bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Death Evaluation in Children With Suspected or Confirmed Coronavirus Disease 2019
Authors: Kirschen Matthew P. , McGowan Nancy , Topjian Alexis
Published: December 2020

Objectives:

To discuss the challenges of conducting a death by neurologic criteria or brain death evaluation in the coronavirus disease 2019 era and provide guidance to mitigate viral transmission risk and maintain patient safety during testing.

Design:

Not applicable.

Setting:

Not applicable.

Patients:

Children with suspected or confirmed coronavirus disease 2019 who suffer catastrophic brain injury due to one of numerous neurologic complications or from an unrelated process and require evaluation for death by neurologic criteria.

Interventions:

Not applicable.

Measurements and Main Results:

There is a risk to healthcare providers from aerosol generation during the neurologic examination and apnea test for determination of death by neurologic criteria. In this technical note, we provide guidance to mitigate transmission risk and maintain patient safety during each step of the death by neurologic criteria evaluation. Clinicians should put on appropriate personal protective equipment before performing the death by neurologic criteria evaluation. Risk of aerosol generation and viral transmission during the apnea test can be mitigated by using continuous positive airway pressure delivered via the ventilator as a means of apneic oxygenation. Physicians should assess the risk of transporting coronavirus disease 2019 patients to the nuclear medicine suite to perform a radionucleotide cerebral blood flow study, as disconnections to and from the ventilator for transport and inadvertent ventilator disconnections during transport can increase transmission risk.

Conclusions:

When conducting the neurologic examination and apnea test required for death by neurologic criteria determination in patients with suspected or confirmed coronavirus disease 2019, appropriate modifications are needed to mitigate the risk of viral transmission and ensure patient safety.
Pre-examinations Improve Automated Metastases Detection on Cranial MRI
Authors: Deike-Hofmann Katerina , Dancs Dorottya , Paech Daniel , Schlemmer Heinz-Peter , Maier-Hein Klaus , Bäumer Philipp , Radbruch Alexander , Götz Michael
Published: December 2020

Objective

The aim of this study was to assess the diagnostic value of inclusion of prediagnosis magnetic resonance imaging (MRI) and different MRI sequences when training a convolutional neural network (CNN) in detection of metastases from malignant melanoma (MM) on an annotated real-life cranial MRI dataset.

Diagnostic performance was challenged by extracerebral-intracranial MM and by inclusion of MRI with varying sequence parameters.

Materials and Methods

Our local ethics committee approved this retrospective monocenter study.

First, a dual-time approach was assessed, for which the CNN was provided sequences of the MRI that initially depicted new MM (diagnosis MRI) as well as of a prediagnosis MRI: inclusion of only contrast-enhanced T1-weighted images (CNNdual_ce) was compared with inclusion of also the native T1-weighted images, T2-weighted images, and FLAIR sequences of both time points (CNNdual_all).

Second, results were compared with the corresponding single time approaches, in which the CNN was provided exclusively the respective sequences of the diagnosis MRI.

Casewise diagnostic performance parameters were calculated from 5-fold cross-validation.

Results

In total, 94 cases with 494 MMs were included. Overall, the highest diagnostic performance was achieved by inclusion of only the contrast-enhanced T1-weighted images of the diagnosis and of a prediagnosis MRI (CNNdual_ce, sensitivity = 73%, PPV = 25%, F1-score = 36%). Using exclusively contrast-enhanced T1-weighted images as input resulted in significantly less false-positives (FPs) compared with inclusion of further sequences beyond contrast-enhanced T1-weighted images (FPs = 5/7 for CNNdual_ce/CNNdual_all, P < 1e-5). Comparison of contrast-enhanced dual and mono time approaches revealed that exclusion of prediagnosis MRI significantly increased FPs (FPs = 5/10 for CNNdual_ce/CNNce, P < 1e-9).

Approaches with only native sequences were clearly inferior to CNNs that were provided contrast-enhanced sequences.

Conclusions

Automated MM detection on contrast-enhanced T1-weighted images performed with high sensitivity. Frequent FPs due to artifacts and vessels were significantly reduced by additional inclusion of prediagnosis MRI, but not by inclusion of further sequences beyond contrast-enhanced T1-weighted images. Future studies might investigate different change detection architectures for computer-aided detection.
The Macrocyclic Gadolinium-Based Contrast Agents Gadobutrol and Gadoteridol Show Similar Elimination Kinetics From the Brain After Repeated Intravenous Injections in Rabbits
Authors: Frenzel Thomas , Ulbrich Hannes-Friedrich , Pietsch Hubertus
Published: December 2020

Objective

The gadolinium (Gd) concentrations in the cerebellum and cerebrum of rabbits and the elimination kinetics were compared after repeated injection of the macrocyclic Gd-based contrast agents (GBCAs) gadobutrol and gadoteridol.

