, and depression can be cyclical, so findings on changes from baseline to follow-up should be interpreted cautiously. We did not use an experimental design to assess intervention effect; we believed that it was premature to use such a design because of the small amount of research available on the integration and evaluation of mental health services in employment training settings. The lack of a comparison group limits the interpretation of findings on the effect of the intervention on mental health outcomes. Our study was implemented at a single employment training program. Future studies could be implemented at multiple programs, thereby increasing the number of study participants and allowing greater generalizability of study results.Study investigators and community partners learned several lessons, which have shaped the development and implementation of a more comprehensive mental health intervention currently being assessed through a quasi-experimental design. First, thorough training is needed to ensure that paraprofessionals — in our case, peer leaders — feel adequately prepared to deliver the intervention content. In our new intervention , peer leThis the first study to our knowledge to examine the effects of an intervention aimed at improving the mental health of adolescents and young adults in employment training programs — a population shown to exhibit worse health and greater health risk than similarly aged in-school peers . This st


Z-scores for high-risk procedures have steadily improved from 1.78 to 2.35. The initiatives resulted in sustained reductions of failure-mode risks as measured by a set of evidence-based metrics over a 3-years period. These augment or incorporate many of the published recommendations for patient safety in radiation medicine by translating them to clinical practice.By combining incident learning and process failure-mode-and-effects-analysis (FMEA) in a structure-process-outcome framework we have created a risk profile for our radiation medicine practice and implemented evidence-based risk-mitigation initiatives focused on patient safety. Based on reactive reviews of incidents reported in our departmental incident-reporting system and proactive FMEA, high safety-risk procedures in our paperless radiation medicine process and latent risk factors were identified. Six initiatives aimed at the mitigation of associated severity, likelihood-of-occurrence, and detectability risks were implemented. These were the standardization of care pathways and toxicity grading, pre-treatment-planning peer review, a policy to thwart delay-rushed processes, an electronic whiteboard to enhance coordination, and the use of six sigma metrics to monitor operational efficiencies. The effectiveness of these initiatives over a 3-years period was assessed using process and outcome specific metrics within the framework of the department structure. There has been a 47% increase in incident-reporting, with no increase in adverse events. Care pathways have been used with greater than 97% clinical compliance rate. The implementation of peer review prior to treatment-planning and use of the whiteboard have provided opportunities for proactive detection and correction of errors. There has been a twofold drop in the occurrence of high-risk procedural delays. Patient treatment start delays are routinely enforced on cases that would have historically been rushed.  The preparation of a treatment plan for delivery of radiation therapy to a patient requires several process steps and checks spread over about a week with interactions and handoffs between a heterogeneous set of caregivers, hardware, and software interfaces. Thus pathways for errors to propagate toward an unsafe event for any patient are multifold. Yet the rate of serious or adverse errors in radiation therapy is estimated to be around 0.2% per patient –4. WhileRecommendations to do better in this regard are typically summarized in reports published by radiotherapy quality and safety organizations worldwide. A recent study of seven such reports from influential radiation therapy safety organizations worldwide yielded 117 recommendations, 61 one of which were deemed to be unique  or event-reporting database in our radiation medicine department suggested we were at a substantially higher risk than we would have perceived . Recogniper se is that for every effect there must be a set of causes and for every cause there must be some set of effects (In this work we reviewed incidents reported in our Aspects-of-Care (AOC) incident-reporting database to extract causes and contributory factors for known failures  and cond effects . Based o effects , 24. We Our department of Radiation Medicine is spread across the New York metropolitan area over five sites within a major healthcare system. The sites that provide radiation therapy are characterized by a blend of academic, private, and community-practice traits that may be representative to some extent, of a range of practice cultures in many other departments in the country. We treat over 2000 new patients each year with external beam radiation and brachytherapy utilizing eight linear accelerators and three high-dose-rate brachytherapy systems. Our operations are paperless, driven by quality checklists (QCLs) in our EMR and policies and procedures that are updated regularly. Internal and external dosimetric audits and reviews of our programs are conducted regularly by various accreditation agencies. Our QM program encompasses all aspects of patient care using the AOC database as a catchment framework for the registry and analysis of events that represent departures from standard operations or expected patient outcomes.The AOC database is electronically available to all staff members with an anonymous reporting option. Incidents are reported with a brief narrative and associated reporting elements. The events are reviewed weekly by a multidisciplinary QM team and reported department and health-system wide on monthly and quarterly bases. The taxonomy for analysis of events evolved historically from a drop-down menu with shorthand notations for typical causes prior to 2010 to a more structured and recursive approach that mapped patient effects with underlying structure-process elements. The primary reason for the change was the observation that reviews of the incidents were being overwhelmingly