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1.  Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis 
BMC Pediatrics  2014;14(1):261.
Infection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants.
Claims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003–2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, ≥ one palivizumab administration from August 1st to end of season, and high-risk status (≤34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed.
Of the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV-related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34).
RSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2431-14-261) contains supplementary material, which is available to authorized users.
PMCID: PMC4287588  PMID: 25308481
Prophylaxis; Respiratory syncytial virus; Palivizumab; Non-compliance
2.  The Beneficial Effects of n-3 Polyunsaturated Fatty Acids on Diet Induced Obesity and Impaired Glucose Control Do Not Require Gpr120 
PLoS ONE  2014;9(12):e114942.
GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.
PMCID: PMC4277291  PMID: 25541716
3.  Retrospective Analysis of Long-Term Adherence to and Persistence with DPP-4 Inhibitors in US Adults with Type 2 Diabetes Mellitus 
Advances in Therapy  2014;31:1287-1305.
Patients with type 2 diabetes mellitus (T2DM) must remain adherent and persistent on antidiabetic medications to optimize clinical benefits. This analysis compared adherence and persistence among adults initiating dipeptidyl peptidase-4 inhibitors (DPP-4is), sulfonylureas (SUs), and thiazolidinediones (TZDs) and between patients initiating saxagliptin or sitagliptin, two DPP-4is.
This retrospective cohort study utilized the US MarketScan® (Truven Health Analytics, Ann Arbor, MI, USA) Commercial and Medicare Supplemental health insurance claims databases. Adults aged ≥18 years with T2DM who initiated a DPP-4i, SU, or TZD from January 1, 2009 to January 31, 2012 were included. Patients must have been continuously enrolled for ≥1 year prior to and ≥1 year following initiation. Adherence was measured using proportion of days covered (PDC), with PDC ≥ 0.80 considered adherent. Persistence was measured as time to discontinuation, defined as last day with drug prior to a 60+ days gap in therapy. Multivariable logistic regression and Cox proportional hazards models compared the outcomes between cohorts, controlling for baseline differences.
The sample included 238,372 patients (61,399 DPP-4i, 134,961 SU, 42,012 TZD). During 1-year follow-up, 47.3% of DPP-4i initiators, 41.2% of SU initiators, and 36.7% of TZD initiators were adherent. Adjusted odds of adherence were significantly greater among DPP-4i initiators than SU (adjusted odds ratio [AOR] = 1.678, P < 0.001) and TZD initiators (AOR = 1.605, P < 0.001). During 1-year follow-up, 55.0% of DPP-4i initiators, 47.8% of SU initiators, and 42.9% of TZD initiators did not discontinue therapy. Adjusted hazards of discontinuation were significantly greater for SU (adjusted hazard ratio [AHR] = 1.390, P < 0.001) and TZD initiators (AHR = 1.402, P < 0.001) compared with DPP-4i initiators. Saxagliptin initiators had significantly better adherence (AOR = 1.213, P < 0.001) compared with sitagliptin initiators, and sitagliptin initiators had significantly greater hazard of discontinuation (AHR = 1.159, P < 0.001). Results were similar over a 2-year follow-up.
US adults with T2DM who initiated DPP-4i therapy, particularly saxagliptin, had significantly better adherence and persistence compared with patients who initiated SUs or TZDs.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0171-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4271133  PMID: 25504156
Adherence; Dipeptidyl peptidase-4 inhibitors; Persistence; Type 2 diabetes mellitus
4.  Mechanism of gate opening in the 20S proteasome by the proteasomal ATPases 
Molecular cell  2008;30(3):360-368.
Substrates enter the cylindrical 20S proteasome through a gated channel that is regulated by the ATPases in the 19S regulatory particle in eukaryotes or the homologous PAN ATPase complex in archaea. These ATPases contain a conserved C-terminal hydrophobic-tyrosine-X (HbYX) motif that triggers gate opening upon ATP binding. Using electron cryomicroscopy, we identified the sites in the archaeal 20S where PAN’s C-terminal residues bind and determined the structures of the gate in its closed and open forms. Peptides containing the HbYX motif bind to 20S in the pockets between neighboring α-subunits where they interact with conserved residues required for gate opening. This interaction induces a rotation in the α-subunits and displacement of a reverse turn loop that stabilizes the open-gate conformation. This mechanism differs from that of PA26/28, which lacks the HbYX motif and does not cause α-subunit rotation. These findings demonstrated how the ATPases C-termini functions to facilitate substrate entry.
