Adherence rates of person-centered language in amputation research: A cross-sectional analysis.
Person-centered language (PCL) is the recommended method of addressing patients by the American Medical Association Manual of Style in medical research, thus requiring published manuscripts to be free of non-PCL. Although individuals, communities, and organizations have the autonomy to use non-PCL, it is imperative for medical researchers to use PCL in an effort to reduce the transfer of stigmatization into clinical practice. To determine current adherence to PCL related to individuals with limb or digit amputations in scientific journals. A cross-sectional analysis was performed by systematically searching PubMed from May 1, 2018 to April 30, 2020 for publications focused on amputations. Journals with less than 20 articles were excluded, and remaining publications were randomized, with the first 500 articles selected. Articles were screened for inclusion criteria, and data were extracted in masked, duplicate fashion, for predetermined non-PCL terms. A chi-squared test and logistic regression were used to quantify PCL adherence study characteristics. Of 500 articles, 81 were excluded, and 419 articles from 13 journals were examined-64.6% containing non-PCL. The most common non-PCL terms used were "amputee" in 148 articles and "limb loss" in 138 articles. PCL was significantly associated with article type, research funding, and journal requirements for PCL. Results indicate that one-third of research articles were PCL-adherent, which we speculate may contribute to the stigma that individuals with amputations experience. Our findings suggest that PCL adherence is higher among surgery research and lower among engineering and prosthetic research.


The critical factor: The role of quality in the performance of supported accommodation services for complex mental illness in England.
Rehabilitation services have a key role in ensuring integrated and comprehensive mental health (MH) care in the community for people suffering from long-term and severe mental disorders. MH-supported accommodation services aim to promote service users' autonomy and independence. Given the complexity associated with MH-supported accommodation services in England, a comparative evaluation of critical performance indicators, including service provision and quality of care, seems to be necessary in designing evidence-informed policies. This study aims to explore the influence of service quality indicators on the performance of MH-supported accommodation services in England. The analysed sample includes supported accommodation services from 14 nationally representative local authorities in England from the QuEST study grouped by three main types of care: residential care homes (divided into two subgroups: move-on and non-move-on oriented), supported housing and floating outreach. EDeS-MH (efficient decision support-mental health) was used to assess the performance indicators for the selected services by combining a Monte Carlo simulation engine, data envelopment analysis and a fuzzy inference engine for integrating expert knowledge. Depending on the type of care, six/seven quality domains were sequentially included after a baseline scenario (only technical) was analysed. Relative technical efficiency scores for the baseline scenarios revealed high performance in all the selected supported accommodation services, but the statistical variability was high. Quality domains significantly improved performance in every type of care. The inclusion of quality indicators has a positive impact on the global performance of each type of care. Remaining at the corresponding services more than expected for two years has a negative impact on performance. These findings can be considered from a planning perspective to facilitate the design of pathways of care with more realistic expectations about gaining autonomy in two years.


RET rearrangements in archival oxyphilic thyroid tumors: new insights in tumorigenesis and classification of Hürthle cell carcinomas?
Oncocytic carcinomas (Hürthle cell carcinomas [HCCs]) are commonly considered a subgroup of follicular thyroid carcinomas (FTCs). Recent characterization of a subgroup of "Hürthle cell" papillary thyroid carcinomas (PTCs) was based on the identification of PTC-specific RET hybrid oncogenes in HCCs. We examined 27 HCCs, 4 oxyphilic FTCs, 5 oxyphilic PTCs, 2 poorly differentiated carcinomas arising from HCCs (HCC-UTCs), and 16 oxyphilic adenomas. Total RNA was extracted from paraffin-embedded thyroid neoplasms by a novel macrodissection technique that uses a cylindric punch. After reverse transcription-polymerase chain reaction-based screening for RET rearrangements, the samples were tested for all known RET/PTC 1 to 11 hybrids with the use of artificially constructed chimeric sequences as controls. The elimination of C cells by punching dissection significantly reduced RET wild-type expression. RET hybrid oncogenes (7x RET/PTC1, 1x RET/PTC1L, 2x RET/PTC3, 5 uncharacterized RET/PTCx) were demonstrated in 7 of 27 HCCs, in 0 of 4 oxyphilic FTCs, in 4 of 5 oxyphilic PTCs, in 1 of 2 HCC-UTCs, and in 3 of 16 oxyphilic adenomas. Our results suggest that the expression of rearranged RET hybrid oncogenes (1) is present in a similar percentage of HCCs when compared with the literature on nonoxyphilic PTCs, (2) defines PTC-like HCCs better than histomorphologic characterization, (3) excludes HCCs as a subgroup of FTCs, and (4) may play a role in the early tumorigenesis of oncocytic tumors.


Crystal structures of the GCaMP calcium sensor reveal the mechanism of fluorescence signal change and aid rational design.
The genetically encoded calcium indicator GCaMP2 shows promise for neural network activity imaging, but is currently limited by low signal-to-noise ratio. We describe x-ray crystal structures as well as solution biophysical and spectroscopic characterization of GCaMP2 in the calcium-free dark state, and in two calcium-bound bright states: a monomeric form that dominates at intracellular concentrations observed during imaging experiments and an unexpected domain-swapped dimer with decreased fluorescence. This series of structures provides insight into the mechanism of Ca2+-induced fluorescence change. Upon calcium binding, the calmodulin (CaM) domain wraps around the M13 peptide, creating a new domain interface between CaM and the circularly permuted enhanced green fluorescent protein domain. Residues from CaM alter the chemical environment of the circularly permuted enhanced green fluorescent protein chromophore and, together with flexible inter-domain linkers, block solvent access to the chromophore. Guided by the crystal structures, we engineered a series of GCaMP2 point mutants to probe the mechanism of GCaMP2 function and characterized one mutant with significantly improved signal-to-noise. The mutation is located at a domain interface and its effect on sensor function could not have been predicted in the absence of structural data.


Smad4 controls proliferation of interstitial cells in the neonatal kidney.
Expansion of interstitial cells in the adult kidney is a hallmark of chronic disease, whereas their proliferation during fetal development is necessary for organ formation. An intriguing difference between adult and neonatal kidneys is that the neonatal kidney has the capacity to control interstitial cell proliferation when the target number has been reached. In this study, we define the consequences of inactivating the TGFβ/Smad response in the mouse interstitial cell lineage. We find that pathway inactivation through loss of Smad4 leads to overproliferation of interstitial cells regionally in the kidney medulla. Analysis of markers for BMP and TGFβ pathway activation reveals that loss of Smad4 primarily reduces TGFβ signaling in the interstitium. Whereas TGFβ signaling is reduced in these cells, marker analysis shows that Wnt/β-catenin signaling is increased. Our analysis supports a model in which Wnt/β-catenin-mediated proliferation is attenuated by TGFβ/Smad to ensure that proliferation ceases when the target number of interstitial cells has been reached in the neonatal medulla.


Utilization and costs of home-based and community-based care within a social HMO: trends over an 18-year period.
Our objective was to describe the utilization and costs of services from 1985 to 2002 of a Social Health Maintenance Organization (SHMO) demonstration project providing a benefit for home-based and community-based as well as short-term institutional (HCB) care at Kaiser Permanente Northwest (KPNW), serving the Portland, Oregon area. The HCB care benefit was offered by KPNW as a supplement to Medicare's acute care medical benefits, which KPNW provides in an HMO model. KPNW receives a monthly per capita payment from Medicare to provide medical benefits, and Medicare beneficiaries who choose to join pay a supplemental premium that covers prescription drugs, HCB care benefits, and other services. A HCB care benefit of up to 12,000 dollars per year in services was available to SHMO members meeting requirement for nursing home certification (NHC). We used aggregate data to track temporal changes in the period 1985 to 2002 on member eligibility, enrollment in HCB care plans, age, service utilization and co-payments. Trends in the overall costs and financing of the HCB care benefit were extracted from quarterly reports, management data, and finance data. During the time period, 14,815 members enrolled in the SHMO and membership averaged 4,531. The proportion of SHMO members aged 85 or older grew from 12 to 25%; proportion meeting requirements for NHC rose from 4 to 27%; and proportion with HCB care plans rose from 4 to 18%. Costs for the HCB care benefit rose from 21 dollars per SHMO member per month in 1985 to 95 dollars in 2002. The HCB care costs were equivalent to 12% to 16% of Medicare reimbursement. The HCB program costs were covered by member premiums (which rose from 49 dollars to 180 dollars) and co-payments from members with care plans. Over the 18-year period, spending shifted from nursing homes to a range of community services, e.g. personal care, homemaking, member reimbursement, lifeline, equipment, transportation, shift care, home nursing, adult day care, respite care, and dentures. Rising costs per month per SHMO member reflected increasing HCB eligibility rather than costs per member with HCB care, which actually fell from 6,164 dollars in 1989 to 4,328 dollars in 2002. Care management accounted for about one-quarter of community care costs since 1992. The Kaiser Permanente Northwest SHMO served an increasingly aged and disabled membership by reducing costs per HCB member care plan and shifting utilization to a broad range of community care services. Supported by a disability-based Medicare payment formula and by SHMO beneficiaries willing to pay increasing premiums, KPNW has been able to offer comprehensive community care. The model could be replicated by other HMOs with the support of favorable federal policies.


