bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological Treatment of Agitation and/or Aggression in Patients With Traumatic Brain Injury: A Systematic Review of Reviews
Authors: Rahmani Elham , Lemelle Tricia M. , Samarbafzadeh Ehsan , Kablinger Anita S.
Published: March 2021

Objective:

To systematically review the available literature on the pharmacological management of agitation and/or aggression in patients with traumatic brain injury (TBI), synthesize the available data, and provide guidelines.

Design:

Systematic review of systematic reviews.

Main Measures:

A literature review of the following websites was performed looking for systematic reviews on the treatment of agitation and/or aggression among patients with TBI: PubMed, CINAHL, DynaMed, Health Business Elite, and EBSCO (Psychology and behavioral sciences collection). Two researchers independently assessed articles for meeting inclusion/exclusion criteria. Data were extracted on year of publication, reviewed databases, dates of coverage, search limitations, pharmacological agents of interest, and a list of all controlled studies included. The included controlled studies were then examined to determine potential reasons for any difference in recommendations.

Results:

The literature review led to 187 citations and 67 unique publications after removing the duplicates. Following review of the title/abstracts and full texts, a total of 11 systematic reviews were included. The systematic reviews evaluated the evidence for safety and efficacy of the following medications: amantadine, amphetamines, methylphenidate, antiepileptics, atypical and typical antipsychotics, benzodiazepines, β-blockers, and sertraline.

Conclusions:

On the basis of the results of this literature review, the authors recommend avoiding benzodiazepines and haloperidol for treating agitation and/or aggression in the context of TBI. Atypical antipsychotics (olanzapine in particular) can be considered as practical alternatives for the as-needed management of agitation and/or aggression in lieu of benzodiazepines and haloperidol. Amantadine, β-blockers (propranolol and pindolol), antiepileptics, and methylphenidate can be considered for scheduled treatment of agitation and/or aggression in patients with TBI.
Research Letter: PTSD Symptom Severity and Multiple Traumatic Brain Injuries Are Associated With Elevated Memory Complaints in Veterans With Histories of Mild TBI
Authors: Sorg Scott F. , Werhane Madeleine L. , Merritt Victoria C. , Clark Alexandra L. , Holiday Kelsey A. , Hanson Karen L. , Jak Amy J. , Schiehser Dawn M. , Delano-Wood Lisa
Published: March 2021

Objective:

The evaluation of memory complaints in mild traumatic brain injury (mTBI) remains an important clinical consideration, especially in the context of comorbid psychiatric symptoms such as posttraumatic stress disorder (PTSD). We compared subjective memory complaints in veterans with and without a history of mTBI, examined ratings between those with single versus multiple mTBIs, and investigated associations between memory complaints and PTSD symptom severity.

Methods:

117 outpatient veterans (mTBI: n = 79 [single mTBI: n = 22, multiple mTBI: n = 57], military controls [MCs]: n = 38) completed a TBI history assessment, the Prospective-Retrospective Memory Questionnaire (PRMQ), and the PTSD Checklist–Military Version (PCL-M).

Results:

Hierarchical multiple regression showed that greater PCL-M scores significantly predicted elevated PRMQ-Total scores, accounting for 38% of the variance explained (P < .001). mTBI status predicted an additional 5% of variance in memory complaints (P < .01). The multiple-mTBI group endorsed more memory complaints than either MCs (P < .01) or the single-mTBI group (P < .05), who did not differ from MCs (P > .50).

Conclusions:

Comorbid PTSD symptoms are an important factor when considering memory complaints in veterans with a reported history of mTBI. However, independent of comorbid PTSD symptoms, mTBI status—particularly in the context of repetitive neurotrauma—uniquely contributes to memory complaints. Findings suggest that veterans with a history of multiple mTBIs may be a particularly vulnerable group in need of specialized interventions and/or psychoeducation.
Staff Traumatic Brain Injury Skill Builder: Evaluation of an Online Training Program for Paraprofessional Staff Serving Adults With Moderate-Severe TBI
Authors: Powell Laurie E. , Gau Jeff , Glang Ann , Corrigan John D. , Ramirez Meghan , Slocumb Jody
Published: March 2021

Objective:

To evaluate the online, self-guided, interactive Staff TBI Skill Builder training program for paraprofessional staff.

Design:

A within-subjects, nonexperimental evaluation involving 79 paraprofessionals and professionals working across a range of settings. Participants completed a pretest (T1), a posttest immediately upon program completion (T2), and follow-up (T3) 60 days after program completion.

Measures:

(1) Knowledge of basic traumatic brain injury facts; (2) knowledge application; (3) self-efficacy in responding to text-based application scenarios; (4) self-report of skill utilization and effectiveness; and (5) program satisfaction (ease-of-use and usefulness).

