Earlier Switch Research Articles

P19 IV antimicrobial duration in practice

BackgroundTackling antimicrobial resistance by reducing unnecessary or inappropriate prescribing is a key priority.ObjectivesTo review current clinical practice at Guy's and St Thomas’ Hospital around duration of IV antimicrobial therapy framed with Start Smart Then Focus national guidelines.MethodsNewly started inpatient prescriptions for IV antimicrobials over three consecutive Mondays were reviewed. Prescriptions not for treatment of acute infections were excluded, as were patients admitted to critical care, obstetrics/gynaecology and paediatric wards. Each patient's record was reviewed at Day 0, 3 and 5. Data were analysed using IBM® SPSS Statistics version 27.ResultsIn total, 80 patients with 89 antibiotic prescriptions (71 = β-lactam, 5 = aminoglycoside, 2 = glycopeptide, 1 = ciprofloxacin, 9 = metronidazole, 1 = linezolid) were included. Median age was 66 (IQR 53–75). Documented indications were for suspected or proven infection of urinary tract (15%), respiratory tract (25%), skin/soft tissue (14%), sepsis (1.25%), intra-abdominal (15%), bacteraemia (7.5%), bone and joint infections (2.5%) or other (20%). Median initial NEWS2 on Day 0 was 3 (IQR 1–4), WCC 11.45 (IQR 8.27–14.15) and CRP 121 (IQR 47–208). Median length of stay was 7.5 days. Median duration of IV antimicrobial was 4 (IQR 2–6) days. By D3, 3 patients had died and 16 had been discharged. Of 61 remaining inpatients on D3, 4 had their antimicrobials switched, 14 had been switched to PO antimicrobials, 43 were continued on IV antibiotics. By D5, 17 further patients had been discharged, 44 remained inpatients. Twenty-two had stopped antimicrobials with 22 continuing IV therapy. A number of patients could have been switched from IV to oral therapy by current guidance but were not (D3 x = 11, D5 n = 8). Higher median D0 CRP was seen in those who continued on IV therapy on D3 (139 versus 79 mg/dL) as was higher D3 WCC (13.9 versus 11.9 × 109/L). There was no significant relationship between a NEWS2 score ≥3 and IV to PO switch at D3 or D5. Thirty-two patients had input from the Infection team within 7 days of first prescription. Fifteen patients (21%) received IV antibiotics for more than 7 days, and 14/15 had Infection team input. Three patients were discharged with OPAT.ConclusionsMedian duration of IV therapy for suspected/proven infections in our centre is less than 5 days and only 28% of patients were still receiving IV antibiotics by D5. A number of missed opportunities for earlier switch to oral therapy were identified. The potential for earlier safe discontinuation of IV therapy using patient-specific measures should be explored. A minority of patients received IV therapy for >7 days, and this was almost universally associated with specialist Infection involvement in complex infections with a view to optimizing patient management and antimicrobial stewardship.

1704P Early switch to oral antibiotic therapy in patients with low-risk neutropenic sepsis (EASI-SWITCH trial)

Neutropenic sepsis (NS) is common after systemic anticancer therapy (SACT). Consensus guidelines recommend switching from intravenous (IV) to oral antibiotics after 48 hours of IV therapy but evidence is lacking on earlier switch.

SPEAR-Bladder (Study informing treatment Pathway dEcision in bladder cAnceR): Influence of treatment sequencing on time to treatment failure and overall survival in the United States.

