bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world outcomes of COVID-19 treatment with remdesivir in a Spanish hospital
Authors: Hidalgo-Tenorio Carmen , García-Vallecillos Coral , Sequera-Arquelladas Sergio
Published: September 2021

Remdesivir is the only antiviral approved for lower respiratory tract infection produced by SARS-CoV-2. The main objective of this study was to determine the mortality rate, readmissions, mean hospital stay, need for higher levels of oxygen support, and adverse effect-induced abandonment rate in hospitalized patients diagnosed with COVID-19 and treated with remdesivir (RDSV). The secondary objective was to determine mortality-related risk factors in these patients.

The study included a prospective cohort of patients admitted to a third level Spanish hospital between July 5, 2020 and February 3, 2021 for COVID-19 diagnosed by SARS-CoV-2 polymerase chain reaction and/or antigen test and treated with RDSV.

Remdesivir was received by 185 patients (69.7% males) with a mean age of 62.5 years, median Charlson index of 3 (interquartile range [IQR]: 1–4), and median ambient air oxygen saturation of 91% (IQR: 90–93); 61.6% of patients had hyper-inflammatory syndrome at admission. Median time with symptoms before RDSV treatment was 5 days (IQR: 3–6) and the median hospital stay was 10 days (IQR: 7–15); 19 patients (10.3%) died after a median stay of 13.5 days (IQR: 9.7–24 days), 58 patients (12.9%) were admitted to ICU, 58 (31.4%) needed higher levels of oxygen support, 0.5% abandoned the treatment due to adverse effects, and there were no readmissions. The only mortality-related factor was the need for higher levels of oxygen support (odds ratio 12.02; 95% confidence interval 2.25–64.2).

All studied patients were admitted to hospital with a diagnosis of COVID-19 and in respiratory failure, needing initial low-flow oxygen support, and all received RDSV within 1 week of symptom onset. The percent mortality was lower in these patients than was observed in all patients with severe COVID-19 admitted to our center (10.3% vs 20.3%, respectively). Despite receiving RDSV, 1 in 3 patients needed higher levels of oxygen support, the sole mortality-related factor.
Distribution of normal and pathological OGTTs among pregnant population and non-pregnant women with PCOS – the cross-sectional study
Authors: Gojnic-Dugalic Miroslava , Stefanovic Katarina , Stefanovic Aleksandar , Jotic Aleksandra , Lalic Nebojsa , Petronijevic-Vrzic Svetlana , Petronijevic Milos , Milicic Tanja , Lukic Ljiljana , Todorovic Jovana , Dugalic Stefan , Pantic Igor , Nesic Dejan , Stoiljkovic Milica , Stanisavljevic Dejana , Perovic Milan
Published: September 2021

Both pregnancy, as physiological, and polycystic ovary syndrome (PCOS), as a pathological condition, carry the risk for developing glucose metabolism abnormalities. In this retrospective cross-sectional study, we hypothesized that pregnancy as a physiological condition carries a higher likelihood for abnormal oral glucose tolerance test (OGTT) results than PCOS as a pathological condition.

We have compared the prevalence and likelihood ratios for abnormal OGTT results between non-pregnant women with PCOS (Group A) and pregnant women at 24 to 28 weeks of gestation (Group B). Participants of both study groups underwent glucose tolerance testing with 75 g glucose OGTT. During the study period, 7411 women were tested, 3932 women encompassed Group A, and 3479 women comprised Group B.

The numbers of yearly tested pregnant women and the corresponding proportion of tested women among all study participants have decreased during the study period, from 766 to 131 and 89.1% to 20.5%, respectively. Group A had a significantly lower prevalence (4.4%) of pathological OGTT results compared to Group B (8.1%). This has resulted in a 45.427 likelihood ratio (P < .001) for abnormal OGTT results in pregnant women compared to non-pregnant women with PCOS.

We might conclude that pregnancy could have a more challenging influence on glucose metabolism and that carries higher risks for abnormal glucose metabolism than PCOS. The awareness of obstetricians regarding physiological changes during pregnancy that predisposes abnormal glucose metabolism is decreasing over time and the compliance concerning OGTT testing of pregnant women is decreasing too.
Exploring community-dwelling stroke survivors’ experiences of receiving a nurse-led theory-based stroke self-management programme
Authors: Lo Suzanne Hoi Shan , Chau Janita Pak Chun
Published: September 2021

