bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of a mobile technology-enabled primary care intervention for cardiovascular disease risk management in rural Indonesia
Authors: Angell Blake , Lung Thomas , Praveen Devarsetty , Maharani Asri , Sujarwoto Sujarwoto , Palagyi Anna , Oceandy Delvac , Tampubolon Gindo , Patel Anushka , Jan Stephen
Published: February 2021

Cardiovascular diseases (CVD) are the leading cause of death in Indonesia, and there are large disparities in access to recommended preventative treatments across the country, particularly in rural areas. Technology-enabled screening and management led by community health workers have been shown to be effective in better managing those at high risk of CVD in a rural Indonesian population; however, the economic impacts of implementing such an intervention are unknown. We conducted a modelled cost-effectiveness analysis of the SMARThealth intervention in rural villages of Malang district, Indonesia from the payer perspective over a 10-year period. A Markov model was designed and populated with epidemiological and cost data collected in a recent quasi-randomized trial, with nine health states representing a differing risk for experiencing a major CVD event. Disability-Adjusted Life Years (DALYs) were estimated for the intervention and usual care using disability weights from the literature for major CVD events. Annual treatment costs for CVD treatment and prevention were $US83 under current care and $US144 for those receiving the intervention. The intervention had an incremental cost-effectiveness ratio of $4288 per DALY averted and $3681 per major CVD event avoided relative to usual care. One-way and probabilistic sensitivity analyses demonstrated that the results were robust to plausible variations in model parameters and that the intervention is highly likely to be considered cost-effective by decision-makers across a range of potentially acceptable willingness to pay levels. Relative to current care, the intervention was a cost-effective means to improve the management of CVD in this rural Indonesian population. Further scale-up of the intervention offers the prospect of significant gains in population health and sustainable progress toward universal health coverage for the Indonesian population.
Workplace health promotion interventions for Australian workers with intellectual disability
Authors: Meacham Hannah , Cavanagh Jillian , Bartram Timothy , Pariona-Cabrera Patricia , Shaw Amie
Published: February 2021

Workplace health promotion (WHP) and the general wellbeing of workers in the Australian workforce should be a priority for all management. Our study argues that management support for workers with an intellectual disability (WWID) can make a difference to their health promotion and ultimately their participation in the workforce. We adopt a qualitative approach, through semi-structured interviews with 22 managers, across various organizations, to examine their perspectives around the WHP of WWID. We integrate the key values of WHP; rights for health, empowerment for health and participation for health (Spencer, Corbin and Miedema, Sustainable development goals for health promotion: a critical frame analysis, Health Promot Int 2019;34:847–58) into the four phases of WHP interventions; needs assessment, planning, implementation and evaluation (Bortz and Döring, Research Methods and Evaluation for Human and Social Scientists, Heidelberg: Springer, 2006) and examine management perspectives (setting-based approach) on WHP of WWID. Where this integration had taken place, we found some evidence of managers adopting more flexible, innovative and creative approaches to supporting the health promotion of WWID. This integration seemed to drive continuous improvement for WWID health promotion at the workplace. We also found evidence that some organizations, such an exemplar film company, even over deliver in terms of supporting WWID needs by encouraging their capabilities in film making interventions, whilst others are more direct in their support by matching skills to routine jobs. Our approach demonstrates that incorporating key WHP values into the four-phase WHP framework is critical for the effective health promotion of WWID.
Political discourse and the Nine Years’ War in late Elizabethan Ireland, c.1593–1603
Authors: Heffernan David
Published: February 2021

In the late Elizabethan period Ireland became a critical focus of the Tudor regime as the Nine Years War (c.1593-1603) threatened English rule in the second Tudor kingdom and the country became a theatre of the Anglo-Spanish War (1585-1604). As a result of this military emergency officials in Ireland began composing a deluge of policy papers from the mid-1590s onwards. Over two hundred of these treatises are extant. This paper provides the first systematic overview of this war-time discourse on Ireland. In doing so it sheds light on these writings and their significance for the history of late Elizabethan Ireland.
Imputed gene expression risk scores: a functionally informed component of polygenic risk
Authors: Pain Oliver , Glanville Kylie P , Hagenaars Saskia , Selzam Saskia , Fürtjes Anna , Coleman Jonathan R I , Rimfeld Kaili , Breen Gerome , Folkersen Lasse , Lewis Cathryn M
Published: February 2021

Integration of functional genomic annotations when estimating polygenic risk scores (PRS) can provide insight into aetiology and improve risk prediction. This study explores the predictive utility of gene expression risk scores (GeRS), calculated using imputed gene expression and transcriptome-wide association study (TWAS) results.

The predictive utility of GeRS was evaluated using 12 neuropsychiatric and anthropometric outcomes measured in two target samples: UK Biobank and the Twins Early Development Study. GeRS were calculated based on imputed gene expression levels and TWAS results, using 53 gene expression–genotype panels, termed single nucleotide polymorphism (SNP)-weight sets, capturing expression across a range of tissues. We compare the predictive utility of elastic net models containing GeRS within and across SNP-weight sets, and models containing both GeRS and PRS. We estimate the proportion of SNP-based heritability attributable to cis-regulated gene expression.

