bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer
Authors: Sun Dantong , Wu Weizheng , Wang Li , Qu Jialin , Han Qiman , Wang Huiyun , Song Shanai , Liu Ning , Wang Yongjie , Hou Helei
Published: February 2023

Introduction

Alterations in the MET gene, including amplifications and exon 14 skipping mutations, have been identified as actionable oncogenic alterations. However, MET fusions are rarely detected in lung cancer, and their sensitivity to therapeutics has not been systematically analyzed.

Methods

The data from 30876 lung cancer patients from the LAVA database and 7966 patients from cBioPortal database were screened. Basic demographic and clinical information for the patients harboring MET fusions were collected. A lung squamous cell cancer patient harboring a novel EML4-MET fusion was treated with crizotinib. Additionally, a literature review was performed to summarize the cases of patients harboring MET fusions and their treatment information.

Results

MET fusions were found in only 0.2% to 0.3% of lung cancer patients and appeared in almost all exons of the MET gene. Intragenic MET fusions were found in 52.6% (41/78) of the included patients. Crizotinib was effective for MET fusions, including a novel identified EML4-MET fusion, even after the failure of multiple lines of treatment. This result suggested that acquired MET fusions become more regionally selective, as they usually occurred in exons encoding the extracellular region. Interestingly, the MET-fused genes in primary MET fusions or acquired MET fusions were very different, which indicated the different functions and influences of the disease.

Conclusion

MET fusions are rare, and half of the fusion types were intragenic fusions. Lung cancer patients harboring primary or acquired MET fusions could benefit from crizotinib. In addition, EML4-MET was first reported in this study as a novel MET fusion type.
Concerted phenotypic flexibility of avian erythrocyte size and number in response to dietary anthocyanin supplementation
Authors: Dzialo Maciej , Bryła Amadeusz , DeMoranville Kristen J. , Carbeck Katherine M. , Fatica Olivia , Trost Lisa , Pierce Barbara , Sadowska Edyta T. , McWilliams Scott R. , Bauchinger Ulf
Published: February 2023

Background

Endurance flight impose substantial oxidative costs on the avian oxygen delivery system. In particular, the accumulation of irreversible damage in red blood cells can reduce the capacity of blood to transport oxygen and limit aerobic performance. Many songbirds consume large amounts of anthocyanin-rich fruit, which is hypothesized to reduce oxidative costs, enhance post-flight regeneration, and enable greater aerobic capacity. While their antioxidant benefits appear most straightforward, the effects of anthocyanins on blood composition remain so far unknown. We fed thirty hand-raised European starlings (Sturnus vulgaris) two semisynthetic diets (with or without anthocyanin supplement) and manipulated the extent of flight activity in a wind tunnel (daily flying or non-flying for over two weeks) to test for their interactive effects on functionally important haematological variables.

Results

Supplemented birds had on average 15% more and 4% smaller red blood cells compared to non-supplemented individuals and these diet effects were independent of flight manipulation. Haemoglobin content was 7% higher in non-supplemented flying birds compared to non-flying birds, while similar haemoglobin content was observed among supplemented birds that were flown or not. Neither diet nor flight activity influenced haematocrit.

Conclusion

The concerted adjustments suggest that supplementation generally improved antioxidant protection in blood, which could prevent the excess removal of cells from the bloodstream and may have several implications on the oxygen delivery system, including improved gas exchange and blood flow. The flexible haematological response to dietary anthocyanins may also suggest that free-ranging species preferentially consume anthocyanin-rich fruits for their natural blood doping, oxygen delivery-enhancement effects.
Translating knowledge into action for child obesity treatment in partnership with Parks and Recreation: study protocol for a hybrid type II trial
Authors: Neshteruk Cody D. , Skinner Asheley C. , Counts Julie , D’Agostino Emily M. , Frerichs Leah , Howard Janna , Story Mary , Armstrong Sarah C.
Published: February 2023

Background

Safe and effective treatment exists for childhood obesity, but treatment recommendations have largely not been translated into practice, particularly among racial and ethnic minorities and low-wealth populations. A key gap is meeting the recommended treatment of ≥26 h of lifestyle modification over 6–12 months. Fit Together is an effective treatment model that meets these recommendations by integrating healthcare and community resources. Pediatric providers screen children for obesity, deliver counseling, and treat co-morbidities, while Parks and Recreation partners provide recreation space for a community nutrition and physical activity program.

Methods

This study will use a hybrid type II implementation-effectiveness design to evaluate the effectiveness of an online implementation platform (the Playbook) for delivering Fit Together. Clinical and community partners in two North Carolina communities will implement Fit Together, using the Playbook, an implementation package designed to facilitate new partnerships, guide training activities, and provide curricular materials needed to implement Fit Together. An interrupted time series design anchored in the Process Redesign Framework will be used to evaluate implementation and effectiveness outcomes in intervention sites. Implementation measures include semi-structured interviews with partners, before and after the implementation of Fit Together, and quantitative measures assessing several constructs within the Process Redesign Framework. The participants will be children 6–11 years old with obesity and their families (n=400). Effectiveness outcomes include a change in child body mass index and physical activity from baseline to 6 and 12 months, as compared with children receiving usual care. Findings will be used to inform the design of a dissemination strategy guided by the PCORI Dissemination Framework.