attributed to just a handful of causes. A focused independent review of these however revealed that the causes typically picked were more the result of deeper issues not being considered. Thus efforts to make changes until then were not directed at the correct underlying issues, rendering our reporting system ineffective. The changes in the database taxonomy in 2010 thus allowed for more comprehensive analyses. Events are broken down into the observed patient effect  and the Given the cascaded steps and handoffs evident in the radiation medicine process, our goal was to reorganize the chronologically arranged process-map into one that was risk-sorted for patient safety. The QCL process-map (QPM) in use at our facility and similar to others , 26 was The exercise was conducted by 15 staff members across the various functional groups in the department including radiation oncologists, physicists, dosimetrists, nurses, therapists, and one non-clinical observer. There were two to four participants in each functional group bracketing the hierarchical spread within. The participants were asked to scrutinize the process-map, prospectively consider various modes of failure for each step and list their causes and safety consequences. In addition to individual experience, the AOC database, group discussions, and other event-reporting databases or publications –29 serveGiven the observed (AOC) and predicted (FMEA) propensity for either delays or defects in high-risk procedures, mitigation strategies were developed to reduce their severity, likelihood-of-occurrence, and detectability risks. The AOC findings were scrutinized to seek evidence for resident pathogens – or latent error-provoking conditions in the clinic and to ascertain if these had any bearing on the performance of the high-risk procedures , 31. StaIncident-reporting increased by 47% following the AOC database restructure in 2010. There was significant variation in reporting by functional group: therapists (62.9%), nurses (26.7%), dosimetrists (6.4%), physicists (1.5%), support staff (1.2%), anonymous (0.9%), and radiation oncologists (0.4%). About 89.6% of the reports were logged by therapists and nurses while 8.3% were logged by the treatment-planning team. A high level of inter-rater agreement  was noted amongst QM team members who routinely analyzed incident reports.Patient effects reported included treatment delays (25.2%), treatment-planning delays (20.9%), incomplete treatments (14.5%), safety: preventive incidents (12.8%), treatment interruptions (6.9%), safety: reactive incidents (6.7%), mortality (5.3%), patients not starting treatment (4.2%), and morbidity (3.5%). Patient treatment-planning or initiation delays and safety incidents (preventive and reactive) comprised 65.6% of the reports in the AOC database. Under-reporting of treatment-planning delays by the treatment-planning group in the AOC database was partially compensated by reporting by the therapist group, albeit at a later day than when the delays were potentially known to be imminent to the planning team. The planning delay issues were typically identified and reported instead during the routine pre-treatment audit of plans in the EMR 2 days prior to treatment initiation conducted by therapists in our department, when expected documentation was determined to be incomplete or missing in the EMR.Treatment-planning delays (some of which lead to treatment delays) are attributed to planning procedural delays (58%), plan verification delays 23%), environmental issues (10%), coordination-of-care with other caregivers (5%), and patient factors (4%)  dropped with the addition of a new team member (to 0.747), and by the low kappa score (0.140) for the likelihood-of-occurrence risks for the high-severity risk tasks during the FMEA exercise. This emphasized the need for the continual assessment of inter-rater reliability in the use and development of taxonomies for incident learning. In regard to the FMEA, there was a wider variation in perceptual differences for the likelihood-of-occurrence assessments for two reasons. First, the FMEA was conducted by members across all functional groups and thus some of the failure-modes for a particular type of procedure were less understood by or familiar to those who did not routinely perform them. As errors started by one professional group however are often caught by another , an obseDespite the limitations of failure analyses mentioned above, the use of various incident-reporting systems, differing taxonomies, and FMEA study designs (including grading schemes used) at different institutions, in comparing our findings Figures  and 3 wiThe first was the timeliness and accuracy of the execution of high-risk-process steps identified in our FMEA. In particular, contours, prescription, the completion of the treatment plan and second checks are complex in nature, requiring many inter-related subtasks, pre-requisite information, and handoffs, and have a tight coupling with observed treatment delays or safety incidents Tables  and 3 3, 64. DelRisk-mitigation was therefore geared toward these three factors, using the mitigation strategies of the FMEA process – namely reduction of associated severity metrics, likelihood-of-occurrence and the likelihood of detection of errors if these occurred. The main focus was on building robustness within our radiation medicine process with the awareness that it may be formidable to completely eliminate failures  but thatad hoc care, we instituted detailed evidence-based treatment pathways that encompassed all domains of care including prescription, simulation, planning, nursing interventions and follow-up assessments , we felt we needed more than a set of policies or checklists in order to transform our culture to one that was actively focused on safety. Driving these risk-mitigation initiatives has challenged traditional norms of operations such as expediting treatment initiation in delay-rushed environments or sustaining care pathways that are more experience based than evidence-based. Therefore their implementation has met with substantial cultural barriers for adoption. Working practices evolve over decades, and changing them with such initiatives creates uncertainty. The inertia of sustaining past cultures and arguments for not changing tend to perseverate . Direct The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.