bluuebunny/crossref_metadata_2025 huggingface dataset:
Modality-specific facilitation of noninjurious sharp mechanical pain by topical capsaicin
Authors: Shabes Polina , C. Rosenberger Daniela , Henrich Florian , Greffrath Wolfgang , Treede Rolf-Detlef , Baumgärtner Ulf , Magerl Walter
Published: July 2020

We had previously shown that a “blunt blade” stimulator can mimic the noninjurious strain phase of incisional pain, but not its sustained duration. Here, we tested whether acute sensitization of the skin with topical capsaicin can add the sustained phase to this noninvasive surrogate model of intraoperative pain. Altogether, 110 healthy volunteers (55 male and 55 female; 26 ± 5 years) participated in several experiments using the “blunt blade” (0.25 × 4 mm) on normal skin (n = 36) and on skin pretreated by a high-concentration capsaicin patch (8%, Qutenza; n = 36). These data were compared with an experimental incision (n = 40) using quantitative and qualitative pain ratings by numerical rating scale and SES Pain Perception Scale descriptors. Capsaicin sensitization increased blade-induced pain magnitude and duration significantly (both P < 0.05), but it failed to fully match the sustained duration of incisional pain. In normal skin, the SES pattern of pain qualities elicited by the blade matched incision in pain magnitude and pattern of pain descriptors. In capsaicin-treated skin, the blade acquired a significant facilitation only of the perceived heat pain component (P < 0.001), but not of mechanical pain components. Thus, capsaicin morphed the descriptor pattern of the blade to become more capsaicin-like, which is probably explained best by peripheral sensitization of the TRPV1 receptor. Quantitative sensory testing in capsaicin-sensitized skin revealed hyperalgesia to heat and pressure stimuli, and loss of cold and cold pain sensitivity. These findings support our hypothesis that the blade models the early tissue-strain-related mechanical pain phase of surgical incisions.
Burden of idiopathic pulmonary fibrosis on patients’ emotional well being and quality of life: a literature review
Authors: Antoniou Katerina , Kamekis Apostolos , Symvoulakis Emmanouil K. , Kokosi Maria , Swigris Jeffrey J.
Published: July 2020

Purpose of review

To present an overview of the impact of idiopathic pulmonary fibrosis (IPF) on patients’ emotional well being and quality of life (QoL).

Recent findings

IPF is an interstitial lung disease which causes irreversible, progressive lung scarring in a pathological pattern of usual interstitial pneumonia. The incidence of IPF is increasing at a global level, subjecting an increasing number of people to its high morbidity and risk of mortality. Diagnosis is based on a multidisciplinary team approach and the exclusion of other interstitial lung diseases. Two novel antifibrotic treatments, pirfenidone and nintedanib, were recently approved by regulatory agencies around the globe, thus providing many IPF patients with treatment options for the first time. Several other drugs have entered the investigational pipeline, including many in early-phase or late-phase clinical trials. Given the incurable and progressive nature of IPF, even with antifibrotic therapy, depression and anxiety are common among patients; these and burdensome symptoms of breathlessness, cough and fatigue are factors that impact patients’ emotional well being and QoL. In addition to even more effective drugs, there is a need for psychosocial interventions and mental health support strategies focused on improving patients’ QoL so they are better equipped to live with this devastating condition.

The current article highlights the effects of IPF on patients’ emotional well being and QoL and offers suggestions for strategies to help patients with IPF live as well as possible in their daily lives.
LDL-cholesterol reduction in chronic kidney disease: options beyond statins
Authors: Goonasekera Michelle A. , Mafham Marion M. , Haynes Richard J.
Published: July 2020

Purpose of review

Individuals with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) events. LDL cholesterol (LDL-C) is a key modifiable cause of ASCVD and lowering LDL-C with statins reduces the risk of ASCVD events in a wide range of populations, including those with CKD. This review considers the utility of recently developed nonstatin LDL-C-lowering therapies in CKD.

Recent findings

The cholesterol absorption inhibitor, ezetimibe, reduces LDL-C by 15–20% and is well tolerated in CKD. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) reduce LDL-C by 50–60% and reduce the risk of ASCVD events. However, these agents require self-administration by subcutaneous injection every 2–4 weeks. The PCSK9 synthesis inhibitor, inclisiran, is administered approximately 6 monthly and may be more suitable for widespread use, although outcome trials are awaited. These PCSK9 targeting therapies require no dose adjustment in CKD and have no drug interactions.

Statins and ezetimibe are safe and reduce ASCVD risk in CKD populations. PCSK9 targeting agents may be useful in high-risk CKD patients, including those with prior ASCVD.
Iron deficiency and iron therapy in heart failure and chronic kidney disease
Authors: Walther Carl P. , Triozzi Jefferson L. , Deswal Anita
Published: July 2020

Purpose of review

Iron deficiency is common and associated with adverse outcomes in heart failure, regardless of anemia. Iron deficiency, absolute and functional, with and without anemia, is associated with adverse outcomes in chronic kidney disease (CKD). Heart failure and CKD frequently occur together. Intravenous iron therapy has been shown to reduce heart failure symptoms and improve physical function in heart failure with reduced ejection fraction with iron deficiency. In CKD, intravenous or oral iron therapy are often used for management of anemia, along with erythropoiesis stimulating agents, yet the risks and benefits of intravenous iron use is controversial. In this review, we survey available evidence and ongoing studies of iron deficiency and iron supplementation in heart failure, and integrate with recent evidence on effectiveness and safety of intravenous iron therapy in CKD.