Discussion

This project addresses the knowledge-to-action gap by developing evidence-based implementation tools that allow clinicians and communities to deliver effective pediatric obesity treatment recommendations. Future dissemination of these tools will allow more children who have obesity and their families to have access to effective, evidence-based care in diverse communities.

Trial registration

ClinicalTrials.gov identifier: NCT05455190. Registered on 13 July 2022
Cutaneous protothecosis in a dog successfully treated with oral itraconazole in pulse dosing
Authors: Gmyterco Vanessa Cunningham , Jagielski Tomasz , Baldasso Gustavo , Bacher Louise Helene , Ribeiro Márcio Garcia , de Farias Marconi Rodrigues
Published: February 2023

Background

Protothecosis is a rare infectious disease caused by unicellular, achlorophyllous, microalgae of the genus Prototheca, ubiquitously distributed in nature. The algae are emerging pathogens, whose incidence is increasing in both human and animal populations and serious systemic infections related to this pathogen have been increasingly described in humans in recent years. After mastitis in dairy cows, canine protothecosis is the second most prevalent form of the protothecal disease in animals. Here, we report the first case of chronic cutaneous protothecosis due to P. wickerhamii in a dog in Brazil, successfully treated with a long-term therapy with itraconazole in pulse.

Case presentation

Upon clinical examination, exudative nasolabial plaque, ulcered, and painful lesions in central and digital pads and lymphadenitis were observed in a 2-year-old mixed-breed dog, with a 4-month history of cutaneous lesions and contact with sewage water. Histopathological examination revealed intense inflammatory reaction, with numerous spherical to oval, encapsulated structures stained with Periodic Acid Schiff, compatible with Prototheca morphology. Tissue culture on Sabouraud agar revealed yeast-like, greyish-white colonies after 48 h of incubation. The isolate was subjected to mass spectrometry profiling and PCR-sequencing of the mitochondrial cytochrome b (CYTB) gene marker, leading to identification of the pathogen as P. wickerhamii. The dog was initially treated with oral itraconazole at a dosage of 10 mg/kg once daily. After six months, the lesions resolved completely, yet recurred shortly after cessation of therapy. The dog was then treated with terbinafine at a dose of 30 mg/kg, once daily for 3 months, with no success. The resolution of clinical signs, with no recurrence over a 36-months follow-up period, was achieved after 3 months of treatment with itraconazole (20 mg/kg) in pulse intermittently on two consecutive days a week.

Conclusions

This report highlights the refractoriness of skin infections by Prototheca wickerhamii with therapies proposed in the literature and suggests a new treatment option with oral itraconazole in pulse dosing for long-term disease control successfully performed in a dog with skin lesions.
Fluid balance control in critically ill patients: results from POINCARE-2 stepped wedge cluster-randomized trial
Authors: Bollaert Pierre-Edouard , Monnier Alexandra , Schneider Francis , Argaud Laurent , Badie Julio , Charpentier Claire , Meziani Ferhat , Bemer Michel , Quenot Jean-Pierre , Buzzi Marie , Outin Hervé , Bruel Cédric , Ziegler Laurent , Gibot Sébastien , Virion Jean-Marc , Alleyrat Camille , Louis Guillaume , Agrinier Nelly
Published: February 2023

Background

In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients.

Methods

POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for > 48 and ≤ 72 h, and had an expected length of stay after inclusion > 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA).

Results

A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2–34.8 vs. 33.9%, 95% CI 29.6–38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results.

Conclusion

The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it.

Trial registration POINCARE-2 trial was registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.
DIMPLE: deep insertion, deletion, and missense mutation libraries for exploring protein variation in evolution, disease, and biology
Authors: Macdonald Christian B. , Nedrud David , Grimes Patrick Rockefeller , Trinidad Donovan , Fraser James S. , Coyote-Maestas Willow
Published: February 2023

Insertions and deletions (indels) enable evolution and cause disease. Due to technical challenges, indels are left out of most mutational scans, limiting our understanding of them in disease, biology, and evolution. We develop a low cost and bias method, DIMPLE, for systematically generating deletions, insertions, and missense mutations in genes, which we test on a range of targets, including Kir2.1. We use DIMPLE to study how indels impact potassium channel structure, disease, and evolution. We find deletions are most disruptive overall, beta sheets are most sensitive to indels, and flexible loops are sensitive to deletions yet tolerate insertions.
Efficacy and auditory biomarker analysis of fronto-temporal transcranial direct current stimulation (tDCS) in targeting cognitive impairment associated with recent-onset schizophrenia: study protocol for a multicenter randomized double-blind sham-controlled trial
Authors: Dondé Clément , Bastin Julien , Pouchon Arnaud , Costes Nicolas , Fakra Eric , Galvão Filipe , Gay Aurélia , Haesebaert Frédéric , Lamalle Laurent , Mérida Inès , Rigon Maxence , Schneider Fabien , Troprès Irène , Brunelin Jérôme , Polosan Mircea
Published: February 2023

Background

In parallel to the traditional symptomatology, deficits in cognition (memory, attention, reasoning, social functioning) contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS (transcranial direct current stimulation). However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Furthermore, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear.

