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1.  Patterns of Change in ACGME-Accredited Residency Programs and Positions: Implication for the Adequacy of GME Positions and Supply of Physicians in the United States 
Recent studies suggest that the supply of primary care physicians and generalist physicians in other specialties may be inadequate to meet the needs of the US population. Data on the numbers and types of physicians-in-training, such as those collected by the Accreditation Council for Graduate Medical Education (ACGME), can be used to help understand variables affecting this supply.
We assessed trends in the number and type of medical school graduates entering accredited residencies, and the impact those trends could have on the future physician workforce.
Since 2004, the ACGME has published annually its data on accredited institutions, programs, and residents to help the graduate medical education community understand major trends in residency education, and to help guide graduate medical education policy. We present key results and trends for the period between academic years 2003–2004 and 2012–2013.
The data show that increases in trainees in accredited programs are not uniform across specialties, or the types of medical school from which trainees graduated. In the past 10 years, the growth in residents entering training that culminates in initial board certification (“pipeline” specialties) was 13.0%, the number of trainees entering subspecialty education increased 39.9%. In the past 5 years, there has been a 25.8% increase in the number of osteopathic physicians entering allopathic programs.
These trends portend challenges in absorbing the increasing numbers of allopathic and osteopathic graduates, and US international graduates in accredited programs. The increasing trend in subspecialization appears at odds with the current understanding of the need for generalist physicians.
PMCID: PMC4054773  PMID: 24949178
2.  Effects of Potential Federal Funding Cuts on Graduate Medical Education: Results of a Survey of Designated Institutional Officials 
Proposed reductions in federal funding for physician education may affect the United States' ability to produce the number of physicians needed to provide care.
Using a survey similar to that used by the ACGME in 2011, we assessed designated institutional officials' (DIOs) perceptions of the impact of potential GME funding reductions.
In August 2013, we sent a survey link to all DIOs of ACGME-accredited institutions (N  =  678). A 9-item survey asked how future federal funding would affect the number of residency programs in their institutions under 4 different funding scenarios: stable funding, and reductions of 10%, 33%, and 50%. We also asked about changes in the number of residency positions during the last 2 years.
The response rate was 47.9% (325 of 678 DIOs); respondents represent 58.9% of accredited institutions with more than 1 program. Most respondents reported no change or an increase under the stable funding scenario. Under a 33% funding reduction, an estimated 17 379 (14.8% of all current) positions would be lost, and a 50% reduction would result in a loss of 33 562 positions (28.6%). Primary care specialties (eg, family medicine, internal medicine) would be most affected under the greatest funding reductions.
The findings of the 2013 survey are consistent with 2011 data, with DIOs projecting significant reductions in programs and positions under more severe budget cuts. DIO comments highlighted reduced optimism (compared to data obtained in 2011) about the effect of funding cuts and concerns about the impact of reductions on patient care and health care personnel at teaching institutions.
PMCID: PMC3963787  PMID: 24701338
3.  Multiple drivers of decline in the global status of freshwater crayfish (Decapoda: Astacidea) 
Rates of biodiversity loss are higher in freshwater ecosystems than in most terrestrial or marine ecosystems, making freshwater conservation a priority. However, prioritization methods are impeded by insufficient knowledge on the distribution and conservation status of freshwater taxa, particularly invertebrates. We evaluated the extinction risk of the world's 590 freshwater crayfish species using the IUCN Categories and Criteria and found 32% of all species are threatened with extinction. The level of extinction risk differed between families, with proportionally more threatened species in the Parastacidae and Astacidae than in the Cambaridae. Four described species were Extinct and 21% were assessed as Data Deficient. There was geographical variation in the dominant threats affecting the main centres of crayfish diversity. The majority of threatened US and Mexican species face threats associated with urban development, pollution, damming and water management. Conversely, the majority of Australian threatened species are affected by climate change, harvesting, agriculture and invasive species. Only a small proportion of crayfish are found within the boundaries of protected areas, suggesting that alternative means of long-term protection will be required. Our study highlights many of the significant challenges yet to come for freshwater biodiversity unless conservation planning shifts from a reactive to proactive approach.