GeRS significantly predicted a range of outcomes, with elastic net models combining GeRS across SNP-weight sets improving prediction. GeRS were less predictive than PRS, but models combining GeRS and PRS improved prediction for several outcomes, with relative improvements ranging from 0.3% for height (P = 0.023) to 4% for rheumatoid arthritis (P = 5.9 × 10−8). The proportion of SNP-based heritability attributable to cis-regulated expression was modest for most outcomes, even when restricting GeRS to colocalized genes.

GeRS represent a component of PRS and could be useful for functional stratification of genetic risk. Only in specific circumstances can GeRS substantially improve prediction over PRS alone. Future research considering functional genomic annotations when estimating genetic risk is warranted.
Maximum sustainable yield in the EU’s Common Fisheries Policy - a political history
Authors: Earle Michael
Published: February 2021

The incorporation of MSY into the EU’s Common Fisheries Policy (CFP) is traced from the original fisheries objectives in the Treaty of Rome of 1957 through its first mention in the CFP basic regulation of 2013 up to the recent Baltic Sea management plan, in which it has become operationalized. Emphasis is placed on the dynamics of the EU’s political processes, the impact of non-fisheries-related institutional power struggles and the consequences of political negotiations that include scientific concepts. Criticisms by Sidney Holt, of both MSY as a management objective and the use of surplus production models, are included.
Unearthing Ambiguities: Post-Genocide Justice in Raoul Peck’s Sometimes in April and the ICTR case Nahimana et al.
Authors: Katila Anna
Published: February 2021

This article examines Raoul Peck’s portrayal of post-genocide justice in Rwanda in his film Sometimes in April (2005). The film, which depicts the 1994 genocide against the Tutsi and its aftermath a decade later, resonates with the ICTR case Prosecutor v. Nahimana et al. with its focus on hate speech as genocide. The shared questions connect the two distinct narrative forms that are part of the global social discourse on Rwanda, allowing them to be analysed side by side. Building upon close readings, this article asks: Who is guilty and what counts as a crime? What kind of impact do justice mechanisms have? Whose interests does the ICTR serve? Extending interdisciplinary research on Rwanda across law and cultural studies, I argue that analysing Sometimes in April helps unearth ambiguities within and surrounding the ICTR. Peck’s film and the legal case together communicate a rounded understanding of post-genocide justice to outside audiences, as it is experienced or perceived from local and international perspectives.
Ambient Prime Geodesic Theorems on Hyperbolic 3-Manifolds
Authors: Dever Lindsay , Milićević Djordje
Published: February 2021

We prove prime geodesic theorems counting primitive closed geodesics on a compact hyperbolic 3-manifold with length and holonomy in prescribed intervals, which are allowed to shrink. Our results imply effective equidistribution of holonomy and have both the rate of shrinking and the strength of the error term fully symmetric in length and holonomy.
IT Leaders Report: Cloud, Security & Soft Skills Come Into Their Own
Authors: Runciman Brian
Published: February 2021

Each January BCS produce a report informed by IT leaders. This year it was also the basis of the inaugural IT Leaders Forum event — ‘The Adaptive CIO’. Brian Runciman MBCS looks at some of the takeaways on concerns, priorities and skills gaps.
EU Roadmap to Cleaner, Greener Data Centres
Authors: Booth John
Published: February 2021

While our exit from the European Union is very much in the news, our shared purpose and collaboration with our neighbours isn't so widely celebrated. John Booth MBCS, Vice Chair of the Green IT SG and Managing Director of Carbon3IT, looks at energy hungry data centres and explains how (and why) the green tide is turning.
Covid-19 and Digital Education: a Catalyst For Change?
Authors: Crick Tom
Published: February 2021

While education still faces huge challenges, including the rapid shift to online learning, teaching and assessment, there may be some light at the end of the tunnel, writes Tom Crick MBE FBCS, Professor of Digital Education & Policy at Swansea University.
Insight: Business Analysis
Authors: Lovelock Christina
Published: February 2021

Christina Lovelock MBCS explores the derivation of the word ‘analysis’ and explains how the word's true meanings can help us all become better analysts ourselves.
Visualising Business Analysis
Authors: Wright Grant
Published: February 2021

Visual thinking opens up new possibilities that can take your business analysis practices to the next level, writes Grant Wright, Principal Consultant at Scarlett Solutions and co-founder of The Visual Jam.
Introducing John Higgins
Authors: Runciman Brian
Published: February 2021

From the AGM in March, BCS has a new President. Brian Runciman MBCS speaks to John Higgins against a backdrop of a year when we hope some of the worst effects of COVID-19 will be starting to recede, and new priorities start emerging.
An international inventory of antimicrobial stewardship (AMS) training programmes for AMS teams
Authors: Weier Naomi , Nathwani Dilip , Thursky Karin , Tängdén Thomas , Vlahović-Palčevski Vera , Dyar Oliver , Beović Bojana , Levy Hara Gabriel , Patel Rahul , Pulcini Céline , Zaidi Syed Tabish R
Published: February 2021

Background

Healthcare professionals are increasingly expected to lead antimicrobial stewardship (AMS) initiatives. This role in complex healthcare environments requires specialized training.

