bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Functional Androgen Receptor Pathway Activity in Response to Radiotherapy Using hK2-targeted PET Imaging
Authors: Storey Claire M , Altai Mohamed , Bicak Mesude , Veach Darren R , Lückerath Katharina , Adrian Gabriel , McDevitt Michael R , Kalidindi Teja , Park Julie E , Herrmann Ken , Abou Diane , Zedan Wahed , Peekhaus Norbert , Klein Robert J , Damoiseaux Robert , Larson Steven M , Lilja Hans , Thorek Daniel , Ulmert David
Published: June 2022

External beam radiotherapy (EBRT) remains a common treatment for all stages of PCa, but DNA damage induced by EBRT upregulates androgen receptor (AR) pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied if [89Zr]11B6-PET can accurately assess EBRT-induced AR activity. PCa mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue. EBRT increased AR pathway activity in LNCaP-AR tumors. EBRT increased prostate-specific [89Zr]11B6 uptake and hK2 levels in PCa-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice. Thus, [89Zr]11B6-PET specifically detects activation of AR pathway activity after EBRT in PCa. Further clinical evaluation of hK2-PET for monitoring EBRT is warranted.
Reconstructing the functional effect ofTP53somatic mutations on its regulon using causal signalling network modelling
Authors: Triantafyllidis Charalampos P. , Barberis Alessandro , Cuervo Ana Miar , Gjerga Enio , Charlton Philip , Hartley Fiona , Van Bijsterveldt Linda , Rodriguez Julio Saez , Buffa Francesca M.
Published: June 2022

Abstract

The gene encoding tumor proteinp53(TP53) is the most frequently mutated gene in human cancer. Mutations in both coding and non-coding regions ofTP53can disrupt the regulatory function of the transcription factor, but the functional impact of different somatic mutations on the globalTP53regulon is complex and poorly understood. To address this, we first proceed with a machine learning (ML) approach, and then propose an integrated computational network modelling approach that reconstructs signalling networks using a comprehensive collection of experimental and predicted regulons, and compares their topology. We evaluate both these approaches in a scrutinized pan-cancer analysis of matched genomics and transcriptomics data from 1,457 cell lines (22 cancer types) and 12,531 clinical samples (54 cancer sub-types). Using a ML approach based on penalized generalized linear regression we were able to predictTP53mutation, but failed to resolve different mutation types. Thus, to infer the impact of differentTP53mutations we compared the topological characteristics of the optimized and reconstructed (upwards of twenty thousand) gene networks and extracted gene signatures for each mutation type using network analysis. We demonstrate that by accounting forTP53mutation characteristics such as i) mutation type (e.g. missense, nonsense), ii) deleterious consequences of the mutation, or iii) mapping to previously identified hotspots, we can infer a much richer understanding of gene expression regulation, than when simply grouping samples based on their mutation/wild type or gene expression status. Our study highlights a powerful strategy exploiting signalling networks to systematically characterize the functional impact of the full spectrum of somatic mutations. This approach can be applied in general to genetic variation, with clear implications for, but not limited to, the biomedical domain and precision medicine.
Insect cell plasma membranes do, while soluble enzymes do not, need stabilization by accumulated cryoprotectant molecules during freezing stress
Authors: Grgac Robert , Rozsypal Jan , Des Marteaux Lauren , Štětina Tomáš , Koštál Vladimír
Published: June 2022

Ability to survive freezing of extracellular body fluids evolved in several species of vertebrate ectotherms, many plants, and occurs relatively often in freeze-tolerant insects. Most of the multicellular organisms, however, are freeze-sensitive. Here we test coupled hypotheses postulating that: (i) irreversible denaturation of proteins and loss of integrity of biological membranes are two ultimate molecular mechanisms of freezing injury in freeze-sensitive insects; and (ii) seasonally accumulated small cryoprotective molecules (CPs) protect the proteins and membranes against the injury in freeze-tolerant insects. We show that seven different enzymes exhibit no or only partial loss of activity upon lethal freezing stress appliedin vivoto whole freeze-sensitive larva of drosophilid fly,Chymomyza costata. In contrast, the enzymes lost activity when extracted and frozenin vitroin a diluted buffer solution. This loss of activity was fully prevented by adding to buffer relatively low concentrations of a wide array of different compounds includingC. costatanative CPs, other metabolites, bovine serum albumin (BSA), and even biologically inert artificial compounds Histodenz and Ficoll. Next, we show that the plasma membranes of fat body cells lose integrity when frozenin vivoin freeze-sensitive but not in freeze-tolerant larvae. Freezing fat body cellsin vitro, however, resulted in loss of membrane integrity in both freeze-sensitive and freeze-tolerant larvae. Different additives showed widely different capacities (from none to high) to protect membrane integrity when added toin vitrofreezing medium. A complete rescue of membrane integrity was observed for a mixture of proline, trehalose and BSA.

