Caspase-3 Regulates YAP-Dependent Cell Proliferation and Organ Size.

Apoptosis culminates in the activation of caspase-3, which plays an important role in implementing the cell death program. Here, we reveal a non-apoptotic role of caspase-3 as a key regulator of cell proliferation and organ size. Caspase-3 is specifically activated in the proliferating cells of the sebaceous gland, but does not instruct cell elimination. Deletion or chemical inhibition of caspase-3 diminishes cell proliferation, decreases cell number and reduces sebaceous gland size in vivo. Exploring the underlying mechanism, we demonstrate that α-catenin is cleaved by caspase-3, thus facilitating the activation and nuclear translocation of yes-associated protein (YAP), a vital regulator of organ size. Accordingly, activation of caspase-3 leads to YAP-dependent organ size augmentation. Finally, we show that X-linked inhibitor of apoptosis protein (XIAP) serves as an endogenous feedback antagonist for the caspase-3/YAP signaling module. Taken together, we report here a molecular mechanism wherein the apoptotic machinery is refocused to regulate cell proliferation and orchestrate organ size.

Correction of aberrant growth preserves tissue homeostasis.

Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/ß-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutation-independent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.

Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool.

Tissue homeostasis is achieved through a balance of cell production (growth) and elimination (regression). In contrast to tissue growth, the cells and molecular signals required for tissue regression remain unknown. To investigate physiological tissue regression, we use the mouse hair follicle, which cycles stereotypically between phases of growth and regression while maintaining a pool of stem cells to perpetuate tissue regeneration. Here we show by intravital microscopy in live mice that the regression phase eliminates the majority of the epithelial cells by two distinct mechanisms: terminal differentiation of suprabasal cells and a spatial gradient of apoptosis of basal cells. Furthermore, we demonstrate that basal epithelial cells collectively act as phagocytes to clear dying epithelial neighbours. Through cellular and genetic ablation we show that epithelial cell death is extrinsically induced through transforming growth factor (TGF)-ß activation and mesenchymal crosstalk. Strikingly, our data show that regression acts to reduce the stem cell pool, as inhibition of regression results in excess basal epithelial cells with regenerative abilities. This study identifies the cellular behaviours and molecular mechanisms of regression that counterbalance growth to maintain tissue homeostasis.

Can Statewide Emergency Department, Hospital Discharge, and Violent Death Reporting System Data Be Used to Monitor Burden of Firearm-Related Injury and Death in Rhode Island?

CONTEXT: National data on the epidemiology of firearm injuries and circumstances of firearm deaths are difficult to obtain and often are nonreliable. Since firearm injury and death rates and causes can vary substantially between states, it is critical to consider state-specific data sources. OBJECTIVE: In this study, we illustrate how states can systematically examine demographic characteristics, firearm information, type of wound, toxicology tests, precipitating circumstances, and costs to provide a comprehensive picture of firearm injuries and deaths using data sets from a single state with relatively low rates of firearm injury and death. DESIGN: Cross-sectional study. SETTING: Firearm-related injury data for the period 2005-2014 were obtained from the Rhode Island emergency department and hospital discharge data sets; death data for the same period were obtained from the Rhode Island Violent Death Reporting System. MAIN OUTCOME MEASURE: Descriptive statistics were used. Healthcare Cost and Utilization Project cost-to-charge ratios were used to convert total hospital charges to costs. RESULTS: Most firearm-related emergency department visits (55.8%) and hospital discharges (79.2%) in Rhode Island were from assaults; however, most firearm-related deaths were suicides (60.1%). The annual cost of firearm-related hospitalizations was more than $830 000. Most decedents who died because of firearms tested positive for illicit substances. Nearly a quarter (23.5%) of firearm-related homicides were due to a conflict between the decedent and suspect. More than half (59%) of firearm suicide decedents were reported to have had current mental or physical problems prior to death. CONCLUSIONS: Understanding the state-specific magnitude and patterns (who, where, factors, etc) of firearm injury and death may help inform local injury prevention efforts. States with similar data sets may want to adopt our analyses. Surveillance of firearm-related injury and death is essential. Dissemination of surveillance findings to key stakeholders is critical in improving firearm injury prevention. States that are not part of the National Violent Death Reporting System (NVDRS) could work with their other data sources to obtain a better picture of violent injuries and deaths to make the best use of resources.

