Associations of prenatal exposure to NO2 and near roadway residence with placental gene expression.

INTRODUCTION: Traffic-related air pollution (TRAP), a common exposure, potentially impacts pregnancy through altered placental function. We investigated associations between prenatal TRAP exposure and placental gene expression. METHODS: Whole transcriptome sequencing was performed on placental samples from CANDLE (Memphis, TN) (n = 776) and GAPPS (Seattle and Yakima, WA) (n = 205), cohorts of the ECHO-PATHWAYS Consortium. Residential NO2 exposures were computed via spatiotemporal models for full-pregnancy, each trimester, and the first/last months of pregnancy. Individual cohort-specific, covariate-adjusted linear models were fit for 10,855 genes and respective exposures (NO2 or roadway proximity [≤150 m]). Infant-sex/exposure interactions on placental gene expression were tested with interaction terms in separate models. Significance was based on false discovery rate (FDR<0.10). RESULTS: In GAPPS, final-month NO2 exposure was positively associated with MAP1LC3C expression (FDR p-value = 0.094). Infant-sex interacted with second-trimester NO2 on STRIP2 expression (FDR interaction p-value = 0.011, inverse and positive associations among male and female infants, respectively) and roadway proximity on CEBPA expression (FDR interaction p-value = 0.045, inverse among females). In CANDLE, infant-sex interacted with first-trimester and full-pregnancy NO2 on RASSF7 expression (FDR interaction p-values = 0.067 and 0.013, respectively, positive among male infants and inverse among female infants). DISCUSSION: Overall, pregnancy NO2 exposure and placental gene expression associations were primarily null, with exception of final month NO2 exposure and placental MAP1LC3C association. We found several interactions of infant sex and TRAP exposures on placental expression of STRIP2, CEBPA, and RASSF7. These highlighted genes suggest influence of TRAP on placental cell proliferation, autophagy, and growth, though additional replication and functional studies are required for validation.

Co-production of a nature-based intervention for children with ADHD study (CONIFAS): Protocol for co-production phases.

Children with Attention Deficit Hyperactivity Disorder can face difficulties with inattention, hyperactivity, and impulsivity, which can impact many areas of their lives, including their educational attainment and social and emotional wellbeing. Involvement in nature-based activities can reduce these difficulties and improve wellbeing, but there are limited resources for supporting children with this diagnosis to access these approaches and no nature-based interventions designed with and for this group. This protocol describes a co-production study in which children diagnosed with Attention Deficit Hyperactivity Disorder aged 5-11 years old, their parents/guardians, and professionals will attend a series of workshops to share their knowledge to co-produce a new nature-based intervention for this population of children. We aim to understand how the children's' experiences of Attention Deficit Hyperactivity Disorder may affect their interactions with nature, identify how activity in and with nature may help with symptom reduction and general wellbeing, and co-produce an intervention for families which applies our learning. The result of this study will be the designed intervention and insights into how children and young people with Attention Deficit Hyperactivity Disorder interact with nature. The prototype intervention will then undergo feasibility testing in a future study. Trail registration: NIHR203043; ISRCTN11763460.

Prenatal exposure to particulate matter and placental gene expression.