Results:

Participants demonstrated high levels of knowledge, knowledge application, and self-efficacy at pretest. Despite the high pretest levels, participants showed significant improvements in knowledge application (d = 0.50) after using the program. Nonsignificant gains in knowledge (d = 0.13) and self-efficacy (d = 0.02) were found. The use of selected skills significantly increased from posttest to follow-up. Participants reported high program satisfaction; 99% of the participants indicated that they would recommend the program to others.

Conclusion:

These results demonstrate the feasibility of providing interactive, online training for paraprofessionals serving adults with moderate-severe traumatic brain injury.
Research Letter: Sleep Mediates the Association Between Prior Concussion and Depressive Symptoms
Authors: Brett Benjamin L. , Meier Timothy B. , Savitz Jonathan , Guskiewicz Kevin M. , McCrea Michael A.
Published: March 2021

Objective:

To test sleep quality as one mechanistic pathway through which repeated concussion increases risk of depression later in life among former contact sport athletes.

Setting:

Multicenter study enrolled former American collegiate football players from 16 different National Collegiate Athletic Association member institutions.

Participants:

Fifty-eight former American collegiate football players approximately 15 years following sport discontinuation.

Design:

Participants completed in-person evaluations including comprehensive semistructured interviews with detailed concussion history and sport history, as well as self-reported measures of depression symptom severity (Beck Depression Inventory-II) and sleep quality (Pittsburgh Sleep Quality Index). Years of football participation were included as a covariate. Mediation modeling examined the degree to which sleep quality accounted for the association between repeated concussion and depression symptoms.

Results:

Within the mediation model, concussion history significantly predicted sleep quality (B = 1.03; 95% CI, 0.37 to 1.65; P = .002) and sleep quality significantly predicted depressive symptom severity (controlling for the effects of concussion history; B = 0.15; 95% CI, 0.06 to 0.24; P = .001). The association between prior concussion and depressive symptom severity was fully mediated by sleep quality. With inclusion of the indirect effects, concussion history did not predict depressive symptom severity (direct effect: B = 0.14; 95% CI, −0.09 to 0.41; P = .249; indirect effect: 0.15; 95% CI, 0.03 to 0.29; P = .016).

Conclusions:

Current findings raise the possibility that the greater risk of depression reported in those with a history of mTBI/concussion is mediated by sleep quality, a common sequela of mTBI. These findings highlight potential opportunities for prophylactic sleep-related intervention among individuals with multiple prior concussions to mitigate the risk of depression.
The Effects of Educational Programs on Knowledge, International Normalized Ratio, Warfarin Adherence, and Warfarin-Related Complications in Patients Receiving Warfarin Therapy
Authors: Lo Flora M. W. , Wong Eliza M. L. , Hong Felix K. W.
Published: March 2021

Background

Education is considered a crucial element in anticoagulation management for patients with atrial fibrillation, valvular disease, ischemic heart disease, and venous thromboembolism. However, the effects of education on the patients prescribed warfarin are seldom investigated.

Objectives

This integrative review was conducted to explore the effects of educational programs on patients prescribed warfarin for the aforementioned cardiovascular diseases and to identify the components of effective programs.

Methods

A systematic search of clinical trials was performed in 8 databases from inception to August 2020. Two reviewers performed the eligibility assessment, methodological evaluation, and data extraction. A total of 9 studies were included and analyzed via narrative synthesis.

Results

Nine studies involving a combined total of 1335 patients were included in the review. The findings suggest that educational programs have potential benefits related to international normalized ratio control and warfarin knowledge. However, their effects on major bleeding and thromboembolic events are unremarkable. Stronger evidence is recommended to confirm these findings, and the limited evidence examining the effects of education on warfarin adherence, minor bleeding, abnormal international normalized ratio, readmission rate, and warfarin-related mortality requires further exploration. Verbal education supported by written materials was the main educational delivery mode. A lecture length of approximately 45 minutes was likely appropriate. Notably, the integration of educational strategies, application of follow-up interventions and monitoring measures, adoption of psychological theories in program development, and inclusion of nurses or pharmacists in program conduction seemed to be effective program components.

Conclusions

The effects of educational programs on patients prescribed warfarin mainly for atrial fibrillation, valvular disease, ischemic heart disease, and venous thromboembolism remain inconclusive. Further research using randomized controlled trials is warranted.
Effectiveness and safety of warm needle acupuncture on lumbar muscles strain
Authors: Huang Yashuang , Cheng Cheng , Xie Li , Zhu Xinghui , Chen Dongmei , Cheng Cisong
Published: March 2021

Background:

Lumbar muscle strain (LMS) is the most common orthopedic syndrome, with high incidence globally and lingering disease, which seriously affects patients’ work efficiency and quality of life. Warm needle acupuncture (WNA) is a treatment method combining acupuncture technology with warm and medicinal effect of moxibustion. It has outstanding curative effect and wide range of treatment, especially in the treatment of pain diseases. We aim to collect clinical evidence and demonstrate the efficacy and safety of WNA on LMS.

