bluuebunny/crossref_metadata_2025 huggingface dataset:
Co‐expression of IL‐7 and PH20 promote anti‐GPC3 CAR‐T tumour suppressor activity in vivo and in vitro
Authors: Xiong Xingcheng , Xi Juanli , Liu Qian , Wang Cixiao , Jiang Zeyou , Yue Su‐Yang , Shi Lei , Rong Yuping
Published: December 2020

Background

While CAR‐T therapy has successfully treated haematological malignancies, it has proved sub‐optimal for solid tumours. The main limitation is the inability of CAR‐T cells to infiltrate and then proliferate within tumours.

Method

We co‐expressed IL‐7 and PH20, a type of hyaluronidase, with CAR targeting GPC3 (G3CAR‐7 × 20). We test the anti‐tumour ability in vitro and in vivo. Moreover the capacity of infiltration and proliferation of G3CAR‐7 × 20 was measured.

Result

We found (G3CAR‐7 × 20) exhibited better proliferation in vivo and in vitro than G3CAR, reduced the level of apoptosis after stimulation by tumour cells, and maintained the memory phenotype of CAR‐T cells. G3CAR‐7 × 20 also increased the ability of CAR‐T cells to infiltrate tumour tissue.

Conclusion

co‐expressed IL‐7 and PH20 may significantly enhance the efficacy of targeted GPC3 CAR‐T cells in solid tumours treatment.
Protein intakes of pregnant women and children in India—protein quality implications
Authors: Bandyopadhyay Sulagna , Shivakumar Nirupama , Kurpad Anura V.
Published: December 2020

The recent National Family Health Survey (NFHS‐4, 2016) reports a national average of 18% for low birthweight (LBW) and 38% for stunting in children <5 years. Nutrition and environmental influences (chronic enteric pathogenic exposure through poor water, sanitation, and hygiene) are two critical factors that impact the health outcomes of the populxation. This is particularly relevant for vulnerable age groups such as pregnant women and children <5 years, who bear long‐lasting and intergenerational consequences of impoverished nutrition and suboptimal living conditions. The present review provides, for the first time, an analysis of indispensable amino acid (IAA) requirements for pregnant women, separately for the second and third trimesters, using protein accretion data from a recent Indian study. Furthermore, using these estimates for pregnancy, and the current IAA requirements for young children, the quality of protein was assessed in Indian diets consumed by pregnant women and children (1–3 and 4–6 years) from national representative rural National Nutrition Monitoring Bureau survey. The assessment was considered in the context of an adverse environment and in relation to outcomes such as LBW, stunting, and underweight. Finally, an assessment was made of the proportion of the surveyed population at risk of dietary quality protein inadequacy and implications for planning nutrition intervention programmes. Specifically, state‐wise estimates of the risk of quality protein inadequacy are provided, in addition to evaluations of additional dietary supplementation, which could inform the policy of supplementary nutrition programmes to improve health outcomes.
When I say … cultural competence
Authors: Stanyon Maham , Shikama Yayoi , Otani Koji
Published: December 2020

In this month's "When I say…", Stanyon et al. frankly discuss 'cultural competence' in terms of power and privilege in the clinic and in the classroom.
The natural course of cow’s milk allergy and the development of atopic diseases into adulthood
Authors: Hansen Michaela M. , Nissen Susanne P. , Halken Susanne , Høst Arne
Published: December 2020

Background

Previous studies have investigated the natural course of cow's milk allergy (CMA) and development of atopic diseases into adolescence. Studies with long‐term follow‐up into adulthood are lacking. The aim of this study was to investigate (a) the natural course of CMA in a 1‐year birth cohort of Danish children from birth until 15 and 26 years of age and (b) the development of atopic diseases in a group of children with CMA (group A) compared to a random sample of 276 children from the same birth cohort (group B).

Methods

A birth cohort of 1749 newborns was investigated prospectively for the development of CMA and atopic diseases. During the first year of life and at 18 months and 3, 5, 10, 15, and 26 years of age, questionnaire‐based interviews, physical examination, skin prick tests, and specific IgE testing, and from 10 years also spirometry, were carried out.

Results

Thirty‐nine (2.2%) were diagnosed with CMA. The recovery rate was 87%, 92%, and 97% at 3, 5, and 26 years of age. Compared to group B, group A had significantly (P < .05) higher prevalence of asthma and rhinoconjunctivitis at 15 years of age, and at 26 years of age, group A had significantly higher prevalence of asthma and atopic dermatitis. The follow‐up rate was 85% (A) and 70% (B).

