bluuebunny/crossref_metadata_2025 huggingface dataset:
CENTER FOR TRAUMA SURVIVORSHIP IMPROVES POST-DISCHARGE FOLLOW-UP AND RETENTION
Authors: Goldstein Carma , Gore Amy , La Bagnara Susan , Jacniacka-Soto Ilona E. , Sieck Derrick , Yonclas Peter , Livingston David H.
Published: April 2022

BACKGROUND

Although the need for high-level care persists post-discharge, severely injured trauma survivors have historically poor adherence to follow-up. We hypothesized that a dedicated Center for Trauma Survivorship (CTS) improves follow-up and facilitates post-discharge specialty care.

METHODS

Retrospective study of “CTS eligible” trauma patients before (Jan – Dec 2017) and after (Jan – Dec 2019) creation of the CTS. Patients with an ICU stay ≥2 days or a New Injury Severity Score ≥ 16 are CTS eligible. The before (PRE) cohort was followed through Dec 2018 and the after (CTS) cohort through Dec 2020. Primary outcome was follow-up within the hospital system exclusive of mental health and rehabilitative therapy appointments. Secondary outcomes include post-discharge surgical procedures and specialty-specific follow-up.

RESULTS

There were no significant differences in demographics or hospital duration in the PRE (n = 177) and CTS (n = 119) cohorts. Of the CTS group, 91% presented for outpatient follow-up within the hospital system, compared to 73% in the Pre group (p < 0.001). In the PRE cohort, only 39% were seen by the trauma service compared to 62% in the CTS cohort (p < 0.001). CTS patients also had increased follow-up with other providers (80% vs 65%; p = 0.006). Notably, 33% of CTS patients had additional surgery compared to only 20% in the PRE group (p = 0.011). CTS patients had over 20% more outpatient visits (1,280 vs 1,006 visits).

CONCLUSION

Despite the follow-up period for the CTS cohort occurring during the peak of the COVID-19 pandemic, limiting availability of outpatient services, our CTS significantly improved follow-up with trauma providers, as well as with other specialties. The CTS patients also underwent significantly more secondary operations. These data demonstrate that creation of a CTS can improve the post-discharge care of severely injured trauma survivors, allowing for care coordination within the healthcare system, retaining patients, generating revenue and providing needed follow-up care.

LEVEL OF EVIDENCE

Therapeutic, Level IV
Value in acute care surgery, part 2: Defining and measuring quality outcomes
Authors: Ross Samuel Wade , Wandling Michael W. , Bruns Brandon R. , Martin R. Shayn , Scott John W. , Doucet Jay J. , Davis Kimberly A. , Staudenmayer Kristan L. , Minei Joseph P.
Published: April 2022

The prior article in this series delved into measuring cost in acute care surgery, and this subsequent work explains in detail how quality is measured. Specifically, objective quality is based on outcome measures, both from administrative and clinical registry databases from a multitude of sources. Risk stratification is key in comparing similar populations across diseases and procedures. Importantly, a move toward focusing on subjective outcomes like patient-reported outcomes measures and financial well-being are vital to evolving surgical quality measures for the 21st century.
N-acetylcysteine is associated with reduction of postconcussive symptoms in elderly patients: A pilot study
Authors: Mcpherson Ryan A. , Mangram Alicia J. , Barletta Jeffrey F. , Dzandu James K.
Published: April 2022

INTRODUCTION

N-acetylcysteine (NAC) may be neuroprotective by minimizing postconcussion symptoms after mild traumatic brain injury (TBI), but limited data exist. This study evaluated the effects of NAC on postconcussion symptoms in elderly patients diagnosed with mild TBI.

METHODS

This prospective, quasirandomized, controlled trial enrolled patients 60 years or older who suffered mild TBI. Patients were excluded if cognitive function could not be assessed within 3-hours postinjury. Patients were allocated to receive NAC plus standard care, or standard care alone, based on the trauma center where they presented. The primary study outcome was the severity of concussive symptoms measured using the Rivermeade Postconcussion Symptoms Questionnaire (RPQ). Symptoms were evaluated on days 0, 7, and 30. The RPQ scores were compared both within and between treatment groups.

RESULTS

There were 65 patients analyzed (NAC, n = 34; control, n = 31) with an average age of 76 ± 10 years. Baseline demographics and clinical variables were similar. No group differences in head Abbreviated Injury Scale score or Glasgow Coma Scale score were observed. Baseline RPQ scores (6 [0–20] vs. 11 [4–20], p = 0.300) were indistinguishable. The RPQ scores on day 7 (2 [0–8] vs. 10 [3–18], p = 0.004) and 30 (0 [0–4] vs. 4 [0–13], p = 0.021) were significantly lower in the NAC group. Within-group differences were significantly lower in the NAC (p < 0.001) but not control group (p = 0.319).

