Outpatient treatment of decompensated heart failure: A systematic review and study level meta-analysis.

Patients with acutely decompensated heart failure (ADHF) are usually admitted to hospital for management. There is growing interest in delivering intravenous (IV) diuretic therapy at home, in the community or at hospital day-care units; the safety and effectiveness of outpatient-based management (OPM) for ADHF has not been established. We conducted a systematic literature review and meta-analysis to investigate the short-term safety and effectiveness of OPM compared with inpatient management (IPM) of ADHF. Pre-specified endpoints were 30 day mortality and 30 day hospitalization. The meta-analysis was conducted using RevMan 5.4 software. Twenty-nine studies of OPM were identified, including 7683 patients. Only five studies directly compared OPM (n = 1303) with IPM (n = 2047), including three observational studies, and two randomized controlled trials (RCTs). The other 24 studies only stated OPM outcomes. For the five studies comparing IPM versus OPM, patients were generally aged >75 years and of similar age for each strategy, with a similar proportion of men (56%). In a study-level, aggregate analysis, 30 day all-cause mortality was 9.3% (121/1303) for OPM, compared with 15.6% (320/2047) for IPM [OR 0.29 (95% CI 0.09, 0.93) P = 0.04]. Four studies reported 30 day all-cause hospitalization; 22.0% for IPM versus 16.8% for OPM [OR 0.73 (95% CI 0.61, 0.89), P = 0.001]. In the two RCTs, we found no difference in 30 day mortality or hospitalization. In observational studies, OPM of ADHF is associated with lower 30 day hospitalization and lower 30 day mortality; such differences were not observed in two small, single-centre RCTs. A substantial, multicentre RCT is required to confirm the safety and effectiveness of OPM for ADHF.

Polyethylene Degradation by a Rhodococcous Strain Isolated from Naturally Weathered Plastic Waste Enrichment.

Polyethylene (PE) is the most widely produced synthetic polymer and the most abundant plastic waste worldwide due to its recalcitrance to biodegradation and low recycle rate. Microbial degradation of PE has been reported, but the underlying mechanisms are poorly understood. Here, we isolated a Rhodococcus strain A34 from 609 day enriched cultures derived from naturally weathered plastic waste and identified the potential key PE degradation enzymes. After 30 days incubation with A34, 1% weight loss was achieved. Decreased PE molecular weight, appearance of C-O and C═O on PE, palmitic acid in the culture supernatant, and pits on the PE surface were observed. Proteomics analysis identified multiple key PE oxidation and depolymerization enzymes including one multicopper oxidase, one lipase, six esterase, and a few lipid transporters. Network analysis of proteomics data demonstrated the close relationships between PE degradation and metabolisms of phenylacetate, amino acids, secondary metabolites, and tricarboxylic acid cycles. The metabolic roadmap generated here provides critical insights for optimization of plastic degradation condition and assembly of artificial microbial communities for efficient plastic degradation.

Benefits of Mentoring in Oncology Education for Mentors and Mentees: Pre-Post Interventional Study of the British Oncology Network for Undergraduate Societies' National Oncology Mentorship Scheme.