PMCID: PMC4290432  PMID: 25561679
extinction risk; crayfish; IUCN Red List; threatened; freshwater biodiversity
5.  ENaC γ-expressing astrocytes in the circumventricular organs, white matter, and ventral medullary surface: sites for Na+ regulation by glial cells 
Using a double immunofluorescence procedure, we report the discovery of a novel group of fibrous astrocytes that co-express epithelial sodium channel (ENaC) γ-subunit protein along with glial acidic fibrillary protein (GFAP). These cells are concentrated along the borders of the sensory circumventricular organs (CVOs), embedded in the white matter (e.g., optic nerve/chiasm, anterior commissure, corpus callosum, pyramidal tract) and are components of the pia mater. In the CVOs, a compact collection of ENaC γ-immunoreactive glial fibers form the lamina terminalis immediately rostral to the organum vasculosum of the lamina terminalis (OVLT). Astrocyte processes can be traced into the median preoptic nucleus – a region implicated in regulation of sodium homeostasis. In the subfornical organ (SFO), ENaC γ-GFAP astrocytes lie in its lateral border, but not in the ventromedial core. In the AP, a dense ENaC γ-GFAP glial fibers form the interface between the AP and nucleus tractus solitarius; this area is termed the subpostremal region. Antibodies against the ENaC α- or β-subunit proteins do not immunostain these regions. In contrast, the antibodies against the ENaC γ-subunit protein react weakly with neuronal cell bodies in the CVOs. Besides affecting glial-neural functions in the CVOs, the astrocytes found in the white matter may affect saltatory nerve conduction, serving as a sodium buffer. The ENaC γ-expressing astrocytes of the ventral medulla send processes into the raphe pallidus which intermingle with the serotoninergic (5-HT) neurons found in this region as well as with the other nearby 5-HT neurons distributed along ventral medullary surface.
PMCID: PMC3905447  PMID: 24145067
circumventricular organ; epithelial sodium channel; ENaC; glial acidic fibrillary protein; saltatory nerve conduction; ventral medullary surface
6.  A Spatially Distinct History of the Development of California Groundfish Fisheries 
PLoS ONE  2014;9(6):e99758.
During the past century, commercial fisheries have expanded from small vessels fishing in shallow, coastal habitats to a broad suite of vessels and gears that fish virtually every marine habitat on the globe. Understanding how fisheries have developed in space and time is critical for interpreting and managing the response of ecosystems to the effects of fishing, however time series of spatially explicit data are typically rare. Recently, the 1933–1968 portion of the commercial catch dataset from the California Department of Fish and Wildlife was recovered and digitized, completing the full historical series for both commercial and recreational datasets from 1933–2010. These unique datasets include landing estimates at a coarse 10 by 10 minute “grid-block” spatial resolution and extends the entire length of coastal California up to 180 kilometers from shore. In this study, we focus on the catch history of groundfish which were mapped for each grid-block using the year at 50% cumulative catch and total historical catch per habitat area. We then constructed generalized linear models to quantify the relationship between spatiotemporal trends in groundfish catches, distance from ports, depth, percentage of days with wind speed over 15 knots, SST and ocean productivity. Our results indicate that over the history of these fisheries, catches have taken place in increasingly deeper habitat, at a greater distance from ports, and in increasingly inclement weather conditions. Understanding spatial development of groundfish fisheries and catches in California are critical for improving population models and for evaluating whether implicit stock assessment model assumptions of relative homogeneity of fisheries removals over time and space are reasonable. This newly reconstructed catch dataset and analysis provides a comprehensive appreciation for the development of groundfish fisheries with respect to commonly assumed trends of global fisheries patterns that are typically constrained by a lack of long-term spatial datasets.
PMCID: PMC4072628  PMID: 24967973
7.  Method development and analysis of free HS and HS in proteoglycans from pre- and postmenopausal women: Evidence for biosynthetic pathway changes in sulfotransferase and sulfatase enzymes 
Analytical chemistry  2013;85(12):5917-5923.
