Radiomic analysis for early differentiation of lung cancer recurrence from fibrosis in patients treated with lung stereotactic ablative radiotherapy.

Objective. The development of radiation-induced fibrosis after stereotactic ablative radiotherapy (SABR) can obscure follow-up images and delay detection of a local recurrence in early-stage lung cancer patients. The objective of this study was to develop a radiomics model for computer-assisted detection of local recurrence and fibrosis for an earlier timepoint (<1 year) after the SABR treatment.Approach. This retrospective clinical study included CT images (n= 107) of 66 patients treated with SABR. A z-score normalization technique was used for radiomic feature standardization across scanner protocols. The training set for the radiomics model consisted of CT images (66 patients; 22 recurrences and 44 fibrosis) obtained at 24 months (median) follow-up. The test set included CT-images of 41 patients acquired at 5-12 months follow-up. Combinations of four widely used machine learning techniques (support vector machines, gradient boosting, random forests (RF), and logistic regression) and feature selection methods (Relief feature scoring, maximum relevance minimum redundancy, mutual information maximization, forward feature selection, and LASSO) were investigated. Pyradiomics was used to extract 106 radiomic features from the CT-images for feature selection and classification.Main results. An RF + LASSO model scored the highest in terms of AUC (0.87) and obtained a sensitivity of 75% and a specificity of 88% in identifying a local recurrence in the test set. In the training set, 86% accuracy was achieved using five-fold cross-validation. Delong's test indicated that AUC achieved by the RF+LASSO is significantly better than 11 other machine learning models presented here. The top three radiomic features: interquartile range (first order), Cluster Prominence (GLCM), and Autocorrelation (GLCM), were revealed as differentiating a recurrence from fibrosis with this model.Significance. The radiomics model selected, out of multiple machine learning and feature selection algorithms, was able to differentiate a recurrence from fibrosis in earlier follow-up CT-images with a high specificity rate and satisfactory sensitivity performance.

Risk of Cervical Intraepithelial Neoplasia 2 or Worse by Cytology, Human Papillomavirus 16/18, and Colposcopy Impression: A Systematic Review and Meta-analysis.

OBJECTIVE: To calculate pooled risk estimates for combinations of cytology result, human papillomavirus (HPV) 16/18 genotype and colposcopy impression to provide a basis for risk-stratified colposcopy and biopsy practice. DATA SOURCE: A PubMed search was conducted on June 1, 2016, and a ClinicalTrials.gov search was conducted on June 9, 2018, using key words such as "uterine cervical neoplasms," "cervical cancer," "mass screening," "early detection of cancer," and "colposcopy." METHODS OF STUDY SELECTION: Eligible studies must have included colposcopic impression and either cytology results or HPV 16/18 partial genotype results as well as a histologic biopsy diagnosis from adult women. Manuscripts were reviewed for the following: cytology, HPV status, and colposcopy impression as well as age, number of women, and number of cervical intraepithelial neoplasia (CIN) 2, CIN 3, and cancer cases. Strata were defined by the various combinations of cytology, genotype, and colposcopic impression. TABULATION, INTEGRATION, AND RESULTS: Of 340 abstracts identified, nine were eligible for inclusion. Data were also obtained from three unpublished studies, two of which have since been published. We calculated the risk of CIN 2 or worse and CIN 3 or worse based on cytology, colposcopy, and HPV 16/18 test results. We found similar risk patterns across studies in the lowest risk groups such that risk estimates were similar despite different referral populations and study designs. Women with a normal colposcopy impression (no acetowhitening), less than high-grade squamous intraepithelial lesion cytology, and HPV 16/18-negative were at low risk of prevalent precancer. Women with at least two of the following: high-grade squamous intraepithelial lesion cytology, HPV16- or HPV18-positive, and high-grade colposcopic impression were at highest risk of prevalent precancer. CONCLUSION: Our results support a risk-based approach to colposcopy and biopsy with modifications of practice at the lowest and highest risk levels.

