• Effectiveness of app-based self-acupressure for women with menstrual pain compared to usual care: a randomized pragmatic trial

      Blödt, S.; Pach, D.; von Eisenhart-Rothe, S. (Elsevier, 2018)
      Background: Primary dysmenorrhea is common among women of reproductive age. Nonsteroidal anti-inflammatory drugs and oral contraceptives are effective treatments, although the failure rate is around 20% to 25%. Therefore additional evidence-based treatments are needed. In recent years, the use of smartphone applications (apps) has increased rapidly and may support individuals in self-management strategies. Objective: We aimed to investigate the effectiveness of app-based self-acupressure in women with menstrual pain. Materials and Methods: A 2-armed, randomized, pragmatic trial was conducted from December 2012 to April 2015 with recruitment until August 2014 in Berlin, Germany, among women aged 18 to 34 years with self-reported cramping pain of 6 or more on a numeric rating scale (NRS) for the worst pain intensity during the previous menstruation. After randomization, women performed either app-based self-acupressure (n = 111) or followed usual care only (n = 110) for 6 consecutive menstruation cycles. The primary outcome was the mean pain intensity (NRS 0-10) on the days with pain during the third menstruation. Secondary outcomes included worst pain intensity during menstruation, duration of pain, 50% responder rates (reduction of mean pain by at least 50%), medication intake, sick leave days, and body efficacy expectation assessed at the first, second, third, and sixth menstruation cycles. Results: We included 221 women (mean age, 24.0 years; standard deviation [SD], 3.6 years). The mean pain intensity difference during the third menstruation was statistically significant in favor of acupressure (acupressure: 4.4; 95% confidence interval [CI], 4.0-4.7; usual care 5.0; 95% CI, 4.6-5.3; mean difference -0.6; 95% CI, -1.2 to -0.1; P =.026). At the sixth cycle, the mean difference between the groups (-1.4; 95% CI, -2.0 to -0.8; P <.001) reached clinical relevance. At the third and sixth menstruation cycles, responder rates were 37% and 58%, respectively, in the acupressure group, in contrast to 23% and 24% in the usual care group. Moreover, the worst pain intensity (group difference -0.6; 95% CI, -1.2 to -0.02; and -1.4; 95% CI, -2.0 to -0.7), the number of days with pain (-0.4; 95% CI, -0.9 to -0.01; and -1.2; 95% CI, -1.6 to -0.7) and the proportion of women with pain medication at the third and sixth menstruation cycles (odds ratio [OR], 0.5; 95% CI, 0.3-0.9] and 0.3 (95% CI, 0.2-0.5) were lower in the acupressure group. At the third cycle, hormonal contraceptive use was more common in the usual care group than in the acupressure group (OR, 0.5; 95% CI, 0.3-0.97) but not statistically significantly different at the sixth cycle (OR, 0.6; 95% CI, 0.3-1.1]). The number of sick leave days and body efficacy expectation (self-efficacy scale) did not differ between groups. On a scale of 0 to 6, mean satisfaction with the intervention at the third cycle was 3.7 (SD 1.3), recommendation of the intervention to others 4.3 (1.5), appropriateness of acupressure for menstrual pain 3.9 (1.4), and application of acupressure for other pain 4.3 (1.5). The intervention was safe, and after the sixth cycle, two-thirds of the women (67.6%) still applied acupressure on all days with pain. Conclusion: Smartphone app-delivered self-acupressure resulted in a reduction of menstrual pain compared to usual care only. Effects were increasing over time, and adherence was good. Future trials should include comparisons with other active treatment options. Copyright 2017 The Authors
    • Individual differences in regulatory mode moderate the effectiveness of a pilot mHealth trial for diabetes management among older veterans