BACKGROUND: While strong evidence supports adverse maternal and offspring consequences of air pollution, mechanisms that involve the placenta, a key part of the intrauterine environment, are largely unknown. Previous studies of air pollution and placental gene expression were small candidate gene studies that rarely considered prenatal windows of exposure or the potential role of offspring sex. We examined overall and sex-specific associations of prenatal exposure to fine particulate matter (PM2.5) with genome-wide placental gene expression. METHODS: Participants with placenta samples, collected at birth, and childhood health outcomes from CANDLE (Memphis, TN) (n = 776) and GAPPS (Seattle, WA) (n = 205) cohorts of the ECHO-PATHWAYS Consortium were included in this study. PM2.5 exposures during trimesters 1, 2, 3, and the first and last months of pregnancy, were estimated using a spatiotemporal model. Cohort-specific linear adjusted models were fit for each exposure window and expression of >11,000 protein coding genes from paired end RNA sequencing data. Models with interaction terms were used to examine PM2.5-offspring sex interactions. False discovery rate (FDR < 0.10) was used to correct for multiple testing. RESULTS: Mean PM2.5 estimate was 10.5-10.7 µg/m3 for CANDLE and 6.0-6.3 µg/m3 for GAPPS participants. In CANDLE, expression of 13 (11 upregulated and 2 downregulated), 20 (11 upregulated and 9 downregulated) and 3 (2 upregulated and 1 downregulated) genes was associated with PM2.5 in the first trimester, second trimester, and first month, respectively. While we did not find any statistically significant association, overall, between PM2.5 and gene expression in GAPPS, we found offspring sex and first month PM2.5 interaction for DDHD1 expression (positive association among males and inverse association among females). We did not observe PM2.5 and offspring sex interactions in CANDLE. CONCLUSION: In CANDLE, but not GAPPS, we found that prenatal PM2.5 exposure during the first half of pregnancy is associated with placental gene expression.

Placental cadmium, placental genetic variations, and birth size.

BACKGROUND: Maternal cadmium (Cd) burden has been associated with offspring birth size measures, yet associations of placental Cd with birth size are less clear. Further, the role of genetics in these associations has not been examined. We investigated associations of placental Cd with birth size and placental genotypes. We also examined the potential role of placental genotypes as modifiers of placental Cd and birth size associations. METHODS: Participants were 490 mother-child pairs from the Omega and Placenta Microarray studies based in Seattle, WA. Placental Cd was measured using Agilent 7500 ICP-MS. The birth size was characterized using birth weight (BW), ponderal index (PI), and head circumference (HC). Eleven placental single nucleotide polymorphisms (SNPs) related to metal transport, growth regulation, endocrine response, and cell signaling were genotyped. Adjusted multivariable linear regression models were used to examine overall and sex-specific associations of placental Cd with birth size (BW, PI and HC), as well as associations of placental genotypes with placental Cd. Effect modification of placenta Cd and birth size associations by placental SNPs was examined using interaction terms and stratified analyses. RESULTS: Mean maternal age was 33.6 years (SD = 4.4). Mean and median placental Cd levels were 4.0 ng/g tissue (SD = 2.7 ng/g tissue) and 3.6 ng/g (IQR 2.5 - 5.2 ng/g), respectively. Overall, compared with infants in the lowest quartile for placental Cd, infants in the second (ß = -102.8 g, 95% CI: -220.7, 15.1), third (ß = -83.2 g, 95% CI: -199.3, 32.9) and fourth (ß = -109.2 g, 95% CI: -225.4, 7.1) quartiles had lower BW, though associations were not statistically significant (all p-values > .05, trend p-value = .11). Among male infants, infants in the second (ß = -203.3 g, 95% CI: -379.7, -27.0) and fourth quartiles (ß = -198.3 g, 95% CI: -364.2, -32.5) had lower BW compared with those in the first quartiles (p-values < .05, trend p-value = .08). Similar relationships were not observed among female infants, though infant sex-placental Cd interaction terms were not significant. Similarly, male, but not female, infants had marginally significant positive associations between placental Cd and ponderal index (trend p-value = .06). The minor rs3811647 allele of the placental transferrin gene (NCBI Gene ID: 7018) was associated with an increase in Cd among all infants (p-value = .04). We did not find differences in associations of placental Cd with birth size markers among infants stratified by rs3811647 genotype. CONCLUSIONS: Placental Cd was inversely associated with BW among male infants. The rs3811647 SNP of the transferrin gene was associated with placental Cd.

Placental lncRNA expression associated with placental cadmium concentrations and birth weight.