How do RNA binding proteins trigger liquid-liquid phase separation in human health and diseases?
RNA-binding proteins (RBPs) lie at the center of post-transcriptional regulation and protein synthesis, adding complexity to RNA life cycle. RBPs also participate in the formation of membrane-less organelles (MLOs) via undergoing liquid-liquid phase separation (LLPS), which underlies the formation of MLOs in eukaryotic cells. RBPs-triggered LLPS mainly relies on the interaction between their RNA recognition motifs (RRMs) and capped mRNA transcripts and the heterotypic multivalent interactions between their intrinsically disordered regions (IDRs) or prion-like domains (PLDs). In turn, the aggregations of RBPs are also dependent on the process of LLPS. RBPs-driven LLPS is involved in many intracellular processes (regulation of translation, mRNA storage and stabilization and cell signaling) and serves as the heart of cellular physiology and pathology. Thus, it is essential to comprehend the potential roles and investigate the internal mechanism of RPBs-triggered LLPS. In this review, we primarily expound on our current understanding of RBPs and they-triggered LLPS and summarize their physiological and pathological functions. Furthermore, we also summarize the potential roles of RBPs-triggered LLPS as novel therapeutic mechanism for human diseases. This review will help understand the mechanisms underlying LLPS and downstream regulation of RBPs and provide insights into the pathogenesis and therapy of complex diseases.


Nurse-led HIV services and quality of care at health facilities in Kenya, 2014-2016.
To develop a novel measure to characterize human immunodeficiency virus (HIV) programme quality at health facilities in Kenya and explore its associations with patient- and facility-level characteristics. We developed a composite indicator to measure quality of HIV care, comprising: assessment of eligibility for antiretroviral therapy (ART); initiation of ART; and retention on ART or in care, if ineligible for ART, for 12 months. We applied the comprehensive retention indicator to routinely collected clinical data from 13 331 patients enrolled in HIV care and treatment at 63 health facilities in the Eastern and Nyanza regions of Kenya from 1 January 2014 to 31 March 2016. We explored the association between facility- and patient-level characteristics and the primary outcome: appropriate staging and management of HIV, and retention in care over 12 months. Of the enrolled patients, 8404 (63%) achieved comprehensive retention 12 months after enrolment in care. In univariate analyses, patients at facilities where nurses delivered HIV treatment services (including eligibility assessment, initiation and follow up of ART) had significantly higher comprehensive retention rates at 12 months. In multivariate analyses, after adjusting for both facility- and patient-level characteristics, patients at facilities where nurses initiated ART had significantly higher comprehensive retention in care at 12 months (relative risk, RR: 1.22; 95% confidence interval, CI: 1.00-1.48). Nurse-led HIV services were significantly associated with quality of care, confirming the central role of nurses in the achievement of global health goals, and the need for further investment in nursing education, training and mentoring.


Current Status on 1,4-Dihydropyridine Derivatives against Human Pathogenic Parasites.
Infections provoked by parasites are among the most prevalent diseases worldwide and generate important health and socioeconomic problems. Despite the enormous amount of work done, the chemotherapy for most of them remains unsolved. Usually, treatments are based on no specific drugs associated, in several cases, with long-term treatments and severe side effects. In addition, drug resistance and different strains' susceptibility are further drawbacks of the existing chemotherapy. Considering that 1,4-dihydropyridines derivatives constitute an important class of compounds for new drug development, we present in this review an in-depth overview of the work done so far on 1,4-dihydropyridines and their antiparasitic activities. The development of new derivatives or the application of known drugs used for other diseases is described in terms of their potential usefulness for drug design.


Mesenchymal stem cells isolated from peripheral blood and umbilical cord Wharton's jelly.
Mesenchymal stem cells (MSCs) are a promising tool for regenerative medicine, but due to the heterogeneity of their populations, different sources and isolation techniques, the characteristics defining MSCs are inconsistent. The aim of this study was to compare the characteristics of MSCs derived from two different human tissues: peripheral blood (PB-MSCs) and umbilical cord Wharton's Jelly (UC-MSCs). The PB-MSC and UC-MSC were isolated by adherence to plastic after gradient-density separation or an explant culture method, respectively, and compared regarding their morphology, clonogenic efficiency, proliferating rates, immunophenotype and differentiation potential. MSCs derived from both sources exhibit similar morphology, proliferation capacity and multilineage (osteogenic, chondrogenic, adipogenic and myogenic) differentiation potential. Differences were observed in the clonogenic capacity and the immunophenotype, since UC-MSCs showed higher CFU-F (colony-forming units-fibroblastic) cloning efficiency, as well as higher embryonic markers (Na-nog, Sox2, SSEA4) expression. When additional surface antigens were analyzed by flow cytometry (CD44, CD90, CD105, CD33, CD34, CD45, CD11b, CD235a) or immunofluorescent labeling (vimentin, STRO-1 and alpha-smooth muscle actin), most appeared to have similar epitope profiles irrespective of MSC source. The results obtained demonstrated that both MSCs represent good alternative sources of adult MSCs that could be used in cell therapy applications.


The Effects of Experimental Sleep Fragmentation and Sleep Deprivation on the Response of the Genioglossus Muscle to Inspiratory Resistive Loads.
Poor upper airway dilator muscle function may contribute to obstructive sleep apnea (OSA). Sleep deprivation reduces dilator muscle responsiveness, but sleep fragmentation, which is most characteristic of OSA, has not been assessed. This study compared the effects of sleep deprivation and fragmentation on dilator muscle responsiveness during wakefulness. Twenty-four healthy individuals (10 female) participated in two consecutive overnight polysomnography (PSG) sessions. The first was an adaptation PSG of normal sleep. The second was an experimental PSG, where participants were allocated to groups of either normal sleep, no sleep, or fragmented sleep. Inspiratory resistive loading assessment occurred the morning following each PSG. Four 10 cmH2O and four 20 cmH2O loads were presented in random order for 60 seconds while participants were awake and supine. Sleep (electroencephalogram, electrooculogram, electromyogram [EMG]), intramuscular genioglossus activity (EMGGG), and ventilation were measured throughout the loading sessions. Five controls, seven sleep deprivation participants, and seven sleep fragmentation participants provided data. Contrary to expectations, neither EMGGG nor ventilation showed significant interaction effects (group × session × load) during resistive loading. There was a main effect of load, with peak EMGGG (mean % max ± standard error) significantly higher for the 20 cmH2O load (4.1 ± 0.6) than the 10 cmH2O load (3.3 ± 0.6) across both sessions and all groups. Similar results were observed for peak inspiratory flow, duty cycle, and mask pressure. Upper airway function was not affected by 1 night of no sleep or poor-quality sleep. This raises doubt as to whether fragmented sleep in OSA increases disorder severity via reduced upper airway dilator responses.


Central sensorimotor integration assessment reveals deficits in standing balance control in people with chronic mild traumatic brain injury.
Imbalance is common following mild Traumatic Brain Injury (mTBI) and can persist months after the initial injury. To determine if mTBI subjects with chronic imbalance differed from healthy age- and sex-matched controls (HCs) we used both the Central SensoriMotor Integration (CSMI) test, which evaluates sensory integration, time delay, and motor activation properties and the standard Sensory Organization Test (SOT). Four CSMI conditions evoked center-of-mass sway in response to: surface tilts with eyes closed (SS/EC), surface tilts with eyes open viewing a fixed visual surround (SS/EO), visual surround tilts with eyes open standing on a fixed surface (VS/EO), and combined surface and visual tilts with eyes open (SS+VS/EO). The mTBI participants relied significantly more on visual cues during the VS/EO condition compared to HCs but had similar reliance on combinations of vestibular, visual, and proprioceptive cues for balance during SS/EC, SS/EO, and SS+VS/EO conditions. The mTBI participants had significantly longer time delays across all conditions and significantly decreased motor activation relative to HCs across conditions that included surface-tilt stimuli with a sizeable subgroup having a prominent increase in time delay coupled with reduced motor activation while demonstrating no vestibular sensory weighting deficits. Decreased motor activation compensates for increased time delay to maintain stability of the balance system but has the adverse consequence that sensitivity to both internal (e.g., sensory noise) and external disturbances is increased. Consistent with this increased sensitivity, SOT results for mTBI subjects showed increased sway across all SOT conditions relative to HCs with about 45% of mTBI subjects classified as having an "Aphysiologic" pattern based on published criteria. Thus, CSMI results provided a plausible physiological explanation for the aphysiologic SOT pattern. Overall results suggest that rehabilitation that focuses solely on sensory systems may be incomplete and may benefit from therapy aimed at enhancing rapid and vigorous responses to balance perturbations.


Scylla and Charybdis: The MCAT, USMLE, and Degrees of Freedom in Undergraduate Medical Education.
In recent years, medical educators have been making meaningful attempts to rethink how premedical students are prepared for medical school, and how medical students are prepared for residency. Among the many challenges to redesigning premedical and medical school curricula, one that stands out is the constraint imposed by our current methods of assessing aptitude, particularly our use of the Medical College Admissions Test (MCAT) and the United States Medical Licensing Examination (USMLE). For much of the past century, medical school and residency admissions committees have relied heavily on MCAT and USMLE scores to evaluate and rank candidates to their programs. These high-stakes exams determine to a large extent what is taught, and what is stressed, in preparation for and during medical school-despite the fact that scores have limited ability to predict future success in clinical medicine or biomedical research. Additionally, evidence indicates that students from disadvantaged and minority backgrounds do not fare as well on these exams and, as a result, may be disproportionately excluded from the medical profession. While medical school admissions committees have made limited incremental gains in holistic review, residency programs appear to be increasingly focused on USMLE Step scores and veering away from the spirit of holistic review. The authors propose that substantive change will remain slow in coming unless members of the medical education community radically rethink how we report scores from these exams, and how we use them in our selection of future medical students and residents.