Materials and Methods

Male white New Zealand rabbits (2.4–3.1 kg) in 2 study groups (n = 21 each) received 3 injections of either gadobutrol or gadoteridol at 0.9 mmol Gd/kg within 5 days (total dose, 2.7 mmol Gd/kg). Animals in one control group (n = 9) received 3 injections of saline (1.8 mL/kg). After 2, 6, and 12 weeks, 7 animals from each study group and 3 from the control group were killed and the Gd concentrations in the cerebellum, cerebrum, in blood and in urine were determined by inductively coupled plasma mass spectrometry. The chemical species of excreted Gd in urine were determined by high pressure liquid chromatography.

Results

No significant (P > 0.05) differences in the Gd concentrations in the brain of rabbits were observed between the 2 macrocyclic GBCAs gadoteridol and gadobutrol at all time points. In the gadobutrol group, the mean Gd concentrations in the cerebellum and cerebrum decreased from 0.26 and 0.21 nmol Gd/g after 2 weeks, to 0.040 and 0.027 nmol Gd/g after 12 weeks, respectively, and in the gadoteridol group, from 0.25 and 0.21, to 0.037 and 0.023 nmol Gd/g, respectively. The plasma levels decreased from 0.11 and 0.13 nmol Gd/mL at 2 weeks for gadobutrol and gadoteridol to below the limit of quantification (<0.005 nmol Gd/mL) at 12 weeks. The urine concentration dropped in a biphasic course from 2 to 6 and from 6 to 12 weeks for both agents. The Gd excreted after 12 weeks was still present in the urine in the chemical form of the intact Gd complex for both agents.

Conclusions

Contrary to what had been reported in rats, no significant differences in the elimination kinetics from brain tissue in rabbits were observed after intravenous injection of multiple doses of the macrocyclic GBCAs gadobutrol and gadoteridol.
Adults With Unilateral Cleft Lip and Palate Present Reduced Internal Nasal Volumes: Findings of a Three-Dimensional Morphometric Assessment in Cone-Beam Computed Tomography Scans
Authors: dos Inocentes Renan Jhordan Mettelziefen , Marzano-Rodrigues Maria Noel , de Espíndola Guilherme Gonçalves , García-Usó Michele , Yatabe-Ioshida Marília Sayako , Trindade Inge Elly Kiemle , Trindade-Suedam Ivy Kiemle
Published: December 2020

The main purpose was to assess and compare nasal cavity (NC) volumes among adults with unilateral (UCLP) and bilateral cleft lip and palate (BCLP) and in noncleft controls (CON), by means of cone-beam computed tomography (CBCT) three-dimensional reconstructions. Forty-five scans of individuals with class III skeletal pattern, matched by age, were gathered in 3 groups: UCLP (n = 15), BCLP (n = 15) and (CON) (n = 15). The NC volume was assessed three-dimensionally, using Dolphin 11.8 software. Descriptive normally distributed data was presented as mean (±SD). Comparisons of NC volume among groups was performed using ANOVA test (P ≤ 0.05). The NC mean volumes corresponded to 14.7(±2.2) cm3 (UCLP), 17.1(±2.2) cm3 (BCLP) and 18.1(±3.8) cm3 (CON), respectively. UCLP individuals presented a significantly reduced NC volume when compared to controls (P = 0.006). No differences were observed between UCLP versus BCLP or BCLP versus CON. The intraclass correlation coefficient suggested a high intra- and inter-examiners agreement (>.075). Individuals with unilateral cleft lip and palate presented reduced NC when compared to individuals without cleft lip and palate. CBCT scans can be considered a highly accurate tool for morphometric assessments of craniofacial structures.
Sarcoidosis Mimicking Chronic Sialadenitis of Parotid Gland
Authors: Shadamarshan R Arunkumar , Sharma Rohit , Grewal Ritu
Published: December 2020

Non-specific Chronic sialadenitis of the Parotid gland is an inflammatory disorder that leads to several anatomical and functional changes within the glandular structure. The exact etiopathogenesis of this disorder is unknown due to its relatively rare occurrence. Primary sarcoidosis of the Parotid gland masquerading the peripheral changes of Chronic sialadenitis has never been reported in literature. We report such a case of Primary Sarcoidosis of the Parotid gland presenting with non-specific chronic sialadenitis along with ipsilateral non-reducing disc displacement of the Temporomandibular joint along with its management.
Volume of Pancreas-Adjacent Operations Favorably Influences Pancreaticoduodenectomy Outcomes at Lower Volume Pancreas Centers
Authors: de Geus Susanna W. L. , Hachey Krista J. , Nudel Jacob D. , Ng Sing Chau , McAneny David B. , Davies Joshua D. , Tseng Jennifer F. , Sachs Teviah E.
Published: December 2020

Objective:

This study assesses how the volume of pancreatic-adjacent operations (PAO) impacts the outcomes of pancreaticoduodenectomy (PD).

Summary Background Data:

It is well-established that regionalization benefits outcomes after PD. However, due to a multitude of factors, including geographic, financial, and personal, not all patients receive their care at high-volume pancreas surgery centers.

