bluuebunny/crossref_metadata_2025 huggingface dataset:
“I Prefer to Stay Away”: A Qualitative Study of Patients in an Opioid-Sparing Pain Management Protocol
Authors: Johnson Emily , Yoshida Maxwell , Hallway Alexander , Byrnes Mary , Waljee Jennifer , Englesbe Michael , Howard Ryan
Published: July 2021

Objective:

The aim of this study was to explore beliefs and behaviors of opioid pain medications among patients undergoing elective surgery.

Background:

Opioid dependence after surgery is a major contributor to the ongoing opioid epidemic. Recent efforts by surgeons and health systems have sought to improve the education patients receive regarding safe opioid use after surgery; however, little is known about patients’ pre-existing beliefs surrounding opioids.

Methods:

Semistructured interviews were conducted with patients who underwent 1 of 4 common elective surgical procedures at 1 institution. Patients were specifically asked about their knowledge and beliefs about opioids before surgery and their opinions of opioid-sparing recovery after surgery. Coding was conducted through iterative steps, beginning with an initial cycle of rapid analysis, followed by focused coding, and thematic analysis.

Results:

Twenty-one patients were interviewed. Three major themes emerged regarding patient opinions about using opioids after surgery. First, there was widespread awareness among patients about opioid medications, and preoperatively, patients had specific intentions about using opioids, often informed by this awareness. Second, patients described a spectrum of opioid related behavior which both aligned and conflicted with preoperative intentions. Third, there was tension among patients about opioid-free postoperative recovery, with patients expressing support, opposition, and emphasis on tailoring recovery to patient needs.

Conclusions:

Patients undergoing common surgical procedures often arrive at their surgical encounter with strong, pre-formed opinions about opioids. Eliciting these preexisting opinions may help surgeons better counsel patients about safe opioid use after surgery.
Rural Disparities in Lung Cancer-directed Surgery
Authors: Loehrer Andrew P. , Chen Louisa , Wang Qianfei , Colla Carrie H. , Wong Sandra L.
Published: July 2021

Objective:

The primary objective of this study was to determine the influence of rural residence on access to and outcomes of lung cancer-directed surgery for Medicare beneficiaries.

Summary of Background Data:

Lung cancer is the leading cause of cancerrelated death in the United States and rural patients have 20% higher mortality. Drivers of rural disparities along the continuum of lung cancercare delivery are poorly understood.

Methods:

Medicare claims (2015–2018) were used to identify 126,352 older adults with an incident diagnosis of nonmetastatic lung cancer. Rural Urban Commuting Area codes were used to define metropolitan, micropolitan, small town, and rural site of residence. Multivariable logistic regression models evaluated influence of place of residence on 1) receipt of cancer-directed surgery, 2) time from diagnosis to surgery, and 3) postoperative outcomes.

Results:

Metropolitan beneficiaries had higher rate of cancer-directed surgery (22.1%) than micropolitan (18.7%), small town (17.5%), and isolated rural (17.8%) (P < 0.001). Compared to patients from metropolitan areas, there were longer times from diagnosis to surgery for patients living in micropolitan, small, and rural communities. Multivariable models found nonmetropolitan residence to be associated with lower odds of receiving cancer-directed surgery and MIS. Nonmetropolitan residence was associated with higher odds of having postoperative emergency department visits.

Conclusions:

Residence in nonmetropolitan areas is associated with lower probability of cancer-directed surgery, increased time to surgery, decreased use of MIS, and increased postoperative ED visits. Attention to timely access to surgery and coordination of postoperative care for nonmetropolitan patients could improve care delivery.
FLOT-regimen Chemotherapy and Transthoracic en bloc Resection for Esophageal and Junctional Adenocarcinoma
Authors: Donlon Noel E. , Kammili Anitha , Roopnarinesingh Ryan , Davern Maria , Power Robert , King Sinead , Chmelo Jakub , Phillips Alexander W. , Donohoe Claire L. , Ravi Narayanasamy , Lowery Maeve , Mueller Carmen L. , Cools-Lartigue Jonathan , Ferri Lorenzo E. , Reynolds John V.
Published: July 2021

Background and Aims:

The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes.

Study design:

An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology.

Results:

175 patients (cT2-4a, Nany) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%.

Conclusion:

FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway.
Medicare Advantage Networks and Access to High-volume Cancer Surgery Hospitals
Authors: Raoof Mustafa , Jacobson Gretchen , Fong Yuman
Published: July 2021

Objective:

To determine how Medicare Advantage (MA) health plan networks impact access to high-volume hospitals for cancer surgery.

Background:

Cancer surgery at high-volume hospitals is associated with better short- and long-term outcomes. In the United States, health insurance is a major detriment to seeking care at high-volume hospitals. A third of older (>65 years) Americans are enrolled in privatized MA health plans. The impact of MA plan networks on access to high-volume surgery hospitals is unknown.