Optimizing the Use of Linaclotide in Patients with Constipation-Predominant Irritable Bowel Syndrome: An Expert Consensus Report.
Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic or recurrent abdominal pain in association with defecation or a change in bowel habits. A predominant disorder of bowel habits, IBS is classified into three main subtypes: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M). Linaclotide is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GC-CA) that is licensed for the symptomatic treatment of moderate-to-severe IBS-C in adults. This review aims to facilitate and optimize clinical practices, establishing common guidelines to monitor patients with IBS-C that are treated with linaclotide. A group of experts in functional digestive disorders was convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with IBS-C. A search was performed for English, French and Spanish language articles in PubMed. On the basis of the articles identified, an initial document was drafted addressing different issues frequently raised by general practitioners and GI specialists that are related to the prescription, efficacy and safety of linaclotide. This document was then reviewed and modified by the expert panel until a final text was agreed upon and validated. Based on the evidence, the panel addressed the following recommendations: (1) Linaclotide is indicated for the treatment of moderate to severe IBS-C in adults; (2) it is recommended that patients take linaclotide continuously and not sporadically; (3) patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect; (4) the absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time. This document seeks to lay down a set of recommendations and to identify key issues that may be useful for the clinical management of IBS-C patients treated with linaclotide.


[The determination of phoxim in cadaveric material by gas-liquid chromatography].
The developed gas-liquid chromatographic procedure for forensic chemical detection and measurement of phoxim in cadaveric material permits the detection in 25 g of an organ of 44 to 52% of added phoxim. The threshold of phoxim measurement in 100 g of the liver is 0.04 mg, the least volume of phoxim detectable being 0.02 g. The developed gas-liquid chromatographic technique should be used as an additional method together with thin-layer chromatography, for a more objective evaluation of the results of forensic chemical analysis of cadaveric material for phoxim.


Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study.
To investigate the protective effect of NSAIDs and aspirin separately on cognitive decline in elderly subjects, controlling for consistent use of these agents over a prolonged period of time. The study sample consisted of 1007 subjects, drawn from a population-based random sample of elderly individuals, 62-85 years old, who participated in a 3-year follow-up study. From this sample subjects were selected, who did use NSAIDs and completed all cognitive tests at both measurements (n=137), and subjects who did not use NSAIDs and completed all cognitive tests (n=475). Cognitive tests included the Mini-Mental State Examination (MMSE), tests for episodic memory (Auditory Verbal Learning Test) and information processing speed (coding task). Cognitive decline was computed using Edwards-Nunnally method. Multiple logistic regression analyses were performed to examine the association between NSAID (with and without aspirin) and decline in cognitive performance. Besides, the interaction of NSAIDs with age on cognitive decline was determined. The relative risk estimates of decline in episodic memory (immediate recall) adjusted for age, gender, education, baseline MMSE, vascular diseases, diabetes mellitus and (rheumatoid) arthritis for aspirin users only was more than three times reduced (OR: 0.30, 95% CI: 0.09-0.82). The odds ratio for decline in memory of NSAID use without aspirin, adjusted for age, gender, education, baseline MMSE, vascular diseases, diabetes mellitus and (rheumatoid) arthritis was not significant (OR: 1.00, 95% CI: 0.39-2.93). The effect of aspirin was significant only in persons of 75 years and over (OR: 0.10, 95% CI: 0.01-0.81), not in subjects younger than 75 years (OR: 0.52, 95% CI: 0.14-1.96). NSAIDs did not have benefit on information processing speed. In 92% of aspirin users a low dose of 100mg daily or less was used. Low-dose aspirin might be protective for decline in memory in individuals of 75 years and over. The benefit of a low-dose aspirin does not support an anti-inflammatory effect, but suggests an antiplatelet effect. Therefore, a possible protective effect of low-dose aspirin on cognitive decline is likely only in subjects with aspirin use over a prolonged period of time.


A comparative radiological assessment of five European biosphere systems in the context of potential contamination of well water from the hypothetical disposal of radioactive waste.
In the framework of the BioMoSA project for the development of biosphere assessment models for radioactive waste disposal the Reference Biosphere Methodology developed in the IAEA programme BIOMASS was applied to five locations, situated in different European countries. Specific biosphere models were applied to assess the hypothetical contamination of a range of agricultural and environmental pathways and the dose to individuals, following contamination of well water. The results of these site-specific models developed by the different BioMoSA partners, and the individual normalised dose to the exposure groups were compared against each other. Ingestion of drinking water, fruit and vegetables were found to be among the most important pathways for almost all radionuclides. Stochastic calculations revealed that consumption habits, transfer factors, irrigation rates and distribution coefficients (Kd(s)) were the most important parameters that influence the end results. Variations in the confidence intervals were found to be higher for sorbing elements (e.g. (36)Cl, (237)Np, (99)Tc, (238)U, (129)I) than for mobile elements (e.g. (226)Ra, (79)Se, (135)Cs, (231)Pa, (239)Pu). The influence of daughter products, for which the distribution into the biosphere was calculated individually, was also shown to be important. This paper gives a brief overview of the deterministic and stochastic modelling results and the parameter sensitivity. A screening methodology was introduced to identify the most important pathways, simplify a generic biosphere tool and refine the existing models.


A closer look at the spectroscopic properties of possible reaction intermediates in wild-type and mutant (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase.
(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH or LytB) catalyzes the terminal step of the MEP/DOXP pathway where it converts (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) into the two products, isopentenyl diphosphate and dimethylallyl diphosphate. The reaction involves the reductive elimination of the C4 hydroxyl group, using a total of two electrons. Here we show that the active form of IspH contains a [4Fe-4S] cluster and not the [3Fe-4S] form. Our studies show that the cluster is the direct electron source for the reaction and that a reaction intermediate is bound directly to the cluster. This active form has been trapped in a state, dubbed FeS(A), that was detected by electron paramagnetic resonance (EPR) spectroscopy when one-electron-reduced IspH was incubated with HMBPP. In addition, three mutants of IspH have been prepared and studied, His42, His124, and Glu126 (Aquifex aeolicus numbering), with particular attention paid to the effects on the cluster properties and possible reaction intermediates. None of the mutants significantly affected the properties of the [4Fe-4S](+) cluster, but different effects were observed when one-electron-reduced forms were incubated with HMBPP. Replacing His42 led to an increased K(M) value and a much lower catalytic efficiency, confirming the role of this residue in substrate binding. Replacing the His124 also resulted in a lower catalytic efficiency. In this case, however, the enzyme showed the loss of the [4Fe-4S](+) EPR signal upon addition of HMBPP without the subsequent formation of the FeS(A) signal. Instead, a radical-type signal was observed in some of the samples, indicating that this residue plays a role in the correct positioning of the substrate. The incorrect orientation in the mutant leads to the formation of substrate-based radicals instead of the cluster-bound intermediate complex FeS(A). Replacing the Glu126 also resulted in a lower catalytic efficiency, with yet a third type of EPR signal being detected upon incubation with HMBPP. (31)P and (2)H ENDOR measurements of the FeS(A) species incubated with regular and (2)H-C4-labeled HMBPP reveal that the substrate binds to the enzyme in the proximity of the active-site cluster with C4 adjacent to the site of linkage between the FeS cluster and HMBPP. Comparison of the spectroscopic properties of this intermediate to those of intermediates detected in (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase and ferredoxin:thioredoxin reductase suggests that HMBPP binds to the FeS cluster via its hydroxyl group instead of a side-on binding as previously proposed for the species detected in the inactive Glu126 variant. Consequences for the IspH reaction mechanism are discussed.


Uptake of beta-carotene by ovarian and uterine tissues and effects on steroidogenesis during the estrous cycle in cats.
To determine uptake of beta-carotene by ovarian and uterine tissues and influence of dietary beta-carotene on steroidogenesis and production of uterine protein during the estrous cycle in cats. 56 female cats. Cats were fed diets containing 0, 0.4, 2, or 10 mg of beta-carotene daily for 8 weeks prior to detection of estrus. At time of observed estrus, all cats were manually induced to ovulate. Blood samples were obtained at estrus and every 2 days until day 14 after ovulation. On that day, cats underment laparotomy, and the ovaries and uterus were removed. Uterine contents were flushed, and luteal and endometrial tissues were obtained. Concentrations of beta-carotene in plasma and luteal and endometrial tissues increased in a dose-dependent manner. Concentrations of plasma progesterone were higher between days 6 and 10 after ovulation in cats fed diets containing beta-carotene and continued to increase through day 14 after ovulation in cats fed a diet containing 10 mg of beta-carotene. Plasma concentration of estradiol-17beta also was higher between days 0 and 4 after ovulation in cats fed diets containing beta-carotene. Cats fed a diet containing 10 mg of beta-carotene had the highest plasma estradiol concentration. Total uterine protein concentration was higher in cats fed beta-carotene, compared with values for cats fed an unsupplemented diet. Cats readily absorb beta-carotene. Increased concentrations of progesterone, estradiol, and uterine protein may provide more optimal ovarian function or a better uterine environment for embryonic survival and development.