Methods:

The National Cancer Database was queried for pancreatic cancer patients who underwent PD. Hospital volume was calculated for PD and PAO (defined as gastric, hepatic, complex biliary, or pancreatic operations other than PD) and dichotomized as low- and high-volume centers based on the median. Three study cohorts were created: low-volume hospitals (LVH) for both PD and PAO, mixed-volume hospital (MVH) with low-volume PD but high-volume PAO, and high-volume PD hospital (HVH).

Results:

In total, 24,572 patients were identified, with 41.5%, 7.2%, and 51.3% patients treated at LVH, MVH, and HVH, respectively. Thirty-day mortality for PD was 5.6% in LVH, 3.2% in MVH, and 2.5% in HVH. On multivariable analyses, LVH was predictive for higher 30-day mortality compared to HVH [odds ratio (OR) 2.068; 95% confidence interval (CI) 1.770–2.418; P<0.0001]. However, patients at MVH demonstrated similar 30-day mortality to patients treated at HVH (OR 1.258; 95% CI 0.942–1.680; P = 0.1203).

Conclusions:

PD outcomes at low-volume centers that have experience with complex cancer operations near the pancreas are similar to PD outcomes at hospitals with high PD volume. MVH provides a model for PD outcomes to improve quality and access for patients who cannot, or choose not to, receive their care at high-volume centers.
Correlation of Glomerular Size With Donor–Recipient Factors and With Response to Injury
Authors: Grande Joseph P. , Helgeson Erika S. , Matas Arthur J.
Published: December 2020

Background.

Glomerular size in renal allografts is impacted by donor–recipient factors and response to injury. In serial biopsies of patients with well-functioning grafts, increased glomerular size correlates with better survival. However, no previous study has addressed the association of glomerular size at the time of a for-cause biopsy and clinical/histopathologic markers of injury, or effect on long-term graft outcome.

Methods.

Two cohorts of kidney transplant recipients enrolled in the Deterioration of Kidney Allograft Function study were evaluated. The prospective cohort (PC, n = 581): patients undergoing first for-cause kidney biopsy 1.7 ± 1.4 (mean ± SD) y posttransplant; and the cross-sectional cohort (CSC, n = 446): patients developing new-onset renal function deterioration 7.7 ± 5.6 y posttransplant. Glomerular planar surface area and diameter were measured on all glomeruli containing a vascular pole. Kidney biopsy was read centrally in a blinded fashion according to the Banff criteria.

Results.

Glomerular area was significantly higher in the CSC than the PC; time from transplant to indication biopsy was associated with glomerular area in both cohorts (P values ≤ 0.001). Glomerular area was associated with indices of microvascular inflammation (glomerulitis, peritubular capillary infiltrates; P values ≤ 0.001) and segmental glomerulosclerosis (P value < 0.0001). In the CSC, higher glomerular area was associated with higher estimated glomerular filtration rate (P value ≤ 0.001) and increased graft survival after accounting for microvascular inflammation (adjusted hazard ratio = 0.967; 95% confidence interval: 0.948-0.986; hazard ratio in biopsies without evidence of diabetes or antibody mediated rejection = 0.919, 95% confidence interval: 0.856-0.987).

Conclusions.

Glomerular size is associated with histopathologic features present at the time of indication biopsy and with increased graft survival in the CSC.
Success Rate of Obtaining Baseline Somatosensory and Motor Evoked Potentials in 695 Consecutive Cranial and Spine Surgeries
Authors: Gonzalez Andres A. , Droker Brian S. , Kim Eric S. , Parikh Pooja
Published: December 2020

Purpose:

Intraoperative neurophysiological monitoring has been well documented as an adjunctive technique that significantly decreases the risk of developing inadvertent sensory and motor deficits during cranial and spine surgeries. The ability to detect neurologic problems intraoperatively depends largely on accurately identifying changes that occur in somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) during each procedure. Therefore, obtaining accurate and reproducible SSEP and MEP data during the initial setup is paramount for intraoperative monitoring. In 2007, Chen et al. found the overall success rate for establishing reliable MEP responses to be 94.8% in the upper extremities and 66.6% in the lower extremities. Since then, the success rate of obtaining baseline sensory and motor evoked potential responses has not been specifically reevaluated. The main goal of this study was to evaluate the current success rates of obtaining adequate SSEP and MEP baseline data in the current era, as well as take a closer look into some of the factors that can reduce the success rates.

Methods:

Somatosensory evoked potential and MEP monitoring was attempted in a total of 695 consecutive brain and spine surgeries performed by neurosurgeons and orthopedic surgeons between January 2010 and July 2011. Somatosensory evoked potential and MEP baseline data were obtained after initiation of general anesthesia and before skin incision. The primary measure is the ability to obtain adequate SSEP and MEP baseline in each extremity. A secondary measure was to stratify the success rate based on preoperative diagnosis.

Results:

Six hundred ninety-five consecutive cranial and spinal cases that required intraoperative monitoring were reviewed. Baseline upper extremity SSEPs were successfully obtained in 679 cases (98.1%), and baseline lower extremity SSEPs were successfully obtained in 626 cases (90.1%). However, if the preoperative diagnosis was in the category spine trauma or spine infection, the success rate of obtaining adequate baseline in the lower extremities dropped to around 60% for both SSEPs and MEPs.

