bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Way of Looking at Flexibility
Authors: Leupen Bernard
Published: January 2021

Houses have an average life span of about a hundred years, whereas households and habitats can change radically and repeatedly during that time. Consequently house designers are faced with the task of giving form to a shelter for dwelling for a period during which the composition of the household and the associated spatial rituals will go through major changes.

Taking not the changeable but the permanent as a departure−point opens up new perspectives. The permanent, or durable component of the house, constitutes the frame within which change can take place. This frame defines the space for change. The frame itself is specific and has qualities that determine the architecture for a long period of time. The space inside the frame is general, its use unspecified; this space I have called generic space.

In this sense the frame frees other parts of a building. Take, for example, the loadbearing column. It relieves the wall from acting in a loadbearing capacity, it frees the wall. A notion essential to the frame ’s functioning is that of disconnection. The column can free the wall by virtue of the fact that wall and column are not inextricably linked.

A building can be separated up into a number of layers that together defines the building as a whole. Accordingly, the building can be regarded as a composition assembled from these layers. Each layer is distinguished from the others by the special role it fulfils. In the frame concept it is assumed that every layer may in principle serve as a frame. Basing my information on texts by Laugier, Semper, Loos, Duffy and Brand, I have made a distinction between the following five layers:

• Main loadbearing structure

• Skin

• Scenery

• Service elements

• Access

In principle I distinguish three categories of changeability: the alterable, the extendable and the polyvalent. These three forms of changeability can be linked with three types of generic space. Should the generic space contain a layer that can be changed then we may describe it as alterable. Should the generic space not be bordered on all sides then it is a question of extendibility. Should the generic space contain no other layers while the generic space invites different uses through its form and dimensions, then we have polyvalence.

To explore my concept, I present an overview of every imaginable combination of layers. This catalogue of frames is then divided among four distinct series of combinations. The basic combinations and the combination series, constitute the tools for designing houses that proceed from the frame concept. It was the intention of this study to develop the frame concept and the body of concepts attendant on it. Building upon its predecessors, I developed a stimulating resource for anyone involved in designing houses that are able to accommodate change. The potentials and limitations of the frame concept can be further explored as designing proceeds.
Mainstreaming Hiv/Aids in Housing Developments and Planning in Swaziland
Authors: Ndlela William N.
Published: January 2021

Swaziland is one of the countries with the highest Human Immune-deficiency Virus (HIV) rates in the world. Consequently, the increased need for care and support for people living with Acquired Immune-deficiency Syndrome (AIDS), as well as orphaned and vulnerable children, is unprecedented. The response to combat the HIV epidemic has been evident in many areas as the country continues its fight against the HIV epidemic. However, efforts to provide care and support - including Anti-Retroviral Therapy (ART), management of opportunistic infections, and community home-based care - have, so far, largely stemmed from the health sector. Housing care and other non-medical support is continuing to lag behind. Lack of proper housing is one of the deprivations suffered by orphaned children and people living with AIDS, which predisposes them to attacks by opportunistic infections and other vulnerabilities and disrupts the continuum of care, whilst at times denying occupants the required privacy.

This paper focuses on creating an understanding of why housing care and support for HIV and AIDS affected is lagging behind in Swaziland. It suggests cultural, economic, political and policy issues as the underlying reasons for this, and, therefore, concludes that there is need for bold policy reforms in these areas. In order to create a proper framework for such reforms, the paper reviews the following:

1. The national housing policy's implications on the care and support for people living with HIV and AIDS and the orphaned and vulnerable children; and

2. The current human settlements related responses to HIV and AIDS in Swaziland's rural, peri-urban and urban areas.

In this context, urban development planning paradigms and the extent to which HIV and AIDS is being integrated into the development plans are discussed.
Systemic family therapy for severe functional disorders in youths: a qualitative study in a psychiatric setting
Authors: Hulgaard Ditte Roth , Risør Mette Bech , Lambertsen Gitte Dehlholm , Rask Charlotte Ulrikka
Published: January 2021

This study aimed to explore participant experiences of systemic family therapy for youths with functional disorders. After completing family therapy, eight youths and thirteen parents participated in qualitative interviews. The analysis was based on interpretative phenomenological analysis and identified two main themes. The first theme was: ‘Challenges of creating meaning and understanding of child symptoms in family therapy’, with symptom understanding and explanation found to be important, though sometimes challenging, themes in therapy. The second theme was: ‘Clinical encounters in family therapy promote dialogue’, which included the finding that the family therapy setting with joint sessions for family members facilitated in‐family communication.