Methods:

We analyzed in-network hospitals for MA plans offered in Los Angeles county during open enrollment of 2015. For the purposes of this analysis, MA network data from provider directories were linked to hospital volume data from California Office of Statewide Health Planning and Development. Volume thresholds were based on published literature.

Results:

A total of 34 MA plans enrolled 554,754 beneficiaries in Los Angeles county during 2014 open enrollment for coverage starting in 2015 (MA penetration ∼43%). The proportion of MA plans that included high-volume cancer surgery hospital varied by the type of cancer surgery. While most plans (>71%) included at least one high-volume hospital for colon, rectum, lung, and stomach; 59% to 82% of MA plans did not include any high-volume hospitals for liver, esophagus, or pancreatic surgery. A significant proportion of beneficiaries in MA plans did not have access to high-volume hospitals for esophagus (93%), stomach (44%), liver (39%), or pancreas (70%) surgery. In contrast, nearly all MA beneficiaries had access to at least one high-volume hospital for lung (93%), colon (100%), or rectal (100%) surgery. Overall, Centers for Medicare & Medicaid Services plan rating or plan popularity were not correlated with access to high-volume hospital (P > 0.05).

Conclusions:

The study identifies lack of high-volume hospital coverage in MA health plans as a major detriment in regionalization of cancer surgery impacting at least a third of older Americans.
Kidney Transplantation Confers Survival Benefit for Candidates With Pulmonary Hypertension
Authors: Nguyen Michelle C. , Po-Yu Chiang Teresa , Massie Allan B. , Bae Sunjae , Motter Jennifer D. , Brennan Daniel C. , Desai Niraj M. , Segev Dorry L. , Garonzik-Wang Jacqueline M.
Published: July 2021

Background.

Kidney transplantation (KT) is controversial in patients with pretransplant pulmonary hypertension (PtPH). We aimed to quantify post-KT graft and patient survival as well as survival benefit in recipients with PtPH.

Methods.

Using UR Renal Data System (2000–2018), we studied 90 819 adult KT recipients. Delayed graft function, death-censored graft failure, and mortality were compared between recipients with and without PtPH using inverse probability weighted logistic and Cox regression. Survival benefit of KT was determined using stochastic matching and stabilized inverse probability treatment Cox regression.

Results.

Among 90 819 KT recipients, 2641 (2.9%) had PtPH. PtPH was associated with higher risk of delayed graft function (odds ratio, 1.23; 95% CI, 1.10-1.36; P < 0.01), death-censored graft failure (hazard ratio [HR], 1.23; 95% CI, 1.11-1.38; P < 0.01), and mortality (HR, 1.56; 95% CI, 1.44-1.69; P < 0.01). However, patients with PtPH who received a KT had a 46% reduction in mortality (HR, 0.54; 95% CI, 0.48-0.61; P < 0.01) compared with those who remained on the waitlist.

Conclusions.

Although PtPH is associated with inferior post-KT outcomes, KT is associated with better survival compared with remaining on the waitlist. Therefore, KT is a viable treatment modality for appropriately selected patients with PtPH.
Liberal Use of Interposition Grafts for Arterial Reconstruction Is Safe and Effective in Adult Split Liver Transplantation
Authors: Lau Ngee-Soon , Liu Ken , Almoflihi Abdullah , Xu Josephine , McCaughan Geoffrey , Crawford Michael , Pulitano Carlo
Published: July 2021

Background.

Split liver transplantation (SLT) addresses donor shortages by providing 2 partial grafts from a single donor liver. Arterial reconstruction using an interposition graft facilitates the use of split grafts with difficult recipient anatomy. Its use, however, remains controversial because of a reported increased risk of complications.

Methods.

A retrospective review of the prospectively maintained Australian National Liver Transplantation Unit database was performed. Donor, recipient, operative, and complications data for adults receiving an SLT between July 2002 and November 2019 were extracted.

Results.

Arterial reconstruction required an interposition graft in 46 of 155 patients. Overall graft and patient survival were not significantly different between the groups with 1-, 3-, and 5-y graft survivals of 82%, 77%, and 69% for those with interposition grafts and 86%, 79%, and 77% for those without interposition grafts, respectively (P = 0.499). There were more cut liver bile leaks in the interposition graft group (26% versus 9%, P = 0.004), but otherwise, no significant differences in the rate of biliary complications (39% versus 29% P = 0.200), hepatic artery thrombosis (7% versus 10%, P = 0.545), or hepatic artery stenosis (13% versus 10%, P = 0.518).

Conclusions.