Objectives

Little is known about the types of AMS training programmes available to clinicians seeking to play a lead role in AMS. We aimed to identify clinicians’ awareness of AMS training programmes, characteristics of AMS training programmes available and potential barriers to participation.

Methods

AMS training programmes available were identified by members of the ESCMID Study Group for Antimicrobial Stewardship (ESGAP) via an online survey and through an online search in 2018. Individual training programme course coordinators were then contacted (September–October 2018) for data on the target audience(s), methods of delivery, intended outcomes and potential barriers to accessing the training programme.

Results

A total of 166/250 ESGAP members (66%) responded to the survey, nominating 48 unique AMS training programmes. An additional 32 training programmes were identified through an online search. AMS training programmes were from around the world. Less than half (44.4%) of respondents were aware of one or more AMS training programmes available, with pharmacists more aware compared with medical doctors and other professionals (73% versus 46% and 25%, respectively). AMS training programmes were most commonly delivered online (59%) and aimed at medical doctors (46%). Training costs and a lack of recognition by health professional societies were the most frequently cited barriers to participation in AMS training programmes.

Conclusions

The development of a systematic inventory of AMS training programmes around the globe identifies opportunities and limitations to current training available. Improving access and increasing awareness amongst target participants will support improved education in AMS.
Keeping Camouflage Out of the Classroom: The Safe Schools Declaration and the Guidelines for Protecting Schools and Universities from Military Use During Armed Conflict
Authors: Zwanenburg Marten
Published: February 2021

This article discusses the ‘Safe Schools Declaration’ and the ‘Guidelines for Protecting Schools and Universities from Military use during Armed Conflict’. The latter are set of non-binding guidelines that aim to improve the protection of schools and universities during armed conflict. The former is a political declaration through which States can endorse the Guidelines. The article looks at the drafting process of the two documents, which involved non-governmental organizations (NGOs), international organizations and States. The article argues that the involvement of NGOs can be seen as reflective of a trend in which NGOs are increasingly involved in normative International Humanitarian Law (IHL) development. The role of international organizations was less pronounced, but nevertheless notable because international organizations traditionally do not have an active role in the field of IHL. The article contains an analysis of the Declaration and Guidelines, against the background of the applicable legal framework to the protection of schools and universities during armed conflict. It concludes that the principal focus of the Guidelines is the prevention of the use of schools and universities by armed forces in support of the military effort. IHL does not contain a rule prohibiting such use, but it can have far-reaching negative consequences for education. Other guidelines relate to, inter alia (limitations to), destroying or attacking schools and universities. These guidelines, while sometimes using phraseology from provisions of IHL treaty law, also largely go beyond existing obligations under IHL.
Cabazitaxel versus abiraterone or enzalutamide in metastatic castration-resistant prostate cancer: post hoc analysis of the CARD study excluding chemohormonal therapy for castrate-naive disease
Authors: Suzuki Hiroyoshi , Castellano Daniel , de Bono Johann , Sternberg Cora N , Fizazi Karim , Tombal Bertrand , Wülfing Christian , Foster Meredith C , Ozatilgan Ayse , Geffriaud-Ricouard Christine , de Wit Ronald
Published: February 2021

Background

In the CARD study (NCT02485691), cabazitaxel significantly improved clinical outcomes versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen-signalling-targeted inhibitor. However, some patients received docetaxel or the prior alternative androgen-signalling-targeted inhibitor in the metastatic hormone-sensitive (mHSPC) setting. Therefore, the CARD results cannot be directly translated to a Japanese population.

Methods

Patients (N = 255) received cabazitaxel (25 mg/m2 IV Q3W, prednisone, G-CSF) versus abiraterone (1000 mg PO, prednisone) or enzalutamide (160 mg PO) after prior docetaxel and progression ≤12 months on the alternative androgen-signalling-targeted inhibitor. Patients who received combination therapy for mHSPC were excluded (n = 33) as docetaxel is not approved in this setting in Japan.

Results

A total of 222 patients (median age 70 years) were included in this subanalysis. Median number of cycles was higher for cabazitaxel versus androgen-signalling-targeted inhibitors (7 versus 4). Clinical outcomes favoured cabazitaxel over abiraterone or enzalutamide including, radiographic progression-free survival (rPFS; median 8.2 versus 3.4 months; P < 0.0001), overall survival (OS; 13.9 versus 11.8 months; P = 0.0102), PFS (4.4 versus 2.7 months; P < 0.0001), confirmed prostate-specific antigen response (37.0 versus 14.4%; P = 0.0006) and objective tumour response (38.9 versus 11.4%; P = 0.0036). For cabazitaxel versus androgen-signalling-targeted inhibitor, grade ≥ 3 adverse events occurred in 55% versus 44% of patients, with adverse events leading to death on study in 2.7% versus 5.7%.