Method

The study is designed as a randomized, double-blind, 2-arm parallel-group, sham-controlled, multicenter trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active (n=30) or sham (n=30) tDCS (20-min, 2-mA, 10 sessions during 5 consecutive weekdays). The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP (measured with EEG and multimodal MRI) will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS.

Discussion

Besides proposing a new fronto-temporal tDCS protocol by targeting the auditory cortical areas, we aim to conduct a randomized controlled trial (RCT) with follow-up assessments up to 3 months. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficit improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia.

Trial registration

ClinicalTrials.gov NCT05440955. Prospectively registered on July 1st, 2022.
Monoclonal antibody infusion reaction with bamlanivimab and etesevimab in a 5-year-old male with coronavirus disease 2019: a case report
Authors: Pillai Rajapillai L. I. , Dziel Caroline , Vogel Stephanie , Szczerba Frank , Chang Weijen W. , Camelo Ingrid Y. , Paez Armando
Published: February 2023

Background

Bamlanivimab and etesevimab had been granted emergency use authorization in children under 12 years who are at risk of progression from mild/moderate coronavirus disease 2019 to severe disease and hospitalization.

Case report

We report on a 5-year-old white male with preexisting conditions, predisposing him to severe disease, who developed hypoxia and flushing 3 minutes into his infusion, thus meeting the criteria for anaphylaxis.

Conclusions

We believe this patient developed either an immunoglobulin E-mediated anaphylactic or a non-immunoglobulin E-mediated anaphylactoid reaction to bamlanivimab and etesevimab, which is an important possibility to consider on administration.
Interventions to improve the detection of depression in primary healthcare: systematic review
Authors: Habtamu Kassahun , Birhane Rahel , Demissie Mekdes , Fekadu Abebaw
Published: February 2023

Background

Several studies have been conducted on the effect of interventions on the detection of depression in primary healthcare (PHC). Systematic reviews have also been done on the effectiveness of separate interventions. However, systematic reviews are not done on the comparative effectiveness of several interventions. This study, therefore, aimed at synthesizing the global evidence on the effectiveness of interventions to improve the detection of depression in PHC.

Methods

We searched PubMed, Embase, PsycINFO, Web of Science, Cochrane Database of Systematic Reviews, Global Index Medicus, African Index Medicus, and African Journals Online, from the inception of the databases to until the 4th week of April 2020. We also searched references of the included articles. We included randomized trials, cluster randomized trials, or quasi-experimental studies, which evaluated the effectiveness of an intervention to improve detection of depression in the PHC setting. Two of the review authors independently extracted data from the included studies. The methodological quality of the included studies was assessed using the Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project. The protocol for the review was registered on PROSPERO (CRD42020166291).

Results

Of 23,305 records identified, we included 58 articles in the review. Diverse types of interventions were evaluated to improve clinician diagnosis of depression in the PHC setting. Interventions related to implementation of guidelines, screening with feedback, educational interventions which incorporated active learning and clinical practice, and disclosure of screening results were found to be mostly effective. Interventions which combined education, screening, and feedback were particularly more effective. Most of the included studies were weak or moderate in their methodological quality.

Conclusions

Our review indicates that implementation of a single type of intervention does not improve the detection of depression in PHC. Combining aspects of each type of intervention which are more effective may be useful. Education and training interventions which include more simulation and role playing are found to be effective over time. Most of the studies conducted in the area are from high-income countries and are weak in their methodological quality. There is need to conduct more number of studies in low-income settings.
What factors make consumers in the USA buy hemp products? Evidence from Nielsen consumer panel data
Authors: Kim GwanSeon , Mark Tyler
Published: February 2023

