bluuebunny/crossref_metadata_2025 huggingface dataset:
Roots fuel cell produces and stores clean energy
Authors: Shlosberg Yaniv , Huang Ailun , Tóth Tünde N. , Kaner Richard B.
Published: September 2022

In recent years, extensive scientific efforts have been conducted to develop clean bio-energy technologies. A promising approach that has been under development for more than a hundred years is the microbial fuel cell (MFC) which utilizes exo-electrogenic bacteria as an electron source in a bio-electrochemical cell. The viability of bacteria in soil MFCs can be maintained by integrating plant roots which release organic materials that feed the bacteria. In this work, we show that rather than organic compounds, roots also release redox species that can produce electricity in a bio-fuel cell. We first study the reduction of the electron acceptor Cytochrome C by green onion roots. We integrate green onion roots into a bio-fuel cell to produce a continuous bias-free electric current for more than 24 h in the dark. This current is enhanced upon irradiation of light on the onion’s leaves. We apply cyclic voltammetry and 2D-fluorescence measurements to show that NADH and NADPH act as major electron mediators between the roots and the anode, while their concentration in the external root matrix is increased upon irradiation of the leaves. Finally, we show that roots can contribute to energy storage by charging a supercapacitor.
Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1 (DMT1): Preclinical Efficacy Against Iron Overload and Safety Evaluation
Authors: Cutts Alison , Chowdhury Sultan , Ratkay Laszlo G , Eyers Maryanne , Young Clint , Namdari Rostam , Cadieux Jay A , Chahal Navjot , Grimwood Michael , Zhang Zaihui , Lin Sophia , Tietjen Ian , Xie Zhiwei , Robinette Lee , Sojo Luis , Waldbrook Matthew , Hayden Michael , Mansour Tarek , Pimstone Simon , Goldberg Y. Paul , Webb Michael , Cohen Charles J.
Published: September 2022

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of non-heme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or β-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 (hDMT1) inhibitors. Dimeric constructs were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary iron uptake in both rats and pigs, yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiological function of DMT1.

SIGNIFICANCE STATEMENT

This report introduces methodology to develop potent, gut-restricted inhibitors of DMT1 and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.
Recovering birds and mammals across Europe continue to be negatively impacted by threats but benefit from conservation measures
Authors: Gray Claudia , McRae Louise , Deinet Stefanie , Ledger Sophie , Benham Charlotte , Burfield Ian J. , Eaton Mark , Scott-Gatty Kate , Puleston Hannah , Rutherford Claire , Staneva Anna , Schepers Frans , Freeman Robin
Published: September 2022

Even during ongoing global biodiversity losses and extinctions, numerous species have shown recoveries in terms of increased abundance and/or range extent. Understanding the mechanisms that contribute to, or limit, these recoveries is critical not just to ensure they continue, but to promote similar recoveries across broader ecosystems. Here, we explore the changes in abundance and range extent of selected 47 recovering species (24 mammals and 23 birds) in Europe using official data reported by EU Member States and supplemented using the Living Planet Index database. We investigate how the diversity of ongoing threats and conservation measures contribute to the likelihood and extent of recoveries. For birds, long-term recoveries were less likely among species impacted by a greater diversity of threats, although this may be mitigated by the diversity of conservation measures in place. Similarly, for mammals, populations with reported threats recovered less quickly while those with management actions in place recovered more quickly. To achieve the aims of the UN Decade on Restoration, we need to ensure, even for recovering species, that threats continue to be reduced and that conservation management actions are ongoing and effective.
Multiple climate change factors jointly increase the competitiveness of a C4 grass against its C3 competitor
Authors: Hsu Gen-Chang , Ke Po-Ju , Ho Chuan-Kai
Published: September 2022

C3 and C4 plants are the two major terrestrial plant groups that respond differently to temperature, water, and CO2. Although much research has focused on the individual effect of warming, water availability, and elevated CO2 on biomass production and competitive interactions between C3 and C4 plants, the joint effects of these factors remain underexplored. We grew naturally co-occurring C3 (Oplismenus composites) and C4 (Paspalum conjugatum) grass under three temperature warming scenarios (control, +2°C, and +4°C), two water supply intervals (normal 2 days vs. prolonged 7 days [drought]), and two CO2 concentrations (ambient 400 ppm vs. elevated 800 ppm) in growth chambers and measured their above- and below-ground dry biomass in monoculture and mixture to quantify their biomass performances and competitive responses. Warming and elevated CO2 together enhanced the above- and/or below-ground biomass of both C3 and C4 grass. Moreover, temperature, water, and CO2 interacted to increase the below-ground biomass of the C4 grass. Surprisingly, the C3 grass performed worse under interspecific competition (mixture biomass) relative to intraspecific competition (monoculture biomass) at elevated CO2 compared to ambient CO2, while the reverse is true for the C4 grass. Furthermore, the C4 grass was most competitive against the C3 grass under simultaneous 4°C warming, drought, and elevated CO2. Taken together, our results suggest that the competitive balance could potentially shift in favor of C4 plants under the projected temperature warming, increased drought frequencies, and rising atmospheric CO2, with an increase in C4 relative abundance in future plant communities.
Identification of a novel HASPIN inhibitor and its synergism with the PLK1 inhibitor
Authors: Kwon Eun-Ji , Mashelkar Karishma K. , Seo Juhee , Shin Yoonze , Sung Kisu , Jang Sung Chul , Cheon Sang Won , Lee Haeseung , Han Byung Woo , Lee Sang Kook , Jeong Lak Shin , Cha Hyuk-Jin
Published: September 2022

