Preferential reporting of significant p-values in radiology journal abstracts.

AIM: To assess the prevalence of publication bias in the radiology literature, data-mining techniques were used to extract p-values in abstracts published in key radiology journals over the past 20 years. MATERIALS AND METHODS: A total of 34,699 abstracts published in Radiology, Investigative Radiology, European Radiology, American Journal of Roentgenology, and American Journal of Neuroradiology published between January 2000 and December 2019 were included in the analysis. Automated text mining using regular expressions was used to mine abstracts for p-values. RESULTS: The text mining algorithm detected 43,489 p-values, the majority (82.4%) of which were reported as "significant", i.e., p<0.05. There has also been an increased propensity to report more p-values over time. The distribution of p-values showed a step change at the conventional significance threshold of 0.05. The odds ratio of a "significant" p-value being reported in the abstract compared to the full text was calculated to be 2.52 (95% confidence interval 1.78-3.58; p<0.001). Taken together, these results provide strong evidence for selective reporting of significant p-values in abstracts. CONCLUSION: Statistically significant p-values are preferentially reported in radiology journal abstracts.

Leucine-enriched essential amino acid supplementation in mechanically ventilated trauma patients: a feasibility study.

BACKGROUND: Critically ill patients lose up to 2% of muscle mass per day. We assessed the feasibility of administering a leucine-enriched essential amino acid (L-EAA) supplement to mechanically ventilated trauma patients with the aim of assessing the effect on skeletal muscle mass and function. METHODS: A randomised feasibility study was performed over six months in intensive care (ICU). Patients received 5 g L-EAA five times per day in addition to standard feed (L-EAA group) or standard feed only (control group) for up to 14 days. C-reactive protein, albumin, IL-6, IL-10, urinary 3-MH, nitrogen balance, protein turnover ([1-13C] leucine infusion), muscle depth change (ultrasound), functional change (Katz and Barthel indices) and muscle strength Medical Research Council (MRC) sum score to assess ICU Acquired Weakness were measured sequentially. RESULTS: Eight patients (9.5% of screened patients) were recruited over six months. L-EAA doses were provided on 91/124 (73%) occasions. Inflammatory and urinary marker data were collected; serial muscle depth measurements were lacking due to short length of stay. Protein turnover studies were performed on five occasions. MRC sum score could not be performed as patients were not able to respond to the screening questions. The Katz and Barthel indices did not change. L-EAA delivery was achievable, but meaningful functional and muscle mass outcome measures require careful consideration in the design of a future randomised controlled trial. CONCLUSION: L-EAA was practical to provide, but we found significant barriers to recruitment and measurement of the chosen outcomes which would need to be addressed in the design of a future, large randomised controlled trial. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN79066838 . Registered on 25 July 2012.

α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFß antibody to promote durable rejection and immunity in squamous cell carcinomas.

BACKGROUND: Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFß signaling. METHODS: To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFß or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. RESULTS: We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFß monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFß, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFß antibody administration attenuates these effects. We show that α-TGFß acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFß acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. CONCLUSIONS: We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFß-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFß combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFß/α-PD-1 combination therapy (NCT02947165).

Analysis of Craniofacial Remodeling in the Aging Midface Using Reconstructed Three-Dimensional Models in Paired Individuals.

BACKGROUND: Aging leads to a panoply of changes of facial morphology. The present study was conducted to analyze modifications of the facial skeleton with aging, using high-resolution imaging and comparing the same individuals at two time points. METHODS: The electronic medical record system was reviewed since its inception in 2001 for patients for whom two computed tomographic scans of the midface were obtained at least 9 years apart. The computed tomographic scans were converted into three-dimensional craniofacial models for each patient, using the initial and the follow-up computed tomographic scan data. The models were used to highlight areas of bone growth and bone resorption using a color scale and to perform a cephalometric analysis. RESULTS: Seven patients with a mean age of 61 years and computed tomographic scans on average 10.3 years apart were included. Bone resorption was consistently present (100 percent) at the pyriform aperture and the anterior wall of the maxilla. Resorption was noted at the superocentral (71 percent), inferolateral (57 percent), and superomedial (57 percent) aspects of the orbital rim. Resorption occurred earlier at the inferolateral orbital rim followed by the superomedial orbital rim in later decades of life. Paired-analysis of change in the orbital rim height and width demonstrated a mean decrease over time but was not significant. CONCLUSION: Bone remodeling in the same individual, over a period of 10 years, was characterized by resorption at the pyriform aperture; anterior wall of the maxilla; and superocentral, superomedial, and inferolateral aspects of the orbital rims.

Cerclage for sonographic short cervix in singleton gestations without prior spontaneous preterm birth: systematic review and meta-analysis of randomized controlled trials using individual patient-level data.