International evidence-based guidelines recommend self-management support for stroke survivors to improve their health outcomes. We developed a 4-week nurse-led stroke self-management programme (SSMP) and conducted a randomised controlled trial to assess its effects. This paper reports the findings of a qualitative study nested within the randomised controlled trial to explore stroke survivors’ experiences of SSMP participation. Semi-structured interviews were conducted with all adult participants who were clinically diagnosed with a first or recurrent ischaemic or haemorrhagic stroke, residing at home, communicable in Cantonese, had a Montreal Cognitive Assessment score below the second percentile, and participated in at least 1 SSMP session. All interviews were conducted in Cantonese, lasted approximately 45 minutes, and were audio-recorded. Interview data were transcribed verbatim and analysed thematically. Sixty-four stroke survivors (mean age 66.33 years, SD 12.34) were recruited, and 59 were interviewed via phone immediately after completion of SSMP. Three themes were derived. Overall, participants were satisfied with the SSMP. Their understanding of self-management was improved, and they recognised its importance in recovery. Their confidence in self-management was also enhanced through the use of multifaceted strategies. Suggestions were made to enhance their participation experiences, including increased home visits and group sessions, making group session attendance optional and arranging them more accessibly, meeting the survivors who shared their survival experiences in the videos, and access to the videos online. This study concurred that the SSMP enhanced stroke survivors’ self-efficacy in self-management. Rearrangement of the programme format and enhancements in accessibility could be further examined to enable more effective stroke self-management.
Relationship between cardiorespiratory fitness and preoperative evaluation findings in patients with morbid obesity undergoing sleeve gastrectomy
Authors: Myung Jei Hak , Kim Bo Ryun , Yoon Soo Hoon , Kwon Yeong Kuen , Park Sung Soo , Pyun Sung-Bom
Published: September 2021

Evaluating various parameters, including preoperative cardiorespiratory fitness markers, is critical for patients with morbid obesity. Also, clinicians should prescribe suitable exercise and lifestyle guideline based on the tested parameters. Therefore, we investigated cardiorespiratory fitness and its correlation with preoperative evaluation in patients with morbid obesity scheduled for laparoscopic sleeve gastrectomy.

A retrospective cross-sectional study was conducted with 38 patients (13 men and 25 women; mean age, 34.9 ± 10.9 years) scheduled for laparoscopic sleeve gastrectomy. Cardiopulmonary exercise stress tests were also performed. Measured cardiopulmonary responses included peak values of oxygen consumption (VO2), metabolic equivalents (METs), respiratory exchange ratio, heart rate (HR), and rate pressure product. Body composition variables were analyzed using bioimpedance analysis, laboratory parameters (hemoglobin A1c, lipid profile, inflammatory markers), and comorbidities. In addition, self-reported questionnaires were administered, including the Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), Short-Form Health Survey (SF-36), and Moorehead-Ardelt Quality of Life Questionnaire (MAQOL).

The average body mass index (BMI) and percent body fat were 39.8 ± 5.7 kg/m−2 and 46.2 ± 6.1%, respectively. The VO2peak/kg, METs, RERpeak, HRpeak, RPPpeak, age-predicted HR percentage, and VO2peak percentage were 18.6 ± 3.8 mL/min−1/kg−1, 5.3 ± 1.1, 1.1 ± 0.1, 158.5 ± 19.8, 32,414.4 ± 6,695.8 mm Hg/min−1, 85.2 ± 8.8%, and 76.1 ± 14.8%, respectively. BMI (P = .026), percent body fat (P = .001), HRpeak (P = .018), erythrocyte sedimentation rate (P = .007), total BDI (P = .043), HDRS (P = .025), SF-36 (P = .006), and MAQOL (P = .007) scores were significantly associated with VO2peak/kg. Body fat percentage (P < .001) and total SF-36 score (P < .001) remained significant in the multiple linear regression analysis.

Various cardiorespiratory fitness markers were investigated in patients with morbid obesity who underwent the sleeve gastrectomy. Peak aerobic exercise capacity was significantly associated with preoperative parameters such as body fat composition and self-reported quality of life in these patients. These results could be utilized for preoperative and/or postoperative exercise strategies in patients with morbid obesity scheduled for laparoscopic sleeve gastrectomy.
Impact of air temperature on occurrence of bath-related cardiac arrest
Authors: Hiraki Katsushige , Irie Jin , Nomura Osamu , Machino Hiromi , Yaguchi Shinya , Ishizawa Yoshiya , Soma Yuki , Hanada Hiroyuki
Published: September 2021

The mortality of the bath-related cardiac arrest (BRCA) is extremely high. While air temperature is reported to be associated with the BRCA occurrence, it is unclear whether daily minimum temperatures or the difference between maximum and minimum air temperatures influences BRCA occurrence the most.

A retrospective cohort study of adult patients was conducted between January 2015 and February 2020 at Hirosaki University Hospital Emergency Department. The following data were collected: age, sex, day of cardiac arrest event, location of the event, initial cardiac rhythm, presence of return of spontaneous circulation, and overall mortality (status at 1 month after cardiac arrest event). Based on the day of the event and the location in which the event occurred, daily minimum and maximum temperatures were obtained from the Japan Meteorological Agency database.

A total of 215 eligible cardiac arrest cases were identified, including 25 cases of BRCA. Comparing BRCA and non-BRCA, initial shockable cardiac rhythm (4.0% vs 44.7%), presence of return of spontaneous circulation (8.0% vs 34.7%), and overall mortality (96.0% vs 71.6%) differed significantly (P < .05 each). Daily minimum and maximum temperatures showed no significant relationships with BRCA or non-BRCA. Daily minimum temperature was a risk factor of BRCA occurrence after adjusting for age and temperature difference (risk ratio, 0.937; 95% confidence interval, 0.882–0.995).

