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The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor.

2-D electron gas (2DEG) is one of the promising approaches for high thermoelectric (TE) performance. However, high electrical resistance of the film originating from thin 2DEG conduction channel width and thick insulator layer is a bottleneck for obtaining high output power. In this study, we propose stacked GaAs 2DEG thermoelectric generator (TEG), which has a number of stacked channel structures for low electrical resistance. Our GaAs 2DEG TEGs with channels formed in triangular well exhibit ultrahigh TE power factor. In addition, the interfaces of the stacked 2DEG intensify phonon scatterings, resulting in the reduction of thermal conductivity. The stacked 2DEG TEGs exhibit nine times higher sheet electrical conductivity than the unstacked 2DEG one, resulting in ~7.5 times higher output power of stacked 2DEG TEGs (5.1 nW) than that of unstacked 2DEG ones. The cross-sectional TE efficiency factor of stacked 2DEG TEGs reaches $3.7~\mu $ W cm $^{-{2}}$ K $^{-{2}}$ . This value is the highest among various simple planar type film TEGs without cavities under the film. This TEG demonstration will open an avenue for the social application of 2DEG TEG.

IMPORTANCE: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non–small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor–mediated immunosuppression, but further data are needed to support this. OBJECTIVE: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. DESIGN, SETTING, AND PARTICIPANTS: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. INTERVENTIONS: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. RESULTS: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene–positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. CONCLUSIONS AND RELEVANCE: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: jRCT2080224500

A waveguide Josephson array oscillator operating at a frequency of 100 GHz was designed and fabricated to evaluate its pumping capability as a local oscillator (LO) for our proposed SIS mixer-based amplifier, which incorporates SIS up- and down-converters. The LO power requirement was estimated by simulation to be several nanowatts when the SIS up-converter is optimized for noise temperature and conversion gain under the condition that the input port at the microwave frequencies is connected to a practical 50-Ω system. The fabricated waveguide Josephson array oscillator module has 31 Nb Josephson junctions placed at the center of a half-wavelength resonator of an Nb microstripline. The output power from the waveguide oscillator module was evaluated by connecting it to the waveguide SIS detector module in a 4-K cryostat. Photon-assisted tunneling steps were clearly observed, from which the detected power was estimated to be approximately 17 nW at 106 GHz. These results suggest that the Josephson array oscillator is capable of being used in the SIS mixer-based amplifier as the LO.

IMPORTANCE: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. OBJECTIVE: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)–based annotation system. DESIGN, SETTING, AND PARTICIPANTS: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. EXPOSURES: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. RESULTS: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03). CONCLUSIONS AND RELEVANCE: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

We propose a low-noise and low-power-consumption microwave amplifier using superconductor-insulator-superconductor (SIS) mixers as quasi-particle frequency up- and down-converters pumped by a Josephson array oscillator in the millimeter-wave band. A proof-of-concept study of an amplifier with two W-band waveguide mixers using Nb/Al-AlOx/Nb junctions in a cascade connection demonstrated an average gain of 6 dB and a noise temperature of 12 K from nearly DC to 5 GHz. We also designed and fabricated a Josephson array oscillator at 100 GHz, which consisted of 31 overdamped Josephson junctions placed at each half-wavelength in an Nb microstrip line. The estimated output power of the oscillator was 0.2 μW at 100 GHz, which can be increased by increasing the number of the oscillator junctions. These results suggest that the proposed SIS mixer-based amplifier is suitable for on-chip integrated circuits to be implemented in large-scale multipixel SIS receivers and quantum computers.

Low birth weight (LBW) is associated with neonatal mortality and sequelae of lifelong health problems; prioritizing the most promising antenatal interventions may guide resource allocation and improve health outcomes.