Practitioner points

Addressing family dynamics during therapy can be experienced as an invasion of the family domain

Symptom explanations should avoid any suggestion of blame and remove feelings of guilt, be relatable and meaningful and point to solutions for the family

Systemic family therapy can support empowering processes for families of youths with functional disorders
Drivers of farm business capital structure and its speed of adjustment: evidence from Western Australia’s Wheatbelt
Authors: West Steele C. , Mugera Amin W. , Kingwell Ross S.
Published: January 2021

The viability and profitability of a farm business can be influenced by how it chooses to fund its operations and capital investments either using debt or internal funds. This study examines the determinants and speed of adjustment of the capital structure of broadacre farm businesses in Western Australia’s Wheatbelt. Results show that prior period cash flow and equity, farm size and farm location are significant determinants of observed capital structures. Farm businesses are found to quickly adjust their capital structure to desired target levels, suggesting that adjustment costs are not high. The findings support the view that there is a pecking order in the choice of how farm businesses fund working capital and capital investments.
A multitiered sequence capture strategy spanning broad evolutionary scales: Application for phylogenetic and phylogeographic studies of orchids
Authors: Peakall Rod , Wong Darren C. J. , Phillips Ryan D. , Ruibal Monica , Eyles Rodney , Rodriguez‐Delgado Claudia , Linde Celeste C.
Published: January 2021

With over 25,000 species, the drivers of diversity in the Orchidaceae remain to be fully understood. Here, we outline a multitiered sequence capture strategy aimed at capturing hundreds of loci to enable phylogenetic resolution from subtribe to subspecific levels in orchids of the tribe Diurideae. For the probe design, we mined subsets of 18 transcriptomes, to give five target sequence sets aimed at the tribe (Sets 1 & 2), subtribe (Set 3), and within subtribe levels (Sets 4 & 5). Analysis included alternative de novo and reference‐guided assembly, before target sequence extraction, annotation and alignment, and application of a homology‐aware k‐mer block phylogenomic approach, prior to maximum likelihood and coalescence‐based phylogenetic inference. Our evaluation considered 87 taxa in two test data sets: 67 samples spanning the tribe, and 72 samples involving 24 closely related Caladenia species. The tiered design achieved high target loci recovery (>89%), with the median number of recovered loci in Sets 1–5 as follows: 212, 219, 816, 1024, and 1009, respectively. Interestingly, as a first test of the homologous k‐mer approach for targeted sequence capture data, our study revealed its potential for enabling robust phylogenetic species tree inferences. Specifically, we found matching, and in one case improved phylogenetic resolution within species complexes, compared to conventional phylogenetic analysis involving target gene extraction. Our findings indicate that a customized multitiered sequence capture strategy, in combination with promising yet underutilized phylogenomic approaches, will be effective for groups where interspecific divergence is recent, but information on deeper phylogenetic relationships is also required.
The effect of suffering from rheumatoid arthritis, systemic lupus erythematosus, and back pain on sexual functioning and marital satisfaction in Iran
Authors: Yazdi Farzaneh , Shakibi Mohammad Reza , Gharavi Roudsari Ehda , Nakhaee Nozar , Salajegheh Pouria
Published: January 2021

Objective

Sexual functioning is an important component of life quality and musculoskeletal disorders may effect sexual functioning, so, the present study was conducted to evaluate sexual functioning in patients suffering from back pain, rheumatoid arthritis, and systemic lupus erythematosus (SLE).

Methods

This study was conducted on 102 patients with rheumatoid arthritis, 103 patients with back pain, 103 patients with SLE, and 210 people in the control group by the consecutive sampling method. The marital satisfaction questionnaire (Enrich), Arizona Sexual Experience Scale (ASEX) questionnaire, and the General Health Questionnaire (GHQ‐28) were completed by all the subjects. Disease severity was determined in each group of patients by Disease Activity Score of 28 joints, the Roland Morris questionnaire, and the SLE Disease Activity Index questionnaire.

Results

The GHQ in rheumatoid arthritis and lupus patients was meaningfully higher than the control group (P < .05), while there was no meaningful difference between back pain patients and the control group (P = .414). The sexual functioning questionnaire score in all 3 groups showed no statistically meaningful difference with the control group (P < .05). Also, the marital satisfaction questionnaire score in all the groups showed no statistically meaningful difference compared to the control group (P = .791).

Conclusion

The study has shown that the level of sexual function in participants with back pain and the level of mental health and sexual functioning in patients with rheumatoid arthritis and SLE are significantly lower than healthy people and there is a need for intervention for improving mental health as well as sexual functioning in these patients.
α‐ketoglutarate delays age‐related fertility decline in mammals
Authors: Zhang Zhenzhen , He Changjiu , Gao Yu , Zhang Lu , Song Yukun , Zhu Tianqi , Zhu Kuanfeng , Lv Dongying , Wang Jing , Tian Xiuzhi , Ma Teng , Ji Pengyun , Cui Wei , Liu Guoshi
Published: January 2021