Background

HASPIN, a mitotic kinase for Histone H3, is a promising target for anti-cancer therapy. However, as HASPIN is an atypical kinase with low similarity to eukaryotic protein kinases, development of a HASPIN inhibitor from the conventional pharmacophore of kinase inhibitors would be technically challenging.

Methods

Chemical modifications of a cytotoxic 4’-thioadenosine analogue with high genotoxicity and multiple kinomescan profiles were performed to produce a novel non-genotoxic kinase inhibitor, LJ4827. The mode of action of this inhibitor with clear anti-cancer activity was inferred based on transcriptomic and chemical similarity to known drugs.

Results

The specificity and potency of LJ4827 as a HASPIN inhibitor were validated by in vitro kinase screening and subsequent X-ray crystallography. As predicted, LJ4827 treatment delayed mitosis by clear inhibition of the recruitment of Aurora B at the centromere in cancer cells, without a genotoxic response. Through transcriptome analysis of lung cancer patients, PLK1 was predicted as a druggable synergistic partner to complement HASPIN inhibition. Cotreatment with the PLK1 inhibitor BI2536 and LJ4827 led to pronounced cytotoxicity of lung cancers in vitro and in vivo.

Conclusion

Simultaneous inhibition of both HASPIN and PLK1 is a promising therapeutic strategy for lung cancers.
The locus coeruleus mediates behavioral flexibility
Authors: McBurney-Lin Jim , Yang Hongdian
Published: September 2022

Behavioral flexibility refers to the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that the activity of neurons in the locus coeruleus (LC) plays an important role in mediating behavioral flexibility. To test this hypothesis, we developed a novel context-dependent bilateral tactile detection task where mice responded to left and right whisker deflections in a rule-dependent manner and exhibited varying degrees of flexible switching behavior. Recording from optogenetically-tagged neurons in the LC during task performance revealed a prominent graded correlation between baseline LC activity and behavioral flexibility, where higher baseline activity following a rule change was associated with faster behavioral switching to the new rule. Increasing baseline LC activity with optogenetic activation improved task performance and accelerated task switching. Overall, our study provides strong evidence to demonstrate that LC activity mediates behavioral flexibility.
Gell: A GPU-powered 3D hybrid simulator for large-scale multicellular system
Authors: Du Jiayi , Zhou Yu , Jin Lihua , Sheng Ke
Published: September 2022

As a powerful but computationally intensive method, hybrid computational models study the dynamics of multicellular systems by evolving discrete cells in reacting and diffusing extracellular microenvironments. As the scale and complexity of studied biological systems continuously increase, the exploding computational cost starts to limit large-scale cell-based simulations. To facilitate the large-scale hybrid computational simulation and make it feasible on easily accessible computational devices, we develop a fast and memory-efficient open-source GPU-based hybrid computational modeling platform Gell (GPU Cell), for large-scale system modeling. We fully parallelize the simulations on GPU for high computational efficiency and propose a novel voxel sorting method to further accelerate the modeling of massive cell-cell mechanical interaction with negligible additional memory footprint. As a result, Gell efficiently handles simulations involving tens of millions of cells on a personal computer. We compare the performance of Gell with a state-of-the-art paralleled CPU-based simulator on a hanging droplet spheroid growth task and further demonstrate Gell with a ductal carcinoma in situ (DCIS) simulation. Gell affords ~150X acceleration over the paralleled CPU method with one-tenth of the memory requirement.

Author Summary

Numerical cell simulations provide indispensable insight into the cell-to-tumor tissue transition and help reduce biological experimental variables. However, the availability and practicality of large-scale cell simulation tools have been limited by high computational cost, slow performance, or proprietary. Recent developments in open-source simulation codes and GPU implementation have partially addressed the challenge. We further optimized the cell simulation platform for GPU implementation in this work. As a result, benchmark cell simulation experiments can be performed efficiently on a personal computer with a modern GPU. We made the platform open source to encourage community adoption and collective development.
New RDEB intermediate variant with in-frame partial exon skipping in FN III-like domain of type VII collagen
Authors: Evtushenko N.A. , Kubanov A.A. , Martynova A.A. , Kondratyev N.V. , Beilin A.K. , Karamova A.E. , Monchakovskaya E.S. , Azimov К.A. , Nefedova M.A. , Bozhanova N.G. , Zaklyazminskaya E.V. , Gurskaya N.G.
Published: September 2022