BACKGROUND: Formal education of oncology is lacking in many undergraduate medical curricula. Mentoring schemes can expose participants to specific areas of medicine and may address the shortfalls in oncology education. Few mentoring schemes have been designed within the United Kingdom, especially within oncology. There is a need to understand reasons for mentor and mentee participation in such schemes and to identify ways to minimize barriers to engagement. OBJECTIVE: This study identifies motivations for participation in an oncology mentoring scheme and its benefits and limitations to both the mentee and the mentor. METHODS: The British Oncology Network for Undergraduate Societies launched a National Oncology Mentorship Scheme (NOMS) on September 1, 2021. Mentees (medical student or foundation doctor) were paired with mentors (specialty registrar or consultant), for 6 months of mentoring. In total, 86 mentors and 112 mentees were recruited to the scheme. The mentees and mentors were asked to meet at least 3 times during this period and suggestions were provided on the content of mentoring. Mentees and mentors were invited to complete a prescheme questionnaire, exploring motivations for involvement in the scheme, current experiences within oncology, and knowledge and interests in the field. At the end of the scheme, mentors and mentees were asked to complete a postscheme questionnaire exploring experiences and benefits or limitations of participation. Paired analysis was performed using the Wilcoxon signed-rank test. For free text data, content analysis was applied to summarize the main themes in the data. RESULTS: Of the 66 (59%) mentees who completed the prescheme questionnaire, 41 (62%) were clinical, 21 (32%) preclinical medical students, and the remainder were junior doctors. For mentees, networking was the primary reason for joining the scheme (n=25, 38%). Mentees ranked experience of oncology at medical school at 3 on 10 (IQR 2-5). In this, 46 (53%) mentors completed the prescheme questionnaire, 35 (76%) were registrar level, and the remainder were consultant level (n=11). The most common reason for mentor participation was to increase awareness and interest in the field (n=29, 63%). Of those who completed the prescheme questionnaire, 23 (35%) mentees and 25 (54%) mentors completed the postscheme questionnaire. Knowledge in all areas of oncology assessed significantly increased during the scheme (P<.001). Most mentees (n=21, 91%) and mentors (n=18, 72%) felt they had benefited from the scheme. Mentees cited gaining insights into oncology as most beneficial; and mentors, opportunities to develop professionally. Whilst mentees did not report any barriers to participating in the scheme, mentors stated lack of time as the greatest barrier to mentoring. CONCLUSIONS: British Oncology Network for Undergraduate Societies' NOMS is expanding and is beneficial for mentees through increasing knowledge, providing exposure, and career advice in oncology. Mentors benefit from improving their mentoring skills and personal satisfaction.

Target integration of an exogenous ß-glucosidase enhances cellulose degradation and ethanol production in Clostridium cellulolyticum.

The bacteria Clostridium cellulolyticum is a promising candidate for consolidated bioprocessing (CBP). However, genetic engineering is necessary to improve this organism's cellulose degradation and bioconversion efficiencies to meet standard industrial requirements. In this study, CRISPR-Cas9n was used to integrate an efficient ß-glucosidase into the genome of C. cellulolyticum, disrupting lactate dehydrogenase (ldh) expression and reducing lactate production. The engineered strain showed a 7.4-fold increase in ß-glucosidase activity, a 70% decrease in ldh expression, a 12% increase in cellulose degradation, and a 32% increase in ethanol production compared to wild type. Additionally, ldh was identified as a potential site for heterologous expression. These results demonstrate that simultaneous ß-glucosidase integration and lactate dehydrogenase disruption is an effective strategy for increasing cellulose to ethanol bioconversion rates in C. cellulolyticum.

Assessing the biomechanical properties of nitinol staples in normal, osteopenic and osteoporotic bone models: A finite element analysis.

OBJECTIVE: Bone staples are internal fixation devices that are frequently used in the foot, ankle, and hand to provide stabilization. Fixation stability is vital after fusion or fracture surgeries to ensure proper bone healing. Patients undergoing surgeries that require fixation to keep bones aligned and stable may present with diminishing bone mechanical properties, and this may compromise the ability of the fixation hardware to maintain a stable construct. The purpose of this study was to investigate the mechanical performance of shape memory and superelastic nitinol bone staples with different bridge geometries in normal, osteopenic, and osteoporotic bone models. Contact forces and maximum principal stress and strain in the bone were recorded. METHODS: Finite element simulations of a bone staple fixation procedure were performed to examine the initial and post-surgery contact force, as well as the maximum principal stress and strain of 15 mm bridge and 20 mm bridge staple-bone constructs. RESULTS: Shape memory nitinol staples exhibited higher contact forces compared to superelastic nitinol staples. Nitinol bone staples with 20 mm bridge lengths displayed higher contact forces and lower stresses in all bone types, as well as lower strains in osteoporotic bone models compared to nitinol staples with a 15 mm bridge length. CONCLUSION: Nitinol bone staple constructs with 20 mm bridge length staples provide higher contact forces and display lower stresses in the bone than 15 mm bridge staple-bone constructs, which may be beneficial in bone with diminishing mechanical properties. Both superelastic and shape memory effect nitinol staples provide adequate compression and stress relief. However, if osteopenia is present, shape memory effect nitinol staples with a 20 mm bridge length may provide more stress relief and compression, if the bone anatomy allows.

