FHIRing up OpenMRS: Architecture, Implementation and Real-World Use-Cases in Global Health.

HL7 FHIR was created almost a decade ago and is seeing increasingly wide use in high income settings. Although some initial work was carried out in low and middle income (LMIC) settings there has been little impact until recently. The need for reliable and easy to implement interoperability between health information systems in LMICs is growing with large scale deployments of EHRs, national reporting systems and mHealth applications. The OpenMRS open source EHR has been deployed in more than 44 LMIC with increasing needs for interoperability with other HIS. We describe here the development and deployment of a new FHIR module supporting the latest standards and its use in interoperability with laboratory systems, mHealth applications, pharmacy dispensing system and as a tool for supporting advanced user interface designs. We also show how it facilitates date science projects and deployment of machine leaning based CDSS and precision medicine in LMICs.

Preoperative breast MRI and mortality in older women with breast cancer.

PURPOSE: The survival benefit from detecting additional breast cancers by preoperative magnetic resonance imaging (MRI) continues to be controversial. METHODS: We followed a cohort of 4454 women diagnosed with non-metastatic breast cancer (stage I-III) from 2/2005-6/2010 in five registries of the breast cancer surveillance consortium (BCSC). BCSC clinical and registry data were linked to Medicare claims and enrollment data. We estimated the cumulative probability of breast cancer-specific and all-cause mortality. We tested the association of preoperative MRI with all-cause mortality using a Cox proportional hazards model. RESULTS: 917 (20.6%) women underwent preoperative MRI. No significant difference in the cumulative probability of breast cancer-specific mortality was found. We observed no significant difference in the hazard of all-cause mortality during the follow-up period after adjusting for sociodemographic and clinical factors among women with MRI (HR 0.90; 95% CI 0.72-1.12) compared to those without MRI. CONCLUSION: Our findings of no breast cancer-specific or all-cause mortality benefit supplement prior results that indicate a lack of improvement in surgical outcomes associated with use of preoperative MRI. In combination with other reports, the results of this analysis highlight the importance of exploring the benefit of preoperative MRI in patient-reported outcomes such as women's decision quality and confidence levels with decisions involving treatment choices.

False-positive mammography and depressed mood in a screening population: findings from the New Hampshire Mammography Network.

BACKGROUND: False positives occur in approximately 11% of screening mammographies in the USA and may be associated with psychologic sequelae. METHODS: We sought to examine the association of false-positive mammography with depressed mood among women in a screening population. Using data from a state-based mammography registry, women who completed a standardized questionnaire between 7 May 2001 and 2 June 2003, a follow-up questionnaire between 19 June 2003 and 8 October 2004 and who received at least one screening mammogram during this interval were identified. False positives were examined in relation to depressed mood. RESULTS: Eligibility criteria were met by 13 491 women with a median age of 63.9 (SD = 9.6). In the study population, 2107 (15.62%) experienced at least one false positive mammogram and 450 (3.34%) met criteria for depressed mood. Depressed mood was not significantly associated with false positives in the overall population [OR = 0.96; 95% confidence interval (CI) = 0.72-1.28], but this association was seen among Non-White women (OR = 3.23; 95% CI = 1.32-7.91). CONCLUSION: Depressed mood may differentially affect some populations as a harm associated with screening mammography.

Phylogeny of raspberry beetles and other Byturidae (Coleoptera).

Nuclear ribosomal ITS2 and mitochondrial cytochrome oxidase DNA sequences were analysed from the Byturidae (Coleoptera), which includes the raspberry beetles. The secondary structure of ITS2 was plotted and interspecific changes analysed. Evidence for selection on simple sequence repeats within the ITS2 was found. Phylogenetic trees based on the mitochondrial and ribosomal sequences were compared. They were in parity, indicating they reflect the true evolutionary histories of these insects. There was no evidence for hybridization in the populations surveyed, but there was evidence that the American raspberry beetle, Byturus unicolor, is divided into at least three distinct groupings. Despite sharing a related host, the raspberry pests from America were not the most related to the European raspberry beetle. Instead, links between Byturus affinis from Japan and the American raspberry beetle suggest that this lineage originated in Asia and colonized the Western USA.

The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice.