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a debilitating genodermatosis caused by pathogenic mutations in the COL7A1 gene, which induce absence or reduction in the number of anchoring fibrils. The severity of RDEB depends on the mutation type and localization, but many aspects of this dependence remain to be elucidated. Here, we report a novel variant of RDEB Intermediate in two unrelated patients. Their disease manifestation includes early skin and oral mucosa blistering and is associated with localized atrophic scarring. According to the exome and Sanger sequencing results, both investigated Probands are the carriers of complex heterozygosity in the COL7A1 gene with the same deletion in intron 19 of the COL7A1 gene. RT-PCR followed by sequence analysis revealed skipping of the part of exon19, as well as the rescue of the open reading frame (ORF) of COL7A1 in both Probands. We hypothesize that the mutation in the acceptor splice site leads to the activation of the cryptic donor splice site, resulting in the truncated but partially functional protein and the milder phenotype of intermediate RDEB. This rare type of mutation expands our understanding of RDEB etiology and invites further investigation.
Insights on neonatal mortality: differences between public and private health access at São Paulo city between 2012 and 2017
Authors: Beluzo Carlos Eduardo , Zaniboni Marcelo Zaccaro , Carvalho Tiago , Alves Luciana Correia
Published: September 2022

Under-five mortality is a survival measure that reflects the social, economic, and environmental conditions in which children live, including their health care, so they are reasonable measures to identify vulnerable populations. Infant Mortality, also a survival measure, refers to children dying before reaching the first year of life, and can also be disaggregated into events below 28 days, referred to as neonatal mortality, which currently concentrates the higher share of deaths. In 2020, more than 5 million under-five children died in the world, from which almost 50% occurred among newborns. The Sustainable Development Goals call for an end to preventable deaths of newborns and children under-five, but considering the current trends, many countries are not on track to achieve it. Neonatal mortality involves various biological, socioeconomic, and healthcare factors, and understanding its determinants can favor public policy funding planning and help with this problem. The increasing relevance of neonatal deaths aside from online platforms that make available health data in Brazil has enabled more precise analyses and led to a significant number of studies covering different factors, regions, and methods regarding this issue. Among the various determinants, access to private health services is an important one. In Brazil, mainly due to financial restrictions, a huge percentage of the population uses only public health services. In this context, the objective of this paper is to perform an evaluation of the NMR in the city of São Paulo - Brazil, in the period between 2012 and 2017, considering as a determinant for neonatal mortality rate if the delivery has occurred on private or on public health service sphere. Besides that, the determinant mother’s age is also included in the analysis, so it is also possible to evaluate associations between these two variables. A dataset having 8,110 neonatal deaths was analyzed and three graphics were created. The first one is used to assess information regarding the distribution of births by health service sphere and mother’s age. The second brings information on births and neonatal mortality rates combined and compared by year and by health service sphere. Finally, in the last one births and rates are also combined and compared by year, health service sphere, but now are desegregated by mother’s age group. From these results, some insights are raised and discussed, and some need further investigation to obtain more conclusive results, but the currents can already bring important knowledge about the problem.
Amygdala subdivisions exhibit aberrant whole-brain functional connectivity in relation to stress intolerance and psychotic symptoms in 22q11.2DS
Authors: Delavari Farnaz , Rafi Halima , Sandini Corrado , Murray Ryan , Latrech Caren , Van De Ville Dimitri , Eliez Stephan
Published: September 2022

The amygdala is a key region in emotional regulation, which is often impaired in psychosis. However, it is unclear if amygdala dysfunction directly contributes to psychosis, or whether it contributes to psychosis through symptoms of emotional dysregulation. We studied the functional connectivity of amygdala subdivisions in patients with 22q11.2DS, a known genetic model for psychosis susceptibility. We investigated how dysmaturation of each subdivision’s connectivity contributes to positive psychotic symptoms and impaired tolerance to stress in deletion carriers.

Longitudinally-repeated MRI scans from 105 patients with 22q11.2DS (64 at high-risk for psychosis and 37 with impaired tolerance to stress) and 120 healthy controls between the ages of 5 to 30 years were included. We calculated seed-based whole-brain functional connectivity for amygdalar subdivisions and employed a longitudinal multivariate approach to evaluate the developmental trajectory of functional connectivity across groups.

Patients with 22q11.2DS presented a multivariate pattern of decreased basolateral amygdala (BLA)-frontal connectivity alongside increased BLA-hippocampal connectivity. Moreover, associations between developmental drops in centro-medial amygdala (CMA)-frontal connectivity to both impaired tolerance to stress and positive psychotic symptoms in deletion carriers were detected. SFA hyperconnectivity to the striatum was revealed as a specific pattern arising in patients who develop mild to moderate positive psychotic symptoms.

