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Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Sugammadex has been used for more than ten years in Australia and New Zealand and has been implicated as an effective treatment, and in some cases a potential cause, of a critical incident. We aimed to identify and analyse critical incidents involving sugammadex reported to webAIRS, a de-identified voluntary online critical incident reporting system in Australia and New Zealand. We identified 116 incidents where the reporter implicated sugammadex as either a cause (23 cases) or a treatment (93 cases) during anaesthesia. There were 17 incidents suggestive of sugammadex anaphylaxis, although not all were confirmed by skin testing. There were six incidents when bradycardia was temporally related to sugammadex administration, although it was not possible to exclude other causes or contributory factors. There were nine incidents in which sugammadex was used to reverse aminosteroid-related neuromuscular blockade successfully in a ‘can’t intubate, can’t oxygenate’ (CICO) situation, and a further 67 incidents in which sugammadex was used to reverse aminosteroid neuromuscular blockade as part of the management of other critical incidents. While sugammadex was used during the management of 16 cases of anaphylaxis, there was no clear indication that this altered the course of the anaphylaxis in any of the cases. These reports indicate that sugammadex can be a potential trigger for anaphylaxis and that its use may be associated with the development of significant bradycardia. However, it is not possible to estimate or even speculate on the incidence of these sugammadex-related incidents on the basis of voluntary reporting to a database such as webAIRS. The reports also indicate that sugammadex has been used successfully to reverse residual or deep aminosteroid neuromuscular blockade in critical incident situations and to help rescue CICO scenarios. These findings provide further support for ensuring the ready availability of sugammadex wherever aminosteroid muscle relaxants are used.

Introduction: Identifying differences in outcome of basilar artery occlusion (BAO) between males and females may be useful in aiding clinical management. Recent studies have demonstrated widespread underrepresentation of women in acute stroke clinical trials. This international multicentre study aimed to determine sex differences in outcome after mechanical thrombectomy (MT) for patients with acute BAO. Methods: We performed a retrospective analysis of consecutive patients with BAO who had undergone MT in seven stroke centres across five countries (Singapore, Taiwan, United Kingdom, Sweden, and Germany), between 2015 and 2020. Primary outcome was a favourable functional outcome measured by a modified Ranking Scale (mRS) of 0–3 at 90 days. Secondary outcomes were mRS 0–3 upon discharge, mortality, symptomatic intracranial haemorrhage (sICH) and subarachnoid haemorrhage (SAH). Results: Among the 322 patients who underwent MT, 206 (64.0%) patients were male and 116 (36.0%) were female. Females were older than males (mean ± SD 70.9 ± 14.3 years vs. 65.6 ± 133.6 years; p = 0.001) and had higher rates of atrial fibrillation (38.9% vs. 24.2%; p = 0.012). Time from groin puncture to reperfusion was shorter in females than males (mean ± SD 57.2 ± 37.2 min vs. 71.1 ± 50.9 min; p = 0.021). Despite these differences, primary and secondary outcome measures were similar in females and males, with comparable rates of favourable 90-day mRS scores (mean ± SD 46 ± 39.7 vs. 71 ± 34.5; OR = 1.20; 95% confidence interval [CI] = 0.59–2.43; p = 0.611), favourable discharge mRS scores (mean ± SD 39 ± 31.6 vs. 43 ± 25.9; OR = 1.38; 95% CI = 0.69–2.78; p = 0.368) and in-hospital mortality (mean ± SD 30 ± 25.9 vs. 47 ± 22.8; OR = 1.15; 95% CI = 0.55–2.43; p = 0.710. Rates of complications such as sICH (mean ± SD 5 ± 4.3 vs. 9 ± 4.4; OR = 0.46; 95% CI = 0.08–2.66; p = 0.385) and SAH (mean ± SD 4 ± 3.4 vs. 5 ± 2.4; OR = 0.29; 95% CI = 0.03–3.09; p = 0.303) comparably low in both groups. Conclusion: Females achieved comparable functional outcomes compared with males after undergoing MT for BAO acute ischemic stroke.

