Artificial Intelligence: Guidance for clinical imaging and therapeutic radiography professionals, a summary by the Society of Radiographers AI working group.

INTRODUCTION: Artificial intelligence (AI) has started to be increasingly adopted in medical imaging and radiotherapy clinical practice, however research, education and partnerships have not really caught up yet to facilitate a safe and effective transition. The aim of the document is to provide baseline guidance for radiographers working in the field of AI in education, research, clinical practice and stakeholder partnerships. The guideline is intended for use by the multi-professional clinical imaging and radiotherapy teams, including all staff, volunteers, students and learners. METHODS: The format mirrored similar publications from other SCoR working groups in the past. The recommendations have been subject to a rapid period of peer, professional and patient assessment and review. Feedback was sought from a range of SoR members and advisory groups, as well as from the SoR director of professional policy, as well as from external experts. Amendments were then made in line with feedback received and a final consensus was reached. RESULTS: AI is an innovative tool radiographers will need to engage with to ensure a safe and efficient clinical service in imaging and radiotherapy. Educational provisions will need to be proportionately adjusted by Higher Education Institutions (HEIs) to offer the necessary knowledge, skills and competences for diagnostic and therapeutic radiographers, to enable them to navigate a future where AI will be central to patient diagnosis and treatment pathways. Radiography-led research in AI should address key clinical challenges and enable radiographers co-design, implement and validate AI solutions. Partnerships are key in ensuring the contribution of radiographers is integrated into healthcare AI ecosystems for the benefit of the patients and service users. CONCLUSION: Radiography is starting to work towards a future with AI-enabled healthcare. This guidance offers some recommendations for different areas of radiography practice. There is a need to update our educational curricula, rethink our research priorities, forge new strong clinical-academic-industry partnerships to optimise clinical practice. Specific recommendations in relation to clinical practice, education, research and the forging of partnerships with key stakeholders are discussed, with potential impact on policy and practice in all these domains. These recommendations aim to serve as baseline guidance for UK radiographers. IMPLICATIONS FOR PRACTICE: This review offers the most up-to-date recommendations for clinical practitioners, researchers, academics and service users of clinical imaging and therapeutic radiography services. Radiography practice, education and research must gradually adjust to AI-enabled healthcare systems to ensure gains of AI technologies are maximised and challenges and risks are minimised. This guidance will need to be updated regularly given the fast-changing pace of AI development and innovation.

Outbreak-Based Giardia Dose-Response Model Using Bayesian Hierarchical Markov Chain Monte Carlo Analysis.

Giardia is a zoonotic gastrointestinal parasite responsible for a substantial global public health burden, and quantitative microbial risk assessment (QMRA) is often used to forecast and manage this burden. QMRA requires dose-response models to extrapolate available dose-response data, but the existing model for Giardia ignores valuable dose-response information, particularly data from several well-documented waterborne outbreaks of giardiasis. The current study updates Giardia dose-response modeling by synthesizing all available data from outbreaks and experimental studies using a Bayesian random effects dose-response model. For outbreaks, mean doses (D) and the degree of spatial and temporal aggregation among cysts were estimated using exposure assessment implemented via two-dimensional Monte Carlo simulation, while potential overreporting of outbreak cases was handled using published overreporting factors and censored binomial regression. Parameter estimation was by Markov chain Monte Carlo simulation and indicated that a typical exponential dose-response parameter for Giardia is r = 1.6 × 10-2 [3.7 × 10-3 , 6.2 × 10-2 ] (posterior median [95% credible interval]), while a typical morbidity ratio is m = 3.8 × 10-1 [2.3 × 10-1 , 5.5 × 10-1 ]. Corresponding (logistic-scale) variance components were σr = 5.2 × 10-1 [1.1 × 10-1 , 9.6 × 10-1 ] and σm = 9.3 × 10-1 [7.0 × 10-2 , 2.8 × 100 ], indicating substantial variation in the Giardia dose-response relationship. Compared to the existing Giardia dose-response model, the current study provides more representative estimation of uncertainty in r and novel quantification of its natural variability. Several options for incorporating variability in r (and m) into QMRA predictions are discussed, including incorporation via Monte Carlo simulation as well as evaluation of the current study's model using the approximate beta-Poisson.