Conclusions:

The success rates of obtaining adequate baseline SSEP and MEP data are overall higher than previously reported. Preoperative diagnosis like spinal infection or trauma may predict lower success rates for acquiring adequate baseline SSEPs and MEPs.
Poseidonibacter parvus sp. nov., isolated from a squid
Authors: Kim Min Ji , Baek Min-gyung , Shin Su-Kyoung , Yi Hana
Published: December 2020

A Gram-stain-negative, aerobic, short rod-shaped, motile, brownish-coloured bacterium, termed strain LPB0137T, was isolated from a squid. Its cells could grow weakly on marine agar 2216 with 0.04 % 2,3,5-triphenyl tetrazolium chloride (TTC). Each cell of strain LPB0137T has a circular chromosome with a length of 2.87 Mb and 27.7 mol% DNA G+C content. The genome includes 2698 protein-coding genes and six rRNA operons. In 16S rRNA gene sequence trees, strain LPB0137T formed a robust monophyletic clade with

Poseidonibacter antarcticus

SM1702T with a sequence similarity of 98.3 %. However, the average nucleotide identity and in silico DNA–DNA hybridization values between the two type strains were low (83.9 and 28.1 %, respectively). The overall phenotypic and genomic features of strain LPB0137T supported its assignment to the genus

Poseidonibacter

. However, the relatively low gene and genome sequence similarity between this strain and other type strains of the genus

Poseidonibacter

and several enzymatic characteristics indicated the taxonomic novelty of the isolated strain as a new member of the genus

Poseidonibacter

. Therefore, based on the phylogenetic and phenotypic characteristics of LPB0137T, we proposed a novel species of the genus

Poseidonibacter

for it, with the name Poseidonibacter parvus sp. nov. The type strain of this new species is thus LPB0137T (=KACC 18888T=JCM 31548T).
Evaluation of CARBA PAcE, a novel rapid test for detection of carbapenemase-producing Enterobacterales
Authors: Sattler Janko , Brunke Anne , Hamprecht Axel
Published: December 2020

Introduction. Carbapenemase-producing

Enterobacterales

(CPE) are an increasing threat to global health. Fast detection is crucial for patient management and outbreak control.

Hypothesis/Gap statement. Recently, a new commercial colorimetric test, CARBA PAcE, was released that has not yet been scientifically evaluated.

Aim. Our goals were to evaluate the performance of CARBA PAcE using a large variety of different CPE.

Methodology. CARBA PAcE was challenged with 107 molecularly characterized CPE and 53 non-CPE controls. Isolates were grown on Mueller-Hinton agar (MHA); in the case of a false-negative result, isolates were additionally inoculated on Columbia blood agar (CBA) and CARBA PAcE was repeated. The test was performed according to the manufacturer’s protocol.

Results. CARBA PAcE showed an overall sensitivity and specificity of 72 % [confidence interval (CI) 62–80 %] and 91 % (CI 79–97 %), respectively, when isolates were grown on MHA. With growth on CBA, detection improved (especially of metallo-β-lactamases), resulting in an extrapolated sensitivity of 89 % (CI 81–94 %) for all carbapenemases and 96 % (CI 89–99 %) for the four major carbapenemases (NDM, OXA-48-like, KPC, VIM).

Conclusion. CARBA PAcE is a simple and very rapid test for the detection of CPE which performs well for the major carbapenemases when isolates are grown on CBA. Laboratories should be aware of the limitations of this assay, such as moderate sensitivity when isolates are grown on more challenging agars such as MHA and the poor detection of some rare carbapenemases (e.g. IMI, OXA-58).
Application of respiratory metagenomics for COVID-19 patients on the intensive care unit to inform appropriate initial antimicrobial treatment and rapid detection of nosocomial transmission
Authors: Charalampous Themoula , Alcolea-Medina Adela , Snell Luke B. , Williams Tom G.S , Batra Rahul , Camporota Luigi , Meadows Christopher I.S. , Wyncoll Duncan , Barrett Nicholas A. , Hemsley Carolyn J. , Bryan Lisa , Newsholme William , Boyd Sara E. , Green Anna , Mahadeva Ula , Patel Amita , Cliff Penelope R. , Page Andrew J. , O’Grady Justin , Edgeworth Jonathan D.
Published: December 2020

Background

Clinical metagenomics (CMg) is being evaluated for translation from a research tool into routine diagnostic service, but its potential to significantly improve management of acutely unwell patients has not been demonstrated. The SARS-CoV-2 pandemic provides impetus to determine that benefit given increased risk of secondary infection and nosocomial transmission by multi-drug resistant (MDR) pathogens linked with expansion of critical care capacity.

Methods

Prospective evaluation of CMg using nanopore sequencing was performed on 43 respiratory samples over 14 weeks from a cohort of 274 intubated patients across seven COVID-19 intensive care units.

