bluuebunny/crossref_metadata_2025 huggingface dataset:
American Bases in the Philippines: A Journey to the Past
Authors: Mahapatra Chintamani
Published: January 2023

The American Administration is at present confronted with a set of apparently contradictory problems: how to close the unneeded military bases in its territory and how to retain its important military facilities and installations in the Republic of the Philippines, including the well-known Subic Naval Base and Clark Air Force Base. Studies undertaken by various United States’ Government agencies have estimated that the Defence Department could save from $ 1 billion to $ 5 billion annually by closing some of the unneeded bases out of a total of 3,800 located in various parts of the United States.1 And thus important Pentagon officials and key members of the US Congress are reportedly moving to stamp “surplus” on some of these bases with a view to closing them down.2 On the other hand, policy-makers in Washington still consider the US bases in the Philippines as “the irreducible minimum of American security and interests in the Pacific and the Far East.” And as part of the plan to retain the bases in the Philippines the United States Government recently approved a mini-Marshall Plan for the Philippine Republic. Negotiations to review the Military Bases Agreement (MBA) of 1947 began in April between the officials of the United States and the Philippines.

The MBA has undergone more than forty amendments in the past four decades. But the current negotiations are significant because it involves extension of the term of the agreement that expires in 1991. Presence of foreign military bases and troops in a sovereign country has always remained a sensitive issue in international relations. After more than three decades since the signing of the MBA the Filipinos got their sovereignty formally extended over the US military bases in the Islands and the Filipino flags began to fly in US base areas since 1979. Yet the nationalist Fitipinos still continue to ask: Is national sovereignty compatible with American military presence on their soil? Are not these bases likely to invite attacks from America's adversaries? Is Philippines interest being served by US maintenance of bases on the Islands? Some Filipinos raised similar questions way back in the 1940s. But they did enter into a Military Bases Agreement with the Americans by virtue of which the US military presence is still continuing in the Philippine Islands. Why did they sign the agreement? What were the compulsions? How did it all happen? When similar sets of questions, among others of course, are being raised after four decades of changes in the national, regional as well as global power configuration, a journey to the past is perhaps called for, for clearer comprehension of the current situation.

The present paper is based on archival materials and other primary source materials available in the United States. Secondary source materials available in India and the United States have been used in appropriate places.
Indian Books of the Quarter
Authors: Machwe V.
Published: January 2023

The object of this feature is to offer every quarter, scholars and students as well as libraries, a compact bibliography of such current Indian publications in the field of Social Sciences as are received from publishers, but not reviewed in this journal. While no claim is made to exhaustiveness, it is hoped that this section, together with the Review Section of this journal, does list publications of importance useful for libraries and research workers in the Social Sciences.
Nonlinear dynamic performance of the turbine inlet valves in hydroelectric power plants
Authors: Awad Hesham , Parrondo Jorge
Published: January 2023

In practice, vibrations in the turbine inlet valves can develop flow rate and pressure fluctuations in the penstocks of the hydropower plants that can risk the safe operation of the power plant. Accordingly, this study has two aims: the first aim is to explain and simulate the valve’s periodic vibrations while considering the power plant’s relevant physical and geometrical parameters. The second aim is to provide recommendations to improve the dynamic stability of the valve’s vibrations. The theoretical model developed to explain the phenomenon comprises the nonlinear unsteady energy equations representing the fluid flow at the pipelines, the continuity equation modelling fluid flow through different junctions, and the valve’s seal equation of motion to compute the valve’s vibrations. The system governing equations are solved nonlinearly using the MATLAB toolbox SIMULINK. The study demonstrated that the origin of the valve’s vibrations is the leakage of the valve’s service seal. The presented model results exhibited that the unstable valve vibrations (of increasing amplitudes) are more prone to occur at higher input reservoir energy levels. Also, installing a valve that can be closed to a certain degree at the pilot pipeline can enhance the dynamic stability of the valve’s vibrations.
Fear, learning, or self-control? Predictors of Russian citizens’ compliance with mandatory and voluntary Covid-19 prevention measures
Authors: Gurinskaya Anna , Nalla Mahesh K , Jaynes Chae M
Published: January 2023

In this article, we examine citizens’ willingness to comply with Covid-19 prevention strategies of mandatory mask-wearing and recommended social distance/contact limitation measures from competing theoretical perspectives. These include self-control, deterrence, learning, social control theories, and fear of the infection. Data for the study come from 508 respondents from St. Petersburg—Russia’s second largest city—in May 2020, when the Covid-19 regional legislation that mandated citizens to wear masks in public went into effect. Overall, our findings suggest mixed support for various theoretical perspectives. Among the variables included in the analysis, fear of the infection is positively related to compliance with both mandated and recommended measures. Fear of Covid-19 infection, fear of punishment, and fear of disapproval on behalf of significant others that would follow non-compliance appear to be strong predictors of law-abiding behavior. Learning and self-control theories explain compliance with non-mandatory measures, but not with mask-wearing, which carried a penalty for violating the mandate.
Immunotherapy in hepatocellular carcinoma: how will it reshape treatment sequencing?
Authors: Cammarota Antonella , Zanuso Valentina , Manfredi Giulia Francesca , Murphy Ravindhi , Pinato David James , Rimassa Lorenza
Published: January 2023