Recent findings

Intravenous iron therapy improves heart failure symptoms and physical function in heart failure with reduced ejection fraction and iron deficiency, regardless of anemia, and may reduce heart failure hospitalizations and cardiovascular mortality. Sustained intravenous iron therapy regardless of hemoglobin level in selected patients with end-stage kidney disease receiving hemodialysis improves outcomes, and does not appear to cause infectious complications.

Iron therapy has important effects in heart failure and CKD, and appears safe in the short term. Ongoing trials will provide additional important information.
Where to next prostate-specific membrane antigen PET imaging frontiers?
Authors: Donswijk Maarten L. , Morigi Joshua J. , Little Adrienne , Vogel Wouter V. , van Leeuwen Pim J.
Published: July 2020

Purpose of review

Technical improvements in imaging equipment and availability of radiotracers, such as PSMA-ligands have increased the synergy between Urology and Nuclear Medicine. Meanwhile artificial intelligence is introduced in Nuclear Imaging. This review will give an overview of recent technical and clinical developments and an outlook on application of these in the near future.

Recent findings

Digital PET/CT has shown gradual improvement in lesion detection and demarcation over conventional PET/CT, but total-body PET/CT holds promise for a magnitude of improvement in scan duration and quality, quantification, and dose optimization. PET-guided decision-making with the application of PSMA-ligands has been shown useful in demonstrating and biopting primary prostate cancer (PCa) lesions, guiding radiotherapy, guiding surgical resection of recurrent PCa, and assessing therapy response in PCa. Artificial intelligence made its way into Nuclear Imaging just recently, but encouraging progress promises clinical application with unprecedented possibilities.

Evidence is growing on clinical usefulness of PET-guided decision-making with the still relatively new PSMA ligands as a prime example. Rapid evolution of PET instrumentation and clinical introduction of artificial intelligence will be the gamechangers of nuclear imaging in the near future, though its powers should still be mastered and incorporated in clinical practice.
Exploratory analysis of randomized clinical trials in physiotherapy aimed at improving walking speed after stroke
Authors: Menezes Kênia K.P. , Nascimento Lucas R. , Avelino Patrick R. , Teixeira-Salmela Luci F.
Published: July 2020

The purpose of the present study was to examine the main characteristics of clinical trials in physiotherapy aimed at improving walking speed after stroke, as well as the correlation between trials’ methodological quality and journals’ Impact Factor. Searches were conducted on Physiotherapy Evidence Database for all randomized controlled trials aiming at improving walking speed after stroke. Data extracted from the studies were: continent, language, methodological quality, year of publication, number of normalized citations, open access, sample size, measurements of walking speed, interventions, comparators, and prior registration. Data extracted from the journals were: 2018 Impact Factor, open access, endorsement of CONSORT recommendations, predatory classification, PubMed indexing, and Journal Citation Reports category. The main outcomes were journals’ Impact Factor, open access, CONSORT recommendations endorsement by the journal, and methodological quality. Spearman correlation coefficients were calculated to explore the relationships between trials’ methodological quality and journals’ Impact Factor. Two hundred twenty-seven trials were published in 62 journals. The number of trials has increased over the last years. Most of these trials had citations, moderate methodological quality, were published in English, in open access journals, which endorse the CONSORT recommendations, and had Impact Factor ≥2.0. The results indicated a positive, but weak correlation between methodological quality and journals’ Impact Factor. Thus, trials in physiotherapy aimed at improving walking speed after stroke have increased over the last years. Overall, trials had moderate methodological quality and were published in journal with moderate-to-high Impact Factor. Best trials were not necessarily published in journals with high Impact Factor.
Assuring Adequate Treatment for Persons Diagnosed With Gonorrhea in New York State
Authors: Currenti Salvatore , Muse Alison , Qian Feng , Bomma Srikanth , Peravali Sushma
Published: July 2020

Background

From November 2014 to May 2016, 57 local health departments in New York State (NYS) excluding New York City were offered a performance incentive (PI) to promote adherence to federally recommended treatment guidelines for gonorrhea. The rationale of the PI was to delay antibiotic resistance and disrupt transmission through attaining a high percentage of treatment adherence.

Methods

Surveillance data from the NYS Communicable Disease Electronic Surveillance System were used for analysis. We evaluated adherence per Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines for persons 12 years and older reported with uncomplicated gonorrhea during 4 time frames: Pre-PI, PI One, PI Two, and Post-PI. We measured adherence per the Centers for Disease Control and Prevention sexually transmitted disease treatment guidelines during each respective time frame and conducted χ2 tests to test for the association between treatment adequacy and time frame.