Heparan sulfate (HS) is one of the most complex and informative biopolymers found on the cell surface or in the extracellular matrix as either free HS fragments or constituents of HS proteoglycans (HSPGs). Analysis of free HS and HSPG sugar chains in human serum at the disaccharide level has great potential for early disease diagnosis and prognosis, however, the low concentration of HS in human serum, together with the complexity of the serum matrix, limits the information on HS. In this study, we present and validate the development of a new sensitive method for in-depth compositional analysis of free HS and HSPG sugar chains. This protocol involved several steps including weak anion exchange chromatography, ultrafiltration and solid phase extraction for enhanced detection prior to LC-MS/MS analysis. Using this protocol, a total of 51 serum samples from 26 premenopausal and 25 postmenopausal women were analyzed. Statistically significant differences in heparin/HS disaccharide profiles were observed. The proportion of N-acetylation and N-sulfation in both free HS and HSPG sugar chains were significantly different between pre- and postmenopausal women, indicating changes in N-deacetylase/N-sulfotransferases (NDSTs), the enzymes involved in the initial step of the biosynthetic pathway. Differences in the proportion of 6-O-sulfation suggest that 6-O-sulfotransferase and/or 6-O-sulfatase enzymes may also be implicated.
PMCID: PMC3741352  PMID: 23659730
8.  Auraptene and its Effects on the Re-emergence of Colon Cancer Stem Cells 
Phytotherapy research : PTR  2012;27(5):784-786.
Recent studies indicate that auraptene (7-geranyloxycoumarin, AUR), a geranyloxycoumarin extracted from fruits of edible plants belonging to the Rutaceae family, may represent a novel lead compound for dietary colon cancer chemoprevention in rodents. As a continuation of studies aimed to better depict the pharmacological effects and mechanism of action of the title natural compound, the current investigation was undertaken to determine whether AUR would be able to prevent the growth and sphere (surrogate tumors) formation of FOLFOX-resistant colon cancer cells that are highly enriched in cancer stem cells (CSCs). Our results demonstrate that AUR at a concentration of 10 µM was able to inhibit the growth and formation of colonospheres of FOLFOX-resistant colon cancer HT-29 cells in vitro. The corresponding parental cells were also similarly affected by AUR at the same concentration level. The reduction in the growth and colonospheres formation in FOLFOX-resistant HT-29 was also associated with a concomitant decrease in phospho-epidermal growth factor receptor (pEGFR). These findings suggest that AUR could prevent the re-emergence of CSCs.
PMCID: PMC3496036  PMID: 22761031
auraptene; cancer chemoprevention; cancer stem cells; Citrus; colon cancer; geranyloxycoumarins
9.  “There is hunger in my community”: a qualitative study of food security as a cyclical force in sex work in Swaziland 
BMC Public Health  2014;14:79.
Swaziland has the highest HIV prevalence in the world – 32% of adults are currently living with HIV — and many Swazis are chronically food insecure — in 2011 one in four Swazis required food aid from the World Food Programme. In southern Africa, food insecurity has been linked to high-risk sexual behaviors, difficulty with antiretroviral therapy (ART) adherence, higher rates of mother-to-child HIV transmission, and more rapid HIV progression. Sex workers in Swaziland are a population that is most at risk of HIV. Little is known about the context and needs of sex workers in Swaziland who are living with HIV, nor how food insecurity may affect these needs.
In-depth interviews were conducted with 20 female sex workers who are living with HIV in Swaziland. Interviews took place in four different regions of the country, and were designed to learn about context, experiences, and health service needs of Swazi sex workers.
Hunger was a major and consistent theme in our informants’ lives. Women cited their own hunger or that of their children as the impetus to begin sex work, and as a primary motivation to continue to sell sex. Informants used good nutrition and the ability to access “healthy” foods as a strategy to manage their HIV infection. Informants discussed difficulty in adhering to ART when faced with the prospect of taking pills on an empty stomach. Across interviews, discussions of CD4 counts and ART adherence intertwined with discussions of poverty, hunger and healthy foods. Some sex workers felt that they had greater trouble accessing food through social networks as result of both their HIV status and profession.
Informants described a risk cycle of hunger, sex work, and HIV infection. The two latter drive an increased need for ‘healthy foods’ and an alienation from social networks that offer material and emotional support against hunger. Services and interventions for sex workers which address the pathways through which food insecurity generates vulnerability to HIV and social marginalization, build sex workers collective efficacy to mobilize, consider poverty alleviation, and address social and policy level changes are necessary and likely to have the greatest success.