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells.

Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Here, we further study the parthenolide mechanism of action using activity-based protein profiling-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactone-containing sesquiterpenes, covalently modify cysteine 427 of focal adhesion kinase 1 (FAK1), leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility. These studies reveal a functional target exploited by members of a large family of anti-cancer natural products.

Home Environment-Focused Intervention Improves Dietary Quality: A Secondary Analysis From the Healthy Homes/Healthy Families Randomized Trial.

OBJECTIVE: Estimate Healthy Homes/Healthy Families (HHHF) intervention efficacy for improving dietary quality. METHODS: Low-income overweight and obese women (n = 349) recruited from rural community health centers were randomized to receive HHHF, a 16-week home environment-focused coaching intervention or health education materials by mail. Healthy Eating Index-2010 scores were calculated from 2 24-hour dietary recalls collected at baseline and 6- and 12-month follow-up. RESULTS: HHHF participants reported greater improvements in Healthy Eating Index-2010 total scores at 6-month follow-up (+3.41 ± 13.43 intervention vs +2.02 ± 12.26 control; P =.009). Subcomponent analysis indicated greater consumption of total vegetables (P = .02) and greens and beans (P = .001), whole grains (P = .02) and reduced consumption of empty calories (P = .03). Standardized intervention effect sizes were 0.16 at 6 months and 0.13 at 12 months of follow-up. CONCLUSIONS AND IMPLICATIONS: The HHHF resulted in short-term improvements in dietary quality, although more research is needed to interpret the clinical significance of effect sizes of this magnitude.

Fate of Manure-Borne Pathogens during Anaerobic Digestion and Solids Separation.

Anaerobic digestion can inactivate zoonotic pathogens present in cattle manure, which reduces transmission of these pathogens from farms to humans through the environment. However, the variability of inactivation across farms and over time is unknown because most studies have examined pathogen inactivation under ideal laboratory conditions or have focused on only one or two full-scale digesters at a time. In contrast, we sampled seven full-scale digesters treating cattle manure in Wisconsin for 9 mo on a biweekly basis ( = 118 pairs of influent and effluent samples) and used real-time quantitative polymerase chain reaction to analyze these samples for 19 different microbial genetic markers. Overall, inactivation of pathogens and fecal indicators was highly variable. When aggregated across digester and season, log-removal values for several representative microorganisms-bovine , -like CowM3, and bovine polyomavirus-were 0.78 ± 0.34, 0.70 ± 0.50, and 0.53 ± 0.58, respectively (mean ± SD). These log-removal values were up to two times lower than expected based on the scientific literature. Thus, our study indicates that full-scale anaerobic digestion of cattle manure requires optimization with regard to pathogen inactivation. Future studies should focus on identifying the potential causes of this suboptimal performance (e.g., overloading, poor mixing, poor temperature control). Our study also examined the fate of pathogens during manure separation and found that the majority of microbes we detected ended up in the liquid fraction of separated manure. This finding has important implications for the transmission of zoonotic pathogens through the environment to humans.

Effects of a transition home program on preterm infant emergency room visits within 90 days of discharge.

OBJECTIVE: To evaluate effects of a transition home program (THP) and risk factors on emergency room (ER) use within 90 days of discharge for preterm (PT) infants <37 weeks gestation. STUDY DESIGN: This is a prospective 3-year cohort study of 804 mothers and 954 PT infants. Mothers received enhanced neonatal intensive care unit transition support services until 90 days postdischarge. Regression models were run to identify the effects of THP implementation year and risk factors on ER visits. RESULTS: Of the 954 infants, 181 (19%) had ER visits and 83/181 (46%) had an admission. In regression analysis, THP year 3 vs year 1 and human milk at discharge were associated with decreased risk of ER visits, whereas increased odds was associated with non-English speaking, maternal mental health disorders and bronchopulmonary dysplasia. CONCLUSION: Enhanced THP services were associated with a 33% decreased risk of all ER visits by year 3. Social and environmental risk factors contribute to preventable ER visits.

Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products.

Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, and in vivo tumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy.

Chemoproteomic Screening of Covalent Ligands Reveals UBA5 As a Novel Pancreatic Cancer Target.

Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy. Through this coupled approach, we have discovered a covalent ligand DKM 2-93 that impairs pancreatic cancer cell survival and in vivo tumor growth through covalently modifying the catalytic cysteine of the ubiquitin-like modifier activating enzyme 5 (UBA5), thereby inhibiting its activity as a protein that activates the ubiquitin-like protein UFM1 to UFMylate proteins. We show that UBA5 is a novel pancreatic cancer therapeutic target and show DKM 2-93 as a relatively selective lead inhibitor of UBA5. Our results underscore the utility of coupling the screening of covalent ligand libraries with isoTOP-ABPP platforms for mining the proteome for druggable hotspots for cancer therapy.

Are gait characteristics and ground reaction forces related to energy cost of running in elite Kenyan runners?

The aim of this study was to determine whether gait cycle characteristics are associated with running economy in elite Kenyan runners. Fifteen elite Kenyan male runners completed two constant-speed running sets on a treadmill (12 km ·h-1 and 20 km ·h-1). VO2 and respiratory exchange ratio values were measured to calculate steady-state oxygen and energy cost of running. Gait cycle characteristics and ground contact forces were measured at each speed. Oxygen cost of running at different velocities was 192.2 ± 14.7 ml· kg-1· km-1 at 12 km· h-1 and 184.8 ± 9.9 ml· kg-1· km-1 at 20 km· h-1, which corresponded to a caloric cost of running of 0.94 ± 0.07 kcal ·kg-1·km-1 and 0.93 ± 0.07 kcal· kg-1· km-1. We found no significant correlations between oxygen and energy cost of running and biomechanical variables and ground reaction forces at either 12 or 20 km· h-1. However, ground contact times were ~10.0% shorter (very large effect) than in previously published literature in elite runners at similar speeds, alongside an 8.9% lower oxygen cost (very large effect). These results provide evidence to hypothesise that the short ground contact times may contribute to the exceptional running economy of Kenyan runners.

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.

Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways.

The neonatal preventable harm index: a high reliability tool.

OBJECTIVE: The aim of this study is to identify, quantify and disseminate a novel set of safety indicators for monitoring the occurrence of preventable harm in the neonatal intensive care unit (NICU). STUDY DESIGN: Literature review and experiences in an academic, level IV NICU identified prevalent, preventable safety events: hospital-acquired infections (catheter-associated bloodstream infection, ventilator-associated pneumonia), unscheduled extubations, intravenous infiltrates requiring intervention, first week readmissions, serious adverse drug events and miscellaneous events (unanticipated harm or serious near misses). Negative binominal regression evaluated the event incidence trends. RESULTS: Of 226 preventable harm events occurring between March 2013 and January 2015, the most common were unscheduled extubations (98; 2/100 ventilator days) and intravenous infiltrates (62; 2.7/100 admissions). No trends were detected (rate ratio: 0.99; confidence limits: 0.96 to 1.01; P=0.38). CONCLUSION: The Neonatal Preventable Harm Index represents a novel and transparent means to monitor serious safety events and direct harm prevention strategies in the NICU.

Determining the 95% limit of detection for waterborne pathogen analyses from primary concentration to qPCR.