Liberal use of interposition grafts for arterial reconstruction in SLT is safe and does not result in increased complications.
Engaging Diverse Older Adults With Cognitive Impairment and Caregivers in Advance Care Planning
Authors: Kotwal Ashwin A. , Barnes Deborah E. , Volow Aiesha M. , Li Brookelle H. , Boscardin W. John , Sudore Rebecca L.
Published: July 2021

Introduction:

Engaging patients with cognitive impairment in advance care planning (ACP), including completing advance directives and naming health care proxies, before they lose decision-making capacity is important.

Methods:

We determined the feasibility of the PREPAREforYourCare.org ACP program among 20 diverse older adults with mild-to-moderate cognitive impairment and their caregivers in a 1-week, pre-post pilot. We examined ease-of-use, satisfaction, and feasibility using validated scales, and change in ACP Engagement scores, including knowledge, contemplation, self-efficacy, and readiness subscales (5-point scales), from baseline to 1-week.

Results:

Participants were on average 70 years old (SD=9.0), 45% Spanish-speaking, 60% had limited health literacy, and 15% felt comfortable using the internet. Patients and caregivers rated PREPARE a mean of 8.6 (SD=1.6) and 9.4 (SD=1.1) on the 10-point ease-of-use scale, 4.7 (SD=0.4) and 4.7 (SD=0.3) on the 5-point satisfaction scale, and 4.9 (SD=0.4) and 4.8 (SD=0.6) on the 5-point feasibility scale, respectively. ACP engagement scores increased for 16 of 20 (80%) patients (P=0.03) and 16 of 20 (80%) caregivers (P=0.18). Caregivers experienced increased knowledge (3.8 to 4.7, P=0.002) and self-efficacy (3.6 to 4.5, P=0.034) for ACP.

Discussion:

The PREPARE website was feasible and may facilitate ACP engagement among diverse older adults with cognitive impairment and their caregivers.
Advances in the treatment of neuropathic pain
Authors: Attal Nadine , Bouhassira Didier
Published: July 2021

Purpose of review

Neuropathic pain remains difficult to treat. This review provides an update regarding recent advances in therapeutic management, particularly with regards to newer drugs, neurostimulation techniques and original study designs.

Recent findings

Although the mainstay of neuropathic pain management is still represented by drug therapy, particularly antidepressants and antiepileptics, the place of nonpharmacological therapy including in particular brain neuromodulation techniques has substantially increased in recent years. Newer study designs are also increasingly implemented, based on in depth phenotypic profiling to achieve more individualized therapy, or on screening strategies to decrease placebo effect and contribute to increase assay sensitivity. These approaches are now considered the most promising to decrease therapeutic failures in neuropathic pain.

Neuropathic pain management should not be restricted to pharmacotherapy but now encompasses multiple approaches including particularly neuromodulation techniques. Multimodal assessment can also help identify predictors of the response in clinical trials in order to ensure appropriate management.
Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies
Authors: Moster Mark L. , Sergott Robert C. , Newman Nancy J. , Yu-Wai-Man Patrick , Carelli Valerio , Bryan Molly Scannell , Smits Gerard , Biousse Valérie , Vignal-Clermont Catherine , Klopstock Thomas , Sadun Alfredo A. , DeBusk Adam A. , Carbonelli Michele , Hage Rabih , Priglinger Siegfried , Karanjia Rustum , Blouin Laure , Taiel Magali , Katz Barrett , Sahel José Alain ,   for the LHON study group
Published: July 2021

Objective:

This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss.

Methods:

RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion).

Results:

Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, −0.06 mm3, and −6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, −0.01 mm3, and −0.43 μm respectively).

Conclusion:

LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.
A community-based approach to image analysis of cells, tissues and tumors
Authors:   CSBC/PS-ON Image Analysis Working Group, Vizcarra Juan Carlos , Burlingame Erik A. , Hug Clemens B. , Goltsev Yury , White Brian S. , Tyson Darren R. , Sokolov Artem
Published: July 2021

Emerging multiplexed imaging platforms provide an unprecedented view of an increasing number of molecular markers at subcellular resolution and the dynamic evolution of tumor cellular composition. As such, they are capable of elucidating cell-to-cell interactions within the tumor microenvironment that impact clinical outcome and therapeutic response. However, the rapid development of these platforms has far outpaced the computational methods for processing and analyzing the data they generate. While being technologically disparate, all imaging assays share many computational requirements for post-collection data processing. We convened a workshop to characterize these shared computational challenges and a follow-up hackathon to implement solutions for a selected subset of them. Here, we delineate these areas that reflect major axes of research within the field, including image registration, segmentation of cells and subcellular structures, and identification of cell types from their morphology. We further describe the logistical organization of these events, believing our lessons learned can aid others in uniting the imaging community around self-identified topics of mutual interest, in designing and implementing operational procedures to address those topics and in mitigating issues inherent in image analysis (e.g., sharing exemplar images of large datasets and disseminating baseline solutions to hackathon challenges through open-source code repositories).
A plasma metabolite score of three eicosanoids predicts incident type 2 diabetes – a prospective study in three independent cohorts
Authors: Tuomisto Karolina , Palmu Joonatan , Long Tao , Watrous Jeramie D. , Mercader Kysha , Lagerborg Kim A. , Andres Allen , Salmi Marko , Jalkanen Sirpa , Vasan Ramachandran S. , Inouye Michael , Havulinna Aki S. , Jousilahti Pekka , Niiranen Teemu J. , Cheng Susan , Jain Mohit , Salomaa Veikko
Published: July 2021

Aim

Peptide markers of inflammation have been associated with the development of type 2 diabetes. The role of upstream, lipid-derived mediators of inflammation such as eicosanoids, remains less clear. The aim was to examine whether eicosanoids are associated with incident type 2 diabetes.