Wild-type (WT) and targeted-mutant mice incapable of making alphabeta T cells, gammadelta T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-gamma, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of alphabeta T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

Mammography in New Hampshire: characteristics of the women and the exams they receive.

New Hampshire (NH) is one of two states that has developed a population-based mammography registry. The purpose of this paper is to describe what we have learned about mammography use in New Hampshire. After collecting data for 20 months, the database contains almost 110,000 mammographic encounters representing 101,679 NH women, who range in age from 18 to 97 with a mean of 56.7 years (SD=10.91). Education levels are high with 92% having a high school education and 59% with some college. Forty-six percent report their primary insurance is private, 29% report HMO/PPO coverage, and 25% receive federal health care assistance. Risk factors represented in the database include (categories not mutually exclusive) advancing age (60% over age 50), hormone replacement therapy use by menopausal women (40.6%), and a family history of breast cancer (29%). Penetration of mammography relative to the NH population is higher for younger age groups (40-48% for those aged 44-64) than older age groups (34-39% for those aged 65-84). The majority of mammographic encounters are routine screening exams (86%), often interpreted as negative or normal with benign findings (88%). Use of comparison films to interpret either diagnostic or screening mammography occurred in 86% of encounters. We have matched 3,877 breast pathology records to these mammographic encounters. The distribution of pathology outcomes for diagnostic exams was very similar to that for screening exams (approximately 65% benign, 17% invasive breast cancer, and 6% noninvasive breast cancer). Overall, we have designed a system that is well accepted by the NH community. Challenges include careful monitoring of data for coding errors, and a limitation of linking variables in mammography and pathology data. Data represented in this registry are a critical resource for research in mammographic screening and breast cancer early detection.

Plasma fibrinogen and other cardiovascular disease risk factors and cataract.

PURPOSE: To determine whether associations exist between cataract and established cardiovascular risk factors (other than smoking) - hypertension, body mass index, serum lipids and plasma fibrinogen. METHODS: The Blue Mountains Eye Study is a large (n=3654) population-based cross-sectional study conducted among people aged 49-97 years residing in the Blue Mountains, a region west of Sydney, Australia. Risk factor data were collected using standardised clinical procedures. Lens photographs were taken and graded for presence and severity of cortical, nuclear, and posterior subcapsular cataracts. RESULTS: Cortical cataract was associated with a history of myocardial infarction, higher plasma fibrinogen, and higher serum cholesterol. Nuclear cataract was associated with a higher platelet count but hypertension was associated with lower prevalence of nuclear cataract. Posterior subcapsular cataract was associated with higher plasma fibrinogen and lower body mass index. Some of these associations appeared to be stronger in women than in men: fibrinogen and cortical cataract and body mass index and posterior subcapsular cataract. CONCLUSIONS: Several risk factors for cardiovascular disease are associated with presence of cataract, perhaps explaining the observation in several studies that people with cataract have increased mortality rates. The possibility of strong associations between plasma fibrinogen and cataract merits further epidemiological and laboratory research.

Growth rate of mycobacteria in mice as an unreliable indicator of mycobacterial virulence.

The CDC1551 strain of Mycobacterium tuberculosis was compared with the H37Rv strain of M. tuberculosis and the Ravenel strain of Mycobacterium bovis for virulence in mice. Although all three strains gave rise to the same level of stationary infection in major organs, mice infected with the Ravenel strain died much earlier from lung disease.

Health care worker disability due to latex allergy and asthma: a cost analysis.

OBJECTIVES: The reported prevalence of occupational allergy to natural rubber latex is 8% to 17%, and that of latex-induced occupational asthma is 2.5% to 6%. Conversion of medical facilities to "latex-safe" can reduce employee sensitization, impairment, and disability. The purpose of this study was to determine the cost of a latex-safe approach, compared with that of continued latex glove use, and to identify the level of worker disability required to make the latex-safe approach financially preferable to a health care institution. METHODS: The costs of 2 strategies--latex-safe vs the status quo--were calculated from the perspective of 3 health care institutions. A break-even point was calculated for each facility. RESULTS: In all facilities, the cost of using nonlatex gloves exceeded the cost of using latex gloves. In all 3 facilities, however, 1% or fewer of those at risk would have to become fully disabled or fewer than 2% would have to become partially disabled for the continued use of latex gloves to exceed the cost of the latex-safe approach. CONCLUSION: Health care facilities, regardless of size, are likely to benefit financially from becoming latex-safe even if latex-related disability levels are extremely low.