Results

Bacteria or fungi were cultured from 200 (73%) patients, with a predominance of Klebsiella spp. (31%) and C. striatum (7%) amongst other common respiratory pathogens. An 8 hour CMg workflow was 93% sensitive and 81% specific for bacterial identification compared to culture, and reported presence or absence of β-lactam resistance genes carried by Enterobacterales that would modify initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus (4 positive and 39 negative samples). Single nucleotide polymorphism (SNP)-typing using 24 hour sequence data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak potentially involving 14 patients across three ICUs.

Conclusion

CMg testing for ICU patients provides same-day pathogen detection and antibiotic resistance prediction that significantly improves initial treatment of nosocomial pneumonia and rapidly detects unsuspected outbreaks of MDR-pathogens.
Is Point-of-Care testing feasible and safe in care homes in England? An exploratory usability and accuracy evaluation of a point-of-care polymerase chain reaction test for SARS-COV-2
Authors: Micocci Massimo , Gordon Adam L , Seo Mikyung Kelly , Allen A. Joy , Davies Kerrie , Lasserson Dan , Thompson Carl , Spilsbury Karen , Akrill Cyd , Heath Ros , Astle Anita , Sharpe Claire , Perera Rafael , Hayward Gail , Buckle Peter
Published: December 2020

Introduction

Reliable rapid testing on COVID-19 is needed in care homes to reduce the risk of outbreaks and enable timely care. Point-of-care testing (POCT) in care homes could provide rapid actionable results. This study aimed to examine the usability and test performance of point of care polymerase chain reaction (PCR) for COVID-19 in care homes.

Methods

Point-of-care PCR for detection of SARS-COV2 was evaluated in a purposeful sample of four UK care homes. Test agreement with laboratory real-time PCR and usability and use errors were assessed.

Results

Point of care and laboratory polymerase chain reaction (PCR) tests were performed on 278 participants. The point of care and laboratory tests returned uncertain results or errors for 17 and 5 specimens respectively. Agreement analysis was conducted on 256 specimens. 175 were from staff: 162 asymptomatic; 13 symptomatic. 69 were from residents: 59 asymptomatic; 10 symptomatic. Asymptomatic specimens showed 83.3% (95% CI: 35.9%-99.6%) positive agreement and 98.7% negative agreement (95% CI: 96.2%-99.7%), with overall prevalence and bias-adjusted kappa (PABAK) of 0.965 (95% CI: 0.932 – 0.999). Symptomatic specimens showed 100% (95% CI: 2.5%-100%) positive agreement and 100% negative agreement (95% CI: 85.8%-100%), with overall PABAK of 1. No usability-related hazards emerged from this exploratory study.

Conclusion

Applications of point-of-care PCR testing in care homes can be considered with appropriate preparatory steps and safeguards. Agreement between POCT and laboratory PCR was good. Further diagnostic accuracy evaluations and in-service evaluation studies should be conducted, if the test is to be implemented more widely, to build greater certainty on this initial exploratory analysis.

Key points

Point of care tests (POCT) in care homes are feasible and could increase testing capacity for the control of COVID-19 infection.

The test of agreement between POCT and laboratory PCR for care home residents and the staff was good.

Adoption of POCT in care homes can be considered with appropriate preparatory steps and safeguards in place.

Repetitive errors and test malfunctioning can be mitigated with bespoke training for care home staff.

Integrated care pathways should be investigated to test the high variability of the context of use.
Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain
Authors: Rahman Md Shafiqur , Winsvold Bendik S , Chavez S.O. Chavez , Børte Sigrid , Tsepilov Yakov A. , Shapov Sodbo Zh. ,   HUNT All-In Pain, Aulchenko Yurii , Hagen Knut , Fors Egil A. , Hveem Kristian , Zwart John-Anker , van Meurs J.B.J. , Freidin Maxim B. , Williams Frances M.K.
Published: December 2020

Background and Objectives

Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP.

Methods

Northern Europeans from UK Biobank comprising 6,914 cases reporting pain all over the body lasting more than 3 months and 242,929 controls were studied. Replication of three lead genome-wide significant single nucleotide polymorphisms (SNPs) was attempted in 6 independent European cohorts (N=43,080; cases=14,177). Genetic correlations with risk factors, tissue specificity, and colocalization were examined.

Results

Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes RNF123, ATP2C1, and COMT. The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227), and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth, and years of schooling were identified. Tissue specificity and colocalization analysis highlight the relevance of skeletal muscle in CWP.

Conclusions

We report a novel association of RNF123 locus with CWP and suggest a role of ATP2C1, consistent with a role of calcium regulation in CWP. The association to COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

Key messages

What is already known about this subject?

Chronic widespread musculoskeletal pain (CWP) is a primary diagnostic feature of fibromyalgia.

CWP is moderately heritable, but precise genes involved in the pathogenesis of CWP are yet to be identified.

What does this study add?

This is the largest genetic study conducted on CWP to date and identified novel genetic risk loci (RNF123 and ATP2C1).

The genetic signal points to peripheral pain mechanisms in CWP, and shows genetic correlation with other traits, including BMI and depression.