Conclusions

Cabazitaxel significantly improved outcomes including rPFS and OS versus abiraterone or enzalutamide and are reflective of the Japanese patient population. Cabazitaxel should be considered the preferred treatment option over abiraterone or enzalutamide in this setting.
miR-424-5p reduces 5-fluorouracil resistance possibly by inhibiting Src/focal adhesion kinase signalling-mediated epithelial–mesenchymal transition in colon cancer cells
Authors: Liu Youqiang , Wang Guiying , Li Yong , Zhao Qun , Fan Liqiao , Tan Bibo , Li Baokun , Yu Bin , Xi Jinchuan
Published: February 2021

Objectives

miR-424-5p negatively regulates various malignant biological behaviours in tumour cells. We explored the relationship between miR-424-5p and 5-fluorouracil resistance in colon cancer cells.

Methods

We developed 5-fluorouracil-resistant HT-29 cells and detected miR-424-5p expression using real-time fluorescence quantitative PCR. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) assay. Immunofluorescence and western blotting were performed to determine protein levels. Apoptosis was detected by Annexin V-FITC/PI staining.

Key findings

miR-424-5p was downregulated in 5-fluorouracil-resistant HT-29 cells. A miR-424-5p mimic enhanced the sensitivity of the resistant cells to 5-fluorouracil, whereas a miR-424-5p inhibitor promoted 5-fluorouracil resistance in HT-29 cells. Furthermore, the miR-424-5p mimic downregulated vimentin and upregulated E-cadherin in 5-fluorouracil-resistant HT-29 cells, whereas the miR-424-5p inhibitor exhibited opposite effects. The miR-424-5p inhibitor significantly inhibited 5-fluorouracil-induced HT-29 cell apoptosis and Src and focal adhesion kinase phosphorylation, whereas the miR-424-5p mimic showed opposite effects. Pretreatment with Src inhibitor 1 or focal adhesion kinase inhibitor 2 blocked the increase in Src and focal adhesion kinase phosphorylation and vimentin expression level and the decrease in E-cadherin expression level in miR-424-5p inhibitor-exposed HT-29 cells.

Conclusions

miR-424-5p suppressed epithelial–mesenchymal transition by inhibiting the Src/focal adhesion kinase signalling pathway to reduce 5-fluorouracil resistance in colon cancer cells.
A simplified isolation technique for atherosclerotic aortic arch aneurysms surgery
Authors: Kikuchi Yuta , Kikuchi Yoichi , Kamiya Hiroyuki
Published: February 2021

The isolation technique is a useful adjunct that prevents atherosclerotic embolism in the brain when the aneurysm is filled with a massive hematoma or ‘shaggy aorta’. But the technique is not widespread because of the difficulty in performing the cannulation. We modified this technique by simplifying the cannulation procedure using a puncture method with aortic root cannulas.
Rotational excitation of highly excited H2O by H2
Authors: Żóltowski Michal , Lique François , Karska Agata , Żuchowski Piotr S
Published: February 2021

Water is a key molecule for interstellar chemistry. Observations with Herschel telescope show significant population of very high rotational transitions (j ≳ 8) in young stellar objects, indicating significant amounts of water in hot (T ≳ 1500 K) and dense (n ≳ 106 cm−3) gas. Non-local thermodynamic equilibrium (LTE) modelling of these observations requires the knowledge of the collisional and radiative properties of highly excited water at high temperature. The aim of this work is to calculate a new set of excitation rate coefficients for both para- and ortho-H2O induced by collisions with H2 for energy levels up to j = 17. Quantum scattering calculations were performed using a reduced dimensional approach and the coupled states approximation. Rate coefficients were obtained for 97 pure rotational energy levels of both para- and ortho-H2O and for temperatures up to 2000 K. With the forthcoming launch of the James Webb Space Telescope, these new collisional data will allow us to gain more insight into the physical conditions in star- and planet-forming regions.
Impact of photochemical hazes and gases on exoplanet atmospheric thermal structure
Authors: Lavvas P , Arfaux A
Published: February 2021

We investigate the impact of photochemical hazes and disequilibrium gases on the thermal structure of hot Jupiters, using a detailed 1D radiative-convective model. We find that the inclusion of photochemical hazes results in major heating of the upper and cooling of the lower atmosphere. Sulphur containing species, such as SH, S2, and S3, provide significant opacity in the middle atmosphere and lead to local heating near 1 mbar, while OH, CH, NH, and CN radicals produced by the photochemistry affect the thermal structure near 1 $\mu$bar. Furthermore, we show that the modifications on the thermal structure from photochemical gases and hazes can have important ramifications for the interpretation of transit observations. Specifically, our study for the hazy HD 189733 b shows that the hotter upper atmosphere resulting from the inclusion of photochemical haze opacity imposes an expansion of the atmosphere, thus a steeper transit signature in the ultraviolet–visible part of the spectrum. In addition, the temperature changes in the photosphere also affect the secondary eclipse spectrum. For HD 209458 b, we find that a small haze opacity could be present in this atmosphere, at pressures below 1 mbar, which could be a result of both photochemical hazes and condensates. Our results motivate the inclusion of radiative feedback from photochemical hazes in general circulation models for a proper evaluation of atmospheric dynamics.
The former companion of hyper-velocity star S5-HVS1
Authors: Lu Wenbin , Fuller Jim , Raveh Yael , Perets Hagai B , Li Ting S , Hosek Matthew W , Do Tuan
Published: February 2021