453 Background: With the introduction of immunotherapy (IO) for locally advanced or metastatic urothelial carcinoma (mUC), optimal treatment sequence should be considered. This study aimed to compare time to treatment failure (TTF) and overall survival (OS) among these patients (pts) treated with first-line (1L) systemic chemotherapy followed by second-line (2L) IO ( C-IO) vs 1L and 2L chemotherapy ( C-C) sequence within the US community oncology Network (USON). Methods: This was a retrospective study of adult locally advanced or mUC pts who initiated systemic therapy between 1/1/15 – 4/30/17 within USON and had a minimum of two-month follow-up. Descriptive analyses were performed, with Kaplan-Meier used for comparisons between pts who received C-IO vs C-C sequence. Pts considered for this analysis did not receive a third-line treatment. Regression analyses were performed to assess variables associated with TTF and OS. Results: 117 pts were included in the analysis ( C-IO n = 79, C-C n = 38). Median age (range) was 69 years (38, 90+), with 74.4% male. Baseline demographic and clinical characteristics were similar between the groups. The median (range) duration between start of 1L and start of 2L therapy was significantly longer among C-IO vs C-C pts (29.0 [4.1, 102.1] vs 20.0 [0.1, 63.1] weeks; P = 0.0047). Median TTF and OS were longer among C-IO vs C-C pts but the trends were not significant (Table). The duration between initial diagnosis and advanced disease status was associated with TTF (P = 0.0124) in univariate analysis. Conclusions: These results suggest that patients receiving C-IO demonstrated greater (>30 weeks) but statistically non-significant improvement in OS versus those receiving C-C. Considering these OS trends, future research should explore prognostic characteristics of IL chemotherapy treated pts who may benefit from an earlier switch to IO therapy. [Table: see text]

Predicting imminent disease progression in advanced colorectal cancer by a machine-learning algorithm.

645 Background: In advanced cancers, predicting disease progression just before its clinical manifestation enables an earlier switch to the next treatment line, preventing deterioration in the patient's state and potentially improving survival. Yet, given the ambiguity of current tumor markers in alerting to progression, physicians are unable to forecast this key event. We developed a diagnostic algorithm for announcing an approaching disease progression in late-stage colorectal cancer (CRC) patients by processing continuous carcinoembryonic antigen (CEA) input. Methods: Longitudinally measured CEA data of advanced CRC patients treated by standard 1st line chemotherapies, collected from 2 clinical trials (projectdatasphere.org), served for algorithm development by machine-learning and training assisted by receiver-operating-characteristic (ROC) analysis and correlation tests. Performance was validated by cross-validation techniques. Results: CEA and response evaluations of 489 CRC patients (median follow-up time: 168 days) were processed by the algorithm, predicting disease progression with 57% sensitivity (100/175 progression events) and 88% specificity (21/175 false positives). Positive and negative predictive values, accuracy and Cohen’s kappa were 64%, 84%, 79% and 0.46, respectively. The algorithm’s predictive power was superior to that of standard statistical analyses of these CEA data (e.g., ROC). Conclusions: Our study offers a new approach to using tumor markers as prognosticators. The algorithm-amplified ability of CEA to predict progression in CRC complements our recent findings in lung cancer, where integration of CEA and 4 other markers provided 66% sensitivity in predicting progression, surpassing the low capacity of each separate marker. Conceivably, future algorithm-integration of multiple markers in CRC may also exceed the limited signal of a single marker. Clinical use of our algorithm, amplifying weak marker signals of imminent progression, should allow physicians to reliably harness tumor markers for improving treatment and potentially extending survival in cancer patients.

Sevoflurane affects neurogenesis through cell cycle arrest via inhibiting wnt/β-catenin signaling pathway in mouse neural stem cells