The fecundity reduction with aging is referred as the reproductive aging which comes earlier than that of chronological aging. Since humans have postponed their childbearing age, to prolong the reproductive age becomes urgent agenda for reproductive biologists. In the current study, we examined the potential associations of α‐ketoglutarate (α‐KG) and reproductive aging in mammals including mice, swine, and humans. There is a clear tendency of reduced α‐KG level with aging in the follicle fluids of human. To explore the mechanisms, mice were selected as the convenient animal model. It is observed that a long term of α‐KG administration preserves the ovarian function, the quality and quantity of oocytes as well as the telomere maintaining system in mice. α‐KG suppresses ATP synthase and alterations of the energy metabolism trigger the nutritional sensors to down‐regulate mTOR pathway. These events not only benefit the general aging process but also maintain ovarian function and delay the reproductive decline. Considering the safety of the α‐KG as a naturally occurring molecule in energy metabolism, its utility in reproduction of large mammals including humans deserves further investigation.
Sex‐Dependent Alcohol Instrumentalization Goals in Non‐Addicted Alcohol Consumers versus Patients with Alcohol Use Disorder: Longitudinal Change and Outcome Prediction
Authors: Müller Christian P. , Mühle Christiane , Kornhuber Johannes , Lenz Bernd
Published: January 2021

Background

Alcohol can be instrumentalized to achieve goals that without the drug would either not be achievable or would be so only with considerably more workload. While an understanding of the neurobiological mechanisms of alcohol instrumentalization is emerging, little information is available concerning instrumentalization goals in controlled consumers and how these goals change during the development of an alcohol use disorder (AUD).

Methods

We surveyed instrumentalization goals in 103 male and 78 female inpatients with AUD (before / after onset of the disorder) and compared them with the goals of 124 male and 96 female age‐matched non‐addicted controls. We also investigated whether instrumentalization goals predict 24‐month alcohol‐related hospital readmissions in the patients using a false discovery rate (FDR) approach.

Results

Separately for both sexes, the most frequently (>25%) self‐reported alcohol instrumentalization goals in patients were “stress coping,” “craving for alcohol,” and “reduction of anxiety and / or depressive mood” and in controls “facilitation of social interaction.” Relative to controls, and in a sex‐dependent manner, patients with AUD reported the goals “facilitation of social interaction” and “search for a partner” significantly less frequently and “reduction of anxiety and / or depressive mood,” “stress coping,” “improvement of sexual activity,” “improvement of concentration,” “euphoria,” and “craving for alcohol” more frequently. During the transition to addiction, many of the instrumentalization goals changed significantly, some in a sex‐dependent manner. In female AUD patients, a goal of “euphoria” nominally predicted a lower risk of alcohol‐related readmission, although not significantly when FDR corrected.

Conclusions

We identified cross‐sectional and intra‐individual differences in instrumentalization goals that support the assumption that the onset of an AUD coincides with a shift in instrumentalization goals from prosocial instrumentalization toward the self‐management of aversive mental states.
Expert appraisal of criteria for assessing gaming disorder: an international Delphi study
Authors: Castro‐Calvo Jesús , King Daniel L. , Stein Dan J. , Brand Matthias , Carmi Lior , Chamberlain Samuel R. , Demetrovics Zsolt , Fineberg Naomi A. , Rumpf Hans‐Jürgen , Yücel Murat , Achab Sophia , Ambekar Atul , Bahar Norharlina , Blaszczynski Alexander , Bowden‐Jones Henrietta , Carbonell Xavier , Chan Elda Mei Lo , Ko Chih‐Hung , de Timary Philippe , Dufour Magali , Grall‐Bronnec Marie , Lee Hae Kook , Higuchi Susumu , Jimenez‐Murcia Susana , Király Orsolya , Kuss Daria J. , Long Jiang , Müller Astrid , Pallanti Stefano , Potenza Marc N. , Rahimi‐Movaghar Afarin , Saunders John B. , Schimmenti Adriano , Lee Seung‐Yup , Siste Kristiana , Spritzer Daniel T. , Starcevic Vladan , Weinstein Aviv M. , Wölfling Klaus , Billieux Joël
Published: January 2021

Background and aims

Following the recognition of ‘internet gaming disorder’ (IGD) as a condition requiring further study by the DSM‐5, ‘gaming disorder’ (GD) was officially included as a diagnostic entity by the World Health Organization (WHO) in the 11th revision of the International Classification of Diseases (ICD‐11). However, the proposed diagnostic criteria for gaming disorder remain the subject of debate, and there has been no systematic attempt to integrate the views of different groups of experts. To achieve a more systematic agreement on this new disorder, this study employed the Delphi expert consensus method to obtain expert agreement on the diagnostic validity, clinical utility and prognostic value of the DSM‐5 criteria and ICD‐11 clinical guidelines for GD.

Methods

A total of 29 international experts with clinical and/or research experience in GD completed three iterative rounds of a Delphi survey. Experts rated proposed criteria in progressive rounds until a pre‐determined level of agreement was achieved.

Results

For DSM‐5 IGD criteria, there was an agreement both that a subset had high diagnostic validity, clinical utility and prognostic value and that some (e.g. tolerance, deception) had low diagnostic validity, clinical utility and prognostic value. Crucially, some DSM‐5 criteria (e.g. escapism/mood regulation, tolerance) were regarded as incapable of distinguishing between problematic and non‐problematic gaming. In contrast, ICD‐11 diagnostic guidelines for GD (except for the criterion relating to diminished non‐gaming interests) were judged as presenting high diagnostic validity, clinical utility and prognostic value.