Population-Based Surveillance of Birth Defects Potentially Related to Zika Virus Infection - 15 States and U.S. Territories, 2016.

Zika virus infection during pregnancy can cause serious birth defects, including microcephaly and brain abnormalities (1). Population-based birth defects surveillance systems are critical to monitor all infants and fetuses with birth defects potentially related to Zika virus infection, regardless of known exposure or laboratory evidence of Zika virus infection during pregnancy. CDC analyzed data from 15 U.S. jurisdictions conducting population-based surveillance for birth defects potentially related to Zika virus infection.* Jurisdictions were stratified into the following three groups: those with 1) documented local transmission of Zika virus during 2016; 2) one or more cases of confirmed, symptomatic, travel-associated Zika virus disease reported to CDC per 100,000 residents; and 3) less than one case of confirmed, symptomatic, travel-associated Zika virus disease reported to CDC per 100,000 residents. A total of 2,962 infants and fetuses (3.0 per 1,000 live births; 95% confidence interval [CI] = 2.9-3.2) (2) met the case definition.† In areas with local transmission there was a non-statistically significant increase in total birth defects potentially related to Zika virus infection from 2.8 cases per 1,000 live births in the first half of 2016 to 3.0 cases in the second half (p = 0.10). However, when neural tube defects and other early brain malformations (NTDs)§ were excluded, the prevalence of birth defects strongly linked to congenital Zika virus infection increased significantly, from 2.0 cases per 1,000 live births in the first half of 2016 to 2.4 cases in the second half, an increase of 29 more cases than expected (p = 0.009). These findings underscore the importance of surveillance for birth defects potentially related to Zika virus infection and the need for continued monitoring in areas at risk for Zika.

Sept4/ARTS is required for stem cell apoptosis and tumor suppression.

Inhibitor of Apoptosis Proteins (IAPs) are frequently overexpressed in tumors and have become promising targets for developing anti-cancer drugs. IAPs can be inhibited by natural antagonists, but a physiological requirement of mammalian IAP antagonists remains to be established. Here we show that deletion of the mouse Sept4 gene, which encodes the IAP antagonist ARTS, promotes tumor development. Sept4-null mice have increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an Eµ-Myc background. These phenotypes are partially suppressed by inactivation of XIAP. Our results suggest that apoptosis plays an important role as a frontline defense against cancer by restricting the number of normal stem cells.

Can Emergency Department, Hospital Discharge, and Death Data Be Used to Monitor Burden of Drug Overdose in Rhode Island?

CONTEXT: Drug overdoses are a growing public health problem in the United States. Rhode Island is also confronted with a serious epidemic of drug overdose deaths and ranks sixth worst in the United States for age-adjusted drug overdose death rate. OBJECTIVE: To monitor trends of drug overdose-related emergency department (ED) visits, hospitalizations, and deaths and classify the drug overdoses by demographics, discharge status, intent, and specific drug involved to plan for health care resource allocation, mental health services, drug abuse treatment, prevention, and policies. DESIGN: Cross-sectional study. SETTING: The 2005-2014 ED, hospital discharge, and death data were used for this study. MAIN OUTCOME MEASURE: Age-adjusted rates were calculated by using age-specific Rhode Island 2010 standard population. Healthcare Cost and Utilization Project cost-to-charge ratios were used to convert total hospital charges to costs. The descriptive analysis was performed. RESULTS: Hospitalizations generally represent the most severe cases; there are substantially fewer cases than are seen in the ED, and their characteristics are different from ED visits. More than half of the ED cases were an unintentional injury by drug overdose, but more than half of the hospital discharge data cases were a suicide/self-inflicted injury by drug overdose. There were typically much more females than males that result in a hospital admission. In Rhode Island, there were 249 drug overdose deaths in 2014. Drug overdose fatalities were more likely to be young, male, white, and those who reside in suburban regions. IMPLICATIONS: Nonfatal and fatal drug overdose data are important for understanding the scope, incidence, and breadth of this public health epidemic and can guide overdose intervention efforts. In Rhode Island, policy makers can use drug overdose data to target high-risk subpopulations to reduce overdose injuries and fatalities. The Rhode Island study can be shared with other states. CONCLUSIONS: Regardless of the type of drug, overdoses remain a public health crisis in Rhode Island. It is a dynamic epidemic and needs partnership among public health, behavioral health, public safety, clinic, pharmacy, and communities. The ability to track drug overdose in real time will be an essential tool to respond to the constantly evolving drug overdose epidemic in Rhode Island quickly and effectively.