The treatment landscape of advanced hepatocellular carcinoma (HCC) has broadened with immune checkpoint inhibitors (ICIs) setting a novel standard of care. With the increased number of therapies either in first or in further line, disentangling the possible treatment sequences has become much more complex. Yet, all the second-line therapies have been evaluated after sorafenib. After ICIs, offering multikinase inhibitors is a widespread approach, either shifting forward sorafenib or lenvatinib, or choosing among regorafenib or cabozantinib, already approved in the refractory setting. Under specific circumstances, ICIs could be maintained beyond disease progression in patients with proven clinical benefit, as supported by some data emerging from phase III clinical trials with immunotherapy in HCC. Rechallenge with ICIs is an additional attractive alternative, although requiring careful and individual evaluation as efficacy and safety of such a strategy have not been yet clarified. Still, a considerable number of patients displays primary resistance to ICIs and might benefit from antiangiogenics either alone or in addition to ICIs instead. Hopefully, the ongoing clinical trials will enlighten regarding the most effective treatment pathways. The identification of predictive correlates of response to immunotherapy will help treatment allocation at each stage, thus representing an urgent matter to address in HCC research. With programmed death ligand 1 expression, tumor mutational burden, and microsatellite status being inadequate biomarkers in HCC, patient characteristics, drug safety profile, and regulatory approval remain key elements to acknowledge in routine practice. Despite the tissue remaining a preferred source, biomarkers discovery could take advantage of liquid biopsy to overcome the matter of tissue availability and track tumor changes. Lastly, tumor genetic phenotypes, tumor microenvironment features, gut microbiome, and markers of immune response and systemic inflammation are all potential emergent predictors of response to ICIs, pending validation in the clinical setting.
Monitoring of surface cleaning and disinfection in a Brazilian pediatric unit
Authors: Bernardes Lucas de Oliveira , dos Santos Fernando Ribeiro , Angeloni Natália Liberato Norberto , Ribeiro Furlan Mara Cristina , Barcelos Larissa da Silva , Ferreira Adriano Menis , Lopes de Sousa Alvaro Francisco , Andrade Denise de , Valim Marília Duarte , Batista Odinea Maria Amorim , Lapão Luís Velez , dos Santos Junior Aires Garcia , Lima Helder de Pádua
Published: January 2023

Background:

Understanding the correlation between the methods of monitoring surface cleaning and disinfection (SCD) is fundamental for better infection control.

Purpose:

This study aims to correlate the SCD monitoring methods in a Brazilian pediatric unit. This is an exploratory, longitudinal, and correlational study.

Methods:

The study was conducted in a pediatric hospitalization unit of a medium-sized hospital from December 2020 to March 2021. Four high-contact surfaces were analyzed before and after the cleaning and disinfection process by means of visual inspection, quantification of adenosine triphosphate (ATP), and colony-forming unit (CFU) count. The study consisted of three stages: stage I involving situational diagnosis of the SCD process; stage II referring to the implementation of the Surface Cleaning and Disinfection Standardization Program (SCDSP); and stage III involving long-term assessment after implementing the program. A total of 192 assessments were performed in each stage, totaling 576 in the three study stages.

Conclusions:

A significant correlation was found between the ATP quantification methods and microbial count in the bed railing ( p = 0.009) and companion’s armchair ( p = 0.018) surfaces. In both cases, Spearman’s correlation coefficients were positive, indicating a positive correlation between ATP and microbial count scores, that is, the higher the ATP values (in RLUs), the greater the microbial counts (in CFUs/cm2). The analysis of the ROC curves suggests that the surfaces presenting ATP below 108 RLUs can be considered approved. The ATP method yielded 78.6% sensitivity; in turn, microbial count presented a sensitivity of 85.7%. It is important to use different methods to monitor the cleaning and disinfection of surfaces, as each one has different sensitivity and specificity.
Reason and Associated Factors for Nonuse of Contraceptives Among Ethiopian Rural Married Women: A Multilevel Mixed Effect Analysis
Authors: Mulugeta Solomon Sisay , Muluneh Mitiku Wale , Belay Alebachew Taye , Yalew Mequanint Melkam , Agegn Setegn Bayabile
Published: January 2023

Introduction

Contraception has a clear impact on the health of women and families in developing countries. This study aims to identify multilevel determinants of nonuse of modern contraceptives among Ethiopian rural married women in their productive age group.

Method

The study relied on data from the 2016 Ethiopian Demographic and Health Surveys. A multilevel logistic regression model was used for analysis.

