When possible, report a Fisher-exact P value and display its underlying null randomization distribution.

In randomized experiments, Fisher-exact P values are available and should be used to help evaluate results rather than the more commonly reported asymptotic P values. One reason is that using the latter can effectively alter the question being addressed by including irrelevant distributional assumptions. The Fisherian statistical framework, proposed in 1925, calculates a P value in a randomized experiment by using the actual randomization procedure that led to the observed data. Here, we illustrate this Fisherian framework in a crossover randomized experiment. First, we consider the first period of the experiment and analyze its data as a completely randomized experiment, ignoring the second period; then, we consider both periods. For each analysis, we focus on 10 outcomes that illustrate important differences between the asymptotic and Fisher tests for the null hypothesis of no ozone effect. For some outcomes, the traditional P value based on the approximating asymptotic Student's t distribution substantially subceeded the minimum attainable Fisher-exact P value. For the other outcomes, the Fisher-exact null randomization distribution substantially differed from the bell-shaped one assumed by the asymptotic t test. Our conclusions: When researchers choose to report P values in randomized experiments, 1) Fisher-exact P values should be used, especially in studies with small sample sizes, and 2) the shape of the actual null randomization distribution should be examined for the recondite scientific insights it may reveal.

Deep learning enables the automation of grading histological tissue engineered cartilage images for quality control standardization.

OBJECTIVE: To automate the grading of histological images of engineered cartilage tissues using deep learning. METHODS: Cartilaginous tissues were engineered from various cell sources. Safranin O and fast green stained histological images of the tissues were graded for chondrogenic quality according to the Modified Bern Score, which ranks images on a scale from zero to six according to the intensity of staining and cell morphology. The whole images were tiled, and the tiles were graded by two experts and grouped into four categories with the following grades: 0, 1-2, 3-4, and 5-6. Deep learning was used to train models to classify images into these histological score groups. Finally, the tile grades per donor were averaged. The root mean square errors (RMSEs) were calculated between each user and the model. RESULTS: Transfer learning using a pretrained DenseNet model was selected. The RMSEs of the model predictions and 95% confidence intervals were 0.49 (0.37, 0.61) and 0.78 (0.57, 0.99) for each user, which was in the same range as the inter-user RMSE of 0.71 (0.51, 0.93). CONCLUSION: Using supervised deep learning, we could automate the scoring of histological images of engineered cartilage and achieve results with errors comparable to inter-user error. Thus, the model could enable the automation and standardization of assessments currently used for experimental studies as well as release criteria that ensure the quality of manufactured clinical grafts and compliance with regulatory requirements.

Challenges and opportunities for artificial intelligence in oncological imaging.

Imaging plays a key role in oncology, including the diagnosis and detection of cancer, determining clinical management, assessing treatment response, and complications of treatment or disease. The current use of clinical oncology is predominantly qualitative in nature with some relatively crude size-based measurements of tumours for assessment of disease progression or treatment response; however, it is increasingly understood that there may be significantly more information about oncological disease that can be obtained from imaging that is not currently utilized. Artificial intelligence (AI) has the potential to harness quantitative techniques to improve oncological imaging. These may include improving the efficiency or accuracy of traditional roles of imaging such as diagnosis or detection. These may also include new roles for imaging such as risk-stratifying patients for different types of therapy or determining biological tumour subtypes. This review article outlines several major areas in oncological imaging where there may be opportunities for AI technology. These include (1) screening and detection of cancer, (2) diagnosis and risk stratification, (3) tumour segmentation, (4) precision oncology, and (5) predicting prognosis and assessing treatment response. This review will also address some of the potential barriers to AI research in oncological imaging.

Chromatic confocal displacement sensing at oblique incidence angles.

A commercial chromatic confocal displacement sensor, designed for probing a target at normal incidence, is adapted to probe reflective targets at an oblique incidence angle. The sensor is modified by positioning two low-cost optical elements-a collimating lens and a retro-reflector-in the reflection plane.

Automatic Staging of Cancer Tumors Using AIM Image Annotations and Ontologies.