Heavy metal exposures, such as cadmium, can have negative effects on infant birth weight (BW)-among other developmental outcomes-with placental dysfunction potentially playing a role in these effects. In this study, we examined how differential placental expression of long non-coding RNAs (lncRNAs) may be associated with cadmium levels in placenta and whether differences in the expression of those lncRNAs were associated with fetal growth. In the Rhode Island Child Health Study, we used data from Illumina HiSeq whole transcriptome RNA sequencing (n = 199) to examine association between lncRNA expression and measures of infant BW as well as placental cadmium concentrations controlled for appropriate covariates. Of the 1191 lncRNAs sequenced, 46 demonstrated associations (q < 0.05) with BW in models controlling for infant sex, maternal age, BMI, maternal education, and smoking during pregnancy. Furthermore, four of these transcripts were associated with placental cadmium concentrations, with MIR22HG and ERVH48-1 demonstrating increases in expression associated with increasing cadmium exposure and elevated odds of small for gestational age birth, while AC114763.2 and LINC02595 demonstrated reduced expression associated with cadmium, but elevated odds of large for gestational age birth with increasing expression. We identified relationships between lncRNA expression with both placental cadmium concentrations and BW. This study provides evidence that disrupted placental expression of lncRNAs may be a part of cadmium's mechanisms of reproductive toxicity.

Drosophila emerins control LINC complex localization and transcription to regulate myonuclear position.

Mispositioned nuclei are a hallmark of skeletal muscle disease. Many of the genes that are linked to Emery-Dreifuss muscular dystrophy (EDMD) encode proteins that are critical for nuclear movement in various cells, suggesting that disruptions in nuclear movement and position may contribute to disease progression. However, how these genes are coordinated to move nuclei is not known. Here, we focussed on two different emerin proteins in Drosophila, Bocksbeutel and Otefin, and their effects on nuclear movement. Although nuclear position was dependent on both, elimination of either Bocksbeutel or Otefin produced distinct phenotypes that were based in differential effects on the KASH-domain protein Klarsicht. Specifically, loss of Bocksbeutel reduced Klarsicht localization to the nucleus and resulted in a disruption in nuclear separation. Loss of Otefin increased the transcription of Klarsicht and led to premature separation of nuclei and their positioning closer to the edge of the muscle. Consistent with opposing functions, nuclear position is normal in otefin; bocksbeutel double mutants. These data indicate emerin-dependent regulation of Klarsicht levels in the nuclear envelope is a critical determinant of nuclear position.

A new risk to the axillary nerve during percutaneous proximal humeral plate fixation using the Synthes PHILOS aiming system.

BACKGROUND: Percutaneous aiming arms have been developed to minimize injury during placement of submuscular proximal humerus plates. The purpose of this study was to determine the risk of axillary nerve injury during percutaneous proximal humeral plate fixation using the Synthes PHILOS aiming system. METHODS: By use of 10 fresh-frozen cadavers (20 shoulders), a 3.5-mm locking compression proximal humeral plate was fixated percutaneously to the humerus through a lateral deltoid-splitting approach using the PHILOS aiming guide. Dissection of the axillary nerve was then carried out, and measurements of its relation to the screw holes in row A through row G of the plate were taken. The lateral acromion-to-axillary nerve distance was also measured. RESULTS: The axillary nerve traversed row D in every shoulder, whereas it crossed over row C in 11 shoulders and both holes in row E in 16 shoulders. The closest distance to the axillary nerve achieved was 4.5 mm, corresponding to the distal (left) screw in row B. A significant negative correlation was found for the distance from the nerve to the closest proximal and distal screws (row B and row G, respectively) in both right shoulders (ρ = -0.797; 95% confidence interval, -0.916 to -0.548) and left shoulders (ρ = -0.615; 95% confidence interval, -0.831 to -0.237). CONCLUSION: The axillary nerve traverses rows C, D, and E of the proximal humeral plate using the PHILOS aiming system. Importantly, our study is the first to demonstrate that the axillary nerve crosses over row C. Left-sided plate screws also came in closer proximity to the axillary nerve than right-sided plate screws.

Nanoparticle-Cell Interactions: Relevance for Public Health.