Significance statement

Here we suggest that insect soluble enzymes are not primary targets of freezing injury. They are not inactivated in freeze-sensitive insects exposed to lethal freezing stress as they are sufficiently protected from loss of activity by complex composition of native biological solutions. Next we show that cell plasma membranes are likely targets of freezing injury. The membranes lose integrity in freeze-sensitive insects exposed to freezing stress, while their integrity is protected by accumulated small cryoprotective molecules, and also by proteins, in freeze-tolerant insects.
The Future is 2D: Spectral-Temporal Fitting of Dynamic Magnetic Resonance Spectroscopy Data Provides Exponential Gains in Precision Over Conventional Approaches
Authors: Tal Assaf
Published: June 2022

Abstract

Purpose

Many MRS paradigms produce 2D spectral-temporal datasets, including diffusion-weighted, functional, hyperpolarized and enriched (13C, 2H) experiments. Conventionally, temporal parameters – such as T2, T1, or diffusion constants – are assessed by first fitting each spectrum independently, and subsequently fitting a temporal model (1D fitting). We investigated whether simultaneously fitting the entire dataset using a single spectral-temporal model (2D fitting) would improve the precision of the relevant temporal parameter.

Methods

We derived a Cramer Rao Lower Bound for the temporal parameters for both 1D and 2D approaches, for two experiments: A multi-echo (MTE) experiment, designed to estimate metabolite T2s; And a functional (fMRS) experiment, designed to estimate fractional change (δ) in metabolite concentrations. We investigated the dependence of the relative standard deviation of T2 in MTE and δ in fMRS.

Results

When peaks were spectrally distant, 2D fitting improved precision by approximately 20% relative to 1D fitting, regardless of the experiment and other parameter values. These gains increased exponentially as peaks drew closer. Dependence on temporal model parameters was weak to negligible.

Conclusion

Our results strongly support a 2D approach to MRS fitting where applicable, and particularly in nuclei such as 1H and 2H, which exhibit substantial spectral overlap.
Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae
Authors: Allers Maaike , Bakker Petra A. , Spaink Herman P. , Hertog Jeroen den
Published: June 2022

PTPN6encodes SHP1, a protein tyrosine phosphatase that has an essential role in immune cell function. SHP1 missense and splice site mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in mice that lack functional SHP1 partially. Complete lack of SHP1 function in mousemotheatenmutants leads to severe defects and lethality at 2-6 weeks after birth. Here, we investigated the function of Shp1 in developing zebrafish embryos. We generated aptpn6knockout zebrafish line lacking functional Shp1. Zebrafish develop ex utero and are transparent, which facilitates analysis of the function of Shp1 during early hematopoietic development. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development the myeloid lineage was affected, which resulted in a decrease in the number of neutrophils, and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher inptpn6mutants than in siblings at 5 dpf. Finally, directional migration of neutrophils and macrophages was decreased in response to wounding and less macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impairs neutrophil and macrophage function and caused severe inflammation and lethality at the larval stage.
Acis-regulatory sequence of the wing selector gene,vestigial, drives the evolution of scaling relationships inDrosophilaspecies
Authors: Farfán-Pira Keity J. , Martínez-Cuevas Teresa I. , Evans Timothy A. , Nahmad Marcos
Published: June 2022

Scaling between specific organs and overall body size has long fascinated biologists because they are a primary mechanism through which organismal shapes evolve. Yet, the genetic mechanisms that underlie the evolution of allometries remain elusive. Here we measured wings and tibia lengths in fourDrosophilaspecies (D. melanogaster, D. simulans, D. ananassae, andD. virilis) and show that the first three of them follow a single evolutionary allometry. However,D. virilisexhibits a divergent wing-to-tibia allometry due to a dramatic underscaling of their wings with respect to their bodies compared to the other species. We asked whether the evolution of this scaling relationship could be explained by changes in a specificcis-regulatory regulatory region of the wing selector gene,vestigial(vg), whose function is broadly conserved in insects and its expression pattern determines wing size inD. melanogaster. To test this hypothesis directly, we used CRISPR/Cas9 to replace the DNA sequence of the predicted Quadrant Enhancer (vgQE) fromD. virilisfor the correspondingvgQEsequence in the genome ofD. melanogaster. Strikingly, we discovered thatD. melanogasterflies carrying theD. virilis vgQEsequence have wings that are much smaller with respect to controls, partially rescuing the wing-to-tibia ratio observed inD. virilis. Our results show that thiscis-regulatory element inD. viriliscontributes to the underscaling of wings in this species. This provides evidence that scaling relationships may be unconstrained and may evolve gradually through genetic variations incis-regulatory elements.

Summary statement

Using CRISPR/Cas9 replacement of acis-regulatory element, this study suggests that changes within thevestigialQuadrant Enhancer sequence are responsible for the evolution of wing allometries inDrosophilaspecies.
Neural circuits underlying habituation of visually evoked escape behaviors in larval zebrafish
Authors: Fotowat Haleh , Engert Florian
Published: June 2022

Larval zebrafish that are exposed repeatedly to dark looming stimuli will quickly habituate to these aversive signals and cease to respond with their stereotypical escape swims.