A second opinion about cancer stage is crucial when clinicians assess patient treatment progress. Staging is a process that takes into account description, location, characteristics, and possible metastasis of tumors in a patient. It should follow standards, such as the TNM Classification of Malignant Tumors. However, in clinical practice, the implementation of this process can be tedious and error prone. In order to alleviate these problems, we intend to assist radiologists by providing a second opinion in the evaluation of cancer stage. For doing this, we developed a TNM classifier based on semantic annotations, made by radiologists, using the ePAD tool. It transforms the annotations (stored using the AIM format), using axioms and rules, into AIM4-O ontology instances. From then, it automatically calculates the liver TNM cancer stage. The AIM4-O ontology was developed, as part of this work, to represent annotations in the Web Ontology Language (OWL). A dataset of 51 liver radiology reports with staging data, from NCI's Genomic Data Commons (GDC), were used to evaluate our classifier. When compared with the stages attributed by physicians, the classifier stages had a precision of 85.7% and recall of 81.0%. In addition, 3 radiologists from 2 different institutions manually reviewed a random sample of 4 of the 51 records and agreed with the tool staging. AIM4-O was also evaluated with good results. Our classifier can be integrated into AIM aware imaging tools, such as ePAD, to offer a second opinion about staging as part of the cancer treatment workflow.

An evaluation of the implementation of a parent-led, games-based physical activity intervention: the Active Play at Home quasi-randomized trial.

Trial Registration: NCT02058342. Registered 6 February 2014 retrospectively registered.

Correction to: A Mixed Methods Evaluation of Early Childhood Abuse Prevention Within Evidence-Based Home Visiting Programs.

The article "A Mixed Methods Evaluation of Early Childhood Abuse Prevention Within Evidence-Based Home Visiting Programs", written by M. Matone, K. Kellom, H. Griffis, W. Quarshie, J. Faerber, P. Gierlach, J. Whittaker, D. M. Rubin and P. F. Cronholm, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 27 July 2018 to

A Mixed Methods Evaluation of Early Childhood Abuse Prevention Within Evidence-Based Home Visiting Programs.

Objectives In this large scale, mixed methods evaluation, we determined the impact and context of early childhood home visiting on rates of child abuse-related injury. Methods Entropy-balanced and propensity score matched retrospective cohort analysis comparing children of Pennsylvania Nurse-Family Partnership (NFP), Parents As Teachers (PAT), and Early Head Start (EHS) enrollees and children of Pennsylvania Medicaid eligible women from 2008 to 2014. Abuse-related injury episodes were identified in medical assistance claims with ICD-9 codes. Weighted frequencies and logistic regression odds of injury within 24 months are presented. In-depth interviews with staff and clients (n = 150) from 11 programs were analyzed using a modified grounded theory approach. Results The odds of a healthcare encounter for early childhood abuse among clients were significantly greater than comparison children (NFP: 1.32, 95% CI [1.08, 1.62]; PAT: 4.11, 95% CI [1.60, 10.55]; EHS: 3.15, 95% CI [1.41, 7.06]). Qualitative data illustrated the circumstances of and program response to client issues related to child maltreatment, highlighting the role of non-client caregivers. All stakeholders described curricular content aimed at prevention (e.g. positive parenting) with little time dedicated to addressing current or past abuse. Clients who reported a lack of abuse-related content supposed their home visitor's assumption of an absence of risk in their home, but were supportive of the introduction of abuse-related content. Approach, acceptance, and available resources were mediators of successfully addressing abuse. Conclusions for Practice Home visiting aims to prevent child abuse among high-risk families. Adequate home visitor capacity to proactively assess abuse risk, deliver effective preventive curriculum with fidelity to caregivers, and access appropriate resources is necessary.

[Nephrotic syndrome and microhematuria in a patient with nutcracker syndrome: Report of a case and review of the literature]. / Nephrotisches Syndrom und Mikrohämaturie bei einer Patientin mit Nussknacker-Syndrom: Ein Fallbericht mit Literaturübersicht.