Methods/design:

We will search the following database sources for the randomized controlled trials: PubMed, Cochrane Library, Excerpta Medica Database (EMBASE), Web of Science, WHO International Clinical Trials Registry Platform (TCTRP), Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journals Database (VIP), and the Wanfang Database.

All randomized controlled trials of WNA for lumbar muscle strain (LMS) in the above database will be considered for inclusion, and high-quality articles will be screened for data extraction and analysis, to summarize the therapeutic effect of WNA on LMS patients.

Result:

This study will provide a rational synthesis of current evidences for warm needle acupuncture on lumbar muscle strain.

Conclusion:

The conclusion of this study will provide evidence to judge the effectiveness and safety of WNA on LMS.

Trial registration:

INPLASY2020120100 (DOI number: 10.37766/inplasy2020.12.0100).
Effectiveness and safety of Yufeng Ningxin for the treatment of essential hypertension
Authors: Huang Mingyan , Long Linzi , Deng Mi , Yu Zikai , Qu Hua , Tan Ling , Peng Yuxuan , Fu Changgeng
Published: March 2021

Background:

Essential hypertension is the primary cause of death and disability and it has become a major public health problem globally. Yufeng Ningxin (YFNX) is a commonly used Chinese patent medicine in treating essential hypertension. The objective of this protocol is to evaluate the effectiveness and safety of YFNX for the treatment of essential hypertension.

Methods:

Randomized controlled trials (RCTs) in relation to the effectiveness and safety of YFNX in the treatment of essential hypertension will be systematically searched and collected from the following databases: PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database, and Chinese Scientific Journal Database from the database inception to January 1, 2021. The data screening and extraction will be carried out by 2 different reviewers. The quality of randomized controlled trials will be assessed based on the version 2 of the risk-of-bias tool for randomized trials (RoB 2) in the Cochrane Handbook. The reduction of systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be served as the primary outcome. The secondary outcomes will include average SBP and average DBP during the day and the night measured by 24 hours ambulatory blood pressure monitoring, the clinical effectiveness rate, scores of traditional Chinese medicine syndrome, clinical symptoms, the quality of life and adverse events. Statistical analysis will be conducted with Review Manager 5.3 and STATA 14.0 software.

Conclusion:

This systematic review will provide strong evidence to assess the effectiveness and safety of YFNX in the treatment of essential hypertension.

Trial registration number:

INPLASY202110059.
Is Hospital Nurse Staffing Legislation in the Public’s Interest?
Authors: Lasater Karen B. , Aiken Linda H. , Sloane Douglas M. , French Rachel , Anusiewicz Colleen V. , Martin Brendan , Reneau Kyrani , Alexander Maryann , McHugh Matthew D.
Published: March 2021

Background:

The Safe Staffing for Quality Care Act under consideration in the New York (NY) state assembly would require hospitals to staff enough nurses to safely care for patients. The impact of regulated minimum patient-to-nurse staffing ratios in acute care hospitals in NY is unknown.

Objectives:

To examine variation in patient-to-nurse staffing in NY hospitals and its association with adverse outcomes (ie, mortality and avoidable costs).

Research Design:

Cross-sectional data on nurse staffing in 116 acute care general hospitals in NY are linked with Medicare claims data.

Subjects:

A total of 417,861 Medicare medical and surgical patients.

Measures:

Patient-to-nurse staffing is the primary predictor variable. Outcomes include in-hospital mortality, length of stay, 30-day readmission, and estimated costs using Medicare-specific cost-to-charge ratios.

Results:

Hospital staffing ranged from 4.3 to 10.5 patients per nurse (P/N), and averaged 6.3 P/N. After adjusting for potential confounders each additional patient per nurse, for surgical and medical patients, respectively, was associated with higher odds of in-hospital mortality [odds ratio (OR)=1.13, P=0.0262; OR=1.13, P=0.0019], longer lengths of stay (incidence rate ratio=1.09, P=0.0008; incidence rate ratio=1.05, P=0.0023), and higher odds of 30-day readmission (OR=1.08, P=0.0002; OR=1.06, P=0.0003). Were hospitals staffed at the 4:1 P/N ratio proposed in the legislation, we conservatively estimated 4370 lives saved and $720 million saved over the 2-year study period in shorter lengths of stay and avoided readmissions.

Conclusions:

Patient-to-nurse staffing varies substantially across NY hospitals and higher ratios adversely affect patients. Our estimates of potential lives and costs saved substantially underestimate potential benefits of improved hospital nurse staffing.
Current Trends in Pediatric Physical Therapy Practice for Children With Down Syndrome
Authors: Johnson Rebekah , Looper Julia , Fiss Alyssa
Published: March 2021

Background:

Physical therapists (PTs) have a broad range of approaches to the management of Down syndrome (DS).

Purpose:

To examine the breadth of physical therapy practice for children with DS.

Methods:

A survey was distributed to 1000 randomly selected members of the Academy of Pediatric Physical Therapy.

Data Analysis:

Responses were categorized into 13 thematic subcategories and 3 International Classification of Functioning, Disability and Health (ICF) subcategories.

