Seong-Hwan Jun, Samuel W. K. Wong, James V. Zidek, Alexandre Bouchard-Côté.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1678--1707.

Abstract:
In this paper, we consider the knot-matching problem arising in computational forestry. The knot-matching problem is an important problem that needs to be solved to advance the state of the art in automatic strength prediction of lumber. We show that this problem can be formulated as a quadripartite matching problem and develop a sequential decision model that admits efficient parameter estimation along with a sequential Monte Carlo sampler on graph matching that can be utilized for rapid sampling of graph matching. We demonstrate the effectiveness of our methods on 30 manually annotated boards and present findings from various simulation studies to provide further evidence supporting the efficacy of our methods.

M Steriade
Aug 1, 1993; 13:3252-3265
Articles

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [¹¹C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[¹¹C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[¹¹C]ABP688 and [¹¹C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.

SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.

Primary hypertension is a growing concern in adolescents due to its association with the obesity epidemic. Recent studies have examined underdetection and underdiagnosis of hypertension in adolescents but medical management of primary hypertension in adolescents is not well-described.

Our study describes patterns of antihypertensive prescribing for adolescents with primary hypertension including the use of monotherapy versus combination therapy by physicians of different specialties and factors associated with receipt of antihypertensive therapy over a multi-year period. (Read the full article)

Predischarge serum or transcutaneous bilirubinometry (TcB) measurements are recommended as appropriate screening options for identifying infants at risk for neonatal hyperbilirubinemia (NH). Visual inspection for jaundice is not reliable at identifying infants with NH in the community.

When compared with visual inspection alone, coordinated TcB screening for NH in acute-care and community settings is associated with significant improvements in laboratory utilization, patient care, convenience, and safety. (Read the full article)

Pulmonary hypertension is associated with bronchopulmonary dysplasia in extremely low birth weight infants and contributes to morbidity and mortality.

Pulmonary hypertension affects at least 1 in 6 extremely low birth weight infants and persists to discharge in most survivors. Routine screening of these infants with echocardiography at 4 weeks of age identifies only one-third of those affected. (Read the full article)

Infantile hypertrophic pyloric stenosis incidence varies over different regions and time periods. Recently, a decline was reported in the United States, Sweden (concurrent with a decline in sudden infant death syndrome), Scotland, and Denmark. The etiology remains unclear; therefore, epidemiologic data are valuable.

A decline in the incidence of infantile hypertrophic pyloric stenosis in Germany from 2000 to 2008 was noted but with wide regional variations. The regional distribution of infantile hypertrophic pyloric stenosis was different from that of sudden infant death syndrome. (Read the full article)

Insulin is commonly used to treat neonatal hyperglycemia, but there are few data to support its use. Tight glycemic control with insulin improves outcome in diabetic patients, but it is not known whether it is effective in hyperglycemic preterm infants.

Tight glycemic control with insulin in hyperglycemic preterm neonates decreases the rate of linear growth despite increased weight and occipitofrontal head circumference gain and increases the risk of hypoglycemia. Insulin may not be a safe and effective treatment in hyperglycemic preterm neonates. (Read the full article)

Most acute wheezing episodes in preschool children are associated with rhinovirus, which decreases extracellular adenosine triphosphate levels, leading to airway surface liquid dehydration and submucosal edema, which cause failure of mucus clearance. These children respond poorly to available treatments.

Hypertonic saline inhalation, a pro–airway surface liquid hydration therapy, significantly decreases both length of stay by 33% (1 day) and the absolute risk of hospitalization by 30% in preschool children presenting with acute wheezing episode to the emergency department. (Read the full article)

A dose-response relationship exists between light irradiance and decrease of total serum bilirubin concentration (TsB) at relatively low irradiances. It has been questioned whether by increasing irradiance a "saturation point" exists, above which no further decrease of TsB is seen.

We found a linear relation between light irradiance in the range of 20 to 55 μW/cm²/nm and decrease in TsB after 24 hours of therapy, with no evidence of a saturation point. (Read the full article)

Sudden infant death syndrome remains the major cause of postneonatal death in developed countries. Although infant-parent bed-sharing following antenatal smoking or maternal consumption of alcohol on the bed-sharing night increases the risk of death, the mechanism is not known.

Bed-sharing infants experienced more oxygen desaturations and episodes of carbon dioxide rebreathing than cot-sleeping infants but showed appropriate behavioral and physiologic responses. A deficit in these responses in vulnerable infants could link to increased risk of sudden infant death syndrome. (Read the full article)

The higher the predischarge bilirubin percentile reading on the hour of life–specific nomogram, the higher becomes that infant's risk of developing significant hyperbilirubinemia. Neonates in the low-risk zones (≤75th percentile) have a low risk of developing hyperbilirubinemia.

