bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal Tolerance Allocation for Tolerance Stack-Ups
Authors: Dresner Thomas L. , Barkan Philip
Published: March 2021

The allocation of individual tolerances that form critical stack-ups is an important task in mechanical design. It is desirable, but difficult in practice, to allocate tolerances to obtain all required stack-ups at minimum cost. A minimum-cost allocation method is proposed here that works for both a single tolerance stack-up and for multiple tolerance stack-ups that share one or more individual tolerances. Tolerances can be optimally allocated for both worst case and a variety of 6σ statistical cases. The method is applicable to one-dimensional stack-ups and to multi-dimensional stack-ups with known sensitivity functions. It is a numerical Lagrange multiplier method that is more general than the Lagrange multiplier methods that have often been proposed. The basic method will almost always provide the lowest cost result when the manufacturing process to produce each toleranced dimension has been firmly established in advance. An exact method for efficiently extending the basic method to determine the lowest cost process for producing each dimension is also introduced.
Approximating Eigenvalues and Eigenvectors Using Padé Approximants
Authors: Vance Judy M. , Bernard James E.
Published: March 2021

Design optimization of finite element-based structures can be very compute intensive thus inhibiting interactive design. The research presented here outlines a fast method for approximating eigenvalues and eigenvectors across a wide range of design changes. An optimization scheme is described that combines Padé Approximants with curve-fitting techniques to achieve good approximations for large design changes.
On the Semantics of Generative Geometry Representations
Authors: Hoffmann Christoph M.
Published: March 2021

We argue that geometry constructs and solid operations currently emerging in commercial, feature-based CAD systems are without an appropriate semantic foundation, and that a rigorous semantics poses significant research problems. In particular, we argue that a formalization of feature attachment and other generative constructs in the presence of geometric constraints cannot be based solely on conventional boundary representation or on current geometry standards.
A Weighted Algorithm for Sculptured Surface Design
Authors: Wang Qifu , Gao Shande , Zhou Ji , Yu Jun
Published: March 2021

A new algorithm for constructing sculptured surfaces is presented in this paper. The basic idea of the algorithm is to control the shape of a surface by changing the weight values of the drive curves and the generator curves. With this algorithm, the shape of the surface can be designed conveniently. So far this algorithm has been practically used in a modeling system developed by the author, and proven to be flexible and efficient.
Data Probe: A Tool for EXPRESS-Based Data
Authors: Morris K. C.
Published: March 2021

The problem of sharing data has many facets. The need to share data across multiple enterprises, different hardware platforms, different data storage paradigms and systems, and a variety of network architectures is growing. The emerging Standard for The Exchange of Product Model Data (STEP), being developed in the International Organization for Standardization (ISO), addresses this need by providing information models, called application protocols, which clearly and unambiguously describe data. The validity of these information models is essential for success in sharing data in a highly automated engineering environment.

This paper describes the Data Probe: a tool for examining, editing, and managing EXPRESS-based data. The Data Probe tool supports the validation of STEP application protocols. The paper includes a description of the software architecture, the initial implementation, and plans for future enhancements. The software is designed as independent components which can be incorporated into other STEP-related systems or software requiring general purpose editing tools for structured information.

The initial version of the Data Probe tool is based on two implementation mechanisms defined within STEP: the conceptual modeling language EXPRESS and the STEP exchange file format. Future work will focus on integrating a database system into the software. The software architecture and the use of object-oriented techniques enables code reusability and system extensibility and has been instrumental for a phased implementation.

The software is under development at the National Institute of Standards and Technology and is in the public-domain. The software supports the Validation Testing System, part of the Application Protocol Development Environment, at the CALS-sponsored National PDES Testbed. (PDES, Product Data Exchange using STEP, is the U.S. effort in support of the international standard.)
Lubricin as a tool for controlling adhesion in vivo and ex vivo
Authors: Manasa Clayton S. , Silva Saimon M. , Desroches Pauline E. , Dennaoui Jessair , Russo Mathew J. , Han Mingyu , Quigley Anita F. , Greene George W. , Kapsa Robert M. I. , Moulton Simon E.
Published: March 2021

The ability to prevent or minimize the accumulation of unwanted biological materials on implantable medical devices is important in maintaining the long-term function of implants. To address this issue, there has been a focus on materials, both biological and synthetic, that have the potential to prevent device fouling. In this review, we introduce a glycoprotein called lubricin and report on its emergence as an effective antifouling coating material. We outline the versatility of lubricin coatings on different surfaces, describe the physical properties of its monolayer structures, and highlight its antifouling properties in improving implant compatibility as well as its use in treatment of ocular diseases and arthritis. This review further describes synthetic polymers mimicking the lubricin structure and function. We also discuss the potential future use of lubricin and its synthetic mimetics as antiadhesive biomaterials for therapeutic applications.
The Effects of Combined Balance and Complex Training Versus Complex Training Only on Measures of Physical Fitness in Young Female Handball Players
Authors: Chaabene Helmi , Negra Yassine , Sammoud Senda , Moran Jason , Ramirez-Campillo Rodrigo , Granacher Urs , Prieske Olaf
Published: March 2021