Results and Discussion:

One hundred eight PTs participated. Joint stability and alignment were the most common physical therapy–related problem. Functional movement was the most common physical therapy intervention. Most clinicians identified and treated at the ICF level of body functions and structure. Multiple assessment tools were used and tended to include norm-referenced tests. There was diversity of interventions with varying amounts of supporting evidence.

Conclusions:

PTs manage children with DS for a wide variety of needs with a variety of interventions.
Mindfulness-Based Stress Reduction Buffers Glucocorticoid Resistance Among Older Adults: A Randomized Controlled Trial
Authors: Lindsay Emily K. , Creswell J. David , Stern Harrison J. , Greco Carol M. , Dutcher Janine M. , Lipitz Sarah , Walsh Catherine P. , Wright Aidan G.C. , Brown Kirk Warren , Marsland Anna L.
Published: March 2021

Objective

Mindfulness interventions have been effective for improving a range of health outcomes; however, pathways underlying these effects remain unclear. Inflammatory processes may play a role, possibly through increased resistance of immune cells to the anti-inflammatory effects of glucocorticoids (i.e., glucocorticoid resistance, or GCR). Here, we conducted an initial examination of whether mindfulness training mitigates GCR among lonely older adults.

Methods

Lonely older adults (65–85 years; n = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or a matched Health Enhancement Program (HEP). Whole blood drawn before and after the intervention and at 3-month follow-up was incubated with endotoxin and varying concentrations of dexamethasone, and interleukin-6 production was assessed using enzyme-linked immunosorbent assay. GCR was assessed as the concentration of dexamethasone required to decrease the stimulated interleukin-6 response by 50% (half maximal inhibitory concentration), with higher concentrations indicating greater GCR. Mixed-effects linear models tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects.

Results

There was no overall time by condition effect on GCR across all time points. However, a significant time by condition effect was observed from preintervention to postintervention (d = 0.29), such that MBSR buffered increases in GCR observed in the HEP group. Although MBSR showed small, nonsignificant reductions in GCR from preintervention to 3-month follow-up, group differences were not maintained at the 3-month follow-up (d = 0.10).

Conclusions

Results suggest that MBSR may protect against declines in the sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids among at-risk lonely older adults and show value in studying this biological mechanism in future trials.

Trial Registration: Clinical Trials identifier NCT02888600.
Dental Topics for Plastic Surgeons, Part Four: Common Cysts and Tumors of the Jaw
Authors: Zambetti Luke , Agarwal Ravi , Obeid George , Mantilla-Rivas Esperanza , Manrique Monica , Rogers Gary F. , Oh Albert K.
Published: March 2021

Conditions that affect dental and periodontal structures receive sparse coverage in the plastic surgery literature, yet a working knowledge of this subject matter is important in certain areas of clinical practice and a fundamental understanding is part of plastic surgery competency tested on the in-service and written board examinations. This 4-part series was written to provide plastic surgeons with a working knowledge of dental topics that may be relevant to their clinical practice. This section, Part IV, covers common dental cyst and tumors of the jaw.
Schizophrenia during pregnancy
Authors: Dazzan Paola
Published: March 2021

Purpose of review

A diagnosis of schizophrenia has significant implications for women of childbearing age, pregnant or considering a pregnancy, ranging from sexual health, psychopharmacological treatment, to the occurrence of negative pregnancy and foetal outcomes. We provide a short narrative review of recent papers focusing on these issues.

Recent findings

Although pregnancy rates have been increasing in women with a diagnosis of schizophrenia, they also tend to have altogether fewer pregnancies and fewer live births than women without this diagnosis, and also higher rates of induced abortions.

Use of antipsychotics in pregnancy has also increased, and evidence suggests lack of significant contraindications for their use in this period. However, drug levels monitoring may be recommended across the three trimesters, as levels may change in relation to pregnancy-related physiology.

Monitoring of physical health is an increasingly crucial issue, given higher risk of gestational diabetes, negative obstetric and infant outcomes in these women.

There is an urgent need to generate valid and reproducible research that could help implement appropriate treatment protocols and relapse-prevention approaches, and interventions based on strong pharmaceutical targets for the benefit of pregnant women with a diagnosis of schizophrenia, their families and their children.
Marine soundscape variation reveals insights into baleen whales and their environment: a case study in central New Zealand
Authors: Warren Victoria E. , McPherson Craig , Giorli Giacomo , Goetz Kimberly T. , Radford Craig A.
Published: March 2021