Overall, CMA-frontal dysconnectivity was found as a mutual neurobiological substrate in both impaired tolerance to stress and psychosis, suggesting a role in prodromal dysregulation of emotions in psychosis. While BLA dysconnectivity was presented as an early finding in patients with 22q11.2DS, contributing to impaired tolerance to stress.
Changes in Manual Therapy Techniques from the Perspective of Physical Therapists
Authors: Rojas Nelson A. , Jones Krista M. , Goetz Tami , Prashad Shikha
Published: September 2022

Objective

Prior research has focused on comparing the effects of manual therapy techniques used in physical therapy in different conditions to determine which technique is more effective and less invasive for the patient. However, no focus has been placed on identifying and evaluating the changes in manual therapy techniques. This study aims to evaluate the changes in manual therapy techniques from the perspective of current and retired physical therapists who are or were licensed in Washington state.

Methods

Eighteen participants completed a modified Physical Therapy Profile Questionnaire (PTPQ) to explore their experience with manual therapy techniques and whether they implemented changes in their practice of these techniques.

Results

The results suggest that changes in manual therapy techniques occur as physical therapists gain and develop more experience working with many clients and treating different conditions. Joint mobilization, taping, and muscle energy techniques were the most used and recommended manual therapy techniques by physical therapists in this sample. There was no significant correlation between the years of practice and the number of manual therapy techniques selected by participants (r = -0.044, p = 0.887).

Conclusions

This study suggests that changes and adjustments in manual therapy techniques have occurred throughout time as physical therapists gain practice in the field and can identify what manual technique will produce a better patient outcome in a specific patient.

Impact Statement

This study examined how the use of manual therapy techniques has evolved in field of the physical therapy and the factors that contribute to these changes.
Cumulative Febrile, Respiratory, and Diarrheal Illness among Infants in Rural Guatemala and their Association with Neurodevelopmental and Growth Outcomes
Authors: Olson Daniel , Lamb Molly M. , Connery Amy K. , Colbert Alison M. , Calvimontes Mirella , Bauer Desiree , Paniagua-Avila M. Alejandra , Martínez María Alejandra , Arroyave Paola , Hernandez Sara , Colborn Kathryn L. , Roell Yannik , Waggoner Jesse J. , Natrajan Muktha S. , Anderson Evan J. , Bolaños Guillermo A. , El Sahly Hana M. , Munoz Flor M. , Asturias Edwin J.
Published: September 2022

Objective

We aimed to evaluate the association between cumulative illness with neurodevelopment and growth outcomes in a birth cohort of Guatemalan infants.

Study Design

From June 2017 to July 2018, infants 0-3 months of age living in a resource-limited region of rural southwest Guatemala were enrolled and completed weekly at-home surveillance for caregiver-reported cough, fever and vomiting/diarrhea. They also underwent anthropometric assessments and neurodevelopmental testing with the Mullen Scales of Early Learning (MSEL) at enrollment, six months, and one year.

Results

Out of 499 enrolled infants, 430 (86.2%) completed all study procedures and were included in the analysis. At 12-15 months of age, 140 (32.6%) infants had stunting (length-for-age Z [LAZ] score <-2 SD) and 72 (16.7%) had microcephaly (occipital-frontal circumference [OFC] <-2 SD of the mean). In multivariable analysis, greater cumulative weeks of reported cough illness (beta=-0.08/illness-week, p=0.06) and febrile illness (beta=-0.36/illness-week, p<0.001) were marginally or significantly associated with lower MSEL Early Learning Composite (ELC) Score at 12-15 months, respectively; there was no association with any illness (cough, fever, and/or vomiting/diarrhea; p=0.27) or with cumulative weeks of diarrheal/vomiting illness alone (p=0.66). No association was shown between cumulative weeks of illness and stunting or microcephaly at 12-15 months.

Conclusions

These findings highlight the negative cumulative consequences of frequent febrile and respiratory illness on neurodevelopment during infancy. Future studies should explore the inflammatory profile associated with these syndromic illnesses and their impact on neurodevelopment in the first years of life.
The future of computational pathology: expectations regarding the anticipated role of artificial intelligence in pathology by 2030
Authors: Berbís M Alvaro , McClintock David S. , Bychkov Andrey , Cheng Jerome Y , Delahunt Brett , Egevad Lars , Eloy Catarina , Farris Alton B , Fraggetta Filippo , García del Moral Raimundo , Hartman Douglas J. , Herrmann Markus D , Hollemans Eva , Iczkowski Kenneth A , Karsan Aly , Kriegsmann Mark , Lennerz Jochen K , Pantanowitz Liron , Salama Mohamed E. , Sinard John , Tuthill Mark , Van der Laak Jeroen , Williams Bethany , Casado-Sánchez César , Sánchez-Turrión Víctor , Luna Antonio , Aneiros-Fernández José , Shen Jeanne
Published: September 2022

Background

Artificial intelligence (AI) is rapidly fueling a fundamental transformation in the practice of pathology. However, AI’s clinical integration remains challenging, with no AI algorithms to date enjoying routine adoption within typical anatomic pathology (AP) laboratories. This survey gathered current expert perspectives and expectations regarding the role of AI in AP from those with first-hand computational pathology and AI experience.