Daily minimum temperature represents a potential risk factor for BRCA occurrence.
The efficacy and safety of alpha-adrenergic blockers for medical expulsion therapy in patients with ureteral calculi
Authors: Yu Ze-Wei , Wang Rui-Hong , Zhang Chang-Cun , Gao Jian-Gang
Published: September 2021

Purpose:

Alpha-adrenergic blockers are commonly used as a medical expulsive therapy (MET) for patients with ureteral calculi. The aim of this meta-analysis was to evaluate the efficacy and safety of alpha-adrenergic blockers compared with a placebo when used as a MET.

Materials and methods:

We carried out a systematic search of the PubMed, EMBASE, and Web of Science databases, and the Cochrane Library, for relevant articles from inception to November 2020. Our aim was to identify placebo-controlled trails in which patients were randomized to receive either alpha-adrenergic blockers (tamsulosin, alfuzosin, doxazosin, terazosin, naftopidil, or silodosin) or a placebo for the treatment of ureteral calculi.

Results:

According to strict inclusion criteria, database searches identified 8 placebo-controlled studies that included 2284 patients. Generally, α-blockers had no significant effect on the clearance of stones in the urinary tract (risk ratio [RR] = 1.05; 95% confidence interval [CI] = 1.00–1.11). However, subgroup analysis showed that α-blockers were effective in treating distal urinary tract stones (RR = 1.08; 95% CI = 1.02–1.15). With regards to adverse events, our analysis showed that the combination of MET with α-blockers was likely to cause dizziness (RR = 1.37; 95% CI = 1.06–1.79) and retrograde ejaculation (RR = 3.10; 95% CI = 1.81–5.29).

Conclusion:

Although α-blockers cannot improve the overall ureteral stone clearance rate, these drugs are still effective for the treatment of stones in the distal urinary tract. However, the application of α-blockers is likely to cause dizziness and/or retrograde ejaculation.
Prevesicular herpes zoster lumbar radiculopathy with transient motor paresis
Authors: Rhyu Kee-Won , Shin Jae-Hyuk , Kim Yoon-Chung , Cho Sung-Hyun , Kwon Geon-Ho , Lee Han Yong
Published: September 2021

Rationale:

Herpes zoster frequently causes dermatomal vesicular rash accompanied by severe neuralgia, and reaching a differential diagnosis may be challenging before the appearance of the vesicular rash.

Patient concerns:

A 40-year-old male patient visited the emergency department with a complaint of sudden onset motor weakness and ipsilateral radiating neuralgia to the Lt. thigh. He had suffered from chickenpox during childhood.

Diagnoses:

No skin lesion was present at the initial visit. The reverse Straight Leg Raise test was negative. Magnetic resonance imaging showed asymmetrically swollen dorsal root ganglion with Gadolinium enhancement. The vesicular rash that appeared on the sixth day after the symptom onset led to the diagnosis of herpes zoster.

Interventions:

Antiviral agent of valacyclovir (1000 mg t.i.d.) was administered for 7 days.

Outcomes:

The patient recovered from motor weaknesses by 2 weeks from the onset of the symptom. Mild degree post-herpetic neuralgia recovered by 2 months.

Lessons:

A high index of suspicion is necessary to differentiate early herpes zoster radiculitis before the appearance of vesicular rash from compressive radiculopathy. In L2–3 ipsilateral radiating pain along the dermatome or myotome, the absence of reverse Straight Leg Raise sign may be a possible factor in differentiating herpes zoster radiculitis from compressive radiculopathy.
Harm reduction strategies for androgen users: providing appropriate support and improving engagement with healthcare
Authors: Bates Geoff , Shepherd Scott , McVeigh Jim
Published: September 2021

Purpose of review

As evidence continues to emerge of the harms associated with nonmedical androgen use, this review explores the implications from recent studies for designing strategies to reduce harm and support good health amongst androgen users.

Recent findings

Studies have predominantly come from researchers in the UK and Australia. Major themes include questioning the scope and content of harm reduction strategies and identifying approaches to improve engagement between the androgen using community and healthcare providers. Findings suggest that a broader range of interventions and forms of advice are needed than are commonly provided. This must be supported by efforts to increase opportunities to deliver harm reduction through new engagement approaches, better relationships with health professionals and more guidance on identifying and managing associated adverse health impacts.

A fully developed harm reduction-based response to nonmedical androgen use will be one that not only seeks to reduce risk of bloodborne virus transmission and injecting-related harms, but that considers the range of needs amongst the diverse community of androgen users and respects their decisions and rights. Co-producing interventions with members of this community will help develop effective and engaging approaches. Rigorous studies are needed to evaluate new harm reduction interventions as well as those already delivered.
Trends in Differences Across Subgroups of Adults in Preventive Services Utilization
Authors: Abdus Salam
Published: September 2021

Background:

There were large differences across subgroups of adults in preventive services utilization before 2010. The Affordable Care Act had numerous provisions aimed at increasing utilization as well as at reducing disparities.

Objective:

This study examines whether preventive services utilization changed over time, across subgroups of adults defined by race/ethnicity, insurance coverage, poverty status, Census region, and urbanicity.

