bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating chronic pain as a risk factor for COVID-19 complications among New York State Medicaid beneficiaries: a retrospective claims analysis
Authors: Perry Allison , Wheeler-Martin Katherine , Terlizzi Kelly , Krawczyk Noa , Jent Victoria , Hasin Deborah S , Neighbors Charles , Mannes Zachary L , Doan Lisa V , Pamplin II John R , Townsend Tarlise N , Crystal Stephen , Martins Silvia S , Cerdá Magdalena
Published: August 2023

Objective

To assess whether chronic pain increases the risk of COVID-19 complications and whether opioid use disorder (OUD) differentiates this risk among New York State Medicaid beneficiaries.

Design, Setting, and Subjects

This was a retrospective cohort study of New York State Medicaid claims data. We evaluated Medicaid claims from March 2019 through December 2020 to determine whether chronic pain increased the risk of COVID-19 emergency department (ED) visits, hospitalizations, and complications and whether this relationship differed by OUD status. We included beneficiaries 18–64 years of age with 10 months of prior enrollment. Patients with chronic pain were propensity score-matched to those without chronic pain on demographics, utilization, and comorbidities to control for confounders and were stratified by OUD. Complementary log–log regressions estimated hazard ratios (HRs) of COVID-19 ED visits and hospitalizations; logistic regressions estimated odds ratios (ORs) of hospital complications and readmissions within 0–30, 31–60, and 61–90 days.

Results

Among 773 880 adults, chronic pain was associated with greater hazards of COVID-related ED visits (HR = 1.22 [95% CI: 1.16–1.29]) and hospitalizations (HR = 1.19 [95% CI: 1.12–1.27]). Patients with chronic pain and OUD had even greater hazards of hospitalization (HR = 1.25 [95% CI: 1.07–1.47]) and increased odds of hepatic- and cardiac-related events (OR = 1.74 [95% CI: 1.10–2.74]).

Conclusions

Chronic pain increased the risk of COVID-19 ED visits and hospitalizations. Presence of OUD further increased the risk of COVID-19 hospitalizations and the odds of hepatic- and cardiac-related events. Results highlight intersecting risks among a vulnerable population and can inform tailored COVID-19 management.
Ultrasound-guided costovertebral joint injection—technique description and fluoroscopy and computerized tomography combined controlled cadaveric feasibility study
Authors: Ferreira-Silva Nuno , Worthy Lucy , Ribas Rita , Ferreira-Dos-Santos Guilherme , Bestic Joseph , Hurdle Mark Friedrich B
Published: August 2023

Objectives

To describe and assess the feasibility of an ultrasound-guided technique for intra-articular injection of the costovertebral joints, in an unembalmed cadaveric specimen, utilizing fluoroscopy and cone beam computerized tomography for confirmation of contrast spread and needle tip position, respectively.

Methodology

A single unembalmed cadaveric specimen was obtained. A single interventionist performed the placement of the needles under ultrasound guidance. Contrast dye was then injected through each of the needles under real-time fluoroscopy. Finally, the specimen was submitted to a cone beam computerized tomography with 3-dimensional acquisition and multiplanar reformatting to assess final needle tip position relative to the costovertebral joints.

Results

In total, 18 spinal needles were placed under ultrasound guidance. Fluoroscopy showed 4 distinct patterns of contrast spread: intra-articular in the costovertebral joint (13 levels in total), epidural (1 level), intra-articular in the facet joint of the target level (3 levels), and undetermined (1 level). Cone-beam computerized tomography confirmed 13 out of 18 needles to be adequately placed in the costovertebral joints (72% of the total) and 5 out of the 18 needles to be misplaced: 3 needles were placed in the facet joint of the target level, and 2 needles were placed in the epidural space.

Conclusions

This study suggests that, when performed by experienced interventionists, this technique has an accuracy rate of 72%. Further studies are warranted before these results can be extrapolated to daily clinical practice.
Albumin-based nanosystem for dual-modality imaging-guided chem-phototherapy against immune-cold triple-negative breast cancer
Authors: Peng Chen , Zeng Xiaodie , Cai Jiali , Huang Hanyu , Yang Fan , Jin Shaowen , Guan Xiuhong , Wang Zhiyong
Published: August 2023

Triple-negative breast cancer is a highly aggressive and metastatic tumor; diagnosing it in the early stages is still difficult, and the prognosis for conventional radio-chemotherapy and immunotreatment is not promising due to cancer’s immunosuppressive microenvironment. The utilization of protein-based nanosystem has proven to be effective in delivering agents with limited adverse effects, yet the combination of diagnosis and treatment remains a difficult challenge. This research took advantage of natural albumin and organic molecules to construct a self-assemble core-shell nanostructure combining with superparamagnetic iron oxide nanocrystals and heptamethine cyanine dye IR780 through non-covalent interactions. This nanocomposite successfully decreased the transverse relaxation time of the magnetic resonance hydrogen nucleus, resulting in outstanding T2 imaging, as well as emitting near-infrared II fluorescence, thereby the resulting dual-modality imaging tool was applied to improve diagnostic competency. It is noteworthy that the nanocomposites exhibited impressive enzyme-like catalytic and photothermal capabilities, resulting in a successful activation of the immune system to efficiently suppress distant metastatic lesions in vivo. Consequently, this nano-drug-based therapy could be an advantageous asset in reinforcing the immune system and hindering the growth and reappearance of the immune-cold breast cancer.
Impaired Lactate Release in Dorsal CA1 Astrocytes Contributed to Nociceptive Sensitization and Comorbid Memory Deficits in Rodents
Authors: Han Shuang , Jiang Bin , Ren Jiale , Gao Feng , Wen Junjian , Zhou Taihe , Wang Laijian , Wei Xuhong
Published: August 2023

Background

Memory deficits are a common comorbid disorder in patients suffering from neuropathic pain. The mechanisms underlying the comorbidities remain elusive. The hypothesis of this study was that impaired lactate release from dysfunctional astrocytes in dorsal hippocampal CA1 contributed to memory deficits.