PURPOSE To elicit end-user and stakeholder perceptions regarding design and implementation of an inpatient clinical deterioration early warning system (EWS) for oncology patients to better fit routine clinical practices and enhance clinical impact. METHODS In an explanatory-sequential mixed-methods study, we evaluated a stakeholder-informed oncology early warning system (OncEWS) using surveys and semistructured interviews. Stakeholders were physicians, advanced practice providers (APPs), and nurses. For qualitative data, we used grounded theory and thematic content analysis via the constant comparative method to identify determinants of OncEWS implementation. RESULTS Survey respondents generally agreed that an oncology-focused EWS could add value beyond clinical judgment, with nurses endorsing this notion significantly more strongly than other clinicians (nurse: median 5 on a 6-point scale [6 = strongly agree], interquartile range 4-5; doctors/advanced practice providers: 4 [4-5]; P = .005). However, some respondents would not trust an EWS to identify risk accurately (n = 36 [42%] somewhat or very concerned), while others were concerned that institutional culture would not embrace such an EWS (n = 17 [28%]). Interviews highlighted important aspects of the EWS and the local context that might facilitate implementation, including (1) a model tailored to the subtleties of oncology patients, (2) transparent model information, and (3) nursing-centric workflows. Interviewees raised the importance of sepsis as a common and high-risk deterioration syndrome. CONCLUSION Stakeholders prioritized maximizing the degree to which the OncEWS is understandable, informative, actionable, and workflow-complementary, and perceived these factors to be key for translation into clinical benefit.

This article presents the architecture and design methodology for a new type of dual-band Doherty power amplifier (DB-DPA), referred to as 3-Way DB-DPA, which consists of a main amplifier for each band and an auxiliary amplifier handling both bands. The 3-Way DB-DPA improves the average drain efficiency in concurrent dual-band operation compared to the traditional 2-Way DB-DPA, by avoiding early clipping in the main amplifiers, while benefiting from load—pulling from the auxiliary power amplifier (PA). This improvement is verified in theory and simulation at the current-source reference planes and in measurement with a fabricated 1.5- and 2-GHz dual-band PA. A statistical analysis using 2-D continuous-wave (CW) signals with long-term evolution (LTE) probability distribution functions (PDFs) is performed and demonstrated an improvement in the concurrent average efficiency by 15 percentage points compared to the conventional 2-Way DB-DPA. In nonconcurrent operation, the measured CW drain efficiency in the lower band (1.5 GHz) is 82.8% at peak and 66.6% at 9.6-dB backoff, and the measured CW drain efficiency in the upper band (2.0 GHz) is 70.0% at peak and 48.4% at 9.4-dB backoff. The CW concurrent-balanced drain efficiency reaches 66.2/52.0% in the 3-Way DB-DPA at 3-/6-dB backoff. In single-band operation at 1.5/2.0 GHz, the average power and average drain efficiency after linearization by digital predistortion (DPD) are 35.1/37.4 dBm and 65.0/53.7%, respectively, for an LTE signal with 10-MHz bandwidth and 6.1-dB peak-to-average power ratio (PAPR). In concurrent operation, the 3-Way DB-DPA is driven by two 10-MHz LTE uncorrelated signals at 1.5 GHz with 6.86-dB PAPR and at 2.0 GHz with 6.26-dB PAPR, and the average total power and average concurrent drain efficiency after DPD are 37.5 dBm and 54.24%, respectively.