Thirty-two percent of newborns readmitted for hyperbilirubinemia had low-risk zone predischarge bilirubin percentile values, predominantly in the intermediate low-risk zone (41st–75th percentile). The intermediate low-risk zone may not be as low risk as previously thought. (Read the full article)

Although the natural course of bilirubin levels has been extensively studied in general neonatal populations, there is a paucity of data regarding bilirubin trends in neonates before the development of significant hyperbilirubinemia.

This study provides data on the natural course of transcutaneous bilirubin before the development of significant hyperbilirubinemia, and on the effect of different demographic and perinatal risk factors on the rate of bilirubin increase in neonates with borderline bilirubin values. (Read the full article)

The American Academy of Pediatrics and National Heart, Lung, and Blood Institute recommend routine blood pressure measurement in children. Little is known about the frequency with which blood pressure is currently measured in ambulatory pediatric settings in the United States.

Between 2000 and 2009, providers measured blood pressure during only one-third of ambulatory pediatric visits and two-thirds of pediatric preventive visits. The current rate of screening is especially low for children aged 3 to 7 years. (Read the full article)

The false-positive rate of newborn screening for classic congenital adrenal hyperplasia (CAH) remains high and has not been significantly improved by adjusting 17α-hydroxyprogesterone cutoff values for birth weight and/or gestational age. In response, 4 states have initiated second-tier steroid profile screening.

Under second-tier screening, the false-positive rate remains high, and classic CAH cases missed by screening (false-negatives) occur more frequently than reported. Physicians are cautioned that a negative screen does not necessarily rule out CAH. (Read the full article)

Knowledge is limited regarding the epidemiology of persistent pulmonary hypertension of the newborn (PPHN). Previous work has implicated a host of perinatal risk factors and a few antenatal antecedents of PPHN, including maternal consumption during pregnancy of nonsteroidal antiinflammatory medications.

In contrast to results of previous studies, we found no association between PPHN and maternal consumption during late pregnancy of nonsteroidal antiinflammatory drugs in general or ibuprofen in particular. (Read the full article)

Although previous studies indicate that perinatal factors are associated with altered neurodevelopment, data on the association between ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder in children are sparse.

This study demonstrates that preeclampsia, birth asphyxia, and respiratory distress syndrome are independently associated with increased risk of attention-deficit/hyperactivity disorder in a large population-based study. (Read the full article)

Prevalence of hypertension in children increased significantly over the past few decades, tracks into adulthood, and is a major risk factor for cardiovascular disease. However, current prevalence estimates in children have largely been based on studies conducted in school environments.

The current study reports the prevalence of childhood hypertension in community pediatric practice, which provides a typical pediatric examination environment, unlike blood pressure measured in school. The results show a significantly lower prevalence than what has previously been reported. (Read the full article)

Several studies have shown that behavioral problems can be associated with defecation and voiding disorders, although few studies have looked directly at a link between a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and constipation or fecal incontinence.

We identified an increased risk for both constipation and fecal incontinence in children with ADHD. In patients with concomitant ADHD and defecation disorders, more aggressive medical and behavioral treatment of the constipation or fecal incontinence may be warranted. (Read the full article)

Attention-deficit/hyperactivity disorder (ADHD) is the most common mental health condition diagnosed in childhood, is highly heritable, and more common in boys. Although studies have identified perinatal risk factors, no one has investigated perinatal risk factors separately in boys and girls.

Contrary to other studies, low birth weight, postterm pregnancy, low Apgar scores, and fetal distress were not risk factors for ADHD irrespective of gender. Early term deliveries increased the risk of ADHD, and oxytocin augmentation in girls may be protective. (Read the full article)

Hypertonic saline (3% and 5%), has been shown to improve clinical severity scores and reduce inpatient length of stay, and was associated with a trend toward lower admission rate in acute bronchiolitis.

We are not aware of any previous data using 7% hypertonic saline in bronchiolitis. Our results suggest that 7% saline does not lower clinical severity of illness, admission rate, or length of stay, when compared with normal saline. (Read the full article)

Approximately 50% of children diagnosed with attention-deficit/hyperactivity disorder (ADHD) at <7 years of age in the community do not meet criteria for ADHD over time. There is a need to examine predictors of diagnostic stability in young children with ADHD.

Predictors of diagnostic stability from early to middle childhood include child’s baseline externalizing and internalizing symptoms, parental history of psychopathology, and socioeconomic status. These predictors may guide treatment planning at the time of ADHD diagnosis. (Read the full article)

Up to 50% of children with attention-deficit/hyperactivity disorder (ADHD) meet criteria for a comorbid anxiety disorder. Despite the high prevalence of anxiety in these children, the impact of anxiety on the lives of children with ADHD has been largely overlooked.

Presence of ≥2 anxiety comorbidities in children with ADHD was associated with poorer child quality of life, daily functioning, and behavior. Multiple anxiety comorbidities were associated with poorer functioning for children with both ADHD-Inattentive and ADHD-Combined presentation. (Read the full article)

The definition of hypertension in children is complex because of the age-, gender-, and height-specific blood pressure algorithm. Blood pressure to height ratio was reported to easily identify hypertension in Chinese children living in a local area (Hebei Province).