CONCLUSION

N-acetylcysteine was associated with significant improvements in concussion symptoms in elderly patients with mild TBI. These results justify further research into using NAC to treat TBI.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Prospective randomized trial of metal versus resorbable plates in surgical stabilization of rib fractures
Authors: Ashley Dennis W. , Christie Dudley B. , Long Eric L. , Adiga Rajani , Johns Tracy J. , Fabico-Dulin Josephine , Montgomery Anne
Published: April 2022

BACKGROUND

Surgical stabilization of rib fractures has gained popularity as both metal and resorbable plates have been approved for fracture repair. Is there a difference between metal and resorbable plate rib fixation regarding rib fracture alignment, control of pain, and quality-of-life (QOL) scores (Rand SF-36 survey)?

METHODS

Eligible patients (pts) included 18 years or older with one or more of the following: flail chest, one or more bicortical displaced fractures (3–10), nondisplaced fractures with failure of medical management. Patients were randomized to either metal or resorbable plate fixation. Primary outcome was fracture alignment. Secondary outcomes were pain scores, opioid use, and QOL scores.

RESULTS

Thirty pts were randomized (15 metal/15 resorbable). Total ribs plated 167 (88 metal/79 resorbable). Patients with rib displacement at day of discharge (DOD) metal 0/14 (one pt died, not from plating) versus resorbable 9/15 or 60% (p = 0.001). Ribs displaced at DOD metal 0/88 versus resorbable 22/79 or 28% (p < 0.001), 48% in posterior location. Patients with increased rib displacement 3 months to 6 months: metal, 0/11 versus resorbable, 3/9 or 33% (p = 0.043). Ribs with increased displacement 3 months to 6 months metal 0 of 67 versus resorbable 6 of 49 or 12.2% (p < 0.004). Pain scores and narcotic use at postoperative Days 1, 2, 3, DOD, 2 weeks, 3 months and 6 months showed no statistically significant difference between groups. QOL scores were also similar at 3 months and 6 months. Trauma recidivism in outpatient period resulted in fracture of resorbable plates in two pts requiring a second surgery.

CONCLUSION

Metal plates provided better initial alignment with no displacement over time. Clinical outcomes were similar regarding pain, narcotic use, and QOL scores. Routine use of resorbable plates for posterior rib fractures is not warranted. Lateral repairs were technically most feasible for using resorbable plates but still resulted in significant displacement. Resorbable plates may not maintain rib alignment when exposed to subsequent injury.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level II
Which hospital-acquired conditions matter the most in trauma? An evidence-based approach for prioritizing trauma program improvement
Authors: Lee Patrick T. , Krecko Laura K. , Savage Stephanie , O’Rourke Ann P. , Jung Hee Soo , Ingraham Angela , Zarzaur Ben L. , Scarborough John E.
Published: April 2022

BACKGROUND

Prevention of hospital-acquired conditions (HACs) is a focus of trauma center quality improvement. The relative contributions of various HACs to postinjury hospital outcomes are unclear. We sought to quantify and compare the impacts of six HACs on early clinical outcomes and resource utilization in hospitalized trauma patients.

METHODS

Adult patients from the 2013 to 2016 American College of Surgeons Trauma Quality Improvement Program Participant Use Data Files who required 5 days or longer of hospitalization and had an Injury Severity Score of 9 or greater were included. Multiple imputation with chained equations was used for observations with missing data. The frequencies of six HACs and five adverse outcomes were determined. Multivariable Poisson regression with log link and robust error variance was used to produce relative risk estimates, adjusting for patient-, hospital-, and injury-related factors. Risk-adjusted population attributable fractions estimates were derived for each HAC-outcome pair, with the adjusted population attributable fraction estimate for a given HAC-outcome pair representing the estimated percentage decrease in adverse outcome that would be expected if exposure to the HAC had been prevented.

RESULTS

A total of 529,856 patients requiring 5 days or longer of hospitalization were included. The incidences of HACs were as follows: pneumonia, 5.2%; urinary tract infection, 3.4%; venous thromboembolism, 3.3%; surgical site infection, 1.3%; pressure ulcer, 1.3%; and central line-associated blood stream infection, 0.2%. Pneumonia demonstrated the strongest association with in-hospital outcomes and resource utilization. Prevention of pneumonia in our cohort would have resulted in estimated reductions of the following: 22.1% for end organ dysfunction, 7.8% for mortality, 8.7% for prolonged hospitalization, 7.1% for prolonged intensive care unit stay, and 6.8% for need for mechanical ventilation. The impact of other HACs was comparatively small.