Conclusions

This Delphi survey provides a foundation for identifying the most diagnostically valid and clinically useful criteria for GD. There was expert agreement that some DSM‐5 criteria were not clinically relevant and may pathologize non‐problematic patterns of gaming, whereas ICD‐11 diagnostic guidelines are likely to diagnose GD adequately and avoid pathologizing.
A systematic comparison of the global comparative risk assessments for alcohol
Authors: Chrystoja Bethany R. , Rehm Jürgen , Manthey Jakob , Probst Charlotte , Wettlaufer Ashley , Shield Kevin D.
Published: January 2021

Aims

To compare systematically the alcohol‐attributable mortality and burden of disease estimates for 2016 from a recent study by Shield and colleagues and the Global Burden of Disease study 2017 (GBD).

Method

This study compared estimates of alcohol‐attributable mortality and disability adjusted life years (DALYs) lost for 2016 with regards to absolute and relative differences, by region and by cause of disease or injury. Relative differences between the two studies are reported herein as percentage (%) differences. A difference of 10% or more was considered meaningful.

Results

The studies estimated similar global levels of overall alcohol‐attributable mortality for 2016 (Shield and colleagues estimated 5.1% more alcohol‐attributable mortality than the GBD study) but not alcohol‐attributable DALYs lost (18.3% difference). There were marked differences by region and cause of disease or injury. Compared with the results from Shield and colleagues, the GBD study estimated a lower alcohol‐attributable burden in Eastern Europe by 252 770 alcohol‐attributable deaths (45.2% difference) and 6.1 million alcohol‐attributable DALYs lost (32.9% difference) and in Western sub‐Saharan Africa by 124 200 alcohol‐attributable deaths (55.7% difference) and 7.0 million alcohol‐attributable DALYs lost (63.4% difference), and estimated a higher alcohol‐attributable burden in East Asia by 227 100 alcohol‐attributable deaths (48.0% difference) and 2.2 million DALYs lost (11.0% difference). With regard to the cause of disease or injury, Shield and colleagues attributed an overall detrimental effect to alcohol on ischaemic heart disease mortality, whereas the GBD study attributed a net beneficial effect. The GBD study, as compared with Shield and colleagues’ study, estimated a lower alcohol‐attributable mortality because of liver cirrhosis and injuries by 262 500 (44.6% difference) and 398 800 (46.2% difference), respectively.

Conclusions

Differences in estimates of the alcohol‐attributable burden of disease in two recent studies indicate the need to improve the accuracy of underlying data and risk relations to obtain more consistent estimates and to formulate, advocate for, and implement alcohol policies more effectively.
Management of deformity inducing osteochondroma of the temporomandibular joint: a case report
Authors: Hurrell MJL , Khabaz‐Saberi S , Ricciardo PV
Published: January 2021

Maxillofacial osteochondromas are considered benign neoplasms, and compared with their extracranial variant are relatively rare. When they involve the mandibular condyle they can induce significant facial deformity, malocclusion and various temporomandibular joint symptoms. Complete excision is considered the standard of care, but can lead to a reduction in the height of the ipsilateral mandible with resultant complications. In such cases, reconstruction is usually warranted and may be approached in various ways. This case report demonstrates a straightforward, accurate and reproducible approach to reconstructing the TMJ, facial profile and occlusion following resection of a large TMJ osteochondroma, without the need for concomitant orthodontics.
Evaluation of a young adult renal and transplant transition clinic in a regional setting: Supporting young adults and parents' transition to self‐management
Authors: Jose Kim , Le Roux Anneke , Jeffs Lisa , Jose Matthew
Published: January 2021

Objective

This study evaluated the impact of establishing a transition clinic in a regional Australian setting on the lives of young adults living with severe chronic kidney disease and their families.

Design

A qualitative design using the experience‐based co‐design framework.

Setting

Interviews were held at the Royal Hobart Hospital or the Menzies Institute for Medical Research. The co‐design workshop was held at the Royal Hobart Hospital.

Participants

Young people aged 17‐29 years living with a kidney transplant or stage 4‐5 chronic kidney disease, parents/carers and health professionals.

Interventions

Establishment of a young adult renal and transplant clinic.

Main outcome measure

Impact of a transition clinic in a regional setting on the lives of young adults living with chronic kidney disease and their families and suggestions for improvement.

Results

Four key themes were identified as follows: The Model of Care; Peer support; Transition towards self‐management: Building life skills; Suggestions for improvement and limitations of the service model. The non‐institutional, informal clinic setting and social/educational activities facilitated engagement, self‐management and peer support for young people and parents. Suggestions for improvement included involvement of older peers, additional life skills sessions and a youth worker.