Baleen whales reliably produce stereotyped vocalizations, enabling their spatio-temporal distributions to be inferred from acoustic detections. Soundscape analysis provides an integrated approach whereby vocal species, such as baleen whales, are sampled holistically with other acoustic contributors to their environment. Acoustic elements that occur concurrently in space, time and/or frequency can indicate overlaps between free-ranging species and potential stressors. Such information can inform risk assessment framework models. Here, we demonstrate the utility of soundscape monitoring in central New Zealand, an area of high cetacean diversity where potential threats are poorly understood. Pygmy blue whale calls were abundant in the South Taranaki Bight (STB) throughout recording periods and were also detected near Kaikōura during autumn. Humpback, Antarctic blue and Antarctic minke whales were detected in winter and spring, during migration. Wind, rain, tidal and wave activity increased ambient sound levels in both deep- and shallow-water environments across a broad range of frequencies, including those used by baleen whales, and sound from shipping, seismic surveys and earthquakes overlapped in time, space and frequency with whale calls. The results highlight the feasibility of soundscape analysis to quantify and understand potential stressors to free-ranging species, which is essential for conservation and management decisions.
Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil
Authors: Faria Nuno R. , Mellan Thomas A. , Whittaker Charles , Claro Ingra M. , Candido Darlan da S. , Mishra Swapnil , Crispim Myuki A. E. , Sales Flavia C. , Hawryluk Iwona , McCrone John T. , Hulswit Ruben J. G. , Franco Lucas A. M. , Ramundo Mariana S. , de Jesus Jaqueline G. , Andrade Pamela S. , Coletti Thais M. , Ferreira Giulia M. , Silva Camila A. M. , Manuli Erika R. , Pereira Rafael H. M. , Peixoto Pedro S. , Kraemer Moritz U. , Gaburo Nelson , Camilo Cecilia da C. , Hoeltgebaum Henrique , Souza William M. , Rocha Esmenia C. , de Souza Leandro M. , de Pinho Mariana C. , Araujo Leonardo J. T , Malta Frederico S. V. , de Lima Aline B. , Silva Joice do P. , Zauli Danielle A. G. , Ferreira Alessandro C. de S. , Schnekenberg Ricardo P , Laydon Daniel J. , Walker Patrick G. T. , Schlüter Hannah M. , dos Santos Ana L. P. , Vidal Maria S. , Del Caro Valentina S. , Filho Rosinaldo M. F. , dos Santos Helem M. , Aguiar Renato S. , Modena José L. P. , Nelson Bruce , Hay James A. , Monod Melodie , Miscouridou Xenia , Coupland Helen , Sonabend Raphael , Vollmer Michaela , Gandy Axel , Suchard Marc A. , Bowden Thomas A. , Pond Sergei L. K. , Wu Chieh-Hsi , Ratmann Oliver , Ferguson Neil M. , Dye Christopher , Loman Nick J. , Lemey Philippe , Rambaut Andrew , Fraiji Nelson A. , Carvalho Maria do P. S. S. , Pybus Oliver G. , Flaxman Seth , Bhatt Samir , Sabino Ester C.
Published: March 2021

Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite high levels of previous infection there. Through genome sequencing of viruses sampled in Manaus between November 2020 and January 2021, we identified the emergence and circulation of a novel SARS-CoV-2 variant of concern, lineage P.1, that acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around early November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.4–2.2 times more transmissible and 25-61% more likely to evade protective immunity elicited by previous infection with non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

One-Sentence Summary

We report the evolution and emergence of a SARS-CoV-2 lineage of concern associated with rapid transmission in Manaus.
A comprehensive digital phenotype for postpartum hemorrhage
Authors: Zheutlin Amanda B , Vieira Luciana , Li Shilong , Wang Zichen , Schadt Emilio , Gross Susan , Stone Joanne , Schadt Eric , Li Li
Published: March 2021

Objective

We aimed to establish a comprehensive digital phenotype for postpartum hemorrhage (PPH). Current guidelines rely primarily on estimates of blood loss, which can be inaccurate and biased, and ignore a suite of complementary information readily available in electronic medical records (EMR). Inaccurate and incomplete phenotyping contribute to ongoing challenges to track PPH outcomes, develop more accurate risk assessments, and identify novel interventions.

Methods

We constructed a cohort of 71,944 deliveries from the Mount Sinai Health System, 2011-2019. Estimates of postpartum blood loss, shifts in hematocrit intra- and postpartum, administration of uterotonics, surgical treatments, and associated diagnostic codes were combined to identify PPH retrospectively. All clinical features were extracted from structured EMR data and mapped to common data models for maximum interoperability across hospitals. Blinded chart review was done on a randomly selected subset of cases and controls for validation and performance was compared to alternate PPH phenotypes.

Results

We identified 6,639 cases (9% prevalence) using our phenotype – more than three times as many as using blood loss alone (N=1,747), supporting the need to incorporate other diagnostic and treatment data. Blinded chart review revealed our phenotype had 96% sensitivity, 89% precision, 77% specificity, and 89% accuracy to detect PPH. Alternate phenotypes were less accurate, including a common blood loss-based definition (67%) and a previously published digital phenotype (74%).

