Assessing the Risks of Bleeding vs Thrombotic Events in Patients at High Bleeding Risk After Coronary Stent Implantation: The ARC-High Bleeding Risk Trade-off Model.
Patients who are candidates for percutaneous coronary intervention (PCI) and are at high bleeding risk constitute a therapeutic challenge because they often also face an increased risk of thrombotic complications. To develop and validate models to predict the risks of major bleeding (Bleeding Academic Research Consortium [BARC] types 3 to 5 bleeding) and myocardial infarction (MI) and/or stent thrombosis (ST) for individual patients at high bleeding risk and provide assistance in defining procedural strategy and antithrombotic regimens. This prognostic study used individual patient data from 6 studies conducted from July 1, 2009, to September 5, 2017, for 6641 patients at more than 200 centers in Europe, the US, and Asia who underwent PCI and were identified as being at high bleeding risk using the Academic Research Consortium criteria. In 1 year of follow-up (excluding periprocedural events), individual patient risks of MI and/or ST and major bleeding were evaluated using 33 baseline variables. To validate these models, a subgroup of 1458 patients at high bleeding risk from the ONYX ONE trial were analyzed. Statistical analysis was performed from February 1, 2019, to April 30, 2020. All patients underwent PCI with bare metal, drug-coated, or drug-eluting stent implants. Forward, stepwise multivariable proportional hazards models were used to identify highly significant predictors of MI and/or ST and BARC types 3 to 5 bleeding. A total of 6641 patients (4384 men [66.0%]; median age, 77.9 years [interquartile range, 70.0-82.6 years]) were included in this study. Over 365 days, nonperiprocedural MI and/or ST occurred in 350 patients (5.3%), and BARC types 3 to 5 bleeding occurred in 381 patients (5.7%). Eight independent baseline predictors of risk of MI and/or ST and 8 predictors for risk of BARC types 3 to 5 bleeding were identified. Four of these predictors were in both risk models. Both risk models showed moderate discrimination: C statistic = 0.69 for predicting MI and/or ST and 0.68 for predicting BARC types 3 to 5 bleeding. Applying these same models to the validation cohort gave a similar strength of discrimination (C statistic = 0.74 for both MI and/or ST and BARC types 3-5 bleeding). Patients with MI and/or ST had a mortality hazard ratio of 6.1 (95% CI, 4.8-7.7), and those with BARC types 3 to 5 bleeding had a mortality hazard ratio of 3.7 (95% CI, 2.9-4.8) compared with patients free of both events. Taking these data into account, the risk scores facilitate investigation of the individual patient trade-off between these 2 risks: 2931 patients (44.1%) at high bleeding risk in the 6 studies had a greater risk of MI and/or ST than of BARC 3 to 5 bleeding, 1555 patients (23.4%) had a greater risk of BARC 3 to 5 bleeding than of MI and/or ST, and 2155 (32.4%) had a comparable risk of both events. In a large cohort of patients at high bleeding risk undergoing PCI, 2 prognostic models have been developed to identify individual patients' risk of major coronary thrombotic and bleeding events. In future clinical practice, using an application on a smartphone to evaluate the trade-off between these 2 quantifiable risks for each patient may help clinicians choose the most appropriate revascularization strategy and tailor the duration and intensity of antithrombotic regimens.


Long-term follow-up of patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation after primary induction failure.
Primary induction failure (PIF) in acute myeloid leukemia (AML) patients is associated with poor outcome, with allogeneic hematopoietic stem cell transplantation (HCT) being the sole curative therapeutic option. Here, we retrospectively evaluated long-term outcomes of 220 AML patients undergoing allogeneic HCT after PIF who never achieved remission, and identified clinical and molecular risk factors associated with treatment response and ultimate prognosis. In this high-risk population, disease-free survival was 25.2% after 5 years and 18.7% after 10 years, while overall survival rates were 29.8% and 21.6% after 5 and 10 years of HCT, respectively. 10-year non-relapse mortality was 32.5%, and 48.8% of patients showed disease relapse within 10 years after allogeneic HCT. Adverse molecular risk features determined at initial diagnosis, poor performance status at the time of allogeneic HCT, and long diagnosis-to-HCT intervals were associated with unfavorable prognosis. Collectively, our data suggests that immediate allogeneic HCT after PIF offers long-term survival and cure in a substantial subset of cases and that high-risk AML patients who never achieved complete response during induction might benefit from early donor search.


Oral risedronate sodium improves bone mineral density in non-ambulatory patients: a randomized, double-blind, placebo controlled trial.
Investigate the efficacy of risedronate sodium (Procter and Gamble, Cincinnati, USA) for treating reduced lumbar spine (LS) bone mineral density (BMD) in non-ambulatory patients. Nine (10-39 years, mean age 23.0 years, 7 males) in the risedronate arm and 10 (10-35 years, mean age 21.4 years, 8 males) in the placebo arm completed 24 months of therapy at baseline, 6, 12, 18, and 24 months. The primary outcome was change in LS BMD assessed by dual energy x-ray absorptiometry (DXA). Secondary outcomes included changes in serum bone markers, bone specific alkaline phosphatase, osteocalcin, and N-telopeptides. Mixed models examined group, time, and the group by time interaction for the 4 post-baseline time points. The change in LS BMD score from baseline to 24 months was 0.069 (95% CI 0.014 to 0.124) in risedronate participants compared to -0.015 (95% CI -0.073 to 0.042) (t Value = -2.40, P > t=0.03) in the controls. When controlling for baseline scores, the difference was consistent across four post-baseline time points tested (F=5.67, Pr > F=0.03). No differences in serum bone markers were observed. Risedronate increases LS BMD in non-ambulatory patients with minimal side effects.


Identification of novel candidate variants including COL6A6 polymorphisms in early-onset atopic dermatitis using whole-exome sequencing.
The prevalence of atopic dermatitis has increased over the last 10 years. Atopic dermatitis tends to run in families and commonly begins to manifest in childhood. The prevalence of atopic dermatitis is as high as 20% in children. Thus, early diagnosis and treatment of atopic dermatitis are important. Understanding its genetic basis is also needed to facilitate early detection. To identify family-specific candidate genetic variants associated with early-onset atopic dermatitis in Koreans, we carried out whole-exome sequencing of three separate families with this condition. Additional validation was performed in 112 AD patients and 61 controls using Sanger sequencing. We focused on both common functional variants with a minor allele frequency higher than 1% and rare variants with a minor allele frequency less than 1%. The relevance of the respective variants was supported by a program that could predict whether the mutations resulted in damaged protein function. Fourteen overlapping genes were identified during exome sequencing. Three variants of the COL6A6 gene appeared in all three families and were in close proximity to atopic dermatitis-related loci on chromosome 3q21. The homozygous frequency for the rs16830494 minor allele (AA) and the rs59021909 (TT) allele and the rs200963433 heterozygous (CT) frequency were all higher in AD cases compared to controls in a population-based case-control study. Identifying family-specific COL6A6 polymorphisms and genetic variants of other candidate genes associated with AD using WES is a novel approach. Our study suggests that COL6A6 variants may be risk factors for atopic dermatitis. This study provides a genetic basis for early-onset AD diagnosis in Korean patients and the development of new therapies. Trial registration number: IRB NO. C2008030 (133); Name of registry: The collection research of clinical data and patient blood to identify genetic and protein biomarker of atopic dermatitis; Date of registration: 09-July-2008. IRB NO. C2015258 (1716); Name of registry: The collection study of patient blood and clinical data for the development of the prognosis prediction and early diagnosis of atopic dermatitis; Date of registration: 15-jan-2016.


Maternal urine beta-core hCG fragment level and small for gestational age neonates.
To determine whether second-trimester urine beta-core fragments of hCG predict small for gestational age (SGA) neonates. Spot urine beta-core levels were measured in 733 nonhypertensive women with singleton pregnancies who presented for amniocentesis and had karyotypically normal fetuses. The beta-core level was standardized to urine creatinine and expressed as multiples of the median. The area under a receiver operating characteristics curve was used to determine the screening efficiency of the urine analyte for prediction of small for gestational age (SGA) births. In a subgroup of cases, serum markers (alpha-fetoprotein [AFP], hCG, and unconjugated estriol) were compared using stepwise regression analysis to urine beta-core fragment for SGA prediction. There were 23 (3.0%) SGA neonates. The mean +/- standard deviation (SD) gestation at urine collection was 16.4 +/- 1.3 weeks and collection to delivery interval was 23.0 +/- 2.2 weeks. Mean beta-core (+/- SD) fragment levels were significantly higher in those who later had SGA infants compared with appropriately grown infants (2982.8 ng/mg creatinine versus 1447.4 ng/mg creatinine, P <.001). Stepwise logistic regression found that urine beta-core fragment and serum AFP were the only significant predictors of SGA, with statistically significant chi(2) values (P <.001 and P =.038, respectively). The urine analyte was significantly superior. Second-trimester urine beta-core fragment had a 78.3% sensitivity and 70% specificity for SGA prediction. Exclusion of preeclamptic cases resulted in a sensitivity of 84.2% and a specificity of 71.2%. Second-trimester elevated maternal urine beta-core fragment of hCG predicted SGA infants, and was superior to other serum analytes in that prediction.


TGF-beta2 alters the characteristics of the neuromuscular junction by regulating presynaptic quantal size.
The amount of neurotransmitter released from a presynaptic terminal is the product of the quantal content (number of vesicles) and the presynaptic quantal size (QSpre, amount of transmitter per vesicle). QSpre varies with synaptic use, but its regulation is poorly understood. The motor nerve terminals at the neuromuscular junction (NMJ) contain TGF-beta receptors. We present evidence that TGF-beta2 regulates QSpre at the NMJ. Application of TGF-beta2 to the rat diaphragm NMJ increased the postsynaptic response to both spontaneous and evoked release of acetylcholine, whereas antibodies to TGF-beta2 or its receptor had the converse effect. L-vesamicol and bafilomycin blocked the actions of TGF-beta2, indicating that TGF-beta2 acts by altering the extent of vesicular filling. Recordings of the postsynaptic currents from the diaphragm were consistent with TGF-beta2 having this presynaptic action and a lesser postsynaptic effect on input resistance. TGF-beta2 also decreased quantal content by an atropine-sensitive pathway, indicating that this change is secondary to cholinergic feedback on vesicular release. Consequently, the net actions of TGF-beta2 at the NMJ were to amplify the postsynaptic effects of spontaneous transmission and to diminish the number of vesicles used per evoked stimulus, without diminishing the amount of acetylcholine released.