Purpose: To examine the effects of balance exercises conducted prior to complex training (bCT) versus complex training (CT) only on measures of physical fitness in young female elite handball players. Methods: Participants aged 17 years were randomly assigned to bCT (n = 11) or CT (n = 12). The 2 training interventions lasted 8 weeks with 2 sessions per week in replacement of some technical/tactical handball exercises and were matched for total training volume. Before and after training, tests were performed for the evaluation of proxies of muscle power (countermovement jump height, standing long-jump distance, and reactive strength index), muscle strength (back half-squat 1-repetition maximum), dynamic balance (Y-balance test), linear sprint speed (20-m sprint test), and change-of-direction speed (T test). Results: Two-factor repeated-measures analysis of variance revealed significant group × time interactions for the reactive strength index (d = 0.99, P = .03) and Y-balance test score (d = 1.32, P < .01). Post hoc analysis indicated significant pre–post reactive strength index improvements in CT (d = 0.69, P = .04) only. For the Y-balance test, significant pre–post increases were found in bCT (d = 0.71, P = .04) with no significant changes in CT (d = 0.61, P = .07). In addition, significant main effects of time were observed for half-squat 1-repetition maximum, countermovement jump, standing long jump, and T test performance (d = 1.50 to 3.10, P < .05). Conclusions: Both bCT and CT interventions were effective in improving specific measures of physical fitness in young elite female handball players. If the training goal is to improve balance in addition, balance exercises can be conducted within a CT training session and prior to CT exercises.
Baylor University’s Football Stadia: Life Before McLane Stadium
Authors: Seifried Chad , Demiris Tiffany E. , Petersen Jeffrey
Published: March 2021

The present study offers a descriptive history of the football grounds at Baylor from 1894 to 2014. The current review identifies important individuals and notable events that impacted the football facilities at Baylor. Moreover, the contextual factors influencing each period of change were recognized, and it was determined if Baylor’s facilities followed the pattern of other regional peers. In the case of Baylor, football ultimately created social anchors for the institution and Waco because the increasing popularity and commercial interest in college football produced spectacles capable of providing a unique campus spirit. Next, the spectacle of football and spirit both established and improved alumni relationships and corresponded with interest in elevating the prestige of the university and city to attract students, visitors, and businesses to operate in the area. Finally, the construction of various Baylor football playing grounds produced significant media attention capable of boosting enrollments and recognition that Baylor was a major university.
Key human embryo stage mimicked in the lab
Authors: Leslie Mitch
Published: March 2021

Four research teams report growing cellular clusters that resemble human blastocysts.
Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10
Authors: Saxton Robert A. , Tsutsumi Naotaka , Su Leon L. , Abhiraman Gita C. , Mohan Kritika , Henneberg Lukas T. , Aduri Nanda G. , Gati Cornelius , Garcia K. Christopher
Published: March 2021

Cryo-EM helps engineer enhanced IL-10

Interleukin-10 (IL-10) binds to the IL-10 receptor (IL-10R), comprising two high-affinity α chains and two low-affinity β chains. Depending on the cellular context of its recognition, IL-10 can either suppress or activate immune responses. This pleiotropic behavior has complicated efforts to use IL-10 as an anti-inflammatory agent. Saxton
et al.
generated a high-affinity version of IL-10 (super-10), which allowed them to visualize IL-10 in complex with both IL-10Rα and IL-10Rβ by cryo–electron microscopy (cryo-EM). This enabled them to engineer additional variants of IL-10 with variable IL-10Rβ–binding affinities. Some of the partial agonists exhibited biased actions on myeloid cells, which exhibited anti-inflammatory properties without concomitant CD8 T cell activation. These findings may serve as a blueprint for future enhanced cytokine–based therapeutics.

Science
, this issue p.
eabc8433
Tandem In
2
O
3
-Pt/Al
2
O
3
catalyst for coupling of propane dehydrogenation to selective H
2
combustion
Authors: Yan Huan , He Kun , Samek Izabela A. , Jing Dian , Nanda Macy G. , Stair Peter C. , Notestein Justin M.
Published: March 2021

Overcoming propylene oxidation

Catalysts for the oxidative dehydrogenation of propane to propylene and water become less selective with increasing conversion because propylene itself is more readily oxidized than propane. Yan
et al.
created nanoscale tandem catalysts by growing an ∼2-nanometer shell of indium oxide, a selective hydrogen combustion catalyst, over a propane dehydrogenation catalyst, platinum nanoparticles supported on alumina spheres (see the Perspective by Pei and Gong). This overcoat exposed the platinum nanoparticles for propane dehydrogenation. Surface hydrogen atoms were oxidized at the indium oxide–platinum interface. This approach boosted yields of propylene to up to 30%.

Science
, this issue p.
1257
; see also p.
1203
Early developmental asymmetries in cell lineage trees in living individuals
Authors: Fasching Liana , Jang Yeongjun , Tomasi Simone , Schreiner Jeremy , Tomasini Livia , Brady Melanie V. , Bae Taejeong , Sarangi Vivekananda , Vasmatzis Nikolaos , Wang Yifan , Szekely Anna , Fernandez Thomas V. , Leckman James F. , Abyzov Alexej , Vaccarino Flora M.
Published: March 2021

Genomic sleuthing spots early divergence

After fertilization, the human zygote divides into two cells. Fasching
et al.
used genomic analysis from cellular samples taken much later in development to back-calculate the cell division trees that went before. Although the first cell division in human development looks symmetrical from the outside, the fates followed by daughter cells from each of those first two blastomeres are anything but the same. As much as 90% of blood cells are derived from just one of the first two blastomeres.