AimsThe development of central nervous system requires proliferation of neural stem cells followed by differentiation. Cell cycle parameters are closely related with cell fate specification and differentiation. Recent researches indicated that wnt/β-catenin signaling pathway might cause proliferation inhibition and differentiation abnormality through interfering NSCs cell cycle. Our previous research also showed that multiple sevoflurane exposure to neural stem cells inhibited proliferation via repressing transcription factor Pax6 and cyclin D1 through inhibiting wnt/β-catenin pathway. All above encouraged us to figure out the effect of sevoflurane on cell cycle and neurogenesis. Main methodsPrimary mouse cultured neural stem cells were used and exposed to 4.1% sevoflurane for 6 h in this study. The expression of β-catenin, GSK-3β, c-myc and cyclin D1 were determined by western blot and qRT-PCR. FACS was used to measure the cell cycle. The proliferation of NSCs was evaluated by EdU staining while the differentiation was evaluated by Tuj1 and GFAP staining on immunocytochemistry. Key findingsWe found that exposure to sevoflurane at a concentration of 4.1% for 6 h induced inhibition of wnt/β-catenin pathway, cell cycle arrest at G0/G1 phase and an earlier switch from proliferation to differentiation. GSK-3β specific inhibitor, CHIR99021, attenuated sevoflurane-induced cell cycle arrest and abnormality of neurogenesis in neural stem cells. SignificanceOur research suggested that sevoflurane arrested cell cycle at G0/G1 phase through inhibition of wnt/β-catenin signaling pathway thus resulting in a premature differentiation in NSCs. This study presents a deeper understanding of the mechanism on cognitive impairment by sevoflurane exposure.

The causal effect of wrong-hand drive vehicles on road safety

Left-hand drive (LHD) vehicles share higher road accident risks under left-hand traffic because of blind spot areas. Due to low import prices, the number of wrong-hand drive vehicles skyrockets in emerging countries like Georgia, Kyrgyzstan and Russia. I identify the causal effect of wrong-hand drive vehicles on road safety employing a new “backward version” of the synthetic control method. Sweden switched from left-hand to right-hand traffic in 1967. Before 1967, however, almost all Swedish vehicles were LHD for reasons of international trade and Swedish customer demand. I match on accident figures in the period after 1967, when both Sweden and other European countries drove on the right and used LHD vehicles. Results show that right-hand traffic decreased road fatality, injury and accident risk in Sweden by approximately 30%. An earlier switch would have saved more than 4000 lives between 1953 and 1966.

Plant-Specific Histone Deacetylases HDT1/2 Regulate GIBBERELLIN 2-OXIDASE2 Expression to Control Arabidopsis Root Meristem Cell Number.

Root growth is modulated by environmental factors and depends on cell production in the root meristem (RM). New cells in the meristem are generated by stem cells and transit-amplifying cells, which together determine RM cell number. Transcription factors and chromatin-remodeling factors have been implicated in regulating the switch from stem cells to transit-amplifying cells. Here, we show that two Arabidopsis thaliana paralogs encoding plant-specific histone deacetylases, HDT1 and HDT2, regulate a second switch from transit-amplifying cells to expanding cells. Knockdown of HDT1/2 (hdt1,2i) results in an earlier switch and causes a reduced RM cell number. Our data show that HDT1/2 negatively regulate the acetylation level of the C19-GIBBERELLIN 2-OXIDASE2 (GA2ox2) locus and repress the expression of GA2ox2 in the RM and elongation zone. Overexpression of GA2ox2 in the RM phenocopies the hdt1,2i phenotype. Conversely, knockout of GA2ox2 partially rescues the root growth defect of hdt1,2i These results suggest that by repressing the expression of GA2ox2, HDT1/2 likely fine-tune gibberellin metabolism and they are crucial for regulating the switch from cell division to expansion to determine RM cell number. We propose that HDT1/2 function as part of a mechanism that modulates root growth in response to environmental factors.

Decoupling of local and regional dominance in trilobite assemblages from northwestern Argentina: new insights into Cambro-Ordovician ecological changes