We report about a 43-year-old woman with polyvalent drug addiction (i.e. alcohol, nicotine, methadone maintenance program with parallel consumption of heroin) who presented to the emergency department with peripheral edema, generalized weakness, and arthralgia. Laboratory findings revealed, among others, proteinuria, hyperlipoproteinemia and hypoproteinemia defining nephrotic syndrome. Computed tomography of the abdomen and iliocavography further revealed compression of left renal vein between aorta and superior mesenteric artery with distention of left ovarian vein as a possible cause of nephrotic syndrome (i. e. nutcracker syndrome). After excluding other possible causes of nephrotic syndrome, we decided against an interventional procedure due to poor compliance of the patient and potential risk of secondary stent dislocation. Instead, we opted for a surgical approach (i. e. veno-venous bypass, meaning transposition of left vena ovarica on vena cava inferior). The operative and postoperative course was uneventful. Postoperatively, proteinuria, microhematuria, arthralgia and edema receded.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Robust estimation of causal effects of binary treatments in unconfounded studies with dichotomous outcomes.

The estimation of causal effects has been the subject of extensive research. In unconfounded studies with a dichotomous outcome, Y, Cangul, Chretien, Gutman and Rubin (2009) demonstrated that logistic regression for a scalar continuous covariate X is generally statistically invalid for testing null treatment effects when the distributions of X in the treated and control populations differ and the logistic model for Y given X is misspecified. In addition, they showed that an approximately valid statistical test can be generally obtained by discretizing X followed by regression adjustment within each interval defined by the discretized X. This paper extends the work of Cangul et al. 2009 in three major directions. First, we consider additional estimation procedures, including a new one that is based on two independent splines and multiple imputation; second, we consider additional distributional factors; and third, we examine the performance of the procedures when the treatment effect is non-null. Of all the methods considered and in most of the experimental conditions that were examined, our proposed new methodology appears to work best in terms of point and interval estimation.

A common haplotype of carnitine palmitoyltransferase 1b is associated with the metabolic syndrome.

The carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into mitochondria to provide substrates for ß-oxidation. We performed an analysis including three coding SNP in the muscle isoform of the CPT1b gene (rs3213445, rs2269383 and rs470117) and one coding SNP in the CPT2 gene (rs1799821) to find associations with traits of the metabolic syndrome (MetS). Male participants (n 755) from the Metabolic Intervention Cohort Kiel were genotyped and phenotyped for features of the MetS. Participants underwent a glucose tolerance test and a postprandial assessment of metabolic variables after a standardised mixed meal. Carriers of the rare CPT1b 66V (rs3213445) allele had significantly higher γ-glutamyl transpeptidase (GGT), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT) activities (P< 0·0001, P= 0·03 and P= 0·048, respectively) and a higher fatty liver index (FLI, P= 0·026). Fasting and postprandial TAG (P= 0·007 and P= 0·009, respectively) and fasting glucose (P= 0·012) were significantly higher in 66V-allele carriers. The insulin sensitivity index determined after a glucose load was lower in those subjects (P= 0·005). Total cholesterol (P= 0·051) and LDL-cholesterol (P= 0·062) tended to be higher in 66V-allele carriers when compared with I66I homozygotes. Homozygosity of the rare K531E allele presented with lower GGT and GOT activities (P= 0·011 and P= 0·027, respectively). E531E homozygotes tended to have lower GPT and FLI (P= 0·078 and P= 0·052, respectively). CPT2 V368I (rs1799821) genotypic groups did not differ in the investigated anthropometric and metabolic parameters. The present results confirm the association of CPT1b coding polymorphisms with the MetS, with a deleterious effect of the CPT1b I66V and a protective impact of the CPT1b K531E SNP, whereas haplotype analysis indicates a relevance of the E531K polymorphism only.

The effect of perches in cages during pullet rearing and egg laying on hen performance, foot health, and plumage.