PMCID: PMC3905928  PMID: 24460989
HIV/AIDS; Sex work; Food insecurity
10.  “They are human beings, they are Swazi”: intersecting stigmas and the positive health, dignity and prevention needs of HIV-positive men who have sex with men in Swaziland 
Journal of the International AIDS Society  2013;16(4Suppl 3):18749.
Despite the knowledge that men who have sex with men (MSM) are more likely to be infected with HIV across settings, there has been little investigation of the experiences of MSM who are living with HIV in sub-Saharan Africa. Using the framework of positive health, dignity and prevention, we explored the experiences and HIV prevention, care and treatment needs of MSM who are living with HIV in Swaziland.
We conducted 40 in-depth interviews with 20 HIV-positive MSM, 16 interviews with key informants and three focus groups with MSM community members. Qualitative analysis was iterative and included debriefing sessions with a study staff, a stakeholders’ workshop and coding for key themes using Atlas.ti.
The predominant theme was the significant and multiple forms of stigma and discrimination faced by MSM living with HIV in this setting due to both their sexual identity and HIV status. Dual stigma led to selective disclosure or lack of disclosure of both identities, and consequently a lack of social support for care-seeking and medication adherence. Perceived and experienced stigma from healthcare settings, particularly around sexual identity, also led to delayed care-seeking, travel to more distant clinics and missed opportunities for appropriate services. Participants described experiences of violence and lack of police protection as well as mental health challenges. Key informants, however, reflected on their duty to provide non-discriminatory services to all Swazis regardless of personal beliefs.
Intersectionality provides a framework for understanding the experiences of dual stigma and discrimination faced by MSM living with HIV in Swaziland and highlights how programmes and policies should consider the specific needs of this population when designing HIV prevention, care and treatment services. In Swaziland, the health sector should consider providing specialized training for healthcare providers, distributing condoms and lubricants and engaging MSM as peer outreach workers or expert clients. Interventions to reduce stigma, discrimination and violence against MSM and people living with HIV are also needed for both healthcare workers and the general population. Finally, research on experiences and needs of MSM living with HIV globally can help inform comprehensive HIV services for this population.
PMCID: PMC3852123  PMID: 24321112
men who have sex with men; positive health dignity and prevention; people living with HIV; qualitative research; Swaziland
11.  Wnt Signaling Though Beta-catenin is Required for Prostate Lineage Specification 
Developmental biology  2012;371(2):246-255.
Androgens initiate a complex network of signals within the UGS that trigger prostate lineage commitment and bud formation. Given its contributions to organogenesis in other systems, we investigated a role for canonical Wnt signaling in prostate development. We developed a new method to achieve complete deletion of beta-catenin, the transcriptional coactivator required for canonical Wnt signaling, in early prostate development. Beta-catenin deletion abrogated canonical Wnt signaling and yielded prostate rudiments that exhibited dramatically decreased budding and failed to adopt prostatic identity. This requirement for canonical Wnt signaling was limited to a brief critical period during the initial molecular phase of prostate identity specification. Deletion of beta-catenin in the adult prostate did not significantly affect organ homeostasis. Collectively, these data establish that beta-catenin and Wnt signaling play key roles in prostate lineage specification and bud outgrowth.
PMCID: PMC3472417  PMID: 22960283
Wnt signaling; Prostate development; Urogenital sinus; Mouse
12.  Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats 
Neuroscience  2012;218:110-125.
