Quantitative trait loci on chromosomes 9 and 19 modulate AII amacrine cell number in the mouse retina.

Sequence variants modulating gene function or expression affect various heritable traits, including the number of neurons within a population. The present study employed a forward-genetic approach to identify candidate causal genes and their sequence variants controlling the number of one type of retinal neuron, the AII amacrine cell. Data from twenty-six recombinant inbred (RI) strains of mice derived from the parental C57BL/6J (B6/J) and A/J laboratory strains were used to identify genomic loci regulating cell number. Large variation in cell number is present across the RI strains, from a low of ∼57,000 cells to a high of ∼87,000 cells. Quantitative trait locus (QTL) analysis revealed three prospective controlling genomic loci, on Chromosomes (Chrs) 9, 11, and 19, each contributing additive effects that together approach the range of variation observed. Composite interval mapping validated two of these loci, and chromosome substitution strains, in which the A/J genome for Chr 9 or 19 was introgressed on a B6/J genetic background, showed increased numbers of AII amacrine cells as predicted by those two QTL effects. Analysis of the respective genomic loci identified candidate controlling genes defined by their retinal expression, their established biological functions, and by the presence of sequence variants expected to modulate gene function or expression. Two candidate genes, Dtx4 on Chr 19, being a regulator of Notch signaling, and Dixdc1 on Chr 9, a modulator of the WNT-ß-catenin signaling pathway, were explored in further detail. Postnatal overexpression of Dtx4 was found to reduce the frequency of amacrine cells, while Dixdc1 knockout retinas contained an excess of AII amacrine cells. Sequence variants in each gene were identified, being the likely sources of variation in gene expression, ultimately contributing to the final number of AII amacrine cells.

The SAMe-TT2R2 Score Predicts Warfarin Control in an Australian Population with Atrial Fibrillation.

BACKGROUND: Warfarin requires regular monitoring with the time in therapeutic range (TTR), a common indicator of control and TTR > 70% is indicative of efficient anticoagulation. The SAMe-TT2R2 (sex, age, medical history, treatment, tobacco use, race) model has been utilised as a predictor of warfarin control, with a score ≥ 2 indicative of poor control. However, it has been suggested that race may be over-represented in this model. To date, no Australian studies have applied this model, possibly because race is not routinely recorded. Therefore, the aim of this study was to apply the SAMe-TT2R2 model in an Australian population on warfarin managed by both a warfarin care program (WCP) and general practitioner (GP). METHODS: Retrospective data was collected for patients receiving warfarin via a WCP in Queensland and whilst being managed by a GP. Patient data was used to calculate the SAMe-TT2R2 score and the TTR for each patient. Mean TTR was used for analysis and comparison with the categorised SAMe-TT2R2 score. RESULTS: Of the 3911 patients managed by a WCP, there was a significantly lower mean TTR for patients with a SAMe-TT2R2 score ≥ 2 compared to 0-1 (78.6 ± 10.7% vs. 80.9 ± 9.5%, p < 0.0001). Of these patients, 200 were analysed whilst managed by a GP and the categorised SAMe-TT2R2 score did not result in a statistically different mean TTR (69.3 ± 16.3% with 0-1 vs. 63.6 ± 15.0% with ≥2, p = 0.089), but a score ≥2 differentiated patients with a TTR less than 65%. CONCLUSIONS: The SAMe-TT2R2 model differentiated Australian patients with reduced warfarin control, despite the exclusion of race. In Australia, the SAMe-TT2R2 score could assist clinicians in identifying Australian patients who may obtain reduced warfarin control and benefit from additional interventions such as a dedicated WCP.

Xkr8 Modulates Bipolar Cell Number in the Mouse Retina.