Science
, this issue p.
1245
Landmarks of human embryonic development inscribed in somatic mutations
Authors: Bizzotto Sara , Dou Yanmei , Ganz Javier , Doan Ryan N. , Kwon Minseok , Bohrson Craig L. , Kim Sonia N. , Bae Taejeong , Abyzov Alexej ,   NIMH Brain Somatic Mosaicism Network, Park Peter J. , Walsh Christopher A.
Published: March 2021

Mutations provide an enduring record

Somatic mutations pepper our cells with change, but because they are not in the germline, they do not propagate to the next generation. Bizzotto
et al.
leveraged data on the distribution of somatic mutations in adults to take a backward look at the earliest moments of human development. Calculation of cellular lineages on the basis of shared somatic mutations shows the number of cells from which the body will develop when the human embryo gastrulates. The lineage for forebrain cells is identifiable, as are the asymmetrical fates spun out of many of the gastrula cells.

Science
, this issue p.
1249
Timing the SARS-CoV-2 index case in Hubei province
Authors: Pekar Jonathan , Worobey Michael , Moshiri Niema , Scheffler Konrad , Wertheim Joel O.
Published: March 2021

Backtracking a pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have had a history of abortive human infections before a variant established a productive enough infection to create a transmission chain with pandemic potential. Therefore, the Wuhan cluster of infections identified in late December of 2019 may not have represented the initiating event. Pekar
et al.
used genome data collected from the early cases of the COVID-19 pandemic combined with molecular clock inference and epidemiological simulation to estimate when the most successful variant gained a foothold in humans. This analysis pushes human-to-human transmission back to mid-October to mid-November of 2019 in Hubei Province, China, with a likely short interval before epidemic transmission was initiated.

Science
, this issue p.
412
Lewis Wolpert (1929–2021)
Authors: Tickle Cheryll , Slack Jonathan
Published: March 2021

Pioneering developmental biologist
FNR-Type Regulator GoxR of the Obligatorily Aerobic Acetic Acid Bacterium
Gluconobacter oxydans
Affects Expression of Genes Involved in Respiration and Redox Metabolism
Authors: Schweikert Stefanie , Kranz Angela , Yakushi Toshiharu , Filipchyk Andrei , Polen Tino , Etterich Helga , Bringer Stephanie , Bott Michael
Published: March 2021

Gluconobacter oxydans
serves as a cell factory for oxidative biotransformations based on membrane-bound dehydrogenases and as a model organism for elucidating the metabolism of acetic acid bacteria. Surprisingly, to our knowledge none of the more than 100 transcriptional regulators encoded in the genome of
G. oxydans
has been studied experimentally until now.
Separate Upper Pathway Ring Cleavage Dioxygenases Are Required for Growth of Sphingomonas wittichii Strain RW1 on Dibenzofuran and Dibenzo-
p
-Dioxin
Authors: Mutter Thamer Y. , Zylstra Gerben J.
Published: March 2021

S. wittichii
RW1 has been the subject of numerous investigations, because it is one of only a few strains known to grow on DXN as the sole carbon and energy source. However, while the genome has been sequenced and several DBF pathway enzymes have been purified, there has been very little research using physiological techniques to precisely identify the genes and enzymes involved in the RW1 DBF and DXN catabolic pathways.
Microbial Ecological Mechanism for Long-Term Production of High Concentrations of
n
-Caproate via Lactate-Driven Chain Elongation
Authors: Zhu Xiaoyu , Feng Xin , Liang Cheng , Li Jiabao , Jia Jia , Feng Leiyu , Tao Yong , Chen Yinguang
Published: March 2021

Our research revealed the microbial network of the LCE reactor microbiome for
n-
caproate production at high concentrations, which will provide a foundation for designing or engineering the LCE reactor microbiome to recover
n
-caproate from organic waste streams in the future. In addition, the hypothetical model of the reactor microbiome that we proposed may offer guidance for researchers to find the underlying microbial mechanism when they encounter low-efficiency
n
-caproate production from the LCE process.
COVID-19 lockdown impact on the physical activity of adults with progressive muscle diseases
Authors: Roberts-Lewis Sarah F , Ashworth Mark , White Claire M , Rose Michael R
Published: March 2021

Introduction

This short article summarises findings about reduced physical activity of adults with progressive muscle disease as a result of COVID-19 lockdown.

Methods

As part of an ongoing longitudinal cohort study, we prospectively and objectively measured physical activity using accelerometry at baseline in 2019 and follow-up in 2020. A subset of 85 participants incidentally had follow-up data collected during the first UK COVID-19 lockdown from 23 March to 4 July 2020. Thus, for this cohort we had activity data from before and during the COVID-19 pandemic and we were able to prospectively and accurately quantify the changes in their physical activity.