Dermatology on YouTube.
YouTube, reaches upwards of six billion users on a monthly basis and is a unique source of information distribution and communication. Although the influence of YouTube on personal health decision-making is well established, this study assessed the type of content and viewership on a broad scope of dermatology related content on YouTube. Select terms (i.e. dermatology, sun protection, skin cancer, skin cancer awareness, and skin conditions) were searched on YouTube. Overall, the results included 100 videos with over 47 million viewers. Advocacy was the most prevalent content type at 24% of the total search results. These 100 videos were "shared" a total of 101,173 times and have driven 6,325 subscriptions to distinct YouTube user pages. Of the total videos, 35% were uploaded by or featured an MD/DO/PhD in dermatology or other specialty/field, 2% FNP/PA, 1% RN, and 62% other. As one of the most trafficked global sites on the Internet, YouTube is a valuable resource for dermatologists, physicians in other specialties, and the general public to share their dermatology-related content and gain subscribers. However, challenges of accessing and determining evidence-based data remain an issue.


Loneliness and Cultural Hyphenation.
Forever a Work in Progress is a painting that explores complexities of isolation as one consequence of navigating a culturally hyphenated identity.


Endothelin receptor antagonist CPU0213 suppresses ventricular fibrillation in L-thyroxin induced cardiomyopathy.
Arrhythmias correlate with disorders of either K(2+) channels in sarcolemma or calcium modulating system in sarcoplasmic reticulum which handles Ca(2+) intracellularly. We hypothesized that an activated endothelin (ET) signaling pathway, which may be associated with an alteration of K(+) channels and Ca(2+) uptake activity in the myocardium, participated in the exaggerated ventricular fibrillation (VF) incidence in cardiomyopathy (CM) induced by L-thyroxin. We intended to test if a dual endothelin receptor antagonist CPU0213 is effective to suppress VF correlating with a reversal of abnormalities in expression of the ion channels in sarcolemma and sarcoplasmic reticulum. The CM was induced by L-thyroxin administration for 10 days, and the altered expression of ion channels and the ET system was examined and the susceptibility to VF was evaluated by 10-min ischemia followed by reperfusion (I/R). Rats were treated with either propranolol or CPU0213 from day 6-10 of L-thyroxin medication. An increased VF incidence on I/R episode in the CMwas found relative to control. An elevated myocardial ET-1 and preproET-1 expression were associated with abnormal mRNAlevel of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a), phospholamban (PLB), and ERG, MinK, and Kv4.2 in sarcolemma. Propranolol and CPU0213 were equally effective in reversing the alterations of gene phenotype and exaggerated VF in CM hearts. In conclusion, an activated ET receptor signaling plays a role in the progression of augmented VF in association with abnormal expression of ion channels in both sarcolemma and sarcoplasmic reticulum in the CM.


Treatment responses of childhood aplastic anaemia with chromosomal aberrations at diagnosis.
The clinical outcome of childhood aplastic anaemia (AA) with aberrant cytogenetic clones at diagnosis was surveyed. Among 198 children with newly diagnosed AA registered with the AA Committee of the Japanese Society of Paediatric Hematology between 1994 and 1998, cytogenetic studies of bone marrow (BM) cells were completed in 159 patients. Apart from one Robertsonian translocation, seven patients (4.4%) showed clonal chromosomal abnormalities in hypoplastic BM without myelodysplastic features. The patients included six girls and one boy with a median age of 11 years (range 5-14 years). Six patients had del(6), del(5), del(13), del(20), or -7, and one showed add(9). Four patients responded to the first immunosuppressive therapy (IST: cyclosporin A plus anti-thymocyte globulin) and one obtained a spontaneous remission. Cytogenetic abnormalities remained in two patients with an IST response. On the other hand, two patients showed no IST response. One did not respond to repeat IST and died of acute graft-versus-host disease after an unrelated-BM transplant. Another obtained a complete response after a successful BM transplant. No haematological findings at diagnosis predicted the treatment response. No significant morphological changes developed during the course of the illness. A literature review revealed that half of 24 AA patients with chromosomal abnormalities responded to the first IST, and that +6 was the sole predictable marker for IST unresponsiveness. These results suggest that IST can be applied as the initial therapy for AA with cytogenetic abnormalities in the absence of completely matched donors.


Diagnostic assays in cytomegalovirus retinitis: detection of herpesvirus by simultaneous application of the polymerase chain reaction and local antibody analysis on ocular fluid.
To determine the value of the polymerase chain reaction (PCR) technique and the analysis of intraocularly produced antibodies by calculating a Goldmann-Witmer quotient (GWq) as diagnostic assays in the confirmation of a clinically diagnosed cytomegalovirus (CMV) retinitis in a group of unselected AIDS patients. Eleven samples of undiluted ocular fluid, obtained from nine AIDS patients with a clinically diagnosed CMV retinitis were analysed for the presence of genomic DNA from CMV, HSV-1, VZV, and EBV by PCR. Nine of these samples were analysed for the presence of locally produced IgG antibodies against these herpesviruses by calculating a GWq. Ten samples obtained from patients with various entities of clinical non-herpetic uveitis and 17 samples of aqueous humour obtained at cataract surgery were used as controls. In 10 out of 11 samples from AIDS patients (91%) the presence of CMV DNA was demonstrated. In four out of nine (44%) patients this was accompanied by CMV DNA in the blood indicating a CMV viraemia. In one sample, VZV DNA was detected and in another sample both CMV and VZV DNA were detected. No HSV-1 or EBV DNA could be demonstrated in these 11 samples. In contrast, simultaneous analysis of locally produced IgG antibodies against herpesviruses could not confirm the initial diagnosis of CMV retinitis. Ocular fluid samples obtained from 10 control uveitis patients were negative for DNA from CMV, VZV, and EBV by PCR. In one of 10 uveitis control samples HSV-1 DNA was detected; antibody analysis did not confirm this. In the uveitis control group, a significant GWq was calculated in one sample for HSV-1 and in another sample for VZV. The cataract control samples were all herpesvirus DNA negative by PCR. To establish the diagnosis of CMV retinitis in AIDS patients, ophthalmoscopic examination is a sensitive method. In confirming a diagnosis in indistinctive cases, application of a PCR assay detecting CMV DNA is a more sensitive method than analysis of locally produced antibodies by calculating a GWq. In clinical non-herpetic uveitis, secondary release of HSV-1 and VZV should be considered requiring additional therapeutic anticipation.


Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation.
The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.


Experiences from the Swedish determinants-based public health policy.
A comprehensive Swedish public health policy was adopted by the Swedish Parliament, the Riksdag, in April 2003. It pushes health up on the political agenda and affords equity in health high priority. The first phase of implementation of the policy, 2003-5, is described in the 2005 Public Health Policy Report published by the Swedish National Institute of Public Health (SNIPH). For the purpose of investigating the implementation, SNIPH has monitored the development of 42 determinants and used reports from 22 central agencies and eight county administrative boards together with interviews with all Sweden's county councils (21) and a questionnaire sent out to all municipalities (290). The experiences from the implementation of the policy are that: the determinants approach - focusing on structural factors in society, people's living conditions and health behaviours that affect health - is in general well understood and emphasises the role of other sectors in public health; the use of indicators to follow up exposures to determinants is of key importance; the support to actors outside the health service is needed to identify their public health role; a continuous steering from the government and other political bodies is of vital importance; public health promotion on the regional level needs a higher level of co-ordination; municipalities need more skills development; Sweden has a new government that was elected in September 2006; the new government has retracted the former government's public health policy communication submitted to the Riksdag in the spring of 2006, but does not intend to change the public health policy.


Control of biofouling on reverse osmosis polyamide membranes modified with biocidal nanoparticles and antifouling polymer brushes.
Thin-film composite (TFC) polyamide reverse osmosis (RO) membranes are prone to biofouling due to their inherent physicochemical surface properties. In order to address the biofouling problem, we have developed novel surface coatings functionalized with biocidal silver nanoparticles (AgNPs) and antifouling polymer brushes via polyelectrolyte layer-by-layer (LBL) self-assembly. The novel surface coating was prepared with polyelectrolyte LBL films containing poly(acrylic acid) (PAA) and poly(ethylene imine) (PEI), with the latter being either pure PEI or silver nanoparticles coated with PEI (Ag-PEI). The coatings were further functionalized by grafting of polymer brushes, using either hydrophilic poly(sulfobetaine) or low surface energy poly(dimethylsiloxane) (PDMS). The presence of both LBL films and sulfobetaine polymer brushes at the interface significantly increased the hydrophilicity of the membrane surface, while PDMS brushes lowered the membrane surface energy. Overall, all surface modifications resulted in significant reduction of irreversible bacterial cell adhesion. In microbial adhesion tests with E. coli bacteria, a normalized cell adhesion in the range of only 4 to 16% on the modified membrane surfaces was observed. Modified surfaces containing silver nanoparticles also exhibited strong antimicrobial activity. Membranes coated with LBL films of PAA/Ag-PEI achieved over 95% inactivation of bacteria attached to the surface within 1 hour of contact time. Both the antifouling and antimicrobial results suggest the potential of using these novel surface coatings in controlling the fouling of RO membranes.


