bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and safety of maraviroc in neonates
Authors: Rosebush Julia C. , Best Brookie M. , Chadwick Ellen G. , Butler Kevin , Moye John , Smith Elizabeth , Bradford Sarah , Reding Christina A. , Mathiba Sisinyana R. , Hanley Sherika , Aziz Mariam , Homans James , Acosta Edward P. , Murtaugh William , Vourvahis Manoli , Mcfadyen Lynn , Hayward Katy , Mirochnick Mark , Samson Pearl
Published: November 2020

Objective:

The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life.

Design:

A phase I, multicentre, open-label study enrolling two sequential cohorts.

Methods:

IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety.

Results:

Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17–33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred.

Conclusion:

Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.
Impact of rosuvastatin on atherosclerosis in people with HIV at moderate cardiovascular risk: a randomised, controlled trial
Authors: Trevillyan Janine M. , Dart Anthony , Paul Eldho , Cavassini Matthias , Fehr Jan , Staehelin Cornelia , Dewar Elizabeth M. , Hoy Jennifer F. , Calmy Alexandra
Published: November 2020

Background: :

People living with HIV-1 (PLHIV) are at increased risk for cardiovascular disease.

Objective:

This study aimed to determine if PLHIV would benefit from starting statins at a lower threshold than currently recommended in the general population.

Design:

A double-blind multicentre, randomised, placebo-controlled trial was performed.

Methods:

Participants (n = 88) with well controlled HIV, at moderate cardiovascular risk (Framingham score of 10–15%), and not recommended for statins were recruited from Australia and Switzerland. They were randomized 1 : 1 to rosuvastatin (n = 44) 20 mg daily, 10 mg if co-administered with ritonavir/cobicistat-boosted antiretroviral therapy, or placebo (n = 40) for 96 weeks. Assessments including fasting blood collection and carotid--intima media thickness (CIMT) were performed at baseline, and weeks 48 and 96. The primary outcome was the change from baseline to week 96 in CIMT (clinicaltrials.gov: NCT01813357).

Results:

Participants were predominantly men [82 (97.6%); mean age 54 years (SD 6.0)]. At 96 weeks, there was no difference in the progression of CIMT between the rosuvastatin (mean 0.004 mm, SE 0.0036) and placebo (0.0062 mm, SE 0.0039) arms (P = 0.684), leading to no difference in CIMT levels between groups at week 96 [rosuvastatin arm, 0.7232 mm (SE 0.030); placebo arm 0.7785 mm (SE 0.032), P = 0.075].

Adverse events were common (n = 146) and predominantly in the rosuvastatin arm [108 (73.9%)]. Participants on rosuvastatin were more likely to cease study medication because of an adverse event [7 (15.9%) vs. 2 (5.0%), P = 0.011].

Conclusion:

In PLHIV, statins prescribed at a lower threshold than guidelines did not lead to improvements in CIMT but was associated with significant adverse events.
HIV-DNA content in pTfh cells is associated with residual viremia in elite controllers
Authors: García Marcial , Morcilla Vincent , Navarrete-Muñoz Maria Ángeles , Fisher Katie , Cabello Alfonso , López-Bernaldo Juan Carlos , De La Hera Francisco , Barros Carlos , Fernández-Guerrero Manuel , Estrada Vicente , Górgolas Miguel , Benito José Miguel , Palmer Sarah , Rallón Norma
Published: November 2020

Objective:

The source of residual HIV viremia is highly debated and its potential relationship with the HIV reservoir has not been clarified. Herein, we analysed the cell-associated HIV-DNA content in two important cell compartments of the HIV reservoir, resting CD4+ T memory (Trm) and peripheral T follicular helper (pTfh) cells, and the association with the residual HIV viremia in individuals with spontaneous HIV replication control (elite controllers, EC group) and in individuals with antiretroviral therapy (ART)-mediated HIV replication control (cART group).

Design:

A cross-sectional study.

Methods:

Seventeen chronically HIV-infected patients with suppressed HIV replication were included. Cell-associated HIV-DNA was measured by ultrasensitive digital-droplet-PCR in purified Trm and pTfh cells. Residual HIV plasma viremia was quantified using a single-copy assay with a sensitivity of 0.3 HIV-RNA copies/ml.