The parabrachial nucleus (PB) is a brainstem cell group that receives a strong input from the nucleus tractus solitarius regarding the physiological status of the internal organs and sends efferent projections throughout the forebrain. Since the neuroanatomical organization of the PB remains unclear, our first step was to use specific antibodies against two neural lineage transcription factors: Forkhead box protein2 (FoxP2) and LIM homeodomain transcription factor 1 beta (Lmx1b) to define the PB in adult rats. This allowed us to construct a cytoarchitectonic PB map based on the distribution of neurons that constitutively express these two transcription factors. Second, the in situ hybridization method combined with immunohistochemistry demonstrated that mRNA for glutamate vesicular transporter Vglut2 (Slc17a6) was present in most of the Lmx1b+ and FoxP2+ parabrachial neurons, indicating these neurons use glutamate as a transmitter. Third, conscious rats were maintained in a hypotensive or hypertensive state for two hours, and then, their brainstems were prepared by the standard c-Fos method which is a measure of neuronal activity. Both hypotension and hypertension resulted in c-Fos activation of Lmx1b+ neurons in the external lateral-outer subdivision of the PB (PBel-outer). Hypotension, but not hypertension, caused c-Fos activity in the FoxP2+ neurons of the central lateral PB (PBcl) subnucleus. The Kölliker-Fuse nucleus as well as the lateral crescent PB and rostralmost part of the PBcl contain neurons that co-express FoxP2+ and Lmx1b+, but none of these were activated after blood pressure changes. Salt-sensitive FoxP2 neurons in the pre-locus coeruleus and PBel-inner were not c-Fos activated following blood pressure changes. In summary, the present study shows that the PBel-outer and PBcl subnuclei originate from two different neural progenitors, contain glutamatergic neurons, and are affected by blood pressure changes, with the PBel-outer reacting to both hypo- and hypertension, and the PBcl signaling only hypotensive changes.
PMCID: PMC3405558  PMID: 22641087
13.  The Regulatory Easy Street: Self-Regulation Below the Self-Control Threshold Does not Consume Regulatory Resources 
We present and test a theory in which self-control is distinguished from broader acts of self-regulation when it is both effortful and conscious. In two studies, we examined whether acts of behavioral management that do not require effort are exempt from resource depletion. In Study 1, we found that a self-regulation task only reduced subsequent self-control for participants who had previously indicated that completing the task would require effort. In Study 2, we found that participants who completed a self-regulation task for two minutes did not evidence the subsequent impairment in self-control evident for participants who had completed the task for four or more minutes. Our results support the notion that self-regulation without effort falls below the self-control threshold and has different downstream consequences than self-control.
PMCID: PMC3375861  PMID: 22711963
15.  Biomarkers of Maternal and Fetal Exposure to Organochlorine Pesticides Measured in Pregnant Hispanic Women from Brownsville, Texas 
Biomarkers of organochlorine pesticides were measured in both venous and umbilical cord blood from 35 pregnant Hispanic women living in Brownsville, Texas, USA. Gas chromatography with an electron capture detector was used to analyze specimens for 30 individual pesticides or their metabolites. Results indicate that blood concentrations were relatively low for most individual compounds, but that high-end (upper 10th percentile) values for total DDT were comparatively high. Although health effects associated with measured blood concentrations are uncertain, there is concern that fetal exposure to low levels of these OC compounds, either individually or in combination, might contribute to subsequent health problems, including neurodevelopmental effects, cancer, endocrine disruption, obesity and diabetes.
PMCID: PMC3564140  PMID: 23343981
biomarkers; fetal exposure; maternal exposure; organochlorine pesticides
16.  A potent and orally active antagonist of multiple inhibitor of apoptosis proteins (IAPs) (SM-406/AT-406) in clinical development for cancer treatment 
Journal of medicinal chemistry  2011;54(8):2714-2726.
We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.
PMCID: PMC3520070  PMID: 21443232
18.  Serotonergic Inputs to the FoxP2 neurons of the Pre-Locus Coeruleus and Parabrachial Nuclei That Project to the Ventral Tegmental Area 
Neuroscience  2011;193:229-240.
