Instrumental variables are routinely used to recover a consistent estimator of an exposure causal effect in the presence of unmeasured confounding. Instrumental variable approaches to account for ...nonignorable missing data also exist but are less familiar to epidemiologists. Like instrumental variables for exposure causal effects, instrumental variables for missing data rely on exclusion restriction and instrumental variable relevance assumptions. Yet these two conditions alone are insufficient for point identification. For estimation, researchers have invoked a third assumption, typically involving fairly restrictive parametric constraints. Inferences can be sensitive to these parametric assumptions, which are typically not empirically testable. The purpose of our article is to discuss another approach for leveraging a valid instrumental variable. Although the approach is insufficient for nonparametric identification, it can nonetheless provide informative inferences about the presence, direction, and magnitude of selection bias, without invoking a third untestable parametric assumption. An important contribution of this article is an Excel spreadsheet tool that can be used to obtain empirical evidence of selection bias and calculate bounds and corresponding Bayesian 95% credible intervals for a nonidentifiable population proportion. For illustrative purposes, we used the spreadsheet tool to analyze HIV prevalence data collected by the 2007 Zambia Demographic and Health Survey (DHS).
Background
Individuals with subjective cognitive decline (SCD) are at high risk of developing Alzheimer's disease (AD) (Jessen et al., 2014). Changes in cerebral perfusion, particularly cerebral ...blood flow (CBF), are a feature of AD and has also been shown in pre‐dementia stages (Binnewijzend et al., 2016). This study investigates regional CBF and its association with cognition in individuals with SCD and healthy older adults.
Method
Cognitive performance and cerebral perfusion were assessed in 81 individuals with SCD (age 68±5 years) and 46 healthy controls (age 71±6 years). Regional CBF (mL/100g/min) was assessed by arterial spin labeling MRI and quantified in AD‐vulnerable regions (Wirth et al., 2016). The preclinical Alzheimer’s cognitive composite (PACC5) and composite scores for selected cognitive domains were calculated. General linear models were conducted to assess group differences in regional CBF as well as associations between regional CBF and cognitive performance. Interaction effect of group and regional CBF on cognitive performance was determined using the same method. All analyses were adjusted for potential confounders (including sex, age, and body mass index).
Result
Participants with SCD showed decreased CBF in the hippocampus (p=.038) and the basal ganglia (p=.014) compared to healthy controls. Moreover, participants with SCD exhibited greater CBF in the inferior temporal gyrus than healthy controls (p=.006). Across all participants, CBF in the basal ganglia was positively associated with executive function (p=.016), memory (p=.018), and PACC5 (p=.001). Exploratory investigations within each group revealed these associations only in healthy controls (p=.032, .037, .004, respectively). However, no effect of group was found on the relationship between regional CBF and cognitive performance.
Conclusion
Our findings indicate that alterations of cerebral perfusion are already detectable in the stage of SCD, in particular in the hippocampus, basal ganglia, and inferior temporal gyrus. In addition, cognitive performance was positively associated with CBF in the basal ganglia across all subjects; however, this effect was mainly driven by the healthy controls. Thus, our findings may point towards early pathological changes affecting the association between regional CBF and cognition in SCD, which needs to be evaluated in further studies.
Abstract
Background
Individuals with subjective cognitive decline (SCD) are at high risk of developing Alzheimer's disease (AD) (Jessen et al., 2014). Changes in cerebral perfusion, particularly ...cerebral blood flow (CBF), are a feature of AD and has also been shown in pre‐dementia stages (Binnewijzend et al., 2016). This study investigates regional CBF and its association with cognition in individuals with SCD and healthy older adults.
Method
Cognitive performance and cerebral perfusion were assessed in 81 individuals with SCD (age 68±5 years) and 46 healthy controls (age 71±6 years). Regional CBF (mL/100g/min) was assessed by arterial spin labeling MRI and quantified in AD‐vulnerable regions (Wirth et al., 2016). The preclinical Alzheimer’s cognitive composite (PACC5) and composite scores for selected cognitive domains were calculated. General linear models were conducted to assess group differences in regional CBF as well as associations between regional CBF and cognitive performance. Interaction effect of group and regional CBF on cognitive performance was determined using the same method. All analyses were adjusted for potential confounders (including sex, age, and body mass index).
Result
Participants with SCD showed decreased CBF in the hippocampus (p=.038) and the basal ganglia (p=.014) compared to healthy controls. Moreover, participants with SCD exhibited greater CBF in the inferior temporal gyrus than healthy controls (p=.006). Across all participants, CBF in the basal ganglia was positively associated with executive function (p=.016), memory (p=.018), and PACC5 (p=.001). Exploratory investigations within each group revealed these associations only in healthy controls (p=.032, .037, .004, respectively). However, no effect of group was found on the relationship between regional CBF and cognitive performance.
Conclusion
Our findings indicate that alterations of cerebral perfusion are already detectable in the stage of SCD, in particular in the hippocampus, basal ganglia, and inferior temporal gyrus. In addition, cognitive performance was positively associated with CBF in the basal ganglia across all subjects; however, this effect was mainly driven by the healthy controls. Thus, our findings may point towards early pathological changes affecting the association between regional CBF and cognition in SCD, which needs to be evaluated in further studies.
