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.

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.

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.

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).

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.

Cervical length and obstetric history predict spontaneous preterm birth: development and validation of a model to provide individualized risk assessment.

OBJECTIVES: To evaluate the ability of combinations of cervical length and maternal history to assess the risk of spontaneous preterm birth, and to provide a simple procedure for the optimal estimation of risk. METHODS: This prospective observational study was carried out between January 1998 and May 2006. Transvaginal sonographic measurement of cervical length at 20 + 0 to 24 + 6 weeks of gestation was carried out in 58 807 singleton pregnancies as part of routine antenatal care. The outcome measure was spontaneous extreme (< 28 weeks), early (28-30 weeks), moderate (31-33 weeks) and mild (34-36 weeks) preterm birth. Logistic regression analysis was used to derive models for the prediction of spontaneous preterm birth from the maternal obstetric history, demographic characteristics and cervical length. RESULTS: The rates of extreme, early, moderate and mild spontaneous preterm birth were 0.23%, 0.24%, 0.57% and 2.93%, respectively. The best prediction of spontaneous preterm birth was provided by cervical length (area under the receiver-operating characteristics curve (AUC), extreme 0.903, early 0.816, moderate 0.784 and mild 0.617) and this was improved by adding obstetric history (AUC, extreme 0.919, early 0.836, moderate 0.819 and mild 0.650). Addition of other parameters was without material effect. For a 10% screen-positive rate, models using cervical length and obstetric history had a sensitivity of 80.6%, 58.5%, 53.0% and 28.6% for extreme, early, moderate and mild spontaneous preterm birth, respectively. These models were expressed as tables of adjusted likelihood ratios to allow simple estimation of the risk of spontaneous preterm birth. CONCLUSIONS: A model combining cervical length and obstetric history provides a better prediction of spontaneous preterm birth than either factor alone, and the sensitivity of screening improves for increasing degrees of prematurity.

Functional characterization of novel presenilin-2 variants identified in human breast cancers.

We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer's disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Abeta(42)/Abeta(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.

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.

Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma.

The parent Shionogi mouse mammary carcinoma is androgen dependent but cells that survive hormone withdrawal progress and give rise to an androgen-independent tumor. To determine whether renewed growth might be attributed to the persistence or partial recovery of an androgenic stimulus, we compared the amount of dihydrotestosterone and nuclear androgen receptor in parent and recurrent tumors. The whole tissue concentration of dihydrotestosterone in the parent tumor before castration was 1.40 +/- 0.46 (SE) as compared with 0.22 +/- 0.10 pmol/mg of DNA in the recurrent tumor. The initial concentration of nuclear androgen receptor in the parent was 0.65 +/- 0.12 pmol/mg of DNA; this was reduced to zero within 24 h after castration. Also in keeping with the androgen independence, no receptor was detected in the nuclear fraction of the recurrent carcinoma. In an attempt to relate malignant potential to nonhormonal factors associated with progression, we compared the proportions of androgen-dependent and -independent tumorigenic (stem) cells in parent and recurrent tumors using an in vivo limiting dilution assay. The difference observed, i.e., one stem cell per 4000 tumor cells in the parent versus one stem cell per 200 tumor cells in the recurrent carcinoma, was consistent with a marked enrichment of stem cells in the latter. The proportion of androgen-independent stem cells was also determined by assaying tumor takes in female hosts. The difference, i.e., one stem cell per 370,000 tumor cells in the parent versus one stem cell per 800 tumor cells in the recurrent carcinoma, demonstrated a striking 500-fold increase in androgen-independent stem cells resulting from androgen withdrawal. Unexpectedly, no enrichment of androgen-independent stem cells was evident in regressing parent tumors; rather, the proportion of such cells was very small, i.e., one androgen-independent stem cell per 2,200,000 regressing parent cells. This finding implies that the androgen-independent state of cells which survive androgen withdrawal may result from the ability of a small number of initially androgen-dependent stem cells to adapt to an altered hormone environment.

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.

Exon and intron variants in the human tryptophan 2,3-dioxygenase gene: potential association with Tourette syndrome, substance abuse and other disorders.

Defects in serotonin metabolism, and abnormalities in both blood serotonin and tryptophan levels, have been reported in many psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is the rate limiting enzyme for the breakdown of tryptophan to N-formyl kenurenine. Functional variants of this gene could account for the observed simultaneous increases or decreases of both serotonin and tryptophan in various disorders. We have identified four different polymorphisms of the human TDO2 gene. Association studies show a significant association of one or more of these polymorphisms and Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) and drug dependence. The intron 6G-->T variant was significantly associated with platelet serotonin levels. Only the association with TS was significant with a Bonferroni correction (p = 0.005). Our purpose here is not to claim these associations are proven, but rather to report preliminary results and show that easily testable polymorphisms are available. We hope to encourage additional research into the potential role the TDO2 gene in these and other psychiatric disorders.

