Conventional control methods include voltage-mode and current-mode control for power supply engineers to learn and study. Hysteretic control topologies and their advantages are less well known. A ...pure hysteretic control may not be possible for some sensitive engineering applications, such as medical applications. The main practical disadvantage of hysteretic topology in its fundamental form is that switching frequency varies. This is because the switching frequency is not determined by a clock or synchronization signal. Rather, switching frequency is determined by the amount of hysteresis, system delays, and external components of the system. The immediate objective of this research project is to analyze and combine two fundamental control topologies, pulse-width modulation (PWM) and pure hysteretic control, in order to develop a hysteretic-based controller with the speed of pure hysteretic mode and fixed switching frequency.This hysteretic-based controller achieves correction speed equal to pure hysteretic control in part by transferring compensation components from the feedback loop to the power converter stage. The error amplifier was removed as well from the feedback path. As a result, a comparator would perform the functions of an error amplifier and pulse width modulator. Through a passive adder, a synthesized signal was coupled to the minus terminal of the comparator along with the feedback signal from the converter power stage in order to achieve power stage output regulation and fixed switching frequency. On the positive terminal of the comparator, the reference generator was applied. The basic hysteretic-based controller was enhanced with additional components to achieve a solution that can be used in any DC-DC converter application that requires complete control of the power converter.For verification, mathematical modelling and SPICE simulations were performed on the hysteretic-based controller. Finally, a functional prototype was built from standard off-the-shelf components. Key measurements were conducted and compared with simulation results.
Low-rise light-frame wood structures are commonly used for residential construction in North America. It is important that detailed connections be provided to ensure the integrity of such buildings. ...While nails, spikes, and staples are common fastening methods, metal framing connections are becoming increasingly popular. Light metal framing connectors are prefabricated and used to replace conventional joints such as toe-nailing or end-nailing. All purpose framing anchors are a popular type of light metal framing connection, because of their versatility and adaptability to a variety of conventional light-frame wood construction joint applications. A framing anchored joint is more costly than a conventional nailed joint, however, in some applications this increase is justified by considering strength, fabrication time, and convenience. Manufacturers of these connectors provide allowable safe working loads, based on static load tests, which design engineers use in their analysis. Earthquake and wind produce dynamic loads and, therefore, both the static and dynamic performance of these joints must be established in order to achieve an understanding of the behavior of light-frame wood structures. This investigation involved characterizing the static and cyclic behavior of a common framing anchored wood connection experimentally, and analyzing the joint theoretically. This was then compared to the results of a typical end-nailed connection. Static one-directional lateral load tests revealed that the framing anchored joints had a greater ultimate load than the conventional end-nailed joints. Average equivalent viscous damping ratios measured near 16% for both framing anchored and end-nailed connections. Testing of frames subjected to sinusoidal motions revealed that the static stiffness overestimates the dynamic response. Static and dynamic models were formulated which provided a reasonable assessment of the joint behavior.
Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS ...activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.
An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients aged ≤21 years), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001).
Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven 10% of 68 patients in the NTRK fusion-positive safety population and in 18 5% of 355 patients in the overall safety-evaluable population) and anaemia (8 12% and 16 5%). The most common serious treatment-related adverse events were nervous system disorders (three 4% of 68 patients and ten 3% of 355 patients). No treatment-related deaths occurred.
Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.
Ignyta/F Hoffmann-La Roche.
We conducted a phase II study of combination of the anti-insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non-small-cell ...lung cancer (NSCLC).
Patients were randomly assigned (2:1) to paclitaxel 200 mg/m(2), carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI(10-20) patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI(20) was enrolled on completion of the randomized study.
A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI(10) and 50 patients received PCI(20) in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI(20)/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship.
These data suggest that PCI(20) is safe and effective in patients with NSCLC.
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates ...to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation ...procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.
Pentacene stands out as a model molecule among organic semiconductors due to its ability to form well-ordered films that show a high field effect mobility. We discuss the processes involved in ...pentacene film growth, emphasizing differences with respect to inorganic films. The influence of growth parameters such as the substrate nature and temperature, the deposition rate, and the kinetic energy of the molecular beam on the structure and morphology of pentacene films are discussed. Finally, we overview recent attempts to model pentacene film nucleation and growth, and draw attention to the role of dislocations.
Recent literature suggests that the future of surgeon-scientists in the US has been threatened for the past several decades. However, we documented an overall increase in NIH funding for ...surgeon-scientists, as well as the number of NIH-funded surgeons, from 2010 to 2020.
NIH-funded principal investigators (PIs) were identified for June 2010 and June 2020 using the NIH internal data platform iSearch Grants (version 2.4). Biographical sketches were searched for key terms to identify surgeon-scientists. Grant research types and total grant costs were collected. American Association of Medical Colleges data were used to determine total surgeon and physician populations. Bivariate chi-square analyses were performed using population totals and were corroborated using z-tests of population proportions using JMP (version 13.0.0). A 2-tailed p value <0.05 was considered significant.
In June of 2020, a total of 1,031 surgeon-scientists held $872,456,710 in NIH funding. The percentage of funded surgeons significantly increased from 2010 (0.5%) to 2020 (0.7%) (p < 0.05), and the percentage of funded other physicians significantly decreased from 2.2% in 2010 to 1.6% in 2020 (p < 0.05). All surgeons sustained R grant funding at both time points (58% in 2020 and 60% in 2010), and specifically maintained basic science-focused R grants (73% in 2020 and 78% in 2010).
Our study found surgeon-scientists are increasing in number and NIH funding and are becoming more diverse in their research efforts, while maintaining a focus on basic science.
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Use of plasma proteomic and hematological biomarkers represents a promising approach to provide useful diagnostic information for assessment of the severity of hematopoietic acute radiation syndrome. ...Eighteen baboons were evaluated in a radiation model that underwent total-body and partial-body irradiations at doses of Co gamma rays from 2.5 to 15 Gy at dose rates of 6.25 cGy min and 32 cGy min. Hematopoietic acute radiation syndrome severity levels determined by an analysis of blood count changes measured up to 60 d after irradiation were used to gauge overall hematopoietic acute radiation syndrome severity classifications. A panel of protein biomarkers was measured on plasma samples collected at 0 to 28 d after exposure using electrochemiluminescence-detection technology. The database was split into two distinct groups (i.e., "calibration," n = 11; "validation," n = 7). The calibration database was used in an initial stepwise regression multivariate model-fitting approach followed by down selection of biomarkers for identification of subpanels of hematopoietic acute radiation syndrome-responsive biomarkers for three time windows (i.e., 0-2 d, 2-7 d, 7-28 d). Model 1 (0-2 d) includes log C-reactive protein (p < 0.0001), log interleukin-13 (p < 0.0054), and procalcitonin (p < 0.0316) biomarkers; model 2 (2-7 d) includes log CD27 (p < 0.0001), log FMS-related tyrosine kinase 3 ligand (p < 0.0001), log serum amyloid A (p < 0.0007), and log interleukin-6 (p < 0.0002); and model 3 (7-28 d) includes log CD27 (p < 0.0012), log serum amyloid A (p < 0.0002), log erythropoietin (p < 0.0001), and log CD177 (p < 0.0001). The predicted risk of radiation injury categorization values, representing the hematopoietic acute radiation syndrome severity outcome for the three models, produced least squares multiple regression fit confidences of R = 0.73, 0.82, and 0.75, respectively. The resultant algorithms support the proof of concept that plasma proteomic biomarkers can supplement clinical signs and symptoms to assess hematopoietic acute radiation syndrome risk severity.
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