      Dugas, M.; Crowley, K.; Gao, G.G. (Public Library of Science, 2018)
      mHealth tools to help people manage chronic illnesses have surged in popularity, but evidence of their effectiveness remains mixed. The aim of this study was to address a gap in the mHealth and health psychology literatures by investigating how individual differences in psychological traits are associated with mHealth effectiveness. Drawing from regulatory mode theory, we tested the role of locomotion and assessment in explaining why mHealth tools are effective for some but not everyone. A 13-week pilot study investigated the effectiveness of an mHealth app in improving health behaviors among older veterans (n = 27) with poorly controlled Type 2 diabetes. We developed a gamified mHealth tool (DiaSocial) aimed at encouraging tracking of glucose control, exercise, nutrition, and medication adherence. Important individual differences in longitudinal trends of adherence, operationalized as points earned for healthy behavior, over the course of the 13-week study period were found. Specifically, low locomotion was associated with unchanging levels of adherence during the course of the study. In contrast, high locomotion was associated with generally stronger adherence although it exhibited a quadratic longitudinal trend. In addition, high assessment was associated with a marginal, positive trend in adherence over time while low assessment was associated with a marginal, negative trend. Next, we examined the relationship between greater adherence and improved clinical outcomes, finding that greater adherence was associated with greater reductions in glycated hemoglobin (HbA1c) levels. Findings from the pilot study suggest that mHealth technologies can help older adults improve their diabetes management, but a "one size fits all" approach may yield suboptimal outcomes. Copyright 2018 Dugas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    • Disease Ontology: Improving and unifying disease annotations across species

      Bello, S.M.; Shimoyama, M.; Mitraka, E. (Company of Biologists Ltd, 2018)
      Model organisms are vital to uncovering the mechanisms of human disease and developing new therapeutic tools. Researchers collecting and integrating relevant model organism and/or human data often apply disparate terminologies (vocabularies and ontologies), making comparisons and inferences difficult. A unified disease ontology is required that connects data annotated using diverse disease terminologies, and in which the terminology relationships are continuously maintained. The Mouse Genome Database (MGD, http://www.informatics.jax.org), Rat Genome Database (RGD, http://rgd.mcw.edu) and Disease Ontology (DO, http://www.diseaseontology.org) projects are collaborating to augment DO, aligning and incorporating disease terms used by MGD and RGD, and improving DO as a tool for unifying disease annotations across species. Coordinated assessment of MGD's and RGD's disease term annotations identified new terms that enhance DO's representation of human diseases. Expansion of DO term content and cross-references to clinical vocabularies (e.g. OMIM, ORDO, MeSH) has enriched the DO's domain coverage and utility for annotating many types of data generated from experimental and clinical investigations. The extension of anatomy-based DO classification structure of disease improves accessibility of terms and facilitates application of DO for computational research. A consistent representation of disease associations across data types from cellular to whole organism, generated from clinical and model organism studies, will promote the integration, mining and comparative analysis of these data. The coordinated enrichment of the DO and adoption of DO by MGD and RGD demonstrates DO's usability across human data, MGD, RGD and the rest of the model organism database community. Copyright 2018. Published by The Company of Biologists Ltd
    • Establishment of the first International Standard for human anti-typhoid capsular Vi polysaccharide IgG

      Rijpkema, S.; Hockley, J.; Logan, A. (Academic Press, 2018)
      Vi capsular polysaccharide (Vi) conjugate vaccines, which can prevent typhoid in infants and young children, are being developed. Comparative immunogenicity studies are facilitated by an International Standard (IS) for human anti-Vi IgG. 16/138, a pool of sera from volunteers which received either Vi conjugate vaccine or plain Vi vaccine, was assessed as an IS alongside U.S. reference reagent Vi-IgG R1, 2011 . Samples were tested in a commercial ELISA (n = 7), a standardised ELISA based on biotinylated Vi (n = 7) and in-house ELISAs (n = 7). Valid estimates were obtained for the potency of all samples in the commercial ELISA, and the commutability of 16/138 and Vi-IgG R1, 2011 was evident for the commercial ELISA and in-house ELISAs based on a coating of Vi and protein. The WHO Expert Committee on Biological Standardization established 16/138 as the first IS for anti-Vi IgG with 100 IU per ampoule and assigned 163 IU per vial of Vi-IgG R1, 2011 . Copyright 2018
    • Pilot study of the addition of mass treatment for malaria to existing school-based programs to treat neglected tropical diseases