Results:

A significant and positive correlation was demonstrated between HIV-DNA levels in pTfh cells and residual plasma viral load (rpVL) (rho = 0.928, P = 0.008) in HIV-positive elite controllers, but not in HIV-positive treated patients, despite the lower levels of cell-associated HIV-DNA found in elite controllers compared with cART patients in pTfh cells [176 (77–882) vs. 608 (361–860) copies/million cells, respectively; P = 0.05].

Conclusion:

This association suggests that pTfh cells could have an important contribution to persistent viremia in elite controllers. This could be the consequence of a more limited control of HIV replication in elite controllers with higher transcriptional activity of HIV in pTfh cells of elite controllers than that in cART patients.
Isolated Superficial Myxoma Above the Eyebrow
Authors: Kim Woojin , Kim Joohyun , Baek Sehyun
Published: November 2020

A 59-year-old man with a palpable mass above the left eyebrow that had appeared over a 1-year period presented to our clinic. He previously had been administered antiglaucoma eyedrops for pseudophakic glaucoma of the left eye and had undergone Ahmed glaucoma valve implant surgery. The palpable mass above the left eyebrow was soft, nontender, and large. On slit lamp examination, the Ahmed valve was positioned in the superotemporal quadrant of the limbal conjunctiva, and there was no other abnormal finding. Computerized tomography (CT) imaging showed a dense, soft tissue lesion in the left upper lateral periorbital area. The patient underwent tumor excision with biopsy under general anesthesia, and the histopathologic result was myxoma. To rule out Carney complex, dermatological and cardiac evaluation were performed, and the results were normal. Finally, the tumor was diagnosed as isolated myxoma. Isolated myxoma around the upper eyelid is very rare, and complete surgical excision is needed because it has a high recurrence rate.
Assessment of Smell and Taste Disorders in COVID-19: A Cross-sectional Study
Authors: Bulğurcu Suphi , Öztutgan Turgut , Baz Eyup , Yonem Ayşegül , Koç Niyazi Günsu , Erkul Evren , Çekin Engin
Published: November 2020

Background:

It has been reported worldwide that patients with a diagnosis of COVID-19 usually suffer a loss of smell and taste. In this study, we aimed to evaluate the relationship between the severity of the disease and the loss of smell and taste. In addition, we evaluated patients’ smell and taste functions after recovery.

Methods:

Between March and May 2020, 418 patients diagnosed with COVID-19 were divided into 3 groups: home-quarantined, hospitalized, and intensive care patients. The disease, smell, and taste functions of patients were evaluated with visual analog scores before diagnosis of COVID-19, during the disease, and fourth week after recovery. The types of smell loss and types of taste flavor loss occurring during the disease were questioned.

Results:

In all 3 groups, changes in smell and taste loss during the disease were statistically detected (P = 0.001). The smell loss rates determined in groups 1 to 3 were 45%, 43.7%, and 31.2%, respectively. The taste loss rates determined in groups 1 to 3were 46.6%, 32.1%, and 31.2% respectively. The rate of patients with a total recovery of smell loss in groups 1 to 3 were 95.5%, 93.7%, and 100%, respectively (P = 0.768). The rate of patients with a total recovery of taste loss in groups 1 to 3 were 97.1%, 91.4%, and 100%, respectively (P = 0.423).

Conclusion:

COVID-19 causes significant loss of smell and taste in patients. The loss of smell and taste does not correlate with the severity of COVID-19 disease. The loss of smell and taste improves at a high rate after the disease.
Thinning of Calvarial Bone by Skull Growth in a Pediatric Patient After Skull Grinding Injury
Authors: Song Jong Keun , Kim Jae Won , Lee Jun Yong
Published: November 2020

Several treatment options have been suggested for the treatment of scalp defects that occur following head trauma. Growth changes should be considered, especially for children. The authors report a case of delayed cranial bone absorption after successful free latissimus dorsi flap coverage following skull grinding injury in a pediatric patient.

A 3-year-old patient was referred to the reconstructive surgery department because of a 7 × 8 cm-sized scalp defect in the temporoparietal area due to dragging and grinding injury. Debridement and free latissimus dorsi musculocutaneous flap coverage with split-thickness skin graft were performed. The operation was successful and antibiotics were administered for 4 weeks to prevent the occurrence of osteomyelitis (OM). The patient was discharged after confirming the absence of OM via magnetic resonance imaging.