This study aims to identify critical consumer-demographic characteristics associated with the consumption of products containing hemp and investigate their effect on total expenditure in the USA. To estimate the likelihood of market participation and consumption level, the Heckman selection model is employed utilizing Nielsen consumer panel data from 2008 to 2015. Using a Heckman selection model, this study finds that socio-demographic characteristics, especially income, age, and education, play an important role in explaining purchases of and demand for different categories of hemp products. Noteworthy is the finding that the role of the age of the household head is mixed with respect to consumption decisions and consumption level across the products. In most cases, higher education and income households are more likely to buy hemp products, and those are associated with significantly higher consumption levels. The hemp products used in this study are made of hemp seeds, and our findings show that the hemp seed market could be segmented based on the forms. Results provide a basic understanding of a consumer profile and overall hemp market that has had double-digit growth over the last six years. As the industry continues to move forward, policymakers will need a deeper understanding of the factors driving the industry to create regulations supporting the development of the hemp industry.
Impact of energy availability and physical activity on variation in fertility across human populations
Authors: Sadhir Srishti , Pontzer Herman
Published: February 2023

Human reproduction is energetically costly, even more so than other primates. In this review, we consider how the energy cost of physical activity impacts reproductive tasks. Daily energy expenditure appears to be constrained, leading to trade-offs between activity and reproduction expenditures in physically active populations. High workloads can lead to suppression of basal metabolic rate and low gestational weight gain during pregnancy and longer interbirth intervals. These responses lead to variation in fertility, including age at first reproduction and interbirth interval. The influence of energetics is evident even in industrialized populations, where cultural and economic factors predominate. With the decoupling of skills acquisition from food procurement, extrasomatic resources and investment in individual offspring becomes very costly. The result is greater investment in fewer offspring. We present a summary of age at first reproduction and interbirth interval trends across a diverse, global sample representing 44 countries and two natural fertility populations. While economic factors impact fertility, women in energy-rich, industrialized populations are capable of greater reproductive output than women in energy-stressed populations. Thus, energetic factors can be disentangled from cultural and economic impacts on fertility. Future research should focus on objective measurements of energy intake, energy expenditure, and physical activity in a broader sample of populations to elucidate the role of energetics in shaping reproductive outcomes and health.
Managers’ sick leave recommendations for employees with common mental disorders: a cross-sectional video vignette study
Authors: Hultqvist Jenny , Hensing Gunnel , Stansfeld Stephen , Bertilsson Monica
Published: February 2023

Background

To better understand the initial phases of sickness absence due to common mental disorders (CMD), the aim of the present video vignette study was to test the following three hypotheses: (1) Managers who have negative attitudes towards employees with CMD will not recommend sick leave. (2) Managers with experience of CMD recommend sick leave to a significantly higher extent than managers lacking this experience. (3) Managers with previous experience of recommending sick leave for people with CMD will recommend sick leave to a significantly higher extent also based on the vignettes.

Methods

An online survey, including a CMD-labelled video vignette, was sent to 4737 Swedish managers (71% participated, n  = 3358). For aims (1) and (2), a study sample consisting of 2714 managers was used. For aim (3), due to the design of the survey questions, a subsample (n  = 1740) was used.

Results

There was no significant association between negative attitudes towards employee depression and managers’ recommendation of employee sick leave with the vignette case. The bivariate analysis showed that personal experience of CMD was associated with managers’ recommendation of employee sick leave. In the adjusted regression model, it became non-significant. Previous experience of recommending sick leave to one employee and to several employees was associated with recommending sick leave, also when adjusting for gender, level of education, years of managerial experience, and management training on CMDs

Conclusions

The likelihood of a manager recommending sick leave after watching a CMD-labelled video vignette was higher if the manager had previous experience of this situation in real life. This study highlights the importance of including managerial behaviours and attitudes to better understand sick leave among employees with CMD.
Spontaneous intracerebral haemorrhage associated with early-onset cerebral amyloid angiopathy and Alzheimer’s disease neuropathological changes five decades after cadaveric dura mater graft
Authors: Milani Riccardo , Mazzeo Lucio Aniello , Vismara Daniela , Salemi Ilaria , Dainese Emanuele , Maderna Emanuela , Pellencin Elisa , Catania Marcella , Campanella Nicole , Di Fede Giuseppe , Giaccone Giorgio , Salmaggi Andrea
Published: February 2023

Cerebral amyloid angiopathy (CAA) is a small vessel disease, causing spontaneous intracerebral hemorrhage (ICH) in the elderly. It is strongly associated with Alzheimer disease (AD), as most CAA patients show deposition of Aβ—i.e. the basic component of parenchymal Alzheimer amyloid deposits—in the cerebral vessels. Iatrogenic early-onset CAA has been recently identified in patients with a history of traumatic brain injury or other cerebral as well as extra-cerebral lesions that led to neurosurgery or other medical procedures as intravascular embolization by cadaveric dura mater extracts many years before the first ICH event. In those patients, a transmission of Aβ seeds from neurosurgical instruments or from cadaveric dura mater exposure was suggested. We report a 51-year-old woman with unremarkable family history who presented abruptly with aphasia and right hemiparesis. A cerebral left lobar haemorrhagic stroke was documented by neuroimaging. Accurate anamnesis revealed a neurosurgical procedure with cadaveric dura mater graft at the age of 2 years for an arachnoid cyst. The neuropathological examination of the cerebral parietal biopsy showed severe amyloid angiopathy in many leptomeningeal and cortical vessels, as well as abundant parenchymal Aβ deposits, neurofibrillary tangles and neuropil threads. The mechanism involved in the human-to-human transmission of the Aβ proteinopathy remains to be clarified. In our patient the cadaver derived dura used for grafting is a very strong candidate as the source of the transmission. A systematic monitoring of individuals who have had neurosurgical procedures in early life, especially those involving cadaveric dural grafts, is required to determine the ratio of those affected by CAA many years later and unaffected. Moreover, our report confirms that in addition to vascular and parenchymal Aβ pathology, neurofibrillary changes indistinguishable from AD may develop in specific conditions with long latency period from the neurosurgical or embolization procedure.
Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients
Authors: Nasser Syed M. T. , Rana Anas A. , Doffinger Rainer , Kafizas Andreas , Khan Tauseef A. , Nasser Shuaib
Published: February 2023