The limit of detection (LOD) for qPCR-based analyses is not consistently defined or determined in studies on waterborne pathogens. Moreover, the LODs reported often reflect the qPCR assay alone rather than the entire sample process. Our objective was to develop an approach to determine the 95% LOD (lowest concentration at which 95% of positive samples are detected) for the entire process of waterborne pathogen detection. We began by spiking the lowest concentration that was consistently positive at the qPCR step (based on its standard curve) into each procedural step working backwards (i.e., extraction, secondary concentration, primary concentration), which established a concentration that was detectable following losses of the pathogen from processing. Using the fraction of positive replicates (n = 10) at this concentration, we selected and analyzed a second, and then third, concentration. If the fraction of positive replicates equaled 1 or 0 for two concentrations, we selected another. We calculated the LOD using probit analysis. To demonstrate our approach we determined the 95% LOD for Salmonella enterica serovar Typhimurium, adenovirus 41, and vaccine-derived poliovirus Sabin 3, which were 11, 12, and 6 genomic copies (gc) per reaction (rxn), respectively (equivalent to 1.3, 1.5, and 4.0 gc L(-1) assuming the 1500 L tap-water sample volume prescribed in EPA Method 1615). This approach limited the number of analyses required and was amenable to testing multiple genetic targets simultaneously (i.e., spiking a single sample with multiple microorganisms). An LOD determined this way can facilitate study design, guide the number of required technical replicates, aid method evaluation, and inform data interpretation.

Human and Bovine Viruses and Bacteria at Three Great Lakes Beaches: Environmental Variable Associations and Health Risk.

Waterborne pathogens were measured at three beaches in Lake Michigan, environmental factors for predicting pathogen concentrations were identified, and the risk of swimmer infection and illness was estimated. Waterborne pathogens were detected in 96% of samples collected at three Lake Michigan beaches in summer, 2010. Samples were quantified for 22 pathogens in four microbial categories (human viruses, bovine viruses, protozoa, and pathogenic bacteria). All beaches had detections of human and bovine viruses and pathogenic bacteria indicating influence of multiple contamination sources at these beaches. Occurrence ranged from 40 to 87% for human viruses, 65-87% for pathogenic bacteria, and 13-35% for bovine viruses. Enterovirus, adenovirus A, Salmonella spp., Campylobacter jejuni, bovine polyomavirus, and bovine rotavirus A were present most frequently. Variables selected in multiple regression models used to explore environmental factors that influence pathogens included wave direction, cloud cover, currents, and water temperature. Quantitative Microbial Risk Assessment was done for C. jejuni, Salmonella spp., and enteroviruses to estimate risk of infection and illness. Median infection risks for one-time swimming events were approximately 2 × 10(-5), 8 × 10(-6), and 3 × 10(-7) [corrected] for C. jejuni, Salmonella spp., and enteroviruses, respectively. Results highlight the importance of investigating multiple pathogens within multiple categories to avoid underestimating the prevalence and risk of waterborne pathogens.

Radiographic, computed tomographic and surgical anatomy of the equine sphenopalatine sinus in normal and diseased horses.

REASONS FOR PERFORMING STUDY: Knowledge of imaging anatomy, surgical anatomy and disorders affecting the sphenopalatine sinus are currently lacking. OBJECTIVES: To describe the computed tomographic (CT) and surgical anatomy of the sphenopalatine sinus and diagnosis, treatment and outcome in clinical cases with sphenopalatine sinus disease. STUDY DESIGN: Cadaver observational study and retrospective case series. METHODS: The sphenopalatine sinuses of 10 normal cadaver heads were examined with digital radiography, CT and sinoscopic examination prior to anatomical sectioning. Sphenopalatine sinus anatomy was described and compared between cadaver specimens across the imaging modalities. Medical records (January 2004-2014) of cases diagnosed with sphenopalatine sinus disease were reviewed. RESULTS: The anatomy of the sphenopalatine sinus was variable. The borders of the sphenopalatine sinus were not identifiable on plain radiographs, whereas CT provided useful anatomical information. The palatine portion of the sphenopalatine sinus was consistently accessible sinoscopically and the sphenoidal portion was accessible in 6/10 cadaver heads. Fourteen cases of sphenopalatine sinus disease were identified, presenting with one or more clinical signs of exophthalmos, blindness, unilateral epistaxis or unilateral nasal discharge. Diagnoses included neoplasia (7), progressive ethmoidal haematoma (4), sinus cyst (2) and empyema (1). Computed tomography provided diagnostic information but could not differentiate the nature of soft tissue masses. Standing sinoscopic access to the palatine portion of the sphenopalatine sinus was possible for evaluation, biopsy and resection of abnormal soft tissues. Surgical access to the sphenoidal portion was limited. Eight horses were alive at 1 year after diagnosis, with a worse outcome associated with CT evidence of bone loss and a diagnosis of neoplasia. CONCLUSIONS: Sphenopalatine sinus disease should be considered a rare cause of the clinical signs described. Knowledge of the anatomical variation of the sphenopalatine sinus is vital for interpreting CT images. A combination of CT and sinoscopy provides the most comprehensive approach for diagnosis and treatment of sphenopalatine sinus disease.