BACKGROUNDWhile inhaled corticosteroids (ICS) are considered the essential foundation of most asthma therapy, ICS inhaler nonadherence is a notoriously common problem and a significant cause of asthma-related morbidity. Partially acknowledging the problem of nonadherence, international organizations recently made paradigm-shifting recommendations that all patients with mild-to-moderate persistent asthma be considered for symptom-driven ICScontaining inhalers rather than relying on adherence to traditional maintenance ICS inhalers and symptom-driven short-acting beta-agonists (SABA). With this new approach, asthma patients are at least exposed to the important anti-inflammatory effects of ICS-containing inhalers when their symptom reliever inhaler is deployed due to acute symptoms. METHODSThis study will ( Part 1 ) complete a pragmatic randomized-controlled trial to evaluate if an inhaler strategy that utilizes symptom-driven ICS inhalers is particularly beneficial in maintenance ICS inhaler non-adherent asthma patients, and ( Part 2 ) use a dissemination and implementation (D&I) science conceptual framework to better understand patients’ and providers’ views of inhaler nonadherence. This study, which will have an option of taking place entirely remotely, will use a Food and Drug Administration (FDA)-approved electronic sensor (Hailie® sensor) to monitor inhaler adherence and includes semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR). DISCUSSIONThis study is assessing the problem of nonadherence using a D&I implementation science research lens while testing a new inhaler approach to potentially ameliorate the detrimental consequences of maintenance inhaler nonadherence. We hypothesize that the use of a symptom-driven ICS/LABA management strategy, as compared to traditional maintenance ICS treatment and symptom-driven SABA, will lead to improved adherence to an asthma treatment strategy, decreased asthma-related morbidity, less cumulative ICS exposure, and greater patient satisfaction with an inhaler approach. TRIAL REGISTRATIONThe study was registered via ClinicalTrials.gov on November 8, 2021. The registration number is NCT05111262.

A new type of wideband dual-input hybrid Doherty outphasing power amplifier (HDO-PA) is developed in which the load-modulation scheme continuously converts as the frequency increase, from the previously reported HDO-PA mode with maximum flat efficiency response versus power to the conventional Doherty PA mode. For a symmetric HDO-PA implementation, this corresponds to the peak-to-backoff fundamental voltage ratio of the auxiliary amplifier linearly varying from 9/7 to 2 with frequency. A transmission-line-based wideband HDO-PA prototype is first established at the current-source reference planes to cover the frequency band from 1.4-GHz to 2.5-GHz. The wideband HDO-PA is implemented next at the package reference planes by synthesizing the wideband combiner circuit required to sustain the intrinsic load-modulation behavior across the entire frequency bandwidth. A 1.4-GHz to 2.5-GHz wideband HDO-PA is fabricated and characterized using both continuous-wave and modulated signals. The 6-dB backoff efficiency varies from 60% to 44% and the maximum power from 44.8 dBm to 42.9 dBm as the frequency increases. When the PA is excited with a 20 MHz bandwidth long-term evolution signal at 1.7 GHz with 6.5 dB peak-to-average-power ratio (PAPR), the PA achieves an average drain efficiency of 50.3% with −32.0 dBc adjacent-channel-power leakage ratio (ACLR) and an average drain efficiency of 47.8% with −54.0 dBc ACLR after digital predistortion linearization.

Although photoactivated localization microscopy offers the potential to interrogate protein interactions in the physiological environment of a cell, uncertainties in the detection efficiency of photoactivatable proteins lead to complications with data interpretation. Here, we present a numerical model that provides probabilities to detect neighboring molecules dependent on their oligomerization status, density, detection efficiency, and radius, and can be used to assess oligomeric states or detection efficiencies of two molecular species. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry., This numerical model provides nearest neighbor probabilities as a function of oligomerization, detection efficiency, molecular density, and detection radius. Thereby, the model does not only clarify the theoretical basis for the correct interpretation of primary PALM data ‐ we define minimal detection efficiencies required to resolve oligomers as a function of molecular density and detection radius ‐, but also provides the PALM user with a tool to differentiate distinct oligomers of one or two proteins.