Development of an automated human sperm quality system.

A computer-automated system, including hardware and software components, is developed for objective assessment of human sperm density and other characteristics, including morphological abnormalities and motility. The hardware component essentially consists of an IBM AT, a relatively low-cost image processing board and other inexpensive commercially available instruments. On the other hand, the software component is developed through the incorporation of image analysis, pattern recognition and modelling techniques with the knowledge of human reproduction from the available literature. The whole system is expected to produce a practical and cost-effective means for the routine assessment of human semen quality.

Peripheral nerve regeneration in CNTF knockout mice.

OBJECTIVES: To determine the role of ciliary neurotrophic factor (CNTF) in the regeneration of the mouse sciatic nerve following injury by studying the CNTF knockout mouse in a blinded, randomized and controlled evaluation. STUDY DESIGN: Fifty-eight wild-type and 57 CNTF knockout mice were randomly assigned to one of four treatment groups: sham surgery (sciatic nerve exposure), sciatic nerve crush, nerve transection without repair, and nerve transection followed by epineurial suture repair using 10-0 monofilament suture. Walking track analysis was performed before and after surgery at weekly intervals for 7 weeks, using a previously described formula. At the completion of walking track analysis, morphometric histological analysis of axon number and axon diameter in the distal sciatic nerves was performed. RESULTS: The wild-type and knockout mice that underwent only sham surgery had no change in their walking tracks during the study interval (P = .30 on postoperative day 49). The wild-type mice that underwent sciatic nerve crush showed complete functional recovery (P = .66 on postoperative day 28), but the CNTF knockout mice whose sciatic nerves were crushed did not fully recover (P = .05 on postoperative day 49). The CNTF knockout and wild-type mice showed similar levels of recovery after transection without repair (P = .78), and the rate of contracture formation was not significantly different (P = .40). The CNTF knockout and wild-type mice showed similar levels of recovery after epineurial repair (P>.31), however the rate of severe contractures was greater in the CNTF knockout mice (6 of 13) than in the wild-type mice (2 of 12) (P = .11). CONCLUSION: The absence of CNTF impairs the ability of mice to recover from a sciatic nerve crush injury. There is also a trend toward a greater rate of contracture formation after sciatic nerve transection and epineurial suture repair when CNTF is unavailable. These findings suggest that CNTF is important for recovery of neuronal function following crush and transection nerve injuries.

Delayed repair of transected nerves: effect of brain-derived neurotrophic factor.

OBJECTIVE: To determine if administration of brain-derived neurotrophic factor (BDNF) after peripheral nerve transection can improve the functional outcome in situations where epineurial repair must be delayed. DESIGN: Randomized, blinded, controlled trial. SUBJECTS: Thirty-four Sprague-Dawley rats. INTERVENTION: Sciatic nerves were transected and, after a 2-week delay, repaired with epineurial sutures. Animals were assigned to receive daily administration of lactated Ringer solution (LR [control] group); BDNF delivered at the time of nerve transection through 2 weeks after nerve repair, for a total of 4 weeks (BDNF-early group); or BDNF delivered at the time of nerve repair through 2 weeks after repair (BDNF-late group). Outcome was assessed using sciatic functional indices (SFIs) and histomorphometric analysis. RESULTS: The SFI maximal recovery was superior in the BDNF groups, but this difference did not reach statistical significance (SFI, -90.1+/-9.6 [LR group], -85.7+/-7.6 [BDNF-early group], and -84.6+/-4.8 [BDNF-late group], where normal function is 0 and complete loss of function is -100; P = .27). The mean axon diameter tended to be greater in the BDNF groups compared with the LR group, i.e., 2.43+/-0.23 microm (LR group), 2.80+/-0.44 microm (BDNF-early group), and 2.83+/-0.38 microm (BDNF-late group) (P = .05). CONCLUSIONS: The local administration of BDNF to nerves that underwent transection and then repair after a delay resulted in an increase in axonal diameters and maximal SFIs, a difference that did not reach statistical significance. The timing of BDNF administration after nerve transection did not affect neuronal regeneration.

Pre-exposure prophylaxis of humans against rabies: I. Studies on personnel at the Burma Pharmaceutical Industry.

This is the first time in Burma where personnel at risk against rabies have been pre-immunized and the effectiveness of such a procedure has been studied for nearly two years. The first batch of lyophilized, Semple-type, beta propiolactone inactivated anti rabies vaccine produced by the Burma Pharmaceutical Industry (B.P.I.) was used to immunize 55 B.P.I. workers previously unexposed to rabies and with no history of rabies vaccination. Three doses of 0.25 ml of the vaccine were given intradermally at one week intervals. Booster doses were given on the 98th, 392nd and 592nd day after the first dose. Blood samples were taken and serum neutralization tests were performed at varying time intervals after basic immunization and booster doses. Satisfactory antibody responses were obtained. The course of immunological response is presented and discussed.