Prediction of a Non-Valence Temporary Anion State of (NaCl)2.

The equation-of-motion coupled cluster method is used to characterize the low-lying anion states of (NaCl)2 in its rhombic structure. This species is known to possess a non-valence bound anion of Ag symmetry. Our calculations also demonstrate that it has a non-valence temporary anion of B2u symmetry, about 14 meV above threshold. The potential energy curves of the two anion states and of the ground state of the neutral molecule are reported as a function of distortion along the symmetric stretch normal coordinate. Implications for experimental detection of the temporary anion state are discussed. The sensitivity of the results to the inclusion of high-order correlation effects and of core correlation is examined.

Effects of Catechin, Quercetin and Taxifolin on Redox Parameters and Metabolites Linked with Renal Health in Rotenone-toxified Rats.

Nephrotoxicity, with the attendant risk of progression to kidney failure, is a growing problem in many parts of the world. Current orthodox treatment options for nephrotoxicity and kidney failure are limited and there is need for alternative or complementary approaches. This study aimed at evaluating the effect of three structurally related flavonoids, catechin, quercetin and taxifolin on renal redox and metabolite biochemical disturbances in rotenone intoxicated animals. Male Wistar rats were administered 1.5 mg/kg rotenone (s.c.) for ten days followed by post-treatment with catechin (5, 10 or 20 mg/kg), quercetin (5, 10, or 20 mg/kg) and taxifolin (0.25, 0.5 or 1.0 mg/kg) (s.c.), for 3 days. Renal redox indices and levels of renal-related metabolites (creatinine, urea and uric acid) were assessed after sacrifice of animals. Catechin, quercetin and taxifolin significantly attenuated rotenone-induced effects on oxidative stress markers and metabolites linked to renal health.  Quercetin was clearly more effective than catechin. The activity demonstrated by taxifolin, despite being administered at the lowest doses, was compelling. The results highlight the potential of these phytochemicals in the management of renal dysfunction. The findings additionally suggest a correlation between the structure of the flavonoids and their activity but also indicate that additional structural considerations beyond conventionally acknowledged ones may be involved.

Plasma Interleukin-1ß (IL-1ß) Concentrations at the Different Phases of the Oestrus Cycle in Clomiphene Treated Female Rats.

Interleukin - 1ß (IL-1ß) is a signal molecule known for its role in inflammation and immune response. However,there are reports on the possible effects of IL-1ß in ovulation and various aspects on female reproduction. It was thereforenecessary to determine plasma IL-1ß levels in female rats administered ovulation inducing agent clomiphene citrate. In thiswork, a total of forty (40) female wistar rats weighing between 150g and 225g were used. Twenty of the rats wereadministered 0.14mg/kg clomiphene citrate orally daily for five days while the other twenty which served as control, receivednormal saline. The phases of the oestrus cycle (proestrus, estrus, metestrus and diestrus) were determined between the hoursof 8.30am and 10.00am on the sixth day prior to collection of blood sample by cardiac puncture. The plasma IL-1ßconcentrations were determined using rat IL-1ß ELISA kits. From the experiment, 41.2% of the control rats were in thediestrus phase while 42.1% of the clomiphene citrate treated rats were in the estrus phase. The IL-1ß plasma concentrationswere higher in clomiphene treated rats at all the phases of the oestrus cycle of experimental rats when compared with thecontrol. The increase in plasma IL-1ß was significant (p˂0.05) in the estrus phase of the clomiphene citrate treated rats(550.53pg/ml) when compared with the control (304.42pg/ml). The high plasma concentration of IL-1ß at the estrus phaseof clomiphene citrate treated rats suggests its possible involvement in oocyte maturation and ovulation which characterizesthe phase.

Lateral Flow Immunoassays for Ebola Virus Disease Detection in Liberia.