Results

During the Pre-PI, treatment was adequate in 82.0% of persons diagnosed with gonorrhea. After program implementation, treatment adequacy increased significantly (92.1% of diagnosed persons during PI One, 90.4% during PI Two, and 90.5% during the Post-PI; P ≤ 0.0001). The most common reason for inadequate or missing treatment was patient lost to follow-up.

Conclusions

Public health intervention by the NYS Department of Health improved local health department adherence to federally recommended gonorrhea treatment guidelines, and improvements were maintained after the completion of the PI.
Endotracheal Administered Epinephrine Is Effective in Return of Spontaneous Circulation Within a Pediatric Swine Hypovolemic Cardiac Arrest Model
Authors: Yauger Young J. , Beaumont Denise M. , Brady Kerianne , Schauer Steven G. , O’Sullivan Joseph , Hensler Julie G. , Johnson Don
Published: July 2020

Objective

Early administration of epinephrine increases the incidence of return of spontaneous circulation (ROSC) and improves outcomes among pediatric cardiac arrest victims. Rapid endotracheal (ET) intubation can facilitate early administration of epinephrine to pediatric victims. To date, no studies have evaluated the use of ET epinephrine in a pediatric hypovolemic cardiac arrest model to determine the incidence of ROSC.

Methods

This prospective, experimental study evaluated the pharmacokinetics and/or incidence of ROSC following ET administered epinephrine and compared it to these experimental groups: intravenous (IV) administered epinephrine, cardiopulmonary resuscitation only (CPR), and CPR + defibrillation (CPR + Defib).

Results

Endotracheal administered epinephrine, at the Pediatric Advanced Life Support (PALS) recommended dose, was not significantly different than IV administered epinephrine in maximum plasma concentrations, time to maximum plasma concentration, area under the curve, or ROSC, or mean plasma concentrations at various time points (P > 0.05). The odds of ROSC in the ET group were 2.4 times greater than the IV group. The onset to ROSC in the ET group was significantly shorter than the IV group (P < 0.0001).

Conclusions

These data support that ET epinephrine administration remains an alternative to IV administered epinephrine and faster at restoring ROSC among pediatric hypovolemic cardiac arrest victims in the acute setting when an endotracheal tube is present. Although further research is required to determine long-term outcomes of high-dose ET epinephrine administration, these data reinforce the therapeutic potential of ET administration of epinephrine to restore ROSC before IV access.
Improving Point-of-Care Ultrasound Documentation and Billing Accuracy in a Pediatric Emergency Department
Authors: Ng Carrie , Payne Asha S. , Patel Amit K. , Thomas-Mohtat Rosemary , Maxwell Angela , Abo Alyssa
Published: July 2020

Objective:

The performance and interpretation of point-of-care ultrasound (POCUS) should be documented appropriately in the electronic medical record (EMR) with correct billing codes assigned. We aimed to improve complete POCUS documentation from 62% to 80% and improve correct POCUS billing codes to 95% or higher through the implementation of a quality improvement initiative.

Methods:

We collected POCUS documentation and billing data from the EMR. Interventions included: (1) staff education and feedback, (2) standardization of documentation and billing, and (3) changes to the EMR to support standardization. We used P charts to analyze our outcome measures between January 2017 and June 2018.

Results:

Six hundred medical records of billed POCUS examinations were included. Complete POCUS documentation rate rose from 62% to 91%, and correct CPT code selection for billing increased from 92% to 95% after our interventions.

Conclusions:

The creation of a standardized documentation template incorporated into the EMR improved complete documentation compliance.
Entrapment neuropathies: a contemporary approach to pathophysiology, clinical assessment, and management
Authors: Schmid Annina B. , Fundaun Joel , Tampin Brigitte
Published: July 2020

Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potential mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.
Comorbidity indices in people with HIV and considerations for coronavirus disease 2019 outcomes
Authors: Winston Alan , De Francesco Davide , Post Frank , Boffito Marta , Vera Jaime , Williams Ian , Anderson Jane , Mallon Patrick W.G. , Sabin Caroline A.
Published: July 2020

Objective:

To determine comorbidity indices in people with HIV (PWH) and lifestyle-similar HIV-negative controls.

Design:

Cross-sectional analysis of the Pharmacokinetic and clinical Observations in PeoPle over fiftY cohort study in the United Kingdom and Ireland.

Methods:

The Elixhauser Comorbidity Index (ECI), Charlson Comorbidity Index and the Comorbidity Burden Index were compared between older PWH and HIV-negative controls using the Mann–Whitney U test; the magnitude of the difference between groups was quantified using the r effect size.

Results:

The 699 PWH and 304 HIV-negative controls were predominantly male (87.5% vs. 64.0%), white (86.3% vs. 90.0%) and had median ages of 57 and 58 years, respectively. Among PWH, the median (interquartile range) CD4+ T-cell count was 624 (475, 811) cells/μl; 98.7% were on antiretroviral therapy. The median (interquartile range) ECI was 0 (0, 8) and 0 (−3, 1), Charlson Comorbidity Index was 2 (1, 5) and 1 (0, 1) and Comorbidity Burden Index 8.6 (2.2, 16.8) and 5.9 (0.6, 10.8), respectively. While all three indices were significantly higher in PWH than in controls (P < 0.001 for each), the magnitude of the differences between the two groups were small to medium, with effect sizes (95% confidence interval) of 0.21 (0.16, 0.27), 0.38 (0.32, 0.42) and 0.18 (0.11, 0.23), respectively.