Methods

A spared nerve injury model was established to induce both pain and memory deficits in rats and mice of both sexes. von Frey tests, novel object recognition, and conditioned place preference tests were applied to evaluate the behaviors. Whole-cell recording, fiber photometry, Western blotting, and immunohistochemistry combined with intracranial injections were used to explore the underlying mechanisms.

Results

Animals with spared sciatic nerve injury that had displayed nociception sensitization or memory deficit comorbidities demonstrated a reduction in the intrinsic excitability of pyramidal neurons, accompanied by reduced Ca2+ activation in astrocytes (ΔF/F, sham: 6 ± 2%; comorbidity: 2 ± 0.4%) and a decrease in the expression of glial fibrillary acidic protein and lactate levels in the dorsal CA1. Exogenous lactate supply or increasing endogenous lactate release by chemogenetic activation of astrocytes alleviated this comorbidity by enhancing the cell excitability (129 ± 4 vs. 88 ± 10 for 3.5 mM lactate) and potentiating N-methyl-d-aspartate receptor–mediated excitatory postsynaptic potentials of pyramidal neurons. In contrast, inhibition of lactate synthesis, blocking lactate transporters, or chemogenetic inhibition of astrocytes resulted in comorbidity-like behaviors in naive animals. Notably, β2-adrenergic receptors in astrocytes but not neurons were downregulated in dorsal CA1 after spared nerve injury. Microinjection of a β2 receptor agonist into dorsal CA1 or activation of the noradrenergic projections onto the hippocampus from the locus coeruleus alleviated the comorbidity, possibly by increasing lactate release.

Conclusions

Impaired lactate release from dysfunctional astrocytes, which could be rescued by activation of the locus coeruleus, led to nociception and memory deficits after peripheral nerve injury.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Composite measures to assess disease damage, disease severity and treatment response in systemic sclerosis clinical trials
Authors: Ross Laura , Nikpour Mandana
Published: August 2023

Purpose of review

The aim of this study was to summarize the composite outcome measures available to assess disease damage, severity and treatment response in systemic sclerosis (SSc).

Recent findings

There have been many recent efforts to rigorously develop and validate composite outcome measures to assess the totality of the impact of SSc on patients. All initiatives have used both consensus and data-driven methods. Recently developed are a SSc-specific damage index, a patient-reported disease impact questionnaire (ScleroID) and a treatment response index (ACR-CRISS).

Multiorgan, composite measures are being increasingly applied to assess treatment efficacy in clinical trials. Although a fully validated, disease-specific composite measure is not yet available, there has been significant recent progress towards developing measures of treatment response, damage and overall impact of SSc for application in randomized controlled trials.
Overview of Noninvasive Prenatal Testing (NIPT) for the Detection of Fetal Chromosome Abnormalities; Differences in Laboratory Methods and Scope of Testing
Authors: BENN PETER , CUCKLE HOWARD
Published: August 2023

Although nearly all noninvasive prenatal testing is currently based on analyzing circulating maternal cell-free DNA, the technical methods usedvary considerably. We review the different methods. Based on validation trials and clinical experience, there are mostly relatively small differences in screening performance for trisomies 21, 18, and 13 in singleton pregnancies. Recent reports show low no-call rates for all methods, diminishing its importance when choosing a laboratory. However, method can be an important consideration for twin pregnancies, screening for sex chromosome abnormalities, microdeletion syndromes, triploidy, molar pregnancies, rare autosomal trisomies, and segmental imbalances, and detecting maternal chromosome abnormalities.
SCLERAL SUTURED TORIC INTRAOCULAR LENS WITH PARS PLANA VITRECTOMY FOR THE CORRECTION OF CORNEAL ASTIGMATISM WITHOUT CAPSULAR SUPPORT
Authors: Starr Matthew R. , Ferenchak Kevin , Mogil Rachel
Published: August 2023

Purpose:

To describe the repair of a patient with bilateral subluxed cataract and corneal astigmatism in the setting of a coloboma of the iris, zonules, lens, and retina. Preoperatively, his best-corrected acuity was 20/500 in the right eye and 20/200 in the left eye. His preoperative refraction was −7.25 +1.00 at 080 in the right eye and −7.75 +3.00 at 040 in the left eye. On corneal topography, he had 1.95D and 1.45D of regular astigmatism in the right and left eye, respectively.

Methods:

This technique involves pars plana vitrectomy in combination with the placement of a MX60 toric intraocular lens fixated to the sclera using 8-0 Gore-Tex in line with the axis of steep corneal astigmatism. The lens is affixed through two pairs of nasal and temporal sclerotomies, with each pair located 3 mm posterior to the limbus and 5 mm apart, centered along the axis of steep astigmatism.