PMCID: PMC4141531  PMID: 18471981
Proteasome; proteasomal ATPase; Electron cryomicroscopy; protein degradation; AAA ATPases
5.  Cues, context, and long-term memory: the role of the retrosplenial cortex in spatial cognition 
Spatial navigation requires memory representations of landmarks and other navigation cues. The retrosplenial cortex (RSC) is anatomically positioned between limbic areas important for memory formation, such as the hippocampus (HPC) and the anterior thalamus, and cortical regions along the dorsal stream known to contribute importantly to long-term spatial representation, such as the posterior parietal cortex. Damage to the RSC severely impairs allocentric representations of the environment, including the ability to derive navigational information from landmarks. The specific deficits seen in tests of human and rodent navigation suggest that the RSC supports allocentric representation by processing the stable features of the environment and the spatial relationships among them. In addition to spatial cognition, the RSC plays a key role in contextual and episodic memory. The RSC also contributes importantly to the acquisition and consolidation of long-term spatial and contextual memory through its interactions with the HPC. Within this framework, the RSC plays a dual role as part of the feedforward network providing sensory and mnemonic input to the HPC and as a target of the hippocampal-dependent systems consolidation of long-term memory.
PMCID: PMC4122222  PMID: 25140141
retrosplenial cortex; hippocampus; context; navigation; long-term memory; learning; allocentric; consolidation
6.  The Anterior Thalamus is Critical for Overcoming Interference in a Context-Dependent Odor Discrimination Task 
Behavioral neuroscience  2012;126(5):710-719.
The anterior thalamus (AT) is anatomically interconnected with the hippocampus and other structures known to be involved in memory, and the AT is involved in many of the same learning and memory functions as the hippocampus. For example, like the hippocampus, the AT is involved in spatial cognition and episodic memory. The hippocampus also has a well-documented role in contextual memory processes, but it is not known whether the AT is similarly involved in contextual memory. In the present study, we assessed the role of the AT in contextual memory processes by temporarily inactivating the AT and training rats on a recently developed context-based olfactory list learning task, which was designed to assess the use of contextual information to resolve interference. Rats were trained on one list of odor discrimination problems, followed by training on a second list in either the same context or a different context. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. Control rats that learned the two lists in different contexts performed significantly better than rats that learned the two lists in the same context. However, AT lesions completely abolished this contextual learning advantage, a result that is very similar to the effects of hippocampal inactivation. These findings demonstrate that the AT, like the hippocampus, is involved in contextual memory and suggest that the hippocampus and AT are part of a functional circuit involved in contextual memory.
PMCID: PMC3464499  PMID: 23025833
anterior thalamus; learning; memory; interference; context
7.  A Comparison of the Effects of Temporary Hippocampal Lesions on Single and Dual Context Versions of the Olfactory Sequence Memory Task 
Behavioral neuroscience  2012;126(4):588-592.
In recent years, many animal models of memory have focused on one or more of the various components of episodic memory. For example, the odor sequence memory task requires subjects to remember individual items and events (the odors) and the temporal aspects of the experience (the sequence of odor presentation). The well-known spatial context coding function of the hippocampus, as exemplified by place cell firing, may reflect the ‘where’ component of episodic memory. In the present study, we added a contextual component to the odor sequence memory task by training rats to choose the earlier odor in one context and the later odor in another context and we compared the effects of temporary hippocampal lesions on performance of the original single context task and the new dual context task. Temporary lesions significantly impaired the single context task, although performance remained significantly above chance levels. In contrast, performance dropped all the way to chance when temporary lesions were used in the dual context task. These results demonstrate that rats can learn a dual context version of the odor sequence learning task which requires the use of contextual information along with the requirement to remember the ‘what’ and ‘when’ components of the odor sequence. Moreover, the additional requirement of context-dependent expression of the ‘what-when’ memory made the task fully dependent on the hippocampus. Moreover, the addition of the contextual component made the task fully dependent on the hippocampus.
PMCID: PMC3477488  PMID: 22687149
hippocampus; episodic memory; what-where-when; context; sequence memory
8.  GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans 
Diabetologia  2014;57(6):1182-1191.