Methods

Perspectives were solicited using the Delphi method from 24 subject matter experts between December 2020 and February 2021 regarding the anticipated role of AI in pathology by the year 2030. The study consisted of three consecutive rounds: 1) an open-ended, free response questionnaire generating a list of survey items; 2) a Likert-scale survey scored by experts and analyzed for consensus; and 3) a repeat survey of items not reaching consensus to obtain further expert consensus.

Findings

Consensus opinions were reached on 141 of 180 survey items (78.3%). Experts agreed that AI would be routinely and impactfully used within AP laboratory and pathologist clinical workflows by 2030. High consensus was reached on 100 items across nine categories encompassing the impact of AI on (1) pathology key performance indicators (KPIs) and (2) the pathology workforce and specific tasks performed by (3) pathologists and (4) AP lab technicians, as well as (5) specific AI applications and their likelihood of routine use by 2030, (6) AI’s role in integrated diagnostics, (7) pathology tasks likely to be fully automated using AI, and (8) regulatory/legal and (9) ethical aspects of AI integration in pathology.

Interpretation

This is the first systematic consensus study detailing the expected short/mid-term impact of AI on pathology practice. These findings provide timely and relevant information regarding future care delivery in pathology and raise key practical, ethical, and legal challenges that must be addressed prior to AI’s successful clinical implementation.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Real-world genetic screening with molecular ancestry supports comprehensive pan-ethnic carrier screening
Authors: Shewcraft Ryan A. , Higashi Mitchell K. , Zhang Yeting , Tyler Jonathan , Lau Lisa Y. , Webb Bryn D. , Lee Seungwoo , Ramasamudram-Chakravarthi Rajasekar , Cacchione Teresa A. , Copperman Alan B. , Birch Ashley , Francis Marra , Shi Lisong , Edelmann Lisa , Chen Rong , Li Li , Schadt Eric
Published: September 2022

We characterize the clinical utility and economic benefits of a comprehensive pan-ethnic carrier screening panel that spans 282 monogenic disease conditions in a large, diverse population of 397,540 reproductive health patients. For 142,049 of these patients, we were able to accurately estimate genetic ancestries across 7 major population groups. We examined individual carrier and at-risk carrier couple (ARCC) rates with respect to self-reported and genetic ancestries across ancestry-specific and pan-ethnic panels. Our results show that this comprehensive panel identified >10-times the ARCCs compared with a two-gene pan-ethnic panel and provided a substantial benefit over ancestry-specific screening panels across the major population groups. Finally, we generated a universal cost-of-care model across the monogenic disease conditions represented on the comprehensive pan-ethnic carrier screening panel to demonstrate potential healthcare savings in addition to the demonstrated clinical benefits that could be realized adopting this type of panel as standard of care for all.
Prevalence of multimorbidity in migrants, refugees, asylum seekers and displaced persons and association with mortality: A systematic review protocol
Authors: Abrahamsson A , Rozalen Gonzalez A , Nicholl BI , O’Donnell CA , Mair FS
Published: September 2022

Background

Multimorbidity is the presence of two or more physical and/or mental long-term health conditions and is associated with aging, but also with socio-economic deprivation. Immigration status contributes to socio-economic deprivation, potentially increasing prevalence of multimorbidity. Prevalence of multimorbidity in different migrant populations, such as asylum seekers, refugees and displaced persons, and its effect on mortality is poorly understood and no systematic review on the topic exists to date.

Objective

To assess what is known about the prevalence of multimorbidity in refugees, asylum seekers, migrants and displaced persons and about the association, if any, between multimorbidity and mortality in these populations.

Design

Systematic review of the literature. The following electronic medical databases will be searched: MEDLINE, Embase, Scopus, CINAHL and The Cochrane Library. A narrative synthesis of findings will be undertaken, and meta-analysis considered if appropriate. Title, abstract and full paper screening will be undertaken independently by two reviewers. Studies will be limited to English and Spanish language and publication date from 2000 onward. The Newcastle-Ottawa Scale for Cohort Studies will be used as a quality assessment tool. This protocol adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) 2020 guidelines.

Conclusion

Understanding the prevalence of multimorbidity amongst refugees, migrants, asylum seekers and displaced persons, and its association with mortality will provide valuable insights to inform practice and policy responses to increasing global migration.
Metagenomic next-generation sequencing to characterize etiologies of non-malarial fever in a cohort living in a high malaria burden area of Uganda
Authors: Mwakibete Lusajo , Takahashi Saki , Ahyong Vida , Black Allison , Rek John , Ssewanyana Isaac , Kamya Moses , Dorsey Grant , Jagannathan Prasanna , Rodríguez-Barraquer Isabel , Tato Cristina M. , Greenhouse Bryan
Published: September 2022

Background

Causes of non-malarial fevers in sub-Saharan Africa remain understudied. We hypothesized that metagenomic next-generation sequencing (mNGS), which allows for broad genomic-level detection of infectious agents in a biological sample, can systematically identify potential causes of non-malarial fevers.