The hyper-velocity star S5-HVS1, ejected 5 Myr ago from the Galactic Centre at 1800 km s−1, was most likely produced by tidal break-up of a tight binary by the supermassive black hole SgrA*. Taking a Monte Carlo approach, we show that the former companion of S5-HVS1 was likely a main-sequence star between 1.2 and 6 M⊙ and was captured into a highly eccentric orbit with pericentre distance in the range of 1–10 au and semimajor axis about 103 au. We then explore the fate of the captured star. We find that the heat deposited by tidally excited stellar oscillation modes leads to runaway disruption if the pericentre distance is smaller than about $3\rm \, au$. Over the past 5 Myr, its angular momentum has been significantly modified by orbital relaxation, which may stochastically drive the pericentre inwards below $3\rm \, au$ and cause tidal disruption. We find an overall survival probability in the range 5 per cent to 50 per cent, depending on the local relaxation time in the close environment of the captured star, and the initial pericentre at capture. The pericentre distance of the surviving star has migrated to 10–100 au, making it potentially the most extreme member of the S-star cluster. From the ejection rate of S5-HVS1-like stars, we estimate that there may currently be a few stars in such highly eccentric orbits. They should be detectable (typically $K_{\rm s}\lesssim 18.5\,$ mag) by the GRAVITY instrument and by future Extremely Large Telescopes and hence provide an extraordinary probe of the spin of SgrA*.
Synchronized periodic maser flares of multiple OH and CH3OH lines in G323.459–0.079
Authors: MacLeod G C , Smits Derck P , Green J A , van den Heever S P
Published: February 2021

The first confirmed periodically varying 6.031 and 6.035 GHz hydroxyl masers are reported here. They vary contemporaneously with the 6.7 GHz methanol masers in G323.459–0.079. The 1.665 GHz hydroxyl and 12.2  GHz methanol masers associated with G323.459–0.079 are also periodic. Evidence for periodicity is seen in all features in all transitions save a single 1.665 GHz hydroxyl maser feature. Historical excited-state hydroxyl maser observations set a stricter upper limit on the epoch in which a significant accretion event occurred. The associated burst in 6.7 GHz methanol maser activity has subsided significantly while the hydroxyl transitions are brightening possibly the result of changing physical conditions in the masing cloudlets. Time lags in methanol are confirmed and may be the result of the periodic flaring propagating outward from the central region of maser activity. A possible magnetic field reversal occurred during the accretion event.
Correlations between γ-ray luminosity and magnetization of the jet as well as relativistic electron injection power: cases for Mrk 421, 3C 454.3 and 3C 279
Authors: Hu Wen , Yan Dahai , Hu Qianglin
Published: February 2021

By fitting high-quality and simultaneous multiwavelength spectral energy distributions at multiple epochs with a one-zone leptonic jet model, we study the jet properties of three famous blazars: Mrk 421, 3C 454.3 and 3C 279. In the jet model, the emitting electron energy distributions are calculated by solving the kinetic equations of electron injection, escape, adiabatic and radiative energy losses. To explore multidimensional parameter space systematically, we employ a Markov chain Monte Carlo fitting technique. The properties of the emission regions we have derived here are consistent with those in previous studies, for example, the particle-dominated and low-magnetization jet. The new finding is that there is a tight correlation between γ-ray luminosity and electron injection power and an anticorrelation between γ-ray luminosity and the jet magnetization parameter. The results suggest that the same energy-dissipative mechanism (such as a shock) could be operating in the jets of different types of blazars, and that the origin of γ-ray flares is associated with the particle acceleration process.
Targeted-antibacterial-plasmids (TAPs) combining conjugation and CRISPR/Cas systems achieve strain-specific antibacterial activity
Authors: Reuter Audrey , Hilpert Cécile , Dedieu-Berne Annick , Lematre Sophie , Gueguen Erwan , Launay Guillaume , Bigot Sarah , Lesterlin Christian
Published: February 2021

The global emergence of drug-resistant bacteria leads to the loss of efficacy of our antibiotics arsenal and severely limits the success of currently available treatments. Here, we developed an innovative strategy based on targeted-antibacterial-plasmids (TAPs) that use bacterial conjugation to deliver CRISPR/Cas systems exerting a strain-specific antibacterial activity. TAPs are highly versatile as they can be directed against any specific genomic or plasmid DNA using the custom algorithm (CSTB) that identifies appropriate targeting spacer sequences. We demonstrate the ability of TAPs to induce strain-selective killing by introducing lethal double strand breaks (DSBs) into the targeted genomes. TAPs directed against a plasmid-born carbapenem resistance gene efficiently resensitise the strain to the drug. This work represents an essential step toward the development of an alternative to antibiotic treatments, which could be used for in situ microbiota modification to eradicate targeted resistant and/or pathogenic bacteria without affecting other non-targeted bacterial species.
Enhanced brain delivery and therapeutic activity of trastuzumab after blood-brain barrier opening by NEO100 in mouse models of brain-metastatic breast cancer
Authors: Wang Weijun , He Haiping , Marín-Ramos Nagore I , Zeng Shan , Swenson Steven D , Cho Hee-Yeon , Fu Jie , Beringer Paul M , Neman Josh , Chen Ligang , Schönthal Axel H , Chen Thomas C
Published: February 2021

Background

The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity.