The NEFA-responsive G-protein coupled receptor 120 (GPR120) has been implicated in the regulation of inflammation, in the control of incretin secretion and as a predisposing factor influencing the development of type 2 diabetes by regulation of islet cell apoptosis. However, there is still considerable controversy about the tissue distribution of GPR120 and, in particular, it remains unclear which islet cell types express this molecule. In the present study, we have addressed this issue by constructing a Gpr120-knockout/β-galactosidase (LacZ) knock-in (KO/KI) mouse to examine the distribution and functional role of GPR120 in the endocrine pancreas.
A KO/KI mouse was generated in which exon 1 of the Gpr120 gene (also known as Ffar4) was replaced in frame by LacZ, thereby allowing for regulated expression of β-galactosidase under the control of the endogenous GPR120 promoter. The distribution of GPR120 was inferred from expression studies detecting β-galactosidase activity and protein production. Islet hormone secretion was measured from isolated mouse islets treated with selective GPR120 agonists.
β-galactosidase activity was detected as a surrogate for GPR120 expression exclusively in a small population of islet endocrine cells located peripherally within the islet mantle. Immunofluorescence analysis revealed co-localisation with somatostatin suggesting that GPR120 is preferentially produced in islet delta cells. In confirmation of this, glucose-induced somatostatin secretion was inhibited by a range of selective GPR120 agonists. This response was lost in GPR120-knockout mice.
The results imply that GPR120 is selectively present within the delta cells of murine islets and that it regulates somatostatin secretion.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3213-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4018485  PMID: 24663807
Endocrine pancreas; FFAR4; GPR120; Insulin secretion; n-3 fatty acids; n-6 fatty acids; NEFA; Pertussis toxin
9.  Open versus laparoscopic right hemicolectomy in the elderly population 
AIM: To compare short term outcomes of elective laparoscopic and open right hemicolectomy (RH) in an elderly population.
METHODS: All patients over the age of 70 undergoing elective RH at Ninewells Hospital and Perth Royal Infirmary between January 2006 and May 2011 were included in our analysis. Operative details, hospital length of stay, morbidity and mortality was collected by way of proforma from a dedicated prospective database. An extracorporeal anastomosis was performed routinely in the laparoscopic group. The primary endpoints for analysis were morbidity and mortality. Our secondary endpoints were operative duration, length of hospital stay and discharge destination.
RESULTS: Two hundred and six patients were included in our analysis. One hundred and twenty-five patients underwent an open resection and 81 patients had a laparoscopic resection. The mean operating time was significantly longer in the laparoscopic group (139 ±
36 min vs 197 ± 53 min, P = 0.001). The mean length of hospital stay was similar in both groups (11.2 ± 7.8 d vs 9.6 ± 10.7 d, P = 0.28). The incidence of post-operative morbidities was 27% in the open group and 38% in the laparoscopic group (P = 0.12). Overall in-hospital mortality was 0.8% in open procedures vs 1% in laparoscopic.
CONCLUSION: Laparoscopic RH was associated with a significantly longer operative time compared to open RH. In our study, laparoscopic RH was not associated with reduced post-operative morbidity or significantly shorter length of hospital stay.
PMCID: PMC3692954  PMID: 23805362
Right hemicolectomy; Elderly; Laparoscopy; Open
10.  The Role of Adult Hippocampal Neurogenesis in Reducing Interference 
Behavioral neuroscience  2012;126(3):381-391.
Adult neurogenesis in the hippocampal dentate gyrus plays an important role in learning and memory. However, the precise contribution of the new neurons to hippocampal function remains controversial. Emerging evidence suggests that neurogenesis is important for pattern separation and for mitigating interference when similar items must be learned at different times. In the present study, we directly test this prediction using a recently developed olfactory memory task that has those specific features. In this task, rats learn two highly interfering lists of odor pairs, one after the other in either the same or in different contexts. Consistent with our hypothesis, focal cranial irradiation, resulting in selective reduction of neurogenesis within the dentate gyrus, significantly impaired the ability to overcome interference during learning of the second list. The ability to learn a single odor list was unimpaired. We also show that irradiation had no effect on learning in a hippocampal dependent spatial alternation task. Although both tasks involved learning interfering responses, the time course for learning the interfering items differed. Learning the interfering odor lists took place sequentially, over the course of several sessions, whereas learning the interfering spatial locations took place concurrently, within each session. Thus, the gradual addition of new neurons may have provided a pattern separation mechanism for the olfactory task but not for the maze task. These findings demonstrate a role for neurogenesis in resolving interference and they are consistent with models suggesting a critical role for neurogenesis in pattern separation.