A latent class model to identify city/town chronic disease patterns.

OBJECTIVE: Most departments of health grapple with how to most effectively allocate resources to address chronic diseases. We adapted a model created by Massachusetts to create customized city/town profiles in order to identify the patterns of chronic disease among 39 cities/towns in Rhode Island. METHODS: We used four data sources to identify 20 indicators of four domains: demographics and socioeconomic status; health behaviors and chronic diseases prevalence; no regular provider and non-emergent emergency department visits; and chronic disease-related hospitalizations. A latent class model was used to group cities/towns into distinct latent class memberships based on similar patterns of indicators. Data were analyzed in 2014. RESULTS: The latent class model differentiated three distinct classes of city/town, reflecting three levels of economic and health indicators. CONCLUSIONS: Our model was a simplified version of one constructed by Massachusetts that larger states can also use to understand chronic disease patterns among cities/towns. Chronic disease programs and policies can use the findings to direct resources toward targets not always identified by more traditional analyses.

Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression.

Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.

The Association Between Maternal Depressive Symptoms and Toddlers' Developmental and Behavioral Problems: A Population-Based Study.

This study aims to compare the developmental-behavioral profiles of 2-year-olds of mothers who experienced postpartum and/or current depression with profiles of toddlers of mothers without depression at either time using population-based Rhode Island data. Weighted data from Rhode Island Department of Health's Pregnancy Risk Assessment Monitoring System and Rhode Island's follow-up Toddlers Wellness Overview Survey distributed to mothers giving birth between 2006 and 2008 were analyzed. Compared with non-depressed mothers, those with any depression following childbirth reported more concerns with their toddlers' receptive language, social-emotional development, and their sleep and feeding behaviors. When adjusted for demographics, persistent depression remained associated with social-emotional (adjusted odds ratio [aOR] = 7.53, 2.78-20.34) and feeding concerns (aOR = 3.13, 1.36-7.22), and current depression was associated with social-emotional concerns (aOR = 2.52, 1.26-5.01). We conclude that pediatric providers should explore maternal mental health as a mediating and potentially modifiable factor beyond the postpartum period when toddlers present with developmental-behavioral challenges.

GRIN2B gene expression is increased in the anterior cingulate cortex in major depression.

The glutamatergic system may be central to the neurobiology and treatment of major depressive disorder (MDD) and psychosis. Despite the success of N-methyl-D-aspartate receptor (NMDAR) antagonists for the treatment of MDD, little is known regarding the expression of these glutamate receptors in MDD. In this study we measured gene expression, via qRT-PCR, of the major NMDAR subunits, in the anterior cingulate cortex (ACC) in MDD subjects with and without psychosis, and non-psychiatric controls. Overall, GRIN2B mRNA was increased in both MDD with (+32%) and without psychosis (+40%) compared to controls along with a trend increase in GRIN1 mRNA in MDD overall (+24%). Furthermore, in MDD with psychosis there was a significant decrease in the GRIN2A:GRIN2B mRNA ratio (-19%). Collectively these results suggest dysfunction of the glutamatergic system at the gene expression level in the ACC in MDD. Increased GRIN2B mRNA in MDD, along with an altered GRIN2A:GRIN2B ratio in psychotic depression, suggests a disruption to NMDAR composition could be present in the ACC in MDD; this could lead to enhanced signalling via GluN2B-containing NMDARs and greater potential for glutamate excitotoxicity in the ACC in MDD. These results support future research into GluN2B antagonist-based treatments for MDD.