Methods:

Data from the Medical Expenditure Panel Survey Household Component are used to examine service utilization before the passage of the Affordable Care Act (2008/2009), after the implementation of the preventive services mandate and the dependent coverage provision (2012/2013), and after Medicaid expansions (2015/2016). Four preventive services are examined for adults aged 19−64—general checkups, blood cholesterol screening, mammograms, and colorectal cancer screening. Multivariate logistic regression models are used to predict preventive services utilization of adult subgroups in each time period, and to examine how differences across subgroups changed between 2008/2009 and 2015/2016.

Results:

There were modest increases in utilization between 2008/2009 and 2015/2016 for blood cholesterol and colorectal cancer screenings. For 3 of 4 preventive services, differences between the Northeast and the Midwest regions narrowed. However, large gaps in utilization across income groups and between those with and without coverage persisted. Disparities across racial/ethnic groups in general checkups persisted over time as well.

Conclusion:

While some differences have narrowed, large gaps in preventive service utilization across population subgroups remain.
Cost-effectiveness of a Digital Health Intervention for Acute Myocardial Infarction Recovery
Authors: Bhardwaj Vinayak , Spaulding Erin M. , Marvel Francoise A. , LaFave Sarah , Yu Jeffrey , Mota Daniel , Lorigiano Ting-Jia , Huynh Pauline P. , Shan Rongzi , Yesantharao Pooja S. , Lee Matthias A. , Yang William E. , Demo Ryan , Ding Jie , Wang Jane , Xun Helen , Shah Lochan , Weng Daniel , Wongvibulsin Shannon , Carter Jocelyn , Sheidy Julie , McLin Renee , Flowers Jennifer , Majmudar Maulik , Elgin Eric , Vilarino Valerie , Lumelsky David , Leung Curtis , Allen Jerilyn K. , Martin Seth S. , Padula William V.
Published: September 2021

Background:

Acute myocardial infarction (AMI) is a common cause of hospital admissions, readmissions, and mortality worldwide. Digital health interventions (DHIs) that promote self-management, adherence to guideline-directed therapy, and cardiovascular risk reduction may improve health outcomes in this population. The “Corrie” DHI consists of a smartphone application, smartwatch, and wireless blood pressure monitor to support medication tracking, education, vital signs monitoring, and care coordination. We aimed to assess the cost-effectiveness of this DHI plus standard of care in reducing 30-day readmissions among AMI patients in comparison to standard of care alone.

Methods:

A Markov model was used to explore cost-effectiveness from the hospital perspective. The time horizon of the analysis was 1 year, with 30-day cycles, using inflation-adjusted cost data with no discount rate. Currencies were quantified in US dollars, and effectiveness was measured in quality-adjusted life-years (QALYs). The results were interpreted as an incremental cost-effectiveness ratio at a threshold of $100,000 per QALY. Univariate sensitivity and multivariate probabilistic sensitivity analyses tested model uncertainty.

Results:

The DHI reduced costs and increased QALYs on average, dominating standard of care in 99.7% of simulations in the probabilistic analysis. Based on the assumption that the DHI costs $2750 per patient, use of the DHI leads to a cost-savings of $7274 per patient compared with standard of care alone.

Conclusions:

Our results demonstrate that this DHI is cost-saving through the reduction of risk for all-cause readmission following AMI. DHIs that promote improved adherence with guideline-based health care can reduce hospital readmissions and associated costs.
Management of acute kidney injury associated with Covid-19: what have we learned?
Authors: Cottam Daniel , Nadim Mitra K. , Forni Lui G.
Published: September 2021

Purpose of review

Although initially kidney involvement in COVID-19 infection was felt to occur relatively infrequently, this has proved not to be the case. In critically ill patients with COVID-19, multiorgan failure including acute kidney injury (AKI) is common and is associated with an increased risk of mortality and morbidity. This review focuses briefly on the epidemiology and pathophysiology of COVID-19 associated AKI as well as options for management.

Recent findings

The risk factors for AKI are common to both noncovid-related AKI and COVID-19 associated AKI. Kidney injury in COVID-19 associated AKI may arise through several mechanisms, including not only direct effects on the kidney leading to tubular injury but also through the effects of treatment of multiorgan failure complicating infection. During surge conditions, the use of kidney replacement therapy has embraced all modalities including the use of peritoneal dialysis. The use of blood purification techniques has been proposed, but to date, the results are variable.

COVID-19 associated AKI is common, affecting approximately a quarter of patients hospitalized with COVID-19. Glomerular injury can occur, but in the main tubular injury seems most likely leading to AKI, which should be managed following clinical pathways informed by accepted guidelines.
Functional laryngectomy for the dysfunctional larynx: indications and outcomes in setting of prior chemoradiotherapy
Authors: Olinde Lindsay , Evangelista Lisa , Bewley Arnaud F.
Published: September 2021

Purpose of review

To review the recent literature on indications for and functional outcomes following laryngectomy for severe laryngeal dysfunction.

Recent findings

The use of functional laryngectomy as a definitive treatment for severe laryngeal dysfunction is increasing as more patients with head and neck cancer are treated with definitive chemoradiotherapy. Data are emerging on the efficacy of this technique as measured by aspiration, recurrent pneumonias, enteral tube feeding dependence, and surgical complication rates. Though most patients have marked improvement in aspiration and oral intake, difficulties in swallowing and voicing functions may persist.