PMCID: PMC3477487  PMID: 22642883
hippocampus; memory interference; adult neurogenesis; learning and memory; dentate gyrus
11.  Complimentary Roles of the Hippocampus and Retrosplenial Cortex in Behavioral Context Discrimination 
Hippocampus  2011;22(5):1121-1133.
Complex cognitive functions, such as learning and memory, arise from the interaction of multiple brain regions that comprise functional circuits and different components of these circuits make unique contributions to learning. The hippocampus and the retrosplenial cortex (RSC) are anatomically interconnected and both regions are involved in learning and memory. Previous studies indicate that the hippocampus exhibits unique firing patterns for different contexts and that RSC neurons selectively respond to cues that predict reinforcement or the need for a behavioral response, suggesting a hippocampal role in encoding contexts and an RSC role in encoding behaviorally significant cues. To test this, we simultaneously recorded hippocampal and RSC neuronal activity as rats learned to discriminate two behavioral contexts. The rats learned to approach the east arm of a plus maze for reward during the first half of each session and to approach the west arm during the second half. The ‘go east’ and ‘go west’ conditions constitute distinct behavioral contexts, which were cued by the reward location. Neurons in both regions developed highly context-specific responses as subjects learned to discriminate the contexts, but the response patterns differed in the two brain regions. Consistent with a context processing role, hippocampal neurons developed context specific responses to a variety of task stimuli and events. In contrast, RSC neurons only developed context specific responses to the reward location, which served as the context identifying cue. These results suggest that the hippocampus and RSC play distinct, but complimentary roles in mediating context appropriate memories and behaviors.
PMCID: PMC3166541  PMID: 21630374
hippocampus; retrosplenial cortex; cingulate cortex; context; place cell
12.  Hippocampal Context Processing is Critical for Interference Free Recall of Odor Memories in Rats 
Hippocampus  2011;22(4):906-913.
Interference is a critical problem for memory systems and a primary cause of retrieval failure. One strategy for minimizing interference is to associate the items to be remembered with the context in which they were learned. For example, human subjects who learn two lists of words in separate contexts experience less interference and better recall than subjects who learn both lists in the same context. The hippocampus has long been known to be involved in processing contextual information and recent studies have shown that hippocampal neurons exhibit context-unique firing patterns that could serve as a neural representation of the context. These observations suggest that hippocampal context processing may play a critical role in overcoming interference. To test this hypothesis, we adapted the context based list learning procedure for use with rats. Control rats and rats given temporary lesions of the hippocampus were trained on two lists of eight odor pairs, either in the same context or in different contexts. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. As with human subjects, rats that learned the two lists in different contexts performed significantly better than rats that learned the lists in the same context. However, hippocampal lesions completely abolished this contextual learning advantage. We also trained rats on a low interference version of the task by using lists that did not contain any common items. Interestingly, rats with hippocampal lesions were entirely unimpaired when the learning situation did not involve high levels of interference. These findings are consistent with the idea that the hippocampus encodes contexts and further suggest that hippocampal context coding is beneficial because it provides a means of overcoming interference.
PMCID: PMC3151480  PMID: 21542056
hippocampus; context; interference
13.  The inpatient experience and predictors of length of stay for patients hospitalized with systolic heart failure: comparison by commercial, Medicaid, and Medicare payer type 
Journal of medical economics  2012;16(1):43-54.
Descriptions of the inpatient experience for patients hospitalized with systolic heart failure (HF) are limited and lack a cross-sectional representation of the US population. While length of stay (LOS) is a primary determinant of resource use and post-discharge events, few models exist for estimating LOS.
Research design and methods
MarketScan® administrative claims data from 1/1/2005–6/30/2008 were used to select hospitalized patients aged ≥18 years with discharge diagnoses for both HF (primary diagnosis) and systolic HF (any diagnostic position) without prior HF hospitalization or undergoing transplantation.