BACKGROUND: Lateral flow immunoassays (LFIs) are point-of-care diagnostic assays that are designed for single use outside a formal laboratory, with in-home pregnancy tests the best-known example of these tests. Although the LFI has some limitations over more-complex immunoassay procedures, such as reduced sensitivity and the potential for false-positive results when using complex sample matrices, the assay has the benefits of a rapid time to result and ease of use. These benefits make it an attractive option for obtaining rapid results in an austere environment. In an outbreak of any magnitude, a field-based rapid diagnostic assay would allow proper patient transport and for safe burials to be conducted without the delay caused by transport of samples between remote villages and testing facilities. Use of such point-of-care instruments in the ongoing Ebola virus disease (EVD) outbreak in West Africa would have distinct advantages in control and prevention of local outbreaks, but proper understanding of the technology and interpretation of results are important. METHODS: In this study, a LFI, originally developed by the Naval Medical Research Center for Ebola virus environmental testing, was evaluated for its ability to detect the virus in clinical samples in Liberia. Clinical blood and plasma samples and post mortem oral swabs submitted to the Liberian Institute for Biomedical Research, the National Public Health Reference Laboratory for EVD testing, were tested and compared to results of real-time reverse transcription-polymerase chain reaction (rRT-PCR), using assays targeting Ebola virus glycoprotein and nucleoprotein. RESULTS: The LFI findings correlated well with those of the real-time RT-PCR assays used as benchmarks. CONCLUSIONS: Rapid antigen-detection tests such as LFIs are attractive alternatives to traditional immunoassays but have reduced sensitivity and specificity, resulting in increases in false-positive and false-negative results. An understanding of the strengths, weaknesses, and limitations of a particular assay lets the diagnostician choose the correct situation to use the correct assay and properly interpret the results.

A revised birth weight reference for the United States.

OBJECTIVE: To generate birth weight curves based on the obstetric estimate of gestational age as specified in the revised 2003 U.S. birth certificate. METHODS: Using National Center for Health Statistics data from 2011, we constructed birth weight curves for neonates between 24 and 42 weeks of gestation. Curves were developed using the obstetric estimate of gestational age that is included in the revised 2003 U.S. birth certificate, which, when available, incorporates ultrasound dating information. Live-born singleton neonates between 500 and 6,000 g without malformations were included. These curves were compared with curves we generated using 1991 data on which the current national reference of Alexander and colleagues is based, a reference that used only last menstrual period to establish gestational age. RESULTS: The 1991 curves were based on 3,684,778 U.S. live births and the 2011 on 3,252,011 births. Birth weight percentile values were greater from 28 to 36 weeks of gestation in the 1991 data set. That is, the birth weights for preterm neonates were overestimated when 1991 reference curves were used compared with the proposed 2011 reference. For example, in 1991, a birth weight of 2,000 g was at the 50th percentile between 31 and 32 weeks of gestation, whereas in 2011, a birth weight of 2,000 g now corresponds to the 50th percentile between 33 and 34 weeks of gestation. CONCLUSIONS: Our revised reference curve for the United States provides an updated national reference for birth weight. LEVEL OF EVIDENCE: : II.

Primary care survey of the value and effectiveness of the Washington State Opioid Dosing Guideline.

PURPOSE: To evaluate the acceptability and usefulness of the Washington State Opioid Dosing Guideline (Guideline) developed for primary care providers for the treatment of chronic noncancer pain. The Guideline contains innovative tools, such as an online dosing calculator, and recommendations to assist providers, including a "yellow flag" threshold of 120 mg/d morphine equivalent dose (MED) at which specialty consultation is recommended. METHODS: Using a convenience sample, an anonymous web-based survey was conducted among primary care providers in Washington (WA) state. Physician/ administrative leaders in four regional and two statewide healthcare systems and associations distributed the electronic links to primary care providers in their organizations. RESULTS: Six hundred fifty-five (n) providers completed the survey representing 20 percent of the total number contacted. The majority (89 percent) of providers in this sample treat chronic pain patients, and more than half (54 percent) have frequent concerns about addiction, tolerance, and diversion. Forty-five percent had read and applied the Guideline in their practice. The majority of these providers found the Guideline to be helpful and 86 percent find the threshold of 120 mg/d MED dose reasonable or too high. Some key best practices such as tracking pain and function using structured instruments and use of urine drug testing are infrequently used. CONCLUSIONS: Results from this survey suggest that the recommendations and tools given in the Guideline, including the threshold of 120 mg/day MED dose, are acceptable and useful to a large majority of primary care providers in WA state. Substantial additions to the Guideline based on needs identified in this survey were added in June 2010 and wider dissemination is planned.