Conclusion

CMA has a good prognosis regarding recovery rate. However, CMA, especially IgE‐mediated, in early childhood predicts a high prevalence of atopic diseases into adulthood.
El personal de las Compañías Militares y de Seguridad Privadas (CMSP): ¿Contratistas civiles o mercenarios?
Authors: Urueña-Sánchez Mario Iván
Published: December 2020

Este artículo de investigación tiene como propósito explorar la viabilidad y las ventajas derivadas de vincular el estatuto jurídico del personal de las Compañías Militares y de Seguridad Privada con otras figuras jurídicas más desarrolladas para ayudar a dinamizar al derecho internacional. Para tal efecto, se realiza una revisión documental basada en tratados internacionales y jurisprudencia y legislación interna de países emblemáticos.
Notificaciones electrónicas judiciales: una aproximación a la reglamentación y uso en algunos países iberoamericanos
Authors: Namen Baquero David
Published: December 2020

Las notificaciones judiciales cumplen el propósito de darle a conocer la decisión que toma el juez frente a un asunto a las partes. Cada país tiene unas reglas específicas que varían conforme a la decisión que requiere ser notificada. Actualmente, la tecnología ha simplificado la labor del juez al permitir gestionar las notificaciones por medios electrónicos. El presente estudio busca analizar la situación de algunos países iberoamericanos en torno al uso de los recursos tecnológicos para gestionar notificaciones en el ámbito judicial. En la primera parte, se analiza en forma sucinta el marco normativo existente, y en la segunda, se hace una comparación de los elementos más destacados de cada país.
Heat Transfer Enhancement in a Rectangular Cooling Channel With Airfoil Shaped Fins
Authors: Wright Lesley M. , Chen Andrew F. , Wu Hao-Wei , Han Je-Chin , Lee Ching-Pang , Azad Salam , Um Jae
Published: December 2020

This paper experimentally investigates heat transfer in a cooling passage with airfoil shaped fins for channel Reynolds numbers 10,000–40,000. This study uses airfoil shaped fins, instead of circular or oblong-shaped pins, for heat transfer augmentation. The airfoil shaped fins have more surface area than traditional pins. Assuming they both provide similar internal surface heat transfer coefficients, airfoil shaped fins will perform better than circular or oblong fins due to increased surface area. There is a need to obtain the heat transfer enhancement and pressure drop penalty in this cooling passage with airfoil shaped fins. Results are compared to the same rectangular cooling channel with smooth surfaces. The heat transfer can be enhanced 6–8 times while pressure drop is increased 70–90 times, as compared with the same channel with a smooth surface. With the fins significantly increasing the heat transfer area, three different methods are proposed for analyzing the heat transfer enhancement: (a) using the smooth channel area with the endwall temperature, (b) combining the total heat transfer area with the endwall temperature, and (c) coupling the total heat transfer area with the area weighted, average temperature including both the endwall and fin temperatures. Finally, compared directly to round pins, the airfoil shaped fins incur similar pressure penalties while providing slightly less heat transfer. The airfoil shaped fins benefit from a significant increase in the heat transfer area, a characteristic similar to more narrow strip fins.
A Highly Efficient Integrated Silicon-Microchannel Cooler for Multi-Module Electronic Microsystems: Model Design, Optimization, and Performance Validation
Authors: Wang Jiejun , Wang Tao , Li Qiuyan , Li Yiming , Wu Chuangui , Zhang Wanli
Published: December 2020

Recently, the development trend of multi-module and multi-function in electronic microsystems makes the ever-increasing heat flux problem more serious. In this study, a highly efficient integrated single-phase microchannel cooler with four heat sources is presented for handling the challenges from both workings independently of all electronic modules and the high heat flux. Both numerical and experimental studies are conducted. By optimizing the structural design and the fabricated process, the presented microchannel cooler has outstanding cooling performance, which contains desired fluid flow distribution, pressure drop, heat transfer, and combination thereof. Results reveal uniform coolant flow dissipates four individual heaters independently, and their maximal temperature difference below 4 °C. Beyond this, high heat flux removal (707.6 W/cm2) is realized with an extremely low coolant flowrate (45 ml/min), and the maximum temperature rise is less than 60 °C. This study provides a referable solution for the thermal management of multi-module heat sources and high heat flux in compact electronic microsystems.
Modeling of a Complete Morphing Mechanism Covered by a Paneled Morphing Skin
Authors: Yu Aaron , Xi Fengfeng (Jeff) , Ghaemi Hamid , Li Bing
Published: December 2020

Presented in this paper is a method for modeling and simulation of a complete morphing mechanism. The said mechanism has a rigid panel morphing skin that morphs along with a driving mechanism. The said skin is made of segmented panels, inspired by fish scales. Since the gaps between these panels are undesirable, a gapless design is introduced in this paper by using shape-memory polymer (SMP) joints. This paper aims to solve two fundamental problems for the entire system: (1) motion control and (2) force control. The motion control is addressed through the kinematic modeling of two equations including (a) the passive rigid panels and (b) the passive rigid panels to the active mechanism. Force control is achieved through force modeling. This is to develop a relationship of the SMP deformations to the required actuator forces. The experiment is carried out to determine the SMP forces versus deformation, and simulations are conducted to investigate how a complete morphing mechanism behaves. It also reveals that the workspace and singularity of the original mechanism will change after covered by a morphing skin. The developed method sheds light on the design of a complete morphing mechanism.
Protein Dosage of the
lldPRD
Operon Is Correlated with RNase E-Dependent mRNA Processing
Authors: Angel-Lerma Lidia E. , Merino Enrique , Kwon Ohsuk , Medina-Aparicio Liliana , Hernández-Lucas Ismael , Alvarez Adrián F. , Georgellis Dimitris
Published: December 2020