Cancer cells in culture rely on glutamine as an anaplerotic substrate to replenish tricarboxylic acid (TCA) cycle intermediates that have been consumed. but it is uncertain whether cancers in vivo depend on glutamine for anaplerosis. Here, following in vivo infusions of [13C5]-glutamine in mice bearing subcutaneous colon cancer xenografts, we showed substantial amounts of infused [13C5]-glutamine enters the TCA cycle in the tumors. Consistent with our prior observation that colorectal cancers (CRCs) with oncogenic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic (PIK3CA) subunit are more dependent on glutamine than CRCs with wild type PIK3CA, labeling from glutamine to most TCA cycle intermediates was higher in PIK3CA-mutant subcutaneous xenograft tumors than in wild type PIK3CA tumors. Moreover, using orthotopic mouse colon tumors estalished from human CRC cells or patient-derived xenografts, we demonstrated substantial amounts of infused [13C5]-glutamine enters the TCA cycle in the tumors and tumors utilize anaplerotic glutamine to a greater extent than adjacent normal colon tissues. Similar results were seen in spontaneous colon tumors arising in genetically engineered mice. Our studies provide compelling evidence CRCs utilizes glutamine to replenish the TCA cycle in vivo, suggesting that targeting glutamine metabolism could be a therapeutic approach for CRCs, especially for PIK3CA-mutant CRCs.

Low-power consumption and low-voltage operation are critical enabling features for Internet of Things (IoT) devices that are powered from energy harvesting. This paper presents a chaos-based true random number generator (TRNG) that can operate at an ultra-low voltage (ULV) and be integrated into energy-constrained IoT devices for secure communications. Folded Bernoulli maps are adopted for random number generation. Switched-capacitor chaotic circuits utilize bulk-driven amplifiers to mitigate gate leakage issue, two-stage comparators to increase voltage headroom, and low-complexity calibration schemes to ensure robustness. This system covers a wide range of process and temperature variations while consuming 142 nW from a 0.4 V supply at a bit rate of 10 kb/s. The generated bits pass National Institute of Standards and Technology (NIST) Pub-800.22 randomness tests successfully.

Introduction and hypothesis: In patients with acute ischemic stroke with large vessel occlusion (AIS-LVO), the role of intra-arterial adjunctive medications (IAM) like urokinase, tPA or glycoprotein IIb/IIIa inhibitors, during mechanical thrombectomy (MT) has not been clearly established. We hypothesize that AIS-LVO patients treated with both MT + IAM (rescue or concurrent) achieve better safety and efficacy outcomes than patients treated with MT alone and aim to determine the efficacy and safety of concomitant or rescue IAM for AIS-LVO patients undergoing MT. Methods: We searched Medline, Embase and Cochrane Stroke Group Trials Register databases from inception until 13th March 2020. We analysed all studies with patients diagnosed with AIS-LVO in the anterior or posterior circulation, that provided data for the two treatment arms: 1)MT+IAM and 2)MT-only, and also reported on at least one of the following outcomes: reperfusion, 90-days modified Rankin Scale (mRS), symptomatic intracranial hemorrhage (sICH) and 90-days mortality. Data were collated in accordance with the PRISMA guidelines. Results: Sixteen non-randomized observational studies with a total of 4581 patients were analysed. MT-only was performed in 3233 (70.6%) patients, while 1348 (29.4%) patients were treated with both MT+IAM. As compared to patients treated with MT alone, patients treated with combination therapy (MT +IAM) had a higher likelihood of achieving good functional outcome (risk ratio=1.13, 95% CI 1.03-1.24) and a lower risk of 90-day mortality (risk ratio=0.82, 95% CI 0.72-0.94). There was no significant difference in successful reperfusion (risk ratio=1.02, 95% CI 0.99-1.06) and sICH between the two groups (risk ratio = 1.13, 95% CI 0.87-1.46) (Figure 1). Conclusions: In AIS-LVO, use of IAM together with MT may achieve better functional outcomes and lower mortality rates. Randomized controlled trials are warranted to confirm the safety and efficacy of IAM as adjunctive treatment of MT.