Conclusion:

These three comorbidity indices are higher in PWH compared with HIV-negative controls, although the magnitude of differences between groups were small. Differences in the ECI, reportedly associated with poorer coronavirus disease 2019 outcomes, were driven by more individuals with HIV being within the higher end of the range.
Elevation of cervical C-X-C motif chemokine ligand 10 levels is associated with HIV-1 acquisition in pregnant and postpartum women
Authors: Sabo Michelle C. , Lehman Dara A. , Pintye Jillian C. , Wang Bingjie , Drake Alison L. , Kinuthia John , Osborn Lusi , Matemo Daniel , Richardson Barbra A. , Overbaugh Julie , John-Stewart Grace , Graham Susan M.
Published: July 2020

Objective:

To evaluate the relationship between cervical cytokine/chemokine concentrations and HIV-1 acquisition in peripartum Kenyan women.

Design:

Nested case–control study.

Methods:

Women participating in a prospective study of peripartum HIV acquisition in Kenya (the Mama Salama Study), were tested for HIV-1 at 1–3 month intervals during pregnancy and through 9 months postpartum. Cases positive for HIV-1 RNA during follow-up (N = 14), were matched 3 : 1 with HIV-negative controls (N = 42) based on age, marital status, partner HIV-1 status, transactional sex, and timing of cervical swab collection. Concentrations of five cytokines (IL-1β, IL-6, IL-10, IFNγ, and TNFα) and four chemokines (IL-8, C-X-C motif chemokine ligand 10 (CXCL10), macrophage inflammatory protein-1 α, and macrophage inflammatory protein-1 β) were measured from cervical swabs collected at the visit prior to HIV-1 diagnosis (cases) or matched gestational/postpartum time (controls). Cytokine/chemokine concentrations were compared between cases and controls using Wilcoxon rank-sum tests. Principal component analysis was used to create a summary score for closely correlated cytokines/chemokines. Associations with HIV-1 acquisition were analyzed using conditional logistic regression. Path analysis was used to evaluate hypothesized relationships between CXCL10, vaginal washing, Nugent score, and HIV-1 acquisition.

Results:

Conditional logistic regression analysis demonstrated an association between increased concentrations of CXCL10 and HIV-1 acquisition (odds ratio = 1.74, 95% confidence interval 1.04, 2.93; P = 0.034). Path analysis confirmed a positive independent association between higher concentrations of CXCL10 and HIV-1 acquisition (path coefficient = 0.37, 95% confidence interval 0.15, 0.59; P < 0.001).

Conclusion:

HIV-1 acquisition was associated with increased cervical concentrations of CXCL10 in pregnant and postpartum women.
A taxonomy of pragmatic measures of HIV preexposure prophylaxis use
Authors: Pyra Maria , Rusie Laura , Castro Michael , Keglovitz Baker Kristin , McNulty Moira , Bohm Nick , Prokurat Andrei , Schneider John
Published: July 2020

Objectives:

As delivery of preexposure prophylaxis (PrEP) becomes an HIV prevention priority in the United States, standard, pragmatic measures of PrEP use are needed to compare and evaluate prevention implementation programs. By using readily available electronic health record data, we describe and compare measures of persistence and retention.

Design:

Retrospective cohort.

Methods:

Using electronic health record prescription data for patients at a large urban Federally Qualified Health Center from 2015 to 2019, we calculated measures of persistence and retention and compared them to pharmacy claims data, PrEP biomarkers, and HIV outcomes.

Results:

Total PrEP time was 19.8 months on average. During this period, average adherence by medication prescription ratio (MRxR) was 89%; 77% of patients had an MRxR at least 85% and 90% have an MRxR at least 57%. Over the first 6 months, average proportion of days covered (PDC) at least 85% was 53% and PDC at least 57% was 57%. Prescription fill rates, based on claims data from a pharmacy partner, ranged from 45 to 60%. Using tenofovir-diphosphate as the gold standard, PDC had high sensitivity (97%) but low specificity (≤13%). As a measure of retention, over the first 6 months, 59% of patients had quarterly HIV tests.

Conclusion:

Total PrEP time is useful measure of overall persistence, while PDC can assess persistence and adherence at a specific time point. Adherence by PDC is more conservative compared with MRxR; both will overestimate true adherence. Retention in care can be measured by quarterly HIV tests. Using consistent terminology and reporting timepoints and adherence thresholds will help reporting and comparing PrEP delivery programs.
Zidovudine and lamivudine reach higher concentrations in ventricular than in lumbar human cerebrospinal fluid
Authors: Eggers Christian , Hoetelmans Richard , Läer Stephanie
Published: July 2020

Objective:

For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples.

Design:

We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients.

Methods:

Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated.

Results:

High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4.