Enrichment of pullet cages with perches has not been studied. Our objective was to determine if access to metal perches during all or part of the life cycle of caged White Leghorns affected egg traits, foot health, and feather condition. Treatment 1 represented control chickens that never had access to perches during their life cycle. Treatment 2 hens had perches only during the egg laying phase of the life cycle (17 to 71 wk of age), whereas treatment 3 chickens had perches during the pullet phase (0 to 16.9 wk of age). Treatment 4 chickens always had access to perches (0 to 71 wk of age). Comparisons between chickens that always had perches with controls that never had perches showed similar performance relative to egg production, cracked eggs, egg weight, shell weight, % shell, and shell thickness. More dirty eggs occurred in laying cages with perches. Feed usage increased resulting in poorer feed efficiency in hens with perch exposure during the pullet phase with no effect during egg laying. Perches did not affect hyperkeratosis of toes and feet. The back claw at 71 wk of age broke less if hens had prior experience with perches during the pullet phase. In contrast, during egg laying, the back claw at 71 wk of age broke more due to the presence of perches in laying cages. Perches in laying cages resulted in shorter trimmed claws and improved back feather scores, but caused poorer breast and tail feather scores. In conclusion, enriching conventional cages with perches during the entire life cycle resulted in similar hen performance compared with controls. Fewer broken back claws but poorer feed efficiency occurred because of prior experience with perches as pullets. Perch presence during egg laying improved back feather scores with more trimmed nails but caused more dirty eggs, broken back claws, and poorer breast and tail feather scores. Although perches allow chickens to express their natural perching instinct, it was not without causing welfare problems.

The effect of perch availability during pullet rearing and egg laying on musculoskeletal health of caged White Leghorn hens.

A major skeletal problem of conventionally caged hens is increased susceptibility to osteoporosis mainly due to lack of exercise. Osteoporosis is characterized by a progressive decrease in mineralized structural bone. Whereas considerable attention has been given to enriching laying cages, little research has been conducted on providing caged pullets with furnishments, in particular perches. The objective of the current study was to determine if metal perches during all or part of the life cycle of White Leghorns affected hen musculoskeletal health, especially at end of lay. Treatments during the pullet phase (hatch to 16.9 wk) entailed cages with and without perches. Four treatments were used during the laying phase (17 to 71 wk of age). Treatment 1 chickens never had access to perches at any point during their life cycle, typical of egg industry practices in the United States for conventional cages. Treatment 2 chickens had access to perches only during the egg-laying phase, which was from 17 to 71 wk of age. Treatment 3 chickens had access to perches only during the pullet phase (0 to 16.9 wk of age). Treatment 4 chickens had perch access throughout their entire life cycle (0 to 71 wk of age). Musculoskeletal health was assessed by measuring muscle weights, bone mineralization, bone fracture incidence, and keel bone deviations. Muscle deposition of 71-wk-old hens increased when given access to perches as pullets. Bone mineralization of 71-wk-old hens also increased if given perch access as adults. However, the disadvantage of the adult perch was the higher incidence of keel deviations and keel fractures at end of lay. The increase in bone mineralization of the keel bone as a result of perch access during the pullet and laying phases was not great enough to prevent a higher incidence of keel bone fractures at end of lay. Perch redesign and placement of perches within the cage to minimize keel fractures and deviations are possible solutions.

High-dimensional randomization-based inference capitalizing on classical design and modern computing.

A common complication that can arise with analyses of high-dimensional data is the repeated use of hypothesis tests. A second complication, especially with small samples, is the reliance on asymptotic p-values. Our proposed approach for addressing both complications uses a scientifically motivated scalar summary statistic, and although not entirely novel, seems rarely used. The method is illustrated using a crossover study of seventeen participants examining the effect of exposure to ozone versus clean air on the DNA methylome, where the multivariate outcome involved 484,531 genomic locations. Our proposed test yields a single null randomization distribution, and thus a single Fisher-exact p-value that is statistically valid whatever the structure of the data. However, the relevance and power of the resultant test requires the careful a priori selection of a single test statistic. The common practice using asymptotic p-values or meaningless thresholds for "significance" is inapposite in general.

Choice and doses of antibacterial agents for cement spacers in treatment of prosthetic joint infections: review of published studies.