Study design: A cross-sectional explanatory study. Objectives: To clarify the nerve root condition and the association between nerve root cross-sectional area (CA) on ultrasonography (US) and other examinations such as MRI or compound muscle action potentials (CMAPs) in degenerative cervical spine diseases. Setting: A university hospital in Japan. Methods: Fifty-one patients diagnosed with proximal cervical spondylotic amyotrophy (CSA) (13 patients), cervical radiculopathy of C5 or C6 nerve root (CR) (26 patients), or cervical spondylotic myelopathy (CSM) (12 patients), and twenty-nine healthy volunteers were included in this study. Neurological findings, US findings and CMAPs of deltoid and biceps muscles of all participants were evaluated. In addition, CSA, CR, and CSM patients underwent MRI. Results: A significant correlation was not observed between CA and CMAP amplitude or foraminal diameter on MRI (P> 0.05). In the US examination, the C6 CA of the affected side of the CR group was significantly larger than that of both the normal side and the other groups (P< 0.001). The C5 CA of the affected side of the CSA group clearly showed a bimodal distribution: enlarged and small CA groups. In the CMAP findings, CSA cases respectively showed the lower amplitude of deltoid and bicep CMAPs on both the normal and the affected side (P ≦ 0.01). CSM and healthy volunteers were nearly identical in CA and CMAPs. Conclusion: Utilizing US in addition to NCS and MRI can contribute towards an evaluation of the nerve root condition of degenerative cervical spine disease. Sponsorship: no sponsorship.

Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti–PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC.

Background: During esophagectomy for esophageal cancer, meticulous attention is needed to prevent thermal injury to the vital organs, such as the recurrent laryngeal nerve (RLN) and tracheobronchus. In order to clarify the novel mechanism behind thermal injury induced by energy devices, we investigated the temperature of steam with the use of two different devices under wet and dry conditions. Methods: An ultrasonic device (Sonicision™) and a vessel sealing device (Ligasure™) were studied. We evaluated the temperature at the tip of the devices and the steam when the devices were activated under different grasping ranges, under four different combinations of device and muscle, and under four different wet/dry conditions (dry–dry, dry–wet, wet–dry, and wet–wet). Results: Although the maximum temperature of the devices was significantly higher with Sonicision™ than with Ligasure™, the maximum temperature of the steam was significantly higher with Ligasure™ than with Sonicision™ in almost all situations. At 1 mm away from Sonicision™, the critical temperature more than 60 °C was observed only when used with one-third grasping range under the wet–dry or the wet–wet conditions. In case of Ligasure™, high-temperature steam was observed when used with one-third grasping under the wet–dry or the wet–wet condition and two-third grasping under the dry–wet, the wet–dry, or the wet–wet condition. Under the wet condition, the emission of steam from the non-grasping part of Ligasure™ caused a spike in temperature that exceeded the critical temperature. Conclusion: We demonstrated that the use of energy devices under a wet condition generates steam from the non-grasping part of the devices. The temperatures of steam from Ligasure™ were significantly higher than that from Sonicision™. To prevent thermal injury to the vital organs, a very attentive and meticulous surgical technique is imperative considering the characteristics of each device.

ABSTRACTIntroduction: Platinum-based chemotherapy is the current first-line standard therapy for unresectable malignant pleural mesothelioma (MPM). Recently, immune-checkpoint inhibitors (ICI) have been intensively investigated as treatment options for this disease. Nivolumab, an anti-programmed cell death (PD)-1 agent, was one of the first drugs used and is representative of available ICIs.Areas covered: This review discusses previous relevant reports and current ongoing trials of nivolumab. The efficacy and safety of nivolumab have been investigated mostly in second-line or later treatment settings as both monotherapy and in combination with other ICIs. Particularly, nivolumab monotherapy yielded promising efficacy with an objective response rate of 29% and median overall survival of 17.3 months in salvage settings in the single-arm, Japanese phase 2 trial (MERIT). Notably, the study led to Japanese approval of nivolumab for unresectable recurrent MPM. Several trials with monotherapy or cotherapy with nivolumab have commenced, including randomized trials of nivolumab monotherapy vs. placebo in the salvage setting, and cotherapy with nivolumab and ipilimumab vs. the platinum doublet in the frontline setting.Expert opinion: Nivolumab seems like a reasonable option for unresectable, relapsed MPM despite the lack of randomized trial data. Ongoing pivotal trials will confirm its efficacy.