Collecting Social Media Information in a Substance Use Intervention Trial With Adolescent Girls With Lifetime Substance Use History: Observational Study.
Adolescents with juvenile legal system contact face numerous barriers to participation in behavioral health intervention research, including housing disruption, legal privacy concerns, and systems mistrust. Technology, such as social media, may be a novel and developmentally appropriate adolescent research study engagement and retention tool. We examined data on social media information collected for study retention purposes from adolescents participating in a substance use intervention trial. Data were collected as part of a randomized controlled trial determining efficacy of a group-based substance use intervention for girls and young women (12-24 years) with substance use histories referred from legal and school systems in the United States. Baseline demographic and social media information was analyzed from the subset of 114 adolescent girls (mean age 15.7 years; range 13-18 years), of whom 31.6% (36/114) were legally involved, 87.7% (100/114) belonged to minoritized racial/ethnic groups, and 32.5% (37/114) received public assistance. Most girls (74/114, 64.9%) provided at least one social media account (Instagram, 95% [70/74]; Facebook, 27% [20/74]; and Twitter, 11% [8/74]) during study enrollment. Legally involved girls were significantly less likely to provide social media information than school-referred girls (44% [16/36] versus 74% [58/78]; χ21 [N=114]=9.68, P=.002). Obtaining social media information for study retention purposes from adolescent girls with lifetime substance use appears possible; however, particular subgroups (ie, legally involved girls) may be less likely to provide accounts. Factors shaping legally involved girls' willingness to provide social media information, including mistrust and privacy concerns, and the impact of researcher's access to social media information on study retention are critical directions for future research. ClinicalTrials.gov NCT02293057; https://clinicaltrials.gov/ct2/show/NCT02293057.


Fecal hydroxysteroid dehydrogenase activities in vegetarian Seventh-Day Adventists, control subjects, and bowel cancer patients.
Cell-free extracts were prepared from mixed fecal anaerobic bacteria grown from stools of 14 vegetarian Seventh-Day Adventists, 16 omnivorous control subjects, and eight patients recently diagnosed with cancer of the large bowel. Preparations were assayed for NAD- and NADP-dependent 3alpha-, 7alpha- and 12alpha-hydroxysteroid dehydrogenases with bile salts and androsterone as substrates (eight substrate-cofactor combinations were tested). A significant intergroup difference was observed in the amounts of NAD- and NADP-dependent 7alpha-hydroxysteroid dehydrogenase produced: bowel cancer patients exceeded controls, and controls exceeded Seventh-Day Adventists. Other enzyme activity comparisons were not significant. The pH values of the stools were significantly higher in cancer patients compared to Seventh-Day Adventists; values were 7.03 +/- 0.60 and 6.46 +/- 0.58 respectively. The pH value for controls was 6.66 +/- 0.62. A plot of pH value versus NADP-dependent 7alpha-hydroxysteroid dehydrogenase tended to separate the cancer patients from the other groups. Comparative data suggest that much of the 3alpha-hydroxysteroid dehydrogenase active against bile salt is also active against androsterone.


[Breaking bad news].
Breaking bad news is one of the most stressful duties of the physician in oncology. Among other issues, it includes discussion of cancer diagnosis or the failure of therapy. The oncologist is often puzzled by an apprehension regarding the delivery of bad news. The fear to be exposed to unexpected strong emotional reactions by the patient, such as aggression or despair, may cause the oncologist to adopt unproductive coping strategies such as discussion about technical details while avoiding to deliver the main message. However, good communication skills are the key for a satisfying conversation with the patient. The oncologists' discomfort induced by the above mentioned apprehension is one of the most important barriers for a successful conversation.


Factors Affecting Patient Portal Use Among Low-Income Pregnant Women: Mixed-Methods Pilot Study.
Patient portals offer patients personalized and secure Web access to their medical information and enable patients to manage their health care online. However, there is a lack of information about patient acceptance and use of patient portals among low-income pregnant women. This formative research aims to assess the potential of a patient portal, MyChart, for improving prenatal health care and pregnancy outcomes, and identify the barriers and facilitators of MyChart use among low-income pregnant women. A mixed-methods study was conducted with a convenience sample of 18 low-income pregnant women comprising low- and high-risk patients enrolled in a prenatal clinic in eastern North Carolina. MyChart use, patient demographics, and pregnancy information were collected by reviewing electronic medical charts. Health literacy was measured. Reported use and attitudes toward MyChart were collected using a semi-structured interview. Although 39% (7/18) of participants interviewed signed up for MyChart, only 22% (4/18) of them became active users. Another 33% (6/18) had never heard of MyChart or was unsure of how to access it. Users primarily accessed test results and appointment schedules. The main facilitating factors for patient portal use were information and motivation from health care providers and concerns about pregnancy due to a history of miscarriage. Reported barriers were lack of educational resources, lack of care provider encouragement, and technical difficulties possibly exacerbated by low health literacy. Participants also suggested improvements for MyChart, especially the provision of discussion-based support for pregnant women. The one-time verbal introduction of MyChart does not meet current patients' needs. Data reveal the need for more consistent patient education and support programs, tailored to patients' previous pregnancy histories. The clinic also needs to facilitate better provider-patient communication about the importance of MyChart use.


Presence of a Human Diarrheagenic Escherichia coli Clone in Captivity Kept Psittacidaes.
Bacterial cultures of cloaca swabs from 86 captivity kept psittacidaes revealed 17 Escherichia coli bearing birds sharing strains which, on the basis of enterobacterial repetitive intergenic consensus (ERIC) PCR analysis, proved to be genetically similar. Further, triplex PCR specific for the genetic markers chuA, yjaA, and TSPE4.C2 was used to assign the strains to the E. coli reference collection (EcoR) B2 group. One strain of each, from the enteropathogenic (EPEC), enteroaggregative (EAEC) and Shiga toxin (STEC) E. coli pathovars were found among these isolates.


Vomeronasal organ: pheromone recognition with a twist.
Pheromones are detected by the vomeronasal organ using members of two receptor superfamilies: the V1Rs and V2Rs. New studies show that MHC class I molecules are co-expressed in particular combinations with specific V2Rs in the vomeronasal organ. The role of these MHC molecules is unknown, but they may be of considerable biological significance.


Investigation of artifacts in retinal and choroidal OCT angiography with a contrast agent.
Optical coherence tomography angiography (OCTA) has recently emerged for imaging vasculature in clinical ophthalmology. Yet, OCTA images contain artifacts that remain challenging to interpret. To help explain these artifacts, we perform contrast-enhanced OCTA with a custom-designed wide-field ophthalmoscope in rats in vivo. We choose an intravascular contrast agent (Intralipid) with particles that are more isotropically scattering and more symmetrically shaped than red blood cells (RBCs). Then, by examining how OCTA artifacts change after contrast agent injection, we attribute OCTA artifacts to RBC-specific properties. In this work, we investigate retinal and choroidal OCTA in rats with or without melanosomes, both before and after contrast agent injection, at a wavelength at which scattering dominates the image contrast (1300 nm). First, baseline images suggest that high backscattering of choroidal melanosomes accounts for the relatively dark appearance of choroidal vessel lumens in OCTA. Second, Intralipid injection tends to eliminate the hourglass pattern artifact in OCTA images of vessel lumens and highlights vertical capillaries that were previously faint in OCTA, showing that RBC orientation is important in determining OCTA signal. Third, Intralipid injection increases lumen signal without significantly affecting the tails, suggesting that projection artifacts, or tails, are due to RBC multiple scattering. Fourth, Intralipid injection increases the side-to-top signal ratio less in choroidal vessel lumens of pigmented rats, suggesting that melanosome multiple scattering makes the hourglass artifact less prominent. This study provides the first direct experimental in vivo evidence to explain light scattering-related artifacts in OCTA.


Ephrin Receptor A4 is a New Kaposi's Sarcoma-Associated Herpesvirus Virus Entry Receptor.
Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi's sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular receptors. In the current studies, we have found that EphA4 promotes KSHV glycoprotein H/glycoprotein L (gH/gL)-mediated fusion and infection better than does ephrin A2 (EphA2) in HEK293T cells, indicating that EphA4 is a new KSHV entry receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA sequencing (RNA-seq) data analysis of existing data sets. We found that these cell types broadly express both EphA2 and EphA4, with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single- and double-knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2-EphA4 double-knockout cells had the greatest decrease in fusion activity and infection compared to single-knockout cells. Fusion and infection of KSHV were rescued in the EphA2-EphA4 double-knockout cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both Epstein-Barr virus (EBV) and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry receptor for KSHV.IMPORTANCE The overall entry mechanism for herpesviruses is not completely known, including those for the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional receptors need to be identified. In the current study, we found that EphA4 can also function for a KSHV entry receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry receptor for EBV, whereas EphA2 does. The discovery of EphA4 as a KSHV entry receptor has important implications for KSHV pathogenesis in humans, may prove useful in understanding the unique pathogenesis of KSHV infection in humans, and may uncover new potential targets that can be used for the development of novel interventional strategies.


Brucellosis--an under-estimated cause of arthralgia & muscular pains in general population.
Muscular pains, arthralgias and arthritis are among the most common symptoms of the patients attending various OPDs and private clinics every day. While the symptoms could be due to a broad spectrum of the illnesses; the infection with Brucella, often overlooked, is one among such causes. The objective of present study is to determine the extent to which this infection contributes towards the presence of such symptoms, and how important it is to rule out this treatable cause in our society, before labelling and treating these as non-specific aches and pains. This prospective study was conducted on 280 patients at a registered medical specialist clinic between May 2006 and June 2008. The patients of each gender from age 15 years onwards having the symptoms of chronic muscular pains, backache, and arthralgias etc. were included in the study. The exclusion criteria were clear cut bone and joint diseases, connective tissue and systemic disorders. The patients were subjected to evaluation by history taking that especially looked into their involvement with cattle look-after and also the use of milk and other dairy items. The investigations included agglutination test for Brucella. The positive cases were treated and the results followed for satisfactory or mild responses. Out of 280 cases 55 (19.64%) were suffering from infection with Brucella. The above patients had received non-specific treatment with analgesics or even steroids with no benefit. The young females outnumbered males, and rural cases had more incidence than urban; and there was a slight increase in those cases who handled the cattle at home as compared to those who did not. In absence of a good veterinary care of live stock in societies like that of Pakistan, it becomes important to rule out Brucellosis, before labelling the symptoms of a patient as simple, non specific aches and pains; and therefore depriving the patient of a treatable disease if he had one.