Results

Our data highlighted reduced overall activity intensity and reduced light activity time in particular.

Conclusions

From our findings, we can infer specific evidence-based recommendations about how to redress inactivity secondary to COVID-19 restrictions for adults with progressive muscle diseases. These recommendations are likely to be generalisable to other groups who are vulnerable to functional decline secondary to prolonged inactivity.
Changes in central venous to arterial carbon dioxide gap (PCO2gap) in response to acute changes in ventilation
Authors: Shastri Lisha , Kjærgaard Benedict , Rees Stephen Edward , Thomsen Lars Pilegaard
Published: March 2021

Background

Early diagnosis of shock is a predetermining factor for a good prognosis in intensive care. An elevated central venous to arterial PCO2difference (∆PCO2) over 0.8 kPa (6 mm Hg) is indicative of low blood flow states. Disturbances around the time of blood sampling could result in inaccurate calculations of ∆PCO2, thereby misrepresenting the patient status. This study aimed to determine the influences of acute changes in ventilation on ∆PCO2and understand its clinical implications.

Methods

To investigate the isolated effects of changes in ventilation on ∆PCO2, eight pigs were studied in a prospective observational cohort. Arterial and central venous catheters were inserted following anaesthetisation. Baseline ventilator settings were titrated to achieve an EtCO2of 5±0.5 kPa (VT= 8 mL/kg, Freq = 14 ± 2/min). Blood was sampled simultaneously from both catheters at baseline and 30, 60, 90, 120, 180 and 240 s after a change in ventilation. Pigs were subjected to both hyperventilation and hypoventilation, wherein the respiratory frequency was doubled or halved from baseline. ∆PCO2changes from baseline were analysed using repeated measures ANOVA with post-hoc analysis using Bonferroni’s correction.

Results

∆PCO2at baseline for all pigs was 0.76±0.29 kPa (5.7±2.2 mm Hg). Following hyperventilation, there was a rapid increase in the ∆PCO2, increasing maximally to 1.35±0.29 kPa (10.1±2.2 mm Hg). A corresponding decrease in the ∆PCO2was seen following hypoventilation, decreasing maximally to 0.23±0.31 kPa (1.7±2.3 mm Hg). These changes were statistically significant from baseline 30 s after the change in ventilation.

Conclusion

Disturbances around the time of blood sampling can rapidly affect the PCO2, leading to inaccurate calculations of the ∆PCO2, resulting in misinterpretation of patient status. Care should be taken when interpreting blood gases, if there is doubt as to the presence of acute and transient changes in ventilation.
Disability, sexual and reproductive health: a scoping review of healthcare professionals’ views on their confidence and competence in care provision
Authors: Craig Lucy Emma , Chen Zhong Eric , Barrie Joanne
Published: March 2021

Background

The sexual and reproductive needs of people with disabilities are often unmet. Healthcare professionals play an important role in meeting these needs.

Objective

To explore the views of healthcare professionals on their confidence and competence in providing sexual and reproductive healthcare to people with disabilities.

Methodology

Two databases were searched yielding 14 studies included in the review. Studies detailing healthcare professionals’ experiences working in the subject area were included alongside results and evaluations of staff training/workshops within the area. Search results were screened for eligibility by the first and second authors and any discrepancies were resolved by the third author. All subsequent stages were carried out by the first author and reviewed by the second and third authors.

Results

The study's findings indicate that there is a lack of training, guidelines, patient contact, time, teamwork and collaboration between staff, and a lack of awareness/access to resources within this area. Evaluations of training programmes/workshops showed an increase in knowledge, comfort and skills surrounding the subject. Continuous training would be beneficial to ensure these are maintained at a high level.

Conclusions

Overall healthcare professionals felt they lack confidence and competence in providing sexual and reproductive healthcare to people with disabilities. Further research in this area is recommended to assess this in more depth. Development of guidelines, multidisciplinary training programmes and further resources for both staff and patients are recommended.
Access to sexual healthcare during New Zealand’s COVID-19 lockdown: cross-sectional online survey of 15–24-year-olds in a high deprivation region
Authors: Rose Sally B , Garrett Susan M , McKinlay Eileen M , Morgan Sonya J
Published: March 2021

Background

New Zealand’s response to the COVID-19 pandemic involved a nationwide stay-at-home lockdown in March–April 2020 that restricted access to primary healthcare services.

Methods

An online survey of 15–24-year-olds in a high deprivation region of New Zealand asked about the need for, and receipt of, sexual healthcare during lockdown. Experience of telehealth and preferences for future receipt of sexual healthcare were also explored. Social media advertising was used to recruit participants over five weeks in August and October 2020.

Results

The survey sample included 500 respondents comprising 58.8% females, 25.4% Māori (indigenous) ethnicity and 21.4% LGBTQI+ (lesbian, gay, bisexual, transgender, queer, intersex +) young people. During lockdown, 22.2% of respondents reported sexual health needs (111/500), but fewer than half this group got help (45%, 50/111), believing their issue could wait, or due to barriers contacting services and lack of information about service availability. Experience of telehealth consultations (by 28/50 participants) was mostly favourable though only 46% agreed it was easier than going to the clinic. Telehealth methods were the preferred option by some participants for future receipt of sexual healthcare; but for most scenarios suggested, respondents favoured in-person clinic visits.