The effects of preventative cannabidiol in a male neuregulin 1 mouse model of schizophrenia.

Cannabidiol (CBD) is a non-intoxicating cannabinoid with antipsychotic-like properties, however it's potential to prevent schizophrenia development has not been thoroughly investigated. Brain maturation during adolescence creates a window where CBD could potentially limit the development of schizophrenia. The neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mutant mouse shows face, predictive, and construct validity for schizophrenia. Here we sought to determine if CBD given in adolescence could prevent the development of the schizophrenia-relevant phenotype, as well as susceptibility to the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) in Nrg1 TM HET mice. Adolescent male Nrg1 mutants and wild type-like (WT) animals were administered 30 mg/kg CBD i.p. daily for seven weeks, and were tested for locomotion, social behavior, sensorimotor gating and cognition, and sensitivity to acute THC-induced behaviors. GAD67, GluA1, and NMDAR1 protein levels were measured in the hippocampus, striatum, and prefrontal cortex. Chronic adolescent CBD increased locomotion in animals regardless of genotype, was anxiolytic, and increased social behavior when animals were tested for their acute THC response. CBD did not alleviate the schizophrenia-relevant hyperlocomotive phenotype of Nrg1 mutants, nor deficits in social behaviors. Nrg1 mutant mice treated with CBD and THC showed no habituation to a startle pulse, suggesting CBD increased vulnerability to the startle habituation-reducing effects of THC in mutant mice. CBD increased levels of GluA1, but reduced levels of GAD67 in the hippocampus of Nrg1 mutants. These results suggest adolescent CBD is not effective as a preventative of schizophrenia-relevant behavioral deficits in mutants and may actually contribute to pathological changes in the brain that increase sensitivity to THC in particular behavioral domains.

Alterations in the kynurenine pathway and excitatory amino acid transporter-2 in depression with and without psychosis: Evidence of a potential astrocyte pathology.

Evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of depression and disorders involving psychosis. Stimulation of the kynurenine pathway leads to the formation of neuroactive metabolites, including kynurenic acid (predominantly in astrocytes) and quinolinic acid (predominantly in microglia), which are antagonists and agonists of the glutamate NMDA receptor, respectively. In this study, we measured gene expression via qRT-PCR of the main kynurenine pathway enzymes in the anterior cingulate cortex (ACC) in people with major depressive disorder and matched controls. In parallel, we tested for diagnostic differences in gene expression of relevant glial markers. We used total RNA isolated from the ACC from depression subjects with psychosis (n = 12) and without psychosis (n = 12), and non-psychiatric controls (n = 12) provided by the Stanley Medical Research Institute. In the ACC, KYAT1 (KAT I), AADAT (KAT II), and the astrocytic SLC1A2 (EAAT2) mRNAs, were significantly increased in depression, when combining those with and without psychosis. The increased KYAT1 and AADAT mRNA indicates that depression is associated with increased activation of the kynurenic acid arm of the kynurenine pathway in the ACC, suggesting an astrocyte response in depression. Considering EAAT2 and KATs increase astrocytic glutamate uptake and production of the NMDA receptor antagonist kynurenic acid, the observed increases of these markers may relate to changes in glutamatergic signalling in depression. These results suggest dysfunction of the kynurenine pathway in the brain in depression and point to the kynurenine pathway as a possible driver of glutamate dysfunction in depression.

Widespread false gene gains caused by duplication errors in genome assemblies.