Walking Behavior of Zoo Elephants: Associations between GPS-Measured Daily Walking Distances and Environmental Factors, Social Factors, and Welfare Indicators.

Research with humans and other animals suggests that walking benefits physical health. Perhaps because these links have been demonstrated in other species, it has been suggested that walking is important to elephant welfare, and that zoo elephant exhibits should be designed to allow for more walking. Our study is the first to address this suggestion empirically by measuring the mean daily walking distance of elephants in North American zoos, determining the factors that are associated with variations in walking distance, and testing for associations between walking and welfare indicators. We used anklets equipped with GPS data loggers to measure outdoor daily walking distance in 56 adult female African (n = 33) and Asian (n = 23) elephants housed in 30 North American zoos. We collected 259 days of data and determined associations between distance walked and social, housing, management, and demographic factors. Elephants walked an average of 5.3 km/day with no significant difference between species. In our multivariable model, more diverse feeding regimens were correlated with increased walking, and elephants who were fed on a temporally unpredictable feeding schedule walked 1.29 km/day more than elephants fed on a predictable schedule. Distance walked was also positively correlated with an increase in the number of social groupings and negatively correlated with age. We found a small but significant negative correlation between distance walked and nighttime Space Experience, but no other associations between walking distances and exhibit size were found. Finally, distance walked was not related to health or behavioral outcomes including foot health, joint health, body condition, and the performance of stereotypic behavior, suggesting that more research is necessary to determine explicitly how differences in walking may impact elephant welfare.

Elephant Management in North American Zoos: Environmental Enrichment, Feeding, Exercise, and Training.

The management of African (Loxodonta africana) and Asian (Elephas maximus) elephants in zoos involves a range of practices including feeding, exercise, training, and environmental enrichment. These practices are necessary to meet the elephants' nutritional, healthcare, and husbandry needs. However, these practices are not standardized, resulting in likely variation among zoos as well as differences in the way they are applied to individual elephants within a zoo. To characterize elephant management in North America, we collected survey data from zoos accredited by the Association of Zoos and Aquariums, developed 26 variables, generated population level descriptive statistics, and analyzed them to identify differences attributable to sex and species. Sixty-seven zoos submitted surveys describing the management of 224 elephants and the training experiences of 227 elephants. Asian elephants spent more time managed (defined as interacting directly with staff) than Africans (mean time managed: Asians = 56.9%; Africans = 48.6%; p<0.001), and managed time increased by 20.2% for every year of age for both species. Enrichment, feeding, and exercise programs were evaluated using diversity indices, with mean scores across zoos in the midrange for these measures. There were an average of 7.2 feedings every 24-hour period, with only 1.2 occurring during the nighttime. Feeding schedules were predictable at 47.5% of zoos. We also calculated the relative use of rewarding and aversive techniques employed during training interactions. The population median was seven on a scale from one (representing only aversive stimuli) to nine (representing only rewarding stimuli). The results of our study provide essential information for understanding management variation that could be relevant to welfare. Furthermore, the variables we created have been used in subsequent elephant welfare analyses.

Recumbence Behavior in Zoo Elephants: Determination of Patterns and Frequency of Recumbent Rest and Associated Environmental and Social Factors.