Conclusion

We have developed a scalable, accurate, and valid digital phenotype that may be of significant use for tracking outcomes and ongoing clinical research to deliver better preventative interventions for PPH.
Closed-loop automated reaching apparatus (CLARA) for interrogating motor systems
Authors: Bowles S , Williamson WR , Nettles D , Hickman J , Welle CG
Published: March 2021

Objective: Personalized neurostimulation is a rapidly expanding category of therapeutics for a broad range of indications. Development of these innovative neurological devices requires high-throughput systems for closed-loop stimulation of model organisms, while monitoring physiological signals and complex, naturalistic behaviors. To address this need, we developed CLARA, a closed-loop automated reaching apparatus.Approach:Using breakthroughs in computer vision, CLARA integrates fully-automated, markerless kinematic tracking of multiple features we use to classify animal behavior and precisely deliver neural stimulation based on behavioral outcomes. CLARA is compatible with advanced neurophysiological tools, enabling the testing of neurostimulation devices and identification of novel neurological biomarkers.Results: The CLARA system tracks unconstrained skilled reach behavior in 3D at 150hz without physical markers. The system fully automates trial initiation and pellet delivery and is capable of accurately delivering stimulation in response to trial outcome with sub-quarter second latency. Mice perform the skilled reach task in the CLARA system at a proficiency similar to manually trained animals. Kinematic data from the CLARA system provided novel insights into the dynamics of reach consistency over the course of learning, suggesting that changes are driven entirely by unsuccessful reach accuracy. Additionally, using the closed-loop capabilities of CLARA, we demonstrate that vagus nerve stimulation (VNS) delivered on reach success improves skilled reach performance and increases reach trajectory consistency in healthy animals.Significance:The CLARA system is the first mouse behavior apparatus that uses markerless pose tracking to provide real-time closed-loop stimulation in response to the outcome of an unconstrained motor task. Additionally, we demonstrate that the CLARA system was essential for our finding that VNS given after successful completion of a motor task improves performance in healthy animals. This approach has high translational relevance for developing neurostimulation technology based on complex human behavior.
HiCzin: Normalizing metagenomic Hi-C data and detecting spurious contacts using zero-inflated negative binomial regression
Authors: Du Yuxuan , Laperriere Sarah M. , Fuhrman Jed , Sun Fengzhu
Published: March 2021

High-throughput chromosome conformation capture (Hi-C) has recently been applied to natural microbial communities and revealed great potential to study multiple genomes simultaneously. Several extraneous factors may influence chromosomal contacts rendering the normalization of Hi-C contact maps essential for downstream analyses. However, the current paucity of metagenomic Hi-C normalization methods and the ignorance for spurious inter-species contacts weaken the interpretability of the data. Here, we report on two types of biases in metagenomic Hi-C experiments: explicit biases and implicit biases, and introduce HiCzin, a parametric model to correct both types of biases and remove spurious inter-species contacts. We demonstrate that the normalized metagenomic Hi-C contact maps by HiCzin result in lower biases, higher capability to detect spurious contacts, and better performance in metagenomic contig clustering. The HiCzin software and Supplementary Material are available athttps://github.com/dyxstat/HiCzin.
A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein protects against infection
Authors: Bahnan Wael , Happonen Lotta , Khakzad Hamed , Ahnlide Vibha Kumra , de Neergaard Therese , Wrighton Sebastian , André Oscar , Bratanis Eleni , Tang Di , Hellmark Thomas , Björck Lars , Shannon Oonagh , Malmström Lars , Malmström Johan , Nordenfelt Pontus
Published: March 2021

Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis andin vivoprotection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region can not bypass the M protein’s virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, for protective antibody targeting.
High Initial Titres of Anti-Spike Antibodies following SARS-CoV-2 Infection is Associated with Faster Decay Rates at Four Months Follow-Up
Authors: Menon Vidya , Shariff Masood A , Gutierrez Victor Perez , Carreño Juan M , Yu Bo , Jawed Muzamil , Gossai Marcia , Valdez Elisenda , Pillai Anjana , Venugopal Usha , Kasubhai Moiz , Dimitrov Vihren , Krammer Florian
Published: March 2021

Background

Dynamics of humoral immune responses to SARS-CoV-2 antigens following infection suggests an initial decay of antibody followed by subsequent stabilization. We aim to understand the longitudinal humoral responses to SARS-CoV-2 nucleocapsid (N) protein and spike (S) protein and to evaluate their correlation to clinical symptoms among healthcare workers (HCW).

Methods

In this cross-sectional longitudinal cohort study done in two phases over four months, HCW underwent serial qualitative serology testing for anti-N antibody, quantitative MSH-ELISA to detect Receptor Binding Domain and full-length S reactive antibodies and completed online surveys about COVID-19 related symptoms and healthcare/community exposure.

Results

Anti-N antibody positivity was 27% and anti-S positivity was 28% in Phase 1. In Phase 2 anti-S titres were higher in symptomatic than in asymptomatic positive subjects in Phase 1. Marginally higher titers were seen in asymptomatic compared to the symptomatic positive subgroup in Phase 2. A positive correlation was noted between age, number and duration of symptoms, and Phase 1 anti-S antibody titre. A strong correlation was observed between Phase 1 titers and decay of anti-S antibody titres between the two phases. Significant correlation with rate of decay was also noted with fever, GI symptoms, and total number and duration of COVID-19 symptoms.