Lumbosacral foraminal ratios and areas using MRI in medium-sized dogs.

OBJECTIVE: To examine conventional magnetic resonance imaging planes of the lumbosacral foramina to obtain objective measurements of foraminal size in medium-sized (20-28 kg) normal dogs. METHOD: Ten canine cadavers were evaluated using magnetic resonance imaging in neutral, flexed and extended position. Foraminal ratios, areas and lumbosacral angles were calculated and their relationship to body weight was evaluated. RESULTS: Foraminal ratios were found to be independent of body weight in medium sized dogs (p >0.42). Foraminal areas were dependent on body weight (p <0.05). Flexion and extension were shown to significantly change both the foraminal ratio and area. CLINICAL SIGNIFICANCE: Lumbosacral foraminal stenosis is common in working dogs. Foraminal ratios were evaluated in medium-sized dogs and were found to be independent of body weight, which may provide objective evaluation of surgical decompression techniques if calculated pre- and post-surgery. Foraminal areas were not independent of body weight.

Blood urea nitrogen and serum bicarbonate in extremely low birth weight infants receiving higher protein intake in the first week after birth.

OBJECTIVE: To determine correlation between early protein administration and serum blood urea nitrogen (BUN) or bicarbonate (HCO(3)(-)) in extremely low birth weight (ELBW) infants during the first week of life. STUDY DESIGN: A retrospective review of 154 ELBWs was conducted. Laboratory and nutritional data from postnatal days 1, 4 and 7 were collected. Repeated measures models estimated the relationship of protein intake with BUN and HCO(3)(-) in the first week of life. RESULT: In total, 359 separate BUN and HCO(3)(-) values were analyzed. Each gram per kilogram of protein administered was associated with an increase in mean BUN of 3.3 mg/dl. This effect decreased daily by 2.1 mg/dl. Each gram per kilogram of protein administered was associated with a decrease in mean HCO(3)(-) by 0.9 mmol/l. CONCLUSION: The association between protein load and BUN is positive but decreasing over time. Protein is associated with a clinically insignificant decrease in HCO(3)(-). Concerns regarding metabolic derangement from early protein administration in ELBWs are unwarranted.

Tenascins and their implications in diseases and tissue mechanics.

Tenascins are glycoproteins found in the extracellular matrix (ECM) of many tissues. Their role is not only to support the tissue structurally but also to regulate the fate of the different cell types populating the ECM. For instance, tenascins are required when active tissue modeling during embryogenesis or re-modeling after injury occurs. Interestingly, the four members of the tenascin family, tenascin-C, -X, -R and -W, show different and often mutually exclusive expression patterns. As a consequence, these structurally related proteins display distinct functions and are associated with distinct pathologies. The present review aims at presenting the four members of the tenascin family with respect to their structure, expression patterns and implications in diseases and tissue mechanics.

Fluid regimens in the first week of life may increase risk of patent ductus arteriosus in extremely low birth weight infants.