How might this impact on clinical practice or future developments?

The findings add to etiological basis of CWP.
Integrating gene expression, spatial location and histology to identify spatial domains and spatially variable genes by graph convolutional network
Authors: Hu Jian , Li Xiangjie , Coleman Kyle , Schroeder Amelia , Irwin David J. , Lee Edward B. , Shinohara Russell T. , Li Mingyao
Published: December 2020

Recent advances in spatial transcriptomics technologies have enabled comprehensive characterization of gene expression patterns in the context of tissue microenvironment. To elucidate spatial gene expression variation, we present SpaGCN, a graph convolutional network approach that integrates gene expression, spatial location and histology in spatial transcriptomics data analysis. Through graph convolution, SpaGCN aggregates gene expression of each spot from its neighboring spots, which enables the identification of spatial domains with coherent expression and histology. The subsequent domain guided differential expression analysis then detects genes with enriched expression patterns in the identified domains. Analyzing five spatially resolved transcriptomics datasets using SpaGCN, we show it can detect genes with much more enriched spatial expression patterns than existing methods. Furthermore, genes detected by SpaGCN are transferrable and can be utilized to study spatial variation of gene expression in other datasets. SpaGCN is computationally fast, making it a desirable tool for spatial transcriptomics studies.
Spatial population genomics of a recent mosquito invasion
Authors: Schmidt Thomas L , Swan T. , Chung Jessica , Karl Stephan , Demok Samuel , Yang Qiong , Field Matt A , Muzari Mutizwa Odwell , Ehlers Gerhard , Brugh Mathew , Bellwood Rodney , Horne Peter , Burkot Thomas R , Ritchie Scott , Hoffmann Ary A
Published: December 2020

Population genomic approaches can characterise dispersal across a single generation through to many generations in the past, bridging the gap between individual movement and intergenerational gene flow. These approaches are particularly useful when investigating dispersal in recently altered systems, where they provide a way of inferring long-distance dispersal between newly established populations and their interactions with existing populations. Human-mediated biological invasions represent such altered systems which can be investigated with appropriate study designs and analyses. Here we apply temporally-restricted sampling and a range of population genomic approaches to investigate dispersal in a 2004 invasion ofAedes albopictus(the Asian tiger mosquito) in the Torres Strait Islands (TSI) of Australia. We sampled mosquitoes from 13 TSI villages simultaneously and genotyped 373 mosquitoes at genome-wide single nucleotide polymorphisms (SNPs): 331 from the TSI, 36 from Papua New Guinea (PNG), and 4 incursive mosquitoes detected in uninvaded regions. Within villages, spatial genetic structure varied substantially but overall displayed isolation by distance and a neighbourhood size of 232–577. Close kin dyads revealed recent movement between islands 31–203 km apart, and deep learning inferences showed incursiveAe. albopictushad travelled to uninvaded regions from both adjacent and non-adjacent islands. Private alleles and a coancestry matrix indicated direct gene flow from PNG into nearby islands. Outlier analyses also detected four linked alleles introgressed from PNG, with the alleles surrounding 12 resistance-associated cytochrome P450 genes. By treating dispersal as both an intergenerational process and a set of discrete events, we describe a highly interconnected invasive system.
Visual perceptual learning of a primitive feature in human V1/V2 as a result of unconscious processing, revealed by Decoded fMRI Neurofeedback (DecNef)
Authors: Wang Zhiyan , Tamaki Masako , Shibata Kazuhisa , Worden Michael S. , Yamada Takashi , Kawato Mitsuo , Sasaki Yuka , Watanabe Takeo
Published: December 2020

While numerous studies have shown that visual perceptual learning (VPL) occurs as a result of exposure to a visual feature in a task-irrelevant manner, the underlying neural mechanism is poorly understood. In a previous psychophysical study, subjects were repeatedly exposed to a task-irrelevant global motion display that induced the perception of not only the local motions but also a global motion moving in the direction of the spatiotemporal average of the local motion vectors. As a result, subjects enhanced their sensitivity only to the local moving directions, suggesting that early visual areas (V1/V2) that process local motions are involved in task-irrelevant VPL. However, this hypothesis has never been examined by directly examining the involvement of early visual areas (V1/V2). Here, we employed a decoded neurofeedback technique (DecNef) using functional magnetic resonance imaging. During the DecNef training, subjects were trained to induce the activity patterns in V1/V2 that were similar to those evoked by the actual presentation of the global motion display. The DecNef training was conducted with neither the actual presentation of the display nor the subjects’ awareness of the purpose of the experiment. As a result, subjects increased the sensitivity to the local motion directions but not specifically to the global motion direction. The training effect was strictly confined to V1/V2. Moreover, subjects reported that they neither perceived nor imagined any motion during the DecNef training. These results together suggest that that V1/V2 are sufficient for exposure-based task-irrelevant VPL to occur unconsciously.