Case-Control Study of Rotavirus Vaccine Effectiveness Compared to Test-Negative Controls or Hospital Controls.
Selection of test-negative controls takes less time and costs less than traditional control selection for evaluating vaccine effectiveness (VE). Here, rotavirus VE was evaluated using hospital controls and compared with test-negative controls to determine whether using the latter can substitute for the former. We recorded gastroenteritis in children from 2 months to 2 years of age at six medical facilities in Saga City between January 4th and May 31st, 2014. Stools from all identified acute gastroenteritis patients were tested for rotavirus using immunochromatography. Rotavirus gastroenteritis (RVGE) cases had test-positive stool, whereas test-negative controls had gastroenteritis but no rotavirus infection; hospital controls were outpatients visiting the same facility for indications other than gastroenteritis. Vaccination status was verified by inspecting maternal and child health records, and demographic data were obtained from a questionnaire completed by the patients' guardians or from the medical records. Unconditional logistic regression analysis was used to adjust for possible confounding factors. Sixty-four RVGE cases, 260 test-negative controls, and 589 hospital controls were enrolled. The characteristics of the two control groups, including RV vaccination history, were similar. The RVGE cases were more likely to have used daycare services than children from either of the two control groups. The VE against RVGE estimated using hospital controls was 86.6% (95% confidence interval [CI], 55.9-96.0%), very similar to the VE using test-negative controls (84.9% [95% CI, 49.6-95.5%]). The estimated VE using test-negative controls and hospital controls is similar. Therefore, test-negative controls are considered appropriate for establishing VE.


SYD-1C, UNC-40 (DCC) and SAX-3 (Robo) function interdependently to promote axon guidance by regulating the MIG-2 GTPase.
During development, axons must integrate directional information encoded by multiple guidance cues and their receptors. Axon guidance receptors, such as UNC-40 (DCC) and SAX-3 (Robo), can function individually or combinatorially with other guidance receptors to regulate downstream effectors. However, little is known about the molecular mechanisms that mediate combinatorial guidance receptor signaling. Here, we show that UNC-40, SAX-3 and the SYD-1 RhoGAP-like protein function interdependently to regulate the MIG-2 (Rac) GTPase in the HSN axon of C. elegans. We find that SYD-1 mediates an UNC-6 (netrin) independent UNC-40 activity to promote ventral axon guidance. Genetic analysis suggests that SYD-1 function in axon guidance requires both UNC-40 and SAX-3 activity. Moreover, the cytoplasmic domains of UNC-40 and SAX-3 bind to SYD-1 and SYD-1 binds to and negatively regulates the MIG-2 (Rac) GTPase. We also find that the function of SYD-1 in axon guidance is mediated by its phylogenetically conserved C isoform, indicating that the role of SYD-1 in guidance is distinct from its previously described roles in synaptogenesis and axonal specification. Our observations reveal a molecular mechanism that can allow two guidance receptors to function interdependently to regulate a common downstream effector, providing a potential means for the integration of guidance signals.


Is prosocial behaviour a missing link between green space quality and child health-related outcomes?
This study aimed to investigate prosocial behaviour-those behaviours that benefit others or enhance relationships with others-as a mediator of the associations between green space quality and child health-related outcomes (physical activity, mental health, and health-related quality of life (HRQOL)). This study involved data from 4983 children with 10-year follow-up (2004-2014) retrieved from the Longitudinal Study of Australian Children. Green space quality (the exposure), prosocial behaviour (the candidate mediator), and child health-related outcomes were assessed biennially based on caregiver reports. Causal mediation analysis was used, with four mediation models developed for each outcome. Mediation by prosocial behaviour appeared in the late childhood mediation model with higher mediation proportions reported compared to models of earlier and middle childhood. Prosocial behaviour had moderate mediation consistency for the association between green space quality and physical activity enjoyment, but no mediation was evident for other physical activity variables. Prosocial behaviour had low mediation consistency for child mental health (internalising and externalising subscales). Similarly, low mediation consistency of prosocial behaviour was also evident for all HRQOL variables, such as physical, emotional, social, school functioning, psychosocial health, and total quality of life (QOL). Prosocial behaviour partially mediated the association between green space quality and child health-related outcomes (physical activity enjoyment, mental health, and HRQOL). Improving the quality of neighbourhood green space that supports the development of prosocial behaviour may result in better child health-related outcomes. Other physical activity variables might not specifically relate to social interactions, and therefore, no mediation by prosocial behaviour was apparent.


[Applying Collière's theoretical-philosophical ideas to consider new care technologies in obstetric nursing].
Approaching nursing from the perspective of a feminine practice, this article aimed at identifying the possibility to apply Collière's ideas on obstetric nursing care, relating them to the nurse's background. A descriptive method and the technique of content analysis was used to analyze scientific communications, focusing on social, theoretical-philosophical, political, and ideological aspects related to women's health, care technologies and human care in obstetric nursing. Results indicated the following analytical categories: nursing as profession; practice of care: from women to nurses; care provided by women: a sacred or challenged survival practice; identification of care practices with the nurse as an emancipated, citizen, and autonomous woman. We concluded that nurses working in obstetrics need to reconstruct their professional, individual, and social role. We suggest a reflexive critic on the appropriateness and validity of care technological innovations to provide quality women health care.


Global Survey of the Roles, Satisfaction, and Barriers of Home Health Care Nurses on the Provision of Palliative Care.
Background: The World Health Assembly urges members to build palliative care (PC) capacity as an ethical imperative. Nurses provide PC services in a variety of settings, including the home and may be the only health care professional able to access some disparate populations. Identifying current nursing services, resources, and satisfaction and barriers to nursing practice are essential to build global PC capacity. Objective: To globally examine home health care nurses' practice, satisfaction, and barriers, regarding existing palliative home care provision. Design: Needs assessment survey. Setting/Subjects: Five hundred thirty-two home health care nurses in 29 countries. Measurements: A needs assessment, developed through literature review and cognitive interviewing. Results: Nurses from developing countries performed more duties compared with those from high-income countries, suggesting a lack of resources in developing countries. Significant barriers to providing home care exist: personnel shortages, lack of funding and policies, poor access to end-of-life or hospice services, and decreased community awareness of services provided. Respondents identified lack of time, funding, and coverages as primary educational barriers. In-person local meetings and online courses were suggested as strategies to promote learning. Conclusions: It is imperative that home health care nurses have adequate resources to build PC capacity globally, which is so desperately needed. Nurses must be up to date on current evidence and practice within an evidence-based PC framework. Health care policy to increase necessary resources and the development of a multifaceted intervention to facilitate education about PC is indicated to build global capacity.


[Analysis of possible mechanisms of regulation of root branching].
The formation of lateral roots under the influence of growth inhibitors and phytohormons were studied with germs of corn and flax. All corn primordiums develop into the lateral roots without dormancy period, while some flax primordiums are delayed in development. Removal of root apical meristem (decapitation) does not result in the increase in number of lateral roots of corn germs. Decapitation of flax germs induces the development of some dormant primordiums, that leads to the considerable increase in number of lateral roots. Formation of additional primordium under decapitation does not take place. Auxin stimulates the formation of additional primordiums in flax, but does not effect the number of mature lateral roots. In corn germs synthetic auxin stimulates the development of additional primordiums in root zone, where primordiums are forming after the disturbance. It is shown that the time of primordium development does not change under inhibitor influence, if they do not selectively effect mitoses. It seems that auxins regulate initiation of pericycle division and formation of primordiums of lateral roots on the stage of development of meristematic protuberance. Cytokinins influence the development of already existed primordiums of lateral roots but do not effect the formation of new ones. Constancy of time of primordium formation and independence of their development on the state of the main root need future investigations. The authors suppose that regulation of these processes is non-hormonal.


Local-Level Immigration Enforcement and Risk of Pediatric Hospitalization for Ambulatory Care Sensitive Conditions.
Immigration enforcement may disrupt access to health care, potentially increasing hospitalizations for Ambulatory Care Sensitive Conditions (ACSC). We aimed to assess the effect of local-level 287(g) immigration enforcement on North Carolina pediatric ACSC hospitalizations. Pediatric (< 19 year) ACSC hospitalizations were identified based on ICD-9 codes. We compared ACSC hospitalizations pre and post 287(g) implementation using a difference-in-difference analysis of Fiscal Year (FY)2006-2009 data. We used multi-level models to assess the effects of 287(g) programs on ACSC hospitalizations during FY2011-2015. Difference-in-difference analyses showed that ACSC hospitalizations increased by more than 2.48% in the year following 287(g) implementation (95% CI: 0.99%, 3.97%). Among the counties that had ever implemented a 287(g) program, the ACSC-increasing effect of an active 287(g) program was greatest in counties with a shorter tenure of their 287(g) program and for Hispanic/Latino children/adolescents. Our findings underscore the importance of describing the effects of local-level immigration enforcement on pediatric access to care and potentially avoidable hospitalizations.