      Cohee, L.M.; Chilombe, M.; Ngwira, A. (American Society of Tropical Medicine and Hygiene, 2018)
      Malaria and neglected tropical diseases (NTDs), including schistosomiasis and soil transmitted helminths, threaten the health of school aged in sub-Saharan Africa. Established school-based mass drug administration (MDA) programs are used to control NTDs. Recent clinical trials have shown benefit of mass treatment of malaria in schools. The potential of adding malaria treatment to existing NTD programs has not been thoroughly evaluated. We offered malaria treatment with artemether-lumefantrine during routine NTD MDA and developed peer education programs in two primary schools in southern Malawi. We assessed participation, safety, and tolerability of coadministration of artemetherlumefantrine with praziquantel and albendazole. Results were compared with two schools conducting standard NTD MDA with additional monitoring by study staff. A total of 3,387 students (68%) received the standard NTD MDA. Among parents who came to schools on the day of the MDA, malaria treatment was well accepted;87%of students who received the standard NTD MDA in intervention schools also consented for treatment with artemether-lumefantrine. The most frequent treatment emergent adverse events (AEs) were headache and vomiting. However, AEs were rare and were not more frequent in students who received artemether-lumefantrine in addition to praziquantel and albendazole. In this study, we found that the addition of malaria treatment to NTD MDA is well-received and safe. Such integrated programs may leverage existing infrastructures to reduce intervention costs and could become the framework for further integrated school-based health programs. Copyright 2018 by The American Society of Tropical Medicine and Hygiene.
    • Effect of acupuncture on post-hemorrhoidectomy pain: A randomized controlled trial

      Wu, J.; Chen, B.; Yin, X. (Dove Medical Press Ltd., 2018)
      Objectives: To observe the clinical efficacy and safety of electroacupuncture (EA) in relieving pain after hemorrhoidectomy treatment for mixed hemorrhoids. Design: This was a randomized controlled trial. Methods: We conducted a single-center, single-blind, and randomized controlled clinical trial. Seventy-two patients with mixed hemorrhoids who had undergone hemorrhoidectomy were randomly assigned to the following 2 groups: the EA treatment group (EA) received surround needling with EA (n=36), and the control group received sham acupuncture (SA) treatment (n=36). The treatment was conducted within 15 min after the completion of the surgery and lasted for 30 min. The pain intensity was recorded by using the visual analog scale as the primary outcome. Secondary outcomes were verbal rating scale and Wong-Baker Faces Pain Rating. These measurements were evaluated at 11 time points: once every hour in the first 8 h after the treatment, 24 and 48 h after the treatment, and at the first defecation. Besides, quality of life was measured by Symptom Checklist-90 Scale at 24 and 48 h follow-ups. Results: The EA group had significantly lower visual analog scale scores at the 3 time points of 6, 24 h, and during the defecation (p<0.05). Verbal rating scale showed a significantly lower score in the treatment group compared to the SA group at 4 h after the treatment as well as during defecation (p<0.05). The Wong-Baker Faces Pain Rating scores of EA group were significantly lower at 5, 7, and 8 h after treatment and during defecation (p<0.05) compared with those of SA group. Conclusion: Acupuncture is effective in alleviating postoperative pain in patients who have undergone hemorrhoidectomy. Copyright 2018 Wu et al.
    • Pharmacist-led interdisciplinary medication reconciliation using comprehensive medication review in gynaecological oncology patients: A prospective study

      Son, H.; Kim, J.; Kim, C. (BMJ Publishing Group, 2018)
      Objectives: Medication reconciliation is a key part of transitional care. This study examined the implementation of a pharmacist-led medication reconciliation programme for short-term hospitalised patients and explored the barriers and benefits. Methods: A prospective study was conducted in patients admitted to a gynaecological oncology department. Medications were reconciled on admission using a 'comprehensive medication review (CMR)' strategy. Patients received a reminder text message and were asked to bring their medications a day before admission for scheduled chemotherapy. Upon admission, a pharmacist reviewed patients' admission prescriptions and home medications, including non-prescription medications, based on clinical status and laboratory test results. Drug-related problems and unused or expired medications were assessed. Satisfaction with the CMR service and reasons for non-compliance were surveyed by an individual interview. The cost of the unused or expired medications was calculated based on the average drug acquisition cost. Results: Sixty-four interventions in 95 patients were performed during the study - namely, correction of treatment duration (34 cases, 53.1%), recommendation of medications for untreated indications (18 cases, 28.1%), correct drug selection (5 cases, 7.8%), discontinuation of duplicate medications (4 cases, 6.3%), correction of dose, provision of alternatives for drug-drug interactions, unintended omissions (1 case each, 1.6%). The difference in the cost of unused or expired drugs before and after programme implementation was about US$1700. Conclusions: Pharmacist-led medication reconciliation targeting short-term hospitalised patients improved drug use, prevented medication waste and reduced healthcare costs. Copyright 2018 Published by the BMJ Publishing Group Limited.
    • Mobile diabetes intervention study of patient engagement and impact on blood glucose: Mixed methods analysis