Significance Statement

While numerous studies have shown that visual perceptual learning (VPL) occurs as a result of exposure to a visual feature in a task-irrelevant manner, the underlying neural mechanism is poorly understood. Previous psychophysical experiments suggest that early visual areas (V1/V2) are involved in task-irrelevant VPL. However, this hypothesis has never been examined by directly examining the involvement of early visual areas (V1/V2). Here, using decoded fMRI neurofeedback, the activity patterns similar to those evoked by the presentation of a complex motion display were repeatedly induced only in early visual areas. The training sensitized only the local motion directions and not the global motion direction, suggesting that V1/V2 are involved in task-irrelevant VPL.
A fast and robust Bayesian nonparametric method for prediction of complex traits using summary statistics
Authors: Zhou Geyu , Zhao Hongyu
Published: December 2020

Genetic prediction of complex traits has great promise for disease prevention, monitoring, and treatment. The development of accurate risk prediction models is hindered by the wide diversity of genetic architecture across different traits, limited access to individual level data for training and parameter tuning, and the demand for computational resources. To overcome the limitations of the most existing methods that make explicit assumptions on the underlying genetic architecture and need a separate validation data set for parameter tuning, we develop a summary statistics-based nonparametric method that does not rely on validation datasets to tune parameters. In our implementation, we refine the commonly used likelihood assumption to deal with the discrepancy between summary statistics and external reference panel. We also leverage the block structure of the reference linkage disequilibrium matrix for implementation of a parallel algorithm. Through simulations and applications to twelve traits, we show that our method is adaptive to different genetic architectures, statistically robust, and computationally efficient. Our method is available athttps://github.com/eldronzhou/SDPR.
eSCAN: Scan Regulatory Regions for Aggregate Association Testing using Whole Genome Sequencing Data
Authors: Yang Yingxi , Yang Yuchen , Huang Le , Broome Jai G. , Correa Adolfo , Reiner Alexander ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Raffield Laura M. , Li Yun
Published: December 2020

Multiple statistical methods for aggregate association testing have been developed for whole genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes and thus limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here we propose the eSCAN (Scan the Enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG, a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancer, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using TOPMed WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.
Immunoglobulin A Antibody Composition Is Sculpted to Bind the Self Gut Microbiome
Authors: Yang Chao , Chen-Liaw Alice , Moran Thomas M. , Cerutti Andrea , Faith Jeremiah J.
Published: December 2020

Despite being the most abundantly secreted immunoglobulin isotype, the reactivity of IgA antibodies towards each individual’s own gut commensal bacteria still remains elusive. By colonizing germ-free mice with defined commensal bacteria, we found the binding specificity of bulk fecal and serum IgA towards resident gut bacteria resolves well at the species level and has modest strain level specificity. IgA hybridomas generated from lamina propria B cells of gnotobiotic mice showed that most IgA clones recognized a single bacterial species, while a small portion displayed polyreactivity. Species-specific IgAs had a range of strain specificities. Given the unique bacterial species and strain composition in each individual’s gut, our findings suggest the IgA repertoire is uniquely shaped to bind our self gut bacteria.
A novel coalescent method insensitive to population structure
Authors: Yao Zeqi , Liu Kehui , Deng Shanjun , He Xionglei
Published: December 2020

Conventional coalescent inferences of population history make the critical assumption that the population under examination is panmictic. However, most populations are structured. This complicates the prevailing coalescent analyses and sometimes leads to inaccurate estimates. To develop a coalescent method unhampered by population structure, we perform two analyses. First, we demonstrate that the coalescent probability of two randomly sampled alleles from the immediate preceding generation (one generation back) is independent of population structure. Second, motivated by this finding, we propose a new coalescent method:i-coalescent analysis.i-coalescent analysis computes the instantaneous coalescent rate (iCR) by using a phylogenetic tree of sampled alleles. Using simulated data, we broadly demonstrate the capability ofi-coalescent analysis to accurately reconstruct population size dynamics of highly structured populations, although we find this method often requires larger sample sizes for structured populations than for panmictic populations. Overall, our results indicatei-coalescent analysis to be a useful tool, especially for the inference of population histories with intractable structure such as the developmental history of cell populations in the organs of complex organisms.
Regulation of REM Sleep by Inhibitory Neurons in the Dorsomedial Medulla
Authors: Stucynski Joseph A. , Schott Amanda L. , Baik Justin , Chung Shinjae , Weber Franz
Published: December 2020

The two major stages of mammalian sleep – rapid eye movement sleep (REMs) and non-REM sleep (NREMs) – are characterized by distinct brain rhythms ranging from millisecond to minute-long (infraslow) oscillations. The mechanisms controlling transitions between sleep stages and how they are synchronized with infraslow rhythms remain poorly understood. Using opto- and chemogenetic manipulation, we show that GABAergic neurons in the dorsomedial medulla (dmM) promote the initiation and maintenance of REMs, in part through their projections to the dorsal and median raphe nuclei. Fiber photometry revealed that dmM GABAergic neurons are strongly activated during REMs. During NREMs, their activity fluctuated in close synchrony with infraslow oscillations in the spindle band of the electroencephalogram, and the phase of this rhythm modulated the latency of optogenetically induced REMs episodes. Thus, dmM inhibitory neurons powerfully promote REMs, and their slow activity fluctuations may coordinate transitions from NREMs to REMs with infraslow brain rhythms.
Validation testing to determine the effectiveness of lateral flow testing for asymptomatic SARS-CoV-2 detection in low prevalence settings
Authors: Ferguson Jack , Dunn Steven , Best Angus , Mirza Jeremy , Percival Benita , Mayhew Megan , Megram Oliver , Ashford Fiona , White Thomas , Moles-Garcia Emma , Crawford Liam , Plant Tim , Bosworth Andrew , Kidd Michael , Richter Alex , Deeks Jonathan , McNally Alan
Published: December 2020