Result

In rural areas, nonuse of modern contraceptives is surprising high (81.7%), primarily due to fear of side effects (12.89%) and breastfeeding (8.2%). Among women aged 35 to 49 years (adjusted odds ratio [AOR] = 0.66; 95% confidence interval [CI]: 0.540.81), husbands with secondary and above education levels (AOR = 0.83; 95% CI: 0.7–1), those in the high wealth index (AOR = 0.61; 95% CI: 0.51–0.72), and those who have had 1 to 2 children in the past 5 years (AOR  =  0.28; 95% CI: 0.24–0.33), there was a lower chance of not using contraception. Muslims are less likely to want to use modern contraceptives (AOR = 1.2; 95% CI: 0.96–1.4). Women living in Afar (AOR  =  20.9; 95% CI: 9.6–44.7), Oromia (AOR =  1.5; 95% CI: 1.01–2.3), Somali (AOR = 71.1; 95% CI: 24.1–209.2), Gambela (AOR = 2.3; 95% CI: 1.4–3.9), Harari (AOR  =  4.4; 95% CI: 2.24–8.72), and Dire Dawa (AOR = 3.2; 95% CI: 1.5–6.9), regional states, were less likely to want to use modern contraceptives as compared to those in Tigray.

Conclusion

Family planning interventions should target younger women, women living in rural areas, the poor, and Muslim women. In order to maximize the effectiveness of family planning promotion policies, it's important to address the reasons for nonuse of contraceptives identified in each region and contextual differences regarding women of reproductive age.
xcore: an R package for inference of gene expression regulators
Authors: Migdał Maciej , Arakawa Takahiro , Takizawa Satoshi , Furuno Masaaki , Suzuki Harukazu , Arner Erik , Winata Cecilia Lanny , Kaczkowski Bogumił
Published: January 2023

Background

Elucidating the Transcription Factors (TFs) that drive the gene expression changes in a given experiment is a common question asked by researchers. The existing methods rely on the predicted Transcription Factor Binding Site (TFBS) to model the changes in the motif activity. Such methods only work for TFs that have a motif and assume the TF binding profile is the same in all cell types.

Results

Given the wealth of the ChIP-seq data available for a wide range of the TFs in various cell types, we propose that gene expression modeling can be done using ChIP-seq “signatures” directly, effectively skipping the motif finding and TFBS prediction steps. We presentxcore, an R package that allows TF activity modeling based on ChIP-seq signatures and the user's gene expression data. We also providexcoredataa companion data package that provides a collection of preprocessed ChIP-seq signatures. We demonstrate thatxcoreleads to biologically relevant predictions using transforming growth factor beta induced epithelial-mesenchymal transition time-courses, rinderpest infection time-courses, and embryonic stem cells differentiated to cardiomyocytes time-course profiled with Cap Analysis Gene Expression.

Conclusions

xcoreprovides a simple analytical framework for gene expression modeling using linear models that can be easily incorporated into differential expression analysis pipelines. Taking advantage of public ChIP-seq databases,xcorecan identify meaningful molecular signatures and relevant ChIP-seq experiments.
Machine learning for predicting neurodegenerative diseases in the general older population: a cohort study
Authors: Aguayo Gloria A. , Zhang Lu , Vaillant Michel , Ngari Moses , Perquin Magali , Moran Valerie , Huiart Laetitia , Krüger Rejko , Azuaje Francisco , Ferdynus Cyril , Fagherazzi Guy
Published: January 2023

Background

In the older general population, neurodegenerative diseases (NDs) are associated with increased disability, decreased physical and cognitive function. Detecting risk factors can help implement prevention measures. Using deep neural networks (DNNs), a machine-learning algorithm could be an alternative to Cox regression in tabular datasets with many predictive features. We aimed to compare the performance of different types of DNNs with regularized Cox proportional hazards models to predict NDs in the older general population.

Methods

We performed a longitudinal analysis with participants of the English Longitudinal Study of Ageing. We included men and women with no NDs at baseline, aged 60 years and older, assessed every 2 years from 2004 to 2005 (wave2) to 2016–2017 (wave 8). The features were a set of 91 epidemiological and clinical baseline variables. The outcome was new events of Parkinson’s, Alzheimer or dementia. After applying multiple imputations, we trained three DNN algorithms: Feedforward, TabTransformer, and Dense Convolutional (Densenet). In addition, we trained two algorithms based on Cox models: Elastic Net regularization (CoxEn) and selected features (CoxSf).

Results

5433 participants were included in wave 2. During follow-up, 12.7% participants developed NDs. Although the five models predicted NDs events, the discriminative ability was superior using TabTransformer (Uno’s C-statistic (coefficient (95% confidence intervals)) 0.757 (0.702, 0.805). TabTransformer showed superior time-dependent balanced accuracy (0.834 (0.779, 0.889)) and specificity (0.855 (0.0.773, 0.909)) than the other models. With the CoxSf (hazard ratio (95% confidence intervals)), age (10.0 (6.9, 14.7)), poor hearing (1.3 (1.1, 1.5)) and weight loss 1.3 (1.1, 1.6)) were associated with a higher DNN risk. In contrast, executive function (0.3 (0.2, 0.6)), memory (0, 0, 0.1)), increased gait speed (0.2, (0.1, 0.4)), vigorous physical activity (0.7, 0.6, 0.9)) and higher BMI (0.4 (0.2, 0.8)) were associated with a lower DNN risk.