Postoperative cervical hemorrhage is a rare but life-threatening complication that can cause severe morbidity. Different mechanisms leading to asphyxia have been described based only on clinical ...observation.
We performed a series of in vivo animal studies simulating post-thyroidectomy hemorrhage and its effect on respiratory drive. Three series of tests were carried out in 12 German domestic pigs under general anesthesia. The pigs were breathing spontaneously with secured airways. An additional series using functional magnetic resonance imaging of the pigs’ brainstem was also conducted.
The first experimental series carried out on 2 animals revealed an obvious difference between the effects of cervical hemorrhage and external bleeding with development of hemorrhagic shock. An experimental setting for the repeated simulation of cervical hemorrhage was established. A pressure-dependent mechanism was discovered that led to apnea in every animal despite the secured airway. In 8 of 10 animals, relief of cervical pressure led to complete respiratory recovery. The test was repeated up to 6 times per pig. Apnea was induced in 25 of 25 test procedures (100%) and was followed by respiratory recovery in 22 of 25 tests (88%). The threshold pressure at which the respiratory rate started to decrease was 47 ± 14 Torr when blood was used to increase the cervical compartment pressure. When silicone oil was used in a further experimental series, the threshold pressure was similar at 44 ± 21 Torr. The cervical compartment pressure needed to induce apnea was 74 ± 18 Torr using blood and 74 ± 39 Torr using silicone oil, both of which exceeded the mean arterial pressure by 28 Torr during apnea. Functional magnetic resonance imaging revealed a decrease in brainstem activity during phases of increased cervical compartment pressure, which suggests a possible role for cerebral vascular perfusion.
Respiratory drive can be suppressed by increased pressure in the cervical compartment, possibly because of a pressure-dependent impairment in cerebral perfusion through a form of cervical compartment phenomenon or, less likely, a pressure-dependent reflex (nervous) mechanism.
Earth is home to over 350,000 vascular plant species that differ in their traits in innumerable ways. A key challenge is to predict how natural or anthropogenically driven changes in the identity, ...abundance and diversity of co-occurring plant species drive important ecosystem-level properties such as biomass production or carbon storage. Here, we analyse the extent to which 42 different ecosystem properties can be predicted by 41 plant traits in 78 experimentally manipulated grassland plots over 10 years. Despite the unprecedented number of traits analysed, the average percentage of variation in ecosystem properties jointly explained was only moderate (32.6%) within individual years, and even much lower (12.7%) across years. Most other studies linking ecosystem properties to plant traits analysed no more than six traits and, when including only six traits in our analysis, the average percentage of variation explained in across-year levels of ecosystem properties dropped to 4.8%. Furthermore, we found on average only 12.2% overlap in significant predictors among ecosystem properties, indicating that a small set of key traits able to explain multiple ecosystem properties does not exist. Our results therefore suggest that there are specific limits to the extent to which traits per se can predict the long-term functional consequences of biodiversity change, so that data on additional drivers, such as interacting abiotic factors, may be required to improve predictions of ecosystem property levels.
White matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts ...WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition.
We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 IQR 66.0, 74.4 years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5).
Subjects with hypertension or Aβ positivity presented the largest WMH volumes (p
< 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aβ: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aβ: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aβ: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aβ: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aβ: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aβ: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (p
< 0.05). Aβ positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 ± 0.08, p
< 0.001; executive: - 0.21 ± 0.08, p
< 0.001; PACC5: - 0.29 ± 0.09, p
= 0.006; ΔPACC5: - 0.34 ± 0.04, p
< 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 ± 0.02, p
= 0.029; executive: - 0.04 ± 0.02, p
= 0.067; PACC5: - 0.05 ± 0.02, p
= 0.030; ΔPACC5: - 0.09 ± 0.03, p
= 0.043) and WMH in the optic radiation partially mediated that between Aβ positivity and memory (indirect effect-memory: - 0.05 ± 0.02, p
= 0.029).
Posterior white matter is susceptible to hypertension and Aβ accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies.
German Clinical Trials Register (DRKS00007966, 04/05/2015).