Components of biodiversity are strongly scale dependent, but the relative importance of the patterns that operate at different scales and the links between them have been overlooked. To disentangle the ecological structure of Cambro-Ordovician trilobite assemblages from the Argentine Cordillera Oriental at different scales, we explore patterns of abundance, dominance and occupancy across the onshore–offshore profile, and through three time intervals: Furongian, earliest Late Tremadocian (Tr2), latest Middle Floian–earliest Late Floian (Fl2–Fl3). At the regional scale, single taxa are overwhelming dominant in the Furongian (Parabolina) and in the earliest Late Tremadocian (Leptoplastides). Several dominants occur in the Floian, but just one (Famatinolithus) attains high occupancy and, rarely, high dominance. In contrast, only the Furongian records highly dominated local assemblages, whereas dominance distinctly decreases among Tr2 and Fl2–Fl3 ones. Thus, when both scales of analysis are combined, an unexpected scenario becomes evident: Tr2 assemblages resemble those of the Furongian at the regional scale, but mirror those of the Floian at the local scale. These results highlight a decoupling in local versus regional structures triggered by an earlier switch in dominance in local communities and a delayed change at the regional scale. Interestingly, this decrease in local dominance matches previous analyses accounting for a coeval step-up in local evenness, suggesting that the Tr2 appears as a pivotal interval in the reorganization of communities in the Cordillera Oriental. This scenario emphasizes that biogeographical regions witnessed different regional-scale processes, and suggests that scaling local and regional patterns provides new insights to unravel the history of biodiversity among benthic communities.

Earlier switching from intravenous to oral antibiotics owing to eReminders

The impact of electronic reminders encouraging early switches from intravenous to oral administration of antibiotics was studied in a hospital-wide, prospective, controlled trial. The reminders were displayed within electronic health records 60h after onset of intravenously administered antibiotic therapies if some patient-specific conditions were met. This intervention fostered early switching from intravenous to oral antibiotics, and thereby significantly reduced the mean duration of intravenous administration by 17%.

Key Decision Just After 3 Months Following TKI Initiation in CML: Better and not Difficult

The selection of the any first line TKI (tyrosine kinase inhibitor) and earlier switch at 3 months to a most powerful TKI based on the insufficient molecular response seem to be the most rational management strategy in chronic myeloid leukemia (CML). The depth of the molecular response and the time to achieve that response are important for the long-term prognosis of the CML patients. This is a key step for the prevention of disease progression in CML.

Profilin 1 Is Essential for Retention and Metabolism of Hematopoietic Stem Cells in Bone Marrow

Abstract 1224How stem cells interact with the microenvironment to regulate their cell fates and metabolism is largely unknown. Here we show that, in a hematopoietic stem cell (HSC) -specific inducible knockout model, the cytoskeleton-modulating protein profilin 1 (pfn1) is essential for the maintenance of multiple cell fates and metabolism of HSCs. The deletion of pfn1 in HSCs led to bone marrow failure, loss of quiescence, increased apoptosis, and mobilization of HSCs in vivo. In reconstitution analyses, pfn1-deficient cells were selectively lost from mixed bone marrow chimeras. By contrast, pfn1 deletion did not significantly affect differentiation or homing of HSCs. When compared to wild-type cells, levels of expression of Hif-1a, EGR1, and MLL were lower and an earlier switch from glycolysis to mitochondrial respiration with increased ROS level was observed in pfn1-deficient HSCs. This switch preceded the detectable alteration of other cell fates. Importantly, treatment of pfn1-deficient mice with the antioxidant N-acetyl-l-cysteine reversed the ROS level and loss of quiescence of HSCs, suggesting that pfn1 maintained metabolism is required for the quiescence of HSCs. Furthermore, we demonstrated that expression of wild-type pfn1 but not the actin-binding deficient or poly-proline binding-deficient mutants of pfn1 rescued the defective phenotype of pfn1-deficient HSCs. This result indicates that actin-binding and proline-binding activities of pfn1 are required for its function in HSCs. Thus, pfn1 plays an essential role in regulating the retention and metabolism of HSCs in the bone marrow microenvironment. Disclosures:No relevant conflicts of interest to declare.