Adjustment of gene expression is critical for proper cell function. In the case of polycistronic transcripts, posttranscriptional regulatory mechanisms can be used to fine-tune the expression of individual cistrons.
Study To Evaluate the Performance of a Point-of-Care Whole-Blood HIV Viral Load Test (SAMBA II HIV-1 Semi-Q Whole Blood)
Authors: Brook Gary , Stepchenkova Tetiana , Ali Innocent M. , Chipuka Sandra , Goel Neha , Lee Helen
Published: December 2020

Remote areas of many low and middle income (LMI) countries have poor access to HIV viral load (HIV VL) testing. The SAMBA II (simple amplification-based assay) Semi-Q whole-blood test (Diagnostics for the Real World [DRW], Cambridge, UK) is a point-of-care assay, which uses leucodepletion technology to allow whole-blood testing in remote settings.
Can an online exercise prescription tool improve adherence to home exercise programmes in children with cerebral palsy and other neurodevelopmental disabilities? A randomised controlled trial
Authors: Johnson Rowan W , Williams Sian A , Gucciardi Daniel F , Bear Natasha , Gibson Noula
Published: December 2020

Objective

Determine the adherence to and effectiveness of an 8-week home exercise programme for children with disabilities delivered using Physitrack, an online exercise prescription tool, compared with traditional paper-based methods.

Design

Single-blinded, parallel-groups, randomised controlled trial (RCT).

Setting

Intervention took place in participants’ homes in Western Australia.

Participants

Children aged 6 to 17 years, with neurodevelopmental disabilities including cerebral palsy (CP), receiving community therapy services.

Intervention

All participants completed an individualised home exercise programme, which was delivered to the intervention group using Physitrack and conventional paper-based methods for the control group.

Primary outcome measures

Adherence to exercise programme, goal achievement and exercise performance.

Secondary outcome measures

Enjoyment, confidence and usability of Physitrack.

Results

Fifty-four participants with CP (n=37) or other neurodevelopmental disabilities (n=17) were recruited. Fifty-three were randomised after one early withdrawal. Forty-six completed the 8-week programme, with 24 in the intervention group and 22 in the control group. There was no difference between the two groups for percentage of exercises completed (intervention (n=22): 62.8% (SD 27.7), control (n=22): 55.8% (SD 19.4), between group mean difference −7.0% (95% CI: −21.6 to 7.5, p=0.34)). Both groups showed significant improvement in their self-rated performance of individualised goal activities, however there was no statistically significant difference between groups for goal achievement, quality of exercise performance, enjoyment, confidence or preferred method of delivery. There were no adverse events.

Conclusion

Physitrack provides a therapist with a new means of providing an exercise programme with online tools such as exercise videos, but our preliminary findings indicate that it may be no better than a traditional paper-based method for improving exercise adherence or the other outcomes measured. Exercise programmes remain an intervention supported by evidence, but a larger RCT is required to fully evaluate online delivery methods.

Trial registration details

Australian New Zealand Clinical Trials Registry; ACTRN12616000743460.
Metformin use and long-term risk of benign prostatic hyperplasia: a population-based cohort study
Authors: Nørgaard Mette , Darvalics Bianka , Thomsen Reimar Wernich
Published: December 2020

Objective

To assess whether metformin use affects risk of benign prostatic hyperplasia (BPH) by comparing the risk of BPH in men with type 2 diabetes who initiated first-line treatment with either metformin or sulfonylurea monotherapy between 2000 or 2006 in Northern Denmark. In this period, sulfonylurea and metformin were both frequently used as first-line glucose-lowering drug (GLD) treatment.

Design

A population-based cohort study.

Setting

Northern Denmark.

Participants

All men who filled at least two prescriptions for metformin or for sulfonylurea, respectively, during their first 6 months of GLD treatment. Follow-up started 6 months after treatment start.

Primary outcome measures

Rates of subsequent BPH, identified based on community prescriptions for BPH-related treatment or hospital BPH diagnoses, and rates of transurethral resection of the prostate (TURP). Rates in metformin and sulfonylurea users were compared overall and stratified by 6-month haemoglobin A1c (HbA1c) using Cox regression and an intention-to-treat (ITT) approach and an as-treated analysis.