Nanoparticles, especially metal oxide nanoparticles, are used in a wide range of commercial and industrial applications that result in direct human contact, such as titanium dioxide nanoparticles in paints, food colorings, and cosmetics, or indirectly through release of nanoparticle-containing materials into the environment. Workers who process nanoparticles for downstream applications are exposed to especially high concentrations of nanoparticles. For physical chemists, nanoparticles present an interesting area of study as the small size of nanoparticles changes the properties from that of the bulk material, leading to novel properties and reactivity. For the public health community, this reduction in particle size means that exposure limits and outcomes that were determined from bulk material properties are not necessarily valid. Informed determination of exposure limits requires a fundamental understanding of how nanoparticles interact with cells. This Feature Article highlights the areas of intersection between physical chemistry and public health in understanding nanoparticle-cell interactions, with a focus on titanium dioxide nanoparticles. It provides an overview of recent research examining the interaction of titanium dioxide nanoparticles with cells in the absence of UV light and provides recommendations for additional nanoparticle-cell research in which physical chemistry expertise could help to inform the public health community.

Randomization-based adjustment of multiple treatment hazard ratios for covariates with missing data.

Clinical trials are designed to compare treatment effects when applied to samples from the same population. Randomization is used so that the samples are not biased with respect to baseline covariates that may influence the efficacy of the treatment. We develop randomization-based covariance adjustment methodology to estimate the log hazard ratios and their confidence intervals of multiple treatments in a randomized clinical trial with time-to-event outcomes and missingness among the baseline covariates. The randomization-based covariance adjustment method is a computationally straight-forward method for handling missing baseline covariate values.

Morphologic Variability of the Shoulder between the Populations of North American and East Asian.

BACKGROUND: The aim of this study was to determine if there were significant differences in glenohumeral joint morphology between North American and East Asian populations that may influence sizing and selection of shoulder arthroplasty systems. METHODS: Computed tomography reconstructions of 92 North American and 58 East Asian patients were used to perform 3-dimensional measurements. The proximal humeral position was normalized in all patients by aligning it with the scapular plane utilizing anatomic landmarks. Measurements were performed on the humerus and scapula and included coronal and axial humeral head radius, humeral neck shaft and articular arc angles, glenoid height and width, and critical shoulder angle. Glenohumeral relationships were also measured and included lateral distance to the greater tuberosity and acromion, abduction lever arm, and acromial index. Parametric and nonparametric statistical analyses were used to compare population metrics. RESULTS: East Asian glenohumeral measurements were significantly smaller for all linear metrics (p < 0.05), with the exception of acromial length, which was greater than in the North American cohort (p < 0.001). The increase in acromial length affected all measurements involving the acromion including abduction lever arms. No difference was found between the neck shaft and articular angular measurements. CONCLUSIONS: The East Asian population exhibited smaller shoulder morphometrics than their North American cohort, with the exception of an extended acromial overhang. The morphologic data can provide some additional factors to consider when choosing an optimal shoulder implant for the East Asian population, in addition to creating future designs that may better accommodate this population.

Nonparametric randomization-based covariate adjustment for stratified analysis of time-to-event or dichotomous outcomes.

Time-to-event or dichotomous outcomes in randomized clinical trials often have analyses using the Cox proportional hazards model or conditional logistic regression, respectively, to obtain covariate-adjusted log hazard (or odds) ratios. Nonparametric Randomization-Based Analysis of Covariance (NPANCOVA) can be applied to unadjusted log hazard (or odds) ratios estimated from a model containing treatment as the only explanatory variable. These adjusted estimates are stratified population-averaged treatment effects and only require a valid randomization to the two treatment groups and avoid key modeling assumptions (e.g., proportional hazards in the case of a Cox model) for the adjustment variables. The methodology has application in the regulatory environment where such assumptions cannot be verified a priori. Application of the methodology is illustrated through three examples on real data from two randomized trials.

Reverse shoulder arthroplasty for massive rotator cuff tear: risk factors for poor functional improvement.