BACKGROUND: High fluid volumes may increase neonatal morbidity. However, evidence supporting fluid restriction is inconclusive and restricting fluids may restrict caloric intake. OBJECTIVE: To determine if higher fluid intake was associated with increased risk of patent ductus arteriosus (PDA) or bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. STUDY DESIGN: A total of 204 ELBW (170 ml kg(-1) day(-1)) in the first days of life is associated with increased risk of PDA.

Phylogenetic analysis of the tenascin gene family: evidence of origin early in the chordate lineage.

BACKGROUND: Tenascins are a family of glycoproteins found primarily in the extracellular matrix of embryos where they help to regulate cell proliferation, adhesion and migration. In order to learn more about their origins and relationships to each other, as well as to clarify the nomenclature used to describe them, the tenascin genes of the urochordate Ciona intestinalis, the pufferfish Tetraodon nigroviridis and Takifugu rubripes and the frog Xenopus tropicalis were identified and their gene organization and predicted protein products compared with the previously characterized tenascins of amniotes. RESULTS: A single tenascin gene was identified in the genome of C. intestinalis that encodes a polypeptide with domain features common to all vertebrate tenascins. Both pufferfish genomes encode five tenascin genes: two tenascin-C paralogs, a tenascin-R with domain organization identical to mammalian and avian tenascin-R, a small tenascin-X with previously undescribed GK repeats, and a tenascin-W. Four tenascin genes corresponding to tenascin-C, tenascin-R, tenascin-X and tenascin-W were also identified in the X. tropicalis genome. Multiple sequence alignment reveals that differences in the size of tenascin-W from various vertebrate classes can be explained by duplications of specific fibronectin type III domains. The duplicated domains are encoded on single exons and contain putative integrin-binding motifs. A phylogenetic tree based on the predicted amino acid sequences of the fibrinogen-related domains demonstrates that tenascin-C and tenascin-R are the most closely related vertebrate tenascins, with the most conserved repeat and domain organization. Taking all lines of evidence together, the data show that the tenascins referred to as tenascin-Y and tenascin-N are actually members of the tenascin-X and tenascin-W gene families, respectively. CONCLUSION: The presence of a tenascin gene in urochordates but not other invertebrate phyla suggests that tenascins may be specific to chordates. Later genomic duplication events led to the appearance of four family members in vertebrates: tenascin-C, tenascin-R, tenascin-W and tenascin-X.

Guided tissue regeneration for periodontal infra-bony defects.