The present study interrogated a quantitative trait locus (QTL) on Chr 4 associated with the population sizes of two types of bipolar cell in the mouse retina. This locus was identified by quantifying the number of rod bipolar cells and Type 2 cone bipolar cells across a panel of recombinant inbred (RI) strains of mice derived from two inbred laboratory strains, C57BL/6J (B6/J) and A/J, and mapping a proportion of that variation in cell number, for each cell type, to this shared locus. There, we identified the candidate gene X Kell blood group precursor related family member 8 homolog (Xkr8). While Xkr8 has no documented role in the retina, we localize robust expression in the mature retina via in situ hybridization, confirm its developmental presence via immunolabeling, and show that it is differentially regulated during the postnatal period between the B6/J and A/J strains using qPCR. Microarray analysis, derived from whole eye mRNA from the entire RI strain set, demonstrates significant negative correlation of Xkr8 expression with the number of each of these two types of bipolar cells, and the variation in Xkr8 expression across the strains maps a cis-eQTL, implicating a regulatory variant discriminating the parental genomes. Xkr8 plasmid electroporation during development yielded a reduction in the number of bipolar cells in the retina, while sequence analysis of Xkr8 in the two parental strain genomes identified a structural variant in the 3' UTR that may disrupt mRNA stability, and two SNPs in the promoter that create transcription factor binding sites. We propose that Xkr8, via its participation in mediating cell death, plays a role in the specification of bipolar cell number in the retina.

Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis.

Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1ß, G-CSF, TGFß and CXCL4) and activation of an inducible Irf8 and ß-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia.

Impact of an Enduring War on Two Military Psychiatry Residency Programs.

Four active duty military psychiatrists at different points in their careers were asked to reflect on the impact that the wars in Iraq and Afghanistan had on their respective training in military psychiatry residency programs. The result is an inside look from four unique perspectives on how military psychiatry residency training adapted over time to prepare their graduates to practice psychiatry in a wartime setting as many graduates went to the front lines of war shortly after graduation. This article will provide an understanding of the challenges faced by these residency programs striving to meet the behavioral health needs created by war while balancing this with ongoing ACGME requirements, how those challenges were met, and the impact it had on residents.

Service dogs, psychiatric hospitalization, and the ADA.

A service dog is defined as "any dog that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability." Some psychiatric patients may depend on a service dog for day-to-day functioning. The Americans with Disabilities Act (ADA) established certain rights and responsibilities for individuals with disabilities and health care providers. Psychiatric hospitalization of a patient with a service dog may pose a problem and involves balancing the requirement to provide safe and appropriate psychiatric care with the rights of individuals with disabilities. This Open Forum examines issues that arise in such circumstances, reviews the literature, and provides a foundation for the development of policies and procedures.

Independent genomic control of neuronal number across retinal cell types.

The sizes of different neuronal populations within the CNS are precisely controlled, but whether neuronal number is coordinated between cell types is unknown. We examined the covariance structure of 12 different retinal cell types across 30 genetically distinct lines of mice, finding minimal covariation when comparing synaptically connected or developmentally related cell types. Variation mapped to one or more genomic loci for each cell type, but rarely were these shared, indicating minimal genetic coregulation of final number. Multiple genes, therefore, participate in the specification of the size of every population of retinal neuron, yet genetic variants work largely independent of one another during development to modulate those numbers, yielding substantial variability in the convergence ratios between pre- and postsynaptic populations. Density-dependent cellular interactions in the outer plexiform layer overcome this variability to ensure the formation of neuronal circuits that maintain constant retinal coverage and complete afferent sampling.

Dissociative Amnesia and DSM-IV-TR Cluster C Personality Traits.

Dissociative amnesia is a disorder characterized by retrospectively reported memory gaps. These gaps involve an inability to recall personal information, usually of a traumatic or stressful nature. Dissociative amnesia most commonly occurs in the presence of other psychiatric conditions, particularly personality disorders. In the literature and in clinical practice, it is often associated with DSM-IV-TR Cluster B personality disorders. However, there is evidence to suggest that dissociative amnesia may be more likely to occur among individuals with Cluster C personality disorders. Presented here is a discussion of the types of memory loss, two cases of dissociative amnesia occurring in patients with Cluster C psychopathology, and a focused literature review.

Costs of attention deficit-hyperactivity disorder (ADHD) in the US: excess costs of persons with ADHD and their family members in 2000.