Blood pressure to height ratio index is simple and accurate for screening for prehypertension and hypertension in Chinese children aged 6 to 17 years and can be used for early screening or treating Chinese children with hypertension. (Read the full article)

In very preterm infants, outcomes depend not only on the degree of immaturity, but also on the underlying pathologies that trigger preterm delivery. Studies that have addressed this issue have provided unclear results.

Patterns of outcomes differ between maternal hypertension and chorioamnionitis: hypertension is associated with greater risks for bronchopulmonary dysplasia and retinopathy of prematurity, and lower risks for brain injury, necrotizing enterocolitis, early-onset sepsis. For mortality, the effect changes across gestational age weeks. (Read the full article)

Few studies have performed precise cardiovascular assessments and regular follow-up of congenital rubella syndrome (CRS) patients’ clinical courses. A few studies have reported mortalities among children who have CRS; however, the causes of death have not been precisely described.

A total of 38 CRS cases in Vietnam were studied after a rubella outbreak in 2011. The mortality associated with pulmonary hypertension was significantly high if untreated. Conducting careful cardiologic assessments and providing continuous follow-up for each patient is required. (Read the full article)

For newborn infants, extreme hyperbilirubinemia (≥24.5 mg/dL) is associated with risk for severe bilirubin encephalopathy. The causal factor of extreme hyperbilirubinemia is often not established. The genotype of Gilbert syndrome, the UGT1A1*28 allele, is considered a potential risk factor.

The UGT1A1*28 allele was not associated with risk for developing extreme hyperbilirubinemia. (Read the full article)

Total serum bilirubin levels ≥30 mg/dL have been labeled as "hazardous." Levels this high are rare, occurring in 3 to 10 per 100 000 births. Few studies have examined etiologies and long-term outcomes in these infants.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a major identifiable cause, but is under-assessed. Chronic, bilirubin-induced neurotoxicity is rare and only occurred in the setting of additional risk factors (prematurity, G6PD deficiency, sepsis) and at levels far above recommended exchange transfusion thresholds. (Read the full article)

Sleep disorders are common in children and adolescents and have a substantial negative impact on daily life and school performance. Long-term evaluations of the efficacy and safety of pharmacologic treatment options for sleep disorders are lacking in pediatric patients.

These 2 studies provide the first evaluation of the effectiveness and safety of eszopiclone in children and adolescents with insomnia associated with ADHD. Data presented here encompass longer-term (up to 1 year) pediatric exposure to eszopiclone. (Read the full article)

Direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers have a high incidence of hyperbilirubinemia, attributable to increased hemolysis.

DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and a greater degree of hemolysis than DAT ± or DAT + counterparts. DAT strength should be taken into consideration when planning treatment strategies or follow-up of ABO-heterospecific newborns. (Read the full article)

Although existing analyses of inpatient pediatric pulmonary hypertension (PH) care have established an association with substantial morbidity and mortality, these investigations have been limited to small single-institution series or focused registries representative of selected patient subgroups.

This study provides the first contemporary, national trend analysis of inpatient care for children with PH. Pediatric PH is associated with a rapidly increasing number of hospital discharges and magnitude of resource utilization, and the makeup of this population is changing. (Read the full article)

Infants born very prematurely or with a very low birth weight are known to have an increased risk of attention-deficit/hyperactivity disorder (ADHD). Results concerning late preterm children are controversial and studies examining fetal growth represented by weight for gestational age are scarce.

We demonstrate that each declining week of gestation increases the risk of ADHD. Also, late preterm infants have an increased risk. Furthermore, as weight for gestational age becomes smaller than 1 SD below the mean, the risk of ADHD increases. (Read the full article)

Many studies have suggested that autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are commonly co-occuring neurodevelopmental conditions.

In children with co-occurring ASD and ADHD, an initial ADHD diagnosis may be associated with delayed ASD diagnosis and a higher likelihood of ASD diagnosis older than 6 years of age. Clinicians should consider ASD when evaluating young children presenting with ADHD symptoms. (Read the full article)

Guidelines for postdischarge monitoring of hyperbilirubinemia for neonates of white descent are available from the American Academy of Pediatrics; however, such information for healthy term and late preterm Chinese neonates is lacking.

A classification model for predicting the risk of significant hyperbilirubinemia in Chinese neonates was developed that combines a transcutaneous bilirubin–based nomogram with clinical risk factors. It classified newborns into 6 risk groups, which can guide clinicians in planning appropriate follow-up strategies. (Read the full article)

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log₁₀ CFU/mL) and biofilm (>8log₁₀ CFU/cm²) bacteria at 120h (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log₁₀ CFU/mL and ≤6log₁₀ CFU/cm² at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

Vinod K. Bhutani
Jan 1, 1999; 103:6-14
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Hyperion is a runtime encrypter for 32-bit and 64-bit portable executables. It is a reference implementation and bases on the paper "Hyperion: Implementation of a PE-Crypter".

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