Thinning of cranial bone was observed in the skull series taken one year postoperatively. The size gradually increased, but no significant changes in size occurred after 5 years of patient's age. Magnetic resonance imaging was performed used to confirm the occurrence of OM and no specific findings were observed. It is well-known fact that the cranium grows to 90% of its adult capacity by the age of 5. In this regard, we believe that the current case and the demonstrated cranial thinning is due to bone absorption associated with the growth.

In the pediatric population, injuries involving the cranial vault should be considered in the context of bone resorption due to skull growth, which may lead to cranial bone thinning. Reconstructive surgeons should closely observe the presence or absence of skull defects through long-term follow-ups.
The Anxiety and Pain of Fibromyalgia Patients during the COVID-19 Pandemic
Authors: Kharko A. Y. , Hansford K. J. , Furlong P. L. , Hall S. D. , Roser M. E.
Published: November 2020

Background

Early research on the impact of the COVID-19 pandemic found persistent related anxiety in the general population. We hypothesised that this anxiety will be associated with increased pain in chronic pain patients diagnosed with fibromyalgia (FM).

Methods

To study this, we carried out a 10-day online survey with 58 female participants, diagnosed with FM and no other pain condition. We identified which aspects of the COVID-19 pandemic evoked anxiety. We then asked participants to provide daily ratings of both anxiety and pain on 101-point visual analogue scales (VAS). Key participant characteristics were included as mediators in a mixed-effects analysis, where the primary outcome was pain VAS.

Results

We found that participants were most often anxious about“impact on relationships”, “a family member contracting COVID-19”, and“financial hardships”, but on average rated“financial hardship”, “access to medication”, and“home loss/eviction”as evoking the strongest anxiety. Mixed-effects modelling showed that an increase in pain was significantly associated with an increase in anxiety, when taking into account individual variance and daily caffeine intake. Age and intake of some mild analgesics were also linked to stronger pain.

Conclusion

Our results extend the initial findings from the literature about the effects of COVID-19 pandemic on chronic pain sufferers. We found that not only is pandemic anxiety in FM patients present, but it is associated with amplified self-assessed chronic pain.

Significance

The long-term support of fibromyalgia patients is challenging for healthcare professionals due to the nature of the condition. The new normal introduced by the pandemic particularly hinders pain management, which is the leading request from this patient group. Our study demonstrates that mental health decline during the COVID-19 pandemic is directly related to the worsening of pain in fibromyalgia. Core stressors that evoke the strongest anxiety were identified thus providing guidance for where to focus patient support.
County Demographics and COVID-19 Death Rates: Comparison of relationship in the first and current stage of the pandemic in the United States of America
Authors: Urbine Emma , James Madison T , Shah Vishal
Published: November 2020

Previous studies have discovered disparity in death rates associated with SARS-CoV-2 infection in the United States during the initial stages of the pandemic. Specifically, the death rates were higher in the population in poverty and communities of color across the United States. In the current study, we perform the secondary analysis of death rates due to COVID-19 data, obtained from the Center for Disease Control and Prevention (CDC). Results indicate that in the first phase of the pandemic (February 1 to August 1, 2020), counties with higher percentage of White, Native Hawaiian and other Pacific Islanders, and two or more races populations were found to have lower per-capita COVID-19 death rate. Whereas counties with population having higher percentage of females, Black or African American people, and persons in poverty had higher death rates. Analysis of the death rates from August 1 to September 10, 2020, indicate that disparity continues with counties having higher population of Black or African American people and female having higher death rates. Poverty is not a significant variable in determining the death rates due to COVID-19. Based on the current data and lack of detailed molecular mechanism of the disease, we suggest that more resources must be diverted to counties with higher percentages of Black or African American and female populations.
Psychological distress among people with probable COVID-19 infection: analysis of the UK Household Longitudinal Study
Authors: Niedzwiedz Claire L , Benzeval Michaela , Hainey Kirsten , Leyland Alastair H , Katikireddi Srinivasa Vittal
Published: November 2020