OBJECTIVE: The aim of this systematic review and meta-analysis was to quantify the efficacy of cervical cerclage in preventing preterm birth (PTB) in asymptomatic singleton pregnancies with a short mid-trimester cervical length (CL) on transvaginal sonography (TVS) and without prior spontaneous PTB. METHODS: Electronic databases were searched from inception of each database until February 2017. No language restrictions were applied. All randomized controlled trials (RCTs) of asymptomatic singleton pregnancies without prior spontaneous PTB, found to have short CL < 25 mm on mid-trimester TVS and then randomized to management with either cerclage or no cerclage, were included. Corresponding authors of all the included trials were contacted to obtain access to the data and perform a meta-analysis of individual patient-level data. Data provided by the investigators were merged into a master database constructed specifically for the review. Primary outcome was PTB < 35 weeks. Summary measures were reported as relative risk (RR) with 95% CI. The quality of the evidence was assessed using the GRADE approach. RESULTS: Five RCTs, including 419 asymptomatic singleton gestations with TVS-CL < 25 mm and without prior spontaneous PTB, were analyzed. In women who were randomized to the cerclage group compared with those in the control group, no statistically significant differences were found in PTB < 35 (21.9% vs 27.7%; RR, 0.88 (95% CI 0.63-1.23); I2 = 0%; five studies, 419 participants), < 34, < 32, < 28 and < 24 weeks, gestational age at delivery, preterm prelabor rupture of membranes (PPROM) and neonatal outcomes. In women who received cerclage compared with those who did not, planned subgroup analyses revealed a significantly lower rate of PTB < 35 weeks in women with TVS-CL < 10 mm (39.5% vs 58.0%; RR, 0.68 (95% CI, 0.47-0.98); I2 = 0%; five studies; 126 participants) and in women who received tocolytics (17.5% vs 32.7%; RR, 0.54 (95% CI, 0.31-0.93); I2 = 0%; four studies; 169 participants) or antibiotics (18.3% vs 31.5%; RR, 0.58 (95% CI, 0.33-0.98); I2 = 0%; three studies; 163 participants) as additional therapy to cerclage. The quality of evidence was downgraded two levels because of serious imprecision and indirectness, and therefore was judged as low. CONCLUSIONS: In singleton gestations without prior spontaneous PTB but with TVS-CL < 25 mm in the second trimester, cerclage does not seem to prevent preterm delivery or improve neonatal outcome. However, in these pregnancies, cerclage seems to be efficacious at lower CLs, such as < 10 mm, and when tocolytics or antibiotics are used as additional therapy, requiring further studies in these subgroups. Given the low quality of evidence, further well-designed RCTs are needed to confirm the findings of this study. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

An alternative to a randomised control design for assessing the efficacy and effectiveness of bracing in adolescent idiopathic scoliosis.

Randomised controlled trials (RCTs) that assessed the efficacy of bracing for adolescent idiopathic scoliosis have suffered from small sample sizes, low compliance and lack of willingness to participate. The aim of this study was to assess the feasibility of a comprehensive cohort study for evaluating both the efficacy and the effectiveness of bracing in patients with adolescent idiopathic scoliosis. Patients with curves at greater risk of progression were invited to join a randomised controlled trial. Those who declined were given the option to remain in the study and to choose whether they wished to be braced or observed. Of 87 eligible patients (5 boys and 63 girls) identified over one year, 68 (78%) with mean age of 12.5 years (10 to 15) consented to participate, with a mean follow-up of 168 weeks (0 to 290). Of these, 19 (28%) accepted randomisation. Of those who declined randomisation, 18 (37%) chose a brace. Patients who were more satisfied with their image were more likely to choose bracing (Odds Ratio 4.1; 95% confidence interval 1.1 to 15.0; p = 0.035). This comprehensive cohort study design facilitates the assessment of both efficacy and effectiveness of bracing in patients with adolescent idiopathic scoliosis, which is not feasible in a conventional randomised controlled trial.

Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis.

Ras oncogenes (Hras, Kras and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.

Discrimination of natural scenes in central and peripheral vision.

We conducted suprathreshold discrimination experiments to compare how natural-scene information is processed in central and peripheral vision (16° eccentricity). Observers' ratings of the perceived magnitude of changes in naturalistic scenes were lower for peripheral than for foveal viewing, and peripheral orientation changes were rated less than peripheral colour changes. A V1-based Visual Difference Predictor model of the magnitudes of perceived foveal change was adapted to match the sinusoidal grating sensitivities of peripheral vision, but it could not explain why the ratings for changes in peripheral stimuli were so reduced. Perceived magnitude ratings for peripheral stimuli were further reduced by simultaneous presentation of flanking patches of naturalistic images, a phenomenon that could not be replicated foveally, even after M-scaling the foveal stimuli to reduce their size and the distances from the flankers. The effects of the peripheral flankers are very reminiscent of crowding phenomena demonstrated with letters or Gabor patches.

A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer.

Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. De novo mutations such as multiple exon deletion are rarely occurred in BRCA1 and BRCA2. During our mutation screening for BRCA1/2 genes to Chinese women with risk factors for hereditary breast/ovarian cancer, we identified a novel germline mutation, consisting of a deletion from exons 1 to 12 in BRCA1 gene, in a patient diagnosed with early onset triple negative breast cancer with no family history of cancer. None of her parents carried the mutation and molecular analysis showed that this novel de novo germline mutation resulted in down-regulation of BRCA1 gene expression.