      Quinn, C.C.; Butler, E.C.; Swasey, K.K. (JMIR Publications, 2018)
      Background: Successful treatment of diabetes includes patient self-management behaviors to prevent or delay complications and comorbid diseases. On the basis of findings from large clinical trials and professional guidelines, diabetes education programs and health providers prescribe daily regimens of glucose monitoring, healthy eating, stress management, medication adherence, and physical activity. Consistent, long-term commitment to regimens is challenging. Mobile health is increasingly being used to assist patients with lifestyle changes and self-management behaviors between provider visits. The effectiveness of mobile health to improve diabetes outcomes depends on patient engagement with a technology, content, or interactions with providers. Objectives: In the current analysis, we aimed to identify patient engagement themes in diabetes messaging with diabetes providers and determine if differences in engagement in the Mobile Diabetes Intervention Study (MDIS) influenced changes in glycated hemoglobin A1c (HbA1c) over a 1-year treatment period (1.9% absolute decrease in the parent study). Methods: In the primary MDIS study, 163 patients were enrolled into 1 of 3 mobile intervention groups or a usual care control group based on their physician cluster randomization assignment. The control group received care from their physicians as usual. Participants in each intervention group had access to a patient portal where they could record monitoring values for blood glucose, blood pressure, medication changes, or other self-management information while also assigned to varying levels of physician access to patient data. Intervention participants could choose to send and receive messages to assigned certified diabetes educators with questions or updates through the secure Web portal. For this secondary analysis, patient engagement was measured using qualitative methods to identify self-care themes in 4109 patient messages. Mixed methods were used to determine the impact of patient engagement on change in HbA1c over 1 year. Results: Self-care behavior themes that received the highest engagement for participants were glucose monitoring (75/107, 70.1%), medication management (71/107, 66.4%), and reducing risks (71/107, 66.4%). The average number of messages sent per patient were highest for glucose monitoring (9.2, SD 14.0) and healthy eating (6.9, SD 13.2). Compared to sending no messages, sending any messages about glucose monitoring (P=.03) or medication (P=.01) led to a decrease in HbA1c of 0.62 and 0.72 percentage points, respectively. Sending any messages about healthy eating, glucose monitoring, or medication combined led to a decrease in HbA1c of 0.54 percentage points compared to not sending messages in these themes (P=.045). Conclusions: The findings from this study help validate the efficacy of the mobile diabetes intervention. The next step is to determine differences between patients who engage in mobile interventions and those who do not engage and identify methods to enhance patient engagement. Copyright Charlene Connolly Quinn, Erin C Butler, Krystal K Swasey, Michelle D Shardell, Michael D Terrin, Erik A Barr, Ann L Gruber-Baldini.
    • 17-AAG inhibits vemurafenib-associated MAP kinase activation and is synergistic with cellular immunotherapy in a murine melanoma model

      Joshi, S.S.; Jiang, S.; Unni, E. (Public Library of Science, 2018)
      Heat shock protein 90 (HSP90) is a molecular chaperone which stabilizes client proteins with important roles in tumor growth. 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90 ATPase activity, occupies the ATP binding site of HSP90 causing a conformational change which destabilizes client proteins and directs them towards proteosomal degradation. Malignant melanomas have active RAF-MEK-ERK signaling which can occur either through an activating mutation in BRAF (BRAF V600E ) or through activation of signal transduction upstream of BRAF. Prior work showed that 17-AAG inhibits cell growth in BRAF V600E and BRAF wildtype (BRAF WT ) melanomas, although there were conflicting reports about the dependence of BRAF V600E and BRAF WT upon HSP90 activity for stability. Here, we demonstrate that BRAF WT and CRAF are bound by HSP90 in BRAF WT , NRAS mutant melanoma cells. HSP90 inhibition by 17-AAG inhibits ERK signaling and cell growth by destabilizing CRAF but not BRAF WT in the majority of NRAS mutant melanoma cells. The highly-selective BRAF V600E inhibitor, PLX4032 (vemurafenib), inhibits ERK signaling and cell growth in mutant BRAF melanoma cells, but paradoxically enhances signaling in cells with wild-type BRAF. In our study, we examined whether 17-AAG could inhibit PLX4032-enhanced ERK signaling in BRAF WT melanoma cells. As expected, PLX4032 alone enhanced ERK signaling in the BRAF WT melanoma cell lines Mel-Juso, SK-Mel-2, and SK-Mel-30, and inhibited signaling and cell growth in BRAF V600E A375 cells. However, HSP90 inhibition by 17-AAG inhibited PLX4032-enhanced ERK signaling and inhibited cell growth by destabilizing CRAF. Surprisingly, 17-AAG also stimulated melanin production in SK-Mel-30 cells and enhanced TYRP1 and DCT expression without stimulating TYR production in all three BRAF WT cell lines studied as well as in B16F10 mouse melanoma cells. In vivo, the combination of 17-AAG and cellular immunotherapy directed against Tyrp1 enhanced the inhibition of tumor growth compared to either therapy alone. Our studies support a role for 17-AAG and HSP90 inhibition in enhancing cellular immunotherapy for melanoma. Copyright: This is an open access article, free of all opyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
    • Attaching-and-Effacing Pathogens Exploit Junction Regulatory Activities of N-WASP and SNX9 to Disrupt the Intestinal Barrier