BACKGROUND: Some patients unexpectedly have poor functional improvement after reverse shoulder arthroplasty (RSA) for massive rotator cuff tear without glenohumeral arthritis. Our aim was to identify risk factors for this outcome. We also assessed the value of RSA for cases with poor functional improvement vs. METHODS: The study was a retrospective case-control analysis for primary RSA performed for massive rotator cuff tear without glenohumeral arthritis with minimum 2-year follow-up. Cases were defined as Simple Shoulder Test (SST) score improvement of ≤1, whereas controls improved SST score ≥2. Risk factors were chosen on the basis of previous association with poor outcomes after shoulder arthroplasty. Latissimus dorsi tendon transfer results were analyzed as a subgroup. Value was defined as improvement in American Shoulder and Elbow Surgeons (ASES) score per $10,000 hospital cost. RESULTS: In a multivariate binomial logistic regression analysis, neurologic dysfunction (P = .006), age <60 years (P = .02), and high preoperative SST score (P = .03) were independently associated with poor functional improvement. Latissimus dorsi tendon transfer patients significantly improved in active external rotation (-0.3° to 38.7°; P < .01). The value of RSA (ΔASES/$10,000 cost) for cases was 0.8 compared with 17.5 for controls (P < .0001). CONCLUSIONS: Young age, high preoperative function, and neurologic dysfunction were associated with poor functional improvement. Surgeons should consider these associations in counseling and selection of patients. Concurrent latissimus dorsi transfer was successful in restoring active external rotation in a subgroup of patients. The critical economic importance of improved patient selection is emphasized by the very low value of the procedure in the case group.

Outcome and value of reverse shoulder arthroplasty for treatment of glenohumeral osteoarthritis: a matched cohort.

BACKGROUND: Total shoulder arthroplasty (TSA) is commonly used to treat glenohumeral osteoarthritis (GHOA) with an intact rotator cuff. Recently, reverse shoulder arthroplasty (RSA) has been used for GHOA patients who are elderly or have eccentric glenoid wear. We evaluated patients with GHOA scheduled to have TSA but who were changed to RSA because of intraoperative difficulties with the glenoid component or instability and compared them with a cohort that underwent TSA to determine if the groups had similar outcomes. METHODS: We identified 24 consecutive GHOA patients who underwent RSA and matched them to 96 patients who underwent TSA. Glenoid wear and rotator cuff musculature were assessed with preoperative computed tomography scans. Direct hospital costs of the procedure were collected. RESULTS: Postoperative American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, and range of motion were similar between the 2 groups. Five TSA patients had radiographic glenoid loosening, whereas no RSA patients did. Neither group required a revision. One RSA patient required surgery for treatment of a periprosthetic fracture. RSA was $7274 more costly than TSA, related mainly to implant cost. CONCLUSIONS: Patients with GHOA who were converted intraoperatively to RSA because of improper seating of the glenoid trial or persistent posterior subluxation had outcomes comparable to those of a similar group of patients in whom TSA was performed. At midterm follow-up, TSA is associated with lower cost than RSA. The higher rate of radiographic loosening in the TSA group warrants longer follow-up to assess revision costs. In cases in which a TSA cannot be performed with confidence, RSA is a reasonable alternative.

Glenosphere dissociation after reverse shoulder arthroplasty.

BACKGROUND: Reverse shoulder arthroplasty (RSA) is gaining popularity for the treatment of debilitating shoulder disorders. Despite marked improvements in patient satisfaction and function, the RSA complication rate is high. Glenosphere dissociation has been reported and may result from multiple mechanisms. However, few RSA retrieval studies exist. METHODS: We reviewed our RSA database and identified patients with glenosphere dissociation between 1999 and 2013. Prosthesis type, glenosphere size, and contributing factors to dissociation were noted. Five retrieved implants were available for analysis, and evidence of wear or corrosion on the Morse taper was documented. Further, we biomechanically investigated improper Morse taper engagement that may occur intraoperatively as a potential cause of acute dissociation. RESULTS: Thirteen patients with glenosphere dissociation were identified (0.5 months to 7 years postoperatively). Glenosphere size distribution was as follows: 32 mm (n = 1), 36 mm (n = 4), 40 mm (n = 6), and 44 mm (n = 2). Incidence of dissociation was correlated to glenosphere size (P < .001). Taper damage was limited to fretting wear, and there was minimal evidence of taper corrosion. Biomechanically, improper taper engagement reduced the torsional capacity of the glenosphere-baseplate interface by 60% from 19.2 ± 1.0 N-m to 7.5 ± 1.5 N-m. CONCLUSION: We identified several mechanisms contributing to glenosphere dissociation after RSA, including trauma and improper taper engagement. Limited evidence of corrosive wear on the taper interface was identified. Although it is rare, the incidence of glenosphere dissociation was higher when 40- and 44-mm glenospheres were implanted compared with smaller glenospheres (32 and 36 mm), probably because of the larger exposed surface area for potential impingement.