OBJECTIVE: The objective of this study is to provide a comprehensive estimate of the cost of ADHD by consider ing the healthcare and work loss costs of persons with ADHD, as well as those costs imposed on their family members. METHODS: Excess per capita healthcare (medical and prescription drug) and work loss (disability and work absence) costs of treated ADHD patients (ages 7 years-44 years) and their family members (under 65 years of age) were calculated using administrative claims data from a single large company; work loss costs are from disability data or imputed for medically related work loss days. Excess costs are the additional costs of patients and their family members over and above those of comparable control individuals. The excess costs of untreated individuals with ADHD and their family members were also estimated. All per capita costs were extrapolated using published prevalence and treatment rates and population data; the prevalence of persons with ADHD was based upon the literature. RESULTS: The total excess cost of ADHD in the US in 2000 was $31.6 billion. Of this total, $1.6 billion was for the ADHD treatment of patients, $12.1 billion was for all other healthcare costs of persons with ADHD, $14.2 billion was for all other healthcare costs of family members of persons with ADHD, and $3.7 billion was for the work loss cost of adults with ADHD and adult family members of persons with ADHD. CONCLUSION: The annual cost of ADHD in the US is substantial. Both treated and untreated persons with ADHD, as well as their family members, impose consider able economic burdens on the healthcare system as a result of this condition. While these first estimates of the cost of ADHD to the nation are suggestive of its substantial economic burden, future research needs to refine and build on this analysis, particularly in the context of a model to control for related co-morbidities. Similarly, since these results are based on data from a single company for the period 1996-1998, the analysis should be validated with more representative, current data.

Cost of stress urinary incontinence: a claims data analysis.

OBJECTIVES: The primary objectives of this research were to: (i) identify and present methodologies for estimating three types of 'cost-of-illness' measures using healthcare and disability claims data -- specifically 'cost of treatment', 'incremental cost of patient', and 'incremental cost of illness'; and (ii) perform a case-study analysis of these cost measures for women treated for stress urinary incontinence (SUI). STUDY DESIGN AND METHODS: In this paper, we discuss aspects of cost-of-illness methodologies in the context of SUI. We first distinguish between 'cost of treatment' (i.e. the costs of treating a specific condition), 'incremental cost of patient' (i.e. the additional costs associated with patients with a particular condition, irrespective of any comorbid conditions they may also have), and 'incremental cost of illness' (i.e. the additional costs resulting from a particular illness, as distinct from the costs of other conditions that the patient might have, including conditions which might have caused the illness in question). The latter case is in many ways the most complex to model, requiring controls for related causal conditions. We then applied these three methodologies by analysing the costs associated with SUI. Using data from a large employer claims database (n > 100 000), we estimated a series of regression models that reflected cost of treatment, incremental cost of patient, and incremental cost of illness for SUI. RESULTS: The three approaches yielded substantially different results. For many purposes the incremental cost-of-illness model provides the most appropriate results, as it controls for comorbid conditions, as well as patient demographics. On a per capita basis using the incremental cost-of-illness model, patients with SUI had direct costs that were 134% more than those for their controls and indirect costs that were 163% more than those for controls. Estimating costs for the average (i.e. mean) person results in dollar-termed estimates of the costs of SUI. In particular, we found that in 1998, the average direct medical cost of SUI was $US5642 and the indirect workplace cost of SUI was $US4208. CONCLUSIONS: Since the various methods yield substantially different results, it is important that the end user of cost-of-illness analyses of claims data have a clear purpose in mind when reporting the cost of the condition of concern. The incremental cost-of-illness measure for claims data has substantial advantages in terms of enhancing our understanding of the specific cost impact of SUI.

Lifetime medical costs for women: cardiovascular disease, diabetes, and stress urinary incontinence.

PURPOSE: To estimate the absolute and relative lifetime medical costs of treating women with cardiovascular disease (CVD), diabetes, or stress urinary incontinence (SUI). METHODS: Women under 65 years, treated for CVD, diabetes, or SUI, were identified using administrative medical claims data from a large employer (n >100,000). A case-control methodology was used to estimate the annual medical costs of these women. Based on these estimates and published government statistics, annual costs for women 65 years and older were calculated. An incidence-based methodology with steady-state assumptions was used to project to lifetime medical costs. Cost estimates are incremental, measured as the difference between costs of patients and their demographically similar controls without the condition. They therefore represent the additional costs of treating patients with the condition, beyond the average, baseline costs incurred by controls without the condition. FINDINGS: The incremental lifetime medical cost of treating a woman (in 2002 dollars) with CVD is $423,000, with diabetes is $233,000, and with SUI is $58,000 US dollars. Including the baseline medical costs of the control, the total lifetime medical costs (i.e., sum of incremental and baseline lifetime medical costs) of treating a woman with CVD are 3.4 times greater than the costs of a woman without CVD. Similarly, a woman with diabetes has total costs on average, 2.5 times greater than the costs of her control, whereas a woman with SUI has total lifetime medical costs 1.8 times greater than the costs of a similar woman without SUI. CONCLUSIONS: These substantial cost estimates suggest the need for further gender-specific research and policies addressing the long-term implications of health care financing, treatment, and preventive care.