Studies exploring the longer-term effects of experiencing COVID-19 infection on mental health are lacking. We explored the relationship between reporting probable COVID-19 symptoms in April 2020 and psychological distress (measured using the General Health Questionnaire) one, two, three, five and seven months later. Data were taken from the UK Household Longitudinal Study, a nationally representative household panel survey of UK adults. Elevated levels of psychological distress were found up to seven months after probable COVID-19, compared to participants with no likely infection. Associations were stronger among younger age groups and men. Further research into the psychological sequalae of COVID-19 is urgently needed.
Dental practice in Pre- COVID19 and Future Perspectives
Authors: Subramanya Ashwin Parakkaje , Prabhuji MLV
Published: November 2020

Objectives

To assess the trends in dental practice in pre-COVID19 times and future perspectives.

Methods

The cross-sectional study was conducted among the dental professionals across India. The snowball and convenience sampling methods were used to ensure maximum participation of the subjects. An online structured questionnaire was created using free-access Google Forms application and was sent to the dental professionals via E-mail, WhatsApp mobile application and through other social media platforms. Initially, a pilot study was conducted among 30 dentists to check for the validity. The questionnaire was administered between the months of May 2020 – July 2020 and was sent to 650 dentists from various parts of the country. Data were compiled and subjected to statistical analysis.

Results

The questionnaire was sent to 650 dental professionals. Out of 650, 120 (18.4%) participants took part in the survey. Majority of the respondents had 1 to 3 years of experience in dental practice (n=51, 42.5%). It was noted that majority of the participants were into consultation practice (n=69, 57.5%). 65.8% participants reported that they can withstand upto 6 months from economic view point. Difficulty in paying salaries, reduced incomes is some of the main problems encountered by dental professionals. Increasing the price of treatment, reducing co-workers are a few strategies planned by dental professionals to mitigate the economic burden caused by COVID19 pandemic.

Conclusion

Majority of dental professionals in India are dependent on private practice and consultation practice. Due to COVID19, source of income has disrupted for majority of the younger dental professionals.
A Quality Improvement Initiative: Improving Time-to-Antibiotics for Pediatric Oncology Patients with Fever and Suspected Neutropenia
Authors: Kram David E , Salafian Kia , Reel Sarah M , Johnson Emily Nance , Borsheim Brianna , Russell Thomas B , Pearsall Will A , Mitchell Michael , McCalla Chad
Published: November 2020

Background

There is a high risk for adverse outcomes in immunocompromised, neutropenic pediatric oncology patients with fever if antibiotics are not received in a timely manner. As the absolute neutrophil count is typically unknown at the onset of fever, rapid antibiotic administration for all pediatric oncology patients with fever and suspected neutropenia is critical.

Local Problem

Despite efforts over the years to meet the standard of time-to-antibiotic delivery to within 60 minutes of arrival, audits revealed a prolonged and wide-ranging time-to-antibiotics in our pediatric emergency department.

Methods

We conducted a quality improvement initiative to reduce the time to antibiotic delivery for this high risk patient population. The setting was a pediatric emergency department in an academic tertiary care hospital. We assembled a multidisciplinary team to apply quality improvement methods to understand the problem, implement interventions, and evaluate the outcomes.

Interventions

We targeted delays in patient triage, delays in antibiotic ordering, delays in antibiotic choice, and delays in bedside indwelling Port-a-Cath accessing procedure. Among other interventions, we instituted three unique measures: ceftriaxone was administered to all pediatric oncology patients with suspected neutropenia and fever; a system of ordering antibiotics that was driven by the ED pharmacist obtaining a verbal order from the ED attending; and a nurse-driven order set triggered by a unique triage category which empowered nurses to access a patient’s central line, draw and send specified blood work, and deliver an intravenous antibiotic, all potentially before an ED provider sees the patient.

Results

Over a sustained 3 year period of time, the percentage of febrile oncology patients with suspected neutropenia who met the target time-to-antibiotic delivery rose from 51% to 96%. The mean time-to-antibiotic delivery fell from 58 minutes in the pre-intervention period to 28 minutes in the post-intervention period.