The present study demonstrates that serotonin (5-hydroxytryptamine, 5-HT)-containing axons project to two sets of neurons in the dorsolateral pons that have been implicated in salt appetite regulation. These two neuronal groups are the pre-locus coeruleus (pre-LC) and a region in the parabrachial nucleus termed the external lateral-inner subdivision (PBel-inner). Neurons in both regions constitutively express the transcription factor Forkhead protein2 (FoxP2), and become c-Fos activated after prolonged sodium depletion. They send extensive projections to the midbrain and forebrain, including a strong projection to the ventral tegmental area (VTA) – a reward processing site. The retrograde neuronal tracer cholera toxin β-subunit (CTb) was injected into the VTA region; this was done to label the cell bodies of the pre-LC and PBel-inner neurons. After one week, the rats were killed and their brainstems processed by a triple-color immunofluorescence procedure. The purpose was to determine whether the CTb-labeled pre-LC and PBel-inner neurons, which also had FoxP2 immunoreactive nuclei, received close contacts from 5-HT axons. Neurons with these properties were found in both sites. Since the origin of this 5-HT input was unknown, a second set of experiments was carried out in which CTb was injected into the pre-LC or lateral PB. One week later, the rats were perfused and the brainstems from these animals were analyzed for the presence of neurons that co-contained CTb and tryptophan hydroxylase (synthetic enzyme for 5-HT) immunoreactivity. Co-labeled neurons were found mainly in the area postrema and to a lesser degree, in the dorsal raphe nucleus. We propose that the 5-HT inputs to the pre-LC and PBel-inner may modulate the salt appetite-related functions that influence the reward system.
PMCID: PMC3185334  PMID: 21784133
area postrema; dorsal raphe nucleus; parabrachial nucleus; pre-locus coeruleus; salt appetite; ventral tegmental area
19.  FoxP2 Brainstem Neurons Project to Sodium Appetite Regulatory Sites 
The transcription factor Forkhead box protein 2 (FoxP2) is expressed in two cell groups of the brainstem that have been implicated in sodium appetite regulation: the pre-locus coeruleus (pre-LC) and parabrachial nucleus - external lateral-inner subdivision (PBel-inner). Because the connections of these two groups are unknown, neuroanatomical tracing methods were used to define their central projections. The pre-LC outputs were first analyzed using an anterograde axonal tracer - Phaseolus vulgaris leucoagglutinin (PHAL) to construct a brain map. Next, we examined whether the FoxP2 immunoreactive (FoxP2+) neurons of the pre-LC contribute to these projections using a retrograde neuronal tracer - cholera toxin β-subunit (CTb). CTb was injected into selected brain regions identified in the anterograde tracing study. One week later the rats were killed, and brainstem sections were processed by a double immunohistochemical procedure to determine whether the FoxP2+ neurons in the pre-LC and/or PBel-inner contained CTb. FoxP2+ pre-LC neurons project to: 1) ventral pallidum; 2) substantia innominata and bed nucleus of the stria terminalis; 3) paraventricular, central medial, parafascicular, and subparafascicular parvicellular thalamic nuclei; 4) paraventricular (PVH), lateral, perifornical, dorsomedial (DMH), and parasubthalamic hypothalamic nuclei; and 5) ventral tegmental area (VTA), periaqueductal gray matter (PAG), dorsal and central linear raphe nuclei. FoxP2+ PBel-inner neurons project to the PVH and DMH, with weaker connections to the LHA, VTA, and PAG. Both the pre-LC and PBel-inner project to central sites implicated in sodium appetite, and related issues, including foraging behavior, hedonic responses to salt intake, sodium balance, and cardiovascular regulation, are discussed.
PMCID: PMC3148274  PMID: 21605659
bed nucleus of stria terminalis; parabrachial nucleus; pre-locus coeruleus; hypothalamus; thalamus; substantia innominata; ventral pallidum; ventral tegmental area
20.  Pediatric high-impact conditions in the United States: retrospective analysis of hospitalizations and associated resource use 
BMC Pediatrics  2012;12:61.
Child mortality in the United States has decreased over time, with advance in biomedicine. Little is known about patterns of current pediatric health care delivery for children with the leading causes of child death (high-impact conditions). We described patient and hospital characteristics, and hospital resource use, among children hospitalized with high-impact conditions, according to illness severity.
We conducted a retrospective study of children 0–18 years of age, hospitalized with discharge diagnoses of the ten leading causes of child death, excluding diagnoses not amenable to hospital care, using the 2006 version of the Kid’s Inpatient Database. National estimates of average and cumulative hospital length of stay and total charges were compared between types of hospitals according to patient illness severity, which was measured using all-patient refined diagnosis related group severity classification into minor-moderate, major, and extreme severity.