Methods

In the FINRISK 2002 study, a population-based sample of Finnish men and women aged 25-74 years, we used directed, non-targeted liquid chromatography – mass spectrometry to identify 545 eicosanoids and related oxylipins in the participants’ plasma samples (n=8,292). We used multivariable-adjusted Cox regression to examine associations between eicosanoids and incident type 2 diabetes. The findings were replicated in the Framingham Heart Study (FHS, n=2,886) and DILGOM 2007 (n=3,905). Together, these three cohorts had 1070 cases of incident type 2 diabetes.

Results

76 eicosanoids were associated individually with incident type 2 diabetes. We identified three eicosanoids independently associated with incident type 2 diabetes using stepwise Cox regression with forward selection and a Bonferroni-corrected inclusion threshold. A three-eicosanoid risk score produced a hazard ratio (HR) of 1.56 (95% confidence interval 1.41-1.72) per one standard deviation (SD) increment for risk of incident diabetes. The HR for comparing the top quartile to the lowest was 2.80 (2.53-3.07). Meta-analysis of the three cohorts yielded a pooled HR per SD of 1.31 (1.05-1.56).

Conclusion

Plasma eicosanoid profiles predict incident type 2 diabetes and the clearest signals replicate in three independent cohorts. Our findings give new information on the biology underlying type 2 diabetes and suggest opportunities for early identification of people at risk.
Geographical concentration of COVID-19 cases by social determinants of health in 16 large metropolitan areas in Canada – a cross-sectional study
Authors: Xia Yiqing , Ma Huiting , Moloney Gary , Velásquez García Héctor A. , Sirski Monica , Janjua Naveed Z. , Vickers David , Williamson Tyler , Katz Alan , Yu Kristy , Kustra Rafal , Buckeridge David L , Brisson Marc , Baral Stefan D , Mishra Sharmistha , Maheu-Giroux Mathieu
Published: July 2021

Background

There is a growing recognition that strategies to reduce SARS-CoV-2 transmission should be responsive to local transmission dynamics. Studies have revealed inequalities along social determinants of health, but little investigation was conducted surrounding geographic concentration within cities. We quantified social determinants of geographic concentration of COVID-19 cases across sixteen census metropolitan areas (CMA) in four Canadian provinces.

Methods

We used surveillance data on confirmed COVID-19 cases at the level of dissemination area. Gini (co-Gini) coefficients were calculated by CMA based on the proportion of the population in ranks of diagnosed cases and each social determinant using census data (income, education, visible minority, recent immigration, suitable housing, and essential workers) and the corresponding share of cases. Heterogeneity was visualized using Lorenz (concentration) curves.

Results

Geographic concentration was observed in all CMAs (half of the cumulative cases were concentrated among 21-35% of each city’s population): with the greatest geographic heterogeneity in Ontario CMAs (Gini coefficients, 0.32-0.47), followed by British Columbia (0.23-0.36), Manitoba (0.32), and Québec (0.28-0.37). Cases were disproportionately concentrated in areas with lower income, education attainment, and suitable housing; and higher proportion of visible minorities, recent immigrants, and essential workers. Although a consistent feature across CMAs was concentration by proportion visible minorities, the magnitude of concentration by social determinants varied across CMAs.

Interpretation

The feature of geographical concentration of COVID-19 cases was consistent across CMAs, but the pattern by social determinants varied. Geographically-prioritized allocation of resources and services should be tailored to the local drivers of inequalities in transmission in response to SARS-CoV-2’s resurgence.
Disentangling key species interactions in diverse and heterogeneous communities: A Bayesian sparse modeling approach
Authors: Weiss-Lehman Christopher P. , Werner Chhaya M. , Bowler Catherine H. , Hallett Lauren M. , Mayfield Margaret M. , Godoy Oscar , Aoyama Lina , Barabás György , Chu Chengjin , Ladouceur Emma , Larios Loralee , Shoemaker Lauren G.
Published: July 2021