Results:

Postoperatively, uncorrected visual acuity in this patient was 20/25 in the right eye and 20/20 in the left eye with a refraction of −0.75 +0.50 at 180 in the right eye and −0.75 +1.00 at 180 in the left eye.

Conclusion:

Scleral sutured toric intraocular lens placement and pars plana vitrectomy is a viable solution for patients with regular corneal astigmatism and cataract repair in the absence of zonular support.
Management of low astigmatism in implantable collamer lens surgery: opposite clear corneal incisions vs toric implantable collamer lens
Authors: González-Cruces Timoteo , Sánchez-Ventosa Álvaro , Villarrubia Alberto , Sánchez-González José-María , Cano-Ortiz Antonio
Published: August 2023

Purpose:

To compare 2 techniques to correct low astigmatism during implantable collamer lens (ICL) surgery: astigmatic opposite clear corneal incisions (OCCIs) and toric ICL (T-ICL).

Setting:

Arruzafa Ophthalmological Hospital, Cordoba, Spain.

Design:

Randomized prospective comparative study.

Methods:

The study comprised 152 myopic eyes undergoing ICL surgery. Patients were separated into 2 groups: Group 1 (57 patients; 76 eyes) received a spherical ICL with OCCIs and Group 2 (53 patients; 76 eyes) received a T-ICL. The inclusion criteria were refractive astigmatism up to 1.50 diopters (D), regular corneal astigmatism up to 2.00 D (Sim K, Pentacam), and agreement between the refractive and topographic corneal cylinders (discrepancies less than 30 degrees axis or 0.50 D). The outcomes were evaluated after a 1-month follow-up.

Results:

The T-ICL group achieved a mean postoperative spherical equivalent refraction and refractive astigmatism of −0.04 ± 0.17 D and −0.03 ± 0.12 D, respectively, vs −0.14 ± 0.33 D and −0.20 ± 0.36 D, in the OCCI group (P< .001). Postoperative refractive astigmatism of less than 0.25 D was achieved in 94.74% of cases in the T-ICL group vs 73.68% in the OCCI group. Undercorrection of corneal astigmatism occurred in the OCCI group with a surgically induced astigmatism of 0.48 ± 0.24 D and correction index = 0.46.

Conclusions:

Both the T-ICL and OCCI techniques provided excellent results in terms of safety and efficacy. T-ICL surgery was shown to be more predictable and accurate for correcting low astigmatism with a lower postoperative spherical equivalent and less residual astigmatism compared to incisional management.
A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable
Authors: Perazzolo Simone , Stephen Zachary , Eguchi Masa , Xu Xiaolin , Fratte Rachele Delle , Collier Ann C. , Melvin Ann J. , Ho Rodney J.Y.
Published: August 2023

Objective:

To develop an injectable dosage form of the daily oral HIV drugs, tenofovir (T), lamivudine (L), and dolutegravir (D), creating a single, complete, all-in-one TLD 3-drug-combination that demonstrates long-acting pharmacokinetics.

Design:

Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3 HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP. TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina).

Results:

Following single-dose TLD-in-DcNP, all drugs exhibited long-acting profiles in NHP plasma with levels that persisted for 4 weeks above predicted viral-effective concentrations for TLD in combination. Times-to-peak were within 24 hr in all NHP for all drugs. Compared to a free-soluble TLD, TLD-in-DcNP provided exposure enhancement and extended duration 7.0-, 2.1-, and 20-fold as AUC boost and 10-, 8.3-, and 5.9-fold as half-life extension. Additionally, DcNP may provide more drug exposure in cells than plasma with PBMC-to-plasma drug ratios exceeding one, suggesting cell-targeted drug-combination delivery.

Conclusions:

This study confirms that TLD with disparate properties can be made stable by DcNP to enable TLD concentrations of 4 weeks in NHP. Study results highlighted the potential of TLD-in-DcNP as a convenient all-in-one, complete HIV long-acting product for clinical development.
A New Minimally Invasive Procedure for Treating Plantar Heel Pain
Authors: Wu Bihua , Xiao Shune , Yang Sanhong , Wei Zairong , Deng Chengliang
Published: August 2023

Atrophy of the fat pad is considered to be one of the main causes of plantar heel pain. Recent studies showed fat grafting increased fat pad volume and was beneficial for treating pedal fat pad atrophy. However, traditional fat grafting has a high absorption rate because of lower concentration of adipose-derived stem cells. Stromal vascular fraction gel (SVF-gel), as a novel fat grafting and rich in adipose-derived stem cells, is prepared by a simple mechanical process. This study aimed to assess the efficacy of SVF-gel in the treatment of plantar heel pain.

Methods

Fourteen patients who experienced plantar heel pain and underwent plantar heel SVF-gel grafting between January 2019 and June 2020 were included in this retrospective study. Foot pain and disability were measured at the screening visit and at the 3-, 6-, and 12-month follow-up visits. The volume of the heel fat pad was measured by magnetic resonance imaging.

Results

Four of the patients had bilateral plantar heel pain, and 10 patients had unilateral plantar heel pain. All patients showed significant improvements in pain and foot function at 3 months after SVF-gel grafting compared with the baseline, with the greatest improvement at 6 months and the effect lasting 1 year or more. In addition, the thickness of the heel fat pad was significantly greater than at baseline at 3 months, and the effect lasted for 1 year or more.