Conclusions

The interventions implemented by the multidisciplinary team, using quality improvement methodology, successfully improved the percentage of febrile oncology patients receiving antibiotics within 60 minutes of arrival to a pediatric emergency department.
Heritability enrichment implicates microglia in Parkinson’s disease pathogenesis
Authors: Andersen Maren Stolp , Bandres-Ciga Sara , Reynolds Regina H. , Hardy John , Ryten Mina , Krohn Lynne , Gan-Or Ziv , Holtman Inge R. ,   International Parkinson’s Disease Genomics Consortium, Pihlstrøm Lasse
Published: November 2020

Objective

Understanding how different parts of the immune system contribute to pathogenesis in Parkinson’s disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson’s disease stratified by immune and brain cell types.

Methods

We used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson’s disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.

Results

We found significant enrichment of Parkinson’s disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggestingP2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson’s disease association signal on chromosome 3.

Interpretation

Our results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson’s disease.
Performance of prediction models for short term outcome in COVID-19 patients in the emergency department: a retrospective study
Authors: van Dam Paul M.E.L. , Zelis Noortje , van Kuijk Sander M.J. , Linkens Aimée E.M.J.H. , Bruggemann Renée R.A.G. , Spaetgens Bart , van der Horst Iwan C.C. , Stassen Patricia M.
Published: November 2020

Introduction

Coronavirus disease 2019 (COVID-19) has a high burden on the healthcare system and demands information on the outcome early after admission to the emergency department (ED). Previously developed prediction models may assist in triaging patients when allocating healthcare resources. We aimed to assess the value of several prediction models when applied to COVID-19 patients in the ED.

Methods

All consecutive COVID-19 patients who visited the ED of a combined secondary/tertiary care center were included. Prediction models were selected based on their feasibility. The primary outcome was 30-day mortality, secondary outcomes were 14-day mortality, and a composite outcome of 30-day mortality and admission to the medium care unit (MCU) or the intensive care unit (ICU). The discriminatory performance of the prediction models was assessed using an area under the receiver operating characteristic curve (AUC).

Results

A total of 403 ED patients were diagnosed with COVID-19. Within 30 days, 95 patients died (23.6%), 14-day mortality was 19.1%. Forty-eight patients (11.9%) were admitted to the MCU, 66 patients (16.4%) to the ICU and 152 patients (37.7%) met the composite endpoint. Eleven models were included: RISE UP score, 4C mortality score, CURB-65, MEWS, REMS, abbMEDS, SOFA, APACHE II, CALL score, ACP index and Host risk factor score. The RISE UP score and 4C mortality score showed a very good discriminatory performance for 30-day mortality (AUC 0.83 and 0.84 respectively, 95% CI 0.79-0.88 for both), for 14-day mortality (AUC 0.83, 95% CI: 0.79-0.88, for both) and for the composite outcome (AUC 0.79 and 0.77 respectively, 95% CI 0.75-0.84). The discriminatory performance of the RISE UP score and 4C mortality score was significantly higher compared to that of the other models.

Conclusion

The RISE UP score and 4C mortality score have good discriminatory performance in predicting adverse outcome in ED patients with COVID-19. These prediction models can be used to recognize patients at high risk for short-term poor outcome and may assist in guiding clinical decision-making and allocating healthcare resources.
COVID-19 Growth in Rural versus Urban Counties with Major Universities at the Start of the 2020 Academic Year
Authors: Penuliar Mike , Clark Candice , Curti Debbie , Hudson Cathy , Philips Billy
Published: November 2020

Universities play a central role in a rural or small town’s economy. They are often the main forms of enrichment to the lives of the longtime residents, the students, and the employees. Unfortunately, during a global pandemic, the migration and movement of young people in these communities can likely cause a rapid infection spike and drive spread easily, especially relative to larger urban areas. The current study investigates the relationship between COVID-19 case growth, university-county rurality, and time at the beginning of the Fall 2020 academic semester. Findings showed that small metro and non-metro counties with universities had a dramatic infection spike near the beginning of the semester and infection growth remained significantly higher than their large and medium metro counterparts for the duration of the study. Suggestions to slow the spread in rural communities are discussed.
Prevalence of Isolated Systolic Hypertension among People with Diabetes in Indonesia
Authors: Azam Mahalul , Hidayati Fetty Nur , Fibriana Arulita Ika , Bahrudin Udin , Aljunid Syed Mohamed
Published: November 2020