Functional laryngectomy is an effective treatment for end-stage laryngeal dysfunction. There is a clear benefit with regard to prevention of aspiration and alleviation of nothing by mouth status. However, qualitative speech and swallowing outcomes are less well studied, though available data suggest that many patients still suffer some degree of continued chronic impairment. More research is needed on these outcomes in order to appropriately counsel patients regarding long-term functional outcomes.
Culture of Interdisciplinary Collaboration in Nursing Research Training
Authors: Levites Strekalova Yulia A.
Published: September 2021

Background

Establishing and maintaining collaborative scientific environments that can cultivate and benefit from a full range of talents is essential for the quality and influence of science. Inclusion of research training and career development interventions to expose nursing PhD students, postdocs, and junior faculty to team science stands to prepare graduates to effectively engage with interdisciplinary colleagues to conduct cutting-edge nursing research and compete successfully for precious research resources. To be effective, nursing research workforce development programs need to recognize and share a culture of interdisciplinarity.

Objectives

This project aims to develop, validate, and disseminate a theoretically grounded and methodologically rigorous tool for a cultural consensus analysis (CCA) of the culture of interdisciplinary collaboration in nursing research.

Methods

Culture can be defined as shared cognitive structures and consensus around culturally correct values, attitudes, and normative behaviors. This mixed-methods study employs CCA to assess construct validity and empirically determine a set of underlying socially learned and shared notions about the cultural domain of interdisciplinary collaboration in nursing research. The study will include three phases: (a) qualitative data collection and analysis to define the cultural domain of interdisciplinary collaborations in nursing research; (b) validation of the CCA tool with the use of cultural knowledge statements; and (c) application of the CCA tool to assess cultural differences among nursing trainees, junior faculty, and training directors. The study participant pool consists of National Institutes of Health–National Institute of Nursing Research awardees, including training directors of institutional training grants, pre- and postdoctoral trainees with individual fellowship training grants, and junior faculty with career development awards. Qualitative data will be analyzed to formulate cultural statements about the values and behaviors that promote interdisciplinary collaboration in nursing research. Subsequent survey data will be assessed using matrix algebra, principal component analysis, and the Stuart–Maxwell Marginal Homogeneity Test.

Discussion

The development and validation of a CCA tool is a novel approach to assess, support, and systematically examine interdisciplinary collaboration and team science in nursing research and training. However, the investigation of culture needs to remain value neutral, refrain from being prescriptive, and be sensitive to the emergence and dominance of one “right” culture.
Psychological and social risk factors associated with development of psychopathology, controlling for biological influence
Authors: Isaksson Johan , Zetterqvist Vendela , Ramklint Mia
Published: September 2021

Purpose of review

To evaluate and summarize recent research investigating psychological, social and environmental risk factors for development of psychopathology in childhood, while controlling for biological (genetic) influences by using a matched sibling, twin or adoptee design.

Recent findings

Nineteen studies were included, of which eleven were longitudinal and eight were cohort studies. Included studies used adequate designs and statistical methods, controlled for unmeasured confounders and, in many cases, for other measured risk factors. None of the studies used the framework for environmental factors presented in the International Classification of Functioning, Disability and Health (ICF). The outcome variable psychopathology was rarely assessed using a diagnostic standard. The findings were sorted in five themes based on included exposures: ‘Social support, social rejection and perceived identity,’ ‘Early symptoms of psychopathology,’ ‘Antibiotic exposure,’ ‘Factors in the family’ and ‘Nature versus nurture’.

Using twin/sibling/adoptee designs, a number of unique predictors of psychopathology were found, even when controlling for familial confounders and other specified risk factors. Future studies of psychopathology development should benefit from longitudinal, genetically sensitive designs and from use of diagnostic standards for psychopathology outcome, and should also incorporate ICF for classification of risk factors.
Dysregulated immune responses in COVID-19 patients correlating with disease severity and invasive oxygen requirements
Authors: García-González Paulina , Tempio Fabián , Fuentes Camila , Merino Consuelo , Vargas Leonardo , Simon Valeska , Ramirez-Pereira Mirliana , Rojas Verónica , Tobar Eduardo , Landskron Glauben , Araya Juan Pablo , Navarrete Mariela , Bastias Carla , Tordecilla Rocío , Varas Macarena A. , Maturana Pablo , Marcoleta Andrés E. , Allende Miguel L. , Naves Rodrigo , Hermoso Marcela A. , Salazar-Onfray Flavio , Lopez Mercedes , Bono María Rosa , Osorio Fabiola
Published: September 2021

The prognosis of severe COVID-19 patients has motivated research communities to uncover mechanisms of SARS-CoV-2 pathogenesis also on a regional level. In this work, we aimed to understand the immunological dynamics of severe COVID-19 patients with different degrees of illness, and upon long-term recovery.

We analyzed immune cellular subsets and SARS-CoV-2-specific antibody isotypes of 66 COVID-19 patients admitted to the Hospital Clínico Universidad de Chile, which were categorized according to the WHO ten-point clinical progression score. These included 29 moderate patients (score 4-5) and 37 severe patients under either high flow oxygen nasal cannula (18 patients, score 6), or invasive mechanical ventilation (19 patients, score 7-9), plus 28 convalescent patients and 28 healthy controls. Furthermore, six severe patients that recovered from the disease were longitudinally followed over 300 days.