There were an estimated 3,084,548 child hospitalizations nationally for high-impact conditions in 2006, distributed evenly among hospital types. Most (84.4%) had minor-moderate illness severity, 12.2% major severity, and 3.4% were extremely ill. Most (64%) of the extremely ill were hospitalized at children’s hospitals. Mean hospital stay was longest among the extremely ill (32.8 days), compared with major (9.8 days, p < 0.0001), or minor-moderate (3.4 days, p < 0.001) illness severity. Mean total hospital charges for the extremely ill were also significantly higher than for hospitalizations with major or minor-moderate severity. Among the extremely ill, more frequent hospitalization at children’s hospitals resulted in higher annual cumulative charges among children’s hospitals ($ 7.4 billion), compared with non-children teaching hospitals ($ 3.2 billion, p = 0.023), and non-children’s non-teaching hospitals ($ 1.5 billion, p < 0.001). Cumulative annual length of hospital stay followed the same pattern, according to hospital type.
Gradation of increasing illness severity among children hospitalized for high-impact conditions was associated with concomitantly increased resource consumption. These findings have significant implications for children’s hospitals which appear to accrue the highest resource use burden due to preferential hospitalization of the most severely ill at these hospitals.
PMCID: PMC3502249  PMID: 22681875
21.  Therapeutic potential and molecular mechanism of a novel, potent, non-peptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatment 
Molecular cancer therapeutics  2011;10(5):902-914.
Smac mimetics are being developed as a new class of anticancer therapies. Since the single-agent activity of Smac mimetics is very limited, rational combinations represent a viable strategy for their clinical development. The combination of Smac mimetics with TRAIL may be particularly attractive due to the low toxicity of TRAIL to normal cells and the synergistic antitumor activity observed for the combination. In the present study, we have investigated the combination synergy between TRAIL and a potent Smac mimetic, SM-164 in vitro and in vivo and the underlying molecular mechanism of action for the synergy. Our study demonstrates that SM-164 is highly synergistic with TRAIL in vitro in both TRAIL-sensitive and TRAIL-resistant cancer cell lines of breast, prostate, and colon cancer. Furthermore, the combination of SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Our data shows that XIAP and cIAP1, but not cIAP2, work in concert to attenuate the activity of TRAIL; SM-164 strongly enhances TRAIL activity by concurrently targeting XIAP and cIAP1. Moreover, while RIP1 plays a minimal role in TRAIL's activity as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. Our present study provides a strong rationale to develop the combination of SM-164 and TRAIL as a new therapeutic strategy for the treatment of human cancer.
PMCID: PMC3091962  PMID: 21372226
Smac Mimetic; TRAIL; Synergy; Tumor Regression
22.  FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation* 
Brain research  2010;1375:19-27.
Two specific groups of neurons in the dorsolateral pons are activated by dietary sodium deprivation. These two groups are the pre-locus coeruleus (pre-LC) and the inner subdivision of the external lateral parabrachial nucleus (PBel-inner). In each site, after rats are fed an extremely low-sodium diet for over a week, neurons increase their expression of an activity-induced transcription factor, c-Fos. Here, we confirm this observation and extend it by demonstrating that these two groups of neurons express a common marker gene, the constitutively-expressed transcription factor Forkhead box protein 2 (FoxP2). That is, virtually all of the c-Fos activated neurons in both regions also express FoxP2. The expression of FoxP2 by both these groups of neurons suggests that they are developmentally-related subsets derived from the same basic population. Given that FoxP2, unlike c-Fos, is expressed independent of sodium deprivation, this marker may be useful in future studies of the pre-LC and PBel-inner. The molecular definition of these neurons, which project to circuits in the forebrain that influence visceral, appetitive, and hedonic functions, may allow direct experimental exploration of the functional role of these circuits using genetic tools.
PMCID: PMC3034829  PMID: 21108936
nucleus tractus solitarius; parabrachial nucleus; pre-locus coeruleus; salt appetite; sodium intake; transcription factor
23.  Tracking Residents Through Multiple Residency Programs: A Different Approach for Measuring Residents' Rates of Continuing Graduate Medical Education in ACGME-Accredited Programs 
Increased focus on the number and type of physicians delivering health care in the United States necessitates a better understanding of changes in graduate medical education (GME). Data collected by the Accreditation Council for Graduate Medical Education (ACGME) allow longitudinal tracking of residents, revealing the number and type of residents who continue GME following completion of an initial residency. We examined trends in the percent of graduates pursuing additional clinical education following graduation from ACGME-accredited pipeline specialty programs (specialties leading to initial board certification).