Introduction: Endovascular thrombectomy(EVT) is considered standard of care for anterior circulation acute ischemic stroke(AIS) with large vessel occlusion(LVO). Young AIS-LVO patients have distinctly different underlying stroke mechanisms and etiologies. Methods: In this multicenter cohort study conducted from August 2014 to January 2020, we investigated the safety and effectiveness of EVT in young AIS-LVO patients aged≤50 years and evaluated associations between demographics, stroke etiology, neuroimaging factors and clinical outcomes, including functional outcomes, in-hospital mortality and symptomatic intracranial haemorrhage(sICH) in univariable and multivariable regression models. Results: 275 AIS-LVO patients from 10 tertiary centers in Germany, Sweden, Singapore and Taiwan were included. The more common TOAST subtypes included cardioembolism (82/275, 29.8%) and stroke of undetermined etiology (85/275, 30.9%). Arterial dissection was the most prevalent stroke etiology (42/195, 21.5%) and had the highest rate of good functional outcomes (29/42, 69.0%). Successful reperfusion was achieved in 85.1% (234/275). Excellent and good functional outcomes were achieved in 48.0% (132/275) and 66.0% (182/275) respectively. sICH occurred in 6.5% (18/275). National Institute of Health Stroke Scale (NIHSS) at presentation was inversely related with good functional outcomes (aOR0.92, 95% CI 0.88- 0.96 per point increase, p Conclusion: While differences in functional outcomes exist across varying stroke aetiologies, high rates of successful reperfusion and good outcomes are generally achieved in young AIS-LVO patients undergoing EVT.

A front-end adaptive folder with a filter is presented to instantaneously push jammers to higher frequencies while preserving the integrity of small signals of interest. A programmable filter is utilised to further suppress folded jammers for achieving a widely scalable dynamic range over a large frequency range. To achieve maximum programmability with a minimal increase of power and area, combinatorial intrinsic device characteristics are exploited to tune folding points for rapid adaptation to a changing electromagnetic environment.

The putative vector of trachoma, Musca sorbens, prefers to lay its eggs on human faeces on the ground. This study sought to determine whether M. sorbens females were attracted to volatile odours from human faeces in preference to odours from the faeces of other animals, and to determine whether specific volatile semiochemicals mediate selection of the faeces. Traps baited with the faeces of humans and local domestic animals were used to catch flies at two trachoma-endemic locations in The Gambia and one in Ethiopia. At all locations, traps baited with faeces caught more female M. sorbens than control traps baited with soil, and human faeces was the most successful bait compared with soil (mean rate ratios 44.40, 61.40, 10.50 [P, Author summary Musca sorbens, also known as the Bazaar Fly, visits people’s faces to feed on ocular and nasal discharge. While feeding, M. sorbens can transmit Chlamydia trachomatis, the bacterium that causes the infectious eye disease trachoma. Around 1.9 million people worldwide are visually impaired or blind from this disease. Although it is believed that M. sorbens transmits trachoma, very few studies have looked at ways to control this fly. A large-scale trial has shown that control of fly populations with insecticide reduces active trachoma disease prevalence. Odour-baited traps for the suppression of disease vector populations are an attractive option as there is no widespread spraying of insecticide; however, highly attractive baits are critical to their success. Here, we demonstrate that the preference of these flies for breeding in human faeces is probably mediated by odour cues, and we isolate chemicals in the odour of human faeces that cause a response in the antennae of M. sorbens. These compounds may play a role in the specific attractiveness of human faeces to these flies, perhaps by being present in greater amounts or at favourable ratios. These may be developed into a chemical lure for odour-baited trapping to suppress M. sorbens populations.