      Garber, J.J.; Mallick, E.M.; Scanlon, K.M. (Elsevier Inc, 2018)
      Background & Aims: Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9). We hypothesized that N-WASP regulates AJC integrity and AE pathogens use EspF to induce junction disassembly through an N-WASP-and SNX9-dependent pathway. Methods: We analyzed mice with intestine-specific N-WASP deletion and generated cell lines with N-WASP and SNX9 depletion for dynamic functional assays. We generated EPEC and Citrobacter rodentium strains complemented with EspF bearing point mutations abolishing N-WASP and SNX9 binding to investigate the requirement for these interactions. Results: Mice lacking N-WASP in the intestinal epithelium showed spontaneously increased permeability, abnormal AJC morphology, and mislocalization of occludin. N-WASP depletion in epithelial cell lines led to impaired assembly and disassembly of tight junctions in response to changes in extracellular calcium. Cells lacking N-WASP or SNX9 supported actin pedestals and type III secretion, but were resistant to EPEC-induced AJC disassembly and loss of transepithelial resistance. We found that during in vivo infection with AE pathogens, EspF must bind both N-WASP and SNX9 to disrupt AJCs and induce intestinal barrier dysfunction. Conclusions: Overall, these studies show that N-WASP critically regulates AJC homeostasis, and the AE pathogen effector EspF specifically exploits both N-WASP and SNX9 to disrupt intestinal barrier integrity during infection. Copyright 2018 The Authors
    • Efficacy of electrical acupuncture on vascular cognitive impairment with no dementia: Study protocol for a randomized controlled trial

      Li, T.; Wu, H.; Soto-Aguliar, F. (BioMed Central Ltd., 2018)
      Background: Vascular cognitive impairment with no dementia (VCIND), manifested mainly as mild impairment of concentration and executive function, is the early phase of vascular dementia (VD). Currently, there is no specific treatment for VCIND. We hypothesize that electrical acupuncture can improve the mental and motor functions of patients with VCIND. Thus, we designed this randomized controlled trial to test this hypothesis by comparing the therapeutic effect of electrical acupuncture versus sham acupuncture in patients with VCIND. Method/Design: In this single-center 3-year study, 120 eligible patients will be recruited and randomly assigned to receive electrical acupuncture treatment (n = 60) or sham acupuncture (n = 60) for 8 consecutive weeks (24 sessions in total), with the same acupoint prescription (DU20, EX-HN3, DU24, DU17, DU26, EX-HN1, HT7, PC6, GB20, SP6). The primary assessment is the Montreal Cognitive Assessment. The secondary assessments are the Modified Barthel Index and Event-Related Potential. All outcomes will be assessed at baseline, endpoint, and follow-up at 8 and 24 weeks after the end of treatment. Discussion: If the outcome confirms the effectiveness and safety of electrical acupuncture in treating VCIND, this treatment is expected to be promoted in clinical practice to treat such patients. Trial Registration: Chinese Clinical Trial Registry identifier: ChiCTR-IIR-17011513; Registered on 27 May 2017. Copyright 2018 The Author(s).
    • LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer

      Lo, P.-K.; Yao, Y.; Lee, J.S. (eLife Sciences Publications Ltd, 2018)
      Current understanding of aggressive human basal-like triple-negative breast cancer (TNBC) remains incomplete. In this study, we show endothelial lipase (LIPG) is aberrantly overexpressed in basal-like TNBCs. We demonstrate that LIPG is required for in vivo tumorigenicity and metastasis of TNBC cells. LIPG possesses a lipase-dependent function that supports cancer cell proliferation and a lipase-independent function that promotes invasiveness, stemness and basal/ epithelial-mesenchymal transition features of TNBC. Mechanistically, LIPG executes its oncogenic function through its involvement in interferon-related DTX3L-ISG15 signaling, which regulates protein function and stability by ISGylation. We show that DTX3L, an E3-ubiquitin ligase, is required for maintaining LIPG protein levels in TNBC cells by inhibiting proteasome-mediated LIPG degradation. Inactivation of LIPG impairs DTX3L-ISG15 signaling, indicating the existence of DTX3L-LIPG-ISG15 signaling. We further reveal LIPG-ISG15 signaling is lipase-independent. We demonstrate that DTX3L-LIPG-ISG15 signaling is essential for malignancies of TNBC cells. Targeting this pathway provides a novel strategy for basal-like TNBC therapy. Copyright Lo et al.
    • Draft genome sequences of blaKPC-containing Enterobacter aerogenes, Citrobacter freundii, and Citrobacter koseri strains

      Hazen, T.H.; Mettus, R.T.; McElheny, C.L. (American Society for Microbiology, 2018)
      We report here the draft genome sequences of four blaKPC-containing bacteria identified as Klebsiella aerogenes, Citrobacter freundii, and Citrobacter koseri. Additionally, we report the draft genome sequence of a K. aerogenes strain that did not contain a blaKPC gene but was isolated from the patient who had the blaKPC-2- containing K. aerogenes strain. Copyright 2018 Hazen et al.
    • Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis

      O'Malley, K.J.; Bowling, J.L.; Stinson, E. (Public Library of Science, 2018)
      Tularemia, also known as rabbit fever, is a severe zoonotic disease in humans caused by the gram-negative bacterium Francisella tularensis (Ft). While there have been a number of attempts to develop a vaccine for Ft, few candidates have advanced beyond experiments in inbred mice. We report here that a prime-boost strategy with aerosol delivery of recombinant live attenuated candidate Ft S4?aroD offers significant protection (83% survival) in an outbred animal model, New Zealand White rabbits, against aerosol challenge with 248 cfu (11 LD50) of virulent type A Ft SCHU S4. Surviving rabbits given two doses of the attenuated strains by aerosol did not exhibit substantial post-challenge fevers, changes in erythrocyte sedimentation rate or in complete blood counts. At a higher challenge dose (3,186 cfu; 139 LD50), protection was still good with 66% of S4?aroD-vaccinated rabbits surviving while 50% of S4?guaBA vaccinated rabbits also survived challenge. Pre-challenge plasma IgG titers against Ft SCHU S4 corresponded with survival time after challenge. Western blot analysis found that plasma antibody shifted from predominantly targeting Ft O-antigen after the prime vaccination to other antigens after the boost. These results demonstrate the superior protection conferred by a live attenuated derivative of virulent F. tularensis, particularly when given in an aerosol prime-boost regimen. Copyright 2018 O'Malley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    • Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock

      Pati, S.; Peng, Z.; Wataha, K. (Public Library of Science, 2018)
      In severe trauma and hemorrhage the early and empiric use of fresh frozen plasma (FFP) is associated with decreased morbidity and mortality. However, utilization of FFP comes with the significant burden of shipping and storage of frozen blood products. Dried or lyophilized plasma (LP) can be stored at room temperature, transported easily, reconstituted rapidly with ready availability in remote and austere environments. We have previously demonstrated that FFP mitigates the endothelial injury that ensues after hemorrhagic shock (HS). In the current study, we sought to determine whether LP has similar properties to FFP in its ability to modulate endothelial dysfunction in vitro and in vivo. Single donor LP was compared to single donor FFP using the following measures of endothelial cell (EC) function in vitro: permeability and transendothelial monolayer resistance; adherens junction preservation; and leukocyte-EC adhesion. In vivo, using a model of murine HS, LP and FFP were compared in measures of HS- induced pulmonary vascular inflammation and edema. Both in vitro and in vivo in all measures of EC function, LP demonstrated similar effects to FFP. Both FFP and LP similarly reduced EC permeability, increased transendothelial resistance, decreased leukocyte-EC binding and persevered adherens junctions. In vivo, LP and FFP both comparably reduced pulmonary injury, inflammation and vascular leak. Both FFP and LP have similar potent protective effects on the vascular endothelium in vitro and in lung function in vivo following hemorrhagic shock. These data support the further development of LP as an effective plasma product for human use after trauma and hemorrhagic shock. Copyright 2018 Pati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    • Neuroendocrine stress responses predict catecholamine-dependent working memory-related dorsolateral prefrontal cortex activity