A dark looming stimulus can be separated into two independent components: one that is characterized by an overall spatial expansion, where overall luminance is maintained at the same level, and a second, that represents an overall dimming within the whole visual field in the absence of any motion energy. Using specific stimulation patterns that isolate these independent components, we first extracted the behavioral algorithms that dictate how these separate information channels interact with each other and across the two eyes during the habituation process. Concurrent brain wide imaging experiments then permitted the construction of circuit models that suggest the existence of three separate neural pathways. The first is a looming channel which responds specifically to concentrically expanding edges and relays that information to the brain stem escape network to generate directed escapes.

The second is a dimming specific channel that serves to support and amplify the looming pathway. While the looming channel operates in a purely monocular fashion where stimuli are relayed exclusively to the contralateral hemisphere, dimming responses are processed in both monocular and binocular pathways. Finally, we identify a third, separate and largely monocular, dimming channel that appears to specifically inhibit escape responses when activated. We propose that, unlike the first two channels, this third channel is under strong contextual modulation and that it is primarily responsible for the incremental silencing of successive dark looming evoked escapes.
Generation of functional hepatocytes by forward programming with nuclear receptors
Authors: Tomaz Rute A. , Zacharis Ekaterini D. , Bachinger Fabian , Wurmser Annabelle , Yamamoto Daniel , Petrus-Reurer Sandra , Morell Carola M. , Dziedzicka Dominika , Wesley Brandon T. , Geti Imbisaat , Segeritz Charis-Patricia , de Brito Miguel Cardoso , Chhatriwala Mariya , Ortmann Daniel , Saeb-Parsy Kourosh , Vallier Ludovic
Published: June 2022

Production of large quantities of hepatocytes remains a major challenge for a number of clinical applications in the biomedical field. Directed differentiation of human pluripotent stem cells (hPSC) into hepatocyte-like cells (HLCs) provides an advantageous solution and a number of protocols have been developed for this purpose. However, these methods usually follow different steps of liver development in vitro which is time consuming and requires complex culture conditions. In addition, HLCs lack the full repertoire of functionalities characterising primary hepatocytes. Here, we explore the interest of forward programming to generate hepatocytes from hPSCs and to bypass these limitations. This approach relies on the overexpression of 3 hepatocyte nuclear factors (HNF1A, HNF6 and FOXA3) in combination with different nuclear receptors expressed in the adult liver using the OPTi-OX platform. Forward programming allows for the rapid production of hepatocytes (FoP-Heps) with functional characteristics using a simplified process. We also uncovered that the overexpression of nuclear receptors such as RORc can enhance specific functionalities of FoP-Heps thereby validating its role in lipid/glucose metabolism. Together, our results show that forward programming could offer a versatile alternative to direct differentiation for generating hepatocytes in vitro.
The Vacc-SeqQC Project: Benchmarking RNA-Seq for Clinical Vaccine Studies
Authors: Goll Johannes B. , Bosinger Steven E. , Jensen Travis L. , Walum Hasse , Grimes Tyler , Tharp Gregory D. , Natrajan Muktha S , Blazevic Azra , Head Rich , Gelber Casey E. , Patel Nirav B. , Sanz Patrick , Rouphael Nadine G. , Anderson Evan J. , Mulligan Mark J. , Hoft Daniel F
Published: June 2022

Over the last decade, the field of systems vaccinology has emerged, in which high throughput transcriptomics and other omics assays are used to probe changes of the innate and adaptive immune system in response to vaccination. RNA-Seq technology has matured in recent years and is now widely deployed for transcriptional analysis of clinical specimens. The goal of this study was to benchmark technical parameters of RNA-Seq in the context of a multi-site, double-blind randomized clinical trial using primary patient samples. We collected longitudinal peripheral blood mononuclear cell (PBMC) samples from 10 subjects after vaccination with a live attenuated Francisella tularensis vaccine and performed RNA-Seq at two different sites using aliquots from the same sample to generate two large-scale replicate datasets. We evaluated the impact of: (i) filtering lowly-expressed genes, (ii) using external RNA controls, (iii) fold change and false discovery rate (FDR) filtering, (iv) read length, and (v) sequencing depth on differential expressed genes (DEGs) concordance between replicate datasets. Using synthetic mRNA spike-ins, we developed a method for empirically establishing minimal read-count thresholds for maintaining fold change accuracy on a per-experiment basis. We defined a reference PBMC transcriptome by pooling sequence data, and established the impact of read depth and gene filtering on transcript representation. Lastly, we modeled statistical power to detect DE genes for a range of sample sizes, effect sizes, and coverage depths. The results from this study provide RNA sequencing benchmarks and guidelines for planning future similar vaccine studies.
Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics
Authors: Yuen John G. , Fesler Andrew , Hwang Ga-Ram , Chen Lan-Bo , Ju Jingfang
Published: June 2022

MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Its inherently pleiotropic nature make miRNAs strong candidates for the development of cancer therapeutics, yet despite its potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNA interference (RNAi) function. To demonstrate the general applicability of this approach to other tumor suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nM range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.
Time-varying hierarchical core voxels disclosed by k-core percolation on dynamic inter-voxel connectivity resting-state fMRI
Authors: Huh Youngmin , Kang Yeon Koo , Whi Wonseok , Lee Hyekyoung , Kang Hyejin , Lee Dong Soo
Published: June 2022

k-core percolation on the scale-free static brain connectivity revealed hierarchical structure of inter-voxel correlations, which was successfully visualized by hyperbolic disc embedding on resting-state fMRI. In static study, flagplots and brain rendered kmax-core display showed the changes of hierarchical structures of voxels belonging to functional independent components (IC). In this dynamic sliding-window study, temporal progress of hierarchical structure of voxels were investigated in individuals and in sessions of an individual. kmax-core and coreness k values characterizing time-varying core voxels were visualized on animated stacked-histogram/flagplots and animated brain-rendered images. Resting-state fMRI of Human Connectome Project and of Kirby weekly revealed the slow progress and multiple abrupt state transitions of the voxels of coreness k and at the uppermost hierarchy, representing their correlative time-varying mental states in individuals and in sessions. We suggest this characteristic core voxels-IC compositions on dynamic study fingerprint the time-varying resting states of human minds.

One Sentence Summary

Dynamic state transitions of hierarchical functional inter-voxel connectivity implied time-varying mental states at rest on fMRI
Electrophysiological properties of neurons in the intermediate thoracolumbar spinal cord mediating proprioception
Authors: Espinosa Felipe , Pop Iliodora V. , Lai Helen C.
Published: June 2022

Animals must know where their body is in relationship to their environment to move appropriately. Proprioception, the sense of limb and body position, is required to produce feedforward predictions of future movement as well as provide feedback information during movement to update the system. How proprioception is processed at the level of the spinal cord is not well understood. Most work has focused on Clarke’s column (CC) neurons, a component of the dorsal spinocerebellar tract (DSCT). CC neurons receive hindlimb proprioceptive information and send it directly to the cerebellum with no axon collaterals to other neurons in the spinal cord. In contrast to CC neurons, we previously found that a subset of thoracolumbar Atoh1-lineage neurons also receives proprioceptive afferent inputs, but project locally within the spinal cord including synapsing on motor neurons. We set out to understand how CC and Atoh1-lineage neurons in the thoracolumbar spinal cord respond to electrical activity. Using in vitro acute spinal cord slices and whole-cell patch clamp, we characterized the passive and active electrical properties of CC and thoracolumbar Atoh1-lineage neurons. We find that most CC neurons increase their action potential firing frequency linearly upon increased current injection up to high frequencies likely due to a hyperpolarization-activated current (Ih). In contrast, most Atoh1-lineage neurons do not have an Ih current and therefore, their firing frequency fades with increasing current injection. Interestingly, although Atoh1-lineage neurons are classically subdivided into a contralaterally-projecting Medial and ipsilaterally-projecting Lateral population, we find no obvious electrophysiological signatures that could distinguish these spatially distinct populations. Finally, we set out to determine the organization of the inputs to CC and Atoh1-lineage neurons. In a hemisected spinal cord preparation, while recording from neurons in the lower thoracic to upper lumbar segments, we find that CC neurons receive low threshold inputs (proprioceptive or low threshold mechanoreceptor) from lumbar 2 to 4 dorsal roots, while Atoh1-lineage Medial neurons do not. This raises the possibility that Atoh1-lineage Medial neurons receive proprioceptive inputs from more local dorsal roots. Altogether, we find that CC and Atoh1-lineage neurons have distinct membrane properties and sensory input organization even though they are both reported to receive proprioceptive information and are in close proximity in lamina V-VII of the thoracolumbar spinal cord.
The impact of rare protein coding genetic variation on adult cognitive function
Authors: Chen Chia-Yen , Tian Ruoyu , Ge Tian , Lam Max , Sanchez-Andrade Gabriela , Singh Tarjinder , Urpa Lea , Liu Jimmy Z. , Sanderson Mark , Rowley Christine , Ironfield Holly , Fang Terry ,   Biogen Biobank Team,   the SUPER-Finland study,   the Northern Finland Intellectual Disability study, Daly Mark , Palotie Aarno , Tsai Ellen A. , Huang Hailiang , Hurles Matthew E. , Gerety Sebastian S. , Lencz Todd , Runz Heiko
Published: June 2022