Development of a ubiquitin transfer assay for high throughput screening by fluorescence resonance energy transfer.

An assay based on fluorescence resonance energy transfer (FRET) has been developed to screen for ubiquitination inhibitors. The assay measures the transfer of ubiquitin from Ubc4 to HECT protein Rsc 1083. Secondary reagents (streptavidin and antibody to glutathione-S-transferase [GST]), pre-labeled with fluorophores (europium chelate, Eu(3+), and allophycocyanin [APC]), are noncovalently attached via tags (biotin and GST) to the reactants (ubiquitin and Rsc). When Rsc is ubiquitinated, Eu(3+) and APC are brought into close proximity, permitting energy transfer between the two fluorescent labels. FRET was measured as time-resolved fluorescence at the emission wavelength of APC, almost entirely free of nonspecific fluorescence from Eu(3+) and APC. The FRET assay generated a lower ratio of signal to background (8 vs. 31) than an assay for the same ubiquitination step that was developed as a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). However, compared to the DELFIA method, use of FRET resulted in higher precision (4% vs. 11% intraplate coefficient of variation). Quenching of fluorescence was minimal when compounds were screened at 10 microg/ml using FRET. Employing a quick and simple homogeneous method, the FRET assay for ubiquitin transfer is ideally suited for high throughput screening.

Regions of the human neurokinin A receptor involved in the generation of second messengers and in receptor desensitization.

Deletion analysis was used to study sites of human Neurokinin A receptor (HNKAR) necessary for signal transduction in CHO cells. Deletion of 62 and 81 amino acids from the c-terminus of HNKAR forms mutant receptors HNKAR delta 62 and HNKAR delta 81, which bind neurokinin A with high affinity but are functionally different. Wild type HNKAR and HNKAR delta 62 are functionally active whereas HNKAR delta 81 is functionally inactive. In addition, HNKAR and HNKAR delta 62 were both desensitized to the neurokinin A signal within 5 minutes. The data indicates: 1) an intact cytoplasmic tail of the HNKAR is not critical for signal transduction, but the n-terminal amino acids of the cytoplasmic tail are necessary for signaling and 2) the c-terminal 62 amino acids are not necessary for desensitization.

Signal transduction pathway activating interferon-alpha-stimulated gene expression.

Interferon-alpha (IFN alpha) causes profound physiological changes following binding to susceptible target cells. These changes, which include induction of an antiviral state, inhibition of cellular proliferation, and modulation of differentiation, require the transcriptional activation of a set of genes. We have characterized the macromolecular components required for this stimulation of gene expression in order to define the biochemical mechanism of IFN alpha signal transduction. IFN alpha stimulated genes (ISGs) are immediate response genes which utilize a pre-existing set of proteins to mediate their induction. A 15 bp IFN alpha-inducible enhancer element present in the promoters of IFN alpha-stimulated genes, termed the IFN alpha stimulated response element (ISRE), is the genetic target for activation of ISGs. This DNA sequence is both necessary and sufficient for transcriptional activation and is the target for action of a positive transcription factor termed ISGF3. The active, DNA-binding form of ISGF3 is only found in cells which have been exposed to IFN alpha; however, it is activated from a silent form present in all responsive cells. ISGF3 is a multimeric complex assembled from cytoplasmic precursors which are translocated to the nucleus in response to IFN alpha. Assembly and translocation of ISGF3 is the earliest defined event in the IFN alpha response pathway.