      Hernaus, D.; Quaedflieg, C.W.E.M.; Offermann, J.S. (Oxford University Press, 2018)
      It is generally thought that the effect of acute stress on higher-order functions such as working memory is, for an important part, mediated by central catecholamine activity. However, little is known about the association between neuroendocrine stress responses and catecholamine-dependent working memory-related brain function in the absence of stress. Here, we investigate for the first time in healthy humans (n=18) how neuroendocrine responses to stress (cortisol and alphaamylase) relate to fronto-parietal working memory activity changes in response to atomoxetine, a noradrenaline transporter inhibitor that selectively increases extracellular cortical dopamine and noradrenaline. We observed positive correlations between stress-induced cortisol (Pearson's r = 0.75, P < 0.001) and alpha amylase (r = 0.69, P = 0.02) increases and catecholamine-dependent working memory-related activity in dorsolateral prefrontal cortex. Stress-induced cortisol increases furthermore correlated with supramarginal gyrus working memory-related activity (r = 0.79, P < 0.001). Comparing high vs low stress responders revealed that these correlations were driven by decreased working memory activity on placebo and greater working memory activity increases following atomoxetine in high stress responders. These results further corroborate the notion that neuroendocrine responses to stress are an informative proxy of catecholamine function relevant to higher order functions and provide novel hints on the complex relationship between acute stress, catecholamine function and working memory. Copyright The Author (2017).
    • Single-Dose Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate Formulation, in Healthy Adults and in Adolescents and Children with Attention-Deficit/Hyperactivity Disorder

      Childress, A.; Mehrotra, S.; Gobburu, J. (Mary Ann Liebert Inc., 2018)
      Objective: Current extended-release (ER) formulations of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD) provide an extended duration of ADHD symptom control; however, the onset of efficacy can be protracted and variable, leaving the early morning untreated. The primary objective was to characterize the single-dose pharmacokinetics and tolerability of HLD200, an evening-dosed, delayed-release (DR) and ER formulation of methylphenidate (MPH), in healthy adults and in adolescents and children with ADHD. Methods: The pharmacokinetics and tolerability of a single, oral evening dose of HLD200 (54 mg) were evaluated in two single-center open-label studies: the first in healthy adults (n = 12) and the second in adolescents (n = 18) and children (n = 11) with ADHD. Primary pharmacokinetic endpoints were the rate and extent of MPH absorption (Cmax and area under the curve [AUC]) and time to peak concentration (Tmax). These parameters were calculated using noncompartmental analysis. Results: HLD200 produced a pharmacokinetic profile characterized by an 8- to 10-hour delay in MPH release, followed by a period of extended controlled release, resulting in an ascending absorption profile that coincided with the early morning and afternoon. Mean values (coefficient of variation [CV]%) of weight-adjusted pharmacokinetic parameters were similar in adults and in adolescents and children with ADHD: Cmax ([ng/mL]/[mg/kg]) was 9.1 (35.2), 8.8 (34.5), and 7.4 (30.1); AUC0-t ([ng · h/mL]/[mg/kg]) was 126.5 (35.5), 129.4 (34.8), and 129.7 (27.3); and Tmax (hours) was 15.6 (11.1), 17.1 (14.5), and 17.7 (14.1), respectively. Intersubject variability in the mean time to achieve ascending plasma MPH concentrations of 2, 3, 4, and 5 ng/mL was low (CV: 7.8%-17.7%). Conclusions: Evening-dosed HLD200 produces the intended DR and ER pharmacokinetic profile that provides a consistent predictable delay in initial MPH release until the early morning, followed by extended release across the day. The body weight-adjusted pharmacokinetics of HLD200 were similar between adults and adolescents and children with ADHD. Copyright Ann Childress et al. 2017; Published by Mary Ann Liebert, Inc.
    • Increasing uptake of comparative effectiveness and patient-centered outcomes research among stakeholders: Insights from conference discussion