Conclusion:

Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.
Diagnostic Accuracy of the 3-Meter Backward Walk Test in Persons With Parkinson Disease
Authors: Carter Valerie A. , Farley Becky G. , Wing Kay , de Heer Hendrik “Dirk” , Jain Tarang K.
Published: July 2020

Purpose:

To test diagnostic accuracy of the 3-Meter Backward Walk (3MBW) test for falls among 175 persons with Parkinson disease (PwP).

Methods:

Retrospective data analysis was performed on time for 3MBW test, forward walk tests (Timed Up and Go, TUG cognitive, and 10-Meter Walk), and the 5 times Sit-to-Stand test. A receiver operating characteristic curve analysis was completed to determine fall cutoff scores, and the optimal area under the curve (AUC) with sensitivity/specificity values was defined.

Results:

The 3MBW test at 4.2 seconds had the highest AUC (AUC = 0.699). Persons with Parkinson disease with advanced disease were slower for each test; the 3MBW was the only test that was significantly different across disease severity.

Conclusion:

The 3MBW test had the highest overall accuracy for retrospective falls and should be considered as part of battery of tests among persons with Parkinson disease.
Boxing Exercises as Therapy for Parkinson Disease
Authors: Dawson Rachael A. , Sayadi Jamasb , Kapust Lissa , Anderson Lauren , Lee Stacey , Latulippe Al , Simon David K.
Published: July 2020

A noncontact boxing program called “Rock Steady Boxing” (RSB) is a popular exercise option for people with Parkinson disease (PD). This retrospective observational study assessed the impact of RSB on clinically relevant outcome measures in 62 PD patients. The change from program beginning to completion in the 30-second sit-to-stand (STS) test, the Timed Up and Go (TUG) test, a quality-of-life survey (the EQ-5D), and a satisfaction survey was analyzed. Significant improvement was observed in the STS and TUG tests for participants completing their first or second RSB sessions. These results indicate benefits of RSB for people with PD.
HINTS Examination in Acute Vestibular Neuritis: Do Not Look Too Hard for the Skew
Authors: Green Kemar E. , Gold Daniel R.
Published: July 2020

Background:

An ocular tilt reaction (OTR) is a triad of a skew deviation, head tilt, and ocular counter-roll that can be partial or complete. An OTR can occur anywhere along the utriculo-ocular motor pathways from the labyrinth to the interstitial nucleus of Cajal but is almost always central in origin. In acute vestibular neuritis (AVN), case reports have described patients with an OTR due to AVN, although it is unclear whether this examination finding is common or rare.

Methods:

The vestibular and ocular motor features of 7 patients presenting with AVN are described.

Results:

Each of the 7 patients presented with typical features of AVN, including contralesional unidirectional spontaneous nystagmus and an ipsilesional abnormal head impulse test, although each patient also had a complete OTR. None of the patients had vertical diplopia or a skew deviation that was measurable with alternate cover testing (i.e., abnormal “test of skew” according to the Head Impulse, Nystagmus, Test of Skew examination); however, all had a subtle 1 prism diopter hyperphoria that was only measurable with a Maddox rod test.

Conclusion:

Seven cases of typical AVN with an OTR are presented, and in the authors' experience, the presence of a subtle OTR is a common feature of AVN in these patients.
Safety of Hydroxychloroquine among Outpatient Clinical Trial Participants for COVID-19
Authors: Lofgren Sarah M , Nicol Melanie R , Bangdiwala Ananta S , Pastick Katelyn A , Okafor Elizabeth C , Skipper Caleb P , Pullen Matthew F , Engen Nicole W , Abassi Mahsa , Williams Darlisha A , Nascene Alanna A , Axelrod Margaret L , Lother Sylvain A , MacKenzie Lauren J , Drobot Glen , Marten Nicole , Cheng Matthew P , Zarychanski Ryan , Schwartz Ilan S , Silverman Michael , Chagla Zain , Kelley Lauren E , McDonald Emily G , Lee Todd C , Hullsiek Katherine H , Boulware David R. , Rajasingham Radha
Published: July 2020

Introduction

Use of hydroxychloroquine in hospitalized patients with COVID-19, especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from three outpatient randomized clinical trials.

Methods

We conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, post-exposure prophylaxis and early treatment for COVID-19. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings.

Results

We enrolled 2,795 participants. The median age of research participants was 40 (IQR 34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2,324 (84%) participants reported side effect data, and 638 (27%) reported at least one medication side effect. Side effects were reported in 29% with daily, 36% with twice weekly, 31% with once weekly hydroxychloroquine compared to 19% with placebo. The most common side effects were upset stomach or nausea (25% with daily, 18% with twice weekly, 16% with weekly, vs. 10% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for daily, 16% twice weekly, 12% weekly, vs. 6% for placebo). Two individuals were hospitalized for atrial arrhythmias, one on placebo and one on twice weekly hydroxychloroquine. No sudden deaths occurred.

Conclusion

Data from three outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials can safely investigate whether hydroxychloroquine is efficacious for COVID-19.