Lower respiratory tract infections: impact on the workplace.

BACKGROUND: While there is some literature on the cost of specific respiratory infections, much of the existing research focuses only on direct medical treatment costs and does not take into consideration workplace burden due to disability and absenteeism. OBJECTIVE: To evaluate the impact of lower respiratory tract infections (LRTIs) on the workplace, specifically regarding the economic burden from an employer's perspective. DESIGN: Specific LRTI considered here were acute bronchitis, acute exacerbations of chronic bronchitis and pneumonia. Data from medical, prescription drug and disability claims of a large, national company in the US were used. These data provide information on both the healthcare and work loss impacts of LRTI on this major self-insured employer. The annual per capita expenditures for persons with LRTI were determined for beneficiaries (including employees and dependants) of this employer by analysing all claims in 1997. Results were compared with those of a 10% random sample of beneficiaries in the employer's overall beneficiary population. RESULTS: In 1997, total per person expenditures and total medical service utilisation were higher among beneficiaries with LRTI than among beneficiaries in the overall beneficiary population sample. Annual per capita employer expenditures for beneficiaries with LRTI totalled 6,116 US dollars, compared with 2,368 US dollars (1997 values) for the average beneficiary in the overall beneficiary population sample. Employer payments for lost work time through disability and absenteeism accounted for 17% of these expenditures amongst beneficiaries with LRTI and for 35% amongst employees with LRTI. CONCLUSIONS: Annual per capita expenditures for beneficiaries with LRTI were almost three times that of the average beneficiary. We conclude that it is important to consider work loss in analyses of the cost of LRTI.

The economic burden of depression with painful symptoms.

The economic burden of depression is substantial. The condition is highly prevalent, with both psychiatric and physical symptoms that often inflict pain. The chronic and often debilitating nature of depression results in costly medical therapies, as well as impaired workplace productivity. As a result, the overall economic burden of depression is comparable to that of serious physical illnesses, such as cancer and heart disease. This article presents an overview of the economic burden of depression and provides background on the relationship between depression and pain in this context. Research findings are also presented on the economic burden associated with a particular manifestation of pain among depressed patients, fibromyalgia. When painful physical symptoms accompany the already debilitating psychiatric and behavioral symptoms of depression, the economic burden that ensues for patients and their employers increases considerably. On purely economic grounds, more aggressive outreach may be warranted for patients with depression and comorbid pain to initiate treatment before symptoms are allowed to persist. However, more research is needed to assess the comprehensive economic impact that depression with painful physical symptoms can have on society.

The economic consequences of irritable bowel syndrome: a US employer perspective.

BACKGROUND: The objective of this study was to measure the direct costs of treating irritable bowel syndrome (IBS) and the indirect costs in the workplace. This was accomplished through retrospective analysis of administrative claims data from a national Fortune 100 manufacturer, which includes all medical, pharmaceutical, and disability claims for the company's employees, spouses/dependents, and retirees. METHODS: Patients with IBS were identified as individuals, aged 18 to 64 years, who received a primary code for IBS or a secondary code for IBS and a primary code for constipation or abdominal pain between January 1, 1996, and December 31, 1998. Of these patients with IBS, 93.7% were matched based on age, sex, employment status, and ZIP code to a control population of beneficiaries. Direct and indirect costs for patients with IBS were compared with those of matched controls. RESULTS: The average total cost (direct plus indirect) per patient with IBS was 4527 dollars in 1998 compared with 3276 dollars for a control beneficiary (P<.001). The average physician visit costs were 524 dollars and 345 dollars for patients with IBS and controls, respectively (P<.001). The average outpatient care costs to the employer were 1258 dollars and 742 dollars for patients with IBS and controls, respectively (P<.001). Medically related work absenteeism cost the employer 901 dollars on average per employee treated for IBS compared with 528 dollars on average per employee without IBS (P<.001). CONCLUSION: Irritable bowel syndrome is a significant financial burden on the employer that arises from an increase in direct and indirect costs compared with the control group.