Effect of intestinal epithelial cell cytokines on mucosal B-cell IgA secretion: enhancing effect of epithelial-derived IL-6 but not TGF-beta on IgA+ B cells.

A variety of cell types may be involved in the regulation of IgA secretion at the intestinal mucosa. Intestinal epithelial cells (IEC) are known to have the capacity to secrete several cytokines which may exert an important regulatory effect on local immunoglobulin secretion by mucosal B cells. In this study, we have determined the effect of secreted cytokines from the rat non-transformed IEC-6 cell line on IgA secretion by IgA+ mesenteric lymph node B cells. Four day IEC-6 cell culture supernatants (SN) were found to enhance lipopolysaccharide (LPS) stimulated IgA secretion by 3-fold and this enhancement was determined to be due to IEC-derived IL-6. Interestingly, IEC-derived TGF-beta as well as recombinant human latent TGF-beta1 were found to have no effect on IgA secretion by the IgA+ B cells suggesting that these cells may be insensitive to the latent form of this cytokine. Finally, the addition of a culture SN from a 5 h culture of isolated normal rat IEC which contained high levels of IL-6 also greatly enhanced IgA secretion by LPS stimulated IgA+ B cells. These results suggest that the IEC may be an important source of IL-6 to enhance local mucosal IgA+ B cell responses.

Preferential enhancement of B cell IgA secretion by intestinal epithelial cell-derived cytokines and interleukin-2.

Intestinal epithelial cells (IEC) are known to secrete a number of important cytokines. Recently, we determined that IEC-derived IL-6 and TGF-beta could enhance IgA secretion and suppress IgM secretion by isolated mucosal B cells. However, since the IEC-derived cytokines must function in the context of locally produced T cell cytokines, the effect of IEC- and T cell-derived cytokines on mucosal B cell immunoglobulin secretion was determined. Using 4 day culture supernatants (IEC-SN) from the rat IEC-6 intestinal epithelial cell line and lipopolysaccharide (LPS) stimulated Peyer's patch or mesenteric lymph node B cells, the IEC- SN was found to act with IL-2 to greatly enhance IgA secretion but limit or suppress IgM secretion as compared to cultures of LPS stimulated B cells alone. However, neither IL-4, IL- 5, nor IFN-gamma affected IgA secretion with the IEC-SN. Depletion of the IEC-SN with specific anti-cytokine antibodies suggested that IEC-derived TGF-beta and IL-6 were both responsible for the enhancing effect along with IL-2 on IgA secretion, whereas IEC-derived TGF-beta alone limited or suppressed IgM secretion. These results suggest that cytokines derived from local IEC and T cells may create an environment which may contribute to the preferential enhancement of IgA secretion seen in mucosal tissues.

Modified radical hysterectomy in the treatment of early squamous cervical cancer.

OBJECTIVE: The aim of this study was to evaluate the results of modified radical hysterectomy in the treatment of early cervical cancer. MATERIAL AND METHODS: A retrospective chart review of 56 patients with stage I (IA in 35, IB in 21) squamous cervical carcinoma treated with modified radical hysterectomy and followed for a minimum of 5 years (mean, 12 years; range, 5.1-29) was conducted. All pathology slides were reviewed for tumor size, grade, depth of invasion, and lymph-vascular permeation. RESULTS: The mean depth of invasion was 0.5 cm (range, 0.1-2.5 cm), and the mean tumor size was 1.1 cm (range, 0.1-7 cm). Only 3 patients (5.4%) had positive nodes. None of the patients with tumors 2 cm or less in size had positive nodes, whereas 33.3% of the patients with tumors more than 2 cm in size had positive nodes. A recurrence developed in 2 patients (5-year recurrence rate of 3.6%). There were 10 deaths during the entire follow-up period, but only 2 were related to cervical cancer. The disease-specific and overall 5-year survival rates were 96.4 and 94.6%, respectively. The disease-specific 5-year survival rate was 100% among the 47 patients with tumors 2 cm or less and 75% for the 9 patients with tumors larger than 2 cm. Univariate analysis identified stage, lymph node status, and tumor size as statistically significant prognostic factors for overall survival. Tumor grade, lymph-vascular permeation, and depth of invasion (1-3 mm vs >3 mm) were not statistically significant for overall survival. CONCLUSIONS: Modified radical hysterectomy appears to be effective surgical therapy for patients with squamous cervical carcinoma 2 cm or less in size.