Short Summary

Data from three randomized clinical trials using hydroxychloroquine for the prevention and treatment of COVID-19 did not suggest significant safety concerns. Gastrointestinal side effects were common but arrhythmias were rare. There were no sudden deaths in any trial.
Parallelized manipulation of adherent living cells by magnetic nanoparticles-mediated forces
Authors: Bongaerts Maud , Aizel Koceila , Secret Emilie , Audric Jan , Nahar Tasmin , Raudzus Fabian , Neumann Sebastian , Telling Neil , Heumann Rolf , Siaugue Jean-Michel , Ménager Christine , Fresnais Jérôme , Villard Catherine , Haj Alicia El , Piehler Jacob , Gates Monte A. , Coppey Mathieu
Published: July 2020

The remote actuation of cellular processes such as migration or neuronal outgrowth is a challenge for future therapeutic applications in regenerative medicine. Among the different methods that have been proposed, the use of magnetic nanoparticles appears to be promising since magnetic fields can act at a distance without interactions with the surrounding biological system. To control biological processes at a subcellular spatial resolution, magnetic nanoparticles can be used either to induce biochemical reactions locally or to apply forces on different elements of the cell. Here, we show that cell migration and neurite outgrowth can be directed by the forces produced by a switchable parallelized array of micro-magnetic pillars, following passive uptake of nanoparticles. Using live cell imaging, we first demonstrate that adherent cell migration can be biased toward magnetic pillars and that cells can be reversibly trapped onto these pillars. Second, using differentiated neuronal cells we were able to induce events of neurite outgrowth in the direction of the pillars without impending cell viability. Our results show that the range of forces applied needs to be adapted precisely to the cellular process under consideration. We propose that cellular actuation is the result of the force on the plasma membrane caused by magnetically filled endo-compartments, which exert a pulling force on the cell periphery.
Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data
Authors: Spisak Natanael , Walczak Aleksandra M. , Mora Thierry
Published: July 2020

Somatic hypermutations of immunoglobulin (Ig) genes occurring during affinity maturation drive B-cell receptors’ ability to evolve strong binding to their antigenic targets. The landscape of these mutations is highly heterogeneous, with certain regions of the Ig gene being preferentially targeted. However, a rigorous quantification of this bias has been difficult because of phylogenetic correlations between sequences and the interference of selective forces. Here, we present an approach that corrects for these issues, and use it to learn a model of hypermutation preferences from a recently published large IgH repertoire dataset. The obtained model predicts mutation profiles accurately and in a reproducible way, including in the previously uncharacterized Complementarity Determining Region 3, revealing that both the sequence context of the mutation and its absolute position along the gene are important. In addition, we show that hypermutations occurring concomittantly along B-cell lineages tend to co-localize, suggesting a possible mechanism for accelerating affinity maturation.
NO GAMETOPHORES 2is a novel regulator of the 2D to 3D growth transition in the mossPhyscomitrium patens
Authors: Moody Laura A. , Kelly Steven , Clayton Roxaana , Weeks Zoe , Emms David M. , Langdale Jane A.
Published: July 2020

The colonization of land by plants was one of the most transformative events in the history of life on Earth. The transition from water, which coincided with and was likely facilitated by the evolution of 3-dimensional (3D) growth, enabled the generation of morphological diversity on land. In many plants, the transition from 2-dimensional (2D) to 3D growth occurs during embryo development. However, in the early divergent mossPhyscomitrium patens(formerlyPhyscomitrella patens), 3D growth is preceded by an extended filamentous phase that can be maintained indefinitely. Here, we describe the identification of the cytokinin-responsiveNO GAMETOPHORES 2(PpNOG2) gene, which encodes a shikimate o- hydroxycinnamoyltransferase. In mutants lackingPpNOG2function, transcript levels ofCLAVATAandSCARECROWgenes are significantly reduced, excessive gametophore initial cells are produced, and buds undergo premature developmental arrest. Our results suggest that PpNOG2 functions in the ascorbic acid pathway leading to cuticle formation, and that NOG2-related genes were co-opted into the lignin biosynthesis pathway after the divergence of bryophytes and vascular plants. We present a revised model of 3D growth in which PpNOG2 comprises part of a feedback mechanism that is required for the modulation of gametophore initial cell frequency. We also propose that the 2D to 3D growth transition inP. patensis underpinned by complex auxin-cytokinin crosstalk that is regulated, at least in part, by changes in flavonoid metabolism.
Inference and analysis of cell-cell communication using CellChat
Authors: Jin Suoqin , Guerrero-Juarez Christian F. , Zhang Lihua , Chang Ivan , Myung Peggy , Plikus Maksim V. , Nie Qing
Published: July 2020

Understanding global communications among cells requires accurate representation of cell-cell signaling links and effective systems-level analyses of those links. We constructed a database of interactions among ligands, receptors and their cofactors that accurately represents known heteromeric molecular complexes. Based on mass action models, we then developed CellChat, a tool that is able to quantitively infer and analyze intercellular communication networks from single-cell RNA-sequencing (scRNA-seq) data. CellChat predicts major signaling inputs and outputs for cells and how those cells and signals coordinate for functions using network analysis and pattern recognition approaches. Through manifold learning and quantitative contrasts, CellChat classifies signaling pathways and delineates conserved and context-specific pathways across different datasets. Applications of CellChat to several mouse skin scRNA-seq datasets for embryonic development and adult wound healing shows its ability to extract complex signaling patterns, both previously known as well as novel. Our versatile and easy-to-use toolkit CellChat and a web-based Explorer (http://www.cellchat.org/) will help discover novel intercellular communications and build a cell-cell communication atlas in diverse tissues.
The role of Vitamin C in the energy supply of cells Hypothetical structure for energy transformation
Authors: Hunyady János
Published: July 2020