Among 17,597 patients with systolic HF; 4109 had commercial; 2118 had Medicaid; and 11,370 had Medicare payer type. Medicaid patients had longer mean LOS (7.1 days) than commercial (6.3 days) or Medicare (6.7 days). In-hospital mortality was highest for patients with Medicaid (2.4%), followed by Medicare (1.3%) and commercial (0.6%). Commercial patients were more likely to receive inpatient procedures. Renal failure, pressure ulcer, malnutrition, a non-circulatory index admission DRG, receipt of a coronary artery bypass procedure or cardiac catheterization, or need for mechanical ventilation during the index admission were associated with increased LOS; receipt of a pacemaker device at index was associated with shorter LOS.
Selection of patients with systolic HF is limited by completeness and accuracy of medical coding, and results may not be generalizable to patients with diastolic HF or to international populations.
Inpatient care, LOS, and in-hospital survival differ by payer among patients hospitalized with systolic HF, although co-morbidity and inpatient procedures consistently influence LOS across payer types. These findings may refine risk stratification, allowing for targeted intensive inpatient management and/or aggressive transitional care to improve outcomes and increase the efficiency of care.
PMCID: PMC3893694  PMID: 22954063
Heart failure; Systolic; Hospitalization; Length of stay; Payer
14.  Rates and Predictors of 30-Day Readmission Among Commercially Insured and Medicaid-Enrolled Patients Hospitalized With Systolic Heart Failure 
Circulation. Heart failure  2012;5(6):10.1161/CIRCHEARTFAILURE.112.967356.
Heart failure (HF) readmission rates are primarily derived from Medicare enrollees. Given increasing public scrutiny of HF readmissions, understanding the rate and predictors in populations covered by other payers is also important, particularly among patients with systolic dysfunction, for whom most HF-specific therapies are targeted.
Methods and Results
MarketScan Commercial and Medicaid Administrative Claims Databases were used to identify all first hospitalizations with an International Classification of Diseases-9 discharge diagnosis code for HF (primary position) and systolic HF (any position) between January 1, 2005, and June 30, 2008. Among 4584 unique systolic HF index admissions (mean age 55 years), 30-day crude readmission rates were higher for Medicaid than commercially insured patients: all-cause 17.4% versus 11.8%; HF-related 6.7% versus 4.0%, respectively. In unadjusted analysis, higher comorbidity and prior healthcare utilization predicted readmission; age, sex, and plan type did not. After adjustment for case mix, the odds of all-cause and HF-related readmission were 32% and 68% higher, respectively, among Medicaid than commercially insured patients (P<0.02 for both). No significant differences in readmission rates were seen for managed care versus fee-for-service or capitated versus noncapitated plan types.
Compared with commonly cited Medicare HF readmission rates of 20% to 25%, Medicaid patients with systolic HF had lower 30-day readmission rates, and commercially insured patients had even lower rates. Even after adjustment for case mix, Medicaid patients were more likely to be readmitted than commercially insured patients, suggesting that more attention should be focused on readmissions among socioeconomically disadvantaged populations.
PMCID: PMC3873644  PMID: 23072736
heart failure; systolic; hospitalization; readmission; payer
15.  A Structurally Variable Hinged Tetrahedron Framework from DNA Origami 
Journal of Nucleic Acids  2011;2011:360954.
Nanometer-sized polyhedral wire-frame objects hold a wide range of potential applications both as structural scaffolds as well as a basis for synthetic nanocontainers. The utilization of DNA as basic building blocks for such structures allows the exploitation of bottom-up self-assembly in order to achieve molecular programmability through the pairing of complementary bases. In this work, we report on a hollow but rigid tetrahedron framework of 75 nm strut length constructed with the DNA origami method. Flexible hinges at each of their four joints provide a means for structural variability of the object. Through the opening of gaps along the struts, four variants can be created as confirmed by both gel electrophoresis and direct imaging techniques. The intrinsic site addressability provided by this technique allows the unique targeted attachment of dye and/or linker molecules at any point on the structure's surface, which we prove through the superresolution fluorescence microscopy technique DNA PAINT.
PMCID: PMC3176657  PMID: 21941629
16.  Strengthening research capacity through the medical education partnership initiative: the Mozambique experience 
Since Mozambique’s independence, the major emphasis of its higher educational institutions has been on didactic education. Because of fiscal and human resource constraints, basic and applied research activities have been relatively modest in scope, and priorities have often been set primarily by external collaborators. These factors have compromised the scope and the relevance of locally conducted research and have limited the impact of Mozambique’s universities as major catalysts for national development.