CONCLUSION

We describe a method for comparing the contributions of HACs to outcomes of hospitalized trauma patients. Our findings suggest that trauma program improvement efforts should prioritize pneumonia prevention.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Sustained Minimal Residual Disease Negativity in Multiple Myeloma is Associated with Stool Butyrate and Healthier Plant-Based Diets
Authors: Shah Urvi A. , Maclachlan Kylee H. , Derkach Andriy , Salcedo Meghan , Barnett Kelly , Caple Julia , Blaslov Jenna , Tran Linh , Ciardiello Amanda , Burge Miranda , Shekarkhand Tala , Adintori Peter , Cross Justin , Pianko Matthew J. , Mailankody Sham , Korde Neha , Hultcrantz Malin , Hassoun Hani , Tan Carlyn , Lu Sydney , Patel Dhwani , Diamond Benjamin , Shah Gunjan , Scordo Michael , Lahoud Oscar , Chung David J. , Landau Heather , Usmani Saad , Giralt Sergio , Taur Ying , Landgren C. Ola , Block Gladys , Block Torin , Peled Jonathan U. , van den Brink Marcel RM , Lesokhin Alexander M.
Published: April 2022

Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma (MM). The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We examined the relationship of dietary factors, stool metabolites, and microbial diversity with sustained MRD negativity in patients on lenalidomide maintenance. At 3 months, higher stool butyrate concentration (p=0.037), butyrate producers (p=0.025) and α-diversity (p=0.0035) were associated with sustained MRD-negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (p=0.009) and sustained MRD-negativity (p=0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins p=0.01, flavones p=0.01, and flavanols p=0.02). This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production and sustained MRD-negativity in MM; providing rationale to evaluate a prospective dietary intervention.

Statement of Significance

We demonstrate an association between diet, the gut microbiome, and sustained MRD-negativity in MM. A healthy diet, with adequate plant and seafood protein, and containing flavonoids, associates with stool diversity, butyrate production and sustained MRD-negativity. These findings suggest dietary modification should be studied to enhance myeloma control.

Key Points

In MM on lenalidomide maintenance, stool butyrate concentration at 3 months was associated with higher rates of MRD negativity at 12 months.

Increased seafood and plant proteins, dietary flavonoids, and diversity of dietary flavonoids correlated with stool butyrate concentrations.
Adequacy Of Salt Iodization, Retailers’ Knowledge And Associated Factors About Iodized Salt In Oromia Special Zone Surrounding Finfinne, Ethiopia
Authors: kebede Meron , Alemu Zewdie Aderaw , Gutata Dano
Published: April 2022

Background

There are laws to enforce the universal iodization of salt to check the consequences of iodine deficiency in Ethiopia. These laws are to ensure that there are production and sales of iodized salt in the country. Yet, the adequacy of iodized salt in the retailers’ level is not determined.

Objective

This study is aimed to investigate the adequacy of salt iodization, retailers’ knowledge, and associated factors about iodized salt among retailers in Addis Ababa surrounding finfinne Special Zone, Ethiopia.

Methods

A community-based cross-sectional study was conducted among 202 iodized salt retailers that were selected by using a simple random sampling technique. Data among the shop retailers for the assessment of knowledge was collected by using a structured questionnaire, and titration test method was done to determine the adequacy of salt iodization. The data management and analysis were done by using Statistical Packages for Social Scientists Version 23. Descriptive statistics such as mean, median, standard deviation, and frequency were computed to describe the data. Binary logistic regression analysis was done to examine the association between the dependent and independent variables. The strength of association between the dependent and independent variables was explained by using the odds ratio and the level of statistical significance was accepted at a p-value of less than 0.05. Finally, the results were presented by using graphs and tables.

Result

A total of 202 salt retailers were approached in this study with a mean age of 28.78±7.548 years. Nearly around two-thirds of the study participants were male. Of the total retailers’ salt samples, 95(57.2%) were adequately (20-40ppm) iodized, and the educational level of the retailers was significantly associated with the adequacy of salt iodization. From the total salt retailer, 113(55.9%) had good knowledge, and retailers who heard about iodized salt (AOR=0.043, CI: 0.017-0.109, p<0.001) and having legal framework/law (AOR=0.24, CI: 0.098-0.61, p=0.003) that prohibits the selling of non-iodized salt were significantly associated with good knowledge level.

Conclusion and Recommendation

Still policies have been implemented to promote the production and consumption of iodized salt, the iodine content of salt in retail shops in the Oromia Special Zone Finfinne, Oromia regional state is not encouraging. We recommend the establishment of checkpoints along the production and distribution chain to ensure salt with adequate iodine reaches the consumer. Again, traders of iodized salt should have regular training on ways to preserve salt to maintain its iodine content
Racial/Ethnic, Biomedical, and Sociodemographic Risk Factors for COVID-19 Positivity and Hospitalization in the San Francisco Bay Area
Authors: Tam Cho Wendy K. , Hwang David G.
Published: April 2022

BACKGROUND

The COVID-19 pandemic has uncovered clinically meaningful racial/ethnic disparities in COVID-19-related health outcomes. Current understanding of the basis for such an observation remains incomplete, with both biomedical and social/contextual variables proposed as potential factors.

PURPOSE

Using a logistic regression model, we examined the relative contributions of race/ethnicity, biomedical, and socioeconomic factors to COVID-19 test positivity and hospitalization rates in a large academic health care system in the San Francisco Bay Area prior to the advent of vaccination and other pharmaceutical interventions for COVID-19.

RESULTS

Whereas socioeconomic factors, particularly those contributing to increased social vulnerability, were associated with test positivity for COVID-19, biomedical factors and disease co-morbidities were the major factors associated with increased risk of COVID-19 hospitalization. Hispanic individuals had a higher rate of COVID-19 positivity, while Asian persons had higher rates of COVID-19 hospitalization. Diabetes was an important risk factor for COVID-19 hospitalization, particularly among Asian patients, for whom diabetes tended to be more frequently undiagnosed and higher in severity.

CONCLUSIONS

We observed that biomedical, racial/ethnic, and socioeconomic factors all contributed in varying but distinct ways to COVID-19 test positivity and hospitalization rates in a large, multiracial, socioeconomically diverse metropolitan area of the United States. The impact of a number of these factors differed according to race/ethnicity. Improving over-all COVID-19 health outcomes and addressing racial and ethnic disparities in COVID-19 out-comes will likely require a comprehensive approach that incorporates strategies that target both individual-specific and group contextual factors.
Loss of CHGA protein as a potential biomarker for colon cancer diagnosis: a study on biomarker discovery by machine learning and confirmation by immunohistochemistry in colorectal cancer tissue microarrays
Authors: Zhang Xueli , Zhang Hong , Fan Chuanwen , Shen Bairong , Sun Xiao-Feng
Published: April 2022

Background

Incidences of colon and rectal cancers have been parallelly and constantly increased, however, the mortality has been slightly decreased due to early diagnosis and better therapies during the last decades. Precise early diagnosis for colorectal cancer has been a great challenge in order to win chances for the best choices of cancer therapies.

Patients and methods

We have started with searching protein biomarkers based on our colorectal biomarker database (CBD), finding differential expressed genes (GEGs) and non-DEGs from RNA sequencing (RNA-seq) data, and further predicted new biomarkers on protein-protein interaction (PPI) networks by machine learning (ML) methods. The best-selected biomarker was further verified by receiver operating characteristic (ROC) test from microarray and RNA-seq data, biological network and functional analysis, and immunohistochemistry in the tissue arrays from 198 specimens.

Results

There were twelve proteins (MYO5A, CHGA, MAPK13, VDAC1, CCNA2, YWHAZ, CDK5, GNB3, CAMK2G, MAPK10, SDC2, and ADCY5) which were predicted by ML as colon cancer candidate diagnosis biomarkers. These predicted biomarkers showed close relationships with reported biomarkers on PPI network and shared some pathways. ROC test showed CHGA protein with the best diagnostic accuracy (AUC=0.9 in microarray data and 0.995 in RNA-seq data) among these candidate protein biomarkers. Furthermore, CHGA performed well in the immunohistochemistry test.

Conclusions

Protein expression of CHGA in the normal colorectal mucosa was lost in the colorectal cancers and the lose of CHGA protein might be a potential candidate biomarker for colon or even colorectal cancer diagnosis.

Topic

CHGA expression, colon cancer diagnosis

Key Message

The results of this study suggest that lose of CHGA expression from the normal colon and adjacent mucosa to colon cancer may be used as a valuable biomarker for early diagnosis of colon adenocarcinoma
Use of face masks did not impact COVID-19 incidence among 10–12-year-olds in Finland
Authors: Juutinen Aapo , Sarvikivi Emmi , Laukkanen-Nevala Päivi , Helve Otto
Published: April 2022

In fall 2021 in Finland, the recommendation to use face masks in schools for pupils ages 12 years and above was in place nationwide. Some cities recommended face masks for younger pupils as well. Our aim was to compare COVID-19 incidence among 10–12-year-olds between cities with different recommendations on the use of face masks in schools. COVID-19 case numbers were obtained from the National Infectious Disease Registry (NIDR) of the Finnish Institute for Health and Welfare, where clinical microbiology laboratories report all positive SARS-CoV-2 tests with unique identifiers in a timely manner, including information such as date of birth, gender, and place of residence. The NIDR is linked to the population data registry, enabling calculation of incidences. We compared the differences in trends of 14-day incidences between Helsinki and Turku among 10–12-year-olds, and for comparison, also among ages 7–9 and 30–49 by using joinpoint regression. According to our analysis, no additional effect seemed to be gained from this, based on comparisons between the cities and between the age groups of the unvaccinated children (10–12 years versus 7–9 years).
Early SARS-CoV-2 reinfections within 60 days highlight the need to consider antigenic variations together with duration of immunity in defining retesting policies
Authors: Nevejan Louis , Cuypers Lize , Laenen Lies , Van Loo Liselotte , Vermeulen François , Wollants Elke , Van Hecke Ignace , Desmet Stefanie , Lagrou Katrien , Maes Piet , André Emmanuel
Published: April 2022

The emergence of the SARS-CoV-2 Omicron variant, characterized by a significant antigenic diversity compared to the previous Delta variant, had led to a decrease in antibody efficacy in both convalescent and vaccinees’ sera resulting in high number of reinfections and breakthrough cases worldwide. However, to date, reinfections are defined by the ECDC as two positive tests ≥60 days apart, influencing retesting policies after an initial positive test in several European countries. We illustrate by a clinical case supplemental by epidemiological data that early reinfections do occur within 60 days especially in young, unvaccinated individuals. In older patient groups, unvaccinated and patients with a basic vaccination scheme are more vulnerable to reinfections compared to patients who received a first booster vaccine. For this reason, we consider that the duration of protection offered by a previous infection should be reconsidered, in particular when a shift between consecutive SARS-CoV-2 variants occurs.
Toward an optimal contraception dosing strategy
Authors: Gavina Brenda Lyn A. , de los Reyes Aurelio A. , Olufsen Mette S. , Lenhart Suzanne , Ottesen Johnny T.
Published: April 2022

Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.

AUTHOR SUMMARY

Hormonal contraceptives composed of exogenous estrogen and/or progesterone are commonly administered artificial means of birth control. Despite many benefits, adverse side effects associated with high doses such as thrombosis and myocardial infarction, cause hesitation to usage. Our study presents an improved mathematical model for hormonal control of the menstrual cycle and applies optimal control theory to minimize total exogenous estrogen and/or progesterone dose, and determine timing of administration that lead to contraception. We observe a reduction in dosage of about 92% in estrogen monotherapy and 43% in progesterone monotherapy. Our simulations show that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. In addition, we illustrate that combination therapy significantly lower doses further. Our findings may give clinicians insights into optimal dosing scheme for contraception.
State Dependent Anionic Pore Currents Conducted by Single Countercharge Mutants in a Voltage-Sensing Phosphatase
Authors: Shen Rong , Roux Benoît , Perozo Eduardo
Published: April 2022

Mutating gating charge residues in the S4 segment of voltage-sensing domains (VSDs) can cause ionic leak currents through the VSDs. These leak currents, known as gating pore or omega currents, play important pathophysiological role in many diseases. Here, we show that mutations in a key countercharge residue, D129, in the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) facilitate conduction of unique anionic omega currents. Neutralization of D129 causes a dramatic positive shift of activation, facilitates the formation of a continuous water path through the intermediate state VSD, and creates a positive electrostatic potential landscape inside the VSD leading to anion selectivity. Increasing the population or duration of the conducting state by a high external pH or an engineered Cd2+ bridge markedly increases the current magnitude. Our findings uncover a new role of countercharge residues and could inform on the mechanisms of channelopathies linked to countercharge residue mutations.
Advanced transcriptomic analysis reveals the role of efflux pumps and media composition in antibiotic responses ofPseudomonas aeruginosa
Authors: Rajput Akanksha , Tsunemoto Hannah , Sastry Anand V. , Szubin Richard , Rychel Kevin , Chauhan Siddharth M. , Pogliano Joe , Palsson Bernhard O.
Published: April 2022

Pseudomonas aeruginosais an opportunistic pathogen and major cause of hospital acquired infections. The pathogenicity and virulence ofP. aeruginosais largely determined by its transcriptional regulatory network (TRN). We used 411 transcription profiles ofP. aeruginosafrom diverse growth conditions to construct a quantitative TRN by identifying independently modulated sets of genes (called iModulons) and their condition-specific activity levels. The current study focused on the use of iModulons to analyze pathogenicity and antibiotic resistance ofP. aeruginosa. Our analysis revealed: 1) 116 iModulons, 81 of which show strong association with known regulators; 2) novel roles of two-component systems in regulating antibiotics efflux pumps; 3) substrate-efflux pump associations; 4) differential iModulon activity in response to beta-lactam antibiotics in bacteriological and physiological media; 5) differential activation of ‘Cell Division’ iModulon resulting from exposure to different beta-lactam antibiotics; and 6) a role of the PprB iModulon in the stress-induced transition from planktonic to biofilm lifestyle. In light of these results, the construction of an iModulon-based TRN provides a transcriptional regulatory basis for key aspects ofP. aeruginosainfection, such as antibiotic stress responses and biofilm formation. Taken together, our results offer a novel mechanistic understanding ofP. aeruginosapathogenicity.

Significance

Large data sets and machine learning are impacting a growing number of areas of research in the life sciences. Once the compendia of bacterial transcriptomes reached a critical size, we could use source signal extraction algorithms to find lists of co-regulated genes (called iModulons) associated with a transcription factor (TF) to them. The gene composition of iModulons and their condition-dependent activity levels constitute a quantitative description of the composition of bacterial transcriptomes. This study shows how this approach can be used to reveal the responses ofP. aeruginosato antibiotics and thus yield a deep regulatory understanding of pathogenicity properties. This study motivates the execution of similar studies for the other ESKAPEEs to yield a broad understanding of the role of TRNs in antibiotic responses to these urgent threat bacterial pathogens.
Impulse dispersion of aerosols during playing the recorder and evaluation of safety measures
Authors: Köberlein Marie , Hermann Laila , Gantner Sophia , Tur Bogac , Peters Gregor , Westphalen Caroline , Benthaus Tobias , Döllinger Michael , Kniesburges Stefan , Echternach Matthias
Published: April 2022

Introduction

Group musical activities using wind instruments have been restricted during the CoVID19 pandemic due to suspected higher risk of virus transmission. It was presumed that the aerosols exhaled through the tubes while playing would be ejected over larger distances and spread into the room due to jet stream effects. In particular, the soprano recorder is widely used as instrument in school classes and for beginners of all age groups in their musical education, as well as in contexts of leisure activities and in professional concert performances.