Conclusions

Higher initial anti-S antibody titres were associated with larger number and longer duration of symptoms as well as faster decay during the two time points.

Key Points

Question

What is the decay rate of neutralizing antibodies among SARS-CoV-2 infected healthcare workers?

Findings

In this cohort study that included 178 healthcare workers, over a 4-month period following the COVID-19 pandemic, participants had an initial rise in anti-nucleocapsid (N) and anti-spike (S) antibodies, which was followed by decay and stabilization of the titres. Significant correlation with rate of decay was noted with the symptomatic participants.

Meaning

A strong correlation is observed in the decay of anti-S antibody titres based on symptomology, thus eluding to the fact that continued recommendations for infection protection and COVID-19 vaccine campaigns are necessary.
365 days with COVID-19 in Iran: data analysis and epidemic curves
Authors: Sahafizadeh Ebrahim , Azad Saeed Talatian
Published: March 2021

Background

The first confirmed cases of COVID-19 in Iran were reported on February 19, 2020. This study aimed to analyze the epidemic curves and to investigate the correlation between epidemic parameters and furthermore to analyze the impact of control measures on the spread of COVID-19 in Iran during 365 days of the epidemic.

Methods

We used data from February 20, 2020, to February 18, 2021, on the number of COVID-19 cases reported by Iranian governments. Pearson correlation coefficient was applied to investigate the correlation between different epidemic parameters. The number of daily deaths per daily new cases was averaged to calculate daily death rate and the same method was used to investigate the rate of daily positive tests. Furthermore, we employed two different methods to calculate the effective reproduction number using reported data.

Results

The results showed that there was a strong correlation between the number of daily deaths and the number of daily new cases (specially the admitted cases). The results also indicated that the mean of daily death rate of COVID-19 during 365 days was 4.9 percent, and averagely 13.9 percent of daily tests results were positive. Furthermore, epidemic curves showed that implementing strict social distancing measures effectively reduced the number of confirmed cases. The effective reproduction curve indicated that social distancing is still necessary to control the spread of COVID-19 in Iran.

Conclusions

Analyzing the prevention and control measures indicated that the strict social distancing implemented by the government effectively reduces the number of new cases and deaths. The curve of reproduction number also showed that effective reproduction number is still above one; hence, it is necessary to continue strict social distancing and control travelling to prevent causing another wave of outbreak especially in Persian New Year.
A Nonlinear Observer to Estimate the Effective Reproduction Number of Infectious Diseases
Authors: Hasan Agus
Published: March 2021

In this paper, we design a Nonlinear Observer (NLO) to estimate the effective reproduction number (ℛt) of infectious diseases. The NLO is designed from a discrete-time augmented Susceptible-Infectious-Removed (SIR) model. The observer gain is obtained by solving a Linear Matrix Inequality (LMI). The method is used to estimate ℛt in Jakarta using epidemiological data during COVID-19 pandemic. If the observer gain is tuned properly, this approach produces similar result compared to existing approach such as Extended Kalman filter (EKF).
Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength
Authors: Elliot Thomas A.E. , Jennings Emma K. , Lecky David A.J. , Thawait Natasha , Flores-Langarica Adriana , Wraith David C. , Bending David
Published: March 2021

How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a newin vivomodel, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.

Key Points

TCR signal strength-dependent programming of CD4+T cells revealed over time in vivo

Inhibitory receptor expression is dynamic, TCR signal strength dependent, and rapidly re-calibrates T cell activation thresholds

PD1 but not Lag3 blockade leads to a unique and increased TCR signal strength signature (coined TCR.strong)

TCR.strong metric stratifies melanoma patient survival in response to Nivolumab (anti-PD1) therapy
Plant hydraulics coordinated with photosynthetic traits and climate
Authors: Xu Huiying , Wang Han , Prentice I. Colin , Harrison Sandy P. , Wright Ian J.
Published: March 2021

The coupling between water loss and carbon dioxide uptake drives the coordination of plant hydraulic and photosynthetic traits. Analysing multi-species measurements on a 3000 m elevation gradient, we found that hydraulic and leaf-economic traits were less plastic, and more closely associated with phylogeny, than photosynthetic traits. The two trait sets are linked by the sapwood-to-leaf area ratio (Huber value,vH), shown here to be codetermined by sapwood hydraulic conductance (KS), leaf mass-per-area (LMA) and photosynthetic capacity (Vcmax). Substantial hydraulic diversity was related to the trade-off betweenKSandvH. Leaf drought tolerance (inferred from turgor loss point, –πtlp) increased with wood density, but the trade-off between hydraulic efficiency (KS) and –πtlpwas weak. The least-cost optimality framework was extended to predict trait (KS-dominated) and environmental (temperature-dominated) effects onvH. These results suggest an approach to include photosynthetic-hydraulic coordination in land-surface models; however, prediction of non-plastic trait distributions remains a challenge.
Genomic characterization of four novel bacteriophages infecting the clinical pathogenKlebsiella pneumoniae
Authors: Bonilla Boris Estrada , Costa Ana Rita , Rossum Teunke van , Hagedoorn Stefan , Walinga Hielke , Xiao Minfeng , Song Wenchen , Haas Pieter-Jan , Nobrega Franklin L. , Brouns Stan J.J.
Published: March 2021