Protocol for a randomised trial evaluating a preconception-early childhood telephone-based intervention with tailored e-health resources for women and their partners to optimise growth and development among children in Canada: a Healthy Life Trajectory Initiative (HeLTI Canada).
The 'Developmental Origins of Health and Disease' hypothesis suggests that a healthy trajectory of growth and development in pregnancy and early childhood is necessary for optimal health, development and lifetime well-being. The purpose of this paper is to present the protocol for a randomised controlled trial evaluating a preconception-early childhood telephone-based intervention with tailored e-health resources for women and their partners to optimise growth and development among children in Canada: a Healthy Life Trajectory Initiative (HeLTI Canada). The primary objective of HeLTI Canada is to determine whether a 4-phase 'preconception to early childhood' lifecourse intervention can reduce the rate of child overweight and obesity. Secondary objectives include improved child: (1) growth trajectories; (2) cardiometabolic risk factors; (3) health behaviours, including nutrition, physical activity, sedentary behaviour and sleep; and (4) development and school readiness at age 5 years. A randomised controlled multicentre trial will be conducted in two of Canada's highly populous provinces-Alberta and Ontario-with 786 nulliparous (15%) and 4444 primiparous (85%) women, their partners and, when possible, the first 'sibling child.' The intervention is telephone-based collaborative care delivered by experienced public health nurses trained in healthy conversation skills that includes detailed risk assessments, individualised structured management plans, scheduled follow-up calls, and access to a web-based app with individualised, evidence-based resources. An 'index child' conceived after randomisation will be followed until age 5 years and assessed for the primary and secondary outcomes. Pregnancy, infancy (age 2 years) and parental outcomes across time will also be assessed. The study has received approval from Clinical Trials Ontario (CTO 1776). The findings will be published in peer-reviewed journals and disseminated to policymakers at local, national and international agencies. Findings will also be shared with study participants and their communities. ISRCTN13308752; Pre-results.


Increased Na(+)-H+ exchange in jejunal brush border membrane vesicles of spontaneously hypertensive rats.
The spontaneously hypertensive rats and their genetically matched controls, Wistar-Kyoto, serve as models of essential hypertension. The present study was undertaken to determine whether brush border membrane vesicles obtained from jejunal enterocytes of spontaneously hypertensive rats show increased Na(+)-H+ exchange as part of a generalized membrane disorder. Brush border membrane vesicles were prepared from the jejunum of adult spontaneously hypertensive rats and Wistar-Kyoto rats using an Mg2+/ethylene glycol tetraacetic acid precipitation method. Uptake of 22Na by these vesicles was found to be into an osmotically sensitive intravesicular space rather than mere binding. Initial Na+ uptake by brush border membrane vesicles was greater in spontaneously hypertensive rats than in Wistar-Kyoto rats (P less than 0.05). Higher total and amiloride-sensitive Na+ uptake in spontaneously hypertensive rats occurred in the presence of an outwardly directed pH gradient, and uptake became statistically similar to that of Wistar-Kyoto rats in the absence of a pH gradient. Moreover, amiloride-insensitive Na+ uptake under an outwardly directed pH gradient did not differ significantly between the two groups. The enhanced Na(+)-H+ activity in spontaneously hypertensive rats is not due to altered membrane permeability to protons, as is shown by acridine orange-quenching studies. Kinetic studies for amiloride-sensitive Na+ uptake showed a greater Vmax in spontaneously hypertensive rats compared with Wistar-Kyoto rats (1.46 +/- 0.05 vs. 1.08 +/- 0.08 nmol.mg protein-1.7 s-1) but the Km values were similar in the two groups. These finding, along with similar findings previously reported in vascular smooth muscle and renal tissue of SHR, strongly suggest that an increased Na(+)-H+ exchange is related to the development of hypertension.


Using the power of innate immunoprofiling to understand vaccine design, infection, and immunity.
In the field of immunology, a systems biology approach is crucial to understanding the immune response to infection and vaccination considering the complex interplay between genetic, epigenetic, and environmental factors. Significant progress has been made in understanding the innate immune response, including cell players and critical signaling pathways, but many questions remain unanswered, including how the innate immune response dictates host/pathogen responses and responses to vaccines. To complicate things further, it is becoming increasingly clear that the innate immune response is not a linear pathway but is formed from complex networks and interactions. To further our understanding of the crosstalk and complexities, systems-level analyses and expanded experimental technologies are now needed. In this review, we discuss the most recent immunoprofiling techniques and discuss systems approaches to studying the global innate immune landscape which will inform on the development of personalized medicine and innovative vaccine strategies.


Periodontal soft tissue root coverage procedures: a systematic review from the AAP Regeneration Workshop.
This paper aims to create a "bridge" between research and practice by developing a practical, extensive, and clinically relevant study that translates evidence-based findings on soft tissue root coverage (RC) of recession-type defects to daily clinical practice. This review is prepared in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement based on the proposed focused questions. A literature search with no restrictions regarding status or the language of publication was performed for MEDLINE and EMBASE databases up to and including June 2013. Systematic reviews (SRs), randomized clinical trials, controlled clinical trials, case series, and case reports evaluating recession areas that were treated by means of RC procedures were considered eligible for inclusion through the three parts of the study (part I, an overview of the base of SRs; part II, an alternative random-effects meta-analyses on mean percentage of RC and sites exhibiting complete RC; and part III, an SR of non-randomized trials exploring other conditions not extensively evaluated by previous SRs). Data on Class I, II, III, and IV recessions, type of histologic attachment achieved with treatment, recipient- and donor-site anatomic characteristics, smoking-related outcomes, root surface conditions, tooth type and location, long-term effectiveness outcomes, unusual conditions that may be reported during conventional daily practice, and patient-centered outcomes were assessed as well. Of the 2,456 potentially eligible trials, 234 were included. Data on Class I, II, III, and IV gingival recessions, histologic attachment achieved after treatment, recipient- and donor-site anatomic characteristics, smoking-related outcomes, root surface conditions/biomodification, tooth type and location, long-term effectiveness outcomes and unusual conditions that may be reported during conventional daily practice, and patient-centered outcomes (i.e., esthetic, visual analog scale, complications, hypersensitivity, patients perceptions) were assessed. Subepithelial connective tissue (CT)-based procedures and coronally advanced flap plus acellular dermal matrix grafts, enamel matrix derivative, or collagen matrix led to the best improvements of recession depth, clinical attachment level (CAL) gain, and keratinized tissue (KT). Some conditions, such as smoking and use of magnification, may affect RC outcomes. All RC procedures can provide significant reduction in recession depth and CAL gain for Miller Class I and II recession-type defects. Subepithelial CT graft-based procedures provided the best outcomes for clinical practice because of their superior percentages of mean and complete RC, as well as significant increase of KT.


Comparison of different fungal agar for the environmental monitoring of pharmaceutical-grade cleanrooms.
In relation to a growth in reported incidents of fungal contamination of pharmaceutical products, there has been a developing interest by U.S. and U.K. regulators concerning the risk of fungi. This paper describes a study undertaken to examine the suitability of different commercially available mycological agars for the environmental monitoring of pharmaceutical-grade cleanrooms. Five agars were evaluated in relation to the detection of both numbers and different species of fungi (yeasts and moulds). The objective was to determine if one mycological medium is more suitable than another. Data was collected using different sampling techniques (settle plates, active air samples, and contact plates) from different locations within representative cleanrooms. Samples were taken over a 3 month time period. The study results indicated that fungi are not distributed evenly across cleanrooms and that that the prevalence of fungi partly relates to the room design and operation. In relation to the different agar types, the study indicated that Sabouraud dextrose agar was the most effective at detecting the widest number of different types of isolates, and that Sabouraud dextrose agar and malt extract agar were the most efficient in terms of the numbers of recovered isolates. Other media, notably potato dextrose agar, was relatively less effective. There has been an increased regulatory concern about the presence of fungi in cleanrooms. Some environmental monitoring regimes are not especially orientated towards the examination of fungi, and it may be that special agars are required. Given the choice of different agars available, this paper outlines a case study where different fungal agars were evaluated. The study showed that Sabouraud dextrose agar was the optimal agar.


Correlates of bone mineral density in elderly patients with hip fractures.
Ninety-seven elderly patients with acute fractures of the proximal femur sustained as a result of minimal trauma were studied with regard to variables that may potentially influence the incidence or outcome of fractures of the proximal femur. The mean bone mineral density (BMD) measured at the femoral neck was approximately 2 SDs below age- and sex-adjusted normals. There was a preferential loss of bone mineral from the femoral neck in younger patients with hip fractures (Z score -3.10 +/- 0.23) (mean +/- SEM) compared with the lumbar spine (Z score -1.71 +/- 0.41). Mean daily calcium intake was well below the recommended levels and calcium intake < 400 mg/day was associated with lower lumbar spine BMD Z scores (p = 0.01). Ambulatory ability was unassociated with BMD Z scores. The results of this study suggest that the femoral neck is a site of preferential bone loss in younger postmenopausal patients, and screening of patients at risk of hip fracture should measure BMD at this site. Calcium supplementation may play a role in decreasing the incidence of hip fractures.


Effects of a consumer driven home modification intervention on community participation for people with mobility disabilities.
Community participation has become a key outcome measure for people with disabilities. This has resulted in a shift in researchers focus from the individual to the environment. However, research has focused primarily on participation barriers in the community with limited research examining the role of the home environment. For people with mobility disabilities the home environment is the starting place for community participation and research is needed to understand the relationship between the home and participation outcomes. This study explores the effects of a consumer-driven home modification intervention on community participation for people with mobility disabilities. We conducted a randomized control trial (from June 2017-April 2019) of the effects of a consumer-directed home modification intervention on community participation. The intervention, the Home Usability Program, was implemented with consumers at two different Centers for Independent Living (N = 195) and included a self-assessment of their home environment and implementation of a home usability change. The Home Usability program positively affected the community participation of people with mobility disabilities. Overall, intervention participants reported a 39.5% (p < .05) increase in social and recreational activities immediately following the intervention relative to the control group after controlling for health status and month when outcome data were collected. Six months after the intervention, this effect returned to baseline. Community-based, consumer-driven home modification programs show promise for improving community participation outcomes among people with disabilities, however, more research is needed to understand why results did not persist.


Rare bleeding disorders: diagnosis and treatment.
Despite the worldwide prevalence of rare bleeding disorders (RBDs), knowledge of these conditions and their management is suboptimal; health care professionals often have little diagnostic and treatment experience with variable access to diagnostic modalities required for accurate identification. Therefore, patients often experience morbidity and mortality due to delayed diagnosis. As RBDs represent a small potential commercial market, few, if any, specific therapies exist for these conditions. As a result, affected individuals commonly face delayed diagnosis, incomplete laboratory evaluation, and limited treatment options. Standardization and customization of coagulation assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with RBDs. In addition, new therapeutic modalities, both recombinant and plasma derived, are emerging, at least in developed countries. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are appropriately diagnosed and properly treated. Expansion and harmonization of international registries has been initiated to correlate genotype, laboratory, and clinical phenotypes including bleeding severity to improve the diagnosis and therapeutic approach. This review focuses on the latest advances in our understanding, diagnosis, and treatment of RBDs.


Compartment syndrome: diagnosis, management, and unique concerns in the twenty-first century.
Compartment syndrome is an elevation of intracompartmental pressure to a level that impairs circulation. While the most common etiology is trauma, other less common etiologies such as burns, emboli, and iatrogenic injuries can be equally troublesome and challenging to diagnose. The sequelae of a delayed diagnosis of compartment syndrome may be devastating. All care providers must understand the etiologies, high-risk situation, and the urgency of intervention. This study was conducted to perform a comprehensive review of compartment syndrome discussing etiologies, risk stratification, clinical progression, noninvasive and invasive monitoring, documentation, medical-legal implication, and our step-by-step approach to compartment syndrome prevention, detection, and early intervention. A literature search was performed using the PubMed Database and the following search terms: "Compartment syndrome AND Extremity," "Compartment syndrome AND Gluteal," and Compartment syndrome AND Paraspinal." A total of 2,068 articles were identified. Filters allowed for the exclusion of studies not printed in English (359) and those focusing on exertional compartment syndrome (84), leaving a total of 1,625 articles available for review. The literature provides details regarding the etiologies, risk stratification, clinical progression, noninvasive and invasive monitoring, documentation, medical-legal implication, and our step-by-step approach to compartment syndrome prevention, detection, and early intervention. The development and progression of compartment syndrome is multifactorial, and as complexity of care increases, the opportunity for the syndrome to be missed is increased. Recent changes in the structure of in-hospital medical care including resident work hour restrictions and the incorporation of midlevel providers have increased the frequency of "signouts" or "patient handoffs" which present opportunities for the syndrome to be mismanaged. The changing dynamics of the health care team have prompted the need for a more explicit algorithm for managing patients at risk for compartment syndrome to ensure appropriate conveyance of information among team members.


Postresistance exercise ethanol ingestion and acute testosterone bioavailability.
Alcohol (ethanol) and resistance exercise can independently affect circulating bioavailable testosterone concentration. The purpose of this study was to examine the testosterone bioavailability and the anabolic endocrine milieu in response to acute ethanol ingestion after a bout of heavy resistance exercise. Eight resistance-trained men (mean ± SD: 25.3 ± 3.2 yr, 87.7 ± 15.1 kg, 177 ± 7 cm) completed two identical acute heavy resistance exercise tests (AHRET: six sets of 10 repetitions of Smith machine squats) separated by 1 wk. Post-AHRET, participants consumed either 1.09 g of grain ethanol per kilogram lean mass (EtOH condition) or no ethanol (placebo condition). Blood samples were collected immediately before exercise (PRE), immediately after exercise (IP), and every 20 min postexercise for 300 min. Samples after IP were pooled into phases (20-40 min, 60-120 min, and 140-300 min after exercise) and analyzed for total testosterone (TT) and free testosterone (FT), sex hormone-binding globulin (SHBG), cortisol, and estradiol. Peak blood ethanol concentration (0.088 ± 0.015 g·dL) was achieved 60-90 min postexercise. TT and FT were elevated significantly (P ≤ 0.05) at IP for both conditions. At 140-300 min postexercise, TT, FT, and free androgen index were significantly higher for EtOH (TT: 22.5 ± 12.5 nmol·L; FT: 40.5 ± 7.6 pmol·L) than for placebo (TT: 13.9 ± 6.8 nmol·L; FT: 22.7 ± 10.0 pmol·L). No differences between conditions were noted for SHBG, cortisol, or estradiol. Postexercise ethanol ingestion affects the hormonal milieu including testosterone concentration and bioavailability during recovery from resistance exercise.


Determination of silver(I) by electrothermal-AAS in a microdroplet formed from a homogeneous liquid-liquid extraction system using tetraspirocyclohexylcalix[4]pyrroles.
A simple and efficient method for the selective separation and preconcentration of Ag+ using homogeneous liquid-liquid extraction was developed. Tetraspirocyclohexylcalix[4]pyrrole (TSCC4P) was synthesized and investigated as a suitable selective complexing ligand for Ag+. Zonyl FSA (FSA) was applied as a phase-separator agent under mild pH conditions. Under the optimal conditions ([TSCC4P] = 3.4 x 10(-4) M, [THF] = 25.0% v/v, [FSA] = 1.25% w/v, and pH = 4.5), 5 microg of Ag+ in 6.0 ml aqueous phase could be extracted quantitatively into 20 microl of the sedimented phase. The maximum concentration factor was 300-fold. The limit of detection of the proposed method was 0.005 ng/ml. The reproducibility of the proposed method was at most 3.5%. The influence of the pH, type and volume of the water-miscible organic solvent, concentration of FSA, concentration of the complexing ligand and the effect of different diverse ions on the extraction and determination of Ag+ were investigated. The proposed method was applied to the extraction and determination of Ag+ in different water samples.


Chemotaxis of Escherichia coli to L-serine.
A novel experimental technique was used to quantify the motion of E. coli to varying serine concentrations and gradients so as to capture the spatial and temporal variation of the chemotactic response. The average run speed and the cell diffusivity are found to be dependent on the serine concentration. The measured diffusivities were in the range of 1.2-2.5 x 10 (-10) m(2) s(-1). The study revealed that the rotational diffusivity of the cells, induced by the extracellular environment, also varies with the serine concentration. The drift velocity increased with serine gradients reaching a maximum value of approximately 5.5 microm s(-1) at 1.6 microM microm(-1) after which it decreased. Experimental analysis demonstrated the interdependence of run speed, rotational diffusivity and drift velocity that characterizes the motion. Further, the motion was found to critically depend on the oxygen concentration and energy level of the cells.


Streptomyces iakyrus TA 36 as First-Reported Source of Quinone Antibiotic γ-Rubromycin.
A wide range of bioactive compounds with potential medical applications are produced by members of the genus Streptomyces. A new actinomycete producer of the antibiotic γ-rubromycin, designated TA 36, was isolated from an alpine soil sample collected in Peru (Machu Picchu). Morphological, physiological and biochemical characteristics of the strain, together with data obtained via phylogenetic analysis and MALDI-TOF MS, were used for the correct identification of the isolate. The isolate TA 36 showed morphological characteristics that were consistent with its classification within the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequences showed that the TA 36 strain was most similar to S. iakyrus and S. violaceochromogenes with 99% similarity. Phylogenetic analysis together with the profile of whole cell proteins indicated that the strain tested could be identified as S. iakyrus TA 36. The crude extract Ext.5333.TA 36 showed various effects against the tested organisms with strong antimicrobial activity in the growth of Staphylococcus aureus (Newman) (MIC value of 0.00195 µg/µL). HPLC fractionation and LC/MS analysis of the crude extract led to the identification of the quinone antibiotic γ-rubromycin, a promising antitumour and antibacterial antibiotic. To the best of our knowledge, there is currently no report on the production of γ-rubromycin by S. iakyrus. Therefore, this study suggests S. iakyrus TA 36 as the first-reported source of this unique bioactive secondary metabolite.


Stabilization of proteins by guanidination.
Earlier studies have indicated the marked resistance of two pronase endopeptidases to denaturation in high concentrations of urea or guanidine hydrochloride (Siegel, S., and Awad, W. M., Jr. (1973) J. Biol. Chem. 248, 3233--3240). One component has only a single residue of lysine and the other has none. The consideration arose that lysine-containing peptide segments may be less stable than those containing arginine because of the fluctuations of the side groups of the former residue. The small epsilon amino groups may not be able to sustain solvation of the hydrophobic arm in an aqueous medium. Arginine residues have shorter hydrophobic arms, larger hydrophilic groups, and higher pKa values and, thus may be less motile than lysine. The hypothesis was tested by guanidination of seven globular proteins (bovine carbonic anhydrase, chymotrypsinogen, alpha-lactalbumin, serum albumin, ribonuclease, hen egg lysozyme, and horse heart cytochrome c). Conversion of lysine residues to homoarginine was between 90 and 99%. Tritium-hydrogen isotope exchange revealed that all proteins except lysozyme demonstrated reduced out-exchange after guanidination. The results with lysozyme were not unexpected since only this protein has a high arginine to lysine ratio. These findings suggest that high arginine to lysine ratios contribute to protein stability.


Bile acid receptors and the kidney.
Bile acids act as activating signals of endogenous renal receptors: the nuclear receptor farnesoid X receptor (FXR) and the membrane-bound G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). In recent years, bile acids have emerged as important for renal pathophysiology by activating FXR and TGR5 and transcription factors relevant for lipid, cholesterol and carbohydrate metabolism, as well as genes involved in inflammation and renal fibrosis. Activation of bile acid receptors has a promising therapeutic potential in prevention of diabetic nephropathy and obesity-induced renal damage, as well as in nephrosclerosis. During the past decade, progress has been made in understanding the biology and mechanisms of bile acid receptors in the kidney and in the development of specific bile acid receptor agonists. In this review, we discuss current knowledge on the roles of FXR and TGR5 in the physiology of the kidney and the latest advances made in development and characterization of bile acid analogues that activate bile acid receptors for treatment of renal disease.