BACKGROUND: False duplications in genome assemblies lead to false biological conclusions. We quantified false duplications in popularly used previous genome assemblies for platypus, zebra finch, and Anna's Hummingbird, and their new counterparts of the same species generated by the Vertebrate Genomes Project, of which the Vertebrate Genomes Project pipeline attempted to eliminate false duplications through haplotype phasing and purging. These assemblies are among the first generated by the Vertebrate Genomes Project where there was a prior chromosomal level reference assembly to compare with. RESULTS: Whole genome alignments revealed that 4 to 16% of the sequences are falsely duplicated in the previous assemblies, impacting hundreds to thousands of genes. These lead to overestimated gene family expansions. The main source of the false duplications is heterotype duplications, where the haplotype sequences were relatively more divergent than other parts of the genome leading the assembly algorithms to classify them as separate genes or genomic regions. A minor source is sequencing errors. Ancient ATP nucleotide binding gene families have a higher prevalence of false duplications compared to other gene families. Although present in a smaller proportion, we observe false duplications remaining in the Vertebrate Genomes Project assemblies that can be identified and purged. CONCLUSIONS: This study highlights the need for more advanced assembly methods that better separate haplotypes and sequence errors, and the need for cautious analyses on gene gains.

Association between initial opioid prescription diagnosis type and subsequent chronic prescription opioid use in Rhode Island: a population-based cohort study.

OBJECTIVE: To identify initial diagnoses associated with elevated risk of chronic prescription opioid use. DESIGN: Population-based, retrospective cohort study. SETTING: State of Rhode Island. PARTICIPANTS: Rhode Island residents with an initial opioid prescription dispensed between 1 April 2019 and 31 March 2020. PRIMARY OUTCOME MEASURE: Subsequent chronic prescription opioid use, defined as receiving 60 or more days' supply of opioids in the 90 days following an initial opioid prescription. RESULTS: Among the 87 055 patients with an initial opioid prescription, 3199 (3.7%) subsequently became chronic users. Patients who become chronic users tended to receive a longer days' supply, greater quantity dispensed, but a lower morphine milligram equivalents on the initial opioid prescription. Patients prescribed an initial opioid prescription for diseases of the musculoskeletal system and connective tissue (adjusted OR (aOR): 5.9, 95% CI: 4.7 to 7.6), diseases of the nervous system (aOR: 6.3, 95% CI: 4.9 to 8.0) and neoplasms (aOR: 5.6, 95% CI: 4.2 to 7.5) had higher odds of subsequent chronic prescription opioid use, compared with a referent group that included all diagnosis types with fewer than 15 chronic opioid users, after adjusting for confounders. CONCLUSIONS: By focusing interventions and prescribing guidelines on specific types of diagnoses that carry a high risk of chronic prescription opioid use and diagnoses that would benefit equally or more from alternative management approaches, states and healthcare organisations may more efficiently decrease inappropriate opioid prescribing while improving the quality of patient care.

Thy1 marks a distinct population of slow-cycling stem cells in the mouse epidermis.

The presence of distinct stem cells that maintain the interfollicular epidermis is highly debated. Here, we report a population of keratinocytes, marked by Thy1, in the basal layer of the interfollicular epidermis. We find that epidermal cells expressing differential levels of Thy1 display distinct transcriptional signatures. Thy1+ keratinocytes do not express T cell markers, express a unique transcriptional profile, cycle significantly slower than basal epidermal progenitors and display significant expansion potential in vitro. Multicolor lineage tracing analyses and mathematical modeling reveal that Thy1+ basal keratinocytes do not compete neutrally alike interfollicular progenitors and contribute long-term to both epidermal replenishment and wound repair. Importantly, ablation of Thy1+ cells strongly impairs these processes, thus indicating the non-redundant function of Thy1+ stem cells in the epidermis. Collectively, these results reveal a distinct stem cell population that plays a critical role in epidermal homeostasis and repair.

False gene and chromosome losses in genome assemblies caused by GC content variation and repeats.