The present paper represents a hypothetical structure, the structure for energy transformation (SET), which might be responsible for the proper energy transformation steps leading to the continuous production of H+and ATP in living cells. We predict that the electron flow is realized through the electron flow device (EFD). We suppose that there are several versions of the SET. Two of them are described below [Structure of Aerobic Glycolysis (SET-AG) and Structure of Oxidative Phosphorylation (SET-OP)]. The hypothesis is based on the atom properties of the protonated adenine molecule and the docking computations of molecular mechanics involved, suggesting that two ascorbate molecules may occupy the empty NADPH pocket, preferably binding to the adenine binding site. We hypothesize that the adenine originates from uric acid (UA), resulting in an ATP-UA-ADP-ATP-UA cycle. It would also mean that UA is one of the oxygen sources in aerobic glycolysis.

We also suppose that the EFD contains the well-known molecules of the Nicotinamide Adenine Dinucleotide (NAD) and Flavin Adenine Dinucleotide (FAD) supplemented with two additional UA-originated adenine molecules, two L-ascorbic acids, and two D-glucose molecules. Based on all this, we surmise that a tetra adenine octo phosphate ring (TAR) exists, in which the UA originated adenine molecules form a ring. The molecules are linked to each other through the N7-C2 and C8-N1 atoms of the adenine molecules by H2PO4e-molecules. The four N10 atoms of the adenine molecules bind one flavin, one nicotinamide, and two L-ascorbic acid molecules. Six D-glucose molecules complete one Unit of the structure. Both Fe-S and cytochrome clusters, as well as dehydrogenases, ensure the continuous operation of the Unit. The synchronized function of the three-stoke, three twin-cylinder engine results in continuous energy, ATP, and H+production. Eukaryotic cells are equipped with the SET-AG and the SET-OP; thus, they can live in an anoxic and oxygenized environment. It is hoped that the SET concept developed here will help the better understanding the way of action regarding the cancer treatment with Vitamin C or glucose deprivation.
Endogenous zebrafish proneural Cre drivers generated by CRISPR/Cas9 short homology directed targeted integration
Authors: Almeida Maira P. , Welker Jordan M. , Ekker Stephen C. , Clark Karl J. , Essner Jeffrey J. , McGrail Maura
Published: July 2020

The Cre/loxrecombinase system has been widely used for spatiotemporal control of gene expression in animal model systems, however, efficient methods to isolate zebrafish Cre drivers that reliably recapitulate endogenous gene expression patterns are needed. Here, we apply CRISPR/Cas9 targeting to integrate a 2A-Cre recombinase transgene with 48bp homology arms into proneural genesascl1b,olig2andneurod1. We observed high rates of germline transmission ranging from 10%-100% (2/20olig2; 1/5neurod1; 3/3ascl1b). The transgenic linesTg(ascl1b-2A-Cre)is75,Tg(olig2-2A-Cre)is76, andTg(neurod1-2A-Cre)is77expressed functional Cre recombinase in the expected proneural cell populations. The results demonstrate Cre recombinase expression is driven by the native promoter and regulatory elements of the targeted genes. This approach provides a straightforward, efficient, and cost-effective method to generate cell type specific zebrafish Cre drivers whose spatial and temporal restricted expression mimics endogenous genes, surmounting the challenges associated with promoter BAC cloning and transposon mediated transgenesis.
Neurovascular-modulation
Authors: Khadka Niranjan , Bikson Marom
Published: July 2020

Neurovascular-modulation is based on two principles that derive directly from brain vascular ultra-structure, namely an exceptionally dense capillary bed (BBB length density: 972 mm/mm3) and a blood-brain-barrier (BBB) resistivity (ρ~ 1×105Ω.m) much higher than brain parenchyma/interstitial space (ρ~ 4 Ω.m) or blood (ρ~ 1 Ω.m). Principle 1: Electrical current crosses between the brain parenchyma (interstitial space) and vasculature, producing BBB electric fields (EBBB) that are > 400x of the average parenchyma electric field (ĒBRAIN), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λBBB) and wall thickness (dth-BBB): analytical solution for maximum BBB electric field (EABBB) is given as: (ĒBRAIN× λBBB) / dth-BBB. Direct vascular stimulation suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Boosting metabolic capacity impacts all forms of neuromodulation, including those applying intensive stimulation or driving neuroplasticity. Boosting interstitial fluid clearance has broad implications as a treatment for neurodegenerative disease including Alzheimer’s disease. Principle 2: Electrical current in the brain parenchyma is distorted around brain vasculature, amplifying neuronal polarization. Specifically, vascular ultra-structure produces ~50% modulation of the average parenchyma electric field (ĒBRAIN) over the ~40 μm inter-capillary distance. The divergence of EBRAIN(activating function) is thus ~100 kV/m2per unit average parenchyma electric field (ĒBRAIN). This impacts all forms of neuromodulation, including Deep Brain Stimulation (DBS), Spinal Cord Stimulation (SCS), Transcranial Magnetic Stimulation (TMS), Electroconvulsive Therapy (ECT), and transcranial electrical stimulation (tES) techniques such a transcranial Direct Current Stimulation (tDCS). Specifically, whereas spatial profile of EBRAINalong neurons is traditionally assumed to depend on macroscopic anatomy, it instead depends on local vascular ultra-structure.
Topoisomerase 1 dependent R-loop deficiency drives accelerated replication and genomic instability
Authors: Sarni Dan , Shtrikman Alon , Oren Yifat S. , Kerem Batsheva
Published: July 2020