Conclusion

This regional transition clinic is valued by the young people and their parents for generating peer support, building self‐management and life skills. Sustainability of the clinic depends upon having the appropriate expertise available, access to a suitable venue and offering a program that meets the needs of young people.
EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID‐19 vaccines
Authors: Sokolowska Milena , Eiwegger Thomas , Ollert Markus , Torres Maria J. , Barber Domingo , Del Giacco Stefano , Jutel Marek , Nadeau Kari C. , Palomares Oscar , Rabin Ronald L. , Riggioni Carmen , Vieths Stefan , Agache Ioana , Shamji Mohamed H.
Published: January 2021

The first approved COVID‐19 vaccines include Pfizer/BioNTech BNT162B2, Moderna mRNA‐1273 and AstraZeneca recombinant adenoviral ChAdOx1‐S. Soon after approval, severe allergic reactions to the mRNA‐based vaccines that resolved after treatment were reported. Regulatory agencies from the European Union, Unites States and the United Kingdom agree that vaccinations are contraindicated only when there is an allergy to one of the vaccine components or if there was a severe allergic reaction to the first dose. This position paper of the European Academy of Allergy and Clinical Immunology (EAACI) agrees with these recommendations and clarifies that there is no contraindication to administer these vaccines to allergic patients who do not have a history of an allergic reaction to any of the vaccine components. Importantly, as is the case for any medication, anaphylaxis may occur after vaccination in the absence of a history of allergic disease. Therefore, we provide a simplified algorithm of prevention, diagnosis and treatment of severe allergic reactions and a list of recommended medications and equipment for vaccine centres. We also describe potentially allergenic/immunogenic components of the approved vaccines and propose a workup to identify the responsible allergen. Close collaboration between academia, regulatory agencies and vaccine producers will facilitate approaches for patients at risks, such as incremental dosing of the second injection or desensitization. Finally, we identify unmet research needs and propose a concerted international roadmap towards precision diagnosis and management to minimize the risk of allergic reactions to COVID‐19 vaccines and to facilitate their broader and safer use.
Achondroplasia is associated with increased occurrence of apparent life‐threatening events
Authors: Legare Janet M. , Smid Cory J. , Modaff Peggy , Pauli Richard M.
Published: January 2021

Aim

To assess the clinical picture underlying apparent life‐threatening events (ALTEs) occurring in infants with achondroplasia and provide guidance for evaluation after an event.

Methods

A population of 477 individuals with achondroplasia was retrospectively reviewed, and information regarding possible ALTEs was recorded in a REDCap database.

Results

ALTEs occurred in the first year of life in 18 of 477 individuals (3.8%). Most (14/18, 78%) occurred in the first 6 months of life and presented as episodes of apnoea and/or seizures. Of affected infants, 8/18 (44%) had more than one episode. Many of the initial ALTEs arose while infants were in car seats (11/18, 61%). Assessment following ALTEs most often demonstrated either craniocervical junction concerns and/or seizures, with 12/18 (67%) patients undergoing cervicomedullary decompression and 5/18 (28%) starting on anti‐epileptic medications after the event.

Conclusion

Although this study is limited in size and was retrospective, it shows that infants with achondroplasia appear to be at high risk for ALTEs. Evaluation after an event should include neuroimaging of the foramen magnum, inpatient hospital observation including respiratory monitoring and electroencephalography, and a car seat challenge.
Evaluation of intravenous to oral antimicrobial switch at a hospital with a tightly regulated antimicrobial stewardship program
Authors: Khumra Sharmila , Mahony Andrew A. , Bergen Phillip J. , Elliott Rohan A.
Published: January 2021

Timely intravenous (IV) to oral antimicrobial switch (IV‐oral‐switch) is a key antimicrobial stewardship (AMS) strategy. We aimed to explore concordance with IV‐oral‐switch guidelines in the context of a long‐standing, tightly regulated AMS program. Data was retrospectively collected for 107 adult general medical and surgical patients in an Australian hospital. Median duration of IV antimicrobial courses before switching to oral therapy was 3 days (interquartile range [IQR] 2.25‐5.00). Timely IV‐oral‐switch occurred in 57% (n = 61) of patients. The median delay to switching was 0 days (IQR 0 to 1.25). In most courses (92/106, 86.8%), the choice of oral alternative after switching was appropriate. In 45% (47/105) of courses, total duration of therapy (IV plus oral) exceeded the recommended duration by >1.0 day. Excessive IV antimicrobial duration was uncommon at a hospital with a tightly regulated AMS program. Total duration of therapy was identified as an AMS target for improvement.
Molecular mechanism and pharmacokinetics of flavonoids in the treatment of resistant EGF receptor‐mutated non‐small‐cell lung cancer: A narrative review
Authors: Wang Xuewen , Chen Bing , Xu Dafen , Li Zhijun , Liu Hao , Huang Zhengjun , Huang Kangping , Lin Xinhua , Yao Hong
Published: January 2021