The present study aimed to explore the prevalence of isolated systolic hypertension (ISH) and its risk factors among diabetes mellitus (DM) subjects in the community setting study in Indonesia. This cross-sectional study extracted secondary data from basic health survey (Riset Kesehatan Dasar; RISKESDAS) conducted in 2018. DM subjects were defined based on fasting blood glucose level ≥ 126 mg/dL or 2 hours postprandial and random blood glucose level ≥ 200 mg/dL or previously had been diagnosed by a doctor; while ISH was determined based on systolic blood pressure ≥ 140 mmHg and diastolic blood pressure < 90 mmHg. We also observed the subject’s characteristics, such as demography, lipid profile, and subject’s compliance. Data were then analyzed using Chi-square and Binary logistic regression. Study involved 3,911 DM subjects, revealed the overall prevalence of ISH 17.5%. Age category of 35-44 years old (POR= 10.80; 95%CI: 2.595-44.957), 45-54 years old (POR=22.81; 95%CI: 5.616-92.677), 55-64 years old (POR=46.12; 95% CI: 11.393-186.720); 65-74 years old (POR= 81.82; 95% CI: 20.110-332.868); ≥75 years old (POR=109.64; 95% CI: 26.373-455.789), low HDL cholesterol (POR= 0,80; 95% CI: 0.653-0.972); duration of DM (POR= 1.73; 95% CI: 1.257-2.389) were associated with the ISH. The prevalence of ISH among DM subjects was 17.5%. Older DM subjects, low HDL cholesterol, and duration of DM were associated with the ISH, suggesting that modification lipid profile, especially the HDL cholesterol level, is an important measure to delay ISH in elderly and long-duration DM subjects.
A behavioral cascade of HIV seroadaptation among US men who have sex with men in the era of PrEP and U=U
Authors: Goodreau Steven M. , Maloney Kevin M. , Sanchez Travis H. , Morris Martina , Janulis Patrick , Jenness Samuel M.
Published: November 2020

Seroadaptive behaviors help to reduce HIV risk for some men who have sex with men (MSM), and have been well documented in a range of MSM populations. Advancements in biomedical prevention have changed the contexts in which seroadaptive behaviors occur. We thus sought to estimate and compare the prevalence of four stages of the “seroadaptive cascade” in the recent era: knowledge of own serostatus, knowledge of partner serostatus; serosorting (matching by status), and condomless anal intercourse. Serosorting overall appeared to remain common, especially with casual and one-time partners. Although PrEP use did not impact status discussion, it did impact serosorting and the likelihood of having condomless anal intercourse. For respondents not diagnosed with HIV and not on PrEP, condomless anal intercourse occurred in just over half of relationships with partners who were not on treatment. Biomedical prevention has intertwined with rather than supplanted seroadaptive behaviors, while contexts involving neither persist.
Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection
Authors: Bert Nina Le , Clapham Hannah E , Tan Anthony T , Chia Wan Ni , Tham Christine YL , Lim Jane M , Kunasegaran Kamini , Tan Linda , Dutertre Charles-Antoine , Shankar Nivedita , Lim Joey ME , Sun Louisa Jin , Zahari Marina , Tun Zaw Myo , Kumar Vishakha , Lim Beng Lee , Lim Siew Hoon , Chia Adeline , Tan Yee-Joo , Tambyah Paul Anantharajah , Kalimuddin Shirin , Lye David , Low Jenny GH , Wang Lin-Fa , Wan Wei Yee , Hsu Li Yang , Bertoletti Antonio , Tam Clarence C
Published: November 2020

The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic individuals (n=85) with that of symptomatic COVID-19 patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion (IL-2, IFN-γ, IL-4, IL-6, IL-1β, TNF-α and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic individuals. However, we detected an increased IFN-γ and IL-2 production in asymptomatic compared to symptomatic individuals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 and pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2 infected individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 might help to reduce inflammatory events during viral clearance.
Data mining patented antibody sequences
Authors: Krawczyk Konrad , Buchanan Andrew , Marcatili Paolo
Published: November 2020

Patent literature should be a reflection of thirty years of engineering efforts in developing monoclonal antibody therapeutics. Such information is potentially valuable for rational antibody design. Patents however are not designed to convey scientific knowledge, but rather legal protection. It is unclear whether antibody information from patent documents, such as antibody sequences could be useful for the therapeutic antibody sphere in conