Physicochemical Investigations of Homeopathic Preparations: A Systematic Review and Bibliometric Analysis-Part 2.
Objectives: In Part 1 of the review of physicochemical research performed on homeopathic preparations the authors identified relevant publications of sufficient reporting quality for further in-depth analysis. In this article, the authors analyze these publications to identify any empirical evidence for specific physicochemical properties of homeopathic preparations and to identify most promising experimental techniques for future studies. Methods: After an update of the literature search up to 2018, the authors analyzed all publications in terms of individual experiments. They extracted information regarding methodological criteria such as blinding, randomization, statistics, controls, sample preparation, and replications, as well as regarding experimental design and measurement methods applied. Scores were developed to identify experimental techniques with most reliable outcomes. Results: The publications analyzed described 203 experiments. Less than 25% used blinding and/or randomization, and about one third used adequate controls to identify specific effects of homeopathic preparations. The most promising techniques used so far are nuclear magnetic resonance (NMR) relaxation, optical spectroscopy, and electrical impedance measurements. In these three areas, several sets of replicated high-quality experiments provide evidence for specific physicochemical properties of homeopathic preparations. Conclusions: The authors uncovered a number of promising experimental techniques that warrant replication to assess the reported physicochemical properties of homeopathic preparations compared with controls. They further discuss a range of experimental aspects that highlight the many factors that need to be taken into consideration when performing basic research into homeopathic potentization. For future experiments, the authors generally recommend using succussed (vigorously shaken) controls, or comparing different homeopathic preparations with each other to reliably identify any specific physicochemical properties.


How to successfully select and implement electronic health records (EHR) in small ambulatory practice settings.
Adoption of EHRs by U.S. ambulatory practices has been slow despite the perceived benefits of their use. Most evaluations of EHR implementations in the literature apply to large practice settings. While there are similarities relating to EHR implementation in large and small practice settings, the authors argue that scale is an important differentiator. Focusing on small ambulatory practices, this paper outlines the benefits and barriers to EHR use in this setting, and provides a "field guide" for these practices to facilitate successful EHR implementation. The benefits of EHRs in ambulatory practices include improved patient care and office efficiency, and potential financial benefits. Barriers to EHRs include costs; lack of standardization of EHR products and the design of vendor systems for large practice environments; resistance to change; initial difficulty of system use leading to productivity reduction; and perceived accrual of benefits to society and payers rather than providers. The authors stress the need for developing a flexible change management strategy when introducing EHRs that is relevant to the small practice environment; the strategy should acknowledge the importance of relationship management and the role of individual staff members in helping the entire staff to manage change. Practice staff must create an actionable vision outlining realistic goals for the implementation, and all staff must buy into the project. The authors detail the process of implementing EHRs through several stages: decision, selection, pre-implementation, implementation, and post-implementation. They stress the importance of identifying a champion to serve as an advocate of the value of EHRs and provide direction and encouragement for the project. Other key activities include assessing and redesigning workflow; understanding financial issues; conducting training that is well-timed and meets the needs of practice staff; and evaluating the implementation process. The EHR implementation experience depends on a variety of factors including the technology, training, leadership, the change management process, and the individual character of each ambulatory practice environment. Sound processes must support both technical and personnel-related organizational components. Additional research is needed to further refine recommendations for the small physician practice and the nuances of specific medical specialties.


Health and support service needs of individuals with disability from culturally and linguistically diverse backgrounds: a scoping review protocol.
All individuals should have the right to engage meaningfully in occupations that meet their aspirations and life goals as well as promote their health and well-being. For individuals with disability, meaningful engagement in occupations is supported by timely, effective, and adaptive health and support services. However, research has revealed multiple barriers preventing utilization of these services by individuals with disability from culturally and linguistically diverse (CALD) backgrounds. This review aims to identify gaps and solutions in health and support services of individuals with disability from CALD backgrounds to meaningfully engage in occupations. A scoping review will be conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews. A detailed search strategy will be used to search CINAHL, PubMed, Embase, Scopus, PsycInfo, JBI, and Cochrane Library, as well as grey literature in Trove, Mednar, and OpenGrey from January 1974 onwards. Two reviewers will independently screen all citations and full-text articles for eligibility against specific inclusion and exclusion criteria. Potential conflicts will be resolved through discussion. Data will be extracted and presented in a diagrammatic or tabular form accompanied by a narrative summary. The scoping review will present the health and support service needs of individuals with disability from CALD backgrounds and will extend the current reviews as it focuses the engagement in meaningful occupation. Findings from this review have the potential to inform local policy discussions and practice-based disability care. Open Science Framework ( 10.17605/OSF.IO/HW2FB ).


Cilostazol for intermittent claudication.
Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication, characterised by pain in the legs or buttocks that occurs with exercise and which subsides with rest. Compared with age-matched controls, people with intermittent claudication have a three- to six-fold increase in cardiovascular mortality. Symptoms of intermittent claudication, walking distance, and quality of life can be improved by risk factor modification, smoking cessation, and a structured exercise programme. Antiplatelet treatment is beneficial in patients with intermittent claudication for the reduction of vascular events but has not previously been shown to influence claudication distance. This is an update of a review first published in 2007. To determine the effect of cilostazol (an antiplatelet treatment) on improving initial and absolute claudication distances, and in reducing mortality and vascular events in patients with stable intermittent claudication. For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2013) and CENTRAL (2013, Issue 9). Double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other antiplatelet agents in patients with stable intermittent claudication. Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We performed the meta-analysis as a fixed-effect model with weighted mean differences (WMDs) and 95% confidence intervals (CIs) for continuous data, and odds ratios (ORs) with 95% CIs for dichotomous data. We included fifteen double-blind, RCTs comparing cilostazol with placebo, or medications currently known to increase walking distance e.g. pentoxifylline. There were a total of 3718 randomised participants with treatment durations ranging from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Comparisons included cilostazol twice daily, with dosages of 50 mg, 100 mg and 150 mg compared with placebo, and cilostazol 100 mg, twice daily, compared with pentoxifylline 400 mg, three times daily. The methodological quality of the trials was generally low, with the majority being at an unclear risk for selection bias, performance bias, detection bias and other bias. Attrition bias was generally low, but reporting bias was high or unclear in the majority of the studies. For eight studies data were compatible for comparison by meta-analysis, but data for seven studies were too heterogenous to be pooled. For the studies included in the meta-analysis, for initial claudication distance (ICD - the distance walked on a treadmill before the onset of calf pain) there was an improvement in the cilostazol group for the 100 mg and 50 mg twice daily, compared with placebo (WMD 31.41 metres, 95% CI 22.38 to 40.45 metres; P < 0.00001) and WMD 19.89 metres, 95% CI 9.44 to 30.34 metres; P = 0.0002), respectively. ICD was improved in the cilostazol group for the comparison of cilostazol 150 mg versus placebo and cilostazol 100 mg versus pentoxifylline, but only single studies were used for these analyses. Absolute claudication distance (ACD - the maximum distance walked on a treadmill) was significantly increased in participants taking cilostazol 100 mg and 50 mg twice daily, compared with placebo (WMD 43.12 metres, 95% CI 18.28 to 67.96 metres; P = 0.0007) and WMD 32.00 metres, 95% CI 14.17 to 49.83 metres; P = 0.0004), respectively. As with ICD, ACD was increased in participants taking cilostazol 150 mg versus placebo, but with only one study an association cannot be clearly determined. Two studies comparing cilostazol to pentoxifylline had opposing findings, resulting in an imprecise CI (WMD 13.42 metres (95% CI -43.51 to 70.35 metres; P = 0.64). Ankle brachial index (ABI) was lowered in the cilostazol 100 mg group compared with placebo (WMD 0.06, 95% CI 0.04 to 0.08; P < 0.00001). The single study evaluating ABI for the comparison of cilostazol versus pentoxifylline found no change in ABI.There was no association between treatment type and all-cause mortality for any of the treatment comparisons, but there were very few events, and therefore larger, adequately powered studies will be needed to assess if there is a relationship. Only one study evaluated individual cardiovascular events, and from this study there is no clear evidence of a difference between any of the treatment groups and risk of myocardial infarction or stroke. We evaluated adverse side effects, and in general cilostazol was associated with a higher odds of headache, diarrhoea, abnormal stool, dizziness and palpitations. We only reported quality of life measures descriptively as there was insufficient statistical detail within the studies to combine the results, although there was a possible indication in improvement of quality of life in the cilostazol treatment groups. Cilostazol has been shown to be of benefit in improving walking distance in people with intermittent claudication secondary to PAD. Although there is an increase in adverse side effects, they are generally mild and treatable. There is currently insufficient data on whether taking cilostazol results in a reduction of all-cause mortality and cardiovascular events or an improvement in quality of life. Future research into the effect of cilostazol on intermittent claudication should carefully consider comparability, sample size and homogeneity when designing a study.


Tumor-selective killing by selenite in patient-matched pairs of normal and malignant prostate cells.
Selenium compounds have been shown to induce apoptosis in a variety of human prostate cancer cell lines. However, the effects of selenium have yet to be examined in normal and malignant cells derived from the same individual. Selenite metabolism consumes glutathione (GSH) and produces superoxide. The generation of reactive oxygen species is an important mechanism in selenite-induced apoptosis. Three patient-matched pairs of primary prostatic epithelial cell cultures from normal and cancer were evaluated for their response to selenite. Apoptosis was measured and the differential response of normal and cancer cells was correlated with the expression of bcl-2, bax, GSH, and manganese superoxide dismutase (MnSOD). The cancer-derived cells were significantly more sensitive to selenite-induced apoptosis than the corresponding normal cells. Tumor-selective killing was not observed in cells treated with selenomethionine. The ratio of bcl-2:bax was decreased in the cancer-derived cells treated with selenite. Total GSH concentrations were similar in paired normal and cancer cells. Therefore, differences in GSH content do not appear to play a role in tumor-selective killing by selenite. Superoxide is a by-product of selenite metabolism and normal cells showed increased MnSOD expression and SOD activity compared to the cancer-derived cells. Prostate cancer cells treated with the MnSOD mimetic, MnTMPyP, were protected against the cytotoxic effects of selenite. Higher MnSOD expression in normal cells may play an important role in eliminating superoxide radicals produced as a result of selenite metabolism and contribute to the tumor-selective killing by selenite in prostate cancer.


Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes.
Over the past few years, CuH-catalyzed hydroamination has been discovered and developed as a robust and conceptually novel approach for the synthesis of enantioenriched secondary and tertiary amines. The success in this area of research was made possible through the large body of precedent in copper(I) hydride catalysis and the well-explored use of hydroxylamine esters as electrophilic amine sources in related copper-catalyzed processes. This Minireview details the background, advances, and mechanistic investigations in CuH-catalyzed hydroamination.


Viromics of extant insect orders unveil the evolution of the flavi-like superfamily.
Insects are the most diversified and species-rich group of animals and harbor an immense diversity of viruses. Several taxa in the flavi-like superfamily, such as the genus Flavivirus, are associated with insects; however, systematic studies on insect virus genetic diversity are lacking, limiting our understanding of the evolution of the flavi-like superfamily. Here, we examined the diversity of flavi-like viruses within the most complete and up-to-date insect transcriptome collection comprising 1,243 insect species by employing a Flaviviridae RdRp profile hidden Markov model search. We identified seventy-six viral sequences in sixty-one species belonging to seventeen insect, one entognathan, and one arachnidan orders. Phylogenetic analyses revealed that twenty-seven sequences fell within the Flaviviridae phylogeny but did not group with established genera. Despite the large diversity of insect hosts studied, we only detected one virus in a blood-feeding insect, which branched within the genus Flavivirus, indicating that this genus likely diversified only in hematophagous arthropods. Nine new jingmenviruses with novel host associations were identified. One of the jingmenviruses established a deep rooting lineage additional to the insect- and tick-associated clades. Segment co-segregation phylogenies support the separation of tick- and insect-associated groups within jingmenviruses, with evidence for segment reassortment. In addition, fourteen viruses grouped with unclassified flaviviruses encompassing genome length of up to 20 kb. Species-specific clades for Hymenopteran- and Orthopteran-associated viruses were identified. Forty-nine viruses populated three highly diversified clades in distant relationship to Tombusviridae, a plant-infecting virus family, suggesting the detection of three previously unknown insect-associated families that contributed to tombusvirus evolution.


Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers.
Hypoxic cells are common in tumors and contribute to malignant progression, distant metastasis and resistance to radiotherapy. It is well known that tumors are heterogeneous with respect to the levels and duration of hypoxia. Several strategies, including high-oxygen-content gas breathing, radiosensitizers and hypoxic cytotoxins, have been developed to overcome hypoxia-mediated radioresistance. However, with these strategies, an increased tumor control rate is often accompanied by more severe side effects. Consequently, development of assays for prediction of tumor response and early monitoring of treatment responses could reduce both over- and undertreatment, thereby avoiding unnecessary side effects. The purpose of this review is to discuss different assays for measurement of hypoxia that can be used to detect changes in oxygen tension. The main focus is on exogenous bioreductive hypoxia markers (2-nitroimidazoles) such as pimonidazole, CCI-103F, EF5 and F-misonidazole. These are specifically reduced and bind to macromolecules in viable hypoxic cells. A number of these bioreductive drugs are approved for clinical use and can be detected with methods ranging from noninvasive PET imaging (low resolution) to microscopic imaging of tumor sections (high resolution). If the latter are stained for multiple markers, hypoxia can be analyzed in relation to different microenvironmental parameters such as vasculature, proliferation and endogenous hypoxia-related markers, for instance HIF1alpha and CA-IX. In addition, temporal and spatial changes in hypoxia can be analyzed by consecutive injection of two different hypoxia markers. Therefore, bioreductive exogenous hypoxia markers are promising as tools for development of predictive assays or as tools for early treatment monitoring and validation of potential endogenous hypoxia markers.


Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols and other agents.
An association between exposure to phenoxy acids or chlorophenols and soft-tissue sarcoma and malignant lymphoma has previously been reported. An association between exposure to organic solvents and malignant lymphoma has been demonstrated as well. In the present investigation the validity of the assessment of exposure to phenoxy acids and chlorophenols in the previous studies has been further analyzed, partly through a reconsideration of original data and partly through the utilization of another cancer type (colon cancer) for comparison. No observational bias was found which could distort the earlier findings. No significant association was found for these chemicals and colon cancer, whereas exposure to asbestos showed about a twofold increase in risk for colon cancer, an occurrence in agreement with previously reported findings.


Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk.
Genome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk. We examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis. The two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment. Genotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation.


Computer-Mediated Communication to Facilitate Synchronous Online Focus Group Discussions: Feasibility Study for Qualitative HIV Research Among Transgender Women Across the United States.
Novel, technology-based methods are rapidly increasing in popularity across multiple facets of quantitative research. Qualitative research, however, has been slower to integrate technology into research methodology. One method, computer-mediated communication (CMC), has been utilized to a limited extent for focus group discussions. This study aimed to assess feasibility of an online video conferencing system to further adapt CMC to facilitate synchronous focus group discussions among transgender women living in six cities in eastern and southern United States. Between August 2017 and January 2018, focus group discussions with adult transgender women were conducted in English and Spanish by research teams based in Boston, MA, and Baltimore, MD. Participants were sampled from six cities: Baltimore, MD; Boston, MA; New York, NY; Washington, DC; Atlanta, GA; and Miami, FL. This was formative research to inform a technology-enhanced cohort study to assess HIV acquisition among transgender women. This analysis focused on the methodologic use of CMC focus groups conducted synchronously using online software that enabled video or phone discussion. Findings were based on qualitative observations of attendance and study team debriefing on topics of individual, social, technical, and logistical challenges encountered. A total of 41 transgender women from all six cities participated in seven online focus group discussions-five English and two Spanish. There was equal racial distribution of black/African American (14/41, 34%) and white (14/41, 34%) attendees, with 29% (12/41) identifying as Hispanic/Latina ethnicity. Overall, 29 of 70 (41%) eligible and scheduled transgender women failed to attend the focus group discussions. The most common reason for nonattendance was forgetting or having a scheduling conflict (16/29, 55%). A total of 14% (4/29) reported technical challenges associated with accessing the CMC focus group discussion. CMC focus group discussions were found to facilitate geographic diversity; allow participants to control anonymity and privacy (eg, use of pseudonyms and option to use video); ease scheduling by eliminating challenges related to travel to a data collection site; and offer flexibility to join via a variety of devices. Challenges encountered were related to overlapping conversations; variable audio quality in cases where Internet or cellular connection was poor; and distribution of incentives (eg, cash versus gift cards). As with all focus group discussions, establishment of ground rules and employing both a skilled facilitator and a notetaker who could troubleshoot technology issues were critical to the success of CMC focus group discussions. Synchronous CMC focus group discussions provide a secure opportunity to convene participants across geographic space with minimal time burden and without losing the standardized approach that is expected of focus group discussions. This method may provide an optimal alternative to engaging hard-to-reach participants in focus group discussions. Participants with limited technological literacy or inconsistent access to a phone and/or cellular data or service, as well as circumstances necessitating immediate cash incentives may, however, require additional support and accommodation when participating in CMC focus group discussions.


Breast ductal carcinoma and metastatic lymphoma to the contralateral breast in patient with cutaneous non-Hodgkin lymphoma.
Breast lymphoma is a rare condition, both as a primary and a metastatic manifestation. The primary form has an incidence ranging from 0.04% to 0.5% of all breast neoplasms, whereas the metastatic form has an incidence of 0.07%. We hereby report a clinical case of a patient who presented with cutaneous non-Hodgkin lymphoma (NHL) in the left scapulohumeral region treated with surgery followed by radiotherapy (40 Gy total). Three years following radiotherapy, the patient was diagnosed with a left breast infiltrating ductal carcinoma, treated with conservative surgery and adjuvant therapy. The following year, i.e. four years after the initial diagnosis of NHL, two lymphoproliferative relapses occurred: in the left cutaneous scapulohumeral region at the original site of disease, and in the right breast. The aim of this paper is to highlight an uncommon oncologic disorder such as breast lymphoma, highlighting its clinical and radiological manifestations. Some studies reported a possible aetiological role of radiotherapy in the development of breast cancer following treatment of NHL, and in the development of breast cancer following treatment of Hodgkin lymphoma, which could potentially explain our findings.


Intramolecular micellization and nanopatterning in pH- and thermo-responsive molecular brushes.
Conformational transitions and nanoscale self-organization triggered in double pH- and thermo-responsive molecular brushes by varying environmental conditions are studied by means of analytical mean-field theory and numerical Scheutjens-Fleer self-consistent field modelling. Such molecular brushes are composed of multiple thermo-responsive side chains end-grafted onto the main chain (backbone) and are capable of acquiring ionic charges via reversible (de)protonation of the monomer units. Competition of long-range Coulomb repulsion with short-range solvophobic interactions leads to complex patterns in the intramolecular self-organization of molecular brushes. In particular, we observed formation of pearl necklace-like structures with multiple dense nanodomains formed by weakly ionized collapsed side chains and stabilized by a fraction protruding into the solution and strongly ionized ones. Such structures are thermodynamically stable in a certain parameter range and can be termed as intramolecular micelles. The stimuli-induced intramolecular nanopatterning occurs via a sequence of quasi-first order phase transitions corresponding to splitting/fusion of collapsed domains accompanied by jumps in the average degree of ionization and macromolecular dimensions. A re-entrant sequence of transitions is observed when the salt concentration is used as a control parameter. These theoretical predictions provide guidelines for design of smart unimolecular devices, for example multicompartment nanocarriers of active substances or nanosensors.


Protective effect of PCV vaccine against experimental pneumococcal challenge in adults is primarily mediated by controlling colonisation density.
Widespread use of Pneumococcal Conjugate Vaccines (PCV) has reduced vaccine-type nasopharyngeal colonisation and invasive pneumococcal disease. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and reduced bacterial intensity (AUC) as measured by classical culture. We used a multiplex qPCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the colonisation status of the same volunteers. Increase in detection of low-density colonisation resulted in reduced PCV efficacy against colonisation acquisition (29%), compared to classical culture (83%). For experimentally colonised volunteers, PCV had a pronounced effect on decreasing colonisation density. These results obtained in adults suggest that the success of PCV vaccination could primarily be mediated by the control of colonisation density. Studies assessing the impact of pneumococcal vaccines should allow for density measurements in their design.


Exploiting Task Constraints for Self-Calibrated Brain-Machine Interface Control Using Error-Related Potentials.
This paper presents a new approach for self-calibration BCI for reaching tasks using error-related potentials. The proposed method exploits task constraints to simultaneously calibrate the decoder and control the device, by using a robust likelihood function and an ad-hoc planner to cope with the large uncertainty resulting from the unknown task and decoder. The method has been evaluated in closed-loop online experiments with 8 users using a previously proposed BCI protocol for reaching tasks over a grid. The results show that it is possible to have a usable BCI control from the beginning of the experiment without any prior calibration. Furthermore, comparisons with simulations and previous results obtained using standard calibration hint that both the quality of recorded signals and the performance of the system were comparable to those obtained with a standard calibration approach.


RNAs from genetically distinct retroviruses can copackage and exchange genetic information in vivo.
Sequence analysis suggests that ancient recombination events may have occurred between genetically distinct retroviruses. An experimental system was utilized to explore the genetic interaction between different viruses. Moloney murine sarcoma virus and spleen necrosis virus are type C retroviruses that belong to different subgenera. With vectors containing packaging signals from these two viruses, DNA proviruses containing genetic information from both RNAs can be generated. This is the first experimental evidence to indicate that RNA from different retroviruses can copackage and exchange genetic information.


A cell surface arabinogalactan-peptide influences root hair cell fate.
Root hairs (RHs) develop from specialized epidermal trichoblast cells, whereas epidermal cells that lack RHs are known as atrichoblasts. The mechanism controlling RH cell fate is only partially understood. RH cell fate is regulated by a transcription factor complex that promotes the expression of the homeodomain protein GLABRA 2 (GL2), which blocks RH development by inhibiting ROOT HAIR DEFECTIVE 6 (RHD6). Suppression of GL2 expression activates RHD6, a series of downstream TFs including ROOT HAIR DEFECTIVE 6 LIKE-4 (RSL4) and their target genes, and causes epidermal cells to develop into RHs. Brassinosteroids (BRs) influence RH cell fate. In the absence of BRs, phosphorylated BIN2 (a Type-II GSK3-like kinase) inhibits a protein complex that regulates GL2 expression. Perturbation of the arabinogalactan peptide (AGP21) in Arabidopsis thaliana triggers aberrant RH development, similar to that observed in plants with defective BR signaling. We reveal that an O-glycosylated AGP21 peptide, which is positively regulated by BZR1, a transcription factor activated by BR signaling, affects RH cell fate by altering GL2 expression in a BIN2-dependent manner. Changes in cell surface AGP disrupts BR responses and inhibits the downstream effect of BIN2 on the RH repressor GL2 in root epidermis.


Correlates of adverse childhood events among adults with schizophrenia spectrum disorders.
Multiple studies have found that childhood adversity is related to a range of poor mental health, substance abuse, poor physical health, and poor social functioning outcomes in the general population of adults. However, despite the high rates of childhood adversity in schizophrenia, the clinical correlates of these events have not been systematically evaluated. This study evaluated the relationship between adverse experiences in childhood and functional, clinical, and health outcomes among adults with schizophrenia. The authors surveyed 569 adults with schizophrenia regarding adverse childhood events (including physical abuse, sexual abuse, parental mental illnesses, loss of a parent, parental separation or divorce, witnessing domestic violence, and foster or kinship care). The relationships between cumulative exposure to these events and psychiatric, physical, and functional outcomes were evaluated. Increased exposure to adverse childhood events was strongly related to psychiatric problems (suicidal thinking, hospitalizations, distress, and posttraumatic stress disorder), substance abuse, physical health problems (HIV infection), medical service utilization (physician visits), and poor social functioning (homelessness or criminal justice involvement). The findings extend the results of research in the general population by suggesting that childhood adversity contributes to worse mental health, substance abuse, worse physical health, and poor functional outcomes in schizophrenia.


A novel device for measuring long-term oxygen therapy adherence: a preliminary validation.
Current methods for measuring patient adherence to long-term oxygen therapy fail to measure the actual amount of time the patient is inhaling oxygen and the pattern of oxygen use within the day. We have developed a novel oxygen-adherence monitor to address these limitations, and this report introduces the monitor and provides preliminary data validating its use. This battery-powered monitor attaches to the oxygen source and detects respiratory-related pressure fluctuations transmitted through the nasal cannula. The monitor takes a measurement over a 25-second period, at 4-min intervals. It detects and stores data on 4 different states that describe the patient's actual use of the oxygen source and nasal cannula: source-off/cannula-off, source-off/cannula-on, source-on/cannula-off, and source-on/cannula-on. We studied the monitor's performance with 10 patients with chronic obstructive pulmonary disease, during a directly-observed sequence of using and not using supplemental oxygen via nasal cannula, while sitting and walking. The monitor correctly detected 122 out of 129 measurements among all participants, yielding a 95\% detection accuracy. A monitor that objectively measures oxygen inhalation, rather than oxygen expenditure, may help improve the management of patients on long-term oxygen therapy.


Comet west and the scattering function of cometary dust.
Observations of Comet West (1975n) at wavelengths from 0.5 to 18 microns and at a variety of scattering angles are used to infer the scattering phase function for the cometary dust. This function is strongly peaked in the forward direction. The form of the function indicates that the particles are dielectric grains with radii of approximately 1 micron. Abrupt increases in the intrinsic brightness of the coma (both in scattered sunlight and in thermal emission) are consistent with the projected times of comet fragmentation.


Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats.
Hydrogen has been reported to selectively reduce the hydroxyl radical, the most cytotoxic of reactive oxygen species. In this study we investigated the effects of hydrogen-rich saline on the prevention of lung injury induced by intestinal ischemia/reperfusion (I/R) in rats. Male Sprague-Dawley rats (n=30, 200-220g) were divided randomly into three experimental groups: sham operated, intestinal I/R plus saline treatment (5ml/kg, i.v.), and intestinal I/R plus hydrogen-rich saline treatment (5ml/kg, i.v.) groups. Intestinal I/R was produced by 90min of intestinal ischemia followed by a 4h of reperfusion. Hydrogen-rich saline treatment decreased the neutrophil infiltration, the lipid membrane peroxidation, NF-kappaB activation and the pro-inflammatory cytokine interleukin IL-1beta and TNF-alpha in the lung tissues compared with those in saline-treated rat. Hydrogen-rich saline attenuates lung injury induced by intestinal I/R.


Disposition of ethanol and its proximate metabolite, acetaldehyde, in the near-term pregnant ewe for short term maternal administration of moderate-dose ethanol.
The effect of short term maternal ethanol administration on the disposition of ethanol in the ovine maternal-fetal unit was determined. Eleven conscious instrumented near-term pregnant ewes (between 125 and 134 days of gestation; term, 147 days) received 1-hr iv infusion of 1 g of ethanol.kg of maternal body weight-1.day-1 for six days (N = 6 ewes) or an equivalent volume of saline for six days (N = 5 ewes). On the seventh day, the ethanol- and saline-pretreated animals were administered 1 g of ethanol.kg of maternal body weight-1. Ethanol and acetaldehyde concentrations were determined by headspace GLC in maternal blood, fetal blood, and amniotic fluid samples obtained at selected times during the 14-hr study. The data demonstrated that short term maternal administration of once-daily moderate dose ethanol did not produce major changes in the disposition of ethanol and its proximate metabolite, acetaldehyde, in the maternal, fetal, and amniotic fluid compartments during near-term ovine pregnancy.


Operational characteristics of tractors driven by children on farms in the United States and Canada.
Farm tractors are an important source of traumatic injury for children on farms. There is, however, no documentation about the age and size of tractors that children are operating and little information about the frequency with which rollover protective structures (ROPS) are used. This study described tractors that children on farms in the U.S. and Canada were operating by age, horsepower, and the presence of ROPS, according to the age and gender of the farm children involved. As a sub-analysis of data compiled during a randomized controlled trial, a descriptive analysis was completed on work exposure data collected by telephone interview. Of the 1,113 children involved in the trial, 522 (47%) were reported to perform at least one job that involved the operation of a farm tractor, and 408 (36.7%) were operating tractors of at least 20 horsepower. The majority of these children were male. There was a wide range of ages and sizes of tractors operated. However, the majority of tractors were between 20 and 70 horsepower and manufactured after 1970. Nearly one-half of the tractors were equipped with ROPS, and these tended to be newer and larger tractors. This analysis provides new data about the broad range of tractors driven by farm children in the U.S. and Canada. The findings point to a need to re-examine the reliance on a single voluntary standard to mitigate the hazard of tractor rollovers and the need for an enhanced safety policy requiring all tractors operated by children be equipped with ROPS.


Indentation-formed nanocontacts: an atomic-scale perspective.
One-to-one comparisons between indentation experiments and atomistic modelling have until recently been hampered by the discrepancy in length scales of the two approaches. Here, we review progress in atomic-scale nanoindentation experiments employing scanning probe techniques to achieve depth-sensing indentation and field ion microscopy to permit detailed indenter characterization. This perspective addresses both mechanical (dislocation nucleation, defect structures, adhesion, indenter effects) and electronic (interface, disorder, and vacancy scattering) properties of indentation-formed contacts.


Use of Imaging to Predict Complete Response of Colorectal Liver Metastases after Chemotherapy: MR Imaging versus CT Imaging.
Purpose To compare the diagnostic performances of contrast agent-enhanced computed tomography (CT) and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced liver magnetic resonance (MR) imaging (referred to as EOB MR imaging) in the evaluation of disappearing colorectal liver metastases (CRLMs) after chemotherapy. Materials and Methods The eight institutional review boards approved this retrospective study and waived the requirement for informed consent. On the basis of retrospective searches in eight hospitals, 87 patients with 393 CRLMs, each patient with one or more CRLM that later disappeared on contrast-enhanced CT scans after chemotherapy, and subsequently underwent surgery for the CRLMs, were enrolled. The anonymized imaging data and case report forms were sent to the central review system and independently reviewed by four radiologists. All anonymized data were randomly allocated into two groups (groups A and B), which were read by two independent readers. True absence of tumor was defined as pathologic absence of tumor for resected lesions and no in situ recurrence within 1 year after surgery for lesions left unresected at each 3-month follow-up contrast-enhanced CT. Positive predictive values for absence of tumor and for residual tumor on contrast-enhanced CT and EOB MR images were compared by using a generalized estimating equation. Results Among 393 CRLMs, the positive predictive value for absence of tumor on EOB MR images (78.0%; 95% confidence interval [CI]: 63.68%, 87.74%) was significantly higher than that on contrast-enhanced CT scans (35.2%; 95% CI: 25.11%, 46.79%; P < .001). The positive predictive value for residual tumor on CT scans (86.0%; 95% CI: 78.61%, 91.16%) was higher than that on EOB MR images (83.8%; 95% CI: 77.50%, 88.67%) without statistical significance (P = .330). Conclusion EOB MR imaging was superior to contrast-enhanced CT imaging for assessment of disappearing CRLMs after chemotherapy. © RSNA, 2017 Online supplemental material is available for this article.


Spinal motor control differences between the sexes.
Activity-related knee joint dysfunction is more prevalent in females than males. One explanation for the discrepancy is differences in movement patterns between the sexes. However, the underlying mechanisms responsible for these differences remain unidentified. This study tested spinal motor control mechanisms influencing motor neuron pool output and subsequent muscle activation in 17 males and 17 females. The following variables were assessed at the soleus: the gain of the unconditioned H-reflex, gain of both intrinsic pre-synaptic inhibition (IPI) and extrinsic pre-synaptic inhibition (EPI), the level of recurrent inhibition (RI), the level of supraspinal drive determined by the ratio of the Vmax:Mmax (V-wave), electromechanical delay (EMD) and the rate of force development (RFD). The Wilks Lambda multivariate test of overall differences among groups was significant (p = 0.031). Univariate between-subjects tests revealed males had greater RI (p = 0.042). However, the sexes did not differ on any of the other variables tested. In conclusion, the sexes differ on modulation of spinal motor control. Specifically, RI, a post-synaptic regulator of force output, was greater in males.


Inducible nitric oxide synthase promoter polymorphism, cigarette smoking, and urothelial carcinoma risk.
Bladder carcinoma has a high inducible nitric oxide synthase (iNOS) content, and a highly polymorphic (CCTTT)n repeat in the iNOS promoter region has been identified. We explored whether this iNOS promoter polymorphism and cigarette smoking are associated with urothelial carcinoma (UC) risk. A total of 250 patients with pathologically confirmed UC and 250 unrelated noncancer controls were serially recruited at the Chia Yi Christian Hospital from August 2002 to May 2005. Multivariate logistic regression analysis was used to calculate the odds ratio and 95% confidence interval (CI). A significantly increased UC risk was found in those who had smoked more than 30 years (odds ratio 2.4, 95% CI 1.5 to 4.2). The study subjects carrying the 12-repeat allele had a significantly increased UC risk (odds ratio 1.7, 95% CI 1.1 to 2.5). We also found the investigated polymorphism was related to clinical stage (P = 0.043). Of those who had ever smoked, those with the short/long (S/L) and long/long (L/L) genotypes (S, 9 to 11 repeats; L, 12 to 18 repeats) and the 12-repeat allele had a significantly increased UC risk of 3.5 (95% CI 1.7 to 7.3) and 4.5 (95% CI 2.2 to 8.9), respectively. Of the study subjects who had smoked longer than 30 years, those with S/L and L/L genotypes and the 12-repeat allele had significantly increased UC risks of 2.4 (95% CI 1.3 to 4.7) and 3.8 (95% CI 1.8 to 8.0), respectively. These findings suggest that the polymorphic (CCTTT)n repeat in the iNOS promoter region might be involved in the development of UC, especially in those who have ever smoked.


Use of pharmacoeconomics information--report of the ISPOR Task Force on use of pharmacoeconomic/health economic information in health-care decision making.
Despite the growing number of pharmacoeconomic (PE)/health economic (HE) studies, very little is known about their use by decision makers. The objectives of the Task Force were to ensure that the good research practices of PE/HE studies pay attention to the needs of health-care decision makers and to develop a "toolbox" for the health-care decision maker wanting to interpret and use PE/HE studies. The membership of the Task Force consisted of individuals involved in making decisions about the availability or use of medicines and researchers into the use of economic evaluations. The group communicated by E-mail and face-to-face meetings. A literature review of decision makers' attitudes toward PE/HE studies and published economic evaluation guidelines was undertaken. In addition, a focus group discussion was held with opinion leaders in managed care pharmacy. The literature review identified 16 surveys of decision makers' attitudes toward PE/HE studies and 15 published guidelines that outlined reporting requirements for economic evaluations. These were reviewed and classified. Based on the published literature and comments from decision makers, seven additional reporting requirements for studies were specified. While the Task Force's additional reporting requirements may be helpful to decision makers, they raise a number of issues. These include the feasibility of meeting the additional requirements, whether decision makers should receive more education in economic evaluation, and whether there should be more study of health-care decision-making procedures themselves.


Dopaminergic influence on the ventilatory response to sustained hypoxia in the cat.
We examined the effects of the dopamine blocker haloperidol (H) on the ventilatory response to sustained hypoxia in awake cats. Ventilation (VE) was measured plethysmographically, and end-tidal PO2 (PETO2) and PCO2 were measured by sampling tracheal gas. Measurements were made before, during, and after 30 min of isocapnic hypoxia after pretreatment with 0.1 mg/kg of H and placebo (P). Experimental runs were conducted on separate days with the P day being first. Two levels of hypoxia were employed. Six cats were studied at a PETO2 of approximately 61 Torr, and six cats were studied at a PETO2 of approximately 41 Torr. In all experiments, isocapnia was maintained and end-tidal PCO2 did not differ on the H and P days. With mild hypoxia after P, VE increased to 137% of air breathing control in the first 5 min of hypoxia and then declined to 102% of control at 25 min of hypoxia. Results on the H day were similar. With more severe hypoxia after P, VE increased to 173% of control at 5 min and then declined to 127% of control. With H, VE increased to 172% of control in the first 5 min and then declined to 149% of control at 25 min. After 25 min of more severe hypoxia, both VE and tidal volume were significantly greater with H than with P (P < 0.05). H reduced the ventilatory decline observed with more severe hypoxia but had no effect on the ventilatory decline in milder hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)


Monitoring speech production and comprehension: Where is the second-language delay?
Research on error monitoring suggests that bilingual Dutch-English speakers are slower to correct some speech errors in their second language (L2) as opposed to their first language (L1). But which component of self-monitoring is slowed down in L2, error detection or interruption and repair of the error? This study charted the time course of monitoring in monolingual English speakers and bilingual Dutch-English speakers in language production and language comprehension, with the aim of pinpointing the component(s) of monitoring that cause an L2 disadvantage. First, we asked whether phonological errors are interrupted more slowly in L2. An analysis of data from three speech error elicitation experiments indeed showed that Dutch-English bilinguals were slower to stop speaking after an error had been detected in their L2 (English) than in their L1 (Dutch), at least for interrupted errors. A similar L2 disadvantage was found when comparing the L2 of Dutch-English bilinguals to the L1 of English monolinguals. Second, monolingual English speakers and bilingual Dutch-English speakers performed a picture naming task, a production monitoring task, and a comprehension monitoring task. Bilingual English speakers were slower in naming pictures in their L2 than monolingual English speakers. However, the production monitoring task and comprehension monitoring task yielded comparable response latencies between monolinguals in their L1 and bilinguals in their L2, indicating that monitoring processes in L2 are not generally slower. We suggest that interruption and repair are planned concurrently and that the difficulty of repairing in L2 triggers a slow-down in L2 interruption.


Phylodynamics and human-mediated dispersal of a zoonotic virus.
Understanding the role of humans in the dispersal of predominantly animal pathogens is essential for their control. We used newly developed Bayesian phylogeographic methods to unravel the dynamics and determinants of the spread of dog rabies virus (RABV) in North Africa. Each of the countries studied exhibited largely disconnected spatial dynamics with major geopolitical boundaries acting as barriers to gene flow. Road distances proved to be better predictors of the movement of dog RABV than accessibility or raw geographical distance, with occasional long distance and rapid spread within each of these countries. Using simulations that bridge phylodynamics and spatial epidemiology, we demonstrate that the contemporary viral distribution extends beyond that expected for RABV transmission in African dog populations. These results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens.


The structural heterogeneity of the carbohydrate moiety of desialylated human transferrin.
Human transferrin consists of a single chain polypeptide which supports two N-glycosidically linked glycans at sequons a and b. Glycopeptides were released from human transferrin by proteolytic digestion, desialylated by mild acid hydrolysis, and then isolated by chromatographic methods. The structures of the glycans located on each sequon were determined by a combination of analytical techniques including Smith degradation, permethylation, and enzymic degradation. Approximately 79% of the total glycan from sequon a was of the biantennary type as previously described by Dorland and his colleagues (FEBS Lett. 77, 15-20 (1977)). The remaining 21% consisted of a mixture of triantennary and tetraantennary glycans, each amounting to approximately 10% of the total glycan for this sequon. The triantennary structure resembled that described for the N-glycosidic triantennary glycans of bovine fetuin by Nilsson and his colleagues (J. Biol. Chem. 254, 4545-4553 (1979)). Of the tetraantennary glycan, approximately half of the structures were incomplete, i.e., one antenna terminated by N-acetylglucosamine. On sequon b, 81% of the glycan was biantennary, identical to those biantennary glycans of sequon a, and the reminder was triantennary, also of the fetuin type. The glycan structures and their locations on the polypeptide are related to the known subpopulations of human transferrin.


Prognostic factors in patients hospitalised with diabetic ketoacidosis at Kenyatta National Hospital, Nairobi.
In spite of many advances in the management of diabetes in the last 25 years, the mortality associatedwith diabetic ketoacidosis (DKA) remains high, especially in the developing countries. The mortality appears greatest in the first 24-48 hours of their treatment. Most of the previous studies on DKA focused on children and the precipitating factors thereof but not particularly on clinical predictors of outcomes. To determine the clinico-laboratory predictors of outcomes of patients hospitalised with diabetic ketoacidosis who were undergoing treatment. Cross-sectional descriptive study. The accident and emergency department and medical wards of the Kenyatta National Hospital. Fifty one patients hospitalised with diabetic ketoacidosis over a nine month period were evaluated clinically and by laboratory tests. They were managed in the standard way with insulin, intravenous fluids and appropriate supportive care. Serial assays of serum electrolytes, glucose and blood pH, HbA1c and clinical outcome of either discharge home or death. Of the 51 patients enrolled, 47 were included in the final analysis. Fourteen (29.8%) patients died,andthe deaths occurred within less than48 hours of hospitalisation and treatment. Of the patients who died, all (100%) had altered level of consciousness at hospitalisation, 71.4% had abnormal renal functions, 64.3% were newly diagnosed and an equal proportion of 64.3% were females. The alteration in the level of consciousness was significantly associated systolic hypotension and severe metabolic acidosis, (p < 0.001). Patients with altered level of consciousness also had poorer renal function. Apparently DKA still carries high mortality during treatment in hospital. Altered level of consciousness, which is an obvious and easily discernible clinical sign, was a major predictor of mortality in our study patients. The majority of patients with altered level of consciousness also had systolic hypotension, severe metabolic acidosis and impaired renal function. Even where and when detailed laboratory evaluation is elusive, clinical signs, especially altered level of consciousness and systolic hypotension are very important markers of severity of DKA that may be associated with unfavourable outcomes. Further studies are necessary to establish why DKA still carries high mortality in the patients who are already receiving treatment in hospitals in developing countries.


Reducing Hospital Readmissions Through Preferred Networks Of Skilled Nursing Facilities.
Establishing preferred provider networks of skilled nursing facilities (SNFs) is one approach hospital administrators are using to reduce excess thirty-day readmissions and avoid Medicare penalties or to reduce beneficiaries' costs as part of value-based payment models. However, hospitals are also required to provide patients at discharge with a list of Medicare-eligible providers and cannot explicitly restrict patient choice. This requirement complicates the development of a SNF network. Furthermore, there is little evidence about the effectiveness of network development in reducing readmission rates. We used a concurrent mixed-methods approach, combining Medicare claims data for the period 2009-13 with qualitative data gathered from interviews during site visits to hospitals in eight US markets in March-October 2015, to examine changes in rehospitalization rates and differences in practices between hospitals that did and did not develop formal SNF networks. Four hospitals had developed formal SNF networks as part of their care management efforts. These hospitals saw a relative reduction from 2009 to 2013 in readmission rates for patients discharged to SNFs that was 4.5 percentage points greater than the reduction for hospitals without formal networks. Interviews revealed that those with networks expanded existing relationships with SNFs, effectively managed patient data, and exercised a looser interpretation of patient choice.


Integrating community children's nursing in urgent and emergency care: a qualitative comparison of two teams in North West England.
Despite the policy principle that "children are best cared for at home whenever possible" children continue to have high rates of emergency department (ED) attendance and emergency hospital admission. Community Children's Nursing Teams (CCNTs) can care for acutely ill children at home but their potential to provide an alternative to ED attendance and hospitalisation depends on effective integration with other services in the urgent care system, such as EDs and Observation and Assessment Units (OAUs). Although challenges of integrating CCNTs have been identified, there has been no comparative assessment of the factors that facilitate or hinder integration of care of acutely ill children by CCNTs with the urgent care system. The aim of this study was to identify enablers and barriers to integration of CCNTs with urgent and emergency care. Comparative case studies were conducted of two CCNTs serving Primary Care Trusts in North West England. Twenty-two health professionals including CCNT managers and staff; paediatricians; nurses; children's ward, ED and OAU staff; commissioners of children's services; GPs and primary care staff were interviewed between June 2009 and February 2010. Qualitative data were analysed thematically using the Framework approach. Barriers to integration included paediatricians' perceived lack of ownership of the CCNT, poor communication between consultants and community children's nurses (CCNs), and weak personal relationships. This prevented early referral to the CCNT as an alternative to hospital care. Enablers of integration included co-location and rotation of CCNs through urgent care settings including OAUs and EDs. This enabled nurses to develop skills, make decisions about referral to home care and gain the confidence of referring clinicians. Integration of CCNTs at multiple points in the urgent care system is required in order to provide an alternative to inappropriate ED attendances and emergency admission. The principal enablers and barriers are both aspects of normative integration, which involves shared understanding of the contribution of CCNTs and trusting relationships between practitioners. Co-location and rotation of CCNs through acute services can promote integration and appropriate referrals to CCNTs to support families to care for children at home.


Proposal for a standardized pathology report of gastroenteropancreatic neuroendocrine tumors: prognostic significance of pathological parameters.
There is confusion in the diagnosis and biological behaviors of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), because of independently proposed nomenclatures and classifications. A standardized form of pathology report is required for the proper management of patients. We discussed the proper pathological evaluation of GEP-NET at the consensus conference of the subcommittee meeting for the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. We then verified the prognostic significance of pathological parameters from our previous nationwide collection of pathological data from 28 hospitals in Korea to determine the essential data set for a pathology report. Histological classification, grading (mitosis and/or Ki-67 labeling index), T staging (extent, size), lymph node metastasis, and lymphovascular and perineural invasion were significant prognostic factors and essential for the pathology report of GEP-NET, while immunostaining such as synaptophysin and chromogranin may be optional. Furthermore, the staging system, either that of the 2010 American Joint Cancer Committee (AJCC) or the European Neuroendocrine Tumor Society (ENETS), should be specified, especially for pancreatic neuroendocrine neoplasms. A standardized pathology report is crucial for the proper management and prediction of prognosis of patients with GEP-NET.


Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug.
We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.


Improving access and provision of pre-travel healthcare for travellers visiting friends and relatives: a review of the evidence.
Travellers visiting friends and relatives (VFR travellers) in their country of origin are at increased risk of a range of preventable infections. Risks are broadly related to circumstances of travel, risk misconceptions and access to health services. Despite nearly two decades of literature highlighting these increased risks little impact has been made on their risk disparity. This review draws on evidence from travel medicine literature, supplemented by evidence from the broader field of immigrant health, and is structured to include strategies that aim to reduce barriers at the patient, provider and health system level. For the travel medicine provider, tailored risk communication that is cognisant of the unique health beliefs and barriers to travel health for VFR travellers is needed, including enhanced communication through the use of interpreters and supplementary written communication. Primary care providers are uniquely placed to identify future travel plans among immigrant patients, however, greater awareness of VFR traveller risks and training in travel medicine are required. Community health promotion interventions that are culturally appropriate, translated into multiple languages and takes into account the cumulative risk of multiple return visits are key to normalizing travel healthcare seeking behaviours and improving awareness of VFR travel risks. Currently, there are few examples of novel strategies to engage migrant communities in travel health with no formal evaluations of their effectiveness. Best practice includes the use of community-consulted approaches in collaboration with government, primary care and travel medicine. Multifactorial barriers related to health beliefs and access to health services require a range of strategies and interventions in both reaching and providing advice to VFR travellers. To improve the evidence base, future research should focus on the evaluation of novel strategies that address these barriers and improve access and provision of pre-travel healthcare to VFR travellers.


Animals, veterinarians and the sociology of diagnosis.
While sociologists of medicine have focused their efforts on understanding human health, illness, and medicine, veterinary medical practice has not yet caught their attention in any sustained way. In this critical review article, we use insights from the sociology of diagnosis literature to explore veterinary practice, and aim to demonstrate the importance of animals to sociological understandings of health, illness and disease. As in human medicine, our analysis shows the importance of diagnosis in creating and maintaining the power and authority of the veterinary professional. However, we then explore how diagnosis operates as a kind of dance, where professional authority can be challenged, particularly in light of the complex ethical responsibilities and clinical interactions that result from the triad of professional/owner/animal patient. Finally, we consider diagnosis via the precept of entanglement, and raise the intriguing possibility of interspecies health relations, whereby decision-making in human health care may be influenced by experiences in animal health care and vice-versa. In our conclusion, we argue that this analysis provides opportunities to scholars researching diagnosis in human health care, particularly around the impact of commercial drivers; has implications for veterinary and public health practitioners; and should help animate the emerging sociology of veterinary medicine.


Persistent eyelid swelling in a patient with rosacea.
Persistent facial swelling may occur as a rare complication of rosacea. This finding has been referred to as lymphedematous rosacea, Morbihan's disease or persistent solid facial edema. A literature review for cases of lymphedematous rosacea revealed that the chronic inflammatory process that accompanies the disease contributes to an increase in the permeability of blood vessels. With time, the lymphatic drainage system becomes permanently impaired, leading to fluid accumulation in the affected skin. Herein, we report the case of a 58-year-old female with history of rosacea who developed bilateral periorbital swelling with associated erythema of the conjunctiva (ocular rosacea) over a 4 month period that only responded to oral corticosteroids. Biopsy revealed changes of lymphedematous rosacea.


Effects of the COVID-19 pandemic on secondary care for cardiovascular disease in the UK: an electronic health record analysis across three countries.
Although morbidity and mortality from COVID-19 have been widely reported, the indirect effects of the pandemic beyond 2020 on other major diseases and health service activity have not been well described. Analyses used national administrative electronic hospital records in England, Scotland, and Wales for 2016-21. Admissions and procedures during the pandemic (2020-21) related to six major cardiovascular conditions [acute coronary syndrome (ACS), heart failure (HF), stroke/transient ischaemic attack (TIA), peripheral arterial disease (PAD), aortic aneurysm (AA), and venous thromboembolism(VTE)] were compared with the annual average in the pre-pandemic period (2016-19). Differences were assessed by time period and urgency of care.In 2020, there were 31 064 (-6%) fewer hospital admissions [14 506 (-4%) fewer emergencies, 16 560 (-23%) fewer elective admissions] compared with 2016-19 for the six major cardiovascular diseases (CVDs) combined. The proportional reduction in admissions was similar in all three countries. Overall, hospital admissions returned to pre-pandemic levels in 2021. Elective admissions remained substantially below expected levels for almost all conditions in all three countries [-10 996 (-15%) fewer admissions]. However, these reductions were offset by higher than expected total emergency admissions [+25 878 (+6%) higher admissions], notably for HF and stroke in England, and for VTE in all three countries. Analyses for procedures showed similar temporal variations to admissions. The present study highlights increasing emergency cardiovascular admissions during the pandemic, in the context of a substantial and sustained reduction in elective admissions and procedures. This is likely to increase further the demands on cardiovascular services over the coming years.


Correlation between human neutrophil peptide 1-3 secretion and azurophilic granule (CD63) expression in early childhood caries.
In saliva, neutrophil constitutes the most prominent first-line defense of immune cells against pathogenic microbes. The importance of neutrophils to the host immune systems of neutropenic or patients disabled with regard to their neutrophil function results in a tendency toward serious infections, such as early childhood caries (ECC). The cytoplasmic granules present in neutrophils play a major role in neutrophil-mediated inflammation. Azurophilic granules contain antimicrobial proteins, such as defensin, a human antimicrobial peptide (HNP 1-3). The aim of this study is to analyze the correlation of HNP 1-3 secretion with CD63 expression on the surface of salivary neutrophils. This study constituted a cross-sectional, analytical observational study. Saliva taken from preschoolchildren between the ages of 4-6 years who had been divided into two groups, i.e., early childhood caries group with decayed, extracted, filled teeth (def-t) index >6 and caries free with def-t = 0, was subjected to a HNP 1-3 secretion test using ELISA assay and an expression test for CD63 by means of a flow cytometry test. The results obtained were analyzed using independent t-test and Pearson correlation (P < 0.05). The secretion of HNP 1-3 in the saliva of ECC was higher (172.6 ± 41.64) compared to that of caries-free cases (140.39 ± 31.91), whereas the level of CD63 salivary expression in ECC was lower (2.32 ± 0.57) than in the presence of caries (2.67 ± 0.46). In ECC cases, saliva increases HNP 1-3 secretion but decreases CD63 expression on the surface of salivary neutrophils.


Metastatic brain tumors with dural extension.
Twenty-two patients who had solitary metastatic brain tumors with dural extension were treated surgically over a 3-year period. Their cases were reviewed to characterize these lesions and to compare the patients with a similar cohort in which there was no dural involvement. The median age of the patients was 58 years (range 11-68 years) and the male/female ratio was 12:10. The median preoperative Karnofsky Performance Scale (KPS) score in the group was 90 (range 70-100). The most common histological diagnoses seen in these patients included breast cancer, adenocarcinoma and squamous cell carcinoma of the lung, and renal cell carcinoma. All patients underwent gross-total resection of the tumor and 86% received radiation therapy. The median patient survival time was 11 months, with a median time to recurrent intracranial disease of 19 months. Survival was related to the histological diagnosis. Recurrent disease occurred in 41% of cases. Leptomeningeal disease occurred in three patients (14%). The frequency and time course of development of recurrent disease was not affected by dural resection nor was survival. These results for patients having metastatic brain tumors with dural extension were compared with those for a cohort of 26 patients in which there were similar histological diagnosis, age, gender, and preoperative KPS score were distributed similarly but in which each patient had a single subcortical metastatic lesion. Those patients had a median survival of 10 months and the median time to recurrence was not reached. Leptomeningeal disease occurred in one patient (4%). To the authors' knowledge, this is the first reported series of patients with metastatic brain tumors with dural extension. Patients with this disease may be more likely to develop recurrences along the dura and leptomeningeal disease, but the overall survival time in these patients is not different from those patients with intraparenchymal lesions.


Measuring the "whole system" outcomes of an educational innovation: experience from the integrative family medicine program.
Six family medicine residency programs in the United States collaborated on the development and implementation of an integrative family medicine (IFM) program, which is a postgraduate training model that combines family medicine residency training with an integrative medicine fellowship. This paper reports on effects of IFM on residency programs and clinical systems in which it was implemented. We used the Integrative Medicine Attitudes Questionnaire (IMAQ) to assess participants' attitudes toward integrative medicine before and after the program was implemented. We assessed residency program recruitment success before and after the program was implemented. We conducted interviews with key informants at each program to evaluate the effects of the IFM on the six participating residency programs. IMAQ scores demonstrated a significant increase in the acceptance of integrative medicine after implementation of IFM. Recruiting data showed that participating programs filled at a rate consistently above the national average both before and after implementation. Analysis of interview data showed that programs became more open to an integrative medicine (IM) approach and offered a wider range of clinical services to patients. Our mixed-methods strategy for evaluation of IFM showed that implementing the program increased acceptance of IM, did not affect residency fill rates, and increased use of IM in clinical practice. The combination of quantitative and qualitative methods was an effective strategy for documenting the "systems level" effects of a new educational program.


A phase III clinical trial of antibiotics to reduce chorioamnionitis-related perinatal HIV-1 transmission.
A multisite study was conducted in Africa to assess the efficacy of antibiotics to reduce mother-to-child transmission (MTCT) of HIV-1. A randomized, double-blinded, placebo-controlled, phase III clinical trial. HIV-1-infected women were randomly assigned at 20-24 weeks' gestation to receive either antibiotics (metronidazole plus erythromycin antenatally and metronidazole plus ampicillin intrapartum) or placebo. Maternal study procedures were performed at 20-24, 26-30, and 36 weeks antenatally, and at labor/delivery. Infants were seen at birth, 4-6 weeks, and 3, 6, 9 and 12 months. The primary efficacy endpoints were overall infant HIV-1 infection and HIV-1-free survival at 4-6 weeks. All women and infants received single-dose nevirapine prophylaxis in this study. A total of 1510 live-born infants were included in the primary analysis. The proportions of HIV-1-infected infants at birth were similar (antibiotics 7.1%; placebo 8.3%; P = 0.41). Likewise, there were no statistically significant differences at 4-6 weeks in the overall risk of MTCT of HIV-1 (antibiotics 16.2%; placebo 15.8%; P = 0.89) or HIV-1-free survival (79.4% in each study arm). Post-randomization, the proportion of women with bacterial vaginosis at the second antenatal visit was significantly lower in the antibiotics arm compared with the placebo arm (23.8 versus 39.7%; P < 0.001), but the frequency of histological chorioamnionitis was not different (antibiotics 36.9%; placebo 39.7%; P = 0.30). Adverse events in mothers and their infants did not differ by randomization arm. This simple antepartum and peripartum antibiotic regimen did not reduce the risk of MTCT of HIV-1.


Early changes in blood brain barrier permeability to small molecules after transient cerebral ischemia.
Brain unidirectional extraction and flux of leucine were measured simultaneously with cerebral blood flow (CBF) at various times after transient global cerebral ischemia in the rat. The results permit an evaluation of blood-brain barrier permeability in the postischemic period independent of alterations in CBF at the time of measurement. Leucine extraction was higher (p less than 0.001) than that of CBF-matched controls at 15 min and 6 hr after 30 min of global cerebral ischemia, but was not different from control at 30 min and 1 h after ischemia. Leucine flux into brain was increased only at 15 min after reperfusion of the brain. Cerebral edema occurs 15-30 min after reperfusion in this ischemia model, but the permeability of the blood-brain barrier to large molecules is unaltered during this period (Petito et al: J Neuropath Exp Neurol 41:423-436, 1982). Increased barrier permeability to small molecules such as leucine may contribute to the production of this early postischemic edema.


Dapoxetine for premature ejaculation.
Premature ejaculation, also referred to as rapid or early ejaculation, is a poorly understood disorder with no single, widely-recognised, evidence-based definition. Studies based on patient self-reporting indicate that premature ejaculation is a common complaint with estimated prevalence ranging from 4%-39% of men in the general community.(1) However, a lack of an accurate validated definition has made comparison of the results of such studies difficult.(2) In addition, perception of normal ejaculatory latency varies by country and differs when assessed by the patient or their partner.(3) ▾Dapoxetine (Priligy-A. Menarini Farmaceutica Internazionale SRL), a short-acting selective serotonin reuptake inhibitor (SSRI) is the first drug to be licensed in the UK for on-demand management of diagnosed premature ejaculation.(4) In this article we review the evidence for dapoxetine and discuss some of the challenges associated with its introduction.


Selective renal arterial infusion of fenoldopam for the prevention of contrast-induced nephropathy.
Contrast-induced nephropathy (CIN) remains an important complication of angiographic procedures, particularly among patients with significant renal impairment. To date, vasodilator therapies such as fenoldopam have failed to prevent CIN, possibly because significant hypotension as a result of systemic infusion has limited the ability to deliver adequate drug levels to the renal vasculature. We present a case of averted CIN after multivessel coronary intervention in a diabetic patient with severe renal insufficiency, potentially due to bilateral renal arterial infusion of fenoldopam. Our subsequent experience with intrarenal fenoldopam in nine additional procedures in eight other high risk patients resulted in one case of asymptomatic transient CIN. Further studies are warranted to evaluate the efficacy of intrarenal administration of vasodilator therapies such as fenoldopam for the prevention of CIN.


Ancient Soil-Transmitted Parasite Eggs Detected from the Sixth Century Three Kingdom Period Silla Tomb.
The parasitic infection patterns of the Joseon period have begun to be revealed in a series of paleoparasitological studies. However, parasitism prevailing during or before the Three Kingdom period is still relatively unexplored. In the present study, we therefore conducted parasitological examinations of soil and organic-material sediments precipitated upon human hipbone and sacrum discovered inside an ancient Mokgwakmyo tomb dating to the Silla Dynasty (57 BCE-660 CE). Within the samples, we discovered ancient Ascaris lumbricoides (eggs per gram [EPG], 46.6-48.3) and Trichuris trichiura (EPG, 32.8-62.1) eggs, the species commonly detected among Korean populations until just prior to the 1970s. These findings show that soil-transmitted parasitic infection among the Silla nobility might not have been uncommon. This is the first-ever report on the presence of ancient parasite eggs in the samples obtained from a Three Kingdom period tomb; and it also presents the earliest positive results for any of the ancient South Korean tombs paleoparasitologically examined to date.


Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study.
We aimed to study if physical activity could interfere with progression for cognitive impairment and dementia in older people with white matter changes living independently. The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes on the transition of independent elderly subjects into disability. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and cognitive assessment with classification of cognitive impairment and dementia according to usual clinical criteria. Physical activity was recorded during the clinical interview. MRI was performed at entry and at the end of the study. Six hundred thirty-nine subjects were included (74.1±5 years old, 55% women, 9.6±3.8 years of schooling, 64% physically active). At the end of follow-up, 90 patients had dementia (vascular dementia, 54; Alzheimer disease with vascular component, 34; frontotemporal dementia, 2), and 147 had cognitive impairment not dementia. Using Cox regression analysis, physical activity reduced the risk of cognitive impairment (dementia and not dementia: β=-0.45, P=0.002; hazard ratio, 0.64; 95% CI, 0.48-0.85), dementia (β=-0.49, P=0.043; hazard ratio, 0.61; 95% CI, 0.38-0.98), and vascular dementia (β=-0.86, P=0.008; hazard ratio, 0.42; 95% CI, 0.22-0.80), independent of age, education, white matter change severity, medial temporal atrophy, previous and incident stroke, and diabetes. Physical activity reduces the risk of cognitive impairment, mainly vascular dementia, in older people living independently.


Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.


Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice.
Tyrosine 3-hydroxylase (TH, EC 220.127.116.11) catalyzes the first and rate-limiting step of the catecholamine biosynthetic pathway in the nervous and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination. Mice heterozygous for the TH mutation were apparently normal. In these mice, TH activity in the embryos and adult tissues was less than 50% of the wild-type values, but the catecholamine level was decreased only moderately in the developing animals and was maintained normally at adulthood, suggesting the presence of a regulatory mechanism for ensuring the proper catecholamine level during animal development. In contrast, the homozygous mutant mice died at a late stage of embryonic development or shortly after birth. Both TH mRNA and enzyme activity were lacking in the homozygous mutants, which thus explained the severe depletion of catecholamines. These changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels. Analysis of electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice that may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme. These results indicate that TH is essential for survival of the animals during the late gestational development and after birth.