Conclusion

Stromal vascular fraction gel grafting is a safe, minimally invasive, and effective approach to treat plantar heel pain.
How much should we sequence? An analysis of the Swiss SARS-CoV-2 surveillance effort
Authors: Wegner Fanny , Cabrera-Gil Blanca , Araud Tanguy , Beckmann Christiane , Beerenwinkel Niko , Bertelli Claire , Carrara Matteo , Cerutti Lorenzo , Chen Chaoran , Cordey Samuel , Dumoulin Alexis , du Plessis Louis , Friedli Marc , Gerth Yannick , Greub Gilbert , Härri Adrian , Hirsch Hans , Howald Cedric , Huber Michael , Imhof Alexander , Kaiser Laurent , Kufner Verena , Leib Stephen L. , Leuzinger Karoline , Lleshi Etleva , Lucchini Gladys Martinetti , Mäusezahl Mirjam , Moraz Milo , Neher Richard , Nolte Oliver , Ramette Alban , Redondo Maurice , Risch Lorenz , Rohner Lionel , Roloff Tim , Schläpfer Pascal , Schneider Katrin , Singer Franziska , Spina Valeria , Stadler Tanja , Studer Erik , Topolsky Ivan , Trkola Alexandra , Walther Daniel , Wohlwend Nadia , Zehnder Cinzia , Neves Aitana , Egli Adrian ,   the SPSP consortium
Published: August 2023

Background

During the SARS-CoV-2 pandemic, many countries directed substantial resources towards genomic surveillance to detect and track viral variants. There is a debate over how much sequencing effort is necessary in national surveillance programs for SARS-CoV-2 and future pandemic threats.

Aim

We aimed to investigate the effect of reduced sequencing on surveillance outcomes in a large genomic dataset from Switzerland, comprising more than 143k sequences.

Methods

We employed a uniform downsampling strategy using 100 iterations each to investigate the effects of fewer available sequences on the surveillance outcomes: (i) first detection of variants of concern (VOCs), (ii) speed of introduction of VOCs, (iii) diversity of lineages, (iv) first cluster detection of VOCs, (v) density of active clusters, and (vi) geographic spread of clusters.

Results

The impact of downsampling on VOC detection is disparate for the three VOC lineages, but many outcomes including introduction and cluster detection could be recapitulated even with only 35% of the original sequencing effort. The effect on the observed speed of introduction and first detection of clusters was more sensitive to reduced sequencing effort for some VOCs, in particular Omicron and Delta, respectively.

Conclusion

A genomic surveillance program needs a balance between societal benefits and costs. While the overall national dynamics of the pandemic could be recapitulated by a reduced sequencing effort, the effect is strongly lineage dependent – something that is unknown at the time of sequencing – and comes at the cost of accuracy, in particular for tracking the emergence of potential VOCs.
Metagenomic analysis of individual mosquitos reveals the ecology of insect viruses
Authors: Pan Yuan-fei , Zhao Hailong , Gou Qin-yu , Shi Pei-bo , Tian Jun-hua , Feng Yun , Li Kun , Yang Wei-hong , Wu De , Tang Guangpeng , Zhang Bing , Ren Zirui , Peng Shiqin , Luo Geng-yan , Le Shi-jia , Xin Gen-yang , Wang Jing , Hou Xin , Peng Min-wu , Kong Jian-bin , Chen Xin-xin , Yang Chun-hui , Mei Shi-qiang , Liao Yu-qi , Cheng Jing-xia , Wang Juan , Chaolemen  , Wu Yu-hui , Wang Jian-bo , An Tongqing , Huang Xinyi , Eden John-Sebastian , Li Jun , Guo Deyin , Liang Guodong , Jin Xin , Holmes Edward C. , Li Bo , Wang Daxi , Li Junhua , Wu Wei-chen , Shi Mang
Published: August 2023

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Using a meta-transcriptomic approach, we analysed the virome of 2,438 individual mosquitos (79 species), spanning ∼4000 km along latitudes and longitudes in China. From these data we identified 393 core viral species associated with mosquitos, including seven (putative) arbovirus species. We identified potential species and geographic hotspots of viral richness and arbovirus occurrence, and demonstrated that host phylogeny had a strong impact on the composition of individual mosquito viromes. Our data revealed a large number of viruses shared among mosquito species or genera, expanding our knowledge of host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, possibly facilitated by long-distance mosquito migrations. Together, our results greatly expand the known mosquito virome, linked the viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the ecology of viruses of insect vectors.
Validation study for noninvasive single-cell-based prenatal genetic testing
Authors: Bellair Michelle , Amaral Elisabete , Ouren Mason , Roark Cameron , Kim Jaeweon , O’Connor April , Soriano Adrianna , Schindler Margaret L. , Wapner Ronald J. , Stone Joanne L. , Tavella Nicola , Merriam Audrey , Perley Lauren , Breman Amy M. , Beaudet Arthur L.
Published: August 2023

Objective

To clinically validate a cell-based noninvasive prenatal genetic test using sequence-based copy number analysis of single trophoblasts from maternal blood.

Methods

Blood was obtained from 401 individuals (8-22 weeks) and shipped overnight. Red blood cells were lysed, and nucleated cells stained for cytokeratin (CK) and CD45 using fluorescent antibodies and enriched for positive CK staining. Automated microscopic scanning was used to identify and pick single CK+/CD45-trophoblasts which were subjected to whole genome amplification and next-generation sequencing.