Here, we review the molecular mechanism and pharmacokinetics of flavonoids in the treatment of resistant EGF receptor (EGFR)‐mutated non‐small‐cell lung cancer (NSCLC) and particularly the possible mechanism(s) of delicaflavone, a biflavonoid extracted from Selaginella doederleinii Hieron. EGFR TK inhibitors (EGFR‐TKI) are ubiquitously used in the treatment of NSCLC bearing EGFR mutations. However, patients treated with EGFR‐TKI inevitably and continuously develop resistance. In laboratory studies, flavonoids, as potential adjuvants for cancer chemotherapy, exhibited anti‐cancer properties such as inhibition of chemoresistance by interference with ABC transporters‐induced drug efflux, curbing of c‐MET amplification, or reversal of T790M mutation‐mediated resistance. The current review aims at summarizing the association between the anti‐cancer potentials of flavonoids and their possible regulatory roles in certain types of mutation that could trigger EGFR‐TKI resistance in NSCLC. Potential practical applications of these phytochemicals, as well as the relevant pharmacokinetics, are also discussed.
The mechanism of non‐blocking inhibition of sodium channels revealed by conformation‐selective photolabeling
Authors: Földi Mátyás C. , Pesti Krisztina , Zboray Katalin , Toth Adam V. , Hegedűs Tamás , Málnási‐Csizmadia András , Lukacs Peter , Mike Arpad
Published: January 2021

Background and Purpose

Sodium channel inhibitors can be used to treat hyperexcitability‐related diseases, including epilepsies, pain syndromes, neuromuscular disorders and cardiac arrhythmias. The applicability of these drugs is limited by their nonspecific effect on physiological function. They act mainly by sodium channel block and in addition by modulation of channel kinetics. While channel block inhibits healthy and pathological tissue equally, modulation can preferentially inhibit pathological activity. An ideal drug designed to target the sodium channels of pathological tissue would act predominantly by modulation. Thus far, no such drug has been described.

Experimental Approach

Patch‐clamp experiments with ultra‐fast solution exchange and photolabeling‐coupled electrophysiology were applied to describe the unique mechanism of riluzole on Nav1.4 sodium channels. In silico docking experiments were used to study the molecular details of binding.

Key Results

We present evidence that riluzole acts predominantly by non‐blocking modulation. We propose that, being a relatively small molecule, riluzole is able to stay bound to the binding site, but nonetheless stay off the conduction pathway, by residing in one of the fenestrations. We demonstrate how this mechanism can be recognized.

Conclusions and Implications

Our results identify riluzole as the prototype of this new class of sodium channel inhibitors. Drugs of this class are expected to selectively prevent hyperexcitability, while having minimal effect on cells firing at a normal rate from a normal resting potential.
Deep sequencing of prostaglandin‐endoperoxide synthase (PTGE) genes reveals genetic susceptibility for cross‐reactive hypersensitivity to NSAID
Authors: García‐Martín Elena , García‐Menaya Jesús M. , Esguevillas Gara , Cornejo‐García José A. , Doña Inmaculada , Jurado‐Escobar Raquel , Torres María J. , Blanca‐López Natalia , Canto Gabriela , Blanca Miguel , Laguna José J. , Bartra Joan , Rosado Ana , Fernández Javier , Cordobés Concepción , Agúndez José A.G.
Published: January 2021

Background and Purpose

Cross‐reactive hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) is a relatively common adverse drug event caused by two or more chemically unrelated drugs and that is attributed to inhibition of the COX activity, particularly COX‐1. Several studies investigated variations in the genes coding for COX enzymes as potential risk factors. However, these studies only interrogated a few single nucleotide variations (SNVs), leaving untested most of the gene sequence.

Experimental Approach

In this study, we analysed the whole sequence of the prostaglandin‐endoperoxide synthase genes, PTGS1 and PTGS2, including all exons, exon‐intron boundaries and both the 5′ and 3′ flanking regions in patients with cross‐reactive hypersensitivity to NSAIDs and healthy controls. After sequencing analysis in 100 case–control pairs, we replicated the findings in 540 case–control pairs. Also, we analysed copy number variations for both PTGS genes.

Key Results

The most salient finding was the presence of two PTGS1 single nucleotide variations, which are significantly more frequent in patients than in control subjects. Patients carrying these single nucleotide variations displayed a significantly and markedly lower COX‐1 activity as compared to non‐carriers for both heterozygous and homozygous patients.

Conclusion and Implications

Although the risk single nucleotide variations are present in a small proportion of patients, the strong association observed and the functional effect of these single nucleotide variations raise the hypothesis of genetic susceptibility to develop cross‐reactive NSAID hypersensitivity in individuals with an impairment in COX‐1 enzyme activity.
HMGB1 is a key factor for tamoxifen resistance and has the potential to predict the efficacy of CDK4/6 inhibitors in breast cancer
Authors: Zhang Han , Wang Jinlu , Li Jingtong , Zhou Xiaoping , Yin Lei , Wang Yiran , Gu Yucui , Niu Xingjian , Yang Yue , Ji Hongfei , Zhang Qingyuan
Published: January 2021

Breast cancer is the leading cause of cancer death in women. Hormone‐receptor‐positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine‐resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression‐free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine‐resistant breast cancer, compared with HMGB1‐negative patients, HMGB1‐positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll‐like receptor 4 (TLR4) and activating nuclear factor kappa B (NF‐κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4‐NF‐κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.
Therapeutic potential and pharmacological activities of β‐eudesmol
Authors: Acharya Bishwanath , Chaijaroenkul Wanna , Na‐Bangchang Kesara
Published: January 2021