Compelling evidence suggests that cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein coding variants impact cognitive function in the adult population (N=485,930). We identify eight genes associated with adult cognitive function through rare coding variants with large effects. We demonstrate how the dosage of a single gene, KDM5B, may determine the variability of cognitive, behavioral, and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our findings uncover a contribution of rare coding variants to cognitive function and highlight that the spectrum of cognitive function in the normal adult population is influenced by the action of single genes.
Development and implementation of optimized endogenous contrast sequences for delineation in adaptive radiotherapy on a 1.5T MR-Linear-accelerator (MR-Linac): A prospective R-IDEAL Stage 0-2a quantitative/qualitative evaluation of in vivo site-specific quality-assurance using a 3D T2 fat-suppressed platform for head and neck cancer
Authors: Salzillo Travis C. , Dresner M. Alex , Way Ashley , Wahid Kareem A. , McDonald Brigid A. , Mulder Sam , Naser Mohamed A. , He Renjie , Ding Yao , Yoder Alison , Ahmed Sara , Corrigan Kelsey L. , Manzar Gohar S. , Andring Lauren , Pinnix Chelsea , Stafford R. Jason , Mohamed Abdallah S.R. , Christodouleas John , Wang Jihong , Fuller Clifton David
Published: June 2022

Purpose

In order to improve segmentation accuracy in head and neck cancer (HNC) radiotherapy treatment planning for the 1.5T MR-Linac, 3D fat-suppressed T2-weighted MRI sequences were developed and optimized.

Methods

After initial testing of fat suppression techniques, SPectral Attenuated Inversion Recovery (SPAIR) was chosen as the fat suppression technique. Five candidate SPAIR sequences and a non-suppressed T2-weighted sequence were acquired on five HNC patients on the Unity MR-Linac. The primary tumor, metastatic lymph nodes, parotid glands, and pterygoid muscles were delineated by five segmentors. A robust image quality analysis platform was developed to objectively score the SPAIR sequences based on a combination of qualitative and quantitative metrics.

Results

Sequences were analyzed for signal-to-noise (SNR), contrast-to-noise (CNR) compared to fat and muscle, conspicuity, pairwise distance metrics, segmentor assessment, and MR physicist assessment. From this analysis, the non-suppressed sequence was inferior to each of the SPAIR sequences for the primary tumor, lymph nodes, and parotid glands, but was superior for the pterygoid muscles. Two SPAIR sequences consistently received the highest scores among the analysis categories and are recommended for use to Unity MR-Linac users for HNC radiotherapy treatment planning.

Conclusions

Two deliverables resulted from this study. First, an optimized 3D fat-suppressed T2-weighted sequence was developed that can be disseminated to Unity MR-Linac users. Second, a robust image quality analysis process pathway, used to objectively score the various SPAIR sequences, was developed and can be customized and generalized to any image quality optimization. Improved segmentation accuracy with the proposed SPAIR sequence can potentially lead to improved treatment outcomes and reduced toxicity by maximizing target coverage and minimizing organ-at-risk exposure.
Shared genetic architecture between mental health and the brain functional connectome in the UK Biobank
Authors: Roelfs Daniel , Frei Oleksandr , van der Meer Dennis , Tissink Elleke , Shadrin Alexey , Alnæs Dag , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias
Published: June 2022

Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30.701 participants aged 45-82 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular synaptic processes. These findings provide further genetic evidence of an association between brain function and mental health traits in the population.
Hand washing at critical times and associated factors among mothers/caregivers of under-five children in Nefas Silk Lafto Sub-City, Addis Ababa, Ethiopia, 2019: Facility based cross-sectional study
Authors: Wana Ermias Wabeto , Mengesha Nardos Anbese
Published: June 2022

Background

Hand washing is the simplest, most affordable and effective means of limiting spread of infections. It has especial importance for children because they are more susceptible to infections acquired from unwashed hands. Despite increasing efforts to improve hand washing at critical times, mothers/caregivers of under-five children fail to practice; but, the reason is unclear. Thus, this study was aimed to identify the magnitude and factors associated with hand washing at critical times among mothers/caregivers of under-five children.

Methods

An institution based cross-sectional study was conducted in Nefas Silk Lafto Sub-City by April 2019, and 312 mothers/caregivers were participated. The data were collected by interviewing mothers, entered and analyzed with statistical package for social science 20 (SPSS-20). The findings were presented with crude odds ratios (COR) and Adjusted Odds Ratios (AOR) with their respective 95% confidence intervals (CI). A P-value less than 0.05 was used statistical significance level.

Results

232 (74.4%; 95% CI [69.6%-79.2%]) mothers/caregivers washed their hands at critical times. Illiterate mothers had 66% reduced (AOR= 0.34; 95%CI [0.17-0.69]) odds of washing hands at critical times than literate mothers. Mothers who did not own tap water in their back yard had 62% (AOR= 0.38; 95%CI [0.18-0.80]) reduced odds of hand washing at critical times than their counterparts. As compared to the mothers from the poorest households, those from middle, richer and the richest households had 4.56 (AOR= 4.56; 95%CI [1.84-11.33]), 5.61 (AOR= 5.61; 95%CI [2.11-15.30]) and 6.14 (AOR= 6.14; 95%CI [2.24-16.72]) times increased likelihood of washing hands at critical times.

