Modelling Conditions and Health Care Processes in Electronic Health Records : An Application to Severe Mental Illness with the Clinical Practice Research Datalink

BACKGROUND: The use of Electronic Health Records databases for medical research has become mainstream. In the UK, increasing use of Primary Care Databases is largely driven by almost complete computerisation and uniform standards within the National Health Service. Electronic Health Records research often begins with the development of a list of clinical codes with which to identify cases with a specific condition. We present a methodology and accompanying Stata and R commands (pcdsearch/Rpcdsearch) to help researchers in this task. We present severe mental illness as an example. METHODS: We used the Clinical Practice Research Datalink, a UK Primary Care Database in which clinical information is largely organised using Read codes, a hierarchical clinical coding system. Pcdsearch is used to identify potentially relevant clinical codes and/or product codes from word-stubs and code-stubs suggested by clinicians. The returned code-lists are reviewed and codes relevant to the condition of interest are selected. The final code-list is then used to identify patients. RESULTS: We identified 270 Read codes linked to SMI and used them to identify cases in the database. We observed that our approach identified cases that would have been missed with a simpler approach using SMI registers defined within the UK Quality and Outcomes Framework. CONCLUSION: We described a framework for researchers of Electronic Health Records databases, for identifying patients with a particular condition or matching certain clinical criteria. The method is invariant to coding system or database and can be used with SNOMED CT, ICD or other medical classification code-lists

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Additive effect of LRP8/APOER2 R952Q variant to APOE ε2/ε3/ε4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study

BACKGROUND: The R952Q variant in the low density lipoprotein receptor-related protein 8 (LRP8)/apolipoprotein E receptor 2 (ApoER2) gene has been recently associated with familial and premature myocardial infarction (MI) by means of genome-wide linkage scan/association studies. We were interested in the possible interaction of the R952Q variant with another established cardiovascular genetic risk factor belonging to the same pathway, namely apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 genotype, in modulating apolipoprotein E (ApoE) plasma levels and risk of MI. METHODS: In the Italian cohort used to confirm the association of the R952Q variant with MI, we assessed lipid profile, apolipoprotein concentrations, and APOE epsilon2/epsilon3/epsilon4 genotype. Complete data were available for a total of 681 subjects in a case-control setting (287 controls and 394 patients with MI). RESULTS: Plasma ApoE levels decreased progressively across R952Q genotypes (mean levels +/- SD = RR: 0.045 +/- 0.020, RQ: 0.044 +/- 0.014, QQ: 0.040 +/- 0.008 g/l; P for trend = 0.047). Combination with APOE genotypes revealed an additive effect on ApoE levels, with the highest level observed in RR/non-carriers of the E4 allele (0.046 +/- 0.021 g/l), and the lowest level in QQ/E4 carriers (0.035 +/- 0.009 g/l; P for trend = 0.010). QQ/E4 was also the combined genotype with the most significant association with MI (OR 3.88 with 95\%CI 1.08-13.9 as compared with RR/non-carriers E4). CONCLUSION: Our data suggest that LRP8 R952Q variant may have an additive effect to APOE epsilon2/epsilon3/epsilon4 genotype in determining ApoE concentrations and risk of MI in an Italian population

High-normal blood glucose levels may be associated with decreased spatial perception in young healthy adults.

The negative effects of high normal glucose on cognitive function were previously reported in euglycemic individuals of middle age and the elderly population. This study aimed at examining the effect of baseline blood glucose levels on spatial ability, specifically verticality perception on the computerized rod and frame test (CRFT) in young healthy adults. 63 healthy male medical students (age range from 18-23 years), of whom 30 were non-fasting outside the month of Ramadan and 33 fasting during Ramadan of the year 2016, were recruited in order to create varying degrees of glycemia during which verticality perception was carried out. Baseline blood glucose reading was obtained prior to commencing the CRFT test. Blood glucose levels at the time of testing decreased as the duration between the last meal and testing increased. A blood glucose range of 62-117 mg/dl was achieved among participants for this study. Linear regression analysis showed that blood glucose level at testing correlated positively with all alignment spatial error parameters, indicating a probable reduction of spatial perception ability with higher blood glucose levels. These results are consistent with other cognitive studies in older healthy humans and emphasize the critical impact of early glucose dys-homeostasis on cognitive function. They also indicate that elevated blood glucose may affect cognitive functioning outside of the usual complications of diabetes

Moral Distress Amongst American Physician Trainees Regarding Futile Treatments at the End of Life: A Qualitative Study.

