The prevalence of work-related suicides varies by reporting source from the National Violent Death Reporting System.

INTRODUCTION: Both suicides overall and work-related suicides are increasing in the United States, and efforts to reduce suicide risk will require an understanding of the frequency and role of work in suicides. This study examines the incidence of occupational suicides using the National Violent Death Reporting System (NVDRS), which identified the role of work in suicides using the traditional death certificate as well as from death investigations. METHODS: NVDRS suicides among those aged 16 through 65 from 2013 through 2017 were examined to determine if the death certificate identified the death as work-related, if the death investigation identified a job problem as a suicide circumstance, and if the death investigation indicated that the job problem was a crisis at the time of the suicide. RESULTS: Overall, 1.13% of death certificates identified the suicides as work-related, 2.34% of suicides included a job crisis, and 11.2% a job problem, and proportions did not vary over the years of the study. Overlap between the death certificate and death investigation was very low, with only 0.21% of suicides identified as related to work by both sources. Identification of work-relatedness varied by source for demographic characteristics, mechanism of suicide, and occupation. For example, the death certificate identified 2.1% of suicides among those working in protective services as work-related, but death investigations identified 15.2% as having a job problem. CONCLUSION: Work-related factors may be associated with a far higher proportion of suicides than previously documented.

Development and maturation of the fibrous components of the arterial roots in the mouse heart.

The arterial roots are important transitional regions of the heart, connecting the intrapericardial components of the aortic and pulmonary trunks with their ventricular outlets. They house the arterial (semilunar) valves and, in the case of the aorta, are the points of coronary arterial attachment. Moreover, because of the semilunar attachments of the valve leaflets, the arterial roots span the anatomic ventriculo-arterial junction. By virtue of this arrangement, the interleaflet triangles, despite being fibrous, are found on the ventricular aspect of the root and located within the left ventricular cavity. Malformations and diseases of the aortic root are common and serious. Despite the mouse being the animal model of choice for studying cardiac development, few studies have examined the structure of their arterial roots. As a consequence, our understanding of their formation and maturation is incomplete. We set out to clarify the anatomical and histological features of the mouse arterial roots, particularly focusing on their walls and the points of attachment of the valve leaflets. We then sought to determine the embryonic lineage relationships between these tissues, as a forerunner to understanding how they form and mature over time. Using histological stains and immunohistochemistry, we show that the walls of the mouse arterial roots show a gradual transition, with smooth muscle cells (SMC) forming the bulk of wall at the most distal points of attachments of the valve leaflets, while being entirely fibrous at their base. Although the interleaflet triangles lie within the ventricular chambers, we show that they are histologically indistinguishable from the arterial sinus walls until the end of gestation. Differences become apparent after birth, and are only completed by postnatal day 21. Using Cre-lox-based lineage tracing technology to label progenitor populations, we show that the SMC and fibrous tissue within the walls of the mature arterial roots share a common origin from the second heart field (SHF) and exclude trans-differentiation of myocardium as a source for the interleaflet triangle fibrous tissues. Moreover, we show that the attachment points of the leaflets to the walls, like the leaflets themselves, are derived from the outflow cushions, having contributions from both SHF-derived endothelial cells and neural crest cells. Our data thus show that the arterial roots in the mouse heart are similar to the features described in the human heart. They provide a framework for understanding complex lesions and diseases affecting the aortic root.

Direct measurements of the coordination of lever arm swing and the catalytic cycle in myosin V.

Myosins use a conserved structural mechanism to convert the energy from ATP hydrolysis into a large swing of the force-generating lever arm. The precise timing of the lever arm movement with respect to the steps in the actomyosin ATPase cycle has not been determined. We have developed a FRET system in myosin V that uses three donor-acceptor pairs to examine the kinetics of lever arm swing during the recovery and power stroke phases of the ATPase cycle. During the recovery stroke the lever arm swing is tightly coupled to priming the active site for ATP hydrolysis. The lever arm swing during the power stroke occurs in two steps, a fast step that occurs before phosphate release and a slow step that occurs before ADP release. Time-resolved FRET demonstrates a 20-Å change in distance between the pre- and postpower stroke states and shows that the lever arm is more dynamic in the postpower stroke state. Our results suggest myosin binding to actin in the ADP.Pi complex triggers a rapid power stroke that gates the release of phosphate, whereas a second slower power stroke may be important for mediating strain sensitivity.

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26-33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts.

Effect of cumulative dexamethasone dose in preterm infants on neurodevelopmental and growth outcomes: a Western Australia experience.