Results

Blood was obtained from 243 pregnancies scheduled for CVS or amniocentesis. Luna results were normal for 160 singletons while 15 cases were abnormal (14 aneuploidy and one monozygotic twin case with Williams syndrome deletion). These Luna results agreed with CVS/amniocentesis. Placental mosaicism occurred in 7 of 236 (3.0%) Luna cases and in 3 of 188 (1.6%) CVS cases (total 4.6%). No scorable trophoblasts were recovered in 32 of 236 (13.6%) usable samples. Additionally, 158 low-risk pregnancies not undergoing CVS/amniocentesis showed normal results for 133 cases. Seven had aneuploidy results, and there were 3 likely pathogenic deletions or duplications including one15q11-q13 deletion.

Conclusion

This noninvasive cell-based prenatal genetic test detected aneuploidy and deletions/duplications with high sensitivity and specificity based on concordance with CVS/amniocentesis.

Key points

What’s already known about this topic?

As a proof of principle for noninvasive genetic prenatal diagnosis, circulating fetal trophoblasts have been isolated from maternal blood and analyzed for detection of aneuploidy and genomic deletions and duplications.

These trophoblasts reflect the genotype of the current placenta(s) but not necessarily the genotype of the fetus because of placental mosaicism.

What does this study add?

This study demonstrates the advantages of single cell analysis and the feasibility of launching a test for reliable detection of cytogenetic aneuploidy, deletions, and duplications.

This test has improved detection of deletions and duplications compared to cell-free NIPT, but widespread adoption will require improved recovery of fetal cells from maternal blood and reduced cost through automation and high-throughput.
Comparative Analysis of Cytokine Profiles in Cerebrospinal Fluid and Blood Serum in Patients with Acute and Subacute Spinal Cord Injury
Authors: Sabirov Davran , Ogurcov Sergei , Shulman Ilya , Kabdesh Ilyas , Garanina Ekaterina , Sufianov Albert , Rizvanov Albert , Mukhamedshina Yana
Published: August 2023

Background

Cytokines are actively involved in the regulation of the inflammatory and immune responses and play crucial importance for the outcome of spinal cord injury (SCI). Considering the importance of examining more objective and representative indicators of the patient’s condition is still required to reveal the fundamental patterns of abovementioned posttraumatic processes, including identification of changes in the expression of cytokines.

Methods

We performed a dynamic (3, 7 and 14 dpi) extended multiplex analysis of cytokine profiles in both CSF and blood serum of SCI patients with baseline American Spinal Injury Association Impairment Scale grades of A.

Results

The data obtained showed a large elevation of IL-6 (>58 fold) in CSF and IFN-γ (>14 fold) in blood serum at 3 dpi with a downward trend as the post-traumatic period increases. The level of cytokine CCL26 was significantly elevated both CSF and blood serum at 3 days post-SCI while other cytokines did not show the same trend in the different biosamples.

Conclusions

The dynamic changes in cytokine levels observed in our study can explore the relationships with SCI region and injury severity, paving the way for a better understanding of the pathophysiology of SCI and potentially more targeted and personalized therapeutic interventions.
A retrospective longitudinal study of adenovirus group F, norovirus GI and GII, rotavirus, and enterovirus nucleic-acids in wastewater solids at two wastewater treatment plants: Solid-liquid partitioning and relation to clinical testing data
Authors: Boehm Alexandria B. , Hughes Bridgette , Duong Dorothea , Banaei Niaz , White Bradley J. , Wolfe Marlene K.
Published: August 2023

Background

Enteric infections are important causes of morbidity and mortality, yet clinical surveillance is limited. Wastewater-based epidemiology (WBE) has been used to study community circulation of individual enteric viruses and panels of respiratory diseases, but there is limited work studying concurrent circulation of a suite of important enteric viruses.

Methods

A retrospective WBE study was carried out at two wastewater treatment plants located in California, United States. Using droplet digital polymerase chain reaction (PCR), we measured concentrations of human adenovirus group F, enteroviruses, norovirus genogroups I and II, and rotavirus nucleic-acids in wastewater solids two times per week for 26 months (n=459 samples) between 2/1/21 and 4/14/23. A novel probe-based PCR assay was developed and validated for adenovirus. We compared viral nucleic-acid concentrations to positivity rates for viral infections from clinical specimens submitted to a local clinical laboratory to assess concordance between the data sets.

Findings

We detected all viral targets in wastewater solids. At both wastewater treatment plants, human adenovirus group F and norovirus GII nucleic-acids were detected at the highest concentrations (median concentrations greater than 105cp/g), while rotavirus RNA was detected at the lowest concentrations (median on the order of 103cp/g). Rotavirus, adenovirus group F, and norovirus nucleic-acid concentrations were positivity associated with clinical specimen positivity rates. Concentrations of tested viral nucleic-acids exhibited complex associations with SARS-CoV-2 and other respiratory viral nucleic-acids in wastewater, suggesting divergent transmission patterns.