Conclusions

Young people experienced unmet need for sexual healthcare during lockdown in New Zealand, but not because services were unavailable. Findings point to the need for targeted information dissemination to young people about available services and the importance of seeking help during lockdown. More research is needed to understand the advantages and disadvantages of sexual healthcare delivered via telehealth to inform future service provision.
Breathing training improves exercise capacity in patients with tetralogy of Fallot: a randomised trial
Authors: Hock Julia , Remmele Julia , Oberhoffer Renate , Ewert Peter , Hager Alfred
Published: March 2021

Objective

Patients with tetralogy of Fallot (ToF) have limited pulmonary blood flow before corrective surgery and ongoing dysfunction of the pulmonary valve and right ventricle throughout life leading to lower exercise capacity and lung volumes in many patients. Inhalation training can increase lung volumes, improve pulmonary blood flow and consequently exercise capacity. This study tests whether home-based daily breathing training improves exercise capacity and lung volumes.

Methods

From February 2017 to November 2018, 60 patients (14.7±4.8 years, 39% female) underwent spirometry (forced vital capacity (FVC); forced expiratory volume in 1 s (FEV1)), cardiopulmonary exercise testing (peak oxygen uptake (peakV˙O2)) and breathing excursion measurement. They were randomised into immediate breathing exercise or control group (CG) and re-examined after 6 months. The CG started their training afterwards and were re-examined after further 6 months. Patients trained with an inspiratory volume-oriented breathing device and were encouraged to exercise daily. The primary endpoint of this study was the change in peakV˙O2. Results are expressed as mean±SEM (multiple imputations).

Results

In the first 6 months (intention to treat analysis), the training group showed a more favourable change in peakV˙O2(Δ0.5±0.6 vs −2.3±0.9 mL/min/kg, p=0.011), FVC (Δ0.18±0.03 vs 0.08±0.03 L, p=0.036) and FEV1(Δ0.14±0.03 vs −0.00±0.04 L, p=0.007). Including the delayed training data from the CG (n=54), this change in peakV˙O2correlated with self-reported weekly training days (r=0.282, p=0.039).

Conclusions

Daily inspiratory volume-oriented breathing training increases dynamic lung volumes and slows down deconditioning in peakV˙O2in young patients with repaired ToF.
Anti-interleukin 1 agents for the treatment of recurrent pericarditis: a systematic review and meta-analysis
Authors: Imazio Massimo , Andreis Alessandro , Piroli Francesco , Lazaros George , Gattorno Marco , Lewinter Martin , Klein Allan L , Brucato Antonio
Published: March 2021

Aims

Corticosteroid-dependent and colchicine-resistant recurrent pericarditis (RP) is a challenging management problem, in which conventional anti-inflammatory therapy (nonsteroidal anti-inflammatory drugs, colchicine, corticosteroids) is unable to control the disease. Recent data suggest a potential role for anti-interleukin-1 (IL-1) agents for this condition. This study was designed to assess the safety and efficacy of anti-IL-1 agents in this setting.

Methods

We performed a systematic review and meta-analysis of randomised controlled trials and observational studies assessing pericarditis recurrences and drug-related adverse events in patients receiving anti-IL-1 drugs for pericarditis.

Results

The meta-analysis assessed 7 studies including 397 pooled patients with RP. The median age was 42 years, 60% were women and the aetiology was idiopathic in 87%. After a median follow-up of 14 months (IQR,12–39), patients receiving anti-IL-1 agents (anakinra or rilonacept) had a significantly reduction in pericarditis recurrences (incidence rate ratio 0.06, 95% CI 0.03 to 0.14), compared with placebo and/or standard medical therapy. Anti-IL-1 agents were associated with increased risk of adverse events compared with placebo (risk ratio (RR) 5.38, 95% CI 2.08 to 13.92): injection-site reactions occurred in 15/41 (36.6%) vs none (RR 14.98, 95% CI 2.09 to 107.09), infections occurred in 13/51 (25.5%) vs 3/41 (7.3%; RR 3.65, 95% CI 1.23 to 10.85). Anti-IL-1 agents were not associated with increased risk of severe adverse events.

Conclusions

In patients with RP, anti-IL-1 agents (anakinra and rilonacept) are efficacious for prevention of recurrences, without severe adverse events.
Primary results from TAIL: a global single-arm safety study of atezolizumab monotherapy in a diverse population of patients with previously treated advanced non-small cell lung cancer
Authors: Ardizzoni Andrea , Azevedo Sergio , Rubio-Viqueira Belen , Rodríguez-Abreu Delvys , Alatorre-Alexander Jorge , Smit Hans J M , Yu Jinming , Syrigos Konstantinos , Trunzer Kerstin , Patel Hina , Tolson Jonathan , Cardona Andres , Perez-Moreno Pablo D , Newsom-Davis Tom
Published: March 2021

Background

Atezolizumab treatment improves survival, with manageable safety, in patients with previously treated advanced/metastatic non-small cell lung cancer. The global phase III/IV study TAIL (NCT03285763) was conducted to evaluate the safety and efficacy of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer, including those not eligible for pivotal trials.