Resting behaviors are an essential component of animal welfare but have received little attention in zoological research. African savanna elephant (Loxodonta africana) and Asian elephant (Elephas maximus) rest includes recumbent postures, but no large-scale investigation of African and Asian zoo elephant recumbence has been previously conducted. We used anklets equipped with accelerometers to measure recumbence in 72 adult female African (n = 44) and Asian (n = 28) elephants housed in 40 North American zoos. We collected 344 days of data and determined associations between recumbence and social, housing, management, and demographic factors. African elephants were recumbent less (2.1 hours/day, S.D. = 1.1) than Asian elephants (3.2 hours/day, S.D. = 1.5; P < 0.001). Nearly one-third of elephants were non-recumbent on at least one night, suggesting this is a common behavior. Multi-variable regression models for each species showed that substrate, space, and social variables had the strongest associations with recumbence. In the African model, elephants who spent any amount of time housed on all-hard substrate were recumbent 0.6 hours less per day than those who were never on all-hard substrate, and elephants who experienced an additional acre of outdoor space at night increased their recumbence by 0.48 hours per day. In the Asian model, elephants who spent any amount of time housed on all-soft substrate were recumbent 1.1 hours more per day more than those who were never on all-soft substrate, and elephants who spent any amount of time housed alone were recumbent 0.77 hours more per day than elephants who were never housed alone. Our results draw attention to the significant interspecific difference in the amount of recumbent rest and in the factors affecting recumbence; however, in both species, the influence of flooring substrate is notably important to recumbent rest, and by extension, zoo elephant welfare.

Procedures and Uterine-Sparing Surgeries for Managing Postpartum Hemorrhage: A Systematic Review.

IMPORTANCE: Postpartum hemorrhage (PPH) is one of the leading causes of maternal mortality and morbidity worldwide. OBJECTIVE: The aim of this study was to systematically review literature on procedures (eg, uterine artery embolization) and uterine-sparing surgeries for PPH. EVIDENCE ACQUISITION: We searched MEDLINE and other databases from 1990 to November 2014. Two reviewers independently evaluated studies against predetermined criteria, extracted data, and assessed study quality and strength of the evidence (confidence in the effect). RESULTS: Twenty-eight small studies addressed 1 or more procedures (19 studies of embolization, 5 of uterine tamponade) or surgeries (5 studies of arterial ligation, 5 of uterine compression sutures). Studies primarily evaluated bleeding control and adverse effects. Rates of hemostasis were typically greater than 60% in studies reporting such data after failure of conservative management. Postprocedure infertility occurred in 0% to 43% of women in a small number of studies that reported these data. Uterine tamponade successfully controlled bleeding in more than 50% of women, with few harms reported. Success rates for ligation and sutures ranged from 36% to 96%; harms included surgical injury, infection, and fertility-associated effects. CONCLUSIONS AND RELEVANCE: A limited body of evidence addresses these interventions for PPH. Median rates of hemostasis ranged from 36% to 98%; however, these data come from few studies with less than 2100 total participants. Harms were not well characterized. Some studies with longer-term follow-up reported infertility in women undergoing embolization. Few adverse events with tamponade, ligation, or sutures were reported. Given the insufficient evidence, clinicians must continue to make individual care decisions based on each woman's clinical situation and available management options.

Study Design Algorithm.

OBJECTIVES: To aid authors in correctly naming their study design, to assist readers and reviewers who must decide what the design was for some published studies, and to provide consistency in evaluating the design of published studies, especially for those conducting systematic reviews and evidence synthesis. METHODS: An annotated algorithm method is used to prompt serial questions and analysis to identify a single study design. RESULTS: The algorithm begins with a research article. Primary clinical research is divided into experimental and observational studies. Key determinants include identifying the study question and the population, intervention, comparison, and outcome. Experimental therapy and prognosis studies are subdivided into 4 design types. Observational therapy and prognosis studies are subdivided into 7 design types. Experimental diagnosis and screening studies are subdivided into 2 types. Observational diagnosis and screening studies are subdivided into 5 types. CONCLUSIONS: An annotated algorithm may be used by authors, readers, and reviewers to consistently determine the design of clinical research studies.

Pharmacologic Agents That Promote Airway Clearance in Hospitalized Subjects: A Systematic Review.