Methods

An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival.

Results

NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100.

Conclusion

IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.
Antistaphylococcal Penicillin vs Cefazolin for the Treatment of Methicillin-SusceptibleStaphylococcus aureusSpinal Epidural Abscesses
Authors: Corsini Campioli Cristina , Go John Raymond , Abu Saleh Omar , Challener Douglas , Yetmar Zachary , Osmon Douglas R
Published: February 2021

Cefazolin is commonly used as an alternative to antistaphylococcal penicillins (ASPs) in treating methicillin-susceptible Staphylococcus aureus (MSSA) infections; however, no study has compared these agents in MSSA spinal epidural abscess (SEA). We describe our experience in managing MSSA SEA and compare the clinical efficacy of cefazolin with ASPs. This retrospective multicenter study reviewed 79 adult patients diagnosed with SEA between January 2006 and July 2020 using data collected from electronic health records and clinical microbiology laboratory databases. Forty-five patients received cefazolin, while 34 received ASPs. The total antibiotic duration was longer in the ASPs group but not statistically significant. There were no significant differences in treatment failure at week 6 vs week 12, 30-day vs overall mortality, or in 90-day recurrence rates between the treatment groups. Cefazolin was equally as effective as ASPs, and our findings suggest that it can be an alternative to ASPs in the treatment of MSSA SEA.
Cutaneous Findings in SARS-CoV-2-Associated Multisystem Inflammatory Disease in Children
Authors: Blatz Allison M , Oboite Michelle , Chiotos Kathleen , Castelo-Soccio Leslie , Odom John Audrey R ,   Children’s Hospital of Philadelphia MIS-C Research Collaborative, Bassiri Hamid , Behrens Edward M , Diorio Caroline , Fitzgerald Julie C , Giglia Therese , Lambert Michele , Petrosa Whitney , Teachey David T , Vella Laura A , Witmer Char
Published: February 2021

Rash is a common feature of multisystem inflammatory syndrome in children (MIS-C), a postinfectious hyperinflammatory disease associated with prior severe acute respiratory syndrome coronavirus 2 infection. Because the differential diagnosis of fever and rash in children is broad, understanding clinical characteristics of MIS-C may assist with diagnosis. Here we describe the cutaneous findings observed in a series of children with MIS-C-associated rash.
The accessibility and probability of encountering catastrophic health expenditure by Lao patients in Thai hospitals
Authors: Bodhisane Somdeth , Pongpanich Sathirakorn
Published: February 2021

It is common for people in Laos to use health services in Thailand and other foreign countries. This study analyzes and compares the probability of using health care services and the financial catastrophe occurring due to health service utilization in both local and Thai hospitals.

This study includes 390 respondents from Savannakhet Province, Laos. Households’ income levels play an essential role in selected locations of hospital admission. The regression model proves that lower income quintiles were more likely to use local health services, whereas the higher income households preferred Thailand’s hospital services. There is a negative relationship between income level and the probability of experiencing catastrophic health expenditure.

The National Health Insurance (NHI) is recommended to seek greater cooperation with foreign hospitals, to allow Lao patients to use NHI’s coverage as a co-payment system for specific health services not available in Lao hospitals. NHI should have to include proper-nutrition meal services in hospitals for patients to reduce the need for accompanied household members during patients’ time at hospitals. It is proven that NHI successfully enhances accessibility to local health services; in the long run, the government should expand national hospitals’ capacity, medical equipment availability and quantity of health care personnel.
COVID-19 community care in Israel—a nationwide cohort study from a large health maintenance organization
Authors: Shapiro Ben David Shirley , Cohen Daniella , Karplus Rebekah , Irony Angela , Ofer-Bialer Gili , Potasman Israel , Greenfeld Orly , Azuri Joseph , Ash Nachman
Published: February 2021

Background

Among the many medical challenges presented by the COVID-19 pandemic, management of the majority of patients in community outpatient settings is crucial. The aim of this study was to describe the characteristics and outcomes among confirmed COVID-19 cases who were managed at three settings: two outpatient settings and one inpatient.

Methods

A retrospective database cohort study was conducted in a large Israeli Health Maintenance Organization. All COVID-19 cases diagnosed between 28 February 2020 and 20 July 2020 were included. Cases in the community settings were managed through a nationwide remote monitoring center, using preliminary telehealth triage and 24/7 virtual care. Outcome parameters included hospital admission, disease severity, need for respiratory support and mortality.

Results

About 5448 cases, aged range 0–97 years, were enrolled; 88.7% were initially managed as outpatient either at home or in designated hotels, 3.1 and 2.1% of them, respectively, later required hospitalization. The main reason for hospitalization was dyspnea; 12 were diagnosed with severe disease; 56 patients (1.3%) died, five (0.1%) of whom were initially allocated to the outpatient settings.