Understanding the aerosol impulse dispersion characteristics of playing the soprano recorder could assist with the establishment of concepts for safe music-making.

Methods

Five adult professionally trained soprano recorder players (4 female, 1 male) played four bars of the main theme of L. van Beethoven’s “Ode to Joy” in low and in high octaves, as well as with 3 different potential protection devices in the high octave. For comparison they spoke the corresponding text by F. Schiller. Before each task, they inhaled .5 L of vapor from an e-cigarette filled with base liquid. The vapor cloud escaping during speaking or playing was recorded by cameras and its spread was measured as a function of time in the three spatial dimensions. The potential safety devices were rated in practicability with a questionnaire, and their influence on the sound was compared, generating a long-term average spectrum from the audio data.

Results

When playing in the high octave, at the end of the task the clouds showed a median distance of 1.06 m to the front and .57 m diameter laterally (maxima: x: 1.35 m and y: .97 m). It was found that the clouds’ expansion values in playing the recorder with and without safety measures are mostly lower when compared to the ordinary, raised speaking voice of the same subjects.

The safety devices which covered the instrument did not show clear advantages and were rated as unpractical by the subjects. The most effective reduction of the cloud was reached when playing into a suction funnel.

Conclusion

The aerosol dispersion characteristics of soprano recorders seem comparable to clarinets. The tested safety devices which covered holes of the instrument did not show clear benefits.
Antibody responses to SARS-CoV-2 vaccination in patients with acute leukaemia and high risk MDS on active anti-cancer therapies
Authors: Chan W.Y. , Zhu C. , Sanchez E. , Gupta R. , Fielding A.K , Khwaja A. , Payne E.M. , O’Nions J.
Published: April 2022

Patients with haematological malignancies, such as acute leukaemia and high-risk MDS (HR-MDS), have significantly increased mortality and morbidity from COVID-19. However vaccine efficacy in these patients and the impact of systemic anti-cancer therapy (SACT) on vaccine response remains to be fully established. SARS-CoV-2 antibody responses in 53 patients with ALL, AML or HR-MDS receiving SACT were characterised following two doses of either BNT162b2 or ChAdOx1nCoV-19. All patients were tested for anti-S antibodies after 2 doses, 60% after the first dose and anti-N antibody testing was performed on 46 patients (87%). Seropositivity rates after 2 vaccine doses were 95% in AML/HR-MDS patients and 79% in ALL. After stratification by prior SARS-CoV-2 infection, naïve patients with AML/HR-MDS had higher seroconversion rates and median anti-S antibody titres compared to ALL (median 291U/mL versus 5.06U/mL), and significant increases in anti-S titres with consecutive vaccine doses, not seen in ALL. No difference was seen in serological response between patients receiving intensive chemotherapy or non-intensive therapies (HMA) but significantly reduced titres were present in AML/HR-MDS patients who received venetoclax-based regimens compared to other therapies. All ALL patients received intensive chemotherapy, with no further impact of anti-CD20 immunotherapy on serological response. Understanding the impact of disease subtypes and therapy on vaccine response is essential to enable decisions on modifying or delaying treatment in the context of either SARS-CoV-2 infection or vaccination.
Predictors for Reactogenicity and Humoral Immunity to SARS-CoV-2 Following Infection and mRNA Vaccination: A Regularized Mixed-Effects Modelling Approach
Authors: Williams Erin C. , Kizhner Alexander , Stark Valerie S. , Nawab Aria , Muniz Daniel D. , Tribin Felipe Echeverri , Carreño Juan Manuel , Bielak Dominika , Singh Gagandeep , Hoffer Michael E. , Krammer Florian , Pallikkuth Suresh , Pahwa Savita
Published: April 2022

Background

The influence of pre-existing humoral immunity, inter-individual demographic factors, and vaccine-associated reactogenicity on immunogenicity following COVID vaccination remains poorly understood.

Methods

Ten-fold cross-validated least absolute shrinkage and selection operator (LASSO) and linear mixed effects models were used to evaluate symptoms experienced during natural infection and following SARS-CoV-2 mRNA vaccination along with demographics as predictors for antibody (AB) responses in COVID+ participants in a longitudinal cohort study.