State-wide cost recovery for health science audiovisual loan service in Connecticut.
The University of Connecticut Health Center Library has established a successful state-wide cost recovery audiovisual loan service for nurses. Limiting formats to those compatible with the audiovisual playback equipment at the source library and federal support for collection development helped the program to succeed. Connecticut nurses used the service both during the grant period and when a fee-for-service replaced the federal subsidy. The library's collection is now accessed by institutions without libraries.


Thymic necrosis following oral inoculation of mouse thymic virus.
Mouse thymic virus (MTLV;ICTV designation murid herpesvirus 3) infects developing T lymphocytes of neonatal mice, causing thymic necrosis and acute immunosuppression. Infected animals shed virus indefinitely. However, although transmission in nature is presumably by contact and is likely to involve the oral-nasal route, virtually all experimental studies with MTLV have used systemic (intraperitoneal) inoculation. In order to determine whether systemic inoculation causes artifacts in pathogenesis of the infection, effects of intraperitoneal and oral-nasal inoculation were compared in newborn mice. Thymic necrosis occurred with either route of inoculation, although rate of infection was lower with oral inoculation, varying from about 20% to 67%. There were no gross differences in pathogenesis. Orally infected animals seroconverted and shed virus. These data indicate that the apparent lymphotropism of thymic virus, and induction of thymic necrosis, are not dependent on route of inoculation.


Pharmacological therapy of lupus nephritis.
Kidney involvement is common in systemic lupus erythematosus, occurring in up to 60% of affected adults during the course of their disease. Diffuse proliferative lupus nephritis (World Health Organization class IV), the most ominous variant, has traditionally been treated with cyclophosphamide and glucocorticoids. With cyclophosphamide, women of childbearing potential must weigh the risks of sustained amenorrhea, infertility, increased susceptibility to infection, bone marrow suppression, hemorrhagic cystitis, and malignancy against the benefits of better disease control compared with glucocorticoids alone. Because of the host of adverse effects associated with cyclophosphamide, alternative approaches to the treatment of lupus nephritis are desirable. A 31-year-old woman developed class IV lupus nephritis in the postpartum period. Seeking to preserve fertility and avoid other known toxicities of cyclophosphamide, she chose to undergo therapy with mycophenolate mofetil. In the treatment of severe lupus nephritis, mycophenolate mofetil has emerged as an alternative to cyclophosphamide, offering a major advance in the therapy of lupus nephritis.


Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication.
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replication were required to elicit significant alterations. Thus, the ability of 1C8 to alter the SRSF10-dependent splicing of HIV-1 transcripts, with minor effects on cellular splicing, supports the view that SRSF10 may be used as a target for the development of new anti-viral agents.


A Case Series of Thromboelastography-Guided Anticoagulation in COVID-19 Patients with Inherited and Acquired Hypercoagulable States.
One of the complications of the novel coronavirus disease 2019 (COVID-19) is hypercoagulability. For this reason, patients presenting with COVID-19 are often put on therapeutic or intermediate anticoagulation upon hospitalization. A common issue of this anticoagulation is the progression to hypocoagulability resulting in hemorrhage. Therefore, monitoring the hemostatic integrity of critically ill COVID-19 patients is of utmost importance. In this case series, we present the cases of three coagulopathic COVID-19 patients whose anticoagulation was guided by thromboelastography (TEG). In each case, TEG permitted the clinical team to simultaneously prevent thrombotic and hemorrhagic events, a difficult task for COVID-19 patients admitted to the intensive care unit. The first two cases illustrate the utility of TEG to guide anticoagulant dosing for COVID-19 patients when the activated partial thromboplastin time (aPTT) is inaccurate. The first case was a severely ill COVID-19 patient with end-stage renal disease and a falsely elevated aPTT secondary to hypertriglyceridemia. The second case was a severely ill COVID-19 patient with chronic pulmonary disease who demonstrated a falsely elevated aPTT due to polycythemia and hemoconcentration. In both cases, TEG was sensitive to the hypercoagulability caused by the metabolic derangements which enabled the goal-directed titration of anticoagulants. The last case depicts a severely ill COVID-19 patient with an inherited factor V Leiden mutation who required abnormally high dosing to achieve therapeutic anticoagulation, guided by TEG. Hypercoagulopathic COVID-19 patients are difficult to anticoagulate without development of hypocoagulopathy. Treatment of these patients demands goal-directed therapy by diligent laboratory monitoring. This can be accomplished by the use of TEG coupled with aPTT to guide anticoagulation. This case series illustrates the necessity for active hemostatic monitoring of critically ill COVID-19 patients.


On the glottal activity of experimental hiccup.
In cats, rats and rabbits under light barbiturate anesthesia, glottal activity during spontaneous or evoked hiccups was studied. By measuring laryngeal pressure or resistance to flow to a constant current of air, and controlling several sources of error, it was found that glottal closure is an important component of this complex phenomenon. Adductor activity of the vocal cords seemed more labile to the anesthetic action and, under this condition, showed a weaker force of contraction than the abductor one. It is suggested that this can be due to the correlation of glottal adduction with expiratory premotoneurons that are more depressed by anesthesia than the inspiratory ones. In hiccup, both adductor and abductor muscles would act simultaneously but in different proportions. The results add evidence to the idea of considering hiccup as due to a specific complex mechanism integrated at specific networks of the breathing generator.


Selective management of hepatic venous outflow obstruction.
To describe the outcome of selective management of hepatic venous outflow obstruction (HVOO), based on its presentation and liver function, we reviewed the records of 49 consecutive patients managed at our institution between 1984 and 1993. Twenty-six patients were managed surgically, 12 nonsurgically, and 11 were not treated. Portosystemic shunts (PSS) were performed in 18 patients (patency 83%). Two patients (11%) died postoperatively, 11 (61%) did well (mean follow-up 6.4 years), three (17%) required subsequent orthotopic liver transplantation, and two (11%) died of late liver failure. PSS remained patent if the preoperative pressure gradient between the portal vein and the infrahepatic inferior vena cava was greater than 10 mm Hg and across the intrahepatic inferior vena cava 18 mm Hg or less. All six orthotopic liver transplantations (three as primary treatment and three after failed PSS) were successful (mean follow-up 4.8 years). Five patients underwent other procedures. Nine (75%) of the 12 nonsurgically treated patients did well (mean follow-up 3.8 years). The most important predictor of successful outcome after PSS or medical management was the degree of liver function. All 11 untreated patients died either of end-stage liver failure (n = 7; 63%) or of severe comorbid disease (n = 4; 37%). In patients with preserved liver function, medical management of HVOO can be successful early in the course of the disease; a late presentation necessitates PSS. Orthotopic liver transplantation should be employed in patients with liver failure and may decrease the high mortality rate of HVOO.


Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion.
Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear, whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) with measuring tonic levels of striatal DA. Nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, but a change in the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxydopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after dosing with 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we saw an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.


Associations Between Nurse-Guided Variables and Plasma Oxytocin Trajectories in Premature Infants During Initial Hospitalization.
Oxytocin (OT) is a social hormone that may help researchers understand how nurse-guided interventions during initial infant hospitalization, such as supporting human milk expression, promoting comforting touch, and reducing exposure to stressors, affect preterm brain development. To determine whether factors related to human milk, touch, or stressor exposure are related to plasma OT trajectories in premature infants. Plasma from 33 premature infants, born gestational ages 25 to (Equation is included in full-text article.)weeks, was collected at 14 days of life and then weekly until 34 weeks' corrected gestational age (CGA). Variables related to feeding volumes of human milk and formula; touch, as indexed by skin-to-skin contact (SSC) and swaddled holding; and clinical stressors were extracted from the electronic medical record. Linear mixed-models tested associations between nurse-guided variables and plasma OT trajectories. In the final model, same-day SSC was positively related not only to plasma OT levels at 27 weeks' CGA (β= .938, P = .002) but also to a decline in plasma OT levels over time (β=-.177, P = .001). Volume of enteral feeds (mL/kg/d), its interaction with CGA, and number of stressful procedures were not statistically significant (β= .011, P = .077; β=-.002, P = .066; and β= .007, P = .062, respectively). Nurse-guided interventions are associated with infant plasma OT levels, suggesting nurses may impact the neurobiology of the developing premature infant. Replication with larger sample sizes and randomized controlled trial designs is needed to test effects of specific nursing interventions on infant OT.


[Efficacy and safety of astemizole in the treatment of allergic rhinitis and urticaria: a systematic review with meta-analysis].
To compare astemizole with other first or second generation antihistaminics in the treatment of allergic rhinitis or urticaria. Systematic revision of clinical, controlled and randomized tests. 36 controlled, randomized, clinical, double or simple blind tests were made in 6,446 patients; 4,513 of them were assigned to astemizole and 1,933 to other first or second generation antihistaminics. Analyzed outcomes: Rate of global success; global scoring improvement of rhinitis; ocular, nasal or pharingeal pruritus; watering; nasal obstruction; sneeze; urticaria; cutaneous response to histamine; time to get a satisfactory improvent; frequency of sedation and headache. In connection to global success there were significant differences in favor of astemizole (OR 6.72, CI95% 5.36 to 8.41, p 0.0001); alike global scoring improvement of rhinitis (SMD -0.82, CI95% -1.70 to 0.06, p 0.04); rhinorrhea (SMD of -0.70, CI95% -1.47 to -0.03, p 0.02); nasal, pharingeal or ocular pruritus (SMD -0.64, CI95% -1.63 to 0.35, p 0.03); urticaria (SMD of -3.53, CI95% -4.11 to -2.94, p 0.0001), and reduction of cutaneous response to histamine (SMD -2.02, CI95% -2.47 to -1.57, p 0.0001). Differences for watering, nasal obstruction or sneeze were not observed. Finally, the safety area was analyzed considering the existence of sedation and headache; it was demonstrated less sedation (OR 0.23, CI95% 0.18 to 0.30, p 0.0001) and less headache (OR 0.58, CI95% 0.40 to 0.85, p 0.005) in the group treated with astemizole. The available evidence shows a therapeutic superiority of astemizole versus other antihistaminics in relation to the percentage of global success and the global scoring improvement of rhinitis, rhinorrhea, pruritus in general, urticaria symptoms and of the reduction of response to histamine, with a smaller frequency of headache or sedation.