Results

During follow-up, less than five persons were lost to follow-up due to emigration. In 3953 metformin initiators with a median follow-up of 10 years, the 10-year cumulative BPH incidence was 25.7% (95% CI 24.2 to 27.1). Compared with 5958 sulfonylurea users (median follow-up 8 years, 10-year cumulative incidence 27.4% (95% CI 26.2 to 28.6)), the crude HR for BPH was 0.83 (95% CI 0.77 to 0.89) and adjusted HR in the ITT analyses was 0.97 (95% CI 0.88 to 1.06). For TURP, the adjusted HR was 0.96 (95% CI 0.63 to 1.46). In the as-treated analysis, adjusted HR for BPH was 0.91 (95% CI 0.81 to 1.02).

Conclusions

Compared with sulfonylurea, metformin did not substantially reduce the incidence of BPH in men with diabetes.
Prediction of outcomes after acute kidney injury in hospitalised patients: protocol for a systematic review
Authors: Arora Tanima , Martin Melissa , Grimshaw Alyssa , Mansour Sherry , Wilson Francis P
Published: December 2020

Introduction

Acute kidney injury (AKI) is common and is associated with negative long-term outcomes. Given the heterogeneity of the syndrome, the ability to predict outcomes of AKI may be beneficial towards effectively using resources and personalising AKI care. This systematic review will identify, describe and assess current models in the literature for the prediction of outcomes in hospitalised patients with AKI.

Methods and analysis

Relevant literature from a comprehensive search across six databases will be imported into Covidence. Abstract screening and full-text review will be conducted independently by two team members, and any conflicts will be resolved by a third member. Studies to be included are cohort studies and randomised controlled trials with at least 100 subjects, adult hospitalised patients, with AKI. Only those studies evaluating multivariable predictive models reporting a statistical measure of accuracy (area under the receiver operating curve or C-statistic) and predicting resolution of AKI, progression of AKI, subsequent dialysis and mortality will be included. Data extraction will be performed independently by two team members, with a third reviewer available to resolve conflicts. Results will be reported using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Risk of bias will be assessed using Prediction model Risk Of Bias ASsessment Tool.

Ethics and dissemination

We are committed to open dissemination of our results through the registration of our systematic review on PROSPERO and future publication. We hope that our review provides a platform for future work in realm of using artificial intelligence to predict outcomes of common diseases.

PROSPERO registration number

CRD42019137274.
Practicability of lower extremity functional performance tests and their measurement properties in elite athletes: protocol for a systematic review
Authors: Cooke Rosalyn , Rushton Alison , Martin James , Herrington Lee , Heneghan Nicola R
Published: December 2020

Introduction

Lower extremity injury (LEI) is highly prevalent and its occurrence increases the risk of future injury in athletic populations. Identifying athletes at risk of injury is the key to target injury-prevention programmes. Functional performance tests (FPT) assess an athlete’s ability to produce and accept forces during movement tasks reflective of those experienced in sport, and are used to identify deficits in physical qualities or neuromuscular control. This review aims to identify FPT which have potential to predict LEI and assess their measurement properties associated with reliability, validity, responsiveness and practicability (interpretability and feasibility).

Methods/analysis

This protocol will be reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol and the COnsensus-based Standards for the selection of health Measurement INstruments Methodology. The search strategy has two stages: stage 1 will identify lower limb FPT used in athletic populations; and stage 2 will assess the measurement properties of the identified FPT. A sensitive search strategy will use MEDLINE, EMBASE, CINHAL and SPORTdiscus databases; from inception to June 2020. Hand searching reference lists, key journals and grey literature will be completed. One reviewer will complete search 1 and data extraction. Two reviewers will complete the search, data extraction and risk-of-bias assessment for search 2. Evidence will be pooled or summarised by individual measurement property by each individual study and grouped by FPT. Meta-analysis using a random effects model with subgroup analysis will be performed where possible. Pooled or summarised results for each FPT in relation to each measurement property will be rated against the criteria for good measurement properties. Two reviewers will assess the overall body of evidence per measurement property per FPT using the modified Grading of Recommendations, Assessment, Development and Evaluation guidelines. This review will enable clinicians to make an informed choice when selecting FPT.

Ethics and dissemination

No ethical approval is required for this review and the results will be disseminated through peer-reviewed publications and submitted for conference presentation.

PROSPERO registration number

CRD42020188932.
Psychosocial and health behavioural impacts of COVID-19 pandemic on adults in the USA: protocol for a longitudinal cohort study
Authors: Badr Hoda , Oluyomi Abiodun , Adel Fahmideh Maral , Raza Syed Ahsan , Zhang Xiaotao , El-Mubasher Ola , Amos Christopher
Published: December 2020

Introduction

Although social distancing may help contain the spread of COVID-19, the social isolation and loneliness it causes can heighten stress, contribute to unhealthy lifestyle behaviours and have deleterious effects on social relationships. This ongoing longitudinal cohort study aims to (1) characterise the psychological, social and health behavioural impacts of the COVID-19 pandemic over a 12-month period in the USA; (2) determine whether these impacts differ for certain subgroups based on sociodemographics and other individual-level factors; and (3) explore whether there are modifiable factors (eg, coping, social support) that moderate the effects of the pandemic over time.