Optimal monitoring strategies for guiding when to switch first-line antiretroviral therapy regimens for treatment failure in adults and adolescents living with HIV in low-resource settings

Optimal monitoring strategies for guiding when to switch first-line antiretroviral therapy regimens for treatment failure in adults and adolescents living with HIV in low-resource settings

Reciprocal Regulation between SigK and Differentiation Programs inStreptomyces coelicolor

Here we reported that deletion of SigK (SCO6520), a sigma factor in Streptomyces coelicolor, caused an earlier switch from vegetative mycelia to aerial mycelia and higher expression of chpE and chpH than that in the wild type. Loss of SigK also resulted in accelerated and enhanced production of antibiotics, actinorhodin, and undecylprodigiosin and increased expression of actII-orf4 and redD. These results suggested that SigK had a negative role in morphological transition and secondary metabolism. Furthermore, the sigK promoter (sigKp) activity gradually increased and sigK expression was partially dependent on SigK, but this dependence decreased during the developmental course of substrate mycelia. Meanwhile, two potentially nonspecific cleavages occurred between SigK and green fluorescent protein, and the SigK fusion proteins expressed under the constitutive promoter ermEp* sharply decreased and disappeared when aerial mycelia emerged. If expressed under sigKp, 3FLAG-SigK showed similar dynamic patterns but did not decrease as sharply as SigK expressed under ermEp*. These data suggested that the climbing expression of sigK might reduce the prompt degradation of SigK during vegetative hypha development for the proper timing of morphogenesis and that SigK vanished to remove the block for the emergence of aerial mycelia. Thus, we proposed that SigK had inhibitory roles on developmental events and that these inhibitory effects may be released by SigK degradation.

Biomechanical analysis of gait in patients with painful osteoarthritis of the hip treated with WISH-type hip brace

BackgroundA hip brace, the WISH-type S-form brace, improved hip function scores markedly in patients with painful hip osteoarthritis (OA). To evaluate the biomechanical effects of the brace, gait analysis using a force plate was performed. MethodsFor the gait of seven patients with this hip brace, characteristic parameters calculated from three-dimensional (i.e., vertical, forward, and medial) components of the floor reaction force were analyzed using a flat force plate. ResultsGait analyses revealed several tendencies: a shorter time for one step, a stronger step, and a shift of the center of gravity of the body to the contralateral side. in particular, stronger vertical reaction force at the first peak in the early stance and earlier switch from backward to forward reaction force vectors were observed as effects of the hip brace, with statistically significant difference. ConclusionsThese biomechanical assessments suggest that abnormal gait in hip oA may be closer to normal gait in patients using this brace, although the deceleration and weighing-off effects, which are indicators useful for observing gait recovery, did not reach significance.

Cardiac troponin I at birth is of fetal-neonatal origin

Objective:Neonates produce predominantly skeletal muscle troponin I (TnI) in the myocardium; however, in asphyxiated neonates, high levels of cardiac troponin I (cTnI) have been found. We hypothesised that in these...

Traffic performance evaluation of an optical packet switch with multicast operation

We recently proposed a multicast-enabled optical packet switch architecture utilizing multicast modules. In this paper, we evaluate the traffic performance of our earlier proposed packet switch under a hybrid traffic model through simulations. The multicast packets are given higher priority than unicast packets so that only a small number of multicast modules are needed. The results show that the switch can achieve an acceptable packet loss probability in conjunction with a packet scheduling technique.

An on-line phase measurement system for quality assurance of the BSD 2000. Part II: results of the phase measurement system

Phase constancy and accuracy are significant for regional hyperthermia with phased array radiofrequency hyperthermia systems. They are both necessary for a precise target steering in therapy. For the BSD 2000 system (BSD Medical Corp. Salt Lake City, Utah, USA), the phase values of all channels are checked with a self-developed automatic on-line phase measurement system. On different days the phases are measured under identical conditions, where the output paths are cut off with 50Omega dummy loads to suppress the influence of the radiation conditions of the antennae on the measurement values. The results show how the phase values of the four channels change in the first 30min and from day to day. During this time interval after the start the phases drop down by up to 15. For the time later changes are very slight and the differences from day to day are negligible. The phase shift that occurs in the first 30min is as high as a change of the target point by 1cm. Earlier switching on of the amplifiers prevents this shift occurring during the treatment. The measurement system provides a good tool for determination of phase accuracy and is easy to realize.

Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5'HS3 of the beta-globin locus control region.