1

Modeling species interactions in diverse communities traditionally requires a prohibitively large number of species-interaction coefficients, especially when considering environmental dependence of parameters. We implemented Bayesian variable selection via sparsity-inducing priors on non-linear species abundance models to determine which species-interactions should be retained and which can be represented as an average heterospecific interaction term, reducing the number of model parameters. We evaluated model performance using simulated communities, computing out-of-sample predictive accuracy and parameter recovery across different input sample sizes. We applied our method to a diverse empirical community, allowing us to disentangle the direct role of environmental gradients on species’ intrinsic growth rates from indirect effects via competitive interactions. We also identified a few neighboring species from the diverse community that had non-generic interactions with our focal species. This sparse modeling approach facilitates exploration of species-interactions in diverse communities while maintaining a manageable number of parameters.
Fusion-oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers
Authors: Franco Aime T. , Ricarte-Filho Julio C. , Isaza Amber , Jones Zachary , Jain Neil , Mostoufi-Moab Sogol , Surrey Lea , Laetsch Theodore W. , Li Marilyn M. , DeHart Jessica Clague , Reichenberger Erin , Taylor Deanne , Kazahaya Ken , Scott Adzick N. , Bauer Andrew J.
Published: July 2021

Background

In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes,RAS-like andBRAF-like, better reflects clinical behavior than sole reliance on pathological classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer and investigate if mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC.

Methods

Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized intoRAS-mutant (H-K-NRAS),BRAF-mutant (BRAF p.V600E) andRET/NTRKfusion (RET, NTRK1andNTRK3fusions) to determine differences between subtype classification in regard to pathological data (AJCC TNM) as well as response to therapy 1-year after initial treatment had been completed.

Results

Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1-year. Patients withRET/NTRKfusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at one year than patients withinRAS- orBRAF-mutsubgroups.

Conclusions

Our data supports that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathological classification with patients withRET/NTRKfusions having worse outcomes than those withBRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.
AlphaPept, a modern and open framework for MS-based proteomics
Authors: Strauss Maximilian T. , Bludau Isabell , Zeng Wen-Feng , Voytik Eugenia , Ammar Constantin , Schessner Julia , Ilango Rajesh , Gill Michelle , Meier Florian , Willems Sander , Mann Matthias
Published: July 2021

In common with other omics technologies, mass spectrometry (MS)-based proteomics produces ever-increasing amounts of raw data, making their efficient analysis a principal challenge. There is a plethora of different computational tools that process the raw MS data and derive peptide and protein identification and quantification. During the last decade, there has been dramatic progress in computer science and software engineering, including collaboration tools that have transformed research and industry. To leverage these advances, we developed AlphaPept, a Python-based open-source framework for efficient processing of large high-resolution MS data sets. Using Numba for just-in-time machine code compilation on CPU and GPU, we achieve hundred-fold speed improvements while maintaining clear syntax and rapid development speed. AlphaPept uses the Python scientific stack of highly optimized packages, reducing the code base to domain-specific tasks while providing access to the latest advances in machine learning. We provide an easy on-ramp for community validation and contributions through the concept of literate programming, implemented in Jupyter Notebooks of the different modules. A framework for continuous integration, testing, and benchmarking enforces solid software engineering principles. Large datasets can rapidly be processed as shown by the analysis of hundreds of cellular proteomes in minutes per file, many-fold faster than the data acquisiton. The AlphaPept framework can be used to build automated processing pipelines using efficient HDF5 based file formats, web-serving functionality and compatibility with downstream analysis tools. Easy access for end-users is provided by one-click installation of the graphical user interface, for advanced users via a modular Python library, and for developers via a fully open GitHub repository.
Large ecological benefits of small urban greening actions
Authors: Mata Luis , Hahs Amy K. , Palma Estibaliz , Backstrom Anna , King Tyler , Olson Ashley R. , Renowden Christina , Smith Tessa R. , Vogel Blythe
Published: July 2021

The detrimental effects of human-induced environmental change on people and other species are acutely manifested in urban environments. While urban greenspaces are known to mitigate these effects and support functionally diverse ecological communities, evidence of the ecological outcomes of urban greening remains scarce. We use a longitudinal observational design to provide empirical evidence of the putative ecological benefits of greening actions. We show how a small greening action quickly led to large positive changes in the richness, demographic dynamics, and network structure of a depauperate insect community. An increase in the diversity and complexity of the plant community led to, after only three years, a large increase in insect species richness, a greater probability of occurrence of insects within the greenspace, and a higher number and diversity of interactions between insects and plant species. We demonstrate how large ecological benefits may be derived from investing in small greening actions and how these contribute to bring indigenous species back to greenspaces where they have become rare or locally extinct. Our findings provide crucial evidence that support best practice in greenspace design and contribute to re-invigorate policies aimed at mitigating the negative impacts of urbanisation on people and other species.
Capturing variation in metagenomic assembly graphs with MetaCortex
Authors: Martin Samuel , Ayling Martin , Patrono Livia , Caccamo Mario , Murcia Pablo , Leggett Richard M.
Published: July 2021

Motivation

The assembly of contiguous sequence from metagenomic samples presents a particular challenge, due to the presence of multiple species, often closely related, at varying levels of abundance. Capturing diversity within species, for example viral haplotypes, or bacterial strain-level diversity, is even more challenging.