Methods and analysis

Adults (aged ≥18 years) who were fluent in either English or Spanish were recruited via social media and invited to complete an online survey during the 8-week period from 13 April to 8 June 2020 (baseline). Follow-up surveys will be conducted 6 and 12 months after baseline. Data transformations, non-parametric tests or other alternative methods will be used when appropriate. Descriptive statistics and cross-sectional analyses will be performed. Longitudinal associations will be analysed using multilevel modelling with time-variant and time-invariant predictors of change in trajectory over the study period.

Ethics and dissemination

Research ethics approval was received from the Baylor College of Medicine Institutional Review Board (H-47505). Overall, this study will provide timely information that can be used to inform public health messaging strategies and guide development of assessment tools and interventions to support vulnerable individuals dealing with the long-term impacts of the COVID-19 pandemic.
Cohort study evaluating the burden of wounds to the UK’s National Health Service in 2017/2018: update from 2012/2013
Authors: Guest Julian F , Fuller Graham W , Vowden Peter
Published: December 2020

Objective

To evaluate the prevalence of wounds managed by the UK’s National Health Service (NHS) in 2017/2018 and associated health outcomes, resource use and costs.

Design

Retrospective cohort analysis of the electronic records of patients from The Health Improvement Network (THIN) database.

Setting

Primary and secondary care sectors in the UK.

Participants

Randomly selected cohort of 3000 patients from the THIN database who had a wound in 2017/2018.

Primary and secondary outcome measures

Patients’ characteristics, wound-related health outcomes, healthcare resource use and total NHS cost of patient management.

Results

There were an estimated 3.8 million patients with a wound managed by the NHS in 2017/2018, of which 70% healed in the study year; 89% and 49% of acute and chronic wounds healed, respectively. An estimated 59% of chronic wounds healed if there was no evidence of infection compared with 45% if there was a definite or suspected infection. Healing rate of acute wounds was unaffected by the presence of infection. Smoking status appeared to only affect the healing rate of chronic wounds. Annual levels of resource use attributable to wound management included 54.4 million district/community nurse visits, 53.6 million healthcare assistant visits and 28.1 million practice nurse visits. The annual NHS cost of wound management was £8.3 billion, of which £2.7 billion and £5.6 billion were associated with managing healed and unhealed wounds, respectively. Eighty-one per cent of the total annual NHS cost was incurred in the community.

Conclusion

The annual prevalence of wounds increased by 71% between 2012/2013 and 2017/2018. There was a substantial increase in resource use over this period and patient management cost increased by 48% in real terms. There needs to be a structural change within the NHS in order to manage the increasing demand for wound care and improve patient outcomes.
Inappropriate end-of-life cancer care in a generalist and specialist palliative care model: a nationwide retrospective population-based observational study
Authors: Boddaert Manon S , Pereira Chantal , Adema Jeroen , Vissers Kris C P , van der Linden Yvette M , Raijmakers Natasja J H , Fransen Heidi P
Published: December 2020

Objectives

To evaluate the impact of provision and timing of palliative care (PC) on potentially inappropriate end-of-life care to patients with cancer in a mixed generalist—specialist PC model.

Method

A retrospective population-based observational study using a national administrative health insurance database. All 43 067 adults in the Netherlands, who were diagnosed with or treated for cancer during the year preceding their death in 2017, were included. Main exposure was either generalist or specialist PC initiated >30 days before death (n=16 967). Outcomes were measured over the last 30 days of life, using quality indicators for potentially inappropriate end-of-life care.

Results

In total, 14 504 patients (34%) experienced potentially inappropriate end-of-life care; 2732 were provided with PC >30 days before death (exposure group) and 11 772 received no PC or ≤30 days before death (non-exposure group) (16% vs 45%, p<0.001). Most patients received generalist PC (88%). Patients provided with PC >30 days before death were 5 times less likely to experience potentially inappropriate end-of-life care (adjusted OR (AOR) 0.20; (95% CI 0.15 to 0.26)) than those with no PC or PC in the last 30 days. Both early (>90 days) and late (>30 and≤90 days) PC initiation had lower odds for potentially inappropriate end-of-life care (AOR 0.23 and 0.19, respectively).

Conclusion

Timely access to PC in a mixed generalist—specialist PC model significantly decreases the likelihood of potentially inappropriate end-of-life care for patients with cancer. Generalist PC can play a substantial role.
Double-edged MAiD death family legacy: a qualitative descriptive study
Authors: Frolic Andrea N , Swinton Marilyn , Murray Leslie , Oliphant Allyson
Published: December 2020

Background

Individuals who accompany a loved one through medical assistance in dying (MAiD) have to live with the experience and the psychological, moral and social consequences of their involvement in the process long after the death occurs.

Aim

To explore the legacy of a MAiD death for individuals who accompanied a loved one through the process.