Results

In previously infected individuals, AB were more durable and robust following vaccination when compared to natural infection alone. Higher AB were associated with experiencing dyspnea during natural infection, as was the total number of symptoms reported during the COVID-19 disease course. Both local and systemic symptoms following 1st and 2nd dose of SARS-CoV-2 mRNA vaccines were predictive of higher AB after vaccination, as were the demographic factors of age and Hispanic ethnicity. Lastly, there was a significant temporal relationship between AB and days since infection or vaccination.

Conclusion

Vaccination in COVID+ individuals ensures a more robust immune response. Experiencing systemic and local symptoms post-vaccine is suggestive of higher AB, which may confer greater protection. Age and Hispanic ethnicity are predictive of higher AB.
Altered brain network topology in children with Auditory Processing Disorder: a resting-state multi-echo fMRI study
Authors: Alvand Ashkan , Kuruvilla-Mathew Abin , Kirk Ian J. , Roberts Reece P. , Pedersen Mangor , Purdy Suzanne C.
Published: April 2022

Children with auditory processing disorder (APD) experience hearing difficulties, particularly in the presence of competing sounds, despite having normal audiograms. There is considerable debate on whether APD symptoms originate from bottom-up (e.g., auditory sensory processing) and/or top-down processing (e.g., cognitive, language, memory). A related issue is that little is known about whether functional brain network topology is altered in APD. Therefore, we used resting-state functional magnetic resonance imaging data to investigate the functional brain network organization of 57 children from 8 to 13 years old, diagnosed with APD (n=28) and without hearing difficulties (healthy control, HC; n=29). We applied complex network analysis using graph theory to assess the whole-brain integration and segregation of functional networks and brain hub architecture. Our results showed children with APD and HC have similar global network properties and modular organization. Still, the APD group showed different hub architecture. At the nodal level, we observed decreased participation coefficient (PC) in auditory cortical regions in APD, including bilateral superior temporal gyrus and left middle temporal gyrus. Beyond auditory regions, PC was also decreased in APD in bilateral posterior temporo-occipital cortices, left intraparietal sulcus, and right posterior insular cortex. Correlation analysis suggested a positive association between PC in the left parahippocampal gyrus and the listening-in-spatialized-noise-sentences task where APD children were engaged in auditory perception. In conclusion, our findings provide evidence of altered brain network organization in children with APD, specific to auditory networks, and shed new light on the neural systems underlying children’s listening difficulties.
Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
Authors: Pillai Maalavika , Rajaram Gouri , Thakur Pradipti , Agarwal Nilay , Muralidharan Srinath , Ray Ankita , Somarelli Jason A , Jolly Mohit Kumar
Published: April 2022

Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Interestingly, melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more “one-dimensional” EMT that leads to a hybrid epithelial/ mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. Interestingly, as melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and dedifferentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma.
Deploying genomics workflows on high performance computing (HPC) platforms: storage, memory, and compute considerations
Authors: Powers Marissa E. , Mannthey Keith , Sebastian Priyanka , Adsule Snehal , Kiernan Elizabeth , Smith Jonathan T. , Way Jessica , Shifaw Beri , Roazen David , Narvaez Paolo
Published: April 2022

Next Generation Sequencing (NGS) workloads largely consist of pipelines of tasks with heterogeneous compute, memory, and storage requirements. Identifying the optimal system configuration has historically required expertise in both system architecture and bioinformatics. This paper outlines infrastructure recommendations for one commonly used genomics workload based on extensive benchmarking and profiling, along with recommendations on how to tune genomics workflows for high performance computing (HPC) infrastructure. The demonstrated methodology and learnings can be extended for other genomics workloads and for other infrastructures such as the cloud.
Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation, and ssDNA binding kinetics
Authors: Orris Benjamin , Huynh Kevin W. , Ammirati Mark , Han Seungil , Bolaños Ben , Carmody Jason , Petroski Matthew D. , Bosbach Benedikt , Shields David J. , Stivers James T.
Published: April 2022

SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator and dNTP activators/substrates. In addition, the inactive monomeric and dimeric forms of the enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated by CDK1 and CDK2 at its C-terminal threonine 592 (pSAMHD1), enabling the enzyme to localize to stalled replication forks (RFs) and promote their restart. Since localization of a potent dNTPase at stalled RFs is not harmonious with DNA replication, we used a series of kinetic and thermodynamic measurements to explore a hypothesis where the combined effects of T592 phosphorylation and ssDNA binding serves as a dual switch to turn-off SAMHD1 dNTPase activity. We report that phosphorylation has only a small effect on the dNTPase activity and ssDNA binding affinity of SAMHD1. However, perturbation of the native T592 by phosphorylation decreased the thermal stability of tetrameric SAMHD1 and accelerated tetramer dissociation in the absence and presence of ssDNA (~15-fold). In addition, we found that ssDNA binds competitively with GTP to the A1 site. A full-length SAMHD1 cryo-EM structure revealed substantial baseline dynamics in the C-terminal domain (which contains T592) which may be modulated by phosphorylation. We propose that T592 phosphorylation increases tetramer dynamics and allows invasion of ssDNA into the A1 site and the previously characterized DNA binding surface at the dimer-dimer interface. These features are consistent with rapid and regiospecific inactivation of pSAMHD1 dNTPase at RFs or other sites of free ssDNA in cells.
Epistasis between synonymous and nonsynonymous mutations in Dictyostelium discoideum ammonium transporter amtA drives functional complementation in Saccharomyces cerevisiae
Authors: Densi Asha , Iyer Revathi S , Bhat Paike Jayadeva
Published: April 2022