Methods

Patients with stage IIIB/IV non-small cell lung cancer whose disease progressed after 1–2 lines of chemotherapy were eligible for this open-label, single-arm, multicenter study, including those with severe renal impairment, an Eastern Cooperative Oncology Group performance status of 2, prior anti-programmed death 1 (PD-1) therapy, and autoimmune disease. Atezolizumab was administered intravenously (1200 mg every 3 weeks). Coprimary endpoints were treatment-related serious adverse events and immune-related adverse events.

Results

619 patients enrolled and 615 received atezolizumab. At data cutoff, the median follow-up was 12.6 months (95% CI 11.9 to 13.1). Treatment-related serious adverse events occurred in 7.8% and immune-related adverse events in 8.3% of all patients and as follows, respectively, in these subgroups: renal impairment (n=78), 11.5% and 12.8%; Eastern Cooperative Oncology Group performance status of 2 (n=61), 14.8% and 8.2%; prior anti–PD-1 therapy (n=39), 5.1% and 7.7%; and autoimmune disease (n=30), 6.7% and 10.0%. No new safety signals were reported. In the overall population, the median overall survival was 11.1 months (95% CI 8.9 to 12.9), the median progression-free survival was 2.7 months (95% CI 2.1 to 2.8) and the objective response rate was 11%.

Conclusions

This study confirmed the benefit–risk profile of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer. These safety and efficacy outcomes may inform treatment decisions for patients generally excluded from checkpoint inhibitor trials.
T cell infiltration on local CpG-B delivery in early-stage melanoma is predominantly related to CLEC9A+CD141+cDC1 and CD14+antigen-presenting cell recruitment
Authors: Koster Bas D , López González Marta , van den Hout Mari FCM , Turksma Annelies W , Sluijter Berbel JR , Molenkamp Barbara G , van Leeuwen Paul AM , Vosslamber Saskia , Scheper Rik J , van den Eertwegh Alfons JM , van den Tol M Petrousjka , Jordanova Ekaterina J , de Gruijl Tanja D
Published: March 2021

Background

We previously reported CpG-B injection at the primary tumor excision site prior to re-excision and sentinel node biopsy to result in immune activation of the sentinel lymph node (SLN), increased melanoma-specific CD8+T cell rates in peripheral blood, and prolonged recurrence-free survival. Here, we assessed recruitment and activation of antigen-presenting cell (APC) subsets in the SLN and at the injection site in relation to T cell infiltration.

Methods

Re-excision skin specimens from patients with clinical stage I-II melanoma, collected 7 days after intradermal injection of either saline (n=10) or 8 mg CpG-B (CPG7909, n=12), were examined by immunohistochemistry, quantifying immune subsets in the epidermis, papillary, and reticular dermis. Counts were related to flow cytometric data from matched SLN samples. Additional in vitro cultures and transcriptional analyses on peripheral blood mononuclear cells (PBMCs) were performed to ascertain CpG-induced APC activation and chemokine profiles.

Results

Significant increases in CD83+, CD14+, CD68+, and CD123+APC were observed in the reticular dermis of CpG-B-injected skin samples. Fluorescent double/triple staining revealed recruitment of both CD123+BDCA2+plasmacytoid dendritic cells (DCs) and BDCA3/CD141+CLEC9A+type-1 conventional DC (cDC1), of which only the cDC1 showed considerable levels of CD83 expression. Simultaneous CpG-B-induced increases in T cell infiltration were strongly correlated with both cDC1 and CD14 counts. Moreover, cDC1 and CD14+APC rates in the reticular dermis and matched SLN suspensions were positively correlated. Flow cytometric, transcriptional, and chemokine release analyses of PBMC, on in vitro or in vivo exposure to CpG-B, indicate a role for the activation and recruitment of both cDC1 and CD14+monocyte-derived APCs in the release of CXCL10 and subsequent T cell infiltration.

Conclusion

The CpG-B-induced concerted recruitment of cDC1 and CD14+APC to the injection site and its draining lymph nodes may allow for both the (cross-)priming of T cells and their subsequent homing to effector sites.
Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma
Authors: Ma Yuxiang , Chen Xi , Wang Ao , Zhao Hongyun , Lin Qingguang , Bao Hua , Zhang Yang , Hong Shaodong , Tang Wanxiangfu , Huang Yan , Yang Yunpeng , Wu Xue , Shao Yang , Fang Wenfeng , Zhang Li
Published: March 2021

Background

Anti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear.

Methods

Patients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients.

Results

Among 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H (GZMB/H) was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012).