Background

Divergence between deterioration to life-threatening COVID-19 or clinical improvement occurs for most within the first 14 days of symptoms. Life-threatening COVID-19 shares clinical similarities with Macrophage Activation Syndrome, which can be driven by elevated Free Interleukin-18 (IL-18) due to failure of negative-feedback release of IL-18 binding protein (IL-18bp). We, therefore, designed a prospective, longitudinal cohort study to examine IL-18 negative-feedback control in relation to COVID-19 severity and mortality from symptom day 15 onwards.

Methods

662 blood samples, matched to time from symptom onset, from 206 COVID-19 patients were analysed by enzyme-linked immunosorbent assay for IL-18 and IL-18bp, enabling calculation of free IL-18 (fIL-18) using the updated dissociation constant (Kd) of 0.05 nmol. Adjusted multivariate regression analysis was used to assess the relationship between highest fIL-18 and outcome measures of COVID-19 severity and mortality. Re-calculated fIL-18 values from a previously studied healthy cohort are also presented.

Results

Range of fIL-18 in COVID-19 cohort was 10.05–1157.7 pg/ml. Up to symptom day 14, mean fIL-18 levels increased in all patients. Levels in survivors declined thereafter, but remained elevated in non-survivors. Adjusted regression analysis from symptom day 15 onwards showed a 100 mmHg decrease in PaO2/FiO2 (primary outcome) for each 37.7 pg/ml increase in highest fIL-18 (p < 0.03). Per 50 pg/ml increase in highest fIL-18, adjusted logistic regression gave an odds-ratio (OR) for crude 60-day mortality of 1.41 (1.1–2.0) (p < 0.03), and an OR for death with hypoxaemic respiratory failure of 1.90 [1.3–3.1] (p < 0.01). Highest fIL-18 was associated also with organ failure in patients with hypoxaemic respiratory failure, with an increase of 63.67 pg/ml for every additional organ supported (p < 0.01).

Conclusions

Elevated free IL-18 levels from symptom day 15 onwards are associated with COVID-19 severity and mortality. ISRCTN: #13450549; registration date: 30/12/2020.
Harnessing the potential of machine learning and artificial intelligence for dementia research
Authors: Ranson Janice M. , Bucholc Magda , Lyall Donald , Newby Danielle , Winchester Laura , Oxtoby Neil P. , Veldsman Michele , Rittman Timothy , Marzi Sarah , Skene Nathan , Al Khleifat Ahmad , Foote Isabelle F. , Orgeta Vasiliki , Kormilitzin Andrey , Lourida Ilianna , Llewellyn David J.
Published: February 2023

Progress in dementia research has been limited, with substantial gaps in our knowledge of targets for prevention, mechanisms for disease progression, and disease-modifying treatments. The growing availability of multimodal data sets opens possibilities for the application of machine learning and artificial intelligence (AI) to help answer key questions in the field. We provide an overview of the state of the science, highlighting current challenges and opportunities for utilisation of AI approaches to move the field forward in the areas of genetics, experimental medicine, drug discovery and trials optimisation, imaging, and prevention. Machine learning methods can enhance results of genetic studies, help determine biological effects and facilitate the identification of drug targets based on genetic and transcriptomic information. The use of unsupervised learning for understanding disease mechanisms for drug discovery is promising, while analysis of multimodal data sets to characterise and quantify disease severity and subtype are also beginning to contribute to optimisation of clinical trial recruitment. Data-driven experimental medicine is needed to analyse data across modalities and develop novel algorithms to translate insights from animal models to human disease biology. AI methods in neuroimaging outperform traditional approaches for diagnostic classification, and although challenges around validation and translation remain, there is optimism for their meaningful integration to clinical practice in the near future. AI-based models can also clarify our understanding of the causality and commonality of dementia risk factors, informing and improving risk prediction models along with the development of preventative interventions. The complexity and heterogeneity of dementia requires an alternative approach beyond traditional design and analytical approaches. Although not yet widely used in dementia research, machine learning and AI have the potential to unlock current challenges and advance precision dementia medicine.
Bioengineered materials with selective antimicrobial toxicity in biomedicine
Authors: Makvandi Pooyan , Song Hao , Yiu Cynthia K. Y. , Sartorius Rossella , Zare Ehsan Nazarzadeh , Rabiee Navid , Wu Wei-Xi , Paiva-Santos Ana Cláudia , Wang Xiang-Dong , Yu Cheng-Zhong , Tay Franklin R.
Published: February 2023