Conclusion

TabTransformer is promising for prediction of NDs with heterogeneous tabular datasets with numerous features. Moreover, it can handle censored data. However, Cox models perform well and are easier to interpret than DNNs. Therefore, they are still a good choice for NDs.
Predictive markers related to local and systemic inflammation in severe COVID-19-associated ARDS: a prospective single-center analysis
Authors: Lieberum Jan Nikolaus , Kaiser Sandra , Kalbhenn Johannes , Bürkle Hartmut , Schallner Nils
Published: January 2023

Background

As the COVID-19 pandemic strains healthcare systems worldwide, finding predictive markers of severe courses remains urgent. Most research so far was limited to selective questions hindering general assumptions for short- and long-term outcome.

Methods

In this prospective single-center biomarker study, 47 blood- and 21 bronchoalveolar lavage (BAL) samples were collected from 47 COVID-19 intensive care unit (ICU) patients upon admission. Expression of inflammatory markers toll-like receptor 3 (TLR3), heme oxygenase-1 (HO-1), interleukin (IL)-6, IL-8, leukocyte counts, procalcitonin (PCT) and carboxyhemoglobin (CO-Hb) was compared to clinical course. Clinical assessment comprised acute local organ damage, acute systemic damage, mortality and outcome after 6 months.

Results

PCT correlated with acute systemic damage and was the best predictor for quality of life (QoL) after 6 months (r = − 0.4647, p = 0.0338). Systemic TLR3 negatively correlated with impaired lung function (ECMO/ECLS: r = − 0.3810, p = 0.0107) and neurological short- (RASS mean: r = 0.4474, p = 0.0023) and long-term outcome (mRS after 6 m: r = − 0.3184, p = 0.0352). Systemic IL-8 correlated with impaired lung function (ECMO/ECLS: r = 0.3784, p = 0.0161) and neurological involvement (RASS mean: r = − 0.5132, p = 0.0007). IL-6 in BAL correlated better to the clinical course than systemic IL-6. Using three multivariate regression models, we describe prediction models for local and systemic damage as well as QoL. CO-Hb mean and max were associated with higher mortality.

Conclusions

Our predictive models using the combination of Charlson Comorbidity Index, sex, procalcitonin, systemic TLR3 expression and IL-6 and IL-8 in BAL were able to describe a broad range of clinically relevant outcomes in patients with severe COVID-19-associated ARDS. Using these models might proof useful in risk stratification and predicting disease course in the future.

Trial registration The trial was registered with the German Clinical Trials Register (Trial-ID DRKS00021522, registered 22/04/2020).
Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma
Authors: Wang Bangting , Zhang Jiting , Wang Xin , Zhao Lili , Wang Yan , Fan Zhining , Liu Li , Gao Wenqing
Published: January 2023

Background

Colorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA.

Methods

Transcriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein–protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results. 

Results

Screening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC.

Conclusion

Our study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets.
Study protocol of the sweet tooth study, randomized controlled trial with partial food provision on the effect of low, regular and high dietary sweetness exposure on sweetness preferences in Dutch adults
Authors: Čad Eva M. , Tang Claudia S. , de Jong Hanne B. T. , Mars Monica , Appleton Katherine M. , de Graaf Kees
Published: January 2023

Background

Several health organizations recommend lowering the consumption of sweet-tasting foods. The rationale behind this recommendation is that a lower exposure to sweet foods may reduce preferences for sweet tasting foods, thus lowering sugar and energy intake, and in turn aiding in obesity prevention. However, empirical data supporting this narrative are lacking. In fact, relatively little is known about the contribution of long-term sweet taste exposure on one’s sweetness preferences.

Methods

The primary objective of this randomized controlled trial is to assess the effect of low, regular and high dietary sweetness exposure on preference for sweet foods and beverages, and to compare these effects between intervention groups. One hundred and eighty adults aged 18–65 years with a BMI of 18.5–30.0 kg/m2 will be recruited and randomly allocated to either: low dietary sweetness exposure (LSE) (10–15% daily energy from sweet tasting foods), regular dietary sweetness exposure (RSE) (25–30% daily energy from sweet tasting foods), or high dietary sweetness exposure (HSE) (40–45% daily energy from sweet tasting foods), for 6 months, followed by a 4-month follow up. Intervention foods are provided ad libitum, covering approximately 50% of the daily number of food items, to include sugar-sweetened, low-calorie-sweetener-sweetened and non-sweet foods. The primary outcome measure is the difference in change in sweetness preference from baseline to 6 months between intervention groups. Secondary outcomes include: change in sweet taste preferences at different time-points; taste intensity perception; behavioral outcomes: food choice and intake, sweet-liker type, food cravings, dietary taste preferences and dietary taste patterns; anthropometric outcomes: body composition, waist-hip circumference, body weight; and biochemical outcomes: glucose variability and biomarkers related to CVD and diabetes.

Discussion

This study will generate important data on the effect of dietary sweetness exposure on sweetness preferences in terms of effect size and change, duration of change and its impact on food intake, body weight status and associated health outcomes.