BACKGROUND: Conventional treatment of destructive periodontal (gum) disease arrests the disease but does not usually regain the bone support or connective tissue lost in the disease process. Guided tissue regeneration (GTR) is a surgical procedure that specifically aims to regenerate the periodontal tissues when the disease is advanced and could overcome some of the limitations of conventional therapy. OBJECTIVES: To assess the efficacy of GTR in the treatment of periodontal infra-bony defects measured against conventional surgery (open flap debridement (OFD)) and factors affecting outcomes. SEARCH STRATEGY: We conducted an electronic search of the Cochrane Oral Health Group Trials Register, MEDLINE and EMBASE up to April 2004. Handsearching included Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research and bibliographies of all relevant papers and review articles up to April 2004. In addition, we contacted experts/groups/companies involved in surgical research to find other trials or unpublished material or to clarify ambiguous or missing data and posted requests for data on two periodontal electronic discussion groups. SELECTION CRITERIA: Randomised, controlled trials (RCTs) of at least 12 months duration comparing guided tissue regeneration (with or without graft materials) with open flap debridement for the treatment of periodontal infra-bony defects. Furcation involvements and studies specifically treating aggressive periodontitis were excluded. DATA COLLECTION AND ANALYSIS: Screening of possible studies and data extraction was conducted independently. The methodological quality of studies was assessed in duplicate using individual components and agreement determined by Kappa scores. Methodological quality was used in sensitivity analyses to test the robustness of the conclusions. The Cochrane Oral Health Group statistical guidelines were followed and the results expressed as mean differences (MD and 95% CI) for continuous outcomes and risk ratios (RR and 95% CI) for dichotomous outcomes calculated using random-effects models. Any heterogeneity was investigated. The primary outcome measure was change in clinical attachment. MAIN RESULTS: The search produced 626 titles, of these 596 were clearly not relevant to the review. The full text of 32 studies of possible relevance was obtained and 15 studies were excluded. Therefore 17 RCTs were included in this review, 16 studies testing GTR alone and two testing GTR+bone substitutes (one study had both test treatment arms).No tooth loss was reported in any study although these data are incomplete where patient follow up was not complete. For attachment level change, the mean difference between GTR and OFD was 1.22 mm (95% CI Random Effects: 0.80 to 1.64, chi squared for heterogeneity 69.1 (df = 15), P < 0.001, I(2) = 78%) and for GTR + bone substitutes was 1.25 mm (95% CI 0.89 to 1.61, chi squared for heterogeneity 0.01 (df = 1), P = 0.91). GTR showed a significant benefit when comparing the numbers of sites failing to gain 2 mm attachment with risk ratio 0.54 (95% CI Random Effects: 0.31 to 0.96, chi squared for heterogeneity 8.9 (df = 5), P = 0.11). The number needed to treat (NNT) for GTR to achieve one extra site gaining 2 mm or more attachment over open flap debridement was therefore 8 (95% CI 5 to 33), based on an incidence of 28% of sites in the control group failing to gain 2 mm or more of attachment. For baseline incidences in the range of the control groups of 3% and 55% the NNTs are 71 and 4. Probing depth reduction was greater for GTR than OFD: 1.21 mm (95% CI 0.53 to 1.88, chi squared for heterogeneity 62.9 (df = 10), P < 0.001, I(2) = 84%) or GTR + bone substitutes, weighted mean difference 1.24 mm (95% CI 0.89 to 1.59, chi squared for heterogeneity 0.03 (df = 1), P = 0.85). For gingival recession, a statistically significant difference between GTR and open flap debridement controls was evident (mean difference 0.26 mm (95% CI Random Effects: 0.08, 0.43, chi squared for heterogeneity 2.7 (df = 8), P = 0.95), with a greater change in recession from baseline for the control group. Regarding hard tissue probing at surgical re-entry, a statistically significant greater gain was found for GTR compared with open flap debridement. This amounted to a weighted mean difference of 1.39 mm (95% CI 1.08 to 1.71, chi squared for heterogeneity 0.85 (df = 2), P = 0.65). For GTR + bone substitutes the difference was greater, with mean difference 3.37 mm (95% CI 3.14 to 3.61). Adverse effects were generally minor although with an increased treatment time for GTR. Exposure of the barrier membrane was frequently reported with a lack of evidence of an effect on healing. AUTHORS' CONCLUSIONS: GTR has a greater effect on probing measures of periodontal treatment than open flap debridement, including improved attachment gain, reduced pocket depth, less increase in gingival recession and more gain in hard tissue probing at re-entry surgery. However there is marked variability between studies and the clinical relevance of these changes is unknown. As a result, it is difficult to draw general conclusions about the clinical benefit of GTR. Whilst there is evidence that GTR can demonstrate a significant improvement over conventional open flap surgery, the factors affecting outcomes are unclear from the literature and these might include study conduct issues such as bias. Therefore, patients and health professionals need to consider the predictability of the technique compared with other methods of treatment before making final decisions on use. Since trial reports were often incomplete, we recommend that future trials should follow the CONSORT statement both in their conduct and reporting. There is therefore little value in future research repeating simple, small efficacy studies. The priority should be to identify factors associated with improved outcomes as well as investigating outcomes relevant to patients. Types of research might include large observational studies to generate hypotheses for testing in clinical trials, qualitative studies on patient-centred outcomes and trials exploring innovative analytic methods such as multilevel modelling. Open flap surgery should remain the control comparison in these studies.