BACKGROUND: Many short-read genome assemblies have been found to be incomplete and contain mis-assemblies. The Vertebrate Genomes Project has been producing new reference genome assemblies with an emphasis on being as complete and error-free as possible, which requires utilizing long reads, long-range scaffolding data, new assembly algorithms, and manual curation. A more thorough evaluation of the recent references relative to prior assemblies can provide a detailed overview of the types and magnitude of improvements. RESULTS: Here we evaluate new vertebrate genome references relative to the previous assemblies for the same species and, in two cases, the same individuals, including a mammal (platypus), two birds (zebra finch, Anna's hummingbird), and a fish (climbing perch). We find that up to 11% of genomic sequence is entirely missing in the previous assemblies. In the Vertebrate Genomes Project zebra finch assembly, we identify eight new GC- and repeat-rich micro-chromosomes with high gene density. The impact of missing sequences is biased towards GC-rich 5'-proximal promoters and 5' exon regions of protein-coding genes and long non-coding RNAs. Between 26 and 60% of genes include structural or sequence errors that could lead to misunderstanding of their function when using the previous genome assemblies. CONCLUSIONS: Our findings reveal novel regulatory landscapes and protein coding sequences that have been greatly underestimated in previous assemblies and are now present in the Vertebrate Genomes Project reference genomes.

Benchmarking ultra-high molecular weight DNA preservation methods for long-read and long-range sequencing.

BACKGROUND: Studies in vertebrate genomics require sampling from a broad range of tissue types, taxa, and localities. Recent advancements in long-read and long-range genome sequencing have made it possible to produce high-quality chromosome-level genome assemblies for almost any organism. However, adequate tissue preservation for the requisite ultra-high molecular weight DNA (uHMW DNA) remains a major challenge. Here we present a comparative study of preservation methods for field and laboratory tissue sampling, across vertebrate classes and different tissue types. RESULTS: We find that storage temperature was the strongest predictor of uHMW fragment lengths. While immediate flash-freezing remains the sample preservation gold standard, samples preserved in 95% EtOH or 20-25% DMSO-EDTA showed little fragment length degradation when stored at 4°C for 6 hours. Samples in 95% EtOH or 20-25% DMSO-EDTA kept at 4°C for 1 week after dissection still yielded adequate amounts of uHMW DNA for most applications. Tissue type was a significant predictor of total DNA yield but not fragment length. Preservation solution had a smaller but significant influence on both fragment length and DNA yield. CONCLUSION: We provide sample preservation guidelines that ensure sufficient DNA integrity and amount required for use with long-read and long-range sequencing technologies across vertebrates. Our best practices generated the uHMW DNA needed for the high-quality reference genomes for phase 1 of the Vertebrate Genomes Project, whose ultimate mission is to generate chromosome-level reference genome assemblies of all ∼70,000 extant vertebrate species.

New options for child health surveillance by state health departments.

Until recently there were no child health surveillance instruments available to state health departments for children 1-14 years old. In recent years, several states have developed new surveillance instruments. This article includes information about examples of four types of child health surveys: (1) Behavioral Risk Factor Surveillance System (BRFSS) follow-back survey [phone-based in Colorado]; (2) Pregnancy Risk Assessment Monitoring System (PRAMS) re-interviews [PRAMS-based in Rhode Island]; (3) elementary school child health survey combined with dental screening and physical measurements of height and weight [school-based in Maine]; and (4) freestanding elementary school survey [school-based in Oregon]. The PRAMS-based survey was moderate in expense but addressed only issues related to 2 year olds. The phone-based survey was the most expensive but addressed issues of children 1-14 years old. The school-based surveys were moderate in expense, logistically complex, and were least likely to provide robust generalizable data.

The kynurenine pathway in major depression: What we know and where to next.

Major depression is a serious psychiatric disorder, occurring in up to 20 % of the population. Despite its devastating burden, the neurobiological changes associated with depression are not fully understood. A growing body of evidence suggests the kynurenine pathway is implicated in the pathophysiology of depression. In this review, we bring together the literature examining elements of the kynurenine pathway in depression and explore the implications for the pathophysiology and treatment of depression, while highlighting the gaps in the current knowledge. Current research indicates an increased potential for neurotoxic activity of the kynurenine pathway in peripheral blood samples but an increased activation of the putative neuroprotective arm in some brain regions in depression. The disconnect between these findings requires further investigation, with a greater research effort on elucidating the central effects of the kynurenine pathway in driving depression symptomology. Research investigating the benefits of targeting the kynurenine pathway centred on human brain findings and the heterogenous subtypes of depression will help guide the identification of effective drug targets in depression.