Trial Registration

The study protocol has been registered on ClinicalTrials.gov (ID no. NCT04497974, Registered 4 August 2020, https://clinicaltrials.gov/ct2/show/NCT04497974) and approved by Wageningen’s Medical Ethical Committee (ABR no. NL72134).
Cost-utility analysis and net monetary benefit of Platelet Rich Plasma (PRP), intra-articular injections in compared to Plasma Rich in Growth Factors (PRGF), Hyaluronic Acid (HA) and ozone in knee osteoarthritis in Iran
Authors: Raeissadat Seyed Ahmad , Rahimi Mohammad , Rayegani Seyed Mansoor , Moradi Najmeh
Published: January 2023

Purpose

To evaluate the cost-effectiveness of Platelet Rich Plasma (PRP), Plasma Rich in Growth Factors (PRGF), Hyaluronic Acid (HA) and ozone as effective treatment approaches in knee osteoarthritis management from Iran Health care perspective.

Methods

A decision tree model was conducted to assess the cost-effectiveness of four common intra-articular treatment approaches in patients with mild and moderate knee osteoarthritis. The data on clinical effectiveness was obtained from a randomized controlled trial (RCT) conducted in Iran and used to estimate utility values. The direct medical costs were estimated according to tariffs for public medical centers and hospitals, approved by the Iran Ministry of Health and Medical Education in 2021. The incremental cost-effectiveness ratio (ICER) and the net monetary benefit (NMB) were used to evaluate the cost-utility analysis. Deterministic and probabilistic sensitivity analyses are performed to investigate the robustness of the results and account for the different sources of uncertainty.

Results

In this study, HA intra-articular injection-related costs ($581.67/patient) were defined as the highest cost, followed by PRGF ($328.10/patient), PRP (318.58/patient), and Ozone (103.20/patient). According to the utility value, PRP and PRGF (0.68) have the same and the most utility among Intra-articular injections in knee osteoarthritis management. However, the PRP injection method was identified as the most cost-effective intervention due to its high NMB and ICER estimates. Based on the Monte Carlo Simulation, PR intervention, compared to other ones, was introduced as the dominant strategy regarding knee OA management, with a WTP of $10,000 for 100% of cases.

Conclusion

The study result demonstrated that intra-articular injection of PRP, compare to other injections, is a cost-effective treatment option for patients with mild and moderate knee osteoarthritis. In addition, intra-articular injection of PRP was identified as the best injection, with the highest level of net monetary benefit, for knee OA management.
Type 1 diabetes, periodontal health, and a familial history of hyperlipidaemia is associated with oral microbiota in children: a cross-sectional study
Authors: Selway Caitlin A. , Jensen Emilija D. , Pena Alexia S. , Smart Gabrielle , Weyrich Laura S.
Published: January 2023

Background

Hyperlipidaemia may play a significant role in the interrelationship between type 1 diabetes (T1D) and periodontal disease. A potential mechanism that links these three aspects together is the oral microbiota. We wanted to determine if there is an association between hyperlipidaemia, periodontal disease, and the oral microbiota of children with T1D, as this has not yet been explored.

Methods

In a post-hoc, cross-sectional study using 16S rRNA gene sequencing, we explored links between oral bacterial diversity and composition of gingival swab samples from 72 children with T1D to periodontal risk factors and hyperlipidaemia status of first-degree relatives. While multiple periodontal risk factors were assessed, we used periodontal pocket depth of 3 mm to characterise periodontal risk. As periodontal pocket depth confounded the analysis of familial history of hyperlipidaemia, a multivariate analyses were performed (i.e., no periodontal risk markers in children with or without a family history of hyperlipidaemia were compared to counterparts who did not have periodontal risk markers) to examine linkages between these factors and diversity and composition of the microbiome.

Results

In participants with no periodontitis risk, children with a family history of dyslipidemia had different bacterial diversity and composition compared to those without a familar hisitory. In contrast, such differences did not exist in the children with periodontal risk, whether or not they had a family history of hyperlipidaemia. Co-occurrence networks showed that these differences in children with no periodontists risk were linked to the presence of fewer oral microbial networks, but more microbes linked to mature plaque structures. In contrast, children with periodontal risk markers, regardless of family history of hyperlipidaemia, contained co-occurrence networks that were associated with microbes linked to periodontal disease.

Conclusions

In children diagnosed with T1D, our findings support an association between oral microbiota and two different exposure variables: familial history of hyperlipidaemia and periodontal risk factors.
Olfactory sensitivity differentiates morphologically distinct worker castes in Camponotus floridanus
Authors: Ferguson S. T. , Bakis I. , Edwards N. D. , Zwiebel L. J.
Published: January 2023

Background

Camponotus floridanus ant colonies are comprised of a single reproductive queen and thousands of sterile female offspring that consist of two morphologically distinct castes: smaller minors and larger majors. Minors perform most of the tasks within the colony, including brood care and food collection, whereas majors have fewer clear roles and have been hypothesized to act as a specialized solider caste associated with colony defense. The allocation of workers to these different tasks depends, in part, on the detection and processing of local information including pheromones and other chemical blends such as cuticular hydrocarbons. However, the role peripheral olfactory sensitivity plays in establishing and maintaining morphologically distinct worker castes and their associated behaviors remains largely unexplored.