Design

Using a qualitative descriptive approach we conducted semi-structured interviews to collect data from family members who had accompanied a loved one through MAiD. Data were analysed using conventional content analysis.

Setting/participants

16 family members of 14 patients who received MAiD at a Canadian hospital with an interdisciplinary MAiD programme.

Results

The main theme in the analysis is the opposing tensions experienced by individuals who accompany a loved one through a MAiD death, which we conceptualise as a double-edge experience. This double-edge experience is illustrated through four thematic opposing tensions: (1) support for patient autonomy and ambivalence about the MAiD choice, (2) gratitude for suffering relieved for loved one and grief for lost time with loved one, (3) time as a gift and time as a burden and (4) positive legacy and challenging bereavement experience.

Conclusion

The nature of the MAiD experience for involved families is rooted in complexity, ambiguity and ambivalence and thus resists easy categorisation. Families would benefit from structured psychosocial and spiritual supports that acknowledge this complexity, along with MAiD-specific bereavement support following the death.
The Reachability Problem for Petri Nets Is Not Elementary
Authors: Czerwiński Wojciech , Lasota Sławomir , Lazić Ranko , Leroux JÉrôme , Mazowiecki Filip
Published: December 2020

Petri nets, also known as vector addition systems, are a long established model of concurrency with extensive applications in modeling and analysis of hardware, software, and database systems, as well as chemical, biological, and business processes. The central algorithmic problem for Petri nets is reachability: whether from the given initial configuration there exists a sequence of valid execution steps that reaches the given final configuration. The complexity of the problem has remained unsettled since the 1960s, and it is one of the most prominent open questions in the theory of verification. Decidability was proved by Mayr in his seminal STOC 1981 work, and, currently, the best published upper bound is non-primitive recursive Ackermannian of Leroux and Schmitz from Symposium on Logic in Computer Science 2019. We establish a non-elementary lower bound, i.e., that the reachability problem needs a tower of exponentials of time and space. Until this work, the best lower bound has been exponential space, due to Lipton in 1976. The new lower bound is a major breakthrough for several reasons. Firstly, it shows that the reachability problem is much harder than the coverability (i.e., state reachability) problem, which is also ubiquitous but has been known to be complete for exponential space since the late 1970s. Secondly, it implies that a plethora of problems from formal languages, logic, concurrent systems, process calculi, and other areas, which are known to admit reductions from the Petri nets reachability problem, are also not elementary. Thirdly, it makes obsolete the current best lower bounds for the reachability problems for two key extensions of Petri nets: with branching and with a pushdown stack.

We develop a construction that uses arbitrarily large pairs of values with ratioRto provide zero testable counters that are bounded by R. At the heart of our proof is then a novel gadget, the so-called factorial amplifier that, assuming availability of counters that are zero testable and bounded by k, guarantees to produce arbitrarily large pairs of values whose ratio is exactly the factorial of k. Repeatedly composing the factorial amplifier with itself by means of the former construction enables us to compute, in linear time, Petri nets that simulate Minsky machines whose counters are bounded by a tower of exponentials, which yields the non-elementary lower bound. By refining this scheme further, we, in fact, already establish hardness forh-exponential space for Petri nets withh+ 13 counters.
Analytical Assessment of Internal Stress in Cemented Paste Backfill
Authors: Liu Naifei , Cui Liang , Wang Yan
Published: December 2020

To analytically describe the internal stress in a fill mass made of granular man‐made material (cemented paste backfill, CPB), a new 3D effective stress model is developed. The developed model integrates Bishop effective stress principle, water retention relationship, and arching effect. All model parameters are determined from measurable experimental data. The uncertainties of the model parameters are examined by sensitivity analysis. A series of model application is conducted to investigate the effects of field conditions on the internal stress in CPB. The obtained results show that the proposed model is able to capture the influence of operation time, stope geometry, and rock/CPB interface properties on the effective stress in CPB. Hence, the developed model can be used as a useful tool for the optimal design of CPB structure.
A Review of Complicated Cataract in Retinitis Pigmentosa: Pathogenesis and Cataract Surgery
Authors: Hong Yingying , Li Hongzhe , Sun Yang , Ji Yinghong
Published: December 2020

Retinitis pigmentosa (RP) is a set of inherited retinal degenerative diseases that affect photoreceptor and retinal pigment epithelial cells (RPEs), possibly associated with some ocular complications, including cataract. The complicated cataract formation is most likely the result of RP-related inflammation response, and the most common morphology category is posterior subcapsular cataract (PSC). Despite the absence of curative pharmacologic treatment, phacoemulsification with intraocular lens implantation to deal with opacification in the lens is preferred due to the considerable visual outcomes. However, the incidence of intraocular and postoperative complications is higher in RP patients than those without, including intraoperative phototoxic retinal damage, posterior capsular opacification (PCO), capsular contraction syndrome (CCS), pseudophakic cystoid macular edema (PCME), increased postoperative intraocular pressure (IOP), and intraocular lens (IOL) dislocation. Hence, it needs much attention to surgery progress and close follow-up. In this review, we discuss the current understanding of RP patients with complicated cataracts from morphology to potential pathogenesis to cataract surgical procedure and provide a concise description and the recommended management of related surgery complications to broaden the knowledge and lower the latent risks to yield better clinical outcomes.
Risk Assessment of Hip Fracture Based on Machine Learning
Authors: Galassi Alessio , Martín-Guerrero José D. , Villamor Eduardo , Monserrat Carlos , Rupérez María José
Published: December 2020