The economics of women and depression: an employer's perspective.

BACKGROUND: While there is a growing literature on various aspects of depression in women, there is little research about the economic cost of depression in women. This analysis focuses on the direct and indirect cost to employers of female compared to male employees treated for depression, and their service utilization patterns. METHODS: We used a claims database from a national, Fortune 100 company to analyze the direct (medical and prescription drug) and indirect (disability and illness-related work absence) costs to an employer for female and male beneficiaries with depression. RESULTS: In 1998, the average female employee with depression cost this company $9265 compared to $8502 for male employees with depression. These women had significantly greater work absence costs which led to higher total costs than men, even though their medical costs were lower than those of comparable men. LIMITATIONS: Our analysis of the indirect costs associated with depressed female and male employees is limited to the costs of disability and sporadic illness-related work absences. The data available from this one employer did not allow accounting for the cost of reduced productivity while at work. CONCLUSIONS: We recommend that employers consider programs to improve the management of individuals with depression, in particular women. Also, further research is necessary to encourage the medical community to be more sensitive to the symptoms of depression in women.

The economic burden of depression in the United States: how did it change between 1990 and 2000?

BACKGROUND: The economic burden of depression was estimated to be 43.7 billion dollars in 1990. A subsequent study reported a cost burden of 52.9 billion dollars using revised prevalence data and a refined workplace cost estimation approach. The objective of the current report is to provide a 10-year update of these estimates using the same methodological framework. METHOD: Using a human capital approach, we developed prevalence-based estimates of 3 major cost categories: (1) direct costs, (2) mortality costs arising from depression-related suicides, and (3) costs associated with depression in the workplace. Cost-of-illness estimates from 1990 were updated to reflect the experience in 2000 using current epidemiologic data and publicly available population, wage, and cost information. RESULTS: Whereas the treatment rate of depression increased by over 50%, its economic burden rose by only 7%, going from 77.4 billion dollars in 1990 (inflation-adjusted dollars) to 83.1 billion dollars in 2000. Of the 2000 total, 26.1 billion dollars (31%) were direct medical costs, 5.4 billion dollars (7%) were suicide-related mortality costs, and 51.5 billion dollars (62%) were workplace costs. CONCLUSION: The economic burden of depression remained relatively stable between 1990 and 2000, despite a dramatic increase in the proportion of depression sufferers who received treatment. Future research will incorporate additional costs associated with depression sufferers, including the excess costs of their coexisting psychiatric and medical conditions and attention to the role of painful conditions as a driver of these costs.

Productivity and medical costs of diabetes in a large employer population.

OBJECTIVE: The purpose of this study was to assess the economic burden of diabetes from an employer's perspective. We analyzed the costs of diabetes, using claims data for an employed population and the prevalence of selected comorbid conditions. RESEARCH DESIGN AND METHODS: The data source is a claims database from a national Fortune 100 manufacturer. It includes medical, pharmacy, and disability claims for all beneficiaries (n >100,000). Both medical and work productivity costs of diabetes patients are compared by age with those of matched control subjects from the overall beneficiary population. Out-of-pocket and intangible costs are excluded. RESULTS: In 1998, the employer's mean annual per capita costs were higher for all diabetes beneficiaries than for control subjects ($7,778 +/- 16,176 vs. $3,367 +/- 8,783; P < 0.0001), yielding an incremental cost of $4,410 +/- 18,407 associated with diabetes. The medical and productivity costs for employees with diabetes were significantly (P < 0.0008) higher than for control subjects. The incremental cost of diabetes among employees ranged from $4,671 (aged 18-35 years) to $4,369 (aged 56-64 years). CONCLUSIONS: Diabetes imposes a significant economic burden on employers, particularly when including productivity costs. Employers should select health plans that provide enriched benefits to diabetes patients, including ready access to medical and pharmacy services as well as aggressive diabetes management programs.