Case description
We developed a multi-institutional partnership to undertake a comprehensive analysis of the research environment at Mozambique’s major public universities to identify factors that have served as barriers to the development of a robust research enterprise. Based on this analysis, we developed a multifaceted plan to reduce the impact of these barriers and to enhance research capacity within Mozambique.
On the basis of our needs assessment, we have implemented a number of major initiatives within participating institutions to facilitate basic and applied research activities. These have included specialized training programmes, a reorganization of the research administration infrastructure, the development of multiple collaborative research projects that have emphasized local research priorities and a substantial investment in bioinformatics. We have established a research support centre that provides grant development and management services to Mozambique’s public universities and have developed an independent Institutional Review Board for the review of research involving human research subjects. Multiple research projects involving both communicable and non-communicable diseases have been developed and substantial external research support has been obtained to undertake these projects. A sizable investment in biomedical informatics has enhanced both connectivity and access to digital reference material. Active engagement with relevant entities within the Government of Mozambique has aligned institutional development with national priorities.
Although multiple challenges remain, over the past 3 years significant progress has been made towards establishing conditions within which a broad range of basic, translational and clinical and public health research can be undertaken. Ongoing development of this research enterprise will enhance capacity to address critical locally relevant research questions and will leverage resources to accelerate the development of Mozambique’s national universities.
PMCID: PMC3895849  PMID: 24304706
Research; Research capacity building in Mozambique; MEPI Mozambique
17.  Hippocampal Episode Fields Develop with Learning 
Hippocampus  2010;21(11):1240-1249.
Several recent studies have shown that hippocampal neurons fire during the delay period in between trials and that these firing patterns differ when different behaviors are required, suggesting that the neuronal responses may be involved in maintaining the memories needed for the upcoming trial. In particular, one study found that hippocampal neurons reliably fired at particular times, referred to as ‘episode fields’ (EFs), during the delay period of a spatial alternation task (Pastalkova et al, 2008, Science 321:1322-7). The firing of these neurons resulted in distinct sequential firing patterns on left and right turn trials, and these firing patterns could be used to predict the upcoming behavioral response. In the present study, we examined neuronal firing during the delay period of a hippocampal dependent plus maze task which involved learning to approach two different reward locations (east and west) and we examined the development of these firing patterns with learning. As in the previous study, hippocampal neurons exhibited discrete periods of elevated firing during the delay (EFs) and the firing patterns were distinct on the east and west trials. Moreover, these firing patterns emerged and began to differentiate the east and west conditions during the first training session and continued to develop as the rats learned the task. The finding of similar firing patterns in different tasks suggests that the EFs are a robust phenomenon, which may occur whenever subjects must maintain distinct memory representations during a delay period. Additionally, in the previous study (Pastalkova et al, 2008), the distinct firing patterns could have been due to the differing goal locations, behavioral responses (left or right turns) or trajectories. In the present study, neuronal firing varied with the goal location regardless of the trajectories or responses, suggesting that the firing patterns encode the behavioral context rather than specific behaviors.
PMCID: PMC2970708  PMID: 20665593
hippocampus; delay; context; place cell; episode field
18.  Predictors of Initiating Rapid-Acting Insulin Analog Using Vial/Syringe, Prefilled Pen, and Reusable Pen Devices in Patients with Type 2 Diabetes 
Limited data are available on the predictors of insulin delivery device choice. This study assessed the patient- and health-care-system-related factors that predict the initiation of one rapid-acting insulin analog (RAIA) delivery system over another.
A retrospective analysis using a claims database (January 1, 2007, through March 31, 2009) was conducted. Patients were required to be diagnosed with type 2 diabetes mellitus, and have ≥12 months of continuous eligibility prior to their first prescription of a RAIA on or after January 1, 2008. The three cohorts in the study were vial/syringe (n = 6820), prefilled pen (n = 5840), and reusable pen (n = 2052). Multiple factors were examined using stepwise logistic regression.