Detection of Catabacter hongkongensis in polluted European water samples.
The Catabacteriaceae is a new bacterial family with a unique member: Catabacter hongkongensis is a strictly anaerobic, non-sporulating, Gram-positive coccobacillus that is phylogenetically related to some clostridial clusters. Little is known of its epidemiology and environmental distribution, but the inclusion of its 16S rRNA gene sequence in GenBank has allowed it to be detected qualitatively. As a first approach for prospective surveys, a real-time polymerase chain reaction (PCR) procedure to identify C. hongkongensis has been developed. The presence of Catabacteriaceae in 29 water bodies subjected to possible human or animal impact has been investigated. Four of them were positive. The results confirm that highly polluted water can contain C. hongkongensis.


Leucine does not affect mechanistic target of rapamycin complex 1 assembly but is required for maximal ribosomal protein s6 kinase 1 activity in human skeletal muscle following resistance exercise.
We examined how the stimulatory effect of leucine on the mechanistic target of rapamycin complex 1 (mTORC1) pathway is affected by the presence of the remaining essential amino acids (EAAs). Nine male subjects performed resistance exercise on 4 occasions and were randomly supplied EAAs with leucine, EAAs without leucine (EAA-Leu), leucine alone, or flavored water (placebo; control). Muscle biopsies were taken from the vastus lateralis before and 60 and 90 min after exercise. Biopsies were analyzed for protein phosphorylation, kinase activity, protein-protein interactions, amino acid concentrations, and tracer incorporation. Leucine alone stimulated ribosomal protein s6 kinase 1 (S6K1) phosphorylation ∼280% more than placebo and EAA-Leu after exercise. Moreover, this response was enhanced by 60-75% after intake of EAAs compared with that of leucine alone (P < 0.05). Kinase activity of S6K1 reflected that of S6K1 phosphorylation; 60 min after exercise, the activity was elevated 3.3- and 4.2-fold with intake of leucine alone and with EAAs, respectively (P < 0.05). The interaction between mammalian target of rapamycin and regulatory-associated protein of mammalian target of rapamycin was unaltered in response to both resistance exercise and amino acid provision. Leucine alone stimulates mTORC1 signaling, although this response is enhanced by other EAAs and does not appear to be caused by alterations in mTORC1 assembly.


Radiomics for Response and Outcome Assessment for Non-Small Cell Lung Cancer.
Routine follow-up visits and radiographic imaging are required for outcome evaluation and tumor recurrence monitoring. Yet more personalized surveillance is required in order to sufficiently address the nature of heterogeneity in nonsmall cell lung cancer and possible recurrences upon completion of treatment. Radiomics, an emerging noninvasive technology using medical imaging analysis and data mining methodology, has been adopted to the area of cancer diagnostics in recent years. Its potential application in response assessment for cancer treatment has also drawn considerable attention. Radiomics seeks to extract a large amount of valuable information from patients' medical images (both pretreatment and follow-up images) and quantitatively correlate image features with diagnostic and therapeutic outcomes. Radiomics relies on computers to identify and analyze vast amounts of quantitative image features that were previously overlooked, unmanageable, or failed to be identified (and recorded) by human eyes. The research area has been focusing on the predictive accuracy of pretreatment features for outcome and response and the early discovery of signs of tumor response, recurrence, distant metastasis, radiation-induced lung injury, death, and other outcomes, respectively. This review summarized the application of radiomics in response assessments in radiotherapy and chemotherapy for non-small cell lung cancer, including image acquisition/reconstruction, region of interest definition/segmentation, feature extraction, and feature selection and classification. The literature search for references of this article includes PubMed peer-reviewed publications over the last 10 years on the topics of radiomics, textural features, radiotherapy, chemotherapy, lung cancer, and response assessment. Summary tables of radiomics in response assessment and treatment outcome prediction in radiation oncology have been developed based on the comprehensive review of the literature.


[Nail localization of dermatoses].
The nail unit may reflect a dermatological disease by its own. Actually, its involvement may account for the existence of a skin disease that never showed before (i.e. lichen planus). But since the nail apparatus has a limited repertoire of clinical expressions (hyperkeratosis, onycholysis, paronychia...), the diagnosis may be sometimes difficult even for the most trained physician. Nail involvement may be however an additional clue in the diagnosis of an atypical skin disease. In that case, it might help in the final correct diagnosis provided that the physician did not forget that clinical examination of the nails is part of a dermatological examination.


Hydrogen-bonded polymer multilayers probed by neutron reflectivity.
We present a neutron reflectivity study of the internal structure of multilayers made of a weak polyelectrolyte and a neutral component where interactions between adjacent layers are controlled by hydrogen-bonding. We found the degree of interpenetration of polymer layers expressed as the interlayer roughness to be strongly correlated with the strength of intermolecular interactions between the adjacent layers. In addition, polymer layers become more diffuse with a distance from the substrate. Our results demonstrate that hydrogen-bonded films exhibit a close correlation between their structure and properties, which is essential for various applications.


Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents.
For more than 60 years, heparin and coumarin have been mainstays of anticoagulation therapy. They are widely available, inexpensive, effective, and have specific antidotes but are regarded as problematic because of their need for careful monitoring. In addition, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and is paradoxically prothrombotic in certain settings (ie, can precipitate "coumarin necrosis"). Heparin may require monitoring of its therapeutic effect and can also cause thrombosis (heparin-induced thrombocytopenia/thrombosis syndrome). These limitations have led to the development of new anticoagulants with the potential to replace current agents. These newer agents fall into 2 classes, based on whether they are antithrombin dependent (low-molecular-weight heparin, fondaparinux) or antithrombin independent (direct inhibitors of factor Xa and thrombin [factor IIa]). This paper addresses newer anticoagulants, reviewing their efficacy and limitations, and focuses on the risk of major bleeding that may complicate their use. In contrast to heparin and coumarin, none of these newer agents has a specific antidote that completely reverses its anticoagulant effect. Available data on the efficacy and safety of current and experimental agents for anticoagulant reversal are reviewed, and a plan for management of anticoagulant-induced bleeding is presented.


Body size-mediated starvation resistance in an insect predator.
Individual organisms have to endure transient periods of low-food supply with consequences for growth, reproduction and survival. To resist starvation, animals usually store resources in their bodies: the larger the animals are, the more resources they can carry, but the more energy they need to allocate for maintaining bodily functions. It is unclear how survival relates to body size when food is scarce or absent, and how to characterize individual differences in survival within a population. We use a dynamic energy budget (DEB) model to describe food acquisition, subsequent reserve dynamics and allocation of reserve to body maintenance, growth and maturation of an aquatic insect predator, Notonecta maculata. In a DEB context, we can assume that starvation-induced death strikes when the reserve of an organism is depleted to a certain extent. The way reserve dynamics change upon starvation might thereby influence the ability to survive in the absence of food. Moreover, individuals in a starved population do not die at the same time, even though they might be of the same body size with similar life histories. To describe individual differences in starvation resistance, we link the reserve dynamics derived from the DEB model to the general unified threshold model of survival (GUTS). We tested two different special cases within GUTS, individual tolerance (IT) and stochastic death (SD), and three different starvation options for their suitability in representing experimental data on body size-related starvation resistance. The DEB model reproduced laboratory data on the development of juvenile N. maculata under different food conditions well and closely predicted the weight loss of individuals during prolonged starvation. Both the combined IT-model and the combined SD-model closely fit survival for different food conditions including starvation. However, the two models make different predictions for survival under repeated transient starvation periods. Our results suggest that larger N. maculata specimens are able to resist starvation to a greater extent than smaller conspecifics. The DEB model provides a mechanistic explanation for the positive relationship between body size and starvation resistance, and offers testable hypotheses for possible deviations from this general trend.


Challenges and Management of Surgical Site Occurrences.
Postoperative complications such as surgical site infections, dehiscence, seromas, and hematomas prolong wound care and impose significant cost increases to patients and healthcare providers. Clinicians aiming to reduce the incidence of these complications should be aware of risk factors associated with surgical type, procedures used, patient characteristics, and postoperative care. Today, improved guidelines and general practices for managing surgical incisions have reduced the incidence of complications to historic lows. In addition to these standard care options, advanced wound care approaches have been extensively studied and exist as options for clinicians to provide adjunctive postoperative support and facilitate wound healing. These systems include advanced wound dressings and closed-incision negative-pressure therapy. Advanced wound care is not appropriate in all settings, and healthcare providers must assess each case for specific needs to be addressed by the available incision management plans. Emerging therapies that are intended to improve the continuum of postoperative care should continue to be evaluated in controlled clinical trials to determine their effectiveness under different circumstances and to support the creation of more robust guidelines for their use.


Comprehensive therapeutic benefits of Taiji: a critical review.
This literature review offers physical rehabilitation professionals an update on the current breadth and strength of research evidence regarding comprehensive therapeutic benefits of Taiji practice. A critical analysis distinguishes between what is known from controlled clinical research and what is suggested in preliminary research. Of >200 published reports examined, 17 controlled clinical trials were judged to meet a high standard of methodological rigor. Controlled research evidence was found to confirm therapeutic benefits of Taiji practice with regard to improving quality of life, physical function including activity tolerance and cardiovascular function, pain management, balance and risk of falls reduction, enhancing immune response, and improving flexibility, strength, and kinesthetic sense. Preliminary research on implementation feasibility of Taiji programming exists for a variety of clinical populations. Further controlled clinical study is justified for a wide variety of clinical contexts.