The ras oncogene-mediated sensitization of human cells to topoisomerase II inhibitor-induced apoptosis.

BACKGROUND: Among the inhibitors of the enzyme topoisomerase II (an important target for chemotherapeutic drugs) tested in the National Cancer Institute's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubicin) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-[2(dimethylamino)ethyl]carbamoyl)-6H-pyrido -(4,3-b)carbazole] were the only compounds that were more cytotoxic to tumor cells harboring an activated ras oncogene than to tumor cells bearing wild-type ras alleles. Expression of the multidrug resistance proteins P-glycoprotein and MRP (multidrug resistance-associated protein) facilitates tumor cell resistance to topoisomerase II inhibitors. We investigated whether tumor cells with activated ras oncogenes showed enhanced sensitivity to other topoisomerase II inhibitors in the absence of the multidrug-resistant phenotype. METHODS: We studied 20 topoisomerase II inhibitors and individual cell lines with or without activated ras oncogenes and with varying degrees of multidrug resistance. RESULTS: In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were uniformly more sensitive to most topoisomerase II inhibitors than were cell lines containing wild-type ras alleles. The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotype. The ras oncogene-mediated sensitization to topoisomerase II inhibitors was far more prominent with the non-DNA-intercalating epipodophyllotoxins than with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the level of DNA damage generated by etoposide (an epipodophyllotoxin derivative) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enhanced only in the former cells. CONCLUSIONS: Activated ras oncogenes appear to enhance the sensitivity of human tumor cells to topoisomerase II inhibitors by potentiating an apoptotic response. Epipodophyllotoxin-derived topoisomerase II inhibitors should be more effective than the DNA-intercalating inhibitors against tumor cells with activated ras oncogenes.

Regulation of mucosal B cell immunoglobulin secretion by intestinal epithelial cell-derived cytokines.

Intestinal epithelial cells (IEC) secrete a variety of cytokines and, because of their close proximity to B cells in the lamina propria, may affect local antibody production via these cytokines. However, studies have not yet addressed which and to what extent these IEC-derived cytokines may affect B cell antibody production. In this study, rat mesenteric lymph node B cells were cultured with culture supernatants from the rat IEC-6 intestinal epithelial cell line to determine their effect on immunoglobulin (Ig) secretion. Unstimulated IEC-6 cells were found to secrete sufficient levels of IL-6 to enhance IgA, IgG and IgM secretion by unstimulated B cells. However, culture of lipopolysaccharide (LPS)-stimulated B cells with the unstimulated IEC-6 supernatant resulted in an enhancement of IgA secretion while IgM secretion was significantly suppressed. Depletion of the IEC-6 supernatant using cytokine specific antibodies revealed that both interleukin 6 (IL-6) and transforming growth factor beta (TGF-beta) were responsible for the enhanced IgA secretion while TGF-beta suppressed IgM secretion. More importantly, culture supernatants from LPS stimulated IEC-6 cells contained enhanced levels of IL-6 which enhanced both IgG and IgA production and partially overcame the suppressive effect of TGF-beta on IgM secretion. These results suggest that intestinal epithelial cells may secrete IL-6 and TGF-beta to regulate local B cell antibody secretion and their effect may be highly dependent upon the activation state of the epithelial cells.

Enhanced sensitivity to 1-beta-D-arabinofuranosylcytosine and topoisomerase II inhibitors in tumor cell lines harboring activated ras oncogenes.