Conclusion

Three fourth of mothers practiced hand washing at critical times, and improving maternal literacy, household economy and availability of water source in backyard are needed to maintain and enhance the practice.
Rapid progression to death after hepatocellular carcinoma diagnosis particularly among persons with advanced HIV disease in Kampala, Uganda
Authors: Nsibirwa Sara K. , Aizire Jim , Thomas David L. , Ocama Ponsiano , Kirk Gregory D.
Published: June 2022

Background

HIV infection is associated with more rapid progression of some comorbidities. This study assessed the impact of HIV-infection where the presentation and outcome of HCC was different in persons living with HIV (PLWH) compared to those without HIV infection.

Methods

HCC patients attending the Mulago National Referral Hospital in Uganda were enrolled into a natural history study of HCC between March 2015 and February 2019. Standardized methods were used to collect clinical, ultrasound and laboratory data at enrolment. HCC cases were confirmed based on a combination of clinical, ultrasound, tumor marker and pathology data. Follow-up contact was made at one, three, six, and twelve months post-enrolment to determine vital status. Symptoms and signs at diagnosis and subsequent survival were compared by HIV status. Kaplan Meier curves were used to assess HCC survival.

Results

Of 441 persons with HCC, 383 (87.0%) died within 12 months following HCC diagnosis. The median (IQR) survival was 42 (20, 106) days. The most commonly reported symptom clusters were pain (80%), gastrointestinal symptoms (28%) and anorexia / cachexia (10%), and no differences were detected in these presenting symptoms (nor most other initial findings) in the 79 (18%) PLWH compared to those without HIV. After adjusting for baseline demographic and clinical characteristics, HIV infection was associated with increased mortality but only among those with severe HIV-associated immunosuppression (CD4 count <200 cells per cubic milliliter), aHR (95% C) = 2.12 (1.23-3.53), p=0.004, and not among PLWH with ≥200 CD4 cells per cubic milliliter, aHR (95% C) = 1.15 (0.82-1.60), p=0.417.

Conclusion

Among relatively young Ugandans, HCC is a devastating disease with rapid mortality that is especially rapid among PLWH. HIV was associated with slightly higher mortality, notably among PLWH with lower CD4 cell counts. As a substantial majority of PLWH diagnosed with HCC were engaged in HIV care, further investigation should determine the effectiveness of incorporating screening and early identification of HCC among high-risk individuals into existing HIV care programs. Concurrent with growing access to curative localized treatment for HCC in sub-Saharan Africa, leveraging HIV care infrastructure affords opportunities for earlier HCC intervention.
Effect of hybrid immunity, school reopening, and the Omicron variant on trajectory of COVID-19 epidemic in India: A modelling study
Authors: Mozaffer Farhina , Cherian Philip , Krishna Sandeep , Wahl Brian , Menon Gautam I
Published: June 2022

Background

The course of the COVID-19 pandemic has been driven by several dynamic behavioral, immunological, and viral factors. We used mathematical modeling to explore how the concurrent reopening of schools, increasing levels of hybrid immunity, and the emergence of the Omicron variant have affected the trajectory of the pandemic in India, using the model Indian state of Andhra Pradesh (pop: 53 million).

Methods

We constructed an age- and contact-structured compartmental model that allows for individuals to proceed through various states depending on whether they have received zero, one, or two doses of the COVID-19 vaccine. Our model is calibrated using results from other models as well as available serosurvey data. The introduction of the Omicron variant is modelled alongside protection gained from hybrid immunity. We predict disease dynamics in the background of hybrid immunity coming from infections and well as an ongoing vaccination program, given prior levels of seropositivity from earlier waves of infection. We describe the consequences of school reopening on cases across different age-bands, as well as the impact of the Omicron (BA.2) variant.

Results

We show the existence of an epidemic peak that is strongly related to the value of background seroprevalence. As expected, because children were not vaccinated in India, re-opening schools increases the number of cases in children more than in adults, although most such cases are asymptomatic or mild. The height of this peak reduced as the background infection-induced seropositivity was increased from 20% to 40%. At reported values of seropositivity of 64%, no discernable peak was seen. We also explore counterfactual scenarios regarding the effect of vaccination on hybrid immunity. We find that in the absence of vaccination, even at such high levels of seroprevalence, the emergence of the Omicron variant would have resulted in a large rise in cases across all age bands. We conclude that the presence of high levels of hybrid immunity thus resulted in relatively fewer cases in the Omicron wave than in the Delta wave.

Interpretation

In India, the decreasing prevalence of immunologically naïve individuals of all ages helped reduce the number of cases reported once schools were reopened. In addition, hybrid immunity, together with the lower intrinsic severity of disease associated with the Omicron variant, contributed to low reported COVID-19 hospitalizations and deaths.