Purpose:To examine with intravascular ultrasound (IVUS) the crossing pathways of the TruePath reentry device during primary antegrade recanalization of infrainguinal chronic total occlusions (CTOs). Methods:Between July 2017 and September 2018, a prospective multicenter study enrolled 143 consecutive patients (mean age 75±9 years; 101 men) with 146 CTOs treated in an antegrade approach using the TruePath reentry device with IVUS assessment of the crossing pathway in successful cases. Outcome measures were complete success (reentry device reached the distal true lumen), assisted success (reentry device use followed by a conventional guidewire to reach the distal true lumen), reentry device crossing route by IVUS assessment, and procedure- and device-related complications. Regression analyses were employed to identify any relevant associations between baseline patient variables and the outcome measures; results are presented as the odds ratio (ORs) and 95% confidence interval (CI). Results:Complete success was achieved in 82 (56.2%) lesions; any success (complete plus assisted) was documented in 117 (80.1%) lesions. Four (3%) perioperative device-related complications were observed. The crossing route was intraplaque for most of the total crossing distance in both complete success cases (95.3%±13.2%) and any success cases (94.8%±14.4%), with relatively short subintimal (3.6%±10.2% and 4.2%±11.2%, respectively) or intramedial (1.2%±5.8% and 1.0%±5.4%, respectively) crossing. CTO length was a significant risk factor for not achieving complete success (OR 1.74, 95% CI 1.13 to 2.68, p=0.012), and a history of failed revascularization was associated with not achieving any success (OR 6.40, 95% CI 1.28 to 28.9, p=0.038). Conclusion:The intraplaque route was the primary pathway taken by the TruePath reentry device as it crossed infrainguinal CTOs. Crossing rates were acceptable, with few device-related complications. However, a longer CTO length and a failed revascularization history negatively affected the success rate.

SCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial.

Purpose: Clinical trials have demonstrated that high-dose drug-coated balloon (HD-DCB) and polymer-based drug-eluting stent (PB-DES) treatments for femoropopliteal (FP) artery disease have favorable outcomes. However, which one would be better remained unrevealed.Methods: This study used the databases of 2 large-scale multicenter prospective drug-coated balloon (DCB) and drug-eluting stent (DES) registries. The study included 2470 patients with symptomatic FP lesion treated with IN.PACT Admiral DCB or Eluvia DES at 69 centers. A propensity-score–based paired analysis was conducted. Primary endpoint was 1-year restenosis rate. Secondary endpoints were 1-year reocclusion rate, target lesion revascularization (TLR), acute thrombosis, bypass conversion, major amputation, major adverse limb event (MALE), and all-cause death.Results: A total of 1535 patients were treated with HD-DCB, and 935 patients were treated with PB-DES. The propensity-score matching extracted 678 pairs, with no remarkable intergroup difference in baseline characteristics. The 1-year restenosis rate was significantly lower in the PB-DES group than in the HD-DCB group (16.0% vs 22.0%, p=0.016). The other endpoints (reocclusion rate, TLR, acute thrombosis, bypass conversion, major amputation, MALE, and all-cause death) did not differ between the groups. No baseline characteristics had any significant interaction effect on the association of HD-DCB vs PB-DES with restenosis risk (all p>0.05).Conclusions: This study demonstrated that the 1-year TLR, reocclusion rate, and other endpoints did not differ between the PB-DES group and the HD-DCB group despite the lower restenosis in the PB-DES group.Clinical Impact One-year restenosis rate was significantly lower in the polymer-based DES group than in the high-dose DCB group for foemoropopliteal disease. However, there is no difference in the other endpoints between two groups.

Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX.

Byline: Naoko Kozuki You've tried everything on those flaky feet of yours. Maybe you need the Garra rufa treatment? These tiny fish nibble away dead skin and are used as [...]

Research has been conducted on prokaryotic and eukaryotic genomes. The authors describe their study of the di-, tri- and tetranucleotide frequencies in these genomes carried out via the use of self-organized map and the unsupervized neural network algorithms.

Analysis of pooled clinical data has shown the safety of 3 months of dual antiplatelet therapy with everolimus-eluting cobalt–chromium stents (Co-Cr EESs). This study evaluated early and mid-term vascular responses to Co-Cr EESs in patients with stable coronary artery disease.

Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined.