Results

We present MetaCortex, a metagenome assembler that captures intra-species diversity by searching for signatures of local variation along assembled sequences in the underlying assembly graph and outputting these sequences in sequence graph format. We show that MetaCortex produces accurate assemblies with higher genome coverage and contiguity than other popular metagenomic assemblers on mock viral communities with high levels of strain level diversity, and on simulated communities containing simulated strains.

Availability and Implementation

Source code is freely available to download fromhttps://github.com/SR-Martin/metacortex, is implemented in C and supported on MacOS and Linux.

Contact

richard.leggett@earlham.ac.uk

Supplementary information

Supplementary materials are available at the journal’s website. All assemblies, simulated reads, and simulated genomes used in this paper have been deposited online on Zenodo and can be found at DOI 10.5281/zenodo.6616437.
Emotional states as distinct configurations of functional brain networks
Authors: Dan Rotem , Weinstock Marta , Goelman Gadi
Published: July 2021

The conceptualization of emotional states as patterns of interactions between large-scale brain networks has recently gained support. Yet, few studies have directly examined the brain’s network structure during emotional experiences. Here, we investigated the brain’s functional network organization during experiences of sadness, amusement, and neutral states elicited by movies, in addition to a resting-state. We tested the effects of the experienced emotion on individual variability in the brain’s functional connectome. Next, for each state, we defined a community structure of the brain and quantified its segregation and integration. We found that sadness, relative to amusement, was associated with higher modular integration and increased connectivity of cognitive control networks: the salience and fronto-parietal networks. Moreover, in both the functional connectome and the emotional report, the similarity between individuals was dependent on the sex. Our results suggest that the experience of emotion is linked to a reconfiguration of whole-brain distributed, not emotion-specific, functional networks and that the brain’s topological structure carries information about the subjective emotional experience.
Global, Low Amplitude Cortical State Predicts Response Outcomes in a Selective Detection Task
Authors: Marrero Krista , Aruljothi Krithiga , Zareian Behzad , Gao Chengchun , Zhang Zhaoran , Zagha Edward
Published: July 2021

Spontaneous neuronal activity strongly impacts stimulus encoding and behavioral responses. We sought to determine the effects of neocortical prestimulus activity on stimulus detection. We trained mice in a selective whisker detection task, in which they learned to respond (lick) to target stimuli in one whisker field and ignore distractor stimuli in the contralateral whisker field. During expert task performance, we used widefield Ca2+ imaging to assess prestimulus and post-stimulus neuronal activity broadly across frontal and parietal cortices. We found that lower prestimulus activity correlated with enhanced stimulus detection: lower prestimulus activity predicted response versus no response outcomes and faster reaction times. The activity predictive of trial outcome was distributed through dorsal neocortex, rather than being restricted to whisker or licking regions. Using principal component analysis, we demonstrate that response trials are associated with a distinct and less variable prestimulus neuronal subspace. For single units, prestimulus choice probability was weak yet distributed broadly, with lower than chance choice probability correlating with stronger sensory and motor encoding. These findings support a low amplitude, low variability, optimal prestimulus cortical state for stimulus detection that presents globally and predicts response outcomes for both target and distractor stimuli.
Necroptosis increases with age in the brain and contributes to age-related neuroinflammation
Authors: Thadathil Nidheesh , Nicklas Evan H , Mohammed Sabira , Lewis Tommy L , Richardson Arlan , Deepa Sathyaseelan S.
Published: July 2021

Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induce inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which causes membrane binding and permeabilization were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl-/- mice reduced markers (Iba-1 and GFAP) of neuroinflammation in the brains of old mice and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.
Assessing donor-to-donor variability in human intestinal organoid cultures
Authors: Mohammadi Sina , Morell-Perez Carolina , Wright Charles W. , Wyche Thomas P. , White Cory H. , Sana Theodore R. , Lieberman Linda A.
Published: July 2021

Donor-to-donor variability in primary human organoid cultures has not been well characterized. As these cultures contain multiple cell types, there is greater concern that variability could lead to increased noise. In this work we investigated donor-to-donor variability in human gut adult stem cell (ASC) organoids. We examined intestinal developmental pathways during culture differentiation in ileum- and colon-derived cultures established from multiple donors, showing that differentiation patterns were consistent among cultures. This finding indicates that donor-to-donor variability in this system remains at a manageable level. Intestinal metabolic activity was evaluated by targeted analysis of central carbon metabolites and by analyzing hormone production patterns. Both experiments demonstrated similar metabolic functions among donors. Importantly, this activity reflected intestinal biology, indicating that these ASC organoid cultures are appropriate for studying metabolic processes. This work establishes a framework for generating high confidence data using human primary cultures through thorough characterization of variability.
Indomethacin Use for Mild & Moderate hospitalised Covid-19 patients: An open label randomized clinical trial
Authors: Ravichandran Rajan , Mohan Surapaneni Krishna , Sukumaran Suresh Kumar , Kamaraj Devakumar , Daivasuga Sumetha Suga , Samuel Ravi Samson Oliver Abraham , Vijayaraghavalu Sivakumar , Kumar Ramarathnam Krishna
Published: July 2021