Fungi and bacteria afflict humans with innumerous pathogen-related infections and ailments. Most of the commonly employed microbicidal agents target commensal and pathogenic microorganisms without discrimination. To distinguish and fight the pathogenic species out of the microflora, novel antimicrobials have been developed that selectively target specific bacteria and fungi. The cell wall features and antimicrobial mechanisms that these microorganisms involved in are highlighted in the present review. This is followed by reviewing the design of antimicrobials that selectively combat a specific community of microbes including Gram-positive and Gram-negative bacterial strains as well as fungi. Finally, recent advances in the antimicrobial immunomodulation strategy that enables treating microorganism infections with high specificity are reviewed. These basic tenets will enable the avid reader to design novel approaches and compounds for antibacterial and antifungal applications.
Blinatumomab therapy for B cell acute lymphoblastic leukemia accompanied by persistent or relapsed low-level MRD prior to hematopoietic stem cell transplantation in Chinese children: a case series
Authors: Zhou Guichi , Wang Lulu , Tang Xue , Liu Shilin , Li Tonghui , Liu Yi , Chen Fen , Mai Huirong , Liu Sixi , Wen Feiqiu , Wang Ying
Published: February 2023

Background

Blinatumomab could be successfully used to reduce minimal residual disease (MRD) prior to hematopoietic stem cell transplantation (HSCT) in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL), but sound evidence is lacking in China.

Case presentation

This retrospective study assessed the application of blinatumomab in B-ALL accompanied by persistent or relapsed low-level MRD before HSCT from April 2019 to July 2021. Two cases (Cases 1 and 2) initially achieved remission with MRD < 0.01% upon conventional therapy but had MRD relapse with MRD ≥ 0.01% but < 1% during maintenance treatment. Case 3 had no response to routine treatment, with high MRD (9.88% and 1.23% at days 19 and 46, respectively). Nevertheless, all patients had undetectable MRD. Cases 2 and 3 had undetectable fusion gene following blinatumomab therapy. By bone marrow monitoring (bone marrow morphology, bone marrow MRD and fusion gene) post-HSCT, the patients were persistently negative until May 15, 2022. No patient had serious adverse events before or during blinatumomab treatment.

Conclusions

Blinatumomab therapy showed a good performance for three pediatric cases with detectable but low MRD before HSCT in China. However, further prospective studies with large sample sizes are still needed for further clarification.
Impact of Antibiotic Exposure Before Immune Checkpoint Inhibitor Treatment on Overall Survival in Older Adults With Cancer: A Population-Based Study
Authors: Eng Lawson , Sutradhar Rinku , Niu Yue , Liu Ning , Liu Ying , Kaliwal Yosuf , Powis Melanie L. , Liu Geoffrey , Peppercorn Jeffrey M. , Bedard Philippe L. , Krzyzanowska Monika K.
Published: February 2023

PURPOSE

Antibiotic exposure before immune checkpoint inhibitor (ICI) treatment can negatively affect outcomes through alteration in the gut microbiome, but large-scale evaluations are lacking. We performed a population-level retrospective cohort study to evaluate the impact of antibiotic exposure before starting ICI on overall survival (OS).

PATIENT AND METHODS

Patients with cancer, age 65 years or older, who initiated treatment with ICIs between June 2012 and October 2018 in Ontario, Canada, were identified using systemic therapy administration data. The cohort was deterministically linked to other health care databases to obtain covariates and antibiotic prescription claim data at both 1 year and 60 days before ICI therapy. Multivariable Cox models evaluated the association between exposure and OS.

RESULTS

Among the 2,737 patients with cancer who received ICIs, 59% and 19% of patients received antibiotics 1 year and 60 days before ICI therapy, respectively. Median OS was 306 days. Any antibiotic exposure within 1 year before ICI was associated with worse OS (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.12 to 1.23; P = .03). In antibiotic class analysis, exposure to fluoroquinolones within 1 year (aHR, 1.26; 95% CI, 1.13 to 1.40; P < .001) or 60 days before ICI (aHR, 1.20; 95% CI, 0.99 to 1.45; P = .06) was associated with worse OS, with a dose effect seen on the basis of total weeks of exposure over 1 year (aHR, 1.07 per week; 95% CI, 1.03 to 1.11; P < .001) and 60 days (aHR, 1.12 per week; 95% CI, 1.03 to 1.23; P = .01).