Our data indicate that severe COVID-19 patients display increased frequencies of plasmablasts, activated T cells and SARS-CoV-2-specific antibodies compared to moderate and convalescent patients. Remarkably, within the severe COVID-19 group, patients rapidly progressing into invasive mechanical ventilation show higher frequencies of plasmablasts, monocytes, eosinophils, Th1 cells and SARS-CoV-2-specific IgG than patients under high flow oxygen nasal cannula. These findings demonstrate that severe COVID-19 patients progressing into invasive mechanical ventilation show a distinctive type of immunity. In addition, patients that recover from severe COVID-19 begin to regain normal proportions of immune cells 100 days after hospital discharge and maintain high levels of SARS-CoV-2-specific IgG throughout the study, which is an indicative sign of immunological memory. Thus, this work can provide a useful benchmark for improvement of disease outcomes.
Yeast cells actively tune their membranes to phase separate at temperatures that scale with growth temperatures
Authors: Leveille Chantelle L. , Cornell Caitlin E. , Merz Alexey J. , Keller Sarah L.
Published: September 2021

Membranes of vacuoles, the lysosomal organelles in yeast, undergo extraordinary changes during the cell’s normal growth cycle. The cycle begins with a stage of rapid cell growth. Then, as glucose becomes scarce, growth slows, and the vacuole membranes phase-separate into micron-scale liquid domains. Recent studies suggest that these domains are important for yeast survival by laterally organizing membrane proteins that play a key role in a central signaling pathway conserved among eukaryotes (TORC1). An outstanding question in the field has been whether yeast stringently regulate the phase transition and how they respond to new physical conditions. Here, we measure transition temperatures – an increase of roughly 15°C returns vacuole membranes to a state that appears uniform across a range of growth temperatures. We find that broad populations of yeast grown at a single temperature regulate the transition to occur over a surprisingly narrow temperature range. Moreover, the transition temperature scales linearly with the growth temperature, demonstrating that the cells physiologically adapt to maintain proximity to the transition. Next, we ask how yeast adjust their membranes to achieve phase separation. Specifically, we test how levels of ergosterol, the main sterol in yeast, induce or eliminate membrane domains. We isolate vacuoles from yeast during their rapid stage of growth, when their membranes do not natively exhibit domains. We find that membrane domains materialize when ergosterol is depleted, contradicting the assumption that increases in ergosterol cause membrane phase separation in vivo, and in agreement with prior studies that use artificial and cell-derived membranes.

SIGNIFICANCE STATEMENT

Phase separation in membranes creates domains enriched in specific components. To date, the best example of micron-scale phase separation in the membrane of an unperturbed, living cell occurs in a yeast organelle called the vacuole. Recent studies indicate that the phases are functionally important, enabling yeast survival during periods of cellular stress. We have discovered that yeast regulate this phase transition; the temperature at which membrane components mix into a single phase is ~15°C above the growth temperature. To maintain this offset, yeast may tune the level of ergosterol (a molecule that is structurally similar to cholesterol) in their membranes. We find that reducing sterol levels in vacuole membranes causes them to phase separate, in contrast to previous assumptions.
SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells
Authors: Wang Ying , Yen Frederick S. , Zhu Xiphias Ge , Timson Rebecca C. , Weber Ross , Xing Changrui , Liu Yuyang , Allwein Benjamin , Luo Hanzhi , Yeh Hsi-Wen , Heissel Søren , Unlu Gokhan , Gamazon Eric R. , Kharas Michael G. , Hite Richard , Birsoy Kivanç
Published: September 2021

Glutathione (GSH) is a small molecule thiol abundantly present in all eukaryotes with key roles in oxidative metabolism1. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions2. GSH is exclusively synthesized in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remain elusive. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, to regulate GSH transport into mitochondria. SLC25A39 loss reduces mitochondrial GSH import and abundance without impacting whole cell GSH levels. Cells lacking both SLC25A39 and its paralog SLC25A40 exhibit defects in the activity and stability of ironsulfur cluster containing proteins. Moreover, mitochondrial GSH import is necessary for cell proliferationin vitroand red blood cell development in mice. Remarkably, the heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enabled mitochondrial GSH production and ameliorated the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH import machinery.
Large-scale mRNA translation and the intricate effects of competition for the finite pool of ribosomes
Authors: Jain Aditi , Margaliot Michael , Gupta Arvind Kumar
Published: September 2021