Pharmacologic agents to promote mucus clearance may reduce the sequelae of obstructive secretions. We systematically reviewed comparative studies of pharmacologic agents for mucus clearance in hospitalized or postoperative subjects without cystic fibrosis and over 12 months of age. We searched MEDLINE and other databases from January 1970 to July 2014 to identify relevant literature. Two reviewers independently assessed each study against predetermined inclusion/exclusion criteria. Two reviewers also independently extracted data regarding subject and intervention characteristics and outcomes and assigned overall quality ratings. The 9 studies meeting review criteria included 5 randomized controlled trials, 3 crossover randomized controlled trials, and one retrospective cohort study. Studies were small and together included a total of 379 subjects (mean of 42 subjects per study). N-acetylcysteine, heparin plus N-acetylcysteine, albuterol, ipratropium bromide, and saline were assessed. Studies reported no benefit of studied agents on expectoration, pulmonary function, and atelectasis and little effect on changes in sputum volume, weight, or viscosity. Adverse effects of agents were not consistently reported. Nausea was reported in 2 studies of N-acetylcysteine (one paper reported 2 experiments and did not clearly identify in which experiment adverse effects occurred), 3 studies reported that there were no adverse events, and 3 studies did not address adverse effects at all. Further research with clearly characterized populations and interventions is needed to understand the potential benefits and adverse effects of mucoactive agents.

Diurnal and nocturnal activity budgets of zoo elephants in an outdoor facility.

The present study examined the activity budgets of 15 African elephants (1 bull, 6 cows, 2 male juveniles, 2 female juveniles, and 4 male calves) living at the San Diego Zoo Safari Park during the summers of 2010 and 2011. Onsite behavioral data (n = 600 hr) were collected for approximately 12 weeks from 0400 to 0830 and 1100 to 2400 during the 2010 and 2011 summer season. Foraging was the most common behavior state during the day followed by resting, and walking. During the evening hours, the elephants spent majority of their time foraging, resting, and sleeping. The average rate of self-maintenance behavior events (dust, wallow, etc.) increased from 0600 to 0700, 1100 to 1500, and from 1700 to 1900. Positive social behavior events (touch other, play, etc.) remained high from 0500 to 2300, with peaks at 0600, 1300, 1500, and 1900. Negative social events occurred at low rates throughout the day and night, with peaks at 0600, 1900, and 2200. The majority of positive behavior events during the daylight and nighttime hours involved the mother-calf pairs. Furthermore, the calves and juveniles initiated approximately 60% of all social events during the daytime and 57% of all social interactions at night. The results of this study demonstrate the differences between diurnal and nocturnal activity budgets of a multi-age and sex elephant herd in a zoological facility, which highlights the importance of managing elephants to meet their 24 hr behavioral needs.

Nonpharmacologic airway clearance techniques in hospitalized patients: a systematic review.

Nonpharmacologic airway clearance techniques are used to reduce the sequelae of obstructive secretions. We systematically reviewed comparative studies of nonpharmacologic interventions that health professionals can employ to achieve mucus clearance in hospitalized or postoperative patients without cystic fibrosis, over the age of 12 months. We searched MEDLINE and other databases from 1990 to 2012 to identify relevant literature. Two reviewers independently assessed each study against predetermined inclusion/exclusion criteria. Two reviewers also independently extracted data regarding subject and intervention characteristics and outcomes, and assigned overall quality ratings. The 32 studies meeting the review criteria included 24 randomized controlled trials, 7 crossover randomized controlled trials, and one prospective cohort study. Studies were typically small and together included a total of 2,453 subjects (mean 76/study). Studies generally examined chest physical therapy/physiotherapy modalities in postoperative or critically ill subjects or those with COPD. Interventions, comparators, and populations varied considerably across studies, hampering our ability to draw firm conclusions. Interventions, including conventional chest physical therapy/physiotherapy, intrapulmonary percussive ventilation, and positive expiratory pressure, typically provided small benefits in pulmonary function, gas exchange, oxygenation, and need for/duration of ventilation, among other outcomes, but differences between groups were generally small and not significant. Harms of the techniques were not consistently reported, though airway clearance techniques were generally considered safe in studies that did comment on adverse effects. Further research with clearly characterized populations and interventions is needed to understand the potential benefits and harms of these techniques.

GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.