CONCLUSION

In this population-level study, exposure to antibiotics and specifically fluoroquinolones before ICI therapy was observed to be associated with worse OS among older adults with cancer. Interventions aimed at altering the gut microbiome to boost immunogenicity may help improve outcomes for patients receiving ICIs with prior antibiotic exposure.

[Media: see text]
Cost of Cancer in Adolescents and Young Adults in the United States: Results of the 2021 Report by Deloitte Access Economics, Commissioned by Teen Cancer America
Authors: Parsons Susan K. , Keegan Theresa H.M. , Kirchhoff Anne C. , Parsons Helen M. , Yabroff K. Robin , Davies Simon J.
Published: February 2023

PURPOSE

The purpose of this report, commissioned by Teen Cancer America and performed by Deloitte Access Economics in 2021, was to estimate the total costs incurred by adolescent and young adults (AYAs) after cancer diagnosis in the United States (US) over their life course.

METHODS

The incidence of cancer in 2019 among AYAs age 15-39 years was estimated from the US Cancer Statistics Public Use Database, and relative survival was projected from the Surveillance, Epidemiology, and End Results Program. Cost domains included health system, productivity, and well-being costs. Components were estimated with published literature and pooled data from the Medical Expenditure Panel Survey from 2008 to 2012 and inflated to 2019 dollars.

RESULTS

The economic and human costs of cancer in AYAs are substantial—$23.5 billion overall, corresponding to $259,324 per person over the lifetime. The majority of costs are borne by AYA cancer survivors themselves in the form of lost productivity, loss of well-being, and loss of life.

CONCLUSION

These findings underscore the need to address the burden of cancer in AYAs through targeted programs for AYAs, such as financial navigation and health insurance literacy interventions, as well as local and national policy initiatives to address access to and enhanced coverage for clinical trials participation, fertility services, and survivorship care.
Inverse Holstein-Primakoff transformation of bosonic operators —Application to a bilayer model
Authors: Pontes Carneiro Carla Maria , Queiroz Pellegrino Giancarlo
Published: February 2023

An inversion of the Holstein-Primakoff transformation is proposed such that creation and annihilation operators for a bosonic field are rewritten as operators of an SU(2) algebra. In association with more common quadratic combinations for fermionic operators, that inverse transformation sets a quantum Hamiltonian fully in terms of SU(2) operators. A subsequent application of the prescription by Lieb, to obtain the classical limit for spin operators, then allows one to write effciently a classical Hamiltonian for the system. This process is illustrated for a bilayer model undergoing an (electron-hole)-to-exciton quantum phase transition.
Lack of Useful Predictors of Dignity-Related Distress Among the Critically Ill as Assessed With the Patient Dignity Inventory
Authors: Hadler Rachel A. , Dexter Franklin , Mergler Blake D.
Published: February 2023

BACKGROUND:

Many intensive care unit patients are awake (ie, alert and engaging in conversation), actively experiencing many facets of their critical care. The Patient Dignity Inventory can be used to elicit sources of distress in these patients. We examined the administrative question as to which awake intensive care unit patients should be evaluated and potentially treated (eg, through palliative care consultation) for distress. Should the decision to screen for distress be based on patient demographics or treatment conditions?

METHODS:

This was a retrospective cohort study of 155 adult patients from 5 intensive care units of one hospital from 2019 to 2020. Each patient had ≥48 hours without delirium, dementia, or sedation. The Patient Dignity Inventory has 25 items to which patients responded on a 1 (not a problem) to 5 (an overwhelming problem) scale. Multiple complete, stepwise forward, and stepwise backward logistic regression models were created among patient and treatment variables for predicting thresholds of the mean among the 25 items.

RESULTS:

There were 50% (78/155; 95% confidence interval [CI], 42–58) of patients with significant dignity-related distress (mean score ≥1.60). There were 34% (52/155; CI, 26–42) of patients with severe dignity-related distress (mean score ≥1.92; previously associated with often feeling like wanting to die). Models including combinations of vasopressor medication (protective of distress), tracheostomy (greater risk of distress), and female gender (greater risk of distress) had some predictive value. However, all combinations of potential predictors had misclassification rates significantly >20%.

CONCLUSIONS:

Identification of subsets of patients with little potential benefit to screening for dignity-related distress would have a reduced workload of palliative care team members (eg, nurses or social workers). Our results show that this is impractical. Given that approximately one-third of critical care patients who are alert and without delirium demonstrate severe dignity-related distress, all such patients with prolonged intensive care unit length of stay should probably be evaluated for distress.
Fractionated Radiotherapy After Gross Total Resection of Clival Chordoma: A Systematic Review of Survival Outcomes
Authors: Gendreau Julian L. , Hameed N. U. Farrukh , Jimenez Adrian , Chakravarti Sachiv , Mehkri Yusuf , Mukherjee Debraj
Published: February 2023

BACKGROUND:

Current treatment guidelines for clival chordomas recommend surgical resection followed by high-dose radiotherapy (RT). However, in patients in whom gross total resection (GTR) is achieved, the benefits of additional RT remain unclear.