Results

We examined the electrophysiological responses to general odorants, cuticular extracts, and a trail pheromone in adult minor and major C. floridanus workers, revealing that the repertoire of social behaviors is positively correlated with olfactory sensitivity. Minors in particular display primarily excitatory responses to olfactory stimuli, whereas major workers primarily manifest suppressed, sub-solvent responses. The notable exception to this paradigm is that both minors and majors display robust, dose-dependent excitatory responses to conspecific, non-nestmate cuticular extracts. Moreover, while both minors and majors actively aggress non-nestmate foes, the larger and physiologically distinct majors display significantly enhanced capabilities to rapidly subdue and kill their adversaries.

Conclusions

Our studies reveal the behavioral repertoire of minors and majors aligns with profound shifts in peripheral olfactory sensitivity and odor coding. The data reported here support the hypothesis that minors are multipotential workers with broad excitatory sensitivity, and majors are dedicated soldiers with a highly specialized olfactory system for distinguishing non-nestmate foes. Overall, we conclude that C. floridanus majors do indeed represent a physiologically and behaviorally specialized soldier caste in which caste-specific olfactory sensitivity plays an important role in task allocation and the regulation of social behavior in ant colonies.
Intra-colony venom diversity contributes to maintaining eusociality in a cooperatively breeding ant
Authors: Robinson Samuel D. , Schendel Vanessa , Schroeder Christina I. , Moen Sarah , Mueller Alexander , Walker Andrew A. , McKinnon Naomi , Neely G. Gregory , Vetter Irina , King Glenn F. , Undheim Eivind A. B.
Published: January 2023

Background

Eusociality is widely considered to evolve through kin selection, where the reproductive success of an individual’s close relative is favored at the expense of its own. High genetic relatedness is thus considered a prerequisite for eusociality. While ants are textbook examples of eusocial animals, not all ants form colonies of closely related individuals. One such example is the ectatommine ant Rhytidoponera metallica, which predominantly forms queen-less colonies that have such a low intra-colony relatedness that they have been proposed to represent a transient, unstable form of eusociality. However, R. metallica is among the most abundant and widespread ants on the Australian continent. This apparent contradiction provides an example of how inclusive fitness may not by itself explain the maintenance of eusociality and raises the question of what other selective advantages maintain the eusocial lifestyle of this species.

Results

We provide a comprehensive portrait of the venom of R. metallica and show that the colony-wide venom consists of an exceptionally high diversity of functionally distinct toxins for an ant. These toxins have evolved under strong positive selection, which is normally expected to reduce genetic variance. Yet, R. metallica exhibits remarkable intra-colony variation, with workers sharing only a relatively small proportion of toxins in their venoms. This variation is not due to the presence of chemical castes, but has a genetic foundation that is at least in part explained by toxin allelic diversity.

Conclusions

Taken together, our results suggest that the toxin diversity contained in R. metallica colonies may be maintained by a form of group selection that selects for colonies that can exploit more resources and defend against a wider range of predators. We propose that increased intra-colony genetic variance resulting from low kinship may itself provide a selective advantage in the form of an expanded pharmacological venom repertoire. These findings provide an example of how group selection on adaptive phenotypes may contribute to maintaining eusociality where a prerequisite for kin selection is diminished.
Predicting mortality in acutely hospitalised older patients: the impact of model dimensionality
Authors: Tsui Alex , Tudosiu Petru-Daniel , Brudfors Mikael , Jha Ashwani , Cardoso Jorge , Ourselin Sebastien , Ashburner John , Rees Geraint , Davis Daniel , Nachev Parashkev
Published: January 2023

Background

The prediction of long-term mortality following acute illness can be unreliable for older patients, inhibiting the delivery of targeted clinical interventions. The difficulty plausibly arises from the complex, multifactorial nature of the underlying biology in this population, which flexible, multimodal models based on machine learning may overcome. Here, we test this hypothesis by quantifying the comparative predictive fidelity of such models in a large consecutive sample of older patients acutely admitted to hospital and characterise their biological support.

Methods

A set of 804 admission episodes involving 616 unique patients with a mean age of 84.5 years consecutively admitted to the Acute Geriatric service at University College Hospital were identified, in whom clinical diagnoses, blood tests, cognitive status, computed tomography of the head, and mortality within 600 days after admission were available. We trained and evaluated out-of-sample an array of extreme gradient boosted trees-based predictive models of incrementally greater numbers of investigational modalities and modelled features. Both linear and non-linear associations with investigational features were quantified.

Results

Predictive models of mortality showed progressively increasing fidelity with greater numbers of modelled modalities and dimensions. The area under the receiver operating characteristic curve rose from 0.67 (sd = 0.078) for age and sex to 0.874 (sd = 0.046) for the most comprehensive model. Extracranial bone and soft tissue features contributed more than intracranial features towards long-term mortality prediction. The anterior cingulate and angular gyri, and serum albumin, were the greatest intracranial and biochemical model contributors respectively.