Lateral flow devices are quickly being implemented for use in large scale population surveillance programs for SARS-CoV-2 infection in the United Kingdom. These programs have been piloted in city wide screening in the city of Liverpool, and are now being rolled out to support care home visits and the return home of University students for the Christmas break. Here we present data on the performance of Lateral Flow devices to test almost 8,000 students at the University of Birmingham between December 2nd and December 9th 2020. The performance is validated against almost 800 samples using PCR performed in the University Pillar 2 testing lab, and theoretically validated on thousands of Pillar 2 PCR testing results performed on low-prevalence care home testing samples. Our data shows that Lateral Flow Devices do not detect infections presenting with PCR Ct values over 29-30, meaning that only 3.2% (95% CI 0.6% to 15.6%) of total cases in the student population were detected, but that as many of 85% of cases tested in the Pillar 2 PCR lab would have been detected theoretically
Impact of the Covid-19 pandemic on the mental health and wellbeing of adults with mental health conditions in the UK: A qualitative interview study
Authors: Burton Alexandra , McKinlay Alison , Aughterson Henry , Fancourt Daisy
Published: December 2020

Background

People with mental health conditions have been identified as particularly vulnerable to poor mental health during the coronavirus disease 2019 (COVID-19) pandemic. However, why this population have faced these adverse effects, how they have experienced them and how they have coped remains under-explored.

Aims

To explore how the COVID-19 pandemic affected the mental health of people with existing mental health conditions, and to identify coping strategies for positive mental health.

Methods

Semi-structured qualitative interviews with 22 people with mental health conditions. Participants were purposively recruited via social media, study newsletters and third sector mental health organisations. Data were analysed using reflexive thematic analysis.

Results

Participants were aged 23-70 (mean age 43), predominantly female (59.1%) and of white ethnicity (68.2%). Fifty percent were unable to work due to illness and the most frequently reported mental health condition was depression. Five pandemic related factors contributed to deteriorating mental health: i) feeling safe but isolated at home ii) disruption to mental health services, iii) cancelled plans and changed routines iv) uncertainty and lack of control, v) rolling media coverage. Five coping strategies were identified for maintaining mental health: i) previous experience of adversity ii) social comparison and accountability iii) engaging in hobbies and activities, iv) staying connected with others, v) perceived social support.

Conclusions

Challenges were identified as a direct result of the pandemic and people with severe mental illnesses were particularly negatively affected. However, some found this period a time of respite, drew upon reserves of resilience and adapted their coping strategies to maintain positive wellbeing.
Impact of social distancing regulations and epidemic risk perception on social contact and SARS-CoV-2 transmission potential in rural South Africa: analysis of repeated cross-sectional surveys
Authors: McCreesh Nicky , Dlamini Vuyiswa , Edwards Anita , Olivier Stephen , Dayi Njabulo , Dikgale Keabetswe , Nxumalo Siyabonga , Dreyer Jaco , Baisley Kathy , Siedner Mark J. , White Richard G. , Herbst Kobus , Grant Alison D. , Harling Guy
Published: December 2020

Background

South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited.

Methods

We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal location once in 2019 and twice in mid-2020. Respondents reported characteristics of physical and conversational (‘close interaction’) contacts over 24 hours. We built age-mixing matrices and estimated the proportional change in the SARS-CoV-2 reproduction number (R0). Respondents also reported counts of others present at locations visited and transport used, from which we evaluated change in potential exposure to airborne infection due to shared indoor space (‘shared air’).

Results

Respondents in March-December 2019 (n=1704) reported a mean of 7.4 close interaction contacts and 196 shared air person-hours beyond their homes. Respondents in June-July 2020 (n=216), as the epidemic peaked locally, reported 4.1 close interaction contacts and 21 shared air person-hours outside their home, with significant declines in others’ homes and public spaces. Adults aged over 50 had fewer close contacts with others over 50, but little change in contact with 15-29 year olds, reflecting ongoing contact within multigenerational households. We estimate potential R0fell by 42% (95% plausible range 14-59%) between 2019 and June-July 2020.

Discussion

Extra-household social contact fell substantially following imposition of Covid-19 distancing regulations in rural South Africa. Ongoing contact within intergenerational households highlighted the limitation of social distancing measures in protecting older adults.

Funding

Wellcome Trust, UKRI, DFID, European Union