The Therapeutic Potential of FLASH-RT for Pancreatic Cancer.
Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.


Heavy resistance training is safe and improves bone, function, and stature in postmenopausal women with low to very low bone mass: novel early findings from the LIFTMOR trial.
The aim of the LIFTMOR (Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation) trial is to determine the safety and efficacy of brief, bone-targeted, high-intensity progressive resistance training (HiPRT) with impact loading for postmenopausal women with low bone mass. Preliminary findings indicate the LIFTMOR program is safe and effective. Despite a lack of notable efficacy, exercise guidelines for osteoporosis typically recommend moderate-intensity exercises, owing to a perceived risk of fracture from high-intensity loading. Indeed, safety concerns alone have prevented the well-recognised preferential response of bone tissue to high-intensity loads from being applied to those who stand to benefit the most. To progress from this therapeutic stalemate, a challenge to conventional wisdom was required. Our goal was to examine the safety and efficacy of HiPRT and impact loading for risk factors of osteoporotic fracture in postmenopausal women with low to very low bone mass. Participants have been randomised to either 8 months of twice-weekly 30-min supervised HiPRT and impact loading or a low-intensity home-based exercise program of the same duration and dose. Testing at baseline and follow-up has included anthropometry; bone, muscle, and fat mass; and functional performance. Twenty-eight women (66.1 ± 4.8 years, mean lumbar spine T-score -2.15 ± 0.72) have completed the study. HiPRT and impact loading (n = 12) improved height (0.4 ± 0.2 cm vs -0.3 ± 0.1 cm, p = 0.003), femoral neck bone mineral density (0.3 ± 0.5 % vs -2.5 ± 0.8 %, p = 0.016), lumbar spine bone mineral density (1.6 ± 0.9 % vs -1.7 ± 0.6 %, p = 0.005), and functional performance (p < 0.05), compared to controls (n = 16). Compliance has been >87 %. There have been no injuries. Brief supervised HiPRT with impact loading is a safe and effective exercise therapy for postmenopausal women with low to very low bone mass.


Monocyte subtype expression patterns in septic patients with diabetes are distinct from patterns observed in obese patients.
Sepsis causes a high rate of mortality and long-term morbidity, associated with an imbalance of innate immunity against infections and inflammation. Obesity and diabetes increase the risk for disease severity. Monocyte dysfunction plays a major role and justify further investigations. To investigate the distribution and inflammatory phenotypes in circulating monocyte subsets in patients manifesting with sepsis including septic shock with and without obesity and diabetes. A total of 235 blood samples were tested from critically ill adult patients registered at the intensive care unit (ICU). The cohorts were divided into non-diabetic groups with or without obesity and diabetic groups with or without obesity, suffering from sepsis or septic shock. We determined frequencies of total monocytes and of monocyte subsets in the circulation and density expression levels of functional markers, including CD14, CD16, HLA-DR, CD33, CD163, CD206, and arginase-1 by flow cytometric analysis. When progressing to septic shock in non-diabetic and diabetic patients, the percentages of total monocytes among the leukocyte population and of CD33+ and CD14+ monocytes among the monocyte population were consistently down-regulated compared to non-sepsis in non-diabetic and diabetic patients, respectively. Non-diabetic sepsis patients further presented with decreased CD33 and up-regulated CD163 expression density, which was absent in diabetic patients. We subsequently addressed obesity-related changes of monocytes in non-diabetic and diabetic septic patients. Obese septic patients with diabetes were unique in displaying increased monocytic CD16 and CD163 expression. However, obese septic patients without diabetes solely presented with lower amounts of non-classical monocytes. Body mass index (BMI) dependent changes were restricted to diabetic septic patients, with a significantly higher diminution of the classical monocyte subset and concomitantly increased CD16 expression densities. Distribution and phenotypes of monocyte subsets were differentially modulated in critically ill patients with and without metabolic disease when progressing to sepsis or septic shock. Only diabetic septic patients displayed decline of classical monocytes and increase of CD16 expression densities. Therefore, diabetes but not obesity appears to promote the inflammatory phenotype of circulating monocytes in critically ill patients.


An interspecific comparison of foraging range and nest density of four bumblebee (Bombus) species.
Bumblebees are major pollinators of crops and wildflowers in northern temperate regions. Knowledge of their ecology is vital for the design of effective management and conservation strategies but key aspects remain poorly understood. Here we employed microsatellite markers to estimate and compare foraging range and nest density among four UK species: Bombus terrestris, Bombus pascuorum, Bombus lapidarius, and Bombus pratorum. Workers were sampled along a 1.5-km linear transect across arable farmland. Eight or nine polymorphic microsatellite markers were then used to identify putative sisters. In accordance with previous studies, minimum estimated maximum foraging range was greatest for B. terrestris (758 m) and least for B. pascuorum (449 m). The estimate for B. lapidarius was similar to B. pascuorum (450 m), while that of B. pratorum was intermediate (674 m). Since the area of forage available to bees increases as the square of foraging range, these differences correspond to a threefold variation in the area used by bumblebee nests of different species. Possible explanations for these differences are discussed. Estimates for nest density at the times of sampling were 29, 68, 117, and 26/km2 for B. terrestris, B. pascuorum, B. lapidarius and B. pratorum, respectively. These data suggest that even among the most common British bumblebee species, significant differences in fundamental aspects of their ecology exist, a finding that should be reflected in management and conservation strategies.


Attractiveness-related recognition bias captures the memory of the beholder.
Earlier electroencephalographic studies have compared attractive and unattractive faces and between faces with other objects, such as flowers, without revealing if a recognition memory bias toward faces and flowers exists or whether humans exhibit enhanced specific components toward all attractive objects or only toward attractive faces. For objects with similar degrees of attractiveness, we sought to determine if the N170, P1, and N250 reflect upon the attractiveness of faces and flowers and demonstrated by comparing event-related potentials of humans' different perceptual mechanisms recognizing high attractive faces and high attractive flowers. The repeated high attractive faces tended to elicit a larger N170. Simultaneously, the P1 was preferentially associated with the repeated high attractive flowers, but both indicated that the repetitive enhancement effect only occurred on repeated attractive faces. Thus, differences existed in the perceptual mechanisms for processing repeated high attractive faces and repeated high attractive flowers. However, there was no significant difference in N250 between repeated faces and repeated flowers or between high attractive faces and high attractive flowers. Consequently, high attractive faces and high attractive flowers capture the beholder's memory bias in different processing stages. The N170 and P1 components are affected by attractiveness, thereby demonstrating the differences between human perceptual mechanisms in recognizing high attractive faces and objects.


[Treatment of phimosis without circumcision and reconstruction of the prepuce following circumcision].
Phimosis of the prepuce can be treated without performing a circumcision. The most common and most effective treatment option is the local application ofcorticosteroid ointment. Should this be insufficiently effective, then the constricted ring can be interrupted with two Z-plasties, which is sufficient to expose the glans penis painlessly. No skin is removed. The intervention may be performed under regional anaesthesia on an outpatient basis. In cases where reconstruction of the prepuce is indicated, this can be accomplished with a distally inverted flap of penile shaft skin combined with the application of free skin grafts.


Preferential re-replication of Drosophila heterochromatin in the absence of geminin.
To ensure genomic integrity, the genome must be duplicated exactly once per cell cycle. Disruption of replication licensing mechanisms may lead to re-replication and genomic instability. Cdt1, also known as Double-parked (Dup) in Drosophila, is a key regulator of the assembly of the pre-replicative complex (pre-RC) and its activity is strictly limited to G1 by multiple mechanisms including Cul4-Ddb1 mediated proteolysis and inhibition by geminin. We assayed the genomic consequences of disregulating the replication licensing mechanisms by RNAi depletion of geminin. We found that not all origins of replication were sensitive to geminin depletion and that heterochromatic sequences were preferentially re-replicated in the absence of licensing mechanisms. The preferential re-activation of heterochromatic origins of replication was unexpected because these are typically the last sequences to be duplicated in a normal cell cycle. We found that the re-replication of heterochromatin was regulated not at the level of pre-RC activation, but rather by the formation of the pre-RC. Unlike the global assembly of the pre-RC that occurs throughout the genome in G1, in the absence of geminin, limited pre-RC assembly was restricted to the heterochromatin by elevated cyclin A-CDK activity. These results suggest that there are chromatin and cell cycle specific controls that regulate the re-assembly of the pre-RC outside of G1.