Interpretation

This study provides evidence for the use of wastewater solids for the sensitive detection of enteric virus targets in WBE programs aimed to better understand the spread of enteric disease at a localized, community level without limitations associated with testing many individuals. Wastewater data can inform clinical, public health, and individual decision making aimed to reduce transmission of enteric disease.
High-resolution diploid 3D genome reconstruction using Pore-C data
Authors: Chen Ying , Lin Zhuo-Bin , Wang Shao-Kai , Wu Bo , Niu Long-Jian , Zhong Jia-Yong , Sun Yi-Meng , Bai Xin , Liu Luo-Ran , Xie Wei , Luo Ruibang , Hou Chunhui , Luo Feng , Xiao Chuan-Le
Published: August 2023

In diploid organisms, spatial variations between homologous chromosomes are essential to many biological phenomena. Currently, it is still challenging to efficiently reconstruct a high-quality diploid 3D human genome. Here, we introduce Dip3D, reconstructing the diploid 3D human genome using Pore-C data of one sample. Dip3D has solved multiple problems in genome-wide SNV calling and haplo-tagging caused by the high sequencing error rates in Pore-C type data. Dip3D capitalizes on the high-order chromosomal interaction characteristics, enabling robust haplotype imputation and intricate haplotype-specific 3D structure discovery. Dip3D outperforms previous methods in data utilization rate, contact matrix resolution, and completeness by one order of magnitude. Moreover, Dip3D allows capturing haplotype high-order interactions that are unseen in Hi-C type data. We demonstrated the identified haplotype substructures such as Topologically Associating Domains (TADs) in the constructed 3D human genome, and unraveled connections between genic haplotype-specific high-order interactions and imbalanced allelic expression.
A trade-off in controlling upstream and downstream noise in signaling networks
Authors: Kong Ka Kit , Luo Chunxiong , Liu Feng
Published: August 2023

Signal transduction, underpinning the function of a variety of biological systems, is inevitably affected by fluctuations. It remains intriguing how the timescale of a signaling network relates to its capability of noise control, specifically, whether long timescale can average out fluctuation or accumulate fluctuation. Here, we consider two noise components of the signaling system: the upstream noise from the fluctuation of the input signal and the downstream noise from the stochastic fluctuations of the network. We discover a fundamental trade-off in controlling the upstream and downstream noise: a longer timescale of the signaling network can buffer upstream noise, while accumulate downstream noise. Moreover, we confirm that this trade-off relation exists in real biological signaling networks such as a fold-change detection circuit and the p53 activation signaling system.

Author Summary

Information transmission is vital in biological systems, such as decoding the information regarding nutrient levels during chemotaxis or morphogen concentrations in tissue development. While fluctuations arising from the stochastic nature of biological processes inevitably affect information transmission, noise control mechanisms have been studied for decades. However, it remains controversial what the role of the slow dynamics (long timescale) is in noise control. On the one hand, it has been reported to attenuate noise by averaging out fluctuations. On the other hand, it is also proposed to amplify noise by accumulating fluctuations. Here we dissect the noise in signaling systems into two components: upstream noise originating from signal fluctuation, and downstream noise from the network stochasticity. Our analysis reveals that upstream noise negatively correlates with timescale, while downstream noise exhibits a positive correlation, indicating a fundamental trade-off in controlling the two noise components. Moreover, we provide an intuitive illustration to understand this phenomenon using the concept of landscape representation. Mathematically, we analytically derive a trade-off relation that agrees well with simulations. Our results uncover a new property of noise in signaling processes, deepening our understanding of noise control and proposing a new perspective in designing signaling network.
Secondary contact, introgressive hybridization and genome stabilization in sticklebacks
Authors: Feng Xueyun , Merilä Juha , Löytynoja Ari
Published: August 2023

Advances in genomic studies have revealed that hybridization in nature is pervasive and raised questions about the dynamics of different genetic and evolutionary factors following the initial hybridization event. While recent research has proposed that the genomic outcomes of hybridization might be predictable to some extent, many uncertainties remain. With comprehensive whole-genome sequence data, we investigated the genetic introgression between two divergent lineages of nine-spined sticklebacks (Pungitius pungitius) in the Baltic Sea. We found that the intensity and direction of selection on the introgressed variation varied across different genomic elements: while functionally important regions had experienced reduced rates of introgression, promoter regions showed enrichment. Despite the general trend of negative selection, we identified specific genomic regions that were enriched for introgressed variants and within these regions, we detected footprints of selection, indicating adaptive introgression. We found the selection against the functional changes to be strongest in the vicinity of the secondary contact zone and weaken as a function of distance from the initial contact. Altogether, the results suggest that the stabilization of introgressed variation in the genomes is a complex, multi-stage process involving both negative and positive selection. In spite of the predominance of negative selection against introgressed variants, we also found evidence for adaptive introgression variants likely associated with adaptation to Baltic Sea environmental conditions.
Population dynamic population delineation in North American birds
Authors: Witting Lars
Published: August 2023

Andrewartha and Birch (1954) envisioned that natural populations are surrounded by ecological barriers, yet statistical estimates of population structure are almost completely driven by genetic analyses void of ecological information. I develop an ecological clustering routine that delineates natural populations from the synchronisation and desynchronisation in the population dynamics of continuously distributed species. The method is applied to the North American Breeding Bird Survey (Sauer et al. 2017), where it identifies two to five populations per species for 160 species, and leaves the population differentiation unresolved for 139 species. This provides one of the first statistical methods for population dynamics delineated population structure.
Human-brown bear conflicts in Türkiye are driven by increased human presence around protected areas
Authors: Sıkdokur Ercan , Naderi Morteza , Çeltik Elif , Aytekin M. Çisel Kemahlı , Kusak Josip , Sağlam İsmail K. , Şekercioğlu Çağan H.
Published: August 2023