BACKGROUND: Ethical challenges are common in end of life care; the uncertainty of prognosis and the ethically permissible boundaries of treatment create confusion and conflict about the balance between benefits and burdens experienced by patients. OBJECTIVE: We asked physician trainees in internal medicine how they reacted and responded to ethical challenges arising in the context of perceived futile treatments at the end of life and how these challenges contribute to moral distress. DESIGN: Semi-structured in-depth qualitative interviews. PARTICIPANTS: Twenty-two internal medicine residents and fellows across three American academic medical centers. APPROACH: This study uses systematic qualitative methods of data gathering, analysis and interpretation. KEY RESULTS: Physician trainees experienced significant moral distress when they felt obligated to provide treatments at or near the end of life that they believed to be futile. Some trainees developed detached and dehumanizing attitudes towards patients as a coping mechanism, which may contribute to a loss of empathy. Successful coping strategies included formal and informal conversations with colleagues and superiors about the emotional and ethical challenges of providing care at the end of life. CONCLUSIONS: Moral distress amongst physician trainees may occur when they feel obligated to provide treatments at the end of life that they believe to be futile or harmful.This study was funded by the Health Resources and Service Administration T32 HP10025-20 Training Grant, the Gates Cambridge Scholarship, Society of General Internal Medicine Founders Grant, and the Ho-Chiang Palliative Care Research Fellowship at the Johns Hopkins School of Medicine.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11606-015-3505-

Adipose Tissue Serves as a Reservoir for Recrudescent Rickettsia prowazekii Infection in a Mouse Model

Brill-Zinsser disease, the relapsing form of epidemic typhus, typically occurs in a susceptible host years or decades after the primary infection; however, the mechanisms of reactivation and the cellular reservoir during latency are poorly understood. Herein we describe a murine model for Brill-Zinsser disease, and use PCR and cell culture to show transient rickettsemia in mice treated with dexamethasone >3 months after clinical recovery from the primary infection. Treatment of similarly infected mice with cyclosporine failed to produce recrudescent bacteremia. Therapy with doxycycline for the primary infection prevented recrudescent bacteremia in most of these mice following treatment with dexamethasone. Rickettsia prowazekii (the etiologic agent of epidemic typhus) was detected by PCR, cell culture, and immunostaining methods in murine adipose tissue, but not in liver, spleen, lung, or central nervous system tissues of mice 4 months after recovery from the primary infection. The lungs of dexamethasone-treated mice showed impaired expression of β-defensin transcripts that may be involved in the pathogenesis of pulmonary lesions. In vitro, R. prowazekii rickettsiae infected and replicated in the murine adipocyte cell line 3T3-L1. Collectively these data suggest a role for adipose tissue as a potential reservoir for dormant infections with R. prowazekii

Effect of thrombin peptide 508 (TP508) on bone healing during distraction osteogenesis in rabbit tibia

Thrombin-related peptide 508 (TP508) accelerates bone regeneration during distraction osteogenesis (DO). We have examined the effect of TP508 on bone regeneration during DO by immunolocalization of Runx2 protein, a marker of osteoblast differentiation, and of osteopontin (OPN) and bone sialoprotein (BSP), two late markers of the osteoblast lineage. Distraction was performed in tibiae of rabbits over a period of 6 days. TP508 (30 or 300 μg) or vehicle was injected into the distraction gap at the beginning and end of the distraction period. Two weeks after active distraction, tissue samples were harvested and processed for immunohistochemical analysis. We also tested the in vitro effect of TP508 on Runx2 mRNA expression in osteoblast-like (MC3T3-E1) cells by polymerase chain reaction analysis. Runx2 and OPN protein were observed in preosteoblasts, osteoblasts, osteocytes of newly formed bone, blood vessel cells and many fibroblast-like cells of the soft connective tissue. Immunostaining for BSP was more restricted to osteoblasts and osteocytes. Significantly more Runx2- and OPN-expressing cells were seen in the group treated with 300 μg TP508 than in the control group injected with saline or with 30 μg TP508. However, TP508 failed to increase Runx2 mRNA levels significantly in MC3T3-E1 cells after 2–3 days of exposure. Our data suggest that TP508 enhances bone regeneration during DO by increasing the proportion of cells of the osteoblastic lineage. Clinically, TP508 may shorten the healing time during DO; this might be of benefit when bone regeneration is slow

The Relationship between Regular Sports Participation and Vigilance in Male and Female Adolescents

The present study investigated the relationship between regular sport participation (soccer) and vigilance performance. Two groups of male and female adolescents differentiated in terms of their sport participation (athletes, n = 39, and non-athletes, n = 36) took part in the study. In one session, participants performed the Leger Multi-stage fitness test to estimate their aerobic fitness level. In the other session, participants completed the Psychomotor Vigilance Task (PVT) to evaluate their vigilance performance. Perceived arousal prior to the task and motivation toward the task were also measured in the PVT session. The results revealed that athletes had better cardiovascular fitness and showed better performance in the PVT. However, correlation analyses did not show any significant relationship between cardiovascular fitness and performance in the PVT. Athletes showed larger scores in motivation and perceived arousal measures with respect to non-athletes, although, once again, these variables were not correlated with PVT performance. Gender differences were observed only in the Leger test, with males showing greater fitness level than females. The major outcome of this research points to a positive relationship between regular sport participation and vigilance during adolescence. This relationship did not seem to be influenced by gender, perceived arousal, motivation toward the task or cardiovascular fitness. We discuss our results in terms of the different hypotheses put forward in the literature to explain the relationship between physical activity and cognitive functioning.This research was supported by a Spanish Ministerio de Educación y Cultura (https://sede. educacion.gob.es) predoctoral grant (FPU13-05605) to the first author, and project research grants: Junta de Andalucia Proyecto de Excelencia SEJ-6414 (http://www.juntadeandalucia.es) and Ministerio de Economía y Competitividad PSI2013-46385 (http://www.mineco.gob.es) to DS and FH