Conclusions

Anti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in eitherGZMBorGZMHgenes was associated with reduced survival.
Extending the conversation over the immune-related hepatotoxicity: author response to Dr. Gauci et al
Authors: Ziogas Dimitrios C , Gogas Helen
Published: March 2021

Immune-related hepatotoxicity (IRH) remains the subject of many immune-oncology debates due to its challenging diagnosis and management. Although it is currently defined by the restrictive Common Terminology Criteria for Adverse Events (CTCAE), the term of IRH covers a wide range of liver pathologies, including hepatitic, cholangitic, mixed, steatotic and nonspecific patterns of injury. Even when liver biopsy is performed, the recognized histopathological findings cannot predict the response to steroids or the need for secondary immunosuppression, and usually do not significantly modify the suggested empirical treatment of IRH. Beyond the CTCAE grading, a more comprehensive assessment of IRH severity, including laboratory biomarkers and clinical features, should be developed and a more patient-oriented management should be established by additional randomized evidence, incorporating hepatology and immune-oncology experience.
Temporal trends of the association between extreme temperatures and hospitalisations for schizophrenia in Hefei, China from 2005 to 2014
Authors: Pan Rubing , Wang Qizhi , Yi Weizhuo , Wei Qiannan , Cheng Jian , Su Hong
Published: March 2021

Objective

We aimed to examine the temporal trends of the association between extreme temperature and schizophrenia (SCZ) hospitalisations in Hefei, China.

Methods

We collected time-series data on SCZ hospitalisations for 10 years (2005–2014), with a total of 36 607 cases registered. We used quasi-Poisson regression and distributed lag non-linear model (DLNM) to assess the association between extreme temperature (cold and heat) and SCZ hospitalisations. A time-varying DLNM was then used to explore the temporal trends of the association between extreme temperature and SCZ hospitalisations in different periods. Subgroup analyses were conducted by age (0–39 and 40+ years) and gender, respectively.

Results

We found that extreme cold and heat significantly increased the risk of SCZ hospitalisations (cold: 1st percentile of temperature 1.19 (95% CI 1.04 to 1.37) and 2.5th percentile of temperature 1.16 (95% CI 1.03 to 1.31); heat: 97.5th percentile of temperature 1.37 (95% CI 1.13 to 1.66) and 99th percentile of temperature 1.38 (95% CI 1.13 to 1.69)). We found a slightly decreasing trend in heat-related SCZ hospitalisations and a sharp increasing trend in cold effects from 2005 to 2014. However, the risk of heat-related hospitalisation has been rising since 2008. Stratified analyses showed that age and gender had different modification effects on temporal trends.

Conclusions

The findings highlight that as temperatures rise the body’s adaptability to high temperatures may be accompanied by more threats from extreme cold. The burden of cold-related SCZ hospitalisations may increase in the future.
Emergency general surgery utilization and disparities during COVID-19: an interrupted time-series analysis
Authors: Greenberg Anya L , Schwartz Hope , Collins Caitlin R , Kelly Yvonne M , Mackersie Robert , Mourad Michelle , Roberts John P , Bongiovanni Tasce
Published: March 2021

Objective

We aimed to compare general surgery emergency (GSE) volume, demographics and disease severity before and during COVID-19.

Background

Presentations to the emergency department (ED) for GSEs fell during the early COVID-19 pandemic. Barriers to accessing care may be heightened, especially for vulnerable populations, and patients delaying care raises public health concerns.

Methods

We included adult patients with ED presentations for potential GSEs at a single quaternary-care hospital from January 2018 to August 2020. To compare GSE volumes in total and by subgroup, an interrupted time-series analysis was performed using the March shelter-in-place order as the start of the COVID-19 period. Bivariate analysis was used to compare demographics and disease severity.

Results

3255 patients (28/week) presented with potential GSEs before COVID-19, while 546 (23/week) presented during COVID-19. When shelter-in-place started, presentations fell by 8.7/week (31%) from the previous week (p<0.001), driven by decreases in peritonitis (β=−2.76, p=0.017) and gallbladder disease (β=−2.91, p=0.016). During COVID-19, patients were younger (54 vs 57, p=0.001), more often privately insured (44% vs 38%, p=0.044), and fewer required interpreters (12% vs 15%, p<0.001). Fewer patients presented with sepsis during the pandemic (15% vs 20%, p=0.009) and the average severity of illness decreased (p<0.001). Length of stay was shorter during the COVID-19 period (3.91 vs 5.50 days, p<0.001).

Conclusions

GSE volumes and severity fell during the pandemic. Patients presenting during the pandemic were less likely to be elderly, publicly insured and have limited English proficiency, potentially exacerbating underlying health disparities and highlighting the need to improve care access for these patients.

Level of evidence

III.
Industry 4.0 Indicators and Their Roles in Strategy Formulation
Authors: Ocampo Lanndon , Himang Celbert , Obiso Jun-Jun , Bongo Miriam , Caballes Shirley Ann , Abellana Dharyll Prince , Jabilles Eula Margareth , Deocaris Custer , Ancheta Rosein
Published: March 2021

This paper attempts to extract Industry 4.0 indicators from relevant literature and integrate these indicators in strategy formulation by providing a categorization system according to technological, organizational, inter-organizational, and social and regulatory clusters. The identified 62 indicators are found to cover a wide range of responsibilities accounted for by specific functional teams and cross-functional teams, which collectively aim to support strategic decision-making among stakeholders. The categorization of indicators is necessary to efficiently facilitate corporate level, business level, and functional level strategies.
The Price of Bounded Preemption
Authors: Alon Noga , Azar Yossi , Berlin Mark
Published: March 2021

In this article we provide a tight bound for the
price of preemption
for scheduling jobs on a single machine (or multiple machines). The input consists of a set of jobs to be scheduled and of an integer parameter
k
≥ 1. Each job has a release time, deadline, length (also called processing time), and value associated with it. The goal is to feasibly schedule a subset of the jobs so that their total value is maximal; while preemption of a job is permitted, a job may be preempted no more than
k
times. The price of preemption is the worst possible (i.e., largest) ratio of the optimal non-bounded-preemptive scheduling to the optimal
k
-bounded-preemptive scheduling.