Using data collected annually by the ACGME, we tracked residents graduating from ACGME-accredited pipeline specialty programs between academic year (AY) 2002–2003 and AY 2006–2007 and those pursuing additional ACGME-accredited training within 2 years. We examined changes in the number of graduates and the percent of graduates continuing GME by specialty, by type of medical school, and overall.
The number of pipeline specialty graduates increased by 1171 (5.3%) between AY 2002–2003 and AY 2006–2007. During the same period, the number of graduates pursuing additional GME increased by 1059 (16.7%). The overall rate of continuing GME increased each year, from 28.5% (6331/22229) in AY 2002–2003 to 31.6% (7390/23400) in AY 2006–2007. Rates differed by specialty and for US medical school graduates (26.4% [3896/14752] in AY 2002–2003 to 31.6% [4718/14941] in AY 2006–2007) versus international medical graduates (35.2% [2118/6023] to 33.8% [2246/6647]).
The number of graduates and the rate of continuing GME increased from AY 2002–2003 to AY 2006–2007. Our findings show a recent increase in the rate of continued training for US medical school graduates compared to international medical graduates. Our results differ from previously reported rates of subspecialization in the literature. Tracking individual residents through residency and fellowship programs provides a better understanding of residents' pathways to practice.
PMCID: PMC3010950  PMID: 22132288
24.  Residency Programs' Evaluations of the Competencies: Data Provided to the ACGME About Types of Assessments Used by Programs 
In 1999, the Accreditation Council for Graduate Medical Education (ACGME) Outcome Project began to focus on resident performance in the 6 competencies of patient care, medical knowledge, professionalism, practice-based learning and improvement, interpersonal communication skills, and professionalism. Beginning in 2007, the ACGME began collecting information on how programs assess these competencies. This report provides information on the nature and extent of those assessments.
Using data collected by the ACGME for site visits, we use descriptive statistics and percentages to describe the number and type of methods and assessors accredited programs (n  =  4417) report using to assess the competencies. Observed differences among specialties, methodologies, and assessors are tested with analysis of variance procedures.
Almost all (>97%) of programs report assessing all of the competencies and using multiple methods and multiple assessors. Similar assessment methods and evaluator types were consistently used across the 6 competencies. However, there were some differences in the use of patient and family as assessors: Primary care and ambulatory specialties used these to a greater extent than other specialties.
Residency programs are emphasizing the competencies in their evaluation of residents. Understanding the scope of evaluation methodologies that programs use in resident assessment is important for both the profession and the public, so that together we may monitor continuing improvement in US graduate medical education.
PMCID: PMC3010956  PMID: 22132294
25.  Expression and Genetic Loss of Function Analysis of the HAT/DESC Cluster Proteases TMPRSS11A and HAT 
PLoS ONE  2011;6(8):e23261.
Genome mining at the turn of the millennium uncovered a new family of type II transmembrane serine proteases (TTSPs) that comprises 17 members in humans and 19 in mice. TTSPs phylogenetically belong to one of four subfamilies: matriptase, hepsin/TMPRSS, corin and HAT/DESC. Whereas a wealth of information now has been gathered as to the physiological functions of members of the hepsin/TMPRSS, matriptase, and corin subfamilies of TTSPs, comparatively little is known about the functions of the HAT/DESC subfamily of proteases. Here we perform a combined expression and functional analysis of this TTSP subfamily. We show that the five human and seven murine HAT/DESC proteases are coordinately expressed, suggesting a level of functional redundancy. We also perform a comprehensive phenotypic analysis of mice deficient in two of the most widely expressed HAT/DESC proteases, TMPRSS11A and HAT, and show that the two proteases are dispensable for development, health, and long-term survival in the absence of external challenges or additional genetic deficits. Our comprehensive expression analysis and generation of TMPRSS11A- and HAT-deficient mutant mouse strains provide a valuable resource for the scientific community for further exploration of the HAT/DESC subfamily proteases in physiological and pathological processes.
PMCID: PMC3154331  PMID: 21853097

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