Conclusions

High-dimensional, multimodal predictive models of mortality based on routine clinical data offer higher predictive fidelity than simpler models, facilitating individual level prognostication and interventional targeting. The joint contributions of both extracranial and intracranial features highlight the potential importance of optimising somatic as well as neural functions in healthy ageing. Our findings suggest a promising path towards a high-fidelity, multimodal index of frailty.
Recommendations for robust and reproducible preclinical research in personalised medicine
Authors: Fosse Vibeke , Oldoni Emanuela , Bietrix Florence , Budillon Alfredo , Daskalopoulos Evangelos P. , Fratelli Maddalena , Gerlach Björn , Groenen Peter M. A. , Hölter Sabine M. , Menon Julia M. L. , Mobasheri Ali , Osborne Nikki , Ritskes-Hoitinga Merel , Ryll Bettina , Schmitt Elmar , Ussi Anton , Andreu Antonio L. , McCormack Emmet ,   on behalf of The PERMIT group, Banzi Rita , Demotes Jacques , Garcia Paula , Gerardi Chiara , Glaab Enrico , Haro Josep Maria , Hulstaert Frank , Miguel Lorena San , Mirete Judit Subirana , Niubo Albert Sanchez , Porcher Raphaël , Rauschenberger Armin , Rodriguez Montserrat Carmona , Superchi Cecilia , Torres Teresa
Published: January 2023

Background

Personalised medicine is a medical model that aims to provide tailor-made prevention and treatment strategies for defined groups of individuals. The concept brings new challenges to the translational step, both in clinical relevance and validity of models. We have developed a set of recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.

Methods

These recommendations have been developed following four main steps: (1) a scoping review of the literature with a gap analysis, (2) working sessions with a wide range of experts in the field, (3) a consensus workshop, and (4) preparation of the final set of recommendations.

Results

Despite the progress in developing innovative and complex preclinical model systems, to date there are fundamental deficits in translational methods that prevent the further development of personalised medicine. The literature review highlighted five main gaps, relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. We identified five points of focus for the recommendations, based on the consensus reached during the consultation meetings: (1) clinically relevant translational research, (2) robust model development, (3) transparency and education, (4) revised regulation, and (5) interaction with clinical research and patient engagement. Here, we present a set of 15 recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.

Conclusions

Appropriate preclinical models should be an integral contributor to interventional clinical trial success rates, and predictive translational models are a fundamental requirement to realise the dream of personalised medicine. The implementation of these guidelines is ambitious, and it is only through the active involvement of all relevant stakeholders in this field that we will be able to make an impact and effectuate a change which will facilitate improved translation of personalised medicine in the future.
Evaluation of a cluster-randomized controlled trial: Communities for Healthy Living, family-centered obesity prevention program for Head Start parents and children
Authors: Gago Cristina , Aftosmes-Tobio Alyssa , Beckerman-Hsu Jacob P. , Oddleifson Carly , Garcia Evelin A. , Lansburg Kindra , Figueroa Roger , Yu Xinting , Kitos Nicole , Torrico Merieka , Leonard Jessie , Jurkowski Janine K. , Mattei Josiemer , Kenney Erica L. , Haneuse Sebastien , Davison Kirsten K.
Published: January 2023

Background

This study reports the outcomes of Communities for Healthy Living (CHL), a cluster randomized obesity prevention trial implemented in partnership with Head Start, a federally-funded preschool program for low-income families.

Methods

Using a stepped wedge design, Head Start programs (n = 16; Boston, MA, USA) were randomly assigned to one of three intervention start times. CHL involved a media campaign and enhanced nutrition support. Parents were invited to join Parents Connect for Healthy Living (PConnect), a 10-week wellness program. At the beginning and end of each school year (2017-2019), data were collected on the primary outcome of child Body Mass Index z-score (BMIz) and modified BMIz, and secondary outcomes of child weight-related behaviors (diet, physical activity, sleep, media use) and parents’ weight-related parenting practices and empowerment. Data from 2 years, rather than three, were utilized to evaluate CHL due to the COVID-19 pandemic. We used mixed effects linear regression to compare relative differences during intervention vs. control periods (n = 1274 vs. 2476 children) in (1) mean change in child BMIz and modified BMIz, (2) the odds of meeting child health behavior recommendations, (3) mean change in parenting practices, and (4) mean change in parent empowerment. We also compared outcomes among parents who chose post-randomization to participate in PConnect vs. not (n = 55 vs. 443).

Results

During intervention periods (vs. control), children experienced greater increases in BMIz and modified BMIz (b = 0.06, 95% CI = 0.02,0.10;b = 0.07, 95% CI = 0.03, 0.12), yet were more likely to meet recommendations related to three of eight measured behaviors: sugar-sweetened beverage consumption (i.e., rarely consume; Odds Ratio (OR) = 1.5, 95% CI = 1.2,2.3), water consumption (i.e., multiple times per day; OR = 1.6, 95% CI = 1.2,2.3), and screen time (i.e., ≤1 hour/day; OR = 1.4, 95% CI = 1.0,1.8). No statistically significant differences for intervention (vs. control) periods were observed in parent empowerment or parenting practices. However, parents who enrolled in PConnect (vs. not) demonstrated greater increases in empowerment (b = 0.17, 95% CI = 0.04,0.31).