Role of Horizontal Gene Transfer (HGT) in evolution transcends across the three domains of life. Ammonium transporters are present in all species and therefore offer an excellent paradigm to study protein evolution following HGT. While investigating HGT through complementation assay, we observed that synonymous and nonsynonymous mutations follow an epistastic relationship. As a proxy for HGT, we attempted to complement a mep1mep2mep3Δ strain of S. cerevisiae (triple deletion strain) which cannot grow on ammonium as a sole nitrogen source below a concentration of 3 mM, with amtA of D. discoideum. As the wild type amtA did not complement, we isolated two mutant derivatives of amtA that complemented the triple deletion strain of S. cerevisiae. amtA M1 bears three nonsynonymous and two synonymous substitutions and these substitutions are necessary for its functionality. amtA M2 bears two nonsynonymous and one synonymous substitution, all of which are necessary for functionality. These mutants were then studied at phenotypic, cell biological, and biochemical level. Interestingly, AmtA M1 transports ammonium but does not confer toxicity to methylamine while AmtA M2 transports ammonium as well as confers methylamine toxicity, demonstrating functional diversification. Based on the results presented, we suggest that protein evolution cannot be fathomed by studying nonsynonymous and synonymous substitutions separately. This is because, protein evolution entails an interaction between synonymous and nonsynonymous substitution, which seems to have gone unnoticed thus far. Above observations have significant implications in various facets of biological processes and are discussed in detail.

Highlights

Ammonium transporters (Amts) from bacteria to humans complement in yeast

AmtA of D. discoideum does not complement yeast defective for ammonium uptake

Synonymous & nonsynonymous mutations are essential for AmtA functionality in yeast

Conformational differences underlie functionality & functional diversification

Protein evolution entails interaction of synonymous & nonsynonymous mutations
A visual representation of the hand in the resting somatomotor regions of the human brain
Authors: El Rassi Yara , Handjaras Giacomo , Leo Andrea , Papale Paolo , Corbetta Maurizio , Ricciardi Emiliano , Betti Viviana
Published: April 2022

Hands are regularly in sight in everyday life. This visibility affects motor control, perception, and attention, as visual information is integrated into an internal model of sensorimotor control. Spontaneous brain activity, i.e., ongoing activity in the absence of an active task (rest), is correlated among somatomotor regions that are jointly activated during motor tasks1. Moreover, recent studies suggest that spontaneous activity patterns do not only replay at rest task activation patterns, but also maintain a model of the statistical regularities (priors) of the body and environment, which may be used to predict upcoming behavior2–4. Here we test whether spontaneous activity in the human somatomotor cortex is modulated by visual stimuli that display hands vs. non-hand stimuli, and by the use/action they represent. We analyzed activity with fMRI and multivariate pattern analysis to examine the similarity between spontaneous (rest) activity patterns and task-evoked patterns to the presentation of natural hands, robot hands, gloves, or control stimuli (food). In the left somatomotor cortex we observed a stronger (multi-voxel) spatial correlation between resting-state activity and natural hand picture patterns, as compared to other stimuli. A trend analysis showed that task-rest pattern similarity was influenced by inferred visual and motor attributes (i.e., correlation for hand>robot>glove>food). We did not observe any task-rest similarity in the visual cortex. We conclude that somatomotor brain regions code at rest for visual representations of hand stimuli and their inferred use.
Understanding the Spin Crossover Dynamical Effects of the Dioxygen Binding and Activation on HOD enzyme
Authors: Du Likai
Published: April 2022

For the cofactor-free 1-H-3-hydroxy-4-oxoquinaldine-2,4-dioxygenase (HOD), the dioxygen (O2) dependent steps are rate-limiting along with a spin state crossover to the singlet spin state. Here, the primary triplet O2 molecule activation on the 2-methyl-3-hydroxy-4(1H)-quinolone (MHQ) is investigated, and the catalytic role of the intersystem crossing effects is highlighted by directly comparing results from the Born-Oppenheimer dynamics and non-adiabatic surface hopping dynamics. This work confirms non-adiabatic dynamical effects are essential to modulate the O2 activation on the substrate MHQ. The time scale of the equilibration and conversion from triplet to singlet state should be in the range of a few hundreds of femtoseconds. We hope this work provides us a fresh look at the underlying physics of dioxygen activation reactions involving more than one spin state.