Factors that increased the likelihood of initiating RAIA using prefilled pen versus vial/syringe included endocrinologist visit [odds ratio (OR) = 3.13, 95% confidence interval (CI) = 2.56, 3.82], prior basal insulin use with pen (OR = 4.85, 95% CI = 4.21, 5.59), and use of ≥1 oral antihyperglycemic agents (OR = 1.32, 95% CI = 1.20, 1.45). Factors that decreased the likelihood included inpatient admission (OR = 0.76, 95% CI = 0.70, 0.83), nursing home visit (OR = 0.22, 95% CI = 0.18, 0.27), and obesity (OR = 0.67, 95% CI = 0.53, 0.83). There were fewer differences between prefilled and reusable pen initiators. Factors that increased the likelihood of initiating with prefilled versus reusable pen included endocrinologist visit (OR = 1.87, CI = 1.50, 2.34) and inpatient admission (OR = 1.46, 95% CI = 1.30, 1.64).
Significant differences in predictors were observed between prefilled pen and vial/syringe initiators. The differences were fewer between prefilled and reusable pen initiators. These differences should be taken into consideration when evaluating outcomes associated with specific insulin delivery systems.
PMCID: PMC2901030  PMID: 20513319
insulin; pen device; type 2 diabetes mellitus; vial
19.  Anticoagulant Use, the Prevalence of Bridging, and Relation to Length of Stay among Hospitalized Patients with Non-Valvular Atrial Fibrillation 
Objective: The objectives of this study were to describe inpatient anticoagulation and bridging in patients with non-valvular atrial fibrillation (NVAF) and to identify whether differences exist in length of stay (LOS) among bridged versus non-bridged NVAF patients.
Design: Administrative claims data were used to select patients ≥18 years with a primary or secondary discharge diagnosis of NVAF and inpatient warfarin use from 1 July 2004 to 30 September 2009. Patients with valvular or transient causes of NVAF or pregnancy were excluded. Inpatient bridging was defined as receipt of an anticoagulant in addition to warfarin during the hospitalization. LOS was reported for non-bridged patients (warfarin only) and compared with three bridging regimens: low molecular weight heparin/pentasaccharide (LMWH/PS); unfractionated heparin (UFH); and two-agent bridging (LMWH/PS and UFH). Multivariate analyses were performed to evaluate the association between bridging and LOS, adjusting for demographic and clinical variables.
Results: Of 6340 NVAF patients, 48% received inpatient warfarin (mean LOS 5.5 days); among them, 64% received bridging therapy (mean LOS 6.3 days) [LMWH/PS 45% (mean LOS 5.6 days), UFH 36% (mean LOS 6.0 days), two-agent bridging 18% (mean LOS 8.4 days)]. Following multivariate analysis, relative to patients who received inpatient warfarin only, LOS was significantly higher for patients with UFH (19.3%) and patients with two-agent bridging (45.1%). Patients with pre-period warfarin, cancer, or diabetes mellitus who received bridging agents had significantly longer LOS than patients with those conditions who were not bridged.
Conclusion: LOS was longer for bridged than non-bridged patients. Further studies are needed to identify predictors of bridging and to explain why bridged NVAF patients had longer LOS.
PMCID: PMC3713944  PMID: 23006024
20.  P. falciparum Enhances HIV Replication in an Experimental Malaria Challenge System 
PLoS ONE  2012;7(6):e39000.
Co-infection with HIV and P. falciparum worsens the prognosis of both infections; however, the mechanisms driving this adverse interaction are not fully delineated. To evaluate this, we studied HIV-1 and P. falciparum interactions in vitro using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial.PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either P. falciparum infected (iRBCs) or uninfected (uRBCs) red blood cells. HIV p24Ag and TNF-α, IFN-γ, IL-4, IL-6, IL-10, IL-17, and MIP-1α were quantified in the co-culture supernatants. In general, iRBCs stimulated more HIV p24Ag production by PBMCs than did uRBCs. HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge). In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence. Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.
PMCID: PMC3383717  PMID: 22745697
21.  Evidence Linking Hypoglycemic Events to an Increased Risk of Acute Cardiovascular Events in Patients With Type 2 Diabetes 
Diabetes Care  2011;34(5):1164-1170.
This retrospective study examined the association between ICD-9-CM–coded outpatient hypoglycemic events (HEs) and acute cardiovascular events (ACVEs), i.e., acute myocardial infarction, coronary artery bypass grafting, revascularization, percutaneous coronary intervention, and incident unstable angina, in patients with type 2 diabetes.