Short lesson plan associated with increased acceptance of evolutionary theory and potential change in three alternate conceptions of macroevolution in undergraduate students.
Undergraduates commonly harbor alternate conceptions about evolutionary biology; these alternate conceptions often persist, even after intensive instruction, and may influence acceptance of evolution. We interviewed undergraduates to explore their alternate conceptions about macroevolutionary patterns and designed a 2-h lesson plan to present evidence that life has evolved. We identified three alternate conceptions during our interviews: that newly derived traits would be more widespread in extant species than would be ancestral traits, that evolution proceeds solely by anagenesis, and that lineages must become more complex over time. We also attempted to measure changes in the alternate conceptions and levels of acceptance of evolutionary theory in biology majors and nonmajors after exposure to the lesson plan. The instrument used to assess understanding had flaws, but our results are suggestive of mixed effects: we found a reduction in the first alternate conception, no change in the second, and reinforcement of the third. We found a small, but significant, increase in undergraduate acceptance of evolutionary theory in two trials of the lesson plan (Cohen's d effect sizes of 0.51 and 0.19). These mixed results offer guidance on how to improve the lesson and show the potential of instructional approaches for influencing acceptance of evolution.


Emerging anticoagulant therapies for atrial fibrillation: new options, new challenges.
Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with an increased risk of stroke and systemic embolism. Oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin, has historically been the mainstay of long-term thromboprophylaxis in AF patients. However, although highly effective, VKAs have a number of limitations that make their use difficult and cumbersome in clinical practice. They have a slow onset and offset of action, narrow therapeutic window, marked dose-response variability, and multiple food and drug interactions, and require frequent coagulation monitoring and dose adjustments. To overcome VKA drawbacks, several new oral anticoagulants have been recently developed for use in AF, and three of them, the direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban, have completed phase III trials. New agents have proven to be noninferior or superior to warfarin for AF-related stroke prevention, with similar or better safety profiles. These new drugs, with their predictable anticoagulant effect that allows for fixed dosing with no need for coagulation monitoring, have the potential to greatly simplify anticoagulation therapy for AF. Dabigatran etexilate and rivaroxaban are already approved in the United States and Europe for stroke prevention in nonvalvular AF, and dabigatran etexilate has entered current AF guidelines as an alternative to warfarin. However, some issues with new compounds are still unresolved, such as the lack of antidotes and standardized tests to measure drug activity. Active postmarketing monitoring surveillance of effectiveness and safety is required in the implementation of new anticoagulant therapies.


Undertaking a face to face Summative OSCE assessment during the COVID-19 Pandemic - a descriptive narrative.
This article was migrated. The article was marked as recommended. The 2020 Covid19 pandemic has caused significant disruption to medical education across the world. At the University of Sheffield final year medical students undertook a virtual OSCE via technology in order to graduate however for our Physician Associate course this was more problematic as following completion of the assessments at the university students are also required to pass a national examination with a formal Objective Structured Clinical Examination (OSCE). Due to this it was felt that it was crucial to run an OSCE examination for our students on a face to face basis but within the context of managing the potential safety and risks inherent in doing so. This piece of work describes the process of running the examination including detail which we feel will be useful to others who may seek to undertake examinations for the same reason within the current health emergency or any future such events. It is important to note that some innovations we put in place with respect to technology enhancing safety will remain for future OSCE examinations in any circumstances.


Genome-wide ORFeome cloning and analysis of Arabidopsis transcription factor genes.
Here, we report our effort in generating an ORFeome collection for the Arabidopsis transcription factor (TF) genes. In total, ORFeome clones representing 1,282 Arabidopsis TF genes have been obtained in the Gateway high throughput cloning pENTR vector, including 411 genes whose annotation lack cDNA support. All the ORFeome inserts have also been mobilized into a yeast expression destination vector, with an estimated 85% rate of expressing the respective proteins. Sequence analysis of these clones revealed that 34 of them did not match with either the reported cDNAs or current predicted open-reading-frame sequences. Among those, novel alternative splicing of TF gene transcripts is responsible for the observed differences in at least five genes. However, those alternative splicing events do not appear to be differentially regulated among distinct Arabidopsis tissues examined. Lastly, expression of those TF genes in 17 distinct Arabidopsis organ types and the cultured cells was profiled using a 70-mer oligo microarray.


Activation of the osteopontin promoter by the orphan nuclear receptor estrogen receptor related alpha.
Estrogen receptor related alpha (ERRalpha) is an orphan nuclear receptor that is closely related to the estrogen receptor. It is expressed in a variety of adult and embryonic tissues (in particular, at the onset of ossification), as well as in several osteoblastic cell lines. ERRalpha acts as a site-specific, cell-specific transcriptional activator. Here, we show that ERRalpha transactivates the promoter of the mouse osteopontin (OPN) gene, the product of which is a marker of the late stages of osteoblastic differentiation. This effect is cell specific and is exerted through derivatives of the ERRalpha response element. Overexpression of ERRalpha in three different osteoblast-like cell lines results in an elevation of the amount of OPN-corresponding mRNA. Therefore, OPN is a target gene for ERRalpha, pointing to the role of the latter in osteoblast differentiation.


Regulation of the kduID operon of Bacillus subtilis by the KdgR repressor and the ccpA gene: identification of two KdgR-binding sites within the kdgR-kduI intergenic region.
Transcription of the Bacillus subtilis kdgRKAT operon, which comprises genes involved in the late stage of galacturonate utilization, is known to be negatively regulated by the KdgR repressor. In this study, Northern analysis was carried out to demonstrate that the kdgR gene also negatively regulates the kduID operon, encoding ketodeoxyuronate isomerase and ketodeoxygluconate reductase. It has also been demonstrated that expression of the kduID operon can be induced by galacturonate and is subject to catabolite repression by glucose. The ccpA gene was found to be involved in this catabolite repression. Primer extension analysis identified a sigma(A)-like promoter sequence preceding kduI. Gel mobility shift assays and DNase I footprinting analyses indicated that KdgR is capable of binding specifically to two sites within the kdgR-kduI intergenic region in vitro. Reporter gene analysis revealed that these two KdgR-binding sites function in vivo. One site is centred 33.5 bp upstream of the translational start site of kdgR and can serve as an operator for controlling expression of the kdgRKAT operon. The other is centred 57.5 bp upstream of the translational start site of kduI and can serve as an operator for controlling expression of the kduID operon. Possible physiological significance of this regulation is discussed.


[Berlition R 300 oral -- alpha-lipoic acid preparation for the correction of body changes associated with high serum iron content].
Medication Berlition 300 oral, produced by "Berlin-Hemie", induces lower serum iron content, decrease in transferrin content of whole blood and serum proportionally to increased urinary iron excretion and lower serum bilirubin and normalizes serum glucose level. Berlition 300 oral, lipoic acid preparation made by "Berlin-He mie" (Menarini group), could be recommended for treatment of high serum iron content and iron overload, especially in association with diabetes mellitus.


Writing the worlds of genomic medicine: experiences of using participatory-writing to understand life with rare conditions.
The diagnostic and treatment possibilities made possible by the development and subsequent mainstreaming of clinical genomics services have the potential to profoundly change the experiences of families affected by rare genetic conditions. Understanding the potentials of genomic medicine requires that we consider the perspectives of those who engage with such services; there are substantial social implications involved. There are increasing calls to think more creatively, and draw on more participatory approaches, in evoking rich accounts of lived experience. In this article, we discuss our rationale for, and experiences of, using 'participatory-writing' to understand the diverse, variable and multilayered everyday lives of families and how these correspond with the emerging, rapidly changing and complex field of genomic medicine. Participatory-writing has many benefits as a method for social inquiry. Writing can be expressive and self-revelatory, providing insight into personal and sensitive topics. Writing together produces new conversations and relationships. Pieces written by participants have the potential to affect readers, evoking and enlivening research and prompting professional change. Working with a writing tutor, we organised a participatory-writing programme for families touched by genetic conditions. This involved a series of workshops with an emphasis on building confidence in expressing lived experience through experimenting with different writing techniques. Afterwards we arranged reflective interviews with participants. We drew on dialogical narrative analysis to engage with participants' written pieces, and highlight what everyday life is like for the people who live with, and care for, those with genetic conditions. The stories produced through our writing-groups unfold the implications of new genomic technologies, illuminating how genomics acts to (and likewise, fails to) reconfigure aspects of people's lives outside of the clinic, while simultaneously existing as a sociotechnical frame that can eclipse the wider contexts, challenges and liveliness of life with rare genetic conditions.


The Diurnal Rhythm of Insulin Receptor Substrate-1 (IRS-1) and Kir4.1 in Diabetes: Implications for a Clock Gene Bmal1.
Diabetes leads to the downregulation of the retinal Kir4.1 channels and Müller cell dysfunction. The insulin receptor substrate-1 (IRS-1) is a critical regulator of insulin signaling in Müller cells. Circadian rhythms play an integral role in normal physiology; however, diabetes leads to a circadian dysrhythmia. We hypothesize that diabetes will result in a circadian dysrhythmia of IRS-1 and Kir4.1 and disturbed clock gene function will have a critical role in regulating Kir4.1 channels. We assessed a diurnal rhythm of retinal IRS-1 and Kir4.1 in db/db mice. The Kir4.1 function was evaluated using a whole-cell recording of Müller cells. The rat Müller cells (rMC-1) were used to undertake in vitro studies using a siRNA. The IRS-1 exhibited a diurnal rhythm in control mice; however, with diabetes, this natural rhythm was lost. The Kir4.1 levels peaked and troughed at times similar to the IRS-1 rhythm. The IRS-1 silencing in the rMC-1 led to a decrease in Kir4.1 and BMAL1. The insulin treatment of retinal explants upregulated Kir4.1 possibly via upregulation of BMAL1 and phosphorylation of IRS-1 and Akt-1. Our studies highlight that IRS-1, by regulating BMAL1, is an important regulator of Kir4.1 in Müller cells and the dysfunctional signaling mediated by IRS-1 may be detrimental to Kir4.1.