Funding

World Health Organization, Mphasis
Routine Urinary Biochemistry Does Not Accurately Predict Stone Type Nor Recurrence in Kidney Stone Formers: A Multi-Centre, Multi-Model, Externally Validated Machine-Learning Study
Authors: Geraghty Robert , Wilson Ian , Olinger Eric , Cook Paul , Troup Susan , Kennedy David , Rogers Alistair , Somani Bhaskar , Dhayat Nasser , Fuster Daniel , Sayer John
Published: June 2022

Objectives: Urinary biochemistry is used to detect and monitor conditions associated with recurrent kidney stones. There are no predictive machine learning (ML) tools for kidney stone type or recurrence. We therefore aimed to build and validate ML models for these outcomes using age, gender, 24-hour urine biochemistry and stone composition.
Materials and Methods: Data from 3 cohorts were used, Southampton, UK (n=3013), Newcastle, UK (n=5984) and Bern, Switzerland (n=794). Of these 3130 had available 24-hour urine biochemistry measurements (calcium, oxalate, urate, pH, volume), and 1684 had clinical data on kidney stone recurrence. Two predictive models were constructed (UK and Swiss) using two ML techniques (Partitioning and Random Forests [RF]) and validated internally with a subset of the same dataset (e.g UK model/UK test set), and externally with the other dataset (UK model/Swiss test set).
Results and Limitations: For kidney stone type, on external validation accuracy of UK RF model=0.79 (95% CI: 0.73-0.84), sensitivity: calcium oxalate=0.99 and calcium phosphate/urate=0.00. Specificity: calcium oxalate=0.00 and calcium phosphate/urate=0.99. For the Swiss RF model accuracy=0.87 (95% CI: 0.83-0.89), sensitivity: calcium oxalate=0.99 and calcium phosphate/urate=0.00. Specificity: calcium oxalate=0.00, calcium phosphate=0.00 and urate=1.00.
For stone recurrence, on external validation accuracy of UK RF model=0.22 (95% CI: 0.19-0.25), sensitivity=0.93 and specificity=0.09. Swiss RF model accuracy=0.42 (95% CI: 0.39-0.47), sensitivity=0.03 and specificity=0.97.
Conclusions: Neither kidney stone type nor kidney stone recurrence can be accurately predicted using modelling tools built using specific 24-hour urinary biochemistry values alone. Further studies to delineate accurate predictive tools should be undertaken using both known and novel risk factors.
The mental wellbeing of prison staff in England during the COVID-19 pandemic: a cross-sectional study
Authors: Johnson Luke , Czachorowski Maciej , Gutridge Kerry , McGrath Nuala , Parkes Julie , Plugge Emma
Published: June 2022

Objectives

To examine the mental wellbeing of prison staff in England within the pandemic, and determine factors associated with wellbeing.

Design

Cross-sectional study, with self-completed hardcopy and online surveys.

Setting

26 prisons across England, chosen to be representative of the wider closed prison estate in England

Participants

All staff within the 26 prisons from 20th July 2020 and 2nd October 2020 were eligible.

Primary outcome measure

Wellbeing, measured using the Short-version of Warwick-Edinburgh Wellbeing Scale (SWEMWBS). Staff wellbeing was compared to that of the English population using indirectly standardised data from the Health Survey for England 2010-13 and a one-sample t-test. Multivariate linear regression modelling explored associations with mental wellbeing score.

Results

2534 individuals were included (response rate 22.2%). The mean age was 44 years, 53% were female, and 93% were white. The sample mean SWEMWBS score was 23.84 and the standardised population mean score was 23.57. The difference in means was statistically significant (95% CI 0.09 to 0.46), but not of at a clinically meaningful level. The multivariate linear regression model was adjusted for age category, sex, ethnicity, smoking status, presence of comorbidities, occupation, and HMPPS region. Higher wellbeing was significantly associated with older age, male sex, Black/Black British ethnicity, never having smoked, working within the health staff team, and working in certain prison regions. The overall model had a low predictive value (adjusted R2 = 0.0345).

Conclusions

Unexpectedly, prison staff wellbeing as measured by SWEMWBS was similar to that of the general population. Reasons for this are unclear but could include the reduction in violence within prisons since the start of the pandemic. Qualitative research across a diverse sample of prison settings would enrich understanding of staff wellbeing within the pandemic.

Strengths and limitations of this study

This is the largest study to date to explore the mental wellbeing of prison staff in the UK (n=2534) and the first peer-reviewed study examining this during the COVID-19 pandemic.

The sampling frame used (all staff at 26 prisons in England) is more likely to be representative of the prison staff population than other studies which have measured prison staff wellbeing and recruited through trade union channels

Wellbeing was measured using SWEMWBS, which has been validated within the UK population

Response rate was low (22.2%) and a number of variables adjusted for in the regression model were self-reported which could lead to a degree of bias
Health facility assessments of cervical cancer prevention, screening, and treatment services in Gulu, Uganda
Authors: Chongsuwat Tana , Ibrahim Aaliyah O , Evensen Ann , Conway James H , Zwick Margaret , Oloya William
Published: June 2022

Background

Cervical cancer is ranked globally in the top 3 cancers for women younger than 45 years, with the average age of death at 59 years of age. The highest burden of disease is in low- and low-to-middle income countries (LLMICs), responsible for 90% of the 311,000 cervical cancer deaths in 2018. This growing health disparity is due to the lack of quality screening and treatment programs, low human papillomavirus (HPV) vaccination rates, and high human immunodeficiency virus (HIV) co-infection rates. To address these gaps in care, we need to develop a clear understanding of the resources and capability of LLMIC’s health care facilities to provide prevention, screening, and treatment for cervical cancer.