We present a new theoretical framework for large-scale mRNA translation using a network of models called the ribosome flow model with Langmuir kinetics (RFMLK), interconnected via a pool of free ribosomes. The input to each RFMLK depends on the pool density, and it affects the initiation rate and the internal ribosome entry rates at each site along each RFMLK. Ribosomes that detach from an RFMLK due to termination or premature drop-off are fed back into the pool. We prove that the network always converges to a steady-state, and study its sensitivity to variations in the parameters. For example, we show that if the drop-off rate at some site in some RFMLK is increased then the pool density increases and consequently the steady-state production rate in all the other RFMLKs increases. Surprisingly, we also show that modifying a parameter of a certain RFMLK can lead to arbitrary effects on the densities along the modified RFMLK, depending on the parameters in the entire network. We conclude that the competition for shared resources generates an indirect and intricate web of mutual effects between the mRNA molecules, that must be accounted for in any analysis of translation.
RNANetMotif: identifying sequence-structure RNA network motifs in RNA-protein binding sites
Authors: Ma Hongli , Wen Han , Xue Zhiyuan , Li Guojun , Zhang Zhaolei
Published: September 2021

RNA molecules can adopt stable secondary and tertiary structures, which is essential in mediating physical interactions with other partners such as RNA binding proteins (RBPs) and in carrying out their cellular functions. In vivo and in vitro experiments such as RNAcompete and eCLIP have revealed in vitro binding preferences of RBPs to RNA oligomers and in vivo binding sites in cells. Analysis of these binding data showed that the structure properties of the RNAs in these binding sites are important determinants of the binding events; however, it has been a challenge to incorporate the structure information into an interpretable model. Here we describe a new approach, RNANetMotif, which takes predicted secondary structure of thousands of RNA sequences bound by an RBP as input and uses a graph theory approach to recognize enriched subgraphs. These enriched subgraphs are in essence shared sequence-structure elements that are important in RBP-RNA binding. To validate our approach, we performed RNA structure modeling via discrete molecular dynamics folding simulations for selected 4 RBPs, and RNA-protein docking for LIN28. The simulation results, e.g., solvent accessibility and energetics, further support the biological relevance of the discovered network subgraphs.

Author Summary

RNA binding proteins (RBPs) regulate every aspect of RNA biology, including splicing, translation, transportation, and degradation. High-throughput technologies such as eCLIP have identified thousands of binding sites for a given RBP throughout the genome. It has been shown by earlier studies that, in addition to nucleotide sequences, the structure and conformation of RNAs also play important role in RBP-RNA interactions. Analogous to protein-protein interactions or protein-DNA interactions, it is likely that there exist intrinsic sequence-structure motifs common to these RNAs that underlie their binding specificity to specific RBPs. It is known that RNAs form energetically favorable secondary structures, which can be represented as a graph, with nucleotides being nodes and backbone covalent bonds and base-pairing hydrogen bonds representing edges. We hypothesize that these graphs can be mined by graph theory approaches to identify sequence-structure motifs as enriched sub-graphs. In this article, we described the details of this approach, termed RNANetMotif and associated new concepts, namely EKS (Extended K-mer Subgraphs) and GraphK graph search algorithm. To test the utility of our approach, we conducted 3D structure modeling of selected RNA sequences through molecular dynamics (MD) folding simulation and evaluated the significance of the discovered RNA motifs by comparing their spatial exposure with other regions on the RNA. We believe that this approach has the novelty of treating the RNA sequence as a graph and RBP binding sites as enriched subgraph, which has broader applications beyond RBP-RNA interactions.
Epigenetic Remodeling by Vitamin C Potentiates the Differentiation of Mouse and Human Plasma Cells
Authors: Chen Heng-Yi , Alamonte-Loya Ana , Lay Fang-Yun , Johnson Eric , Gonzalez-Avalos Edahi , Yin Jieyun , Ma Qin , Wozniak Daniel J. , Harrison Fiona E. , Lio Chan-Wang Jerry
Published: September 2021

Ascorbate (vitamin C) is an essential micronutrient in humans. The chronic severe deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. Here, from a micronutrient screen, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique, as other antioxidants failed to promote plasma cell differentiation. Ascorbate is critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. Consistent with its role as a cofactor for epigenetic enzymes, ascorbate potentiates plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translocation), the enzymes responsible for DNA demethylation by oxidizing 5-methylcytosines into 5-hydroxymethylcytosine (5hmC). Genome-wide 5hmC profiling identified ascorbate responsive elements (EAR) at the Prdm1 locus, including a distal element with a STAT3 motif overlapped with a CpG that was methylated and modified by TET in the presence of ascorbate. The results suggest that an adequate level of VC is required for antibody response and highlight how micronutrients regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions.
Modelling spatiotemporal trends in the frequency of genetic mutations conferring insecticide target-site resistance in African malaria vector species
Authors: Hancock Penelope A. , Lynd Amy , Wiebe Antoinette , Devine Maria , Essandoh Johnathan , Wat’senga Francis , Manzambi Emile Z. , Agossa Fiacre , Donnelly Martin J. , Weetman David , Moyes Catherine L.
Published: September 2021