Introduction

Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been presented as a broad-spectrum antiviral agent. This randomised clinical trial in a hospital setting evaluated the efficacy and safety of this drug in RT-PCR-positive coronavirus disease 2019 (COVID-19) patients.

Materials & Methods

A total of 210 RT-PCR-positive COVID-19 patients, who provided consent were allotted, to control or case arm, based on block randomisation. The control arm received standard of care comprising paracetamol, ivermectin, and other adjuvant therapies. The patients in the case arm received indomethacin instead of paracetamol, with other medications retained. The primary endpoint was the development of hypoxia/desaturation with SpO2≤ 93, while time to become afebrile and time for cough and myalgia resolution were the secondary endpoints.

Results

The results of 210 patients were available, with 103 and 107 patients in the indomethacin and paracetamol arms, respectively. We monitored patient profiles along with everyday clinical parameters. Blood chemistry at the time of admission and discharge was assessed.

As no one in either of the arms required high-flow oxygen, desaturation with SpO2level of 93 and below was an important goal. In the indomethacin group, none of the 103 patients developed desaturation. On the other hand, 20 of the 107 patients in the paracetamol arm developed desaturation. Patients who received indomethacin also experienced more rapid symptomatic relief than those in the paracetamol arm, with most symptoms disappearing in half the time. 56 patients out of 107 in the paracetamol arm had fever on the seventh day, while no patient in the indomethacin group had fever. Neither arm reported any adverse event. The fourteenth-day follow-up revealed that the paracetamol arm patients had faced several discomforts, including myalgia, joint pain, and tiredness; indomethacin arm patients mostly complained only of tiredness.

Conclusion

Indomethacin is a safe and effective drug for treating patients with mild and moderate covid-19.
Novel risk factors for Coronavirus disease-associated mucormycosis (CAM): a case control study during the outbreak in India
Authors: Arora Umang , Priyadarshi Megha , Katiyar Varidh , Soneja Manish , Garg Prerna , Gupta Ishan , Bharadiya Vishwesh , Berry Parul , Ghosh Tamoghna , Patel Lajjaben , Sarda Radhika , Garg Shreya , Agarwal Shubham , Arora Veronica , Ramprasad Aishwarya , Kumar Amit , Garg Rohit Kumar , Kodan Parul , Nischal Neeraj , Singh Gagandeep , Jorwal Pankaj , Kumar Arvind , Baitha Upendra , Meena Ved Prakash , Ray Animesh , Sethi Prayas , Xess Immaculata , Vikram Naval , Sinha Sanjeev , Biswas Ashutosh , Thakar Alok , Bhatnagar Sushma , Trikha Anjan , Wig Naveet
Published: July 2021

Background

The epidemiology of the Coronavirus-disease associated mucormycosis (CAM) syndemic is poorly elucidated. We aimed to identify risk factors that may explain the burden of cases and help develop preventive strategies.

Methods

We performed a case-control study comparing cases diagnosed with CAM and those who had recovered from COVID-19 without developing mucormycosis (controls). Information on comorbidities, glycemic control, and practices related to COVID-19 prevention and treatment was recorded.

Results

352 patients (152 cases and 200 controls) diagnosed with COVID-19 during April-May 2021 were included. In the CAM group, symptoms of mucormycosis began a mean 18.9 (SD 9.1) days after onset of COVID-19, and predominantly rhino-sinus and orbital involvement was present. All, but one, CAM cases carried conventional risk factors of diabetes and steroid use. On multivariable regression, increased odds of CAM were associated with the presence of diabetes (adjusted OR 3.5, 95%CI 1.1-11), use of systemic steroids (aOR 7.7,95% CI 2.4-24.7), prolonged use of cloth and surgical masks (vs no mask, aOR 6.9, 95%CI 1.5-33.1), and repeated nasopharyngeal swab testing during the COVID-19 illness (aOR 1.6,95% CI 1.2-2.2). Zinc therapy, probably due to its utility in immune function, was found to be protective (aOR 0.05, 95%CI 0.01-0.19). Notably, the requirement of oxygen supplementation or hospitalization did not affect the risk of CAM.