We used human tumor cell lines from the National Cancer Institute's In Vitro Antineoplastic Drug Screen to assess whether sensitivity to any of the approximately 45,000 compounds tested previously correlated with the presence of a ras oncogene. Among these cell lines, the mutations in Ki-ras2 clustered in non-small cell lung and colon carcinoma subpanels, and five of the six leukemia lines contained mutations in either N-ras or Ki-ras2. These analyses revealed a striking correlation with 1-beta-D-arabinofuranosylcytosine (Ara-C) and 2,2'-O-cyclocytidine sensitivity in the cell lines harboring ras mutations compared to the tumor lines with wild-type ras alleles. Strong correlations were also found with topoisomerase (topo) II inhibitors, especially 3'-hydroxydaunorubicin and an olivacine derivative. These differential sensitivities persisted in an additional 22 non-small cell lung carcinoma lines (ras mutations, n = 12 and wild-type ras, n = 10). Thus, the association with Ara-C sensitivity was greatest while topo II inhibitors showed a lower, but significant, correlation. These results suggest that the ras oncogene may play a determinant role in rendering tumor cells sensitive to deoxycytidine analogues and topo II inhibitors.

Polarized secretion of IL-6 by IEC-6 intestinal epithelial cells: differential effects of IL-1 beta and TNF-alpha.

Intestinal epithelial cells (IEC) can exist as polarized cells and are capable of secreting interleukin-6 (IL-6), yet it has not been determined if this IL-6 is secreted in a polarized fashion. Using the non-transformed rat IEC-6 intestinal epithelial cell line grown on microporous membrane inserts, we have determined that these cells were capable of secreting IL-6 preferentially to the basal surface when stimulated basally with IL-1 beta. In contrast, stimulation of the cells with TNF-alpha resulted in an equal level of IL-6 secretion to the apical and basal surfaces, regardless of whether the cells were stimulated by the apical or basal route. Experiments designed to test the permeability of the IEC-6 cell layer to apically added sodium fluorescein confirmed that neither IL-1 beta nor TNF-alpha altered the integrity of the cell layer after three days. These results suggest that IEC may have the capacity to secret IL-6 in different patterns depending upon the stimulation received. This would allow communication between the IEC and lamina propria cells via basal secretion and rapid communication between IEC via apical secretion.

Modified radical hysterectomy: morbidity and mortality.

Among 375 patients who underwent a modified radical hysterectomy at the Mayo Clinic, the complication rate was 24%, and the operative mortality was 0.5%. When compared with radical hysterectomy, this procedure is associated with a lower overall incidence of complications, particularly those related to the urinary tract.

Magnetic resonance imaging of pelvic floor relaxation: dynamic analysis and evaluation of patients before and after surgical repair.

OBJECTIVE: To evaluate structures involved in pelvic support using conventional and snapshot magnetic resonance imaging (MRI). METHODS: We used conventional spin-echo MRI and dynamic snapshot GRASS MRI at various levels of the Valsalva maneuver to describe and quantitate the anatomy of pelvic floor relaxation and to assess anatomical changes produced by surgical repair. Ten female volunteers were evaluated to define normal anatomy and reference measurements. Five women with pelvic floor relaxation were evaluated before and after surgical repair. RESULTS: Static and dynamic MRI were more sensitive than clinical pelvic examination in assessing and grading pelvic floor relaxation. Quantitative results showed widening of the levator hiatus and more vertical lie of the levator plate postoperatively. Descent of the pelvic organs on maximal straining postoperatively was the same as that in normal volunteers. The posterior urethrovesical angle on MRI was more than 110 degrees in 14 of 15 continent subjects. CONCLUSIONS: Magnetic resonance imaging may be valuable in analyzing and assessing pelvic floor relaxation and in understanding anatomical changes occurring before and after surgical repair. The increased sensitivity of MRI in grading prolapse may make it useful in evaluating women with symptoms of pelvic floor relaxation but who have negative findings on clinical examination.

Portal vein thrombosis associated with pregnancy. A case report.

This report illustrates a case of portal vein thrombosis that developed in the second trimester of pregnancy. The patient did not have any of the known associations or predisposing factors for portal vein thrombosis or any past medical history of thrombosis or bleeding disorders. Antepartum and postpartum laboratory studies showed no evidence of a coagulation disorder; therefore, it seems that the sole cause of this thrombotic event was the hypercoagulable state of pregnancy.