The aim of the present study was to evaluate the development of the circadian rhythm of the salivary cortisol in premature infants and its correlation with the onset of the sleep-activity behavior ...pattern during the first 3 weeks of life under controlled light:dark conditions. Furthermore, we investigated the influence of acoustic stimulation by audiotaped lullabies or the maternal voice on the cortisol values and long-term sleep-activity patterns. The study was a block-randomized, prospective clinical trial with a study population of 62 preterm neonates (30 < 37 gestational age). We compared two study groups who listened either to music or to the maternal voice (music: N = 20; maternal voice: N = 20) with a matched control group (N = 22). The acoustic stimulation took place every evening between 20:00 and 21:00 h for 30 min over a period of 2 weeks. The cortisol values and activity-rest behavior of the neonates were determined during the first 3 weeks of life on the 1st, 7th and 14th day. Actigraphic monitoring was used to record the activity pattern continuously over 24 h and a validated algorithm for neonates was used to estimate sleep and wakefulness. The saliva samples were obtained 10 min before and 10 min after the acoustic interventions for the study groups. Additionally, saliva samples were obtained from the control group seven times over a 24-h period (20:00, 21:00, 01:00, 05:00, 08:00, 13:00 and 17:00 h). The cortisol data were analyzed by fast Fourier transformation to assess periodic characteristics and frequencies. Hierarchical linear modeling was further performed for the statistical analysis. Results: The cortisol rhythm analysis indicated a circadian rhythm pattern for only one premature infant, all others of the neonates showed no circadian or ultradian rhythm in cortisol. Cortisol level of the premature neonates was significantly higher during the first day of the study period at night-time (median: 17.1 nmol/L, IQR = 9.7-24.4 nmol/L) than on days 7 (median: 9.6 nmol/L, IQR = 4.7-14.6 nmol/L; Tukey-HSD, z = 4.12, p < 0.001) and 14 (IQR = 5.8-13.7 nmol/L; Tukey-HSD, z = 2.89, p < 0.05). No significant effect of acoustic stimulation was observed on the cortisol concentration and sleep-wake behavior. The activity-sleep rhythm of preterm neonates was dominated by ultradian rhythm patterns with a prominent period length of 4 h (30.5%). Activity frequencies of neonates were also significantly higher overnight on the first study day (mean: 329 ± 185.1 U) than of night seven (mean: 260.2 ± 132.4 U; Tukey-HSD, z = 2.50, p < 0.05). Quiet-activity patterns increased, whereas high-activity patterns decreased during the observation period. Average sleep time increased significantly during the study time from day 1 to day 7 (Tukey-HSD, z = 2.51, p < 0.05). In conclusion, premature infants showed higher cortisol levels - without a circadian rhythmicity - and higher activity frequencies in the first days after birth which may reflect an adaptation process of neonates after birth. Cortisol concentrations and the activity patterns were not influenced by music interventions.
Background
Inguinal hernia repair belongs to the most frequently performed surgical procedures. Endoscopic techniques like TAPP and TEP have become standard of care together with the conventional ...open techniques. Especially in endoscopic techniques, there is a confusing amount of different meshes and fixation techniques with impact on perioperative and long-term outcome. We present the first single-center data on the use of titanized extra lightweight meshes and fibrin glue fixation compared to staple fixation regarding long-term outcome, especially chronic pain.
Materials and methods
A clinical trial with retrospective analysis of patient- and procedure-related data and questionnaire-based follow-up of TAPP procedures performed in 2012–2014 was conducted in a specialized hernia center. Standard TAPP technique was used with placement of TiMesh extra light (16 g/m
2
) and either fibrin glue or staple fixation. Procedure- and patient-related data are compared after propensity score matching regarding perioperative complications and long-term outcome.
Results
Of 612 TAPP procedures 372 procedures were included in analysis after propensity score matching. Fibrin glue was used in
n
= 279 and staple fixation in
n
= 93 cases. There were significant differences regarding duration of the surgical procedures (
p
= 0.001) and distribution of mesh size. No differences were noted regarding perioperative complications such as seroma or hematoma formation and need for re-laparoscopy. During a mean follow-up of 32.1 ± 20.6 month with a follow-up rate of 79%, there was no difference in long-term outcome, especially for rate of recurrence (
p
= 0.112) and development of chronic pain (
p
= 0.846). The overall rate of recurrence was 3.0% (
n
= 11), and in 2.4% (
n
= 9) patients complained of chronic pain.
Conclusion
Inguinal hernia repair using extra lightweight titanized meshes and fibrin glue fixation is safe and feasible compared to staple fixation even in large and combined hernia defects, if mesh size is adjusted to size of hernia defect. The rate of chronic pain was extremely low at 2.4%.
Spinal muscular atrophy (SMA), a common motor neuron disease in humans, results from loss of functional survival motor neuron ( SMN1 ) alleles. A nearly identical copy of the gene, SMN2 , fails to ...provide protection from SMA because of a single translationally silent nucleotide difference in exon 7. This likely disrupts an exonic splicing enhancer and causes exon 7 skipping, leading to abundant production of a shorter isoform, SMN2Δ 7 . The truncated transcript encodes a less stable protein with reduced self-oligomerization activity that fails to compensate for the loss of SMN1. This report describes the identification of an in vivo regulator of SMN mRNA processing. Htra2-β1, an SR-like splicing factor and ortholog of Drosophila melanogaster transformer-2, promoted the inclusion of SMN exon 7, which would stimulate full-length SMN 2 expression. Htra2-β1 specifically functioned through and bound an AG-rich exonic splicing enhancer in SMN exon 7. This effect is not species-specific as expression of Htra2-β1 in human or mouse cells carrying an SMN2 minigene dramatically increased production of full-length SMN2. This demonstrates that SMN2 mRNA processing can be modulated in vivo . Because all SMA patients retain at least one SMN2 copy, these results show that an in vivo modulation of SMN RNA processing could serve as a therapeutic strategy to prevent SMA.
PDF