Methods and Findings

The 212 participants in this study were of all ages and were enrolled in a longitudinal malaria cohort in eastern Uganda. Between December 2020 and August 2021, respiratory swabs and plasma samples were collected at 313 study visits where participants presented with fever and were negative for malaria by microscopy. Samples were analyzed using CZ ID, a web-based platform for microbial detection in mNGS data. Overall, viral pathogens were detected at 123 of 313 visits (39%). SARS-CoV-2 was detected at 11 visits, from which full viral genomes were recovered from nine. Other prevalent viruses included Influenza A (14 visits), RSV (12 visits), and three of the four strains of seasonal coronaviruses (6 visits). Notably, 11 influenza cases occurred between May and July 2021, coinciding with when the Delta variant of SARS-CoV-2 was circulating in this population. The primary limitation of this study is that we were unable to estimate the contribution of bacterial microbes to non-malarial fevers, due to the difficulty of distinguishing bacterial microbes that were pathogenic from those that were commensal or contaminants.

Conclusions

These results revealed the co-circulation of multiple viral pathogens likely associated with fever in the cohort during this time period. This study illustrates the utility of mNGS in elucidating the multiple causes of non-malarial febrile illness. A better understanding of the pathogen landscape in different settings and age groups could aid in informing diagnostics, case management, and public health surveillance systems.
Spatial determination of COVID-19 mortality
Authors: Arun GC
Published: September 2022

COVID-19 has affected at the global scale. However, its impacts are not evenly distributed. The article aims to explore the spatial determination of the COVID-19 related death. The data for the analysis has been accessed from the World Health Organization (WHO). Both descriptive and statistical analysis has been done to assess the COVID-19 related death and spatial explanation. The regression models suggested the explanatory power of spatial difference in the COVID-19 related death. However, further addition of various COVID-19 vaccine did not produce expected result.
Neurodoron® in patients with neurasthenia – A randomized, double-blind, placebo-controlled clinical trial
Authors: Hellhammer Juliane , Spitznagel-Schminke Luitgard , Semaca Cristina , Hufnagel Rebecca
Published: September 2022

1

Introduction

The term neurasthenia has been introduced in the late 19th century. Stress was indicated as one of the main triggers. Many treatment options are available to reduce the associated symptoms. Complementary and alternative medicine (CAM) is widely used due to its long tradition and positive safety profile. This Phase IV placebo-controlled clinical trial was designed to demonstrate efficacy and safety of the CAM-product Neurodoron® in patients with neurasthenia.

Methods

This monocentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted in a dedicated outpatient German trial site. Women and men aged 18 and above were randomized to receive either Neurodoron® or matching placebo if they reported typical symptoms of neurasthenia and a severe psychiatric disorder could be excluded. The primary objectives were a reduction in characteristic symptoms of nervous exhaustion and perceived stress as well as improvement in general health status after 6 weeks of treatment.

Results

204 patients underwent screening, 78 were randomized in each treatment group, and 77 patients each received treatment (intention-to-treat (ITT) population = 154 patients). For none of the primary efficacy variables, an advantage in favor of Neurodoron® could be demonstrated in the pre-specified analysis (p-values between 0.505 to 0.773, Student’s t-test). In a post-hoc analysis of intra-individual differences after 6 weeks treatment, a significant advantage of Neurodoron® vs. placebo was shown for characteristic symptoms of nervous exhaustion (irritability (p = 0.020); nervousness (p = 0.045), Student’s t-test). Adverse Event (AE) rates were similar between treatment groups, in both groups 6 AEs were assessed as causally related to treatment (severity mild or moderate). No AE resulted in discontinuation of treatment.

Conclusion

A significant improvement of neurasthenia was seen for the total study population at the end of the treatment period. Superiority of Neurodoron® vs. placebo could not be demonstrated with the pre-specified analysis. However, the post-hoc analysis suggests Neurodoron® as a beneficial option over placebo for the treatment of neurasthenia, especially given its confirmed markedly good safety.
Machine learning in the identification of prognostic DNA methylation biomarkers among patients with cancer: a systematic review of epigenome-wide studies
Authors: Yuan Tanwei , Edelmann Dominic , Fan Ziwen , Alwers Elizabeth , Kather Jakob Nikolas , Brenner Hermann , Hoffmeister Michael
Published: September 2022

Background

DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques might help overcome the challenges of analyzing high-dimensional data in relatively small sample sizes. This systematic review summarizes the current use of ML-based methods in epigenome-wide studies for the identification of DNA methylation signatures associated with cancer prognosis.

Methods

We searched three electronic databases including PubMed, EMBASE, and Web of Science for articles published until 8 June 2022. ML-based methods and workflows used to identify DNA methylation signatures associated with cancer prognosis were extracted and summarized. Two authors independently assessed the methodological quality of included studies by a seven-item checklist adapted from relevant guidelines.

Results

Seventy-six studies were included in this review. Three major types of ML-based workflows were identified: 1) unsupervised clustering, 2) supervised feature selection, and 3) deep learning-based feature transformation. For the three workflows, the most frequently used ML techniques were consensus clustering, least absolute shrinkage and selection operator (LASSO), and autoencoder, respectively. The systematic review revealed that the performance of these approaches has not been adequately evaluated yet and that methodological and reporting flaws were common in the identified studies using ML techniques.