Loss of Response to Vedolizumab and Ability of Dose Intensification to Restore Response in Patients With Crohn's Disease or Ulcerative Colitis: A Systematic Review and Meta-analysis.
Vedolizumab is effective and safe for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Little is known about the incidence rate of loss of response to vedolizumab maintenance therapy or whether dose intensification restores response to this drug. We searched PubMed, Scopus and conference abstracts (Digestive Disease Week, European Crohn's and Colitis Organization, and United European Gastroenterology Week), through December 2017, for experimental or observational cohort studies of vedolizumab use in adult patients with CD or UC; we identified studies that provided sufficient data to determine the incidence rate of loss of response among initial responders and the ability of dose intensification to restore response. Two reviewers independently abstracted study data and outcomes and rated each study's risk of bias. The studies were evaluated for heterogeneity and publication bias. Summary estimates were calculated using random effects models. We analyzed data from 10 eligible cohorts; most patients had received prior treatment with a tumor necrosis factor antagonist. The pooled incidence rates of loss of response were 47.9 per 100 person-years of follow up (95% CI, 26.3‒87.0; I2 = 74%) among patients with CD and 39.8 per 100 person-years of follow up (95% CI, 35.0‒45.3; I2 = 0%) among patients with UC. Dose intensification restored response to the drug in 53.8% of secondary non-responders (95% CI, 21.8%‒82.9%; I2 = 77%). In a systematic review and meta-analysis, we found high proportions of patients with CD or UC to lose responsiveness to vedolizumab maintenance therapy. Dose intensification restores responsiveness to more than half of these patients. Additional studies are warranted to inform clinical decision making.


Effect of intramucosal infiltration of different concentrations of adrenaline on hemodynamics during transsphenoidal surgery.
Neurosurgeons routinely instill vasopressors, with or without local anesthetics, to prepare nasal passages prior to transsphenoidal surgeries. As there is a paucity of data comparing the effect of intramucosal nasal infiltration of different concentrations of adrenaline that is, 1:200,000 and 1:400,000 in patients undergoing transsphenoidal surgery, we conducted this study to evaluate the effect of these two concentrations of adrenaline with 2% lignocaine on hemodynamics as well as bleeding. Fifty-two American Society of Anesthesiologists I/II patients, aged 15-70 years, undergoing transsphenoidal surgery for pituitary or sellar masses were enrolled. Prior to surgical incision, nasal septal mucosa was infiltrated with lignocaine-adrenaline solution, after randomly allocating them to one of the two groups, with patients in Group A receiving intramucosal infiltration using 2% lignocaine with 1:200,000 adrenaline and those in Group B receiving 2% lignocaine with 1:400,000 adrenaline. Following infiltration, hemodynamic parameters were recorded every 1 min for 5 min and thereafter at every 5 min interval. Fewer patients (3/24 [12.5%]) in Group B had a rise of >50% in systolic blood pressure, from baseline values, after nasal mucosa infiltration as compared with patients in Group A (9/24 [37.5%]). In addition, mean rise in systolic, diastolic and mean arterial pressure was also significantly lower in Group B as compared with Group A. Adrenaline in a concentration of 1:400,000 added to 2% lignocaine for nasal mucosa infiltration produces less hemodynamic response as compared with adrenaline 1:200,000 added to 2% lignocaine while at the same time providing similar operating conditions.


Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study.
Childhood cancer survivors (CCS) are at increased risk to develop differentiated thyroid cancer predominantly after radiotherapy (subsequent DTC). It is insufficiently known whether subsequent DTC in CCS has a different presentation or outcome than sporadic DTC. Patients with subsequent DTC (n = 31) were matched to patients with sporadic DTC (n = 93) on gender, age and year of diagnosis to compare presentation and DTC outcomes. Clinical data were collected retrospectively. Among the CCS with subsequent DTC, all but one had received chemotherapy for their childhood cancer, 19 (61.3%) had received radiotherapy including the thyroid region, 3 (9.7%) 131I-MIBG and 8 (25.8%) had received treatment with chemotherapy only. Subsequent DTC was detected by surveillance through neck palpation (46.2%), as a self-identified mass (34.6%), or by chance. Among sporadic DTC patients, self detection predominated (68.8%). CCS with subsequent DTC tended to have on average smaller tumors (1.9 vs 2.4 cm, respectively, (P = 0.051), and more often bilateral (5/25 (60.0%) vs 28/92 (30.4%), P = 0.024). There were no significant differences in the occurrence of surgical complications, recurrence rate or disease-related death. When compared to patients with sporadic DTC, CCS with subsequent DTC seem to present with smaller tumors and more frequent bilateral tumors. Treatment outcome seems to be similar. The finding that one-third of subsequent DTC cases had been treated with chemotherapy only needs further investigation. These results are important for the development of surveillance programs for CCS at risk for DTC and for treatment guidelines of subsequent DTC.


Characterization and pharmacokinetic evaluation of gamma sterilized ketorolac tromethamine loaded albumin microspheres for intramuscular administration.
Pharmacokinetic parameters of ketorolac tromethamine (KT) loaded albumin (KTAL) microspheres were determined using New Zealand white rabbits. Each rabbit (n=6) was injected 5 mg/kg body weight of plain KT or an equivalent dose in microsphere form in 2 mL water for injection. Prior to animal studies microspheres were tested for toxic residues and were gamma sterilized. Sterilized microspheres were evaluated for their integrity by physico-chemical characterization. Test for toxic residues was negative, the sterilization process utilized was effective and did not alter any physicochemical characteristics and showed good syringeability. When KT was administered in the form of microspheres there was a significant increase in Cmax, AUC, t1/2 and MRT (P < 0.05). When administered as microspheres, plasma concentration of drug sustained for 24 hours. It was concluded that KTAL microsphere formulation improved the systemic exposure and sustained the drug release and could be used for once-a-day administration of KT.


Frequency mixing of photorefractive and ferroelectric gratings in lithium niobate crystals.
Holographically recorded photorefractive gratings in periodically poled lithium niobate crystals (PPLNs) are investigated. The principal spatial frequency K of the grating is strongly suppressed. Sideband gratings with grating vectors K +/- G appear. From the measurements the domain grating vector G and the duty cycle of the domain structure can be obtained. These findings allow for fast nondestructive quality inspection of PPLN and are of importance for any optical application combining holography and PPLN.


Prognostic assessment in COPD without lung function: the B-AE-D indices.
Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function.The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.


Retrospective study of the epidemiology and clinical manifestations of Cryptococcus gattii infections in Colombia from 1997-2011.
Cryptococcosis due to Cryptococcus gattii is endemic in various parts of the world, affecting mostly immunocompetent patients. A national surveillance study of cryptococcosis, including demographical, clinical and microbiological data, has been ongoing since 1997 in Colombia, to provide insights into the epidemiology of this mycosis. From 1,209 surveys analyzed between 1997-2011, 45 cases caused by C. gattii were reported (prevalence 3.7%; annual incidence 0.07 cases/million inhabitants/year). Norte de Santander had the highest incidence (0.81 cases/million/year), representing 33.3% of all cases. The male: female ratio was 3.3∶1. Mean age at diagnosis was 41±16 years. No specific risk factors were identified in 91.1% of patients. HIV infection was reported in 6.7% of patients, autoimmune disease and steroids use in 2.2%. Clinical features included headache (80.5%), nausea/vomiting (56.1%) and neurological derangements (48.8%). Chest radiographs were taken in 21 (46.7%) cases, with abnormal findings in 7 (33.3%). Cranial CT scans were obtained in 15 (33.3%) cases, with abnormalities detected in 10 (66.7%). Treatment was well documented in 30 cases, with most receiving amphotericin B. Direct sample examination was positive in 97.7% cases. Antigen detection was positive for all CSF specimens and for 75% of serum samples. C. gattii was recovered from CSF (93.3%) and respiratory specimens (6.6%). Serotype was determined in 42 isolates; 36 isolates were serotype B (85.7%), while 6 were C (14.3%). The breakdowns of molecular types were VGII (55.6%), VGIII (31.1%) and VGI (13.3%). Among 44 strains, 16 MLST sequence types (ST) were identified, 11 of them newly reported. The results of this passive surveillance study demonstrate that cryptococcosis caused by C. gattii has a low prevalence in Colombia, with the exception of Norte de Santander. The predominance of molecular type VGII is of concern considering its association with high virulence and the potential to evolve into outbreaks.


Development of a next-generation field-free atmospheric pressure photoionization source for liquid chromatography/mass spectrometry.
Atmospheric pressure photoionization (APPI) is considered a candidate ionization method suitable for a broad range of liquid chromatography/mass spectrometry (LC/MS) applications. Questions remain, however, regarding the ultimate potential of the technique. We propose that sensitivity and thus detection limits may be restricted by geometric source design, limiting widespread acceptance of the technique. The relative performance of two geometrically distinct APPI source configurations was evaluated through comprehensive performance comparison upon a single MS platform. To facilitate a fair comparison, a prototype orthogonal geometry, field-free APPI source was developed and tested against two currently commercially available open-geometry APPI sources. The prototype device was engineered based upon the geometry and functionality of first-generation, co-axial field-free APPI sources. Initial characterization experiments were performed by flow injection analysis using a range of analyte standards exhibiting a variety of chemical properties. A standard panel of 16 polycyclic aromatic hydrocarbons (PAHs) identified as priority pollutants by the EPA was also analyzed, demonstrating relative performance using an LC/MS workflow. The prototype field-free APPI source demonstrated the potential for order-of-magnitude performance enhancement over open-geometry sources that lack a confined field-free reaction region. An APPI source configuration that includes an extended field-free reaction region was demonstrated to have the potential to provide enhanced sensitivity relative to commercially available open-geometry source designs. Improved performance will no doubt lead to increased acceptance and widespread application of the technique.