Data were derived from healthcare claims for individuals with employer-sponsored primary or Medicare supplemental insurance. A baseline period (30 September 2006 to 30 September 2007) was used to identify eligible patients and collect information on their clinical and demographic characteristics. An evaluation period (1 October 2007 to 30 September 2008) was used to identify HEs and ACVEs. Patients aged ≥18 years with type 2 diabetes were selected for analysis by a modified Healthcare Effectiveness Data and Information Set algorithm. Data were analyzed with multiple logistic regression and backward stepwise selection (maximum P = 0.01) with adjustment for important confounding variables, including age, sex, geography, insurance type, comorbidity scores, cardiovascular risk factors, diabetes complications, total baseline medical expenditures, and prior ACVEs.
Of the 860,845 patients in the analysis set, 27,065 (3.1%) had ICD-9-CM–coded HEs during the evaluation period. The main model retained 17 significant independent variables. Patients with HEs had 79% higher regression-adjusted odds (HE odds ratio [OR] 1.79; 95% CI 1.69–1.89) of ACVEs than patients without HEs; results in patients aged ≥65 years were similar to those for the entire population (HE OR 1.78, 95% CI 1.65–1.92).
ICD-9-CM–coded HEs were independently associated with an increased risk of ACVEs. Further studies of the relationship between hypoglycemia and the risk of ACVEs are warranted.
PMCID: PMC3114512  PMID: 21421802
22.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
23.  ATP binds to proteasomal ATPases in pairs with distinct functional effects implying an ordered reaction cycle 
Cell  2011;144(4):526-538.
In the eukaryotic 26S proteasome, the 20S particle is regulated by six AAA ATPase subunits, and in archaea by a homologous ring complex, PAN. To clarify the role of ATP in proteolysis, we studied how nucleotides bind to PAN. Although PAN has six identical subunits it binds ATPs in pairs, and its subunits exhibit three conformational states with high, low, or no affinity for ATP. When PAN binds two ATPγS molecules, or two ATPγS plus two ADP molecules it is maximally active in binding protein substrates, associating with the 20S particle, and promoting 20S gate-opening. However, binding of four ATPγS molecules reduces these functions. The 26S proteasome shows similar nucleotide dependence. These findings imply an ordered cyclical mechanism in which two ATPase subunits bind ATP simultaneously and dock into the 20S. These results can explain how these hexameric ATPases interact with and “wobble” on top of the heptameric 20S proteasome.
PMCID: PMC3063399  PMID: 21335235
24.  A conserved F-box–regulatory complex controls proteasome activity in Drosophila 
Cell  2011;145(3):371-382.
The Ubiquitin-Proteasome System catalyzes the degradation of intracellular proteins. Although ubiquitination of proteins determines their stabilities, there is growing evidence that proteasome function is also regulated. We report the functional characterization of a conserved proteasomal regulatory complex. We identified DmPI31 as a binding partner of the F-box protein Nutcracker, a component of an SCF ubiquitin ligase (E3) required for caspase activation during sperm differentiation in Drosophila. DmPI31 binds Nutcracker via a conserved mechanism that is also used by mammalian FBXO7 and PI31. Nutcracker promotes DmPI31 stability, which is necessary for caspase activation, proteasome function and sperm differentiation. DmPI31 can activate 26S proteasomes in vitro, and increasing DmPI31 levels suppresses defects caused by diminished proteasome activity in vivo. Furthermore, loss of DmPI31 function causes lethality, cell-cycle abnormalities and defects in protein degradation, demonstrating that DmPI31 is physiologically required for normal proteasome activity.
PMCID: PMC3108249  PMID: 21529711
25.  11β-Hydroxysteroid Dehydrogenase Type 1 Regulates Glucocorticoid-Induced Insulin Resistance in Skeletal Muscle 
Diabetes  2009;58(11):2506-2515.
Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11β-HSD1 inhibitors improve insulin sensitivity.
Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11β-HSD1 inhibition upon insulin signaling and action.
Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer307 insulin receptor substrate (IRS)-1. 11β-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11β-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer307 IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11β-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer307 IRS1 decreased and pThr308 Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.
Prereceptor facilitation of glucocorticoid action via 11β-HSD1 increases pSer307 IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11β-HSD1 inhibition decreases pSer307 IRS1, increases pThr308 Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.
PMCID: PMC2768185  PMID: 19675138

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