Conclusions

There is great heterogeneity in ML-based methodological strategies used by epigenome-wide studies to identify DNA methylation markers associated with cancer prognosis. Benchmarking studies are needed to compare the relative performance of various approaches for specific cancer types. Adherence to relevant methodological and reporting guidelines is urgently needed.
Factors associated with viral load suppression and indicators of stigma among people living with HIV in Dar es Salaam tertiary hospitals, Tanzania
Authors: Kilapilo Mary Spicar , Mosha Idda Hubert , Bwire George Msema , Sambayi Godfrey Leonard , Sangeda Raphael Zozimus , Killewo Japhet
Published: September 2022

Perception of stigma can contribute to virological failure among people living with HIV (PLHIV). This study was conducted to assess the effect of stigmatization and self-discrimination on viral load suppression among PLHIV at tertiary hospitals in Dar es Salaam, Tanzania. This was a hospital-based cross-sectional study conducted in Temeke Regional Referral Hospital (RRH) and Amana RRH at the Care and Treatment Clinic (CTC) between July and August 2020 using a structured questionnaire with open and close-ended questions. Factors for stigmatization and viral load suppression were compared using the Chi-square test, while factors for viral load suppression were analyzed using multinomial logistic regression analysis. Altogether, 406 PLHIV participated, with most female respondents, 298 (73.2%). The majority (50%) were aged between 25 and 44 years, whereas 171 (42.5%) respondents were married. Most of the participants, 382 (94.6%), were on a dolutegravir-based regimen, with the majority, 215 (52.8%), having a refilling interval of three months. The majority of the respondents, 379 (93.1%), disclosed their status. Most participants, 355 (87.4%), preferred having a separate HIV clinic, while 130 (32.1%) participants were not ready to be attended by the health care workers (HCWs) familiar to them. Male patients were 60% less likely to suppress their viral load as compared to female patients (adjusted odds ratio [aOR]: 0.4, 95% confidence interval [95%]: 0.19 – 0.77, p = 0.007). Refill interval was significantly associated with viral load suppression. For example, patients with a one-month refill interval had odds of 0.01 (95% CI: 0.003-0.42, p < 0.0001) compared to six-month refill intervals. Stigmatization elements appeared to influence the viral load suppression among PLHIV. Factors such as gender and refill time interval were significantly associated with viral load suppression among HIV patients in the Dar es Salaam region.
Performance Characteristics of Six Immunoglobulin M (IgM) ELISA Assays Used for Laboratory Confirmation of Measles
Authors: Sowers Sun B. , Anthony Kiana , Mercader Sara , Colley Heather , Crooke Stephen N. , Rota Paul A. , Latner Donald R. , Hickman Carole J.
Published: September 2022

Laboratory confirmation of infection is an essential component of measles surveillance. Detection of measles specific IgM in serum by enzyme linked immunosorbent assay (ELISA) is the most used method for confirming measles infection. ELISA formats vary as does the sensitivity and specificity of each assay. Specimens collected within 3 days of rash onset can yield a false negative result, which can delay confirmation of measles cases. Interfering substances can yield a false positive result, leading to unnecessary public health interventions. The IgM capture assay developed at the Centers for Disease Control (CDC) was compared against 5 commercially available ELISA kits for the ability to detect measles virus-specific IgM in a panel of 90 well-characterized specimens. Serum samples were tested in triplicate using each commercial kit as recommended by the manufacturer. Using the CDC measles IgM capture assay as the reference test; sensitivity and specificity for the commercial kits ranged from 50 to 83% and 86.9 to 98%, respectively. Discrepant results were observed for samples tested with all five commercial kits and ranged from 13.8 to 28.8% of the specimens tested. False positive results occurred in 2.0 to 13.1% of sera while negative results were observed in 16.7 to 50% of sera that were positive by the CDC measles IgM capture assay. Evaluation and interpretation of measles IgM serologic results can be complex, particularly in measles elimination settings. The performance characteristics of a measles IgM assay should be carefully considered when selecting an assay to achieve high quality measles surveillance.
Fine Motor Skill Decline after Brain RT – A Multivariate Normal Tissue Complication Probability Study of a Prospective Trial
Authors: Connor Michael , Salans Mia , Karunamuni Roshan , Unnikrishnan Soumya , Huynh-Le Minh-Phuong , Tibbs Michelle , Qian Alexander , Reyes Anny , Stasenko Alena , McDonald Carrie , Moiseenko Vitali , El-Naqa Issam , Hattangadi-Gluth Jona
Published: September 2022

Purpose

Brain radiotherapy can impair fine motor skills (FMS). FMS are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for decline in FMS after fractionated brain RT.