Conclusions

Care for appropriately selected COVID-19 patients in the community provides a safe and effective option. This can contribute to reducing the hospitalization burden, with no evidence of increased morbidity or mortality.
COVID-19: back to healthcare basics in Philippine prisons
Authors: Arambulo Hannah Kristianne Marie , Sahagun Caroline Therese , Biana Hazel T
Published: February 2021

Prisons have not escaped the effects of COVID-19. In countries where there are limited resources and spaces available, there is a need to find innovative ways to keep detainees safe and healthy. We can see various approaches such as the Irish model, which gives due importance to the establishment of contact tracing teams (CTT). In the case of Philippine prisons with high congestion rates, however, we may have to go back to certain healthcare basics to address COVID-19 transmissions.
Comparison of presentations to the emergency department during the COVID-19 pandemic (COPED-C)
Authors: Kociejowski A , Hobart C , Jina R , Aberman I , Backhurst E , Beaumont A , Crompton J , Sneep R , Cantle F , Dodhia H
Published: February 2021

Background

Concerns have been raised that patients requiring emergency care may not have accessed healthcare services during coronavirus disease 2019 (COVID-19) lockdown.

Methods

This case control study aimed to understand changes in characteristics and diagnosis of patients attending a large UK Emergency Department (ED) during the first wave of the COVID-19 pandemic (March–May 2020) compared with equivalent weeks in 2019.

Results

We found a 50.7% drop in first attendances to the ED in 2020. Likelihood of attendance and admission decreased for paediatric patients and increased for patients ≥ 46 years, and for men. Likelihood of admission increased for all Black ethnic groups and for patients from the most deprived index of multiple deprivation quintiles. This shift to an older, male, more deprived patient population with greater representation of ethnic minority groups was amplified in the ‘Infections’ diagnostic category.

Conclusions

COVID-19 has dramatically impacted ED usage. Our analysis contributes to local resource planning and understanding of changes in healthcare-seeking behaviour during the pandemic. Future research to identify positive behaviour changes could help sustain a reduction in non-urgent visits in the longer term.
Cautious and gradual reopening of limited face-to-face classes in Philippine tertiary schools
Authors: Gopez Jose Ma W
Published: February 2021

In a recent correspondence, the authors suggested that secondary schools must adhere to health protocols and national and international guidelines so that the delivery of face-to-face classes will not risk students’ and educators’ health. With this, this paper proposes that even in higher education, a well-planned execution of face-to-face classes must be done. Thus, the gradual reopening of face-to-face classes becomes a necessity in order to gain a sense of normalcy in the middle of a pandemic.
Patient perceptions of co-morbidities in inflammatory arthritis
Authors: Koduri Gouri M , Gullick Nicola J , Hayes Fiona , Dubey Shirish , Mukhtyar Chetan
Published: February 2021

Objective

Longer life expectancy has resulted in people living with an increasing number of co-morbidities. The average individual with inflammatory arthritis has two co-morbidities, which contribute to higher mortality, poorer functional outcomes and increased health-care utilization and cost. A number of studies have investigated the prevalence of co-morbidities, whereas this study was designed to look at patient perspectives.

Methods

The study comprised two parts: a patient questionnaire and an interview. Individuals with physician-verified inflammatory arthritis along with one or more Charlson co-morbidities were invited to participate. In-depth data were obtained by interviews with 12 willing participants.

Results

One hundred and forty-six individuals were recruited; 50 (35%) had one co-morbidity, 69 (48%) had two and 25 (17%) had more than four co-morbidities. Seventy-seven individuals (53%) reported that co-morbidities affected their health as much as their arthritis, and 82 (56%) reported dependence on others for activities of daily living. Lack of education was highlighted by 106 (73%) participants. Qualitative data provided further support for the challenges, with participants highlighting the lack of time to discuss complex or multiple problems, with no-one coordinating their care. This, in turn, led to polypharmacy and insufficient discussion around drug and disease interactions, complications and self-help measures.

Conclusion

This study highlights the challenges for individuals with inflammatory arthritis who suffer with multiple co-morbidities. The challenges result from limited resources or support within the current health-care environments. Individuals highlighted the poor quality of life, which is multifactorial, and the need for better educational strategies and coordination of care to improve outcomes.
Production performance of cows raised with different postweaning growth patterns
Authors: Freetly Harvey C , Cushman Robert A , Bennett Gary L
Published: February 2021