Purpose:To assess calcium patterns in superficial femoral artery (SFA) disease before and after balloon angioplasty ± stent implantation using fluoroscopy, angiography, and intravascular ultrasound (IVUS) imaging and then correlate calcification severity and midterm clinical outcomes. Materials and Methods:A multicenter investigation was carried out to retrospectively review 130 symptomatic patients (mean age 73.2±8.4 years; 86 men) with de novo SFA lesions who had successfully undergone endovascular therapy (EVT) at 7 centers between January and October 2015. The primary outcome was lumen gain measured as minimum lumen area (MLA) in post-EVT IVUS images according to calcification severity. The secondary outcomes included rates of stent malapposition, restenosis, and clinically-driven target lesion revascularization (TLR). Results:A total of 102 (78.5%) cases had calcification in the lesions over a mean length of 64.3±72.8 mm. Of these, 70 cases were classified as having bilateral calcification according to fluoroscopy and angiography; 50 (49%) lesions had ≥180° calcification according to IVUS. The lumen gain in calcified lesions was significantly smaller than in the 28 noncalcified lesions (14.1±4.4 vs 17.8±5.2 mm2, p<0.001). IVUS-evaluated circumferential distribution of calcium (<180° or ≥180°) was independently associated with lumen gain after EVT (p<0.001). Among the calcification characteristics, a calcification angle ≥180° showed the strongest correlation to postprocedure MLA. Moreover, the restenosis rate was significantly higher in the severe (≥180°) calcification group (p<0.018). The severity of calcification was also associated with the risk of stent malapposition (p=0.022 for trend) but not TLR (p=0.57). Conclusion:IVUS evaluation of calcification in SFA lesions predicted lumen gain after EVT. Severe calcification in a ≥180° arc prevented successful dilation of the lesion with either plain balloon angioplasty or a nitinol stent. Accurate assessment of calcification patterns by IVUS is useful in maximizing the efficacy of endovascular therapy.

Abstract The fatigue crack retardation mechanisms operating after an overload event are investigated for a bainitic steel using high spatial resolution energy dispersive synchrotron X-ray diffraction. The elastic crack-tip strain fields are mapped at mid-thickness of compact tension samples at R-ratios of 0.1 and 0.4. The same overload stress intensity factor (KOL = 60 MPa m1/2) is applied in each case with the cracks then propagating under the same applied stress intensity range, ΔKapp = 27 MPa m1/2. The competing retardation mechanisms are directly quantified and separated, with the associated fatigue crack growth (FCG) rates then being predicted according to a 2-parameter Walker-type assessment and validated against those measured. The stress intensity factor associated with the overload residual stress field is calculated using a weight function approach. For R = 0.1 , shielding from residual stress controls retardation when crack growth through the overload plastic zone, r p O L , is small (specifically < 0.6 r p O L ). For more extensive crack growth, discontinuous crack closure controls the retardation behaviour, with significant load transfer across opposing crack faces being observed at minimum load (for R = 0.1). These crack face tractions are associated with the plastic asperity created during overload. The traction forces holding the crack faces open at minimum load are, for the first time, used to directly quantify the associated stress intensity factor, K m i n t r a c t as a function of crack growth. While no crack shielding is expected, nor observed, for R = 0.4 , the variation in FCG rate after overload is explained by changes in effective R-ratio. [ABSTRACT FROM AUTHOR]

Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown.

High-level METamplification (METamp) is a primary driver in ∼1%–2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1–63.4), and the median duration of response is 14.3 months (95% CI, 2.8–not estimable). In exploratory biomarker analyses, focal METamp, RB1wild-type, MYCdiploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992).

We have successfully demonstrated low-noise and wideband SIS mixers for the 275-500-GHz radio-frequency (RF) band, aiming to cover Atacama Large Millimeter/submillimeter Array band 7 (275-373 GHz) and band 8 (385-500 GHz) simultaneously. The waveguide SIS mixers integrate a multisection impedance transformer with a parallel-connected-twin-junction or single-junction circuits based on Nb/AlN/Nb trilayers with a critical current density of 31 kA/cm2. In order to achieve the targeted broadband performance, we designed an asymmetric one-side waveguide probe placed across a reduced height waveguide with dimensions 100 μm × 580 μm. The shape of the waveguide probe was optimized to have nearly constant impedance at around 35 Ω in the desired RF range. For evaluation of the receiver performance, we have established a dual-band noise temperature measurement system. The system implements a broadband corrugated horn antenna and a 15-dB RF/local oscillator (LO) waveguide coupler based on WR-2.3 (290 μm × 580 μm) waveguide size. The target bandwidth is too wide for typical LO sources at these high frequencies, and, therefore, we applied a dual-band LO injection system utilizing two different LO sources and an LO diplexer. The IF chain uses a cryogenic isolator and a low-noise amplifier with a typical noise temperature of 2.1 K over the 4-8-GHz range. The measured double sideband receiver noise temperature is two to three times the quantum noise at all LO frequencies for both the twin-junction and the single-junction circuits.