Identifying patients with high risk of hip fracture is a great challenge in osteoporosis clinical assessment. Bone Mineral Density (BMD) measured by Dual-Energy X-Ray Absorptiometry (DXA) is the current gold standard in osteoporosis clinical assessment. However, its classification accuracy is only around 65%. In order to improve this accuracy, this paper proposes the use of Machine Learning (ML) models trained with data from a biomechanical model that simulates a sideways-fall. Machine Learning (ML) models are models able to learn and to make predictions from data. During a training process, ML models learn a function that maps inputs and outputs without previous knowledge of the problem. The main advantage of ML models is that once the mapping function is constructed, they can make predictions for complex biomechanical behaviours in real time. However, despite the increasing popularity of Machine Learning (ML) models and their wide application to many fields of medicine, their use as hip fracture predictors is still limited. This paper proposes the use of ML models to assess and predict hip fracture risk. Clinical, geometric, and biomechanical variables from the finite element simulation of a side fall are used as independent variables to train the models. Among the different tested models, Random Forest stands out, showing its capability to outperform BMD-DXA, achieving an accuracy over 87%, with specificity over 92% and sensitivity over 83%.
Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer
Authors: Joshu Corinne E. , Heaphy Christopher M. , Barber John R. , Lu Jiayun , Zarinshenas Reza , Davis Christine , Han Misop , Lotan Tamara L. , Sfanos Karen S. , De Marzo Angelo M. , Meeker Alan K. , Platz Elizabeth A.
Published: December 2020

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4′,6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (<25), overweight (25 ≤ BMI < 30), or obese (≥30). Analyses were stratified by grade and stage. Men were divided into tertiles of TMA- (overall) or TMA- and disease aggressiveness- (stratified) specific distributions; short CAS telomere status was defined by the bottom two tertiles. We used generalized linear mixed models to estimate the association between obesity and short CAS telomeres, adjusting for age, race, TMA set, pathologic stage, and grade. Obesity was not associated with short CAS telomeres overall, or among men with nonaggressive disease. Among men with aggressive disease (Gleason≥4+3 and stage>T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07–8.75; Ptrend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis.

Prevention Relevance:

This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.
DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells
Authors: Chung Jiil , Maruvka Yosef E. , Sudhaman Sumedha , Kelly Jacalyn , Haradhvala Nicholas J. , Bianchi Vanessa , Edwards Melissa , Forster Victoria J. , Nunes Nuno M. , Galati Melissa A. , Komosa Martin , Deshmukh Shriya , Cabric Vanja , Davidson Scott , Zatzman Matthew , Light Nicholas , Hayes Reid , Brunga Ledia , Anderson Nathaniel D. , Ho Ben , Hodel Karl P. , Siddaway Robert , Morrissy A. Sorana , Bowers Daniel C. , Larouche Valérie , Bronsema Annika , Osborn Michael , Cole Kristina A. , Opocher Enrico , Mason Gary , Thomas Gregory A. , George Ben , Ziegler David S. , Lindhorst Scott , Vanan Magimairajan , Yalon-Oren Michal , Reddy Alyssa T. , Massimino Maura , Tomboc Patrick , Van Damme An , Lossos Alexander , Durno Carol , Aronson Melyssa , Morgenstern Daniel A. , Bouffet Eric , Huang Annie , Taylor Michael D. , Villani Anita , Malkin David , Hawkins Cynthia E. , Pursell Zachary F. , Shlien Adam , Kunkel Thomas A. , Getz Gad , Tabori Uri
Published: December 2020

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy.

Significance:

Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.

This article is highlighted in the In This Issue feature, p. 995
Histopathologic Evaluation of Intralabyrinthine Schwannoma
Authors: Bagattini Michael , Quesnel Alicia M. , Röösli Christof
Published: December 2020