Glenoid subchondral bone density distribution in male total shoulder arthroplasty subjects with eccentric and concentric wear.

BACKGROUND: Glenoid component loosening in total shoulder arthroplasty may be prevented by component placement on a congruent and adequate bony surface. Glenoid subchondral bone density (SBD) variability may be correlated with this concept. This study analyzed the 3-dimensional distribution of glenoid SBD in total shoulder arthroplasty patients with osteoarthritis. MATERIALS AND METHODS: Three-dimensional computed tomography osteoabsorptiometry (CT-OAM) was performed in 42 men (21 with eccentric and 21 with concentric wear patterns) with glenohumeral arthritis. Glenoid SBD was measured from the joint surface based on 5 clinically relevant topographic zones. The correlation of the wear pattern with the SBD distribution was investigated. RESULTS: The glenoid subarticular layers could be separated into distinct regions: calcified cartilage (≤ 1.5 mm), subchondral plate (2-4.5 mm) and cancellous bone (≥ 5 mm). There were significant differences in SBD among these layers within and between patients with concentric and eccentric wear patterns. In concentric glenoids, the SBD distribution was homogeneous, with greater mineralization in the central zone, 1,749.1 ± 162.3 Hounsfield units (HU) (at 2.5 mm), compared with the posterior, anterior, and superior zones (P < .001). In the eccentric group, the SBD distribution was inhomogeneous. Mineralization was greatest in the posterior zone, 1,739.0 ± 172.6 HU (at 2.5 mm), followed by the inferior zone, 1,722.1 ± 186.6 HU (at 3 mm). CONCLUSION: This study represents the first study using CT-OAM to evaluate the 3-dimensional SBD distribution of the glenoid vault for different arthritic wear patterns. The study findings indicate that the SBD distribution is dependent on (1) depth from the articular surface, (2) topographic zone, and (3) wear pattern. CT-OAM may be an effective tool to assist in preoperative planning for shoulder arthroplasty.

The effects of glenoid wear patterns on patients with osteoarthritis in total shoulder arthroplasty: an assessment of outcomes and value.

BACKGROUND: Despite the success of total shoulder arthroplasty (TSA), concerns remain about the longevity of the implant, in particular, glenoid component survivorship. The purpose of this study was to determine whether preoperative glenoid wear patterns affect clinical outcomes and value in patients undergoing TSA. METHODS: A comparative cohort study was conducted of 309 patients with a total of 344 TSA procedures, performed for primary glenohumeral osteoarthritis. Computed tomography scans were obtained in all patients, with preoperative glenoid wear pattern characterized as either concentric (n = 196; follow-up time, 49.2 months) or eccentric (n = 148; follow-up time, 52.3 months) according to a modified Levine classification. A clinical, radiographic, and economic assessment was performed between the 2 wear patterns. RESULTS: There was no significant difference in American Shoulder and Elbow Surgeons (ASES) score in the concentric group (80.8 ± 20.8) compared with the eccentric group (77.6 ± 21.2) at final follow-up (P = .159). Range of motion and final visual analog scale for pain score were similar between the 2 groups. Radiographic evidence of gross glenoid loosening was significantly lower in the concentric group [11 of 195 (5.6%)] compared with the eccentric group [18 of 147 (12.2%)] (P = .030). Revision rates were similar between the concentric group [4 of 195 (2.0%)] and the eccentric group [3 of 147 (2.0%)]. A value assessment also showed no significant difference between the concentric and eccentric groups [concentric 26.1 vs. eccentric 25.5 (ΔASES score/$10,000 hospital cost) (P = .479)]. CONCLUSIONS: Similar clinical results and value can be expected with both concentric and eccentric glenoid wear patterns in TSA. Concerns arise, however, as the eccentric group demonstrated a more than 2-fold increased rate of glenoid component loosening compared with the concentric group.