Supplemental Digital Content is available in the text.

Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years; male sex, 47%; performance status of 0 to 1, 80%; HER2 status IHC 3+, 33%; HER status IHC 2+/fluorescence in situ hybridization–positive, 20%; and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging; thus, additional molecular approaches are warranted.

A novel scale that lets nurses assess the levels of nausea and vomiting that a patient feels is described. This tool can help in the assessment of these two well-known problems for postoperative and oncology patients.

Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.

Time-lapse microscopy is the only method that can directly capture the dynamics and heterogeneity of fundamental cellular processes at the single-cell level with high temporal resolution. Successful application of single-cell time-lapse microscopy requires automated segmentation and tracking of hundreds of individual cells over several time points. However, segmentation and tracking of single cells remain challenging for the analysis of time-lapse microscopy images, in particular for widely available and non-toxic imaging modalities such as phase-contrast imaging. This work presents a versatile and trainable deep-learning model, termed DeepSea, that allows for both segmentation and tracking of single cells in sequences of phase-contrast live microscopy images with higher precision than existing models. We showcase the application of DeepSea by analyzing cell size regulation in embryonic stem cells.

Although drug-eluting stents have significantly reduced the midterm incidence of target lesion revascularization (TLR), in vivostudies on long-term vessel healing of sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs) are limited. The aim of this study was to compare long-term arterial healing with SESs and PESs.

Background:Intrapartum hypoxic events (“birth asphyxia”) may result in stillbirth, neonatal or postneonatal mortality, and impairment. Systematic morbidity estimates for the burden of impairment outcomes are currently limited. Neonatal encephalopathy (NE) following an intrapartum hypoxic event is a strong predictor of long-term impairment.Methods:Linear regression modeling was conducted on data identified through systematic reviews to estimate NE incidence and time trends for 184 countries. Meta-analyses were undertaken to estimate the risk of NE by sex of the newborn, neonatal case fatality rate, and impairment risk. A compartmental model estimated postneonatal survivors of NE, depending on access to care, and then the proportion of survivors with impairment. Separate modeling for the Global Burden of Disease 2010 (GBD2010) study estimated disability adjusted life years (DALYs), years of life with disability (YLDs), and years of life lost (YLLs) attributed to intrapartum-related events.Results:In 2010, 1.15 million babies (uncertainty range: 0.89–1.60 million; 8.5 cases per 1,000 live births) were estimated to have developed NE associated with intrapartum events, with 96% born in low- and middle-income countries, as compared with 1.60 million in 1990 (11.7 cases per 1,000 live births). An estimated 287,000 (181,000–440,000) neonates with NE died in 2010; 233,000 (163,000–342,000) survived with moderate or severe neurodevelopmental impairment; and 181,000 (82,000–319,000) had mild impairment. In GBD2010, intrapartum-related conditions comprised 50.2 million DALYs (2.4% of total) and 6.1 million YLDs.Conclusion:Intrapartum-related conditions are a large global burden, mostly due to high mortality in low-income countries. Universal coverage of obstetric care and neonatal resuscitation would prevent most of these deaths and disabilities. Rates of impairment are highest in middle-income countries where neonatal intensive care was more recently introduced, but quality may be poor. In settings without neonatal intensive care, the impairment rate is low due to high mortality, which is relevant for the scale-up of basic neonatal resuscitation.

Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries.

We studied the high-resolution imaging of a new bio-electron microscope that uses a DLC film as a bulkhead to separate the electron beam source and the sample room. The electron beam source can be setup in a vacuum container, thus placing the sample being observed through the microscope under atmospheric pressure. In order to observe the sample, a thin film penetrable by electrons is required as the bulkhead. In addition, it needs to be strong enough to endure the atmospheric pressure, and the material must be medically safe. This investigation has shown that DLC film is the best film for this purpose, given the influence that the distance of the atmospheric layer has on image acquisition. Moreover, although the acceleration voltage of the present system is 30 kV, it is advised that observations are made at the lowest acceleration possible.