DNA replication is a complex process that is tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Replication stress is commonly associated with slow and stalled replication forks. Recently, accelerated replication has emerged as a non-canonical form of replication stress. However, the molecular basis underlying fork acceleration is largely unknown. Here we show that increased topoisomerase 1 (TOP1) expression induces aberrant replication fork acceleration and DNA damage by decreasing RNA-DNA hybrids (R-loops). Degradation of R-loops by overexpression of RNaseH1 also accelerates replication and generates DNA damage. Furthermore, upregulation of TOP1 by activation of the mutated HRAS oncogene leads to fork acceleration and DNA damage in pre-senescent cells. In these cells, restoration of TOP1 expression level or mild replication inhibition rescues the perturbed replication and reduces DNA damage. These findings highlight the importance of TOP1 equilibrium in the regulation of R-loop homeostasis to ensure faithful DNA replication and genome integrity.
Ranking the direct threats to biodiversity in sub-Saharan Africa
Authors: Leisher Craig , Robinson Nathaniel , Brown Matthew , Kujirakwinja Deo , Schmitz Mauricio Castro , Wieland Michelle , Wilkie David
Published: July 2020

Sub-Saharan Africa benefits from large investments in biodiversity conservation, yet there is no prioritization of the many direct threats to biodiversity available to inform organizations developing sub-Saharan or sub-regional conservation strategies. Consequently, regional investments by funders of biodiversity conservation such as international conservation organizations, foundations, and bilateral and multilateral donors may be suboptimal. To identify the priority threats to biodiversity in sub-Saharan Africa, we classified the direct threats to biodiversity using standardized threats categories and triangulated data from a Delphi consensus of sub-Saharan Africa biodiversity experts, known threats to IUCN Red-listed sub-Saharan African species, and National Biodiversity Strategy and Action Plans from 47 sub-Saharan African countries. After ranking the threats from each source and averaging the rankings, we find that the highest threats are: annual and perennial crops (non-timber); logging and wood harvesting (natural forests); fishing and harvesting aquatic resources (marine and freshwater); and hunting and collecting terrestrial animals. Within the sub-regions of sub-Saharan Africa there is considerable variation. The highest ranked threat in Central Africa is hunting. In East Africa, it is agriculture. In Southern Africa, it is invasive non-native/alien species, and in West Africa, agriculture and logging are tied as the highest threats. There are known ways to address all of these threats, and concentrating investments on these threats while accounting for unique socio-ecological contexts across sub-Saharan Africa is essential for the sustained conservation of biodiversity.
Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19
Authors: Bell Lucy CK , Meydan Cem , Kim Jacob , Foox Jonathan , Butler Daniel , Mason Christopher E. , Shapira Sagi D. , Noursadeghi Mahdad , Pollara Gabriele
Published: July 2020

Dysregulated IL-1β and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokinesin vivoare urgently needed to complement clinical trials of therapeutic targeting of IL-1β and IL-6 in COVID-19. We show that the expression of IL-1β or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1β and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood, but is not associated with severity of COVID-19 disease, length of stay or mortality. We propose that IL-1β and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activityin vivo, aiding quantification of the biological effects of immunomodulatory therapies in COVID-19.
ABCB-mediated auxin transport in outer root tissues regulates lateral root spacing inArabidopsis
Authors: Chen Jian , Hu Yangjie , Hao Pengchao , Zhang Yuqin , Roth Ohad , Njo Maria F. , Sterck Lieven , Hu Yun , Zhao Yunde , Geisler Markus , Shani Eilon , Beeckman Tom , Vanneste Steffen
Published: July 2020

Root branching is an important strategy to explore efficiently large volumes of soil. To economize this process, lateral roots (LR) are formed along the growing root at discrete positions that are instructed by oscillating auxin signals derived from the lateral root cap (LRC). This assumes that auxin moves from the LRC across multiple layers to accumulate in the pericycle. Here, we identified, using gene silencing and CRISPR based approaches, a group of five genetically linked, closely related ABCBs that control LR spacing by modulating the amplitude of the auxin oscillation. The transporters localize to the plasma membrane and reveal significant auxin export activity. These ABCBs are mainly expressed in the LRC and epidermis where they contribute to auxin transport towards the root oscillation zone. Our findings highlight the importance of auxin transport in the outer tissues of the root meristem to regulate LR spacing.