Resistance in malaria vectors to pyrethroids, the most widely used class of insecticides for malaria vector control, threatens the continued efficacy of vector control tools. Target-site resistance is an important genetic resistance mechanism caused by mutations in the voltage-gated sodium channel (Vgsc) gene that encodes the pyrethroid target-site. Understanding the geographic distribution of target-site resistance, and temporal trends across different vector species, can inform strategic deployment of vector control tools. Here we develop a Bayesian statistical spatiotemporal model to interpret species-specific trends in the frequency of the most common resistance mutations, Vgsc-995S and Vgsc-995F, in three major malaria vector species Anopheles gambiae, An. coluzzii, and An. arabiensis. For nine selected countries, we develop annual predictive maps which reveal geographically-structured patterns of spread of each mutation at regional and continental scales. The results show associations, as well as stark differences, in spread dynamics of the two mutations across the three vector species. The coverage of ITNs was an influential predictor of Vgsc allele frequencies in our models. Our mapped Vgsc allele frequencies are a significant partial predictor of phenotypic resistance to the pyrethroid deltamethrin in An. gambiae complex populations, highlighting the importance of molecular surveillance of resistance mechanisms.
Magnetic DNA random access memory with nanopore readouts and exponentially-scaled combinatorial addressing
Authors: Lau Billy , Chandak Shubham , Roy Sharmili , Tatwawadi Kedar , Wootters Mary , Weissman Tsachy , Ji Hanlee P.
Published: September 2021

The storage of data in DNA typically involves encoding and synthesizing data into short oligonucleotides, followed by reading with a sequencing instrument. Major challenges include the molecular consumption of synthesized DNA, issues with basecalling errors, and limitations with scaling up read access operations for individual data elements. Addressing these challenges, we describe a DNA storage system called MDRAM (Magnetic DNA-based Random Access Memory) that enables repetitive and efficient readouts of targeted files with nanopore-based sequencing. Through conjugation of synthesized DNA to magnetic beads, we enabled repeated readouts of data while preserving the original DNA analyte and maintaining data readout quality. MDRAM also utilizes an efficient convolutional coding scheme that leverages soft information in raw nanopore sequencing signals to achieve information reading costs comparable to Illumina sequencing despite substantially higher error rates. Finally, we demonstrate a proof-of-concept DNA-based proto-filesystem that enables an exponentially-scalable data address space using only small numbers of targeting primers for assembly and readout.

ONE-SENTENCE SUMMARY

We demonstrate a novel DNA data storage system that leverages conjugation of DNA onto magnetic beads, new computational advances in data encoding, and exponentially scalable access of individual data elements.
Predicting base editing outcomes using position-specific sequence determinants
Authors: Pallaseni Ananth , Peets Elin Madli , Koeppel Jonas , Weller Juliane , Crepaldi Luca , Allen Felicity , Parts Leopold
Published: September 2021

Nucleotide-level control over DNA sequences is poised to power functional genomics studies and lead to new therapeutics. CRISPR/Cas base editors promise to achieve this ability, but the determinants of their activity remain incompletely understood. We measured base editing frequencies in two human cell lines for two cytosine and two adenine base editors at ∼14,000 target sequences. Base editing activity is sequence-biased, with largest effects from nucleotides flanking the target base, and is correlated with measures of Cas9 guide RNA efficiency. Whether a base is edited depends strongly on the combination of its position in the target and the preceding base, with a preceding thymine in both editor types leading to a wider editing window, while a preceding guanine in cytosine editors and preceding adenine in adenine editors to a narrower one. The impact of features on editing rate depends on the position, with guide RNA efficacy mainly influencing bases around the centre of the window, and sequence biases away from it. We use these observations to train a machine learning model to predict editing activity per position for both adenine and cytosine editors, with accuracy ranging from 0.49 to 0.72 between editors, and with better generalization performance across datasets than existing tools. We demonstrate the usefulness of our model by predicting the efficacy of potential disease mutation correcting guides, and find that most of them suffer from more unwanted editing than corrected outcomes. This work unravels the position-specificity of base editing biases, and provides a solution to account for them, thus allowing more efficient planning of base edits in experimental and therapeutic contexts.
Single residue substitution in protamine 1 disrupts sperm genome packaging and embryonic development in mice
Authors: Moritz Lindsay , Schon Samantha B. , Rabbani Mashiat , Sheng Yi , Pendlebury Devon F. , Agrawal Ritvija , Sultan Caleb , Jorgensen Kelsey , Zheng Xianing , Diehl Adam , Ragunathan Kaushik , Hu Yueh-Chiang , Nandakumar Jayakrishnan , Li Jun Z. , Boyle Alan P. , Orwig Kyle E. , Redding Sy , Hammoud Saher Sue
Published: September 2021

Conventional dogma presumes that protamine-mediated DNA compaction in sperm is achieved by passive electrostatics between DNA and the arginine-rich core of protamines. However, phylogenetic analysis reveals several non-arginine residues that are conserved within, but not across, species. The functional significance of these residues or post-translational modifications are poorly understood. Here, we investigated the functional role of K49, a rodent-specific lysine residue in mouse protamine 1 (P1) that is acetylated early in spermiogenesis and retained in sperm. In vivo, an alanine substitution (P1 K49A) results in ectopic histone retention, decreased sperm motility, decreased male fertility, and in zygotes, premature P1 removal from paternal chromatin. In vitro, the P1 K49A substitution decreases protamine-DNA binding and alters DNA compaction/decompaction kinetics. Hence, a single amino acid substitution outside the P1 arginine core is sufficient to profoundly alter protein function and developmental outcomes, suggesting that protamine non-arginine residues are essential to ensure reproductive fitness.