The period of heifer development is a relatively small fraction of a cow’s life; however, her pattern of growth may have permanent effects on her productivity as a cow. We hypothesized that altering the growth pattern during the peri-pubertal period would increase life-time productivity across genetic types of Bos taurus cows. The objective was to determine the stayability, calf production, and weight of calf weaned across six calf crops. Heifers (n = 685) were placed on one of two developmental programs at 256 ± 1 d of age. Control heifers received a diet that provided 228 kcal ME·(body weight [BW], kg) −0.75 daily, and stair-step heifers were allocated 157 kcal ME·(BW, kg)−0.75 daily for 84 or 85 d, and then the daily allocation was increased to 277 kcal ME·(BW, kg)−0.75. Stair-step heifers (0.33 ± 0.02 kg/d) had a lower average daily gain (ADG) than control heifers (0.78 ± 0.02 kg/d; P < 0.001) during Period 1, and stair-step heifers (0.93 ± 0.03 kg/d) had a greater ADG than controls (0.70 ± 0.03 kg/d; P < 0.001) during Period 2. There were no treatment (P = 0.28) or breed type differences (P = 0.42) for the proportion of cows weaning a calf; however, the proportion of cows weaning a calf decreased with cow age (P < 0.001). Calves from stair-step dams had heavier weaning weights (193 ± 1 kg) compared to control calves (191 ± 1 kg; P = 0.007). There was not a treatment (P = 0.25) or breed type differences in cumulative BW weaned (P = 0.59). A diverse genetic population of cattle within B. taurus was tested and responses in calf production did not differ between stair-step growth pattern and a more constant nonobese growth pattern.
Combining data assimilation and machine learning to infer unresolved scale parametrization
Authors: Brajard Julien , Carrassi Alberto , Bocquet Marc , Bertino Laurent
Published: February 2021

In recent years, machine learning (ML) has been proposed to devise data-driven parametrizations of unresolved processes in dynamical numerical models. In most cases, the ML training leverages high-resolution simulations to provide a dense, noiseless target state. Our goal is to go beyond the use of high-resolution simulations and train ML-based parametrization using direct data, in the realistic scenario of noisy and sparse observations. The algorithm proposed in this work is a two-step process. First, data assimilation (DA) techniques are applied to estimate the full state of the system from a truncated model. The unresolved part of the truncated model is viewed as a model error in the DA system. In a second step, ML is used to emulate the unresolved part, a predictor of model error given the state of the system. Finally, the ML-based parametrization model is added to the physical core truncated model to produce a hybrid model. The DA component of the proposed method relies on an ensemble Kalman filter while the ML parametrization is represented by a neural network. The approach is applied to the two-scale Lorenz model and to MAOOAM, a reduced-order coupled ocean-atmosphere model. We show that in both cases, the hybrid model yields forecasts with better skill than the truncated model. Moreover, the attractor of the system is significantly better represented by the hybrid model than by the truncated model.

This article is part of the theme issue ‘Machine learning for weather and climate modelling’.
Learning earth system models from observations: machine learning or data assimilation?
Authors: Geer A. J.
Published: February 2021

Recent progress in machine learning (ML) inspires the idea of improving (or learning) earth system models directly from the observations. Earth sciences already use data assimilation (DA), which underpins decades of progress in weather forecasting. DA and ML have many similarities: they are both inverse methods that can be united under a Bayesian (probabilistic) framework. ML could benefit from approaches used in DA, which has evolved to deal with real observations—these are uncertain, sparsely sampled, and only indirectly sensitive to the processes of interest. DA could also become more like ML and start learning improved models of the earth system, using parameter estimation, or by directly incorporating machine-learnable models. DA follows the Bayesian approach more exactly in terms of representing uncertainty, and in retaining existing physical knowledge, which helps to better constrain the learnt aspects of models. This article makes equivalences between DA and ML in the unifying framework of Bayesian networks. These help illustrate the equivalences between four-dimensional variational (4D-Var) DA and a recurrent neural network (RNN), for example. More broadly, Bayesian networks are graphical representations of the knowledge and processes embodied in earth system models, giving a framework for organising modelling components and knowledge, whether coming from physical equations or learnt from observations. Their full Bayesian solution is not computationally feasible but these networks can be solved with approximate methods already used in DA and ML, so they could provide a practical framework for the unification of the two. Development of all these approaches could address the grand challenge of making better use of observations to improve physical models of earth system processes.

This article is part of the theme issue ‘Machine learning for weather and climate modelling’.
Physics-informed machine learning: case studies for weather and climate modelling
Authors: Kashinath K. , Mustafa M. , Albert A. , Wu J-L. , Jiang C. , Esmaeilzadeh S. , Azizzadenesheli K. , Wang R. , Chattopadhyay A. , Singh A. , Manepalli A. , Chirila D. , Yu R. , Walters R. , White B. , Xiao H. , Tchelepi H. A. , Marcus P. , Anandkumar A. , Hassanzadeh P. , Prabhat
Published: February 2021

Machine learning (ML) provides novel and powerful ways of accurately and efficiently recognizing complex patterns, emulating nonlinear dynamics, and predicting the spatio-temporal evolution of weather and climate processes. Off-the-shelf ML models, however, do not necessarily obey the fundamental governing laws of physical systems, nor do they generalize well to scenarios on which they have not been trained. We survey systematic approaches to incorporating physics and domain knowledge into ML models and distill these approaches into broad categories. Through 10 case studies, we show how these approaches have been used successfully for emulating, downscaling, and forecasting weather and climate processes. The accomplishments of these studies include greater physical consistency, reduced training time, improved data efficiency, and better generalization. Finally, we synthesize the lessons learned and identify scientific, diagnostic, computational, and resource challenges for developing truly robust and reliable physics-informed ML models for weather and climate processes.

This article is part of the theme issue ‘Machine learning for weather and climate modelling’.