Disruption of the gene for transcription factor EKLF (erythroid Krüppel-like factor) results in fatal anaemia caused by severely reduced expression of the adult beta-globin gene, while other erythroid-specific genes, including the embryonic epsilon- and fetal gamma-globin genes, are expressed normally. Thus, EKLF is thought to be a stage-specific factor acting through the CACC box in the beta-gene promoter, even though it is already present in embryonic red cells. Here, we show that a beta-globin gene linked directly to the locus control region (LCR) is expressed at embryonic stages, and that this is only modestly reduced in EKLF-/- embryos. Thus, embryonic beta-globin expression is not intrinsically dependent on EKLF. To investigate whether EKLF functions in the locus control region, we analysed the expression of LCR-driven lacZ reporters. This shows that EKLF is not required for reporter activation by the complete LCR. However, embryonic expression of reporters driven by 5'HS3 of the LCR requires EKLF. This suggests that EKLF interacts directly with the CACC motifs in 5'HS3 and demonstrates that EKLF is also a transcriptional activator in embryonic erythropoiesis. Finally, we show that overexpression of EKLF results in an earlier switch from gamma- to beta-globin expression. Adult mice with the EKLF transgene have reduced platelet counts, suggesting that EKLF levels affect the balance between the megakaryocytic and erythroid lineages. Interestingly, the EKLF transgene rescues the lethal phenotype of EKLF null mice, setting the stage for future studies aimed at the analysis of the EKLF protein and its role in beta-globin gene activation.

Habitat switching by dark-bellied brent geese Branta b. bernicla (L.) in relation to food depletion.

Seasonal changes in the distribution and feeding behaviour of dark-bellied brent geese Branta b. bernicla (L.) and the biomass of their food plants were studied in three successive winters on the Norfolk coast. The data was used, in conjunction with published information, to show how depletion, productivity and mortality of food plants drive the pattern of habitat switching in this species. It is then possible to explain the habitat shifts observed over the last 35 years and predict future changes. On arrival, geese fed first on algal beds and then on salt marsh, grass and arable fields before returning to feed entirely on the salt marsh in spring. The biomass of green algae, and subsequently the salt marsh vegetation, declined during the autumn and this could be attributed to depletion through goose grazing and natural mortality. As depletion occurred the geese fed more intensively, for a greater percentage of time and with an increasing pace rate, the net result, however, was a declining intake rate (as measured by defaecation rate). The algal biomass at which the geese switched from the algal beds to salt marsh was consistent between years, with heavy storm-induced loss of algae in one year resulting in an earlier switch. That the timing of habitat switches may be explained by depletion of food plants was further supported by historical data: the number of brent geese wintering at the site has increased dramatically over the last 30-35 years and the time of switching from algal beds to salt marsh and from salt marsh to salt marsh and fields has become progressively earlier, as expected from the increased depletion. The expected further increase in brent goose numbers will increase the rate of depletion of intertidal vegetation so that the switches between habitats will be more rapid and the geese will move inland earlier and remain inland longer. The expected increase in the brent goose population will thus result in a disproportionate increase in the levels of conflict between brent geese and agriculture.

The5ESSSwitching System: Operations, Administration, and Maintenance Capabilities

The 5ESS™ switching system is a digital, time-division switching system that is being introduced into a multiplicity of operating environments — local, toll, private networks, and stand-alone applications. Many of these operating environments are currently dominated by analog, space-division switching systems. Furthermore, the 5ESS switching system is being introduced into environments in which there have been increasing trends toward centralization and mechanization of operating procedures through the use of minicomputer-based support systems. The 5ESS switching system has been designed to allow a smooth incorporation into these mechanized operating environments, while still retaining features needed for stand-alone operations in less mechanized environments. This paper describes the operational features, both administrative and maintenance, of the 5ESS switching system. The emphasis is on the features that differ from those of earlier stored program control switching systems. These include features that represent enhancements over those of earlier systems, differences mandated by a digital, time-division technology, and features designed to more readily adapt to operations support systems.