Herbal medicines are attracting the attention of researchers worldwide. β‐Eudesmol is one of the most studied and major bioactive sesquiterpenes, mainly extracted from Atractylodes lancea (Thunb) DC. rhizomes. It has potential anti‐tumor and anti‐angiogenic activities and is an inhibitor of tumor growth by inhibiting angiogenesis by suppressing CREB activation of the growth factor signaling pathway. It also stimulates neurite outgrowth in rat pheochromocytoma cells with activation of mitogen‐activated protein kinases. It may be a promising lead compound for enhancing neural function, and it may help to explain the underlying mechanisms of neural differentiation. In this review, we summarized the currently available clinical and preclinical studies describing the therapeutic applications of β‐eudesmol.
Two‐ and ten‐year follow‐up of patients responding and non‐responding to the surgical treatment of peri‐implantitis: A retrospective evaluation
Authors: Serino Giovanni , Wada Masahiro , Mameno Tomoaki , Renvert Stefan
Published: January 2021

Objectives

To report a follow‐up of patients following the surgical anti‐infective treatment of peri‐implantitis and to identify possible risk indicators for the progression of disease during supportive peri‐implant therapy.

Material and Methods

Following peri‐implant surgery, 41 patients (213 implants) were enrolled in a supportive peri‐implant therapy. At the 2‐year follow‐up, two groups of patients were identified, with or without residual peri‐implant pockets (responding and non‐responding group). Eighteen patients (85 implants) of the non‐responding group were followed for further 8 years.

Results

At the 2‐year examination, 73 of the 117 treated implants (62.4%) presented healthy peri‐implant condition, while 44 (37.6%) presented persisting peri‐implantitis associated with substantial bone loss before treatment.

The 10‐year examination of the non‐responding group revealed that 1) 84% of the implants that regained health following surgery remained healthy during the entire observation period; 2) 66% of the implants with residual pockets following surgery maintained stable peri‐implant condition; and 3) 29% of all treated implants showed disease progression, and 11 of those were extracted. Presence of pockets at 3–4 sites of the implants was identified as risk indicator for progression of peri‐implantitis.

Conclusion

The peri‐implant health achieved following therapy was maintained for most of the implants during the follow‐up. Residual pockets were a frequent finding at implants with substantial bone loss before treatment. Presence of pockets around the entire circumference of the implants resulted as a risk indicator for further disease progression. The probability of progression of peri‐implant disease increased with increased observation time.
Evaluation of peri‐implant tissues condition after 10–15 years of loading in treated chronic periodontitis patients attending a private practice setting: A retrospective study
Authors: Guarnieri Renzo , Di Nardo Dario , Di Giorgio Gianni , Miccoli Gabriele , Testarelli Luca
Published: January 2021

Objectives

To retrospectively evaluate the conditions of the peri‐implant tissues in treated patients with chronic periodontitis (CP) and in patients without chronic periodontitis (noCP).

Materials and methods

A chart review was used to evaluate 267 implants, 134 placed in 42 CP treated patients and 133 placed in 46 noCP patients. The primary outcome was to evaluate the condition of the peri‐implant tissues (health, peri‐mucositis, and peri‐implantitis). The secondary outcome was to evaluate the possible association of some variables, such as, Plaque Index (PI), Bleeding Index (BI), probing pocket depth (PD), bleeding on probing (BoP), bone level (BL), loading time, type of implant placement and loading protocol, type of prosthesis, type of bone, implant manufacturer, and implant diameter and length, with the implant health condition.

Results

The analysis of patient files revealed that after 10–15 years of loading (mean loading time 13.4 ± 2.07 years), six noCP patients (13%) experienced implant loss with a total of nine implants (6.7%) lost. The remaining 124 implants were classified: 54 (43.5%) as healthy, 45 (36.3%) with peri‐implant mucositis, and 25 (20.2%) with peri‐implantitis. Twelve CP subjects (28.5%) experienced implant loss with a total of 19 implants (14.1%) lost. The remaining 115 implants were classified: 34 (29.5%) as healthy, 40 (34.7%) with peri‐implant mucositis and 41 (35.6%) with peri‐implantitis. Compared with noCP subjects, only treated CP subjects with recurrent periodontal disease (RPD) showed differences statistically significant (p < .05).

Conclusions

After 10–15 years of loading, in CP patients treated in a private practice setting, most implants (70.1%) were classified with some type of peri‐implant inflammation. In patients with RPD, a higher tendency for implant loss and peri‐implant biologic complications was found.
Dissolvable intranasal haemostatic agents for acute epistaxis: A systematic review and meta‐analysis
Authors: Milinis Kristijonas , Swords Chloe , Hardman John C. , Slovick Anna , Hutson Kristian , Kuhn Isla , Smith Matthew E. ,   INTEGRATE (The UK ENT Trainee Research Network)
Published: January 2021

Introduction

Nasal packing is the mainstay of epistaxis management; however, packs cause patient discomfort and can lead to hospital admission. Absorbable haemostats provide clotting factors or act as a substrate to stimulate clotting and represent a potential treatment alternative. A systematic review was performed to evaluate the efficacy of topical haemostats in the management of epistaxis.