This article describes the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to classifying the direction and strength of recommendations. The strength of a recommendation, separated into strong and weak, is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects. Alternative terms for a weak recommendation include conditional, discretionary, or qualified. The strength of a recommendation has specific implications for patients, the public, clinicians, and policy makers. Occasionally, guideline developers may choose to make "only-in-research" recommendations. Although panels may choose not to make recommendations, this choice leaves those looking for answers from guidelines without the guidance they are seeking. GRADE therefore encourages panels to, wherever possible, offer recommendations.

Social learning in captive African elephants (Loxodonta africana africana).

Social learning is a more efficient method of information acquisition and application than trial and error learning and is prevalent across a variety of animal taxa. Social learning is assumed to be important for elephants, but evidence in support of that claim is mostly anecdotal. Using a herd of six adult female African bush elephants (Loxodonta africana africana) at the San Diego Zoo's Safari Park, we evaluated whether viewing a conspecific's interactions facilitated learning of a novel task. The tasks used feeding apparatus that could be solved in one of two distinct ways. Contrary to our hypothesis, the method the demonstrating animal used did not predict the method used by the observer. However, we did find evidence of social learning: After watching the model, subjects spent a greater percentage of their time interacting with the apparatus than they did in unmodeled trials. These results suggest that the demonstrations of a model may increase the motivation of elephants to explore novel foraging tasks.

Systematic review of therapies for noncyclic chronic pelvic pain in women.

We synthesized the literature (articles published between 1990 and May 2011) on the treatment of noncyclic and mixed cyclic/noncyclic chronic pelvic pain (CPP) in adult women. Two reviewers assessed studies against predetermined inclusion/exclusion criteria, extracted data regarding participant and intervention characteristics and outcomes, and assigned overall quality and strength of evidence ratings. Of 2081 studies, 21 addressed surgical or nonsurgical interventions. Definitions of CPP and participant characteristics varied across studies, and most studies were of poor quality, which precluded data synthesis. Although surgical and nonsurgical approaches both improved pain, neither was more effective when directly compared in 3 studies. Laparoscopic adhesiolysis or laparoscopic uterosacral nerve ablation did not further improve pain scores over diagnostic laparoscopy. The evidence to conclude that surgical intervention is either effective or ineffective or that one technique is superior to another is insufficient. Most studies on nonsurgical approaches evaluated hormonal therapies in endometriosis-associated CPP and were not placebo controlled. Few studies addressed nonhormonal or nonpharmacologic approaches. Harms reporting was limited. Overall, no nonsurgical treatment was more or less effective than another, except for the clear negative effect of raloxifene. In general, the literature addressing therapies for CPP in women is of poor quality and inconclusive. Improved characterizations of the targeted condition and interventions in CPP research, including a uniform definition and standardized evaluation, are necessary to inform treatment choices.

Estimating daily walking distance of captive African elephants using an accelerometer.

Two central concerns for elephant husbandry and management are whether zoological enclosures are appropriately sized and the degree to which naturalistic exercise and activity are observed in such enclosures. In order to address these issues, accurate data on the daily walking distance of elephants both in situ and ex situ are necessary. We used an accelerometer, a pedometer that measures step count and activity level, to estimate walking distance in African elephants (Loxodonta africana) at the San Diego Zoo's Wild Animal Park. The accelerometer was worn simultaneously with a GPS unit that recorded actual walking distance. Estimates of walking distance were extrapolated from the accelerometer and compared with actual distances determined by GPS data. The accelerometer was found to overestimate step count, and subsequently walking distance, by including false counts of steps. Extrapolating walking distance based upon stride length measurements did not match actual GPS walking distance. However, activity level output from the accelerometer significantly correlated with actual GPS walking distance. In addition, we report that the rate of movement is comparable to that reported in other zoological settings. We provide a linear regression equation that can be utilized by other institutions to estimate daily walking distance of elephants in their collection who are outfitted with accelerometers.

GRADE guidelines 6. Rating the quality of evidence--imprecision.

GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required if clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" [OIS]). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0, and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest an RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.