Fatigue Stress Fracture of the Talar Body: An Uncommon Cause of Ankle Pain.
Fatigue stress fractures of the talus are rare and usually involve the head of the talus in military recruits. We report an uncommon cause of ankle pain due to a fatigue stress fracture of the body of the talus in a 32-year-old male social soccer player. Healing was achieved after weightbearing suppression for 6 weeks. Although rare, a stress fracture of the body of the talus should be considered in an athlete with a gradual onset of chronic ankle pain. Magnetic resonance imaging and bone scan are useful tools for early diagnosis.


Clinical pathways--an evaluation of its impact on the quality of care in an acute care general hospital in Singapore.
A critical or clinical pathway defines the optimal care process, sequencing and timing of interventions by healthcare professionals for a particular diagnosis or procedure. It is a relatively new clinical process improvement tool that has been gaining popularity across hospitals and various healthcare organisations in many parts of the world. It is now slowly gaining momentum and popularity in Asia and Singapore. Clinical pathways are developed through collaborative efforts of clinicians, case managers, nurses, and other allied healthcare professionals with the aim of improving the quality of patient care, while minimising cost to the patient. Clinical pathways have been shown to reduce unnecessary variation in patient care, reduce delays in discharge through more efficient discharge planning, and improve the cost-effectiveness of clinical services. The approach and objectives of clinical pathways are consistent with those of total quality management (TQM) and continuous clinical quality improvement (CQI), and is essentially the application of these principles at the patient's bedside. However, despite the growing popularity of pathways, their impact on clinical outcomes and their clinical effectiveness remains largely untested and unproven through rigorous clinical trials. This paper begins with an overview of the nature of clinical pathways and the analysis of variances from the pathway, their benefits to the healthcare organisation, their application as a tool for CQI activities in direct relation to patient care, and their effectiveness in a variety of healthcare settings. The paper describes an evaluation of the impact of a clinical pathway on the quality of care for patients admitted for uncomplicated acute myocardial infarction (AMI) through an analysis of variances. The author carried out a one year evaluation of a clinical pathway on uncomplicated AMI in Changi General Hospital (CGH) to determine its effectiveness and impact on a defined set of outcomes. A before and after nonrandomized study of two groups of patients admitted to the Hospital for uncomplicated AMI was done. A total of 169 patients were managed on the clinical pathway compared to 100 patients in the control (historical comparison) group. Outcomes were compared between the two groups of patients. Restriction and matching of study subjects in both groups ensured that the patients selected were comparable in terms of severity of illness. The results showed that the patients on the clinical pathway and the comparison group were similar with respect to demographic variables, prevalence of risk factors and comorbidities. There was a statistically significant reduction in the average length of stay after implementation of the clinical pathway. This was achieved without any adverse effect on short term clinical outcomes such as in-hospital mortality, complication rate and morbidity. There were no significant difference in readmission rates at 6 months after discharge. The paper concludes that clinical pathways, implemented in the context of an acute care general hospital, is able to significantly improve care processes through better collaboration among healthcare professionals and improvements in work systems.


A retrospective cohort study to predict severe dengue in Honduran patients.
An important challenge in the identification of dengue is how to predict which patients will go on to experience severe illness, which is typically characterized by fever, thrombocytopenia, haemorrhagic manifestations, and plasma leakage. Accurate prediction could result in the appropriate hospital triage of high risk patients. The objective of this study was to identify clinical factors observed within the first 24 h of hospital admission that could predict subsequent severe dengue. We conducted a retrospective cohort study of 320 patients with febrile illness who had confirmation of dengue within one week of admission, using data from the 2009-2010 Honduras Epidemiological Survey for Dengue. The outcome measure was plasma leakage defined using hemoconcentration ≥15% as determined by serial hematocrit testing. We conducted univariable analysis and multivariable logistic regression analysis to construct a predictive model for severe dengue. Thirty-four (10.6%) of patients in the 320 patient cohort had hemoconcentration ≥15%. In the final multivariable logistic regression model the presence of ascites, OR 7.29, 95% CI 1.85 to 28.7, and a platelet count <50,000 platelets/mm3 at admission, OR 3.02, 95% CI 1.42 to 6.42, were significantly associated with plasma leakage, while the presence of petechiae, OR 0.24 95% CI 0.080 to 0.73, and headache, OR 0.38, 95% CI 0.15 to 0.95, were negatively associated with leakage. Using an estimated probability of 7% as a threshold for a person being considered a severe case correctly predicted 26 of the 34 severe cases (sensitivity 76.4%) and 201 of the 286 non-severe cases (specificity of 70.3%) for a percentage correctly classified of 70.9%. We identified signs and symptoms that can correctly identify a majority of patients who eventually develop severe dengue in Honduras. It will be important to further refine our models and validate them in other populations.


Region-specific decline of cerebral glucose metabolism in patients with frontotemporal dementia: a prospective 18F-FDG-PET study.
The aim of this study was to examine the pattern of glucose uptake and the changes over time of metabolic deficits in patients with frontotemporal dementia (FTD). 10 patients who had received the clinical diagnosis of FTD underwent positron emission tomography scanning at the time of their first examination (baseline) and at follow-up (after 17.1 +/- 6.0 months). For statistical analysis, we used the SPM 99 software. First, we compared the data of the patients at baseline with an age-matched healthy control group. Second, we compared glucose uptake at follow-up with baseline measurements. Compared with normal controls, FTD patients showed significant metabolic deficits primarily in frontal cortical areas, but also in the caudate nuclei and the thalami. At follow-up, a significant progression of metabolic deficit was exclusively observed in the orbitofrontal parts of the frontal lobe and in the subcortical structures. These findings demonstrate that the clinical progression in patients with FTD is accompanied by a region-specific decline in cerebral glucose metabolism.


Blinatumomab for the treatment of B-cell lymphoma.
Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens. Among the various formats of bispecific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or costimulation. Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL). This article reviews the current literature on blinatumomab including its pharmacology, preclinical findings, clinical trials in B-cell NHL and, to a lesser extent, Phase II studies in B-ALL. The authors discuss the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market. The recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers. Although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches. Larger trials are needed to demonstrate blinatumomab's curative potential in aggressive histologies.


Two-Dimensional, pH-Responsive Oligoglycine-Based Nanocarriers.
The nanocarrier capabilities of atomically smooth two-dimensional sheets of a biantennary oligoglycine peptide C8H16(-CH2-NH-Gly5)2 (also called tectomers) are demonstrated. We show that the pH-controlled, rapid, and reversible assembly and disassembly of oligoglycine can be effectively used for controlled loading and release of the anticancer drug and fluorescent probe coralyne. The calculated partition coefficient in water is of the same order of magnitude or higher when compared to other nanocarriers such as liposomes and micelles, signifying the tectomer's impressive loading capabilities. Moreover, the loading of guest molecules in tectomers facilitates the protection from rapid photochemically induced degradation. Such efficient, pH-sensitive, stable, and biocompatible nanocarriers are extremely attractive for biosensing, therapeutic, and theranostic applications. Additionally, our results suggest that these planar self-assembled materials can also act as phase-transfer vehicles for hydrophobic cargoes further broadening their biomedical and technological applications.


The dynamics of Rn-222 cyclic flow within the shallow geological subsurface media as a daily temporal variated source for exhalation into the air.
Extensive research on the dynamics of radon gas (Rn-222) originating from the radioactive decay of radium (Ra-226) in geological subsurface media, sheds light on its periodic release into the atmosphere. Radon is a product of the uranium-238 decay chain found within rock and soil grains. While only a fraction of the generated radon escapes (emanates) into porous spaces due to nuclear recoil, it serves as the source for subsurface gas flows and for cyclic exhalation into the soil-atmosphere interface. Ongoing study of radon movement in shallow and deep subsoil, and its emergence at the surface, reveals complete semi-diurnal, diurnal, and seasonal gas flow cycles in the subsoil. Complementary emissions occur nocturnally as radon is released into the atmosphere. Moreover, two natural driving forces govern complex semi-diurnal and diurnal flows below and above the surface. Subsurface gas movement in porous media exhibits nonlinear behavior influenced by surface temperature gradients, resulting in downward flow to depths of up to 100 m. This flow exhibits daily periodicity with depth-dependent time delays, correlating with the diurnal surface temperature cycle. Additionally, pore gas transport into and out of open boreholes responds linearly to semi-diurnal barometric pressure changes, known as barometric pumping. Beyond subsurface phenomena, Europe and Australia increasingly employ nocturnal radon measurements to study atmospheric stability and air quality, assuming that variations in local stationary near-surface radon concentrations reflect atmospheric mixing processes. Recognizing mechanisms governing radon's temporal changes within geological subsurface media highlights the need for continuous underground radon monitoring to validate variations in daily radon exhalation to the surface. On the other hand, monitoring radon at considerable depths minimizes climatic contributions and enhances the ability to discern non-periodic pre-seismic radon signals, independent of atmospheric compulsion. This research offers potential insights into seismic precursors and the complex interplay between subsurface geodynamics and atmospheric conditions.