Conclusions

Interventions that emphasize parent engagement may increase parental empowerment. Intervention exposure was associated with statistically, but not clinically, significant increases in BMIz and increased odds of meeting recommendations for three child behaviors; premature trial suspension may explain mixed results.

Trial registration

ClinicalTrials.gov,NCT03334669, Registered October 2017.
Elevated neurofilament light chain CSF/serum ratio indicates impaired CSF outflow in idiopathic intracranial hypertension
Authors: Engel Sinah , Halcour Johannes , Ellwardt Erik , Uphaus Timo , Steffen Falk , Zipp Frauke , Bittner Stefan , Luessi Felix
Published: January 2023

Background

Impaired cerebrospinal fluid (CSF) homeostasis is central to the pathogenesis of idiopathic intracranial hypertension (IIH), although the precise mechanisms involved are still not completely understood. The aim of the current study was to assess the CSF/serum ratio of neurofilament light chain levels (QNfL) as a potential indicator of functional CSF outflow obstruction in IIH patients.

Methods

NfL levels were measured by single molecule array in CSF and serum samples of 87 IIH patients and in three control groups, consisting of 52 multiple sclerosis (MS) patients with an acute relapse, 21 patients with an axonal polyneuropathy (PNP), and 41 neurologically healthy controls (HC). QNfL was calculated as the ratio of CSF and serum NfL levels. Similarly, we also assessed the CSF/serum ratio of glial fibrillary acidic protein (QGFAP) levels to validate the QNfL data. Routine CSF parameters including the CSF/serum albumin ratio (QAlb) were determined in all groups. Lumbar puncture opening pressure of IIH patients was measured by manometry.

Results

CSF-NfL levels (r = 0.29, p = 0.008) and QNfL (0.40, p = 0.0009), but not serum NfL (S-NfL) levels, were associated with lumbar puncture opening pressure in IIH patients. CSF-NfL levels were increased in IIH patients, MS patients, and PNP patients, whereas sNfL levels were normal in IIH, but elevated in MS and PNP. Remarkably, QNfL (p < 0.0001) as well as QGFAP (p < 0.01) were only increased in IIH patients. QNfL was positively correlated with CSF-NfL levels (r = 0.51, p = 0.0012) and negatively correlated with S-NfL levels (r = − 0.51, p = 0.0012) in HC, while it was only positively associated with CSF-NfL levels in IIH patients (r = 0.71, p < 0.0001). An increase in blood-CSF barrier permeability assessed by QAlb did not lead to a decrease in QNfL in any cohort.

Conclusions

The observed elevation of QNfL in IIH patients, which was associated with lumbar puncture opening pressure, indicates a reduced NfL transition from the CSF to serum compartment. This supports the hypothesis of a pressure-dependent CSF outflow obstruction to be critically involved in IIH pathogenesis.
Geometric and dosimetric consequences of intra-fractional movement in single isocenter non-coplanar stereotactic radiosurgery
Authors: Fung Nelson Tsz Cheong , Wong Wai Lung , Lee Michael Chi Hang , Cheung Elki Sze Nga , Wu Philip Yuguang
Published: January 2023

Purpose

To investigate the geometric and dosimetric impacts of intra-fractional movement for patients with single or multiple brain metastasis treated using Varian Hyperarc™ mono-isocentric radiosurgery.

Methods

A total of 50 single or hypo-fractionated Hyperarc™ treatment courses (118 lesions) were included in the analysis. Intra-fractional translational and rotational movements were quantified according to the post-treatment cone-beam CT (CBCT). Geometric displacements of all targets were calculated individually based on the assessed head movement in each treatment fraction and their relationships with treatment time and target-to-isocenter distances were studied. For dosimetric analysis, only single-fraction treatments (56 lesions) were included. Re-planning was performed with 0, 1, and 2 mm planning target volume (PTV) margins. Doses were then re-calculated on rotated CT images with isocenter shifted which emulate the change in patient treatment position. Target coverage, target and normal brain doses before and after intra-fractional movement were compared.

Results

The mean 3D target displacements was 0.6 ± 0.3 (SD) mm. Target shifts for patients treated within 10 min were significantly smaller than those treated in longer sessions. No correlation was found between target shift and target-to-isocenter distance as the origin of head rotation was not located at the isocenter. Loss of target coverage and minimum Gross Tumor Volume (GTV) dose due to intra-fractional movement were apparent only when no margin was used, leading to an extra 23% of the targets violating the dose acceptance criteria, in contrast, the effects on normal brain V12Gy were negligible regardless of the margin used. The use of 1 mm PTV margin can compensate clinically significant geographical miss caused by intra-fractional movements while limiting V12Gy to within dose criteria for 88% of the cases. The plan acceptance rate (fulfillment of both target and normal brain dose criteria) after intra-fractional movement was also the highest with the 1 mm margin.

Conclusion

Although intra-fractional movements during Hyperarc™ treatments were small, there were substantial dosimetric effects due to the sharp dose fall-off near target boundaries. These effects could be mitigated by using a 1 mm PTV margin and maintaining the effective treatment time to within 10 min.