Objectives

This project aimed to (1) develop a health facility assessment (HFA) to assess available cervical cancer prevention, screening, and treatment resources and (2) implement the HFA to determine the cervical cancer resources available in Gulu, Uganda.

Methods

We adapted the World Health Organization’s Harmonized Health Facility Assessment for our own HFA and grading scale, deploying it in October 2021 to analyze 21 health centers in Gulu.

Results

Grading of Health Center IIIs (n=16) concluded that 37% had “excellent” or “good” resources available, and 63% of facilities had “poor” or “fair” resources available. Grading of Health Center IVs and above (n=5) concluded that 60% of facilities had “excellent” or “good” resources, and 40% had “fair” resources available.

Discussion

The analysis of health facilities in Gulu demonstrated subpar resources available for cervical cancer prevention, screening, and treatment. Focused efforts are needed to expand health centers’ resources and capability to address rising cervical cancer rates and related health disparities in LLMICs. The development process for the study HFA can be applied to global cervical cancer programming to determine gaps in resources and indicate areas to target improved health equity.
Comparing P300 flashing paradigms in online typing with language models
Authors: Chandravadia Nand , Pendekanti Shrita , Roberts Dustin , Tran Robert , Panchavati Saarang , Arnold Corey , Pouratian Nader , Speier William
Published: June 2022

The P300 Speller is a brain-computer interface system that allows victims of motor neuron diseases to regain the ability to communicate by typing characters into a computer by thought. Since the system has a relatively slow typing speed, different stimulus presentation paradigms have been proposed designed to allow users to input information faster by reducing the number of required stimuli or increase signal fidelity. This study compares the typing speeds of the Row-Column, Checkerboard, and Combinatorial Paradigms to examine how their performance compares in online and offline settings. When the different flashing patterns were tested in conjunction with other established optimization techniques such as language models and dynamic stopping, they did not make a significant impact on P300 speller performance. This result could indicate that further performance improvements on the system lie beyond optimizing flashing patterns.
Ectoparasitism in Polystomatidae (Neodermata, Monogenea): phylogenetic position and mitogenome of Sphyranura euryceae, a parasite of the Oklahoma salamander
Authors: Leeming Samuel J. , Hahn Christoph , Koblmüller Stephan , McAllister Chris T. , Vanhove Maarten P. M. , Kmentová Nikol
Published: June 2022

Background

Polystomatidae represents a monogenean group whose representatives infect mainly (semi)-aquatic tetrapods. Sphyranuridae with its single genus (Sphyranura) exhibits ectoparasitism on salamander hosts and was traditionally considered a sister-group to Polystomatidae based on the presence of a well-developed opisthaptor yet was distinguished due to the presence of a single pair of haptoral suckers, as opposed to the three pairs present in polystomatids. However, more recent molecular work supported its inclusion within Polystomatidae, at an early diverging, yet unresolved, position in the clade of polystomatids that otherwise exhibit endoparasitism of batrachians. Resolving the position of Sphyranura in relation to Polystomatidae is a prerequisite for understanding the factors driving evolution and the shifts between ecto- and endoparasitism in Polystomatidae.

Methods

Various staining methods were used to morphologically characterise collected specimens of Sphyranura. The mitochondrial genome was assembled from WGS data. Based on a combination of nuclear (18S, 28S rRNA) and mitochondrial markers (cox1, 12S) we inferred the phylogeny of Polystomatidae using Bayesian inference and maximum likelihood methods.

Results

Based on morphological examination and comparison with type material, specimens of Sphyranura infecting Oklahoma salamander (Eurycea tynerensis) at Greathouse Spring, Arkansas (USA), were identified as S. euryceae, a new distributional record for the species. Along with an amended diagnosis of Sphyranura we provide the first molecular data for S. euryceae. Mitochondrial level comparison reveals instances of tRNA gene rearrangements in polystomatids. Our phylogeny identifies two clades within polystomatids infecting tetrapods, one infecting exclusively batrachians, the other mainly known from chelonians. Although not fully supported, Sphyranura appears as the earliest branching lineage within the former.

Conclusions

With Sphyranura nested within Polystomatidae, we consider Sphyranuridae invalid. Sphyranura’s apparent early branching position indicates ectoparasitism is an ancestral trait with endoparasitism having evolved later in the ‘Polbatrach’ clade. However, the reduced number of haptoral suckers in representatives of Sphyranura is a derived characteristic potentially resulting from paedomorphic evolution. Whilst there is an indication towards phylogenetic congruence of polystomatids and their batrachian hosts, the same was not true for polystomatid parasites of chelonians with evidence of multiple host switches. Furthermore, geographic distribution of hosts was not found to drive polystomatid phylogeny.