Methods

A systematic literature search of 7 databases was performed. Only eligible randomised controlled trials (RCTs) and observational studies were included. The primary outcome was short‐term haemostatic success (<7 days). Secondary outcomes included long‐term haemostatic control (no rebleeding 7‐30 days), patient discomfort and adverse effects. Meta‐analysis was performed where possible.

Results

Of 2249 records identified, 12 were included in the qualitative synthesis and 4 RCTs were included in meta‐analysis. The following haemostats were reported: gelatin‐thrombin matrix (n = 8), aerosolised/gel tranexamic acid (n = 1), cellulose agents (n = 2) and fibrin sealants (n = 1). Studies involving tranexamic acid on removable delivery devices (eg, pledgets) were excluded. There was heterogeneity in outcome measures and inclusion criteria (coagulopathies/anticoagulants were excluded in 3 RCTs and 2 observational studies). The short‐term haemostatic success varied between studies (13.9% to 100%). No significant post‐procedural complications were reported. The meta‐analysis favoured absorbable haemostatic agent versus packing (risk ratio 1.20; 95% confidence interval 1.05 to 1.37; P = .007). The risk of bias across all studies was moderate to high.

Conclusions

The evidence suggests haemostatic agents are effective at managing acute epistaxis when compared with nasal packing. More data are required before recommendations can be made regarding management in patients on anticoagulants.
Factors impacting time to ileostomy closure after anterior resection: the UK closure of ileostomy timing cohort study (CLOSE‐IT)
Authors:   Dukes’ Club Research Collaborative
Published: January 2021

Aim

Delay to closure of ileostomy following anterior resection for rectal cancer may impair postoperative bowel function and quality of life. We analysed time to ileostomy closure across the UK and investigated factors delaying closure.

Methods

For the retrospective cohort we assessed time to closure and incidence of non‐closure for patients who underwent anterior resection with defunctioning ileostomy during 2015. Multivariate linear/Cox regression analyses were performed. For the prospective cohort we captured patients undergoing ileostomy closure during a 3‐month period in 2018 to validate retrospective findings.

Results

The retrospective cohort involved 788 patients of whom 669 (84.9%) had bowel continuity restored, median time to closure 259 days. Recognized factors associated with delay and risk of non‐closure included anastomotic leak (hazard ratio [HR] 3.65, 2.61–5.08), chemotherapy (HR 2.62, 2.17–3.15) and cancer progression (HR 2.05, 1.62–2.58). Crucially, specific aspects of the surgical pathway were associated with time to closure; for example, waiting list entry prior to outpatient clinic review/imaging was associated with an estimated 133‐day shorter interval to closure (P < 0.001). In the prospective cohort 288 patients underwent closure, at a median of 271 days. Chemotherapy use and cancer progression were associated with delay to closure while listing for surgery prior to clinic and imaging was associated with an estimated shorter interval to closure of 168 days (P = 0.008).

Conclusions

Delays to closure of ileostomy are common in the UK. Listing patients for surgery only after follow‐up outpatient appointment, imaging or chemotherapy delays closure. Findings will inform consensus guidelines towards an optimum treatment pathway to reduce delay and improve post‐closure quality of life.
Endothelial dysfunction and vascular maladaptation in atrial fibrillation
Authors: Qin Shuguang , Boidin Maxime , Buckley Benjamin J. R. , Lip Gregory Y. H. , Thijssen Dick H. J.
Published: January 2021

Atrial fibrillation (AF) is the most common arrhythmia and is associated with worsened morbidity and mortality. The prevalence of AF is estimated to increase with an ageing population resulting in an ever‐increasing burden on the healthcare system. Despite improvements in AF treatment, several questions remain unanswered in relation to the development and progression of AF. In this review, we discuss the evidence supporting the presence of vascular dysfunction in the development of AF, but also as a final common pathway explaining why AF constitutes a markedly increased risk of cardiovascular morbidity and mortality. Specifically, we summarise the work performed in humans related to the impact of AF on vascular structure and function, and whether measures of vascular function predict AF progression and the development of cardiovascular events. Subsequently, we discuss the potential mechanisms linking AF to the development of vascular dysfunction. Finally, we propose future perspectives of vascular health and AF, advocating a strong focus on regular exercise training as a safe and effective strategy to improve vascular function and, hence, reduce the risk for development and progression of AF and its associated risk for cardiovascular events.
Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus
Authors: Jolles Stephen , Michallet Mauricette , Agostini Carlo , Albert Michael H. , Edgar David , Ria Roberto , Trentin Livio , Lévy Vincent
Published: January 2021

Objectives

Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM.

Methods

A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback.

Results

Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert‐type scale) was reached for all three definitions and 18 statements.

Conclusions

Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.