Methods

On a prospective trial, 44 primary brain tumor patients received fractioned RT, underwent high-resolution volumetric MRI and diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], and Grooved Pegboard Dominant/Non-Dominant Hands [PDH/PNDH]) at baseline and 6 months post-RT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, and white matter tracts) were autosegmented using validated methods and manually verified. Dosimetric and clinical variables were included in multivariate NTCP models, using automated bootstrapped logistic regression, least absolute shrinkage and selection operator (LASSO) logistic regression, and random forests with nested cross-validation.

Results

Half of patients showed decline on PNDH, 17 of 42 (40.4%) on PDH, and 11 of 44 (25%) on DKEFS-TM. Automated bootstrapped logistic regression selected a one-term model including maximum dose to dominant postcentral white matter. LASSO selected this term and steroid use. The top five variables in random forest were all dosimetric: mean and maximum dose to dominant corticospinal tract; maximum dose to dominant thalamus; mean dose to dominant caudate; maximum dose to dominant postcentral white matter. This technique performed best with AUC 0.69 (95% CI 0.68 – 0.70) on nested cross-validation.

Conclusion

We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated ROIs correlated with decline in dominant hand fine motor dexterity in primary brain tumor patients, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT.
Principled distillation of multidimensional UK Biobank data reveals insights into the correlated human phenome
Authors: Carey Caitlin E. , Shafee Rebecca , Elliott Amanda , Palmer Duncan S. , Compitello John , Kanai Masahiro , Abbott Liam , Schultz Patrick , Karczewski Konrad J. , Bryant Samuel C. , Cusick Caroline M. , Churchhouse Claire , Howrigan Daniel P. , King Daniel , Smith George Davey , Wedow Robbee , Neale Benjamin M. , Walters Raymond K. , Robinson Elise B.
Published: September 2022

Broad yet detailed data collected in biobanks captures variation reflective of human health and behavior, but insights are hard to extract given their complexity and scale. In the largest factor analysis to date, we distill hundreds of medical record codes, physical assays, and survey items from UK Biobank into 35 understandable latent constructs. The identified factors recapitulate known disease classifications, highlight the relevance of psychiatric constructs, improve measurement of health-related behavior, and disentangle elements of socioeconomic status. We demonstrate the power of this principled data reduction approach to clarify genetic signal, enhance discovery, and identify associations between underlying phenotypic structure and health outcomes such as mortality. We emphasize the importance of considering the interwoven nature of the human phenome when evaluating large-scale patterns relevant to public health.
Segregation of dynamic resting-state reward, default mode and attentional networks after remitted patients transition into a recurrent depressive episode
Authors: Martinez Sonsoles Alonso , Tyborowska Anna , Ikani Nessa , Mocking Roel J. , Figueroa Caroline A. , Schene Aart H. , Deco Gustavo , Kringelbach Morten L. , Cabral Joana , Ruhé Henricus G.
Published: September 2022

Introduction

Recurrence in major depression disorder (MDD) is common, but neurobiological models capturing vulnerability for recurrences are scarce. Disturbances in multiple resting-state networks have been linked to MDD, but most approaches focus on stable (vs. dynamic) network characteristics. We investigated how the brain’s dynamical repertoire changes after patients transition from remission to recurrence of a new depressive episode.

Methods

Sixty drug-free, MDD-patients with ≥2 episodes underwent a baseline resting-state fMRI scan when in remission. Over 30-months follow-up, 11 patients with a recurrence and 17 matched-remitted MDD-patients without a recurrence underwent a second fMRI scan. Recurrent patterns of functional connectivity were characterized by applying leading eigenvector dynamics analysis (LEiDA). Differences between baseline and follow-up were identified for the 11 non-remitted patients, while data from the 17 matched-remitted patients was used as a validation dataset.

Results

After the transition into a depressive state, the reward and a visuo-attentional networks were detected significantly more often, whereas default mode network activity was found to have a longer duration. Additionally, the fMRI signal in the areas underlying the reward network were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). These changes were not observed in the matched-remitted patients who were scanned twice while in remission.

Conclusion

These findings characterize the changes that are specifically associated with the transition from remission to recurrence and provide first evidence of increased segregation in the brain’s dynamical repertoire when a recurrent depressive episode occurs.
Default Mode Network Hypoalignment of Function to Structure Correlates with Depression and Rumination
Authors: Thomas Paul J. , Leow Alex , Klumpp Heide , Phan K. Luan , Ajilore Olusola
Published: September 2022

Recent studies have begun to examine the extent to which signals in the brain correspond to the underlying white matter structure by using tools from the field of graph signal processing to quantify brain function ‘alignment’ to brain network topology. Here, we apply this framework for the first time towards a transdiagnostic cohort of internalizing psychopathologies, including mood and anxiety disorders, to uncover how such alignment within the default mode network (DMN) is related to depression and rumination symptoms. We found that signal alignment within the posterior DMN is greater in IP patients than healthy controls and is anticorrelated with baseline depression and rumination scales. Signal alignment within the posterior DMN was also found to correlate with the ratio of total within-DMN to extra-DMN functional connectivity for these regions. These findings are consistent with previous literature regarding pathologic promiscuity of posterior DMN connectivity and provide the first GSP-based analyses in a transdiagnostic IP cohort.