BACKGROUND: Addition of antibacterial drugs to interim antibacterial cement spacers (ACSs) is considered to be standard of care for surgical revision in prosthetic joint infections (PJIs). We reviewed published studies evaluating the choice and doses of antibacterials in spacers. METHODS: We conducted a PubMed search of all clinical study reports evaluating the use of ACSS in a 2-stage hip or knee arthroplasty for treatment of PJI (1988 through August 2011). The trial design, antibacterials used, and end points studied were analyzed. RESULTS: No randomized trials were found comparing either ACSs with different concentrations of antibacterials or ACSs with or without antibacterials. Most of the studies were uncontrolled and used various time points to evaluate the outcome. Twenty publications that reported doses of antibacterials in spacers and had a follow-up of ≥ 24 months after the second stage were selected for review. Most ACSs included vancomycin and aminoglycosides. The doses of aminoglycosides and vancomycin ranged from 0.25 to 4.8 g and from 1 to 4 g, respectively, per 4 g of cement. No association between reported eradication of the infection and antibacterial load was found. CONCLUSIONS: Published data do not allow evaluation of whether antibacterials in temporary cement spacers provide additional benefits in the treatment of PJI, compared with systemic antibacterials, and are not sufficient to support recommendations on dosages. Complications of ACSs have not been consistently analyzed. Prospective randomized trials comparing spacers with and without antibacterials or spacers with different loads of antibacterials are needed to evaluate the safety and efficacy of ACSs.

Testosterone responses to intensive interval versus steady-state endurance exercise.

Free testosterone (FT) hormonal responses were compared between high-intensity interval exercise (IE) and steadystate endurance exercise (SSE) in endurance trained males (no.=15). IE session was repeated periods of 90-sec treadmill running at 100-110% maximal oxygen uptake (VO2max) and 90-sec active recovery at 40% VO2max for 42-47 min. The SSE session consisted of a continuous 45-min run at 60-65% VO2max. Total work output was equal for each exercise session. A 45-min supine rest control session (CON) was also performed. All three sessions were on separate days. Pre-session (PRE), immediate post-session (POST), and 12-h post-session (12POST) blood samples were collected and used to determine FT, SHBG, LH, 3- α-androstanediol glucuronide (3-α Diol G) and cortisol. Analysis of variance compared IE and SSE biomarker responses to the reference CON session. IE and SSE each caused an increase (p<0.01) in FT, but IE more so than SSE (p<0.05). The 5α-reductase marker 3-α Diol G response at 12POST IE was elevated while FT was reduced (p<0.05); no such change occurred following SSE. These findings suggest IE might produce a more pronounced turnover of FT by androgen sensitive tissue than the SSE form of exercise.

Early access to perches in caged White Leghorn pullets.

Osteoporosis, a progressive decrease in mineralized structural bone, causes 20 to 35% of all mortalities in caged White Leghorn hens. Previous research has focused on manipulating the egg laying environment to improve skeletal health, with little research on the pullet. The objective of the current study was to determine the effect of perch access on pullet health, bone mineralization, muscle deposition, and stress in caged White Leghorns. From 0 to 17 wk of age, half of the birds were placed in cages with 2 round metal perches, while the other half did not have perches (controls). Bone mineralization and bone size traits were determined in the tibia, femur, sternum, humerus, ulna, radius, and phalange (III carpometacarpal) using dual energy x-ray absorptiometry. Muscle weights were obtained for the breast and left leg (drum and thigh). A sample of pullets from each cage was evaluated for foot health, BW, right adrenal weight, and packed cell volume. Most measurements were taken at 3, 6, and 12 wk of age. Access to perches did not affect breast muscle weight, percentage breast muscle, percentage leg muscle, bone mineral density, bone length, bone width, adrenal weight, packed cell volume, and hyperkeratosis of the foot-pad and toes. There were no differences in BW, bone mineral content, and leg muscle weight at 3 and 6 wk of age. However, at 12 wk of age, BW (P = 0.025), bone mineral content of the tibia, sternum, and humerus (P = 0.015), and the left leg muscle weight (P = 0.006) increased in pullets with access to perches as compared with controls. These results suggest that perch access has beneficial effects on pullet health by stimulating leg muscle deposition and increasing the mineral content of certain bones without causing a concomitant decrease in bone mineral density.