Vision out of the corner of the eye.

The margin of the temporal visual field lies more than 90° from the line of sight and is critical for detecting incoming threats and for balance and locomotive control. We show (i) contrast sensitivity beyond 70° is higher for moving stimuli than for stationary, and in the outermost region, only moving stimuli are visible; (ii) sensitivity is highest for motion in directions near the vertical and horizontal axes and is higher for forward than for backward directions; (iii) the former anisotropy arises early in the visual pathway; (iv) thresholds for discriminating direction are lowest for upward and downward motion.

A general rule for sensory cue summation: evidence from photographic, musical, phonetic and cross-modal stimuli.

The Euclidean and MAX metrics have been widely used to model cue summation psychophysically and computationally. Both rules happen to be special cases of a more general Minkowski summation rule , where m = 2 and ∞, respectively. In vision research, Minkowski summation with power m = 3-4 has been shown to be a superior model of how subthreshold components sum to give an overall detection threshold. Recently, we have previously reported that Minkowski summation with power m = 2.84 accurately models summation of suprathreshold visual cues in photographs. In four suprathreshold discrimination experiments, we confirm the previous findings with new visual stimuli and extend the applicability of this rule to cue combination in auditory stimuli (musical sequences and phonetic utterances, where m = 2.95 and 2.54, respectively) and cross-modal stimuli (m = 2.56). In all cases, Minkowski summation with power m = 2.5-3 outperforms the Euclidean and MAX operator models. We propose that this reflects the summation of neuronal responses that are not entirely independent but which show some correlation in their magnitudes. Our findings are consistent with electrophysiological research that demonstrates signal correlations (r = 0.1-0.2) between sensory neurons when these are presented with natural stimuli.

Effectiveness of cerclage according to severity of cervical length shortening: a meta-analysis.

OBJECTIVES: To estimate the effectiveness of cerclage according to degree of cervical length (CL) shortening. METHODS: A meta-analysis was carried out of trials of women with singleton gestations and second-trimester transvaginal sonographic CL < 25 mm randomized to cerclage or no cerclage. The degree of CL shortening was correlated to the efficacy of cerclage in preventing preterm birth. RESULTS: There was a significant reduction in preterm birth < 35 weeks in the cerclage compared with no cerclage groups in 208 singleton gestations with both a previous preterm birth and CL < 25 mm (relative risk, 0.61; 95% CI, 0.40-0.92). In these women, preterm birth < 37 weeks was significantly reduced with cerclage for CL < or = 5.9 mm, < or = 15.9 mm, 16-24.9 mm and < 25 mm. None of the analyses for 344 women without a previous preterm birth was significant. CONCLUSIONS: Cerclage, when performed in women with a singleton gestation, previous preterm birth and cervical length < 25 mm, seems to have a similar effect regardless of the degree of cervical shortening, including CL 16-24 mm, as well as CL < or = 5.9 mm.

Cruciform-silica hybrid materials.

Silica scaffolding: By employing functionalized mesoporous SBA-15 silica, novel fluorescent cruciform-silica hybrid materials are generated which preserve the desirable solution properties of cruciforms in the solid state for potential use in sensory schemes. Preserving the solution properties of functional fluorophores upon incorporation into solid state sensory schemes remains a significant challenge. To address this concern, a silica scaffold was employed to support functional fluorophores in the solid state. Herein, we report an effort to support 1,4-distyryl-2,5-bisarylethynylbenzene cruciforms (XFs) using functionalized mesoporous silica particles. By employing surface-functionalized mesoporous SBA-15 silica, novel fluorescent cruciform-silica hybrid materials are generated which retain the desirable solution properties of cruciforms in the solid state. Organic surface functionalities, such as acidic, basic, and hydrophobic groups employed on the silica scaffold, modulate the observed emissions of the resulting solid state materials. The potential of these XF-silica hybrid materials to display sensory responses to representative vapor-phase analytes is demonstrated.

Summation of perceptual cues in natural visual scenes.

Natural visual scenes are rich in information, and any neural system analysing them must piece together the many messages from large arrays of diverse feature detectors. It is known how threshold detection of compound visual stimuli (sinusoidal gratings) is determined by their components' thresholds. We investigate whether similar combination rules apply to the perception of the complex and suprathreshold visual elements in naturalistic visual images. Observers gave magnitude estimations (ratings) of the perceived differences between pairs of images made from photographs of natural scenes. Images in some pairs differed along one stimulus dimension such as object colour, location, size or blur. But, for other image pairs, there were composite differences along two dimensions (e.g. both colour and object-location might change). We examined whether the ratings for such composite pairs could be predicted from the two ratings for the respective pairs in which only one stimulus dimension had changed. We found a pooling relationship similar to that proposed for simple stimuli: Minkowski summation with exponent 2.84 yielded the best predictive power (r=0.96), an exponent similar to that generally reported for compound grating detection. This suggests that theories based on detecting simple stimuli can encompass visual processing of complex, suprathreshold stimuli.