[Acupuncture Alleviated Depressive-like Behavior by Down-regulating NF-κB, iNOS and NO Levels in Prefrontal Cortex of Depression Rats].
To observe the effect of acupuncture intervention on depressive-like behavior and nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) levels in the prefrontal cortex in chronic stress induced depression rats, so as to explore its mechanism underlying antidepressant effect. SD rats were randomly divided into control, model, acupuncture and medication (Fluoxetine) groups (8 rats/group). The depression model was established by chro-nic unpredictable stress stimulation (fasting, water deprivation, cold water swimming, tail clamping, constraining, etc., and solitary raising) for 28 days. Acupuncture treatment was applied to "Baihui" (GV 20) and unilateral "Neiguan"(PC 6) once every other day for 14 days. Fluoxetine (10 mg/kg) was given to rats of the medication group by gavage (p.o.) before every stress stimulation, once every day for 28 days. The animals' behavior was tested by using sucrose intake and open field tests (number of crossings and rearings in 5 min). The expression of NF-κB in the prefrontal cortex was detected by Western blot, and the contents of prefrontal iNOS and NO were detected by ELISA and nitric reductases, respectively. After modeling, the sucrose intake and the numbers of crossing and rearing times were significantly decreased (P<0.01), and the expression of NF-κB protein and the contents of iNOS and NO in the prefrontal cortex were significantly increased in the model group compared with the control group (P<0.01). Following the treatment, the sucrose intake and the numbers of crossing and rearing times were significantly increased in both acupuncture and medication groups compared with the model group (P<0.05, P<0.01), and the expression level of NF-κB, and iNOS and NO contents in the prefrontal cortex were significantly lower in both acupuncture and medication groups than in the model group (P<0.01). There were no significant differences between the acupuncture and medication groups in the crossing number and rearing times, NF-κB expression, and iNOS and NO levels (P>0.05). Acupuncture treatment can improve the depressive-like behavior of depression rats, which is closely related to its effects in down-regulating the levels of NF-κB protein, iNOS and NO in the prefrontal cortex to reduce brain inflammatory damage.


Ferritin, creatine kinase, and neopterin in subacute sclerosing panencephalitis.
To study the disease process in the brain in subacute sclerosing panencephalitis (SSPE), sequential changes in ferritin, creatine kinase (CK), and neopterin in the cerebrospinal fluid (CSF) of two patients with SSPE were compared with the changes in the clinical signs and symptoms and the findings by magnetic resonance imaging (MRI). On the basis of changes in various substances in the CSF, especially ferritin, CK and neopterin, we concluded that the high-intensity area in MRI might be evidence of local inflammation and the resulting cell damage. Ferritin, CK and neopterin seemed to be biochemical markers in patients with SSPE for detection of the extent of lesions, and their measurement may provide information useful for evaluation of the therapeutic response.


Combating Human Viral Diseases: Will Plant-Based Vaccines Be the Answer?
Molecular pharming or the technology of application of plants and plant cell culture to manufacture high-value recombinant proteins has progressed a long way over the last three decades. Whether generated in transgenic plants by stable expression or in plant virus-based transient expression systems, biopharmaceuticals have been produced to combat several human viral diseases that have impacted the world in pandemic proportions. Plants have been variously employed in expressing a host of viral antigens as well as monoclonal antibodies. Many of these biopharmaceuticals have shown great promise in animal models and several of them have performed successfully in clinical trials. The current review elaborates the strategies and successes achieved in generating plant-derived vaccines to target several virus-induced health concerns including highly communicable infectious viral diseases. Importantly, plant-made biopharmaceuticals against hepatitis B virus (HBV), hepatitis C virus (HCV), the cancer-causing virus human papillomavirus (HPV), human immunodeficiency virus (HIV), influenza virus, zika virus, and the emerging respiratory virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been discussed. The use of plant virus-derived nanoparticles (VNPs) and virus-like particles (VLPs) in generating plant-based vaccines are extensively addressed. The review closes with a critical look at the caveats of plant-based molecular pharming and future prospects towards further advancements in this technology. The use of biopharmed viral vaccines in human medicine and as part of emergency response vaccines and therapeutics in humans looks promising for the near future.


Rapid Blood Transfusion: The Importance of Hemodilution and Needleless Connectors.
Large-bore cannulas are critical to administering IV fluids and blood products during resuscitation and treatment of hemorrhage. Although catheter flow rates for crystalloid solutions are well defined, rapid administration of blood products is poorly characterized. In this in vitro study, we examined the effects of hemodilution and needleless connectors on red blood cell (RBC) flow rates. To determine RBC flow rates through large-bore cannulae, a crystalloid solution (Normosol®, Hospira, Lake Forest, IL) or RBC units were warmed and delivered under pressure (360 mmHg) using a Level 1 H-1200 Fast Flow Fluid Warmer (Smiths Medical, St. Paul, MN). Flow rates for crystalloid, packed RBCs and diluted RBCs were determined using a stopwatch. Additionally, the effect of the MaxPlus® clear needleless connector (CareFusion, San Diego, CA) was measured in all three infusion groups. Flow rates for undiluted RBC units were 53% slower than crystalloid solution (220 mL/min vs. 463 mL/min; p=0.0003), however, when RBC units were diluted to a hematocrit of ~30% flow rate improved to 369 mL/min (p=0.005). The addition of the MaxPlus® needleless connector reduced flow of crystalloid solution by 47% (245 mL/min; p=0.0001), undiluted RBCs by 64% (78 mL/min; p=0.01), and diluted RBCs by 51% (180 mL/min; p=0.00003). Compared to undiluted RBC units, hemodilution increased RBC delivery rate through a MaxPlus® connector by 130% (p=0.004) and by 68% (p=0.02) when the catheter was directly connected to the Level 1 tubing (MaxPlus® excluded). In settings requiring rapid transfusion of RBC units, needleless connectors should not be used and hemodilution should be considered in order to decrease the time required to deliver an equivalent red cell mass.


Insight into the long-term impact of birth weight on intestinal development, microbial settlement, and the metabolism of weaned piglets.
Infant mortality of low birth body weight (LBBW) piglets can reach 10% and is mainly due to gut and immune system immaturity which can lead to a higher risk in the long term. This study aimed to assess the impact of birth body weight (BBW) on piglet metabolism, gut status, and microbial profile from weaning to 21 d postweaning. At birth, 32 piglets were selected for their BBW and inserted into the normal BBW (NBBW:1.38 ± 0.09 g) or the LBBW (0.92 ± 0.07 g) group. The piglets were weighed weekly from weaning (d0) to d21. At d9 and d21, 8 piglets/group were slaughtered to obtain the distal jejunum for morphology, immunohistochemistry, and gene expression analysis, colon content for microbiota and short-chain fatty acid (SCFA) analysis, and intestinal content for pH measurement. Blood was collected for metabolomic, haptoglobin (Hp), and reactive oxygen metabolite (ROM) analysis. The LBBW group had a lower body weight (BW) throughout the study (P < 0.01), a lower average daily gain from d9-d21 (P = 0.002), and lower feed intake (P = 0.02). The LBBW piglets had lower Hp at d9 (P = 0.03), higher ROMs at d21 (P = 0.06), and a net alteration of the amino acid (AA) metabolism at d9 and d21. A higher expression of NFKB2 was observed in the LBBW piglets at d9 (P = 0.003) and d21 (P < 0.001). MYD88 expression was enhanced in NBBW piglets at d9 (P < 0.001). The LBBW piglets had a lower villus height, absorptive mucosal surface (P = 0.01), and villus height:crypt depth ratio (P = 0.02), and a greater number of T-lymphocytes in both the epithelium and the crypts (P < 0.001) at d21. At d21, the LBBW piglets had higher lactic acid, acetate, butyrate, and valerate, and also higher SCFA in the colon (P < 0.05). The LBBW piglets had a higher Shannon index (P = 0.01) at d9 and a higher abundance of SCFA-fermenting bacteria. In conclusion, the present study confirmed that LBBW could impact the gut mucosal structure, immunity, and inflammatory and oxidative status, leading to an altered AA metabolism, and delaying the recovery from weaning.


Assessing Retinal Structure in Patients with Parkinson's Disease.
The retina is an extension of the central nervous system (CNS), and ocular symptoms can precede manifestations of CNS disorders. Given that several neurodegenerative conditions that affect the brain exhibit ocular symptoms, the retina may be an accessible biomarker to monitor disease progression. Dopamine, the key neurotransmitter related to Parkinson's disease (PD), is contained in amacrine and interplexiform cells, which reside in specific retinal layers. Understanding how loss of dopaminergic cells affects retinal anatomy could be relevant for monitoring disease progression. Here, our objective is to evaluate retinal structure (foveal pit morphology and thickness) in patients with PD. Thirty-three Caucasian subjects diagnosed with PD and 40 age-matched Caucasian control subjects underwent retinal imaging with spectral-domain optical coherence tomography (SD-OCT). Axial length measurements were used to correct the lateral scale of each macular volume scan. From these corrected volumes, foveal morphology was quantified with previously described algorithms, and Early Treatment Diabetic Retinopathy Study (ETDRS) grids of retinal thickness were generated and incorporated into a logistic regression model to predict PD. Interocular foveal morphology measurements were highly symmetrical in PD patients and control subjects. There were no significant differences in foveal pit morphology between PD patients and control subjects. Using a model incorporating sex and axial length corrected ETDRS regions, we generated a receiver operating characteristic curve with a C-statistic of 0.80. Our study, which to our knowledge is the first to properly scale OCT measurements when quantifying retinal thickness, demonstrates that PD patients retain foveal symmetry between eyes. When constructing a model to predict PD, sex, along with the center 1 mm and temporal outer ETDRS regions, were significant predictors of PD. In addition to proper scaling of OCT measures, gender and racial differences in retinal anatomy should be considered in building future predictive PD models when using OCT.


Cardiovascular manifestations of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.
Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers-Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.