Reproducibility of blood pressure dipping: relation to day-to-day variability in sleep quality.

Previous studies of the reproducibility of blood pressure (BP) dipping have yielded inconsistent results. Few have examined factors that may influence day-to-day differences in dipping. Ambulatory BP monitoring was performed on three occasions, approximately 1 week apart, in 115 untreated adult subjects with elevated clinic BPs. The mean ± standard deviation BP dip was 18 ± 7/15 ± 5 mm Hg (sleep/awake BP ratio = 0.87 ± 0.05/0.82 ± 0.06), with a median (interquartile range) day-to-day variation of 5.2 (3.1-8.1)/4.3 (2.8-5.6) mm Hg. There was no decrease in variability with successive measurements. The reproducibility coefficient (5.6 [95% confidence interval, 5.1-6.1] mm Hg) was greater and the intraclass correlation coefficient (0.53 [95% confidence interval, 0.42-0.63]) was smaller for the systolic dip than for 24-hour or awake systolic BPs, suggesting greater day-to-day variability in dipping. Variability in systolic dipping was greater in subjects with higher awake BP, but was not related to age, gender, race, or body mass index. Within individuals, day-to-day variations in dipping were related to variations in the fragmentation index (P < .001), a measure of sleep quality. Although mean 24-hour and awake BPs were relatively stable over repeated monitoring days, our study confirms substantial variability in BP dipping. Day-to-day differences in dipping are related to sleep quality.

Analysis of neurovascular safety between superior and anterior plating techniques of clavicle fractures.

OBJECTIVES: Clavicle fractures are commonly plated as a method of fixation, with superior and anterior techniques described. Although advantages and disadvantages have been attributed to both, it is unclear if one approach provides a lower risk of neurovascular injury. The aim of this study was to compare the potential for neurovascular injury between these 2 plate locations in a cadaveric model. METHODS: Seventeen adult fresh frozen cadavers underwent bilateral dissections exposing the clavicle and underlying neurovasculature. After taking baseline anatomical measurements, a superior and anterior clavicle plate was applied, removed and measurements were taken from the nearest screw exit site to the underlying subclavian vein/artery and brachial plexus. The differences between superior and anterior measurements were compared based on proximity with the neurovasculature. RESULTS: Distance to the vessels were unobtainable in 6 specimens (35%) plated with the anterior technique due to the trajectory of the screws projecting cephalad to the vessels. In the remaining specimens, there was no significant difference in the distance to the subclavian vein/artery and brachial plexus in the superior plate position (9.2 ± 4.6, 12.2 ± 5.8, and 9.8 ± 5.2 mm, respectively) compared with the anterior plate position (8.3 ± 3.5, 12.2 ± 6.5, and 9.7 ± 5.3 mm, respectively). In addition, no significant difference in potential neurovascular injury with regard to body size or gender was found. CONCLUSIONS: The majority of our specimens showed no significant difference between superior and anterior plating in regard to potential risk for injury to the underlying neurovasculature. However, there appears to be a subset of the population with a more caudal position of the neurovascular structures in which anterior plating may be potentially safer.

A multistage analysis strategy for a clinical trial to assess successively more stringent criteria for a primary endpoint with a low event rate.

This paper describes how a multistage analysis strategy for a clinical trial can assess a sequence of hypotheses that pertain to successively more stringent criteria for excess risk exclusion or superiority for a primary endpoint with a low event rate. The criteria for assessment can correspond to excess risk of an adverse event or to a guideline for sufficient efficacy as in the case of vaccine trials. The proposed strategy is implemented through a set of interim analyses, and success for one or more of the less stringent criteria at an interim analysis can be the basis for a regulatory submission, whereas the clinical trial continues to accumulate information to address the more stringent, but not futile, criteria. Simulations show that the proposed strategy is satisfactory for control of type I error, sufficient power, and potential success at interim analyses when the true relative risk is more favorable than assumed for the planned sample size.