OBJECTIVE:

To investigate whether RT offers any benefit to progression-free survival (PFS) in patients undergoing GTR of clival chordoma by performing a systematic review of all currently published literature.

METHODS:

A total of 5 databases were searched to include all studies providing data on GTR ± RT for clival chordomas (January 1990-June 2021). Qualitative assessment was performed with Newcastle–Ottawa Scale guidelines for assessing quality of nonrandomized studies. Statistical analysis using individualized patient data of PFS was performed.

RESULTS:

The systematic search yielded 2979 studies, weaned to 22 full-text articles containing 108 patients. All patients underwent GTR of clival chordoma, with 46 (43%) patients receiving adjuvant RT. Mean PFS for RT patients was 31.09 months (IQR: 12.25-37.75) vs 54.92 months (IQR: 14.00-85.75) in non-RT patients. Overall, RT did not increase PFS (HR 0.320, P = .069) to a value that achieved statistical significance. Stratifying by photon therapy vs particle beam therapy yielded no statistically significant benefit for particle beam therapy for PFS (P = .300). Of patients with age ≥65 years, RT did not improve outcomes to statistical significance for PFS (HR 0.450, P = .481). Patients age ≥65 years had lower PFS on both bivariate analysis (HR 3.708, P = .007) and multivariate analysis (HR 3.322, P = .018).

CONCLUSION:

After achieving GTR of clival chordoma, fractionated RT offers unclear benefit upon survival outcomes.
Classification and Management Considerations for Intraosseous Dural Arteriovenous Fistulae
Authors: Howard Brian M. , Manupipatpong Sasicha , Dion Jacques E. , Tamargo Rafael J. , Gailloud Philippe , Hui Ferdinand K.
Published: February 2023

BACKGROUND:

Intraosseous dural arteriovenous fistulas (IODAVFs) are rare DAVFs that communicate with marrow. Given their infrequency, common nomenclature is nonexistent. Patients may present with benign symptoms, such as tinnitus, or venous hypertension symptoms including hemorrhage depending on the venous outflow pattern.

OBJECTIVE:

To describe all available cases of IODAVF in the literature, in addition to our cases, to better define presentation, and treatment outcomes. To advance a classification system to develop common language for these lesions for clinicians and researchers.

METHODS:

Neurointerventional procedure logs at 2 high-volume neurovascular centers were reviewed for all cases of IODAVFs, as was the English-based literature available in PubMed. The angioarchitecture, symptoms, management, and demographics were reviewed and summarized.

RESULTS:

Four institutional cases were identified, 2 of which had shunting within the marrow (clival or petrous), with venous drainage toward the heart. One case involved the dorsum sella with drainage into the superior petrosal sinus with reflux into the anterior and posterior spinal venous plexuses, and one involved the left petroclival junction, resulting in communication with the cavernous sinus with retrograde drainage into the superior ophthalmic veins. Two patients were managed by observation, one was treated with radiosurgery and one with microsurgical skeletonization. Twenty additional cases from the literature are summarized.

CONCLUSION:

IODAVFs of the cerebrocranial vasculature may present incidentally, with tinnitus, or with symptoms related to mass effect or venous hypertension. We propose a classification which accounts for drainage patterns. Further study is needed for these rare lesions.
SUN4 is a spermatid type II inner nuclear membrane protein that forms heteromeric assemblies with SUN3 and interacts with lamin B3
Authors: Thoma Hanna , Grünewald Luisa , Braune Silke , Pasch Elisabeth , Alsheimer Manfred
Published: February 2023

SUN domain proteins are conserved proteins of the nuclear envelope and key components of the LINC complexes (for ‘linkers of the nucleoskeleton and the cytoskeleton’). Previous studies have demonstrated that the testis-specific SUN domain protein SUN4 (also known as SPAG4) is a vital player in the directed shaping of the spermatid nucleus. However, its molecular properties relating to this crucial function have remained largely unknown, and controversial data for the organization and orientation of SUN4 within the spermatid nuclear envelope have been presented so far. Here, we have re-evaluated this issue in detail and show robust evidence that SUN4 is integral to the inner nuclear membrane, sharing a classical SUN domain protein topology. The C-terminal SUN domain of SUN4 localizes to the perinuclear space, whereas the N-terminus is directed to the nucleoplasm, interacting with the spermiogenesis-specific lamin B3. We found that SUN4 forms heteromeric assemblies with SUN3 in vivo and regulates SUN3 expression. Together, our results contribute to a better understanding of the specific function of SUN4 at the spermatid nucleo-cytoplasmic junction and the process of sperm-head formation.