OBJECTIVE: Comparing the long-term neurodevelopmental and growth outcomes of lower and higher cumulative dexamethasone exposure in preterm infants ventilated for a minimum cumulative duration of 7 days. DESIGN: A retrospective cohort medical chart review of infants born in Western Australia <29 weeks' gestation between January 2007 and May 2016 who were mechanically ventilated >7 days. INTERVENTION: No dexamethasone (controls) or a total cumulative dexamethasone dose of <2 mg/kg (lower) and ≥2 mg/kg (higher). MAIN OUTCOME MEASURES: Long-term disability at 2 and 5 years and growth measurement outcomes at 2 years of age. RESULTS: Dexamethasone was given to 104 infants (66 with cumulative dose <2 mg/kg; 38 with cumulative dose ≥2 mg/kg), and 324 infants were controls. There was no difference in odds of long-term disability in infants with any dexamethasone exposure compared with controls (aOR: 0.90, 95% CI 0.34 to 2.02, p=0.784). No difference in long-term disability was found between the lower and higher groups (p=0.494). The prevalence of cerebral palsy (Gross Motor Functional Classification System level ≥2) between the control, lower and high-dose groups did not differ significantly (5.8% vs 4.0% vs 0%). The higher dose group had lower mean weight z-score (mean effect: -0.83, 95% CI: -1.54 to -0.01, p=0.023), height z-score (mean effect: -0.63, 95% CI: -12.5 to -0.01, p=0.048) and head circumference z-score (mean effect: -0.65, 95% CI: -1.25 to -0.05, p=0.035) compared with controls. CONCLUSIONS: In our cohort, dexamethasone use was not associated with increased odds of long-term disability. Dexamethasone use was associated with lower growth measurements compared with controls.

In situ isolation of immunoglobulin sequences expressed by single tumor-infiltrating B cells using laser-assisted microdissection.

The isolation of fully human monoclonal antibodies (MAb) against tumor targets has to date relied largely on combinatorial library-based antibody display techniques, which generally require lengthy antigen selection procedures due to a low frequency of clones expressing compatible heavy (VH) and light chain (VL) variable genes. Here we describe a method to directly isolate immunoglobulin sequences in situ from antibody-producing cells infiltrating human tumor tissue. Single B cells and plasma cells infiltrating cervical cancer were microdissected from tissue sections using laser-assisted microscopy, and VH and VL expressed by each individual cell amplified using nested reverse transcriptase- polymerase chain reaction (RT-PCR), thus retaining the native VH and VL pairing. Sequencing analysis determined that the isolated cells expressed functional immunoglobulin variable genes, consistent with an antitumor antibody response. The immunoglobulin sequences can be reassembled as Fab or scFv fragments using conventional recombinant antibody expression plasmids. This method will allow a more direct assessment of the humoral immune response to cancer, and the potential identification of novel human therapeutic cancer antibodies.

Early adenosine receptor activation ameliorates spinal cord reperfusion injury.

OBJECTIVES: Adenosine receptor activation at reperfusion has been shown to ameliorate ischemia-reperfusion injury of the spinal cord, but the effects of therapy given in response to ischemic injury are unknown. We hypothesized that adenosine receptor activation with ATL-146e would produce similar protection from ischemic spinal cord injury, whether given at reperfusion or in a delayed fashion. METHODS: Twenty-two New Zealand white rabbits were divided into three groups. All three groups, including the ischemia-reperfusion group (IR, n = 8), underwent 45 min of infrarenal aortic occlusion. The early treatment group (early, n = 8) received 0.06 mug/kg/min of ATL-146e for 3 h beginning 10 min prior to reperfusion. The delayed treatment group (delayed, n = 6) received ATL-146e starting 1 h after reperfusion. After 48 h, hind limb function was graded using the Tarlov score. Finally, lumbar spinal cord neuronal cytoarchitecture was evaluated. RESULTS: Hemodynamic parameters were similar among the groups. Hind limb function at 48 h was significantly better in the early group (3.5 +/- 1.0) compared to the IR group (0.625 +/- 0.5, P < or = 0.01). There was a trend towards better hind limb function in the early group compared to the delayed group (2.4 +/- 1.1, P = 0.08). Hind limb function was similar between delayed and IR groups. Hematoxylin-eosin spinal cord sections demonstrated preservation of viable motor neurons in the early group compared to the delayed and IR groups. CONCLUSIONS: Early therapy with ATL-146e provided better protection in this study; therefore, therapy should not be delayed until there is evidence of ischemic neurological deficit. This study suggests that adenosine receptor activation is most effective as a preventive strategy at reperfusion for optimal protection in spinal cord ischemia-reperfusion injury.