Human-wildlife conflict is increasing steadily worldwide and is rapidly becoming an important challenge for the success of conservation programs. Brown bears, which suffer from reduced habitat suitability and quality globally, frequently conflict with humans. These animals need large home ranges to fulfill their habitat requirements. When space and food are restricted, brown bears frequently shift towards human-dominated landscapes that offer reliable food sources. As a country where most of the landscape and habitats are human-dominated, human-brown bear conflict events (HBCs) are frequent in Türkiye. However, there has been no formal analysis of the nature and scope of these conflicts at the country level. Here, using HBC data from 2017 to 2022, we determined the spatial and temporal dynamics of HBC events and generated a risk probability map based on anthropogenic predictors and geographic profiling, to determine the factors driving HBC across Türkiye. HBC events did not show any annual or seasonal trends but varied considerably across biogeographic regions, with most conflicts occurring along the Black Sea coast and Eastern Anatolia. Sixty percent of all conflicts were due to bear foraging behavior in human settlements while twelve percent were the result of human activity in forests, with 57% of all conflict events resulting in direct injury to either humans or bears. We found that distance to villages, distance to protected areas, distance to farmland and human footprint to be the most important factors contributing to conflict risk. Consequently, 21% of the country was found to be under human-bear conflict risk, with 43% of the risks occurring within a 10 km radius from the centers of protected areas. Our analyses indicate that the high occurrence of HBCs is mainly the result of limited natural areas and resources available to brown bears and the increasing human encroachment in and around core bear habitats.
Differentiable simulation to develop molecular dynamics force fields for disordered proteins
Authors: Greener Joe G
Published: August 2023

Implicit solvent force fields are computationally efficient but can be unsuitable for running molecular dynamics on disordered proteins. Here I improve the a99SB-dispforce field and the GBNeck2 implicit solvent model to better describe disordered proteins. Differentiable molecular simulations with 5 ns trajectories are used to jointly optimise 108 parameters to better match explicit solvent trajectories. Simulations with the improved force field better reproduce the radius of gyration and secondary structure content seen in experiments, whilst showing slightly degraded performance on folded proteins and protein complexes. The force field, called GB99dms, reproduces the results of a small molecule binding study and improves agreement to experiment for the aggregation of amyloid peptides. GB99dms, which can be used in OpenMM, is available athttps://github.com/greener-group/GB99dms. This work is the first to show that gradients can be obtained directly from nanosecond-length differentiable simulations of biomolecules and highlights the effectiveness of this approach to training whole force fields to match desired properties.
Modeling effects of variable preBötzinger Complex network topology and cellular properties on opioid-induced respiratory depression and recovery
Authors: Chou Grant M. , Bush Nicholas E. , Phillips Ryan S. , Baertsch Nathan A. , Harris Kameron Decker
Published: August 2023

The pre-Bötzinger complex (preBotC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBötC to perform severalin silicoexperiments exploring how differences in network topology and the intrinsic properties of preBötC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBötC networksin silicoexhibit variable responses to simulated opioids, similar to the preBötC networkin vitro. This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBötC network that may regulate its susceptibility to opioids.

Significance Statement

The neural network in the brainstem that generates the breathing rhythm is disrupted by opioid drugs. However, this response can be surprisingly unpredictable. By constructing computational models of this rhythm-generating network, we illustrate how random differences in the distribution of biophysical properties and connectivity patterns within individual networks can predict their response to opioids, and we show how modulation of these network features can make breathing more susceptible or resistant to the effects of opioids.
Alternating Polarity as a Novel Strategy for Cultivating Electro-Methanogenic Microbial Communities Capable of Robust Biogas Production
Authors: Yao Shiyun , Swanson Clifford S , Cheng Zhang , He Qiang , Yuan Heyang
Published: August 2023

Electro-methanogenic microbial communities can produce biogas with high efficiency. Extensive efforts have been made to cultivate these communities in engineered systems. Conventional cultivation strategies can select electrotrophic methanogens but not their electron-donating partners, resulting in communities that are sensitive to perturbations. Herein, we developed an alternating polarity strategy to simultaneously select both microbial populations. In two-chamber bioelectrochemical systems amended with activated carbon, the electrode potential was alternated between +0.8 V and -0.4 V vs. standard hydrogen electrode every three days. After eight alternating cycles, cultivated activated carbon was transferred into new bioreactors, and the enrichment procedure was repeated four times. Cumulative biogas production under alternating polarity increased from 45 L/L/kg-activated carbon after start-up to 125 L/L/kg after the 4thenrichment, significantly higher than that under intermittent cathode (-0.4 V/open circuit), continuous cathode (-0.4 V), and open circuit. The communities cultivated under alternating polarity were electroactive and structurally different from those cultivated under other conditions. OneMethanobacteriumpopulation and twoGeobacterpopulations were consistently abundant and active in the communities. Their 16S rRNA was upregulated by electrode potentials. Bayesian networks inferred close associations between these populations. The cultivation strategy can enhance biogas production, and the cultivated communities may serve as a model system for elucidating the mechanisms of extracellular electron uptake.

Synopsis

An alternating polarity strategy was developed in this study to cultivate electro-methanogenic microbial communities. The cultivated communities can produce biogas more efficiently and help us understand the ecophysiology of the key microbial populations.
Multi-omics investigation on the prognostic and predictive factors in metastatic breast cancer using data from Phase III ribociclib clinical trials: A statistical and machine learning analysis plan
Authors: Coroller Thibaud , Sahiner Berkman , Amatya Anup , Gossmann Alexej , Karagiannis Konstantinos , Samala Ravi K. , Santana-Quintero Luis , Solovieff Nadia , Wang Craig , Amiri-Kordestani Laleh , Cao Qian , Cha Kenny H. , Orbach Rosane Charlab , Cross Frank H. , Hu Tingting , Huang Ruihao , Kraft Jeffrey , Krusche Peter , Li Yutong , Li Zheng , Mazo Ilya , Moloney Conor , Paul Rahul , Plawinski Jason , Schnakenberg Susan , Serra Paolo , Smith Sean , Song Chi , Su Fei , Subramaniam Sajanth , Tiwari Mohit , Vechery Colin , Xiong Xin , Zarate Juan Pablo , Ziegler Jonathan , Zhu Hao , Chakravartty Arunava , Liu Qi , Ohlssen David , Petrick Nicholas , Schneider Julie A. , Walderhaug Mark , Zuber Emmanuel
Published: August 2023

Abstract

In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to find novel radiogenomics-based prognostic and predictive factors for HR+/HER2-metastatic breast cancer under a Research Collaboration Agreement. This manuscript aims to detail the guiding principles and methodology for this study. We include a discussion of internal and external clinical, genomics, imaging datasets, data processing workflows, and machine learning model development strategies. We also prospectively define our success criteria to ensure robust scientific outputs.

Disclosure

This publication reflects the views of the authors and should not be construed to represent FDA’s views or policies.
De novo peptide sequencing with InstaNovo: Accurate, database-free peptide identification for large scale proteomics experiments
Authors: Eloff Kevin , Kalogeropoulos Konstantinos , Morell Oliver , Mabona Amandla , Jespersen Jakob Berg , Williams Wesley , van Beljouw Sam P. B. , Skwark Marcin , Laustsen Andreas Hougaard , Brouns Stan J. J. , Ljungers Anne , Schoof Erwin M. , Van Goey Jeroen , auf dem Keller Ulrich , Beguir Karim , Carranza Nicolas Lopez , Jenkins Timothy P.
Published: August 2023

Bottom-up mass spectrometry-based proteomics is challenged by the task of identifying the peptide that generates a tandem mass spectrum. Traditional methods that rely on known peptide sequence databases are limited and may not be applicable in certain contexts.De novopeptide sequencing, which assigns peptide sequences to the spectra without prior information, is valuable for various biological applications; yet, due to a lack of accuracy, it remains challenging to apply this approach in many situations. Here, we introduce InstaNovo, a transformer neural network with the ability to translate fragment ion peaks into the sequence of amino acids that make up the studied peptide(s). The model was trained on 28 million labelled spectra matched to 742k human peptides from the ProteomeTools project. We demonstrate that InstaNovo outperforms current state-of-the-art methods on benchmark datasets and showcase its utility in several applications. Building upon human intuition, we also introduce InstaNovo+, a multinomial diffusion model that further improves performance by iterative refinement of predicted sequences. Using these models, we couldde novosequence antibody-based therapeutics with unprecedented coverage, discover novel peptides, and detect unreported organisms in different datasets, thereby expanding the scope and detection rate of proteomics searches. Finally, we could experimentally validate tryptic and non-tryptic peptides with targeted proteomics, demonstrating the fidelity of our predictions. Our models unlock a plethora of opportunities across different scientific domains, such as direct protein sequencing, immunopeptidomics, and exploration of the dark proteome.
Immune Evasion and Membrane Fusion of SARS-CoV-2 XBB Subvariants EG.5.1 and XBB.2.3
Authors: Faraone Julia N. , Qu Panke , Goodarzi Negin , Zheng Yi-Min , Carlin Claire , Saif Linda J. , Oltz Eugene M. , Xu Kai , Jones Daniel , Gumina Richard J. , Liu Shan-Lu
Published: August 2023

Immune evasion by SARS-CoV-2 paired with immune imprinting from monovalent mRNA vaccines has resulted in attenuated neutralizing antibody responses against Omicron subvariants. In this study, we characterized two new XBB variants rising in circulation — EG.5.1 and XBB.2.3, for their ability of neutralization and syncytia formation. We determined the neutralizing antibody in sera of individuals that received a bivalent mRNA vaccine booster, BA.4/5-wave infection, or XBB.1.5-wave infection. Bivalent vaccination-induced antibodies neutralized efficiently ancestral D614G, but to a much less extent, two new EG.5.1 and XBB.2.3 variants. In fact, the enhanced neutralization escape of EG.5.1 appeared to be driven by its key defining mutation XBB.1.5-F456L. Notably, infection by BA.4/5 or XBB.1.5 afforded little, if any, neutralization against EG.5.1, XBB.2.3 and previous XBB variants — especially in unvaccinated individuals, with average neutralizing antibody titers near the limit of detection. Additionally, we investigated the infectivity, fusion activity, and processing of variant spikes for EG.5.1 and XBB.2.3 in HEK293T-ACE2 and CaLu-3 cells but found no significant differences compared to earlier XBB variants. Overall, our findings highlight the continued immune evasion of new Omicron subvariants and, more importantly, the need to reformulate mRNA vaccines to include XBB spikes for better protection.