Objectives: The aim of this study is to perform a histopathologic analysis of temporal bones with an intralabyrinthine schwannoma (ILS) in order to characterize its extension. Methods: Archival temporal bones with a diagnosis of sporadic schwannoma were identified. Both symptomatic and occult nonoperated ILS were included for further analysis. Results: A total of 6 ILS were identified, with 4 intracochlear and 2 intravestibular schwannomas. All intracochlear schwannomas involved the osseous spiral lamina, with 2 extending into the modiolus. The intravestibular schwannomas were limited to the vestibule, but growth into the bone next to the crista of the lateral semicircular canal was observed in 1 patient. Conclusions: Complete removal of an ILS may require partial removal of the modiolus or bone surrounding the crista ampullaris as an ILS may extend into these structures, risking damage of the neuronal structures. Due to the slow growth of the ILS, it remains unclear if a complete resection is required with the risk of destroying neural structures hindering hearing rehabilitation with a cochlear implant.
Demographics, Perceptions, and Use of Medical Marijuana among Patients in Florida
Authors: Rosenthal Martha S. , Pipitone R. Nathan
Published: December 2020

Medical marijuana (MMJ) is currently legal in 35 US states, with an estimated 3.6 million state-legal medical cannabis patients. Although there are currently over 440,000 MMJ patients in the state of Florida, there are limited data on their demographics, reasons and patterns of use, and successes or failures of treatment. The goal of this study is to examine the demographics, perceptions, and use of medical cannabis among patients in Florida, as well as their perceptions of the quality of information received from physicians and dispensaries. One hundred and fifty-seven MMJ patients completed an online survey regarding their characteristics and use. Patients in Florida shared many characteristics with patients in other states, such as race, use frequency, and administration technique. Patients most commonly used MMJ to treat their symptoms of anxiety, pain, and stress and reported great therapeutic effectiveness. A majority (65%) of patients also reported either a reduction or total discontinuation of at least one prescription or over-the-counter drug. The findings highlight the need to further investigate the use of MMJ as a viable treatment for pain and anxiety and to improve access of quality cannabis information to patients, physicians, and dispensary employees.
The Effect of Sodium Butyrate Enemas Compared with Placebo on Disease Activity, Endoscopic Scores, and Histological and Inflammatory Parameters in Inflammatory Bowel Diseases: A Systematic Review of Randomised Controlled Trials
Authors: Jamka Małgorzata , Kokot Marta , Kaczmarek Nina , Bermagambetova Saule , Nowak Jan Krzysztof , Walkowiak Jarosław
Published: December 2020

Introduction: Administration of butyrate enemas might improve the health status of patients with inflammatory bowel disease (IBD). However, the results seem equivocal. Therefore, this systematic review aimed to assess the effect of sodium butyrate enemas on disease activity index (DAI), endoscopic scores, as well as histological and inflammatory parameters in IBD patients. Methods: The PubMed, Scopus, Web of Science, and Cochrane databases were searched. Randomised controlled trials published in English that assessed the effect of butyrate enemas on DAI, clinical symptoms, inflammatory markers, as well as histological and endoscopic scores in patients with Crohn’s disease (CD) and ulcerative colitis (UC) were included in the analysis. Results: Eight studies involving 227 UC patients were included in this analysis. Only one study reported significant differences in DAI between groups. Besides, butyrate treatment groups did not differ significantly from controls concerning the effect on endoscopic and histological scores. Moreover, butyrate enemas exerted a significant effect on few inflammatory parameters measured in colonic mucosal biopsies. Conclusion: The current evidence is limited and does not support the application of butyrate enemas in UC. There are no reliable data regarding the efficacy of butyrate enemas in CD. The systematic review protocol was registered in the PROSPERO database (CRD42020163654).
Algorithms for the Testing of Tissue Donors for Human Immunodeficiency Virus, Hepatitis B Virus, and Hepatitis C Virus
Authors: Pruß Axel , Chandrasekar Akila , Sánchez-Ibáñez Jacinto , Lucas-Samuel Sophie , Kalus Ulrich , Rabenau Holger F.
Published: December 2020

Background: Although transmission of pathogenic viruses through human tissue grafts is rare, it is still one of the most serious dreaded risks of transplantation. Therefore, in addition to the detailed medical and social history, a comprehensive serologic and molecular screening of the tissue donors for relevant viral markers for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) is necessary. In the case of reactive results in particular, clear decisions regarding follow-up testing and the criteria for tissue release must be made. Methods: Based on the clinical relevance of the specific virus markers, the sensitivity of the serological and molecular biological methods used and the application of inactivation methods, algorithms for tissue release are suggested. Results: Compliance with the preanalytical requirements and assessment of a possible hemodilution are mandatory requirements before testing the blood samples. While HIV testing follows defined algorithms, the procedures for HBV and HCV diagnostics are under discussion. Screening and decisions for HBV are often not as simple, e.g., due to cases of occult HBV infection, false-positive anti-HBc results, or early window period positive HBV NAT results. In the case of HCV diagnostics, modern therapies with direct-acting antivirals, which are often associated with successful treatment of the infection, should be included in the decision. Conclusion: In HBV and HCV testing, a high-sensitivity virus genome test should play a central role in diagnostics, especially in the case of equivocal serology, and it should be the basis for the decision to release the tissue. The proposed test algorithms and decisions are also based on current European recommendations and standards for safety and quality assurance in tissue and cell banking.