This paper reports the first demonstration of the behavior modeling and predistortion linearization of a power amplifier (PA) for periodic modulated signals using a vector network analyzer (VNA) operated in the receiver mode. In this demonstration a PA operated at 2.3 GHz is characterized using a 5 MHz LTE signal with a peak-to-average power ratio (PAPR) of 10.2 dB. The phases of the Fourier spectrum of the periodic signal measured by the VNA receiver are calibrated using a 20 MHz OFDM signal. The calibrated phases and amplitudes of the 5 MHz LTE signal in the frequency domain are then used to reconstruct the signal in the time domain. After synchronization, the NMSE, dynamic AM-AM and AM-PM, ACPR, EVM, and BER of the PA before and after predistortion can then be calculated from the measured data. The predistortion linearization of the PA validates the accuracy of the VNA phase calibration and synchronization methodology used for the modulated waveforms. This work demonstrates that the same VNA and calibrated testbed can be used to characterize both the (1) continuous-wave (CW) and (2) modulated nonlinear response of a device without breaking electrical contacts with it.

Photoactivatable and -convertible fluorescent proteins (PA-FPs) have been used in fluorescence live-cell microscopy for analyzing the dynamics of cells and protein ensembles. Thus far, no method has been available to quantify in bulk and in live cells how many of the PA-FPs expressed are photoactivated to fluoresce. Here, we present a protocol involving internal rulers, i.e., genetically coupled spectrally distinct (photoactivatable) fluorescent proteins, to ratiometrically quantify the fraction of all PA-FPs expressed in a cell that are switched on to be fluorescent. Using this protocol, we show that different modes of photoactivation yielded different photoactivation efficiencies. Short high-power photoactivation with a confocal laser scanning microscope (CLSM) resulted in up to four times lower photoactivation efficiency than hundreds of low-level exposures applied by CLSM or a short pulse applied by widefield illumination. While the protocol has been exemplified here for (PA-)GFP and (PA-)Cherry, it can in principle be applied to any spectrally distinct photoactivatable or photoconvertible fluorescent protein pair and any experimental set-up.

A 7GS/s 6b sub-ranging ADC is implemented in 32nm CMOS SOI with reconfigurable comparators, and adjustable input differential pairs are exploited to change converter characteristics for hardware-based cybersecurity. To achieve low-power consumption at high-speed operation with small-size transistors, an on-chip calibration to reduce process mismatches is utilized in the design. The presented ADC achieves an SNDR of 33.06 dB at Nyquist frequency and consumes only 15mW with a figure-of-merit of 58.3 fJ/conv-step.

Low-power time-interleaved ADCs with high sampling rates of over 10GS/s are in high demand for wireline communication systems. However, the time-interleaved channels suffer from process mismatch, particularly for timing skew. Although a power-consuming two-rank track-and-hold (T/H) can prevent such timing-skew problems, distributed T/Hs can be used for lower-power operation with timing-skew calibration to meet the skew specifications of 200fsrms for 6b resolution and 10GHz input signals. Instead of using software calibration with Fourier analysis [1-3], requiring a special input reference signal [4], or relying on the statistics of the input signal [5], this work presents a low-complexity on-chip background calibration technique to reduce gain, offset, and delay mismatches between channels. This enables small-size transistors to be used in comparators and clock delivery circuits to avoid serious noise coupling and save considerable power for such an ultra-high-speed system. The presented 8-way time-interleaved 20GS/s 6b ADC achieves an SNDR of 30.7dB at Nyquist and consumes only 69.5mW.

The crystallization kinetics of barium carbonate crystals in the absorption of CO2 gas and reactive crystallization with barium chloride solution within pH range 12–13 was explored in a continuous lab-scale bubble-column scrubber under a constant pH environment. In considering the agglomeration of crystals, a population balance model with well mixed scrubber was proposed to determine the crystallization kinetic data by simultaneously including nucleation rate, agglomeration kernel and growth rate, using the first three moments. Investigation parameters focused on the pH of the solution, liquid concentration, liquid flow rate, gas concentration and gas flow rate. The effect of these parameters on the crystallization kinetics was explored. Herein, liquid concentration and liquid flow rate were found to be the dominant factors significantly influencing both nucleation rate and agglomeration kernel, while the pH of the solution had a moderate influence. Correlation expressions of the kinetic data were also discovered and analyzed further. Evidence indicated that particle size was limited by the nucleation rate, agglomeration kernel and mean residence time.