Our results show that allowing at most
k
preemptions suffices to guarantee a Θ(min {log

k
+1

n
, log

k
+1

P
}) fraction of the total value achieved when the number of preemptions is unrestricted (where
n
is the number of the jobs and
P
the ratio of the maximal length to the minimal length), giving us an upper bound for the price; a specific scenario serves to prove the tightness of this bound. We further show that when no preemptions are permitted at all (i.e.,
k
=0), the price is Θ (min {
n
, log
P
}).

As part of the proof, we introduce the notion of the
Bounded-Degree Ancestor-Free Sub-Forest (BAS)
. We investigate the problem of computing the maximal-value BAS of a given forest and give a tight bound for the loss factor, which is Θ(log

k
+1

n
) as well, where
n
is the size of the original forest and
k
is the bound on the degree of the sub-forest.
Single Atomic Iron Site Catalysts via Benign Aqueous Synthesis for Durability Improvement in Proton Exchange Membrane Fuel Cells
Authors: Chen Mengjie , Cullen David A. , Karakalos Stavros , Lu Xiner , Cui Jiang , Kropf A. Jeremy , Mistry Hemma , He Kai , Myers Deborah J. , Wu Gang
Published: March 2021

Atomically-dispersed iron-nitrogen-carbon (Fe–N–C) catalysts have arisen as promising candidates for replacing the costly precious metal catalysts in fuel cells but still face some grand challenges, such as insufficient site density and durability. Herein, we report a self-assembly method in an aqueous solution to develop an atomically-dispersed iron catalyst with high oxygen reduction reaction (ORR) activity and stability in acidic electrolytes. As determined by high-resolution transmission electron microscopy (HR-TEM), X-ray absorption spectroscopy (XAS), and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), this benign aqueous synthesis strategy facilitates the formation of homogeneous atomic nitrogen-coordinated iron sites embedded in a popcorn-like porous graphitic carbon matrix. These catalyst properties contribute to the improved ORR kinetic current density and mass transport. By controlling synthesis chemistry, the correlation between structure and property is systematically investigated. The iron content is the most critical material property and can regulate site density and graphitic carbon structures in the catalyst, impacting catalytic activity and stability. The enhanced performance and durability were examined in both acidic aqueous electrolytes and membrane electrode assemblies.
Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions
Authors: Clyburn Courtney , Browning Kirsteen N.
Published: March 2021

The meticulous regulation of the gastrointestinal (GI) tract is required for the coordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders and the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second-order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of GI functions.
Acute overventilation does not cause lung damage in moderately hemorrhaged swine
Authors: Blackburn Megan B. , Hudson Ian L. , Rodriguez Cassandra , Wienandt Nathan , Ryan Kathy L.
Published: March 2021

Appropriate airway management is essential in trauma and critically ill patients. Prolonged mechanical ventilation can result in overventilation-induced lung barotrauma, but few studies have examined the consequence of acute overventilation. We investigated the outcome of hemorrhage followed by 1 h of overventilation in swine. We found that acute overventilation, as could be seen in the prehospital phase of trauma care, does not produce evidence of adverse effects on otherwise healthy lungs following moderate hemorrhage.
Energy metabolism design of the striated muscle cell
Authors: Glancy Brian , Balaban Robert S.
Published: March 2021

The design of the energy metabolism system in striated muscle remains a major area of investigation. Here, we review our current understanding and emerging hypotheses regarding the metabolic support of muscle contraction. Maintenance of ATP free energy, so called energy homeostasis, via mitochondrial oxidative phosphorylation is critical to sustained contractile activity, and this major design criterion is the focus of this review. Cell volume invested in mitochondria reduces the space available for generating contractile force, and this spatial balance between mitochondria acontractile elements to meet the varying sustained power demands across muscle types is another important design criterion. This is accomplished with remarkably similar mass-specific mitochondrial protein composition across muscle types, implying that it is the organization of mitochondria within the muscle cell that is critical to supporting sustained muscle function. Beyond the production of ATP, ubiquitous distribution of ATPases throughout the muscle requires rapid distribution of potential energy across these large cells. Distribution of potential energy has long been thought to occur primarily through facilitated metabolite diffusion, but recent analysis has questioned the importance of this process under normal physiological conditions. Recent structural and functional studies have supported the hypothesis that the mitochondrial reticulum provides a rapid energy distribution system via the conduction of the mitochondrial membrane potential to maintain metabolic homeostasis during contractile activity. We extensively review this aspect of the energy metabolism design contrasting it with metabolite diffusion models and how mitochondrial structure can play a role in the delivery of energy in the striated muscle.