Our study objective was to examine how maternal social support and depressive symptoms are associated with time to completion of childhood vaccinations. We used cross-sectional data from 582 randomly-selected, low-income Brazilian children. Adjusted Cox proportional hazard models were used to estimate time to completing the first three recommended oral polio and diphtheria, pertussis and tetanus (DPT) vaccinations as well as their booster doses. Among only the women with low social support, each ten-point increase on the Medical Outcomes Study—Social Support Scale was associated with a 20% increased chance of completing the first three recommended vaccinations for polio and DPT at any given time (HR = 1.20, 95% CI 1.02–1.42). Although falling short of statistical significance, also among mothers with low social support, we found a suggestive finding of increased social support associated with 25% greater chance of completing polio and DPT booster vaccines at any given time (HR = 1.25, 95% CI 0.98–1.60). There was no association between maternal depressive symptoms and vaccination completion. Among mothers with little social support, increased social support may be important for timely completion of vaccinations in low-income Brazilian children. Longitudinal studies and research on mechanisms explaining associations between maternal social support and childhood vaccination are needed.

A population pharmacokinetic (PK) model for meropenem in Japanese pediatric patients with various infectious diseases was developed based on 116 plasma concentrations from 50 pediatric patients. The population PK parameters developed in this analysis are useful for calculation of the percent time above minimum inhibitory concentration (%T>MIC) and for optimal dosing of meropenem in pediatric patients. After dosing at 20mg/kgt.i.d. by 0.5-h infusion (approved standard dose for pediatric patients in Japan), the target value of 50%T>MIC was achieved, indicating that 20mg/kgt.i.d. by 0.5-h infusion is effective for susceptible bacteria. In contrast, for bacteria with higher MICs such as Pseudomonas aeruginosa(MIC ≥ 2μg/mL), the probability of target attainment of 50%T>MIC was 60.7% at a dose of 40mg/kgt.i.d. by 0.5-h infusion (highest dose approved for pediatric patients in Japan). The simulations described in this article indicated that 40mg/kgt.i.d. with a longer infusion duration (e.g., 4h) is more effective against bacteria with a MIC higher than 2μg/mL. The predicted probability of target attainment for 50%T>MIC (97.0%) was well correlated not only to the microbiological efficacy rate (97.0%) but also to the clinical efficacy rate (95.9%) in the present phase 3 study.

A trend toward the lack of interest in academic careers has been observed in Medicine, including in the area of Anesthesiology. The objective of the present study was to research the interest of physicians specializing in Anesthesiology in following an academic career, as well as identify the determinant factors of this choice.

DNA topoisomerase II enzymes regulate essential cellular processes by altering the topology of chromosomal DNA. These enzymes function by creating transient double-stranded breaks in the DNA molecule that allow the DNA strands to pass through each other and unwind or unknot tangled DNA. Because of the integral role of topoisomerases in regulating DNA metabolism, these enzymes are vital for cell survival. Several clinically active antitumor agents target these enzymes. Mammalian cells contain two topoisomerase II isozymes that are encoded by different genes: topoisomerase II and II. Although, both isozymes are homologous and exhibit similar catalytic activity, they are differentially regulated and are involved in distinct biological functions. The topoisomerase II and topoisomerase II enzymes are regulated by post-translational modifications, including sumoylation, ubiquitination and phosphorylation. These posttranslational modifications influence the biologic and catalytic activity of the enzyme and affect sensitivity of cells to topoisomerase II-targeted drugs. In this review, we describe how the catalytic and biologic activity of the topoisomerase II enzyme is regulated and discuss the mechanisms by which chemotherapeutic agents that target these enzymes function. Given the potential importance of site-specific modifications, in particular phosphorylation, in regulating sensitivity to topoisomerase II-targeted drugs, we discuss the potential role of altered topoisomerase II phosphorylation in development of drug resistance, which is often a limiting factor in the treatment of cancer.