Evaluation of the in vitro activity of ceragenins against Trichomonas vaginalis.
Trichomonosis, caused by the protozoan parasite Trichomonas vaginalis, is a curable sexually transmitted disease that is most commonly encountered worldwide. Increasing importance of trichomoniasis and emerging of resistance against metronidazole lead to search for alternative drugs with different mode of activity. The purpose of this study was to determine in vitro activity of ceragenins (CSA-13, CSA-44, CSA-13, and CSA-138) against the metronidazole-susceptible (ATCC 30001) and metronidazole-resistant (ATCC 50138) strains of T. vaginalis. The effective concentrations were evaluated using two strains of T. vaginalis with different metronidazole susceptibilities (ATCC 30001 and ATCC 50138) in the presence of dilution series of ceragenins in 24-well microtitre assays. Overall, all the ceragenins killed the metronidazole-susceptible (ATCC 30001) and metronidazole-resistant (ATCC 50138) strains of T. vaginalis (p>0.05). With regard to the their effects against the studied strains of T. vaginalis, in order of effectiveness, overall, the ceragenins ordered as CSA-13 (the most effective), CSA-131 and CSA-138 (effective similarly), and CSA-44 (the least effective) (p<0.05). All of the ceragenins reduced the trophozoite numbers of both of studied strains of T. vaginalis with a time- and dose- dependent manner (p<0.05). Although all of the study ceragenins, CSA-13, CSA-44, CSA-13, and CSA-138, killed the studied strains of T. vaginalis. CSA-13 is the leading ceragenin as the most effective anti-trichomonas compound, followed by CSA-131 and CSA-138. They have a potential to have a place in the armemantarium of gynecologic and urologic practice for the management of sexually transmitted diseases.


Variations in basement membrane mechanics are linked to epithelial morphogenesis.
The regulation of morphogenesis by the basement membrane (BM) may rely on changes in its mechanical properties. To test this, we developed an atomic force microscopy-based method to measure BM mechanical stiffness during two key processes in Drosophila ovarian follicle development. First, follicle elongation depends on epithelial cells that collectively migrate, secreting BM fibrils perpendicularly to the anteroposterior axis. Our data show that BM stiffness increases during this migration and that fibril incorporation enhances BM stiffness. In addition, stiffness heterogeneity, due to oriented fibrils, is important for egg elongation. Second, epithelial cells change their shape from cuboidal to either squamous or columnar. We prove that BM softens around the squamous cells and that this softening depends on the TGFβ pathway. We also demonstrate that interactions between BM constituents are necessary for cell flattening. Altogether, these results show that BM mechanical properties are modified during development and that, in turn, such mechanical modifications influence both cell and tissue shapes.


Nonpharmacologic Interventions to Heal Pressure Ulcers in Older Patients: An Overview of Systematic Reviews (The SENATOR-ONTOP Series).
Pressure ulcers (PUs) are more frequent in older patients, and the healing process is usually challenging. Nonpharmacologic interventions may play a role in the treatment of older people with PUs, but most systematic reviews (SRs) have not addressed this specific population using convincing outcome measures. To summarize and critically appraise the evidence from SRs of the primary studies on nonpharmacologic interventions to treat PUs in older patients. SR and meta-analysis of comparative studies. PubMed, Cochrane Database of Systematic Reviews, EMBASE, and CINHAL (from inception to October 2013) were searched. A new search for updates in the Cochrane Database was launched in July 2014. SRs that included at least 1 comparative study evaluating any nonpharmacologic intervention to treat PUs in older patients, in any health care setting, were included. Any primary study with experimental design was then identified and included. From each primary study, quality assessment was undertaken as specified by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation working group. Interventions were identified and compared among different studies to explore the possibility of performing a meta-analysis, using complete ulcer healing as the outcome measure. One hundred ten SRs with 45 primary studies satisfied the inclusion criteria. The most frequent interventions explored in these trials were support surfaces (13 studies), nutrition (8), and electrotherapy (6). High or moderate quality of evidence was found in none of the interventions, mainly because of the very serious risk of bias of most studies and imprecision in the treatment effect. Evidence grade is very low or insufficient to support the use of any support surface, nutrition intervention, multicomponent interventions, repositioning or other adjunctive therapy (ultrasound, negative pressure, laser, electromagnetic, light, shock wave, hydrotherapy, radiofrequency, or vibration therapy) to increase the rates of PU healing in older patients. Electrotherapy showed some beneficial effect in the treatment of PUs, although the quality of evidence is low. In older patients with PUs, evidence to use any nonpharmacologic therapy to increase the rates of wound healing is inconclusive, except for low quality evidence that supports the use of electrotherapy. This situation is especially alarming for interventions that are usually standard clinical practice (repositioning, support surfaces). Although there is some evidence in younger populations and other types of ulcers, studies in older populations with PUs using sound methodology are needed.


Ketamine for continuous sedation of mechanically ventilated patients.
Long-term sedation with midazolam or propofol has been demonstrated to have serious adverse side effects, such as toxic accumulation or propofol infusion syndrome. Ketamine remains a viable alternative for continuous sedation as it is inexpensive and widely available, however, there are few analyses regarding its safety in this clinical setting. To review the data related to safety and efficacy of ketamine as a potential sedative agent in mechanically ventilated patients admitted to the intensive care unit (ICU). This was a single-center retrospective study from September 2011 to March 2012 of patients who required sedation for greater than 24 hours, in whom ketamine was selected as the primary sedative agent. All patients greater than 18 years of age, regardless of admitting diagnosis, were eligible for inclusion. Patients that received ketamine for continuous infusion but died prior to receiving it for 24 hours were not included. Thirty patients received ketamine for continuous sedation. In four patients, ketamine was switched to another sedative agent due to possible adverse side effects. Of these, two patients had tachydysrhythmias, both with new onset atrial fibrillation and two patients had agitation believed to be caused by ketamine. The adverse event rate in our patient population was 13% (4/30). Among ICU patients receiving prolonged mechanical ventilation, the use of ketamine appeared to have a frequency of adverse events similar to more common sedative agents, like propofol and benzodiazepines.


Microstructure-driven self-assembly and rheological properties of multi-responsive soft microgel suspensions.
The deformation and swelling ability of microgels is influenced by the crosslinking distribution. Varying microgels microstructure is expected to obtain suspensions with different flow behavior and thereby, different rheological properties. Different multi-responsive microgels were synthesized using two different crosslinkers and varying their amounts: N,N-methylene bis-acrylamide (MBA) and oligo(ethylene glycol) diacrylate (OEGDA). The rheological results were obtained by zero-shear viscosity and long-time creep measurements on concentrated microgel suspensions Microgel microstructure was analyzed by 1H nuclear magnetic resonance transverse relaxation measurements. At a constant crosslinking rate, we show that the viscosity of OEGDA-crosslinked microgels diverges at a higher concentration than MBA ones, suggesting a looser shell and less restricted dangling chains at the periphery for the later. By scaling with the effective volume fraction, the viscosity curves of the different microgel suspensions reduce into a single curve and closely follow hard sphere models up to ϕeff < 0.45. The results from creep tests revealed a much higher yield stress for MBA-crosslinked microgels, strengthening the hypothesis of a looser shell for the later. Finally, transverse relaxation (T2) NMR measurements demonstrated that, although all microgels exhibit a core-shell microstructure, MBA samples present a less crosslinked shell corroborating with the rheological results.


TSN inhibits cell proliferation, migration, invasion, and EMT through regulating miR-874/HMGB2/β-catenin pathway in gastric cancer.
Gastric cancer (GC) is the second leading cause of cancer-associated deaths worldwide. Tanshinone IIA (TSN) is the pure extract from the root of red-rooted salvia and has been reported to inhibit the progression of GC cells. In this study, we investigated the microRNA (miRNA) mediated gene repression mechanism in TSN-administrated GC condition. The cell viability of GC was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were detected by transwell assays. The expression levels of epithelial-mesenchymal transition (EMT)-associated proteins (N-cadherin, vimentin, E-cadherin), High-mobility group box proteins 2 (HMGB2), β-catenin pathway-related proteins (β-catenin, c-myc, cyclin D1) were detected by western blot analysis in TSN/GC. The expression patterns of miR-874 and HMGB2 in GC were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The potential miR-874-targeted HMGB2 was searched via bioinformatics methods and identified by dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and RNA pull-down assays. Xenograft tumor model was used to evaluate biological function in vivo. TSN limited the proliferation, migration, invasion, EMT progression in GC, and these results could be inverted by the silencing of miR-874. Moreover, the putative binding sites between miR-874 and HMGB2 were predicted by starBase software online. Meanwhile, enforced expression of HMGB2, negatively correlated with that of miR-874, reversed the positive effects of TSN administration on cells. Mechanically, TSN restrained the GC progression by miR-874/HMGB2/β-catenin signaling in vitro. Additionally, in vivo experiments confirmed that TSN inhibited the GC progression as well. TSN restrained the GC progression by regulating miR-874/HMGB2/β-catenin pathways in vitro and in vivo.


Exhaustion of drug benefits and disenrollment of medicare beneficiaries from managed care organizations.
Many Medicare beneficiaries enroll in managed care health plans to obtain outpatient drug benefits. Increasing pharmaceutical utilization and costs and decreasing drug benefits increase the likelihood that medication use by such enrollees will exceed drug benefits, which may lead to health plan disenrollment. To test the hypothesis that exhaustion of managed care drug benefits by Medicare beneficiaries is associated with disenrollment from the health plan. Retrospective cohort study followed up for 1 year (1998) using an enrollment/claims database. Four geographically diverse network-model health plans that had annual drug benefits of $300, $500, $600, or $1000. A total of 61,412 elderly Medicare beneficiaries. Voluntary disenrollment from health plans by members who did or did not exhaust their drug benefits. The likelihood of exhausting 1998 drug benefits ranged from 17% to 25% across health plans (P<.001). The relative hazards of disenrollment from the 4 plans when drug benefits had been exhausted were 2.5 (95% confidence interval [CI], 2.3-2.8), 1.9 (95% CI, 1.7-2.1), 2.7 (95% CI, 2.0-3.6), and 2.1 (95% CI, 1.9-2.4). Statistical adjustments for age, sex, prior enrollment, hospital admissions, physician visits, and county of residence did not alter these estimates. Exhaustion of drug benefits was associated with a significant increase in the likelihood of disenrollment of Medicare beneficiaries. This finding arouses concern that Medicare beneficiaries must change plans to have financial access to medications, which can lead to discontinuity in care and diversion of resources from care to administrative matters. Policymakers should strive to avoid fragmented systems of providing drug benefits.