Bacteriophages are an invaluable source of novel genetic diversity. Sequencing of phage genomes can reveal new proteins with potential uses as biotechnological and medical tools, and help unravel the diversity of biological mechanisms employed by phages to take over the host during viral infection. Aiming to expand the available collection of phage genomes, we have isolated, sequenced, and assembled the genome sequences of four phages that infect the clinical pathogenKlebsiella pneumoniae:vB_KpnP_FBKp16, vB_KpnP_FBKp27, vB_KpnM_FBKp34, and Jumbo phage vB_KpnM_FBKp24. The four phages show very low (0-13%) identity to genomic phage sequences deposited in the Genbank database. Three of the four phages encode tRNAs and have a GC content very dissimilar to that of the host. Importantly, the genome sequences of the phages reveal potentially novel DNA packaging mechanisms as well as distinct clades of tubulin spindle and nucleus shell proteins that some phages use to compartmentalize viral replication. Overall, this study contributes to uncovering previously unknown virus diversity, and provides novel candidates for phage therapy applications against antibiotic-resistantK. pneumoniaeinfections.
A modular, dynamic, DNA-based platform for regulating cargo distribution and transport between lipid domains
Authors: Rubio-Sánchez Roger , Barker Simone Eizagirre , Walczak Michal , Cicuta Pietro , Di Michele Lorenzo
Published: March 2021

Cell membranes regulate the distribution of biological machinery between phase-separated lipid domains to facilitate key processes including signalling and transport, which are among the life-like functionalities that bottom-up synthetic biology aims to replicate in artificial-cellular systems. Here, we introduce a modular approach to program partitioning of amphiphilic DNA nanostructures in co-existing lipid domains. Exploiting the tendency of different hydrophobic “anchors” to enrich different phases, we modulate the lateral distribution of our devices by rationally combining hydrophobes, and by changing nanostructure size and its topology. We demonstrate the functionality of our strategy with a bio-inspired DNA architecture, which dynamically undergoes ligand-induced reconfiguration to mediate cargo transport between domainsvialateral re-distribution. Our findings pave the way to next-generation biomimetic platforms for sensing, transduction, and communication in synthetic cellular systems.
ORT: A workflow linking genome-scale metabolic models with reactive transport codes
Authors: Rubinstein Rebecca L. , Borton Mikayla A. , Zhou Haiyan , Shaffer Michael , Hoyt David W. , Stegen James , Henry Christopher S. , Wrighton Kelly C. , Versteeg Roelof
Published: March 2021

Motivation

Nutrient and contaminant behavior in the subsurface are governed by multiple coupled hydrobiogeochemical processes which occur across different temporal and spatial scales. Accurate description of macroscopic system behavior requires accounting for the effects of microscopic and especially microbial processes. Microbial processes mediate precipitation and dissolution and change aqueous geochemistry, all of which impacts macroscopic system behavior. As ‘omics data describing microbial processes is increasingly affordable and available, novel methods for using this data quickly and effectively for improved ecosystem models are needed.

Results

We propose a workflow (‘Omics to Reactive Transport – ORT) for utilizing metagenomic and environmental data to describe the effect of microbiological processes in macroscopic reactive transport models. This workflow utilizes and couples two open-source software packages: KBase (a software platform for systems biology) and PFLOTRAN (a reactive transport modeling code). We describe the architecture of ORT and demonstrate an implementation using metagenomic and geochemical data from a river system. Our demonstration uses microbiological drivers of nitrification and denitrification to predict nitrogen cycling patterns which agree with those provided with generalized stoichiometries. While our example uses data from a single measurement, our workflow can be applied to spatiotemporal metagenomic datasets to allow for iterative coupling between KBASE and PFLOTRAN.

Availability and Implementation

Interactive models available athttps://pflotranmodeling.paf.subsurfaceinsights.com/pflotran-simple-model/. Microbiological data available at NCBI via BioProject ID PRJNA576070. ORT Python code available athttps://github.com/subsurfaceinsights/ort-kbase-to-pflotran. KBase narrative available athttps://narrative.kbase.us/narrative/71260or static narrative (no login required) athttps://kbase.us/n/71260/258

Contact

rebecca.rubinstein@subsurfaceinsights.comorroelof.versteeg@subsurfaceinsights.com

Supplementary information

Supplementary data are available online.