      Law, E.; Harrington, R.; Alexander, G.C. (Future Medicine Ltd., 2018)
      The goal of comparative effectiveness research (CER) and patient-centered outcomes research (PCOR) is to improve health outcomes by providing stakeholders with evidence directly relevant to decision making. In January 2017, the Pharmaceutical Research and Manufacturers Association Foundation, alongside the Academy for Managed Care Pharmacy, organized a conference aimed at engaging experts and opinion leaders representing clinicians, patients and payers to identify and discuss barriers and strategies to enhancing uptake and use of CER/PCOR. This report summarizes the conference discussion in the following sections: preconference survey; summary of barriers and strategies to the uptake of CER/PCOR identified by conference attendees; and future perspectives on the field. Copyright 2018 2018 Ernest Law.
    • Peripheral Cone Dystrophy: Expanded Clinical Spectrum, Multimodal and Ultrawide-Field Imaging, and Genomic Analysis

      Sisk, R.A.; Hufnagel, R.B.; Laham, A. (Hindawi Limited, 2018)
      Purpose. To present new clinical features, multimodal and ultrawide-field imaging characteristics of peripheral cone dystrophy (PCD), and results of laboratory and genetic investigation to decipher the etiology. Methods. Retrospective observational case-series. Results. Three patients with PCD presented with bilateral paracentral scotomas and a mean visual acuity of 20/25. All exhibited confluent macular hyperautofluorescence with a central bull's eye lesion. Spectral-domain optical coherence tomography revealed loss of outer retinal elements, particularly the inner segment ellipsoid band and external limiting membrane, within the area of macular hyperautofluorescence. This area corresponded with a lightened fundus appearance and variable retinal pigment epithelium (RPE) abnormalities. Full field and multifocal electroretinography distinguished PCD from other photoreceptor dystrophies. Ultrawide-field imaging revealed irregular peripheral retinal lesions in a distribution greater nasally than temporally and not contiguous with the macular lesion. Functional and anatomic testing remained stable over a mean follow-up of 3 years. Laboratory investigation for causes of uveitis was negative. Whole exome sequencing identified rare variants in genes associated with macular or cone dystrophy or degeneration. Conclusions. In contrast to the original description, the funduscopic and fluorescein angiographic appearance of PCD is abnormal, although the defects are subtle. Peripheral lesions may be observed in some patients. Bilateral, symmetric, macular hyperautofluorescence associated with outer retinal atrophy that spares the fovea is a characteristic of PCD. Pathogenic variants in the same gene were not shared across the cohort, suggesting genetic heterogeneity. Further evaluation is warranted. Copyright 2018 Robert A. Sisk et al.
    • Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

      Roesch, C.; Popovici, J.; Bin, S. (Public Library of Science, 2018)
      The interaction between Plasmodium vivax Duffy binding protein (PvDBP) and Duffy antigen receptor for chemokines (DARC) has been described as critical for the invasion of human reticulocytes, although increasing reports of P. vivax infections in Duffy-negative individuals questions its unique role. To investigate the genetic diversity of the two main protein ligands for reticulocyte invasion, PvDBP and P. vivax Erythrocyte Binding Protein (PvEBP), we analyzed 458 isolates collected in Cambodia and Madagascar from individuals genotyped as Duffy-positive. First, we observed a high proportion of isolates with multiple copies PvEBP from Madagascar (56%) where Duffy negative and positive individuals coexist compared to Cambodia (19%) where Duffy-negative population is virtually absent. Whether the gene amplification observed is responsible for alternate invasion pathways remains to be tested. Second, we found that the PvEBP gene was less diverse than PvDBP gene (12 vs. 33 alleles) but provided evidence for an excess of nonsynonymous mutations with the complete absence of synonymous mutations. This finding reveals that PvEBP is under strong diversifying selection, and confirms the importance of this protein ligand in the invasion process of the human reticulocytes and as a target of acquired immunity. These observations highlight how genomic changes in parasite ligands improve the fitness of P. vivax isolates in the face of immune pressure and receptor polymorphisms.