Urinary retention is a common condition in the post-anesthetic care unit (PACU). Vesical overdistension and consequent damage of the detrusor muscle of the urinary bladder represent situations that can be prevented. The ultrasound allows the reliable measurement of the urinary volume, determining the prevalence of postoperative vesical distension. The objective of the present study was to determine the prevalence of postoperative urinary retention and identify independent predictive factors.

This paper examines the market potential for international rail-based intermodal services along the REORIENT Corridor, which spans 11 countries from the Baltic (Scandinavia) to the Mediterranean (Greece) through the accession countries of the European Union. The main approach followed in this assessment is to conduct scenario analyses using a state-of-the-art intermodal freight network modeling capability, which allows the evaluation of various service supply strategies under varying operational and policy scenarios. New service design options, developed through a combination of market-based research and expert opinion, are evaluated in regard to the potential addressable market demand and the likelihood of successfully competing for that demand. The analyses provide realistic assessments of the potential competitiveness of rail in attracting freight demand resulting from (a) operational considerations that pertain to the proposed services and (b) implementation of interoperability directives and barrier-removing or barrier-reducing improvements in physical, operational, or managerial aspects and business practices of the rail system that are aimed toward achieving European Commission policy objectives. In addition, the analysis points to characteristics of the demand, which is most likely to shift toward rail, in regard to commodity types and geographic location. The key question the paper seeks to answer is under what operational and policy conditions can pan- European intermodal rail freight services be competitive? Results show that prerequisites for success are a combination of favorable rail policies and the intermodal operations' high level of service.

A 29-year-old male who underwent a complete tetralogy of Fallot repair at 2 years of age was referred to our hospital for treatment of sustained ventricular tachycardia (VT). The bipolar voltage map using an electroanatomical mapping system (CARTO, Biosense-Webster. during sinus rhythm revealed a low voltage area identical to the site of the right ventricular outflow tract (RVOT. patch on the anterior wall of the RVOT. During the tachycardia, the activation wavefront was found to revolve in a counterclockwise manner around the patch in the RVOT. Two radiofrequency catheter ablation (RFCA. sessions creating a line between the patch in the RVOT and pulmonary artery achieved only transient success. He underwent a pulmonary valve replacement and reconstruction of the RVOT with a transannular patch to treat the VT refractory to RFCA and severe pressure gradient in the RVOT. In postoperative electrophysiological study, a low voltage area in the RVOT connected to the pulmonary artery with the patch was observed, and produced conduction block in the reentry circuit of the VT. The patient has been free from any VT recurrence during 6 months of follow up.

The aim of this paper is to evaluate the cyclic interfacial strength between thin film and its substrate by cyclic nano-indentation tests. The specimen used in this study is PET substrate/ITO coatings layered specimen. From the indentation load and displacement curve, we proposed an evaluation method for the interfacial strength. The results are good agreement with the interfacial strength evaluated by peel test. After cyclic indentations, the surface profile was observed by atomic force microscope. The number of elongates increased with indentation cycles when the indentation load is low, whereas elongates number is almost constant under high load cases. These phenomena can be explained by simple models. In this study, two types of fracture modes are proposed. They are “subsidiary fracture mode” and “buckling mode”.

This pilot study aimed to examine the effectiveness of visual-feedback therapy for individuals with psychotic disorders. Visual-feedback therapy combines structured psychodynamic therapy and visual feedback achieved via an electronic monitoring medication cap to increase insight about medication behaviours. Thirty subjects were randomly assigned either to visual feedback or to a supportive counselling group. Medication adherence was measured by both electronic monitoring and blood plasma drug concentration levels. The results showed that, at the end of the 3-month, intervention (bimonthly sessions), adherence rates of the visual-feedback group slightly increased, but declined during the course of the study for the supportive counselling control group (P0.026).

Cu contamination control is critically important in Cu interconnect device manufacturing lines. The frontside gas protected spin cleaning enables the effective removal of the Cu contaminant from the backside and bevel of a wafer. A small area on the bevel was measured for cleaning efficiency using SOR (Synchrotron Orbital Radiation) X-ray fluorescence. The atomic level Cu removal was detected on the bevel surface with the barrier metal Ta existing wafers. The high energy SOR X-ray analysis makes it possible to measure the Cu contamination, where conventional methods do not work.