Conclusion

Judicious use of steroids and stringent glycemic control are vital to preventing mucormycosis. Use of clean masks, preference for N95 masks if available, and minimizing swab testing after the diagnosis of COVID-19 may further reduce the incidence of CAM.
A yeast lysosomal biogenesis map uncovers the cargo spectrum of lysosomal protein targeting pathways
Authors: Eising Sebastian , Esch Bianca M. , Wälte Mike , Duarte Prado Vargas , Walter Stefan , Ungermann Christian , Bohnert Maria , Fröhlich Florian
Published: July 2021

The lysosome is the major catabolic organelle and a key metabolic signaling center of the cell. Mutations in lysosomal proteins can have catastrophic effects, causing neurodegeneration, cancer, and age-related diseases. The vacuole is the lysosomal analog of Saccharomyces cerevisiae that harbors many conserved proteins. Vacuolar proteins reach their destination via the endosomal vacuolar protein sorting (VPS) pathway, via the alkaline phosphatase (ALP or AP-3) pathway, and via the cytosol-to-vacuole transport (CVT) pathway. While these pathways have been extensively studied, a systematic understanding of the cargo spectrum of each pathway is completely lacking. Here we combine quantitative proteomics of purified vacuoles with mutant analyses to generate the lysosomal biogenesis map. This dataset harbors information on the cargo-receptor relationship of virtually all vacuolar proteins. We map binding motifs of Vps10 and the AP-3 complex and identify a novel cargo of the CVT pathway under nutrient-rich conditions. Our data uncover how organelle purification and quantitative proteomics can uncover fundamental insights into organelle biogenesis.
A dopamine-gated learning circuit underpins reproductive state-dependent odor preference in Drosophila females
Authors: Boehm Ariane C. , Friedrich Anja B. , Hunt Sydney , Bandow Paul , Siju K.P. , De Backer Jean-Francois , Claussen Julia , Link Marie-Helen , Hofmann Thomas F. , Dawid Corinna , Grunwald Kadow Ilona C.
Published: July 2021

Motherhood induces a drastic, sometimes long-lasting, change in internal state and behavior in most female animals. How a change in reproductive state or the discrete event of mating modulates specific female behaviors is still incompletely understood. Using calcium imaging of the whole brain of Drosophila females, we find that mating does not induce a global change in brain activity. Instead, mating modulates the pheromone response of dopaminergic neurons innervating the fly’s learning and memory center, the mushroom body (MB). Using the mating-induced increased attraction to the odor of important nutrients, polyamines, we show that disruption of the female fly’s ability to smell, for instance the pheromone cVA, during mating leads to a reduction in polyamine preference for days later indicating that the odor environment at mating lastingly influences female perception and choice behavior. Moreover, dopaminergic neurons including innervation of the β’1 compartment are sufficient to replace mating experience in virgin females inducing the lasting behavioral increase in polyamine preference. We further show that MB output neurons (MBON) of the β’1 compartment are activated by pheromone odor and their activity during mating bidirectionally modulates preference behavior in mated and virgin females. Their activity is not required, however, for the expression of polyamine attraction. Instead, inhibition of another type of MBON innervating the β’2 compartment enables expression of high polyamine attraction. In addition, the response of a lateral horn (LH) neuron, AD1b2, which output is required for the expression of polyamine attraction, shows a modulated polyamine response after mating. Taken together, our data in the fly suggests that mating-related sensory experience regulates female odor perception and expression of choice behavior through a dopamine-gated learning circuit.
A distinct CD115-erythro-myeloid precursor present at the maternal-embryonic interface and in the bone marrow of adult mice
Authors: Tikoo Shweta , Jain Rohit , Martinez Brendon , Song Renhua , Wielscher Matthias , Rizzetto Simone , Shaw Lisa E , Mitchell Andrew J , Torres-Pacheco Maria Elizabeth , Luciani Fabio , Farlik Matthias , Wong Justin JL , Jung Steffen , Fraser Stuart T , Weninger Wolfgang
Published: July 2021

During ontogeny, macrophages develop from CD115+precursors, including erythro-myeloid progenitors (EMP). EMP arise in the embryonic yolk sac, the primary site of early haematopoiesis. In adults, CD115+bone marrow-derived monocytes represent essential macrophage precursors. Herein, we identify a CD115-macrophage precursor within the adult bone marrow that is unrelated to the classical monocyte lineage but rather shares transcriptomic and functional characteristics of embryonic EMP. These EMPROR (forErythroMyeloidPrecursor) cells are capable of efficiently generating macrophages in disease settings. During early development, EMPROR cells were largely absent from the yolk sac but were instead found at the embryonic-maternal interface in the uterine wall. Unexpectedly, the latter site contains robust haematopoietic activity and harbours defined embryonic haematopoietic progenitor cells, including classical CD115+EMP. Our data suggest the existence of an alternative pathway of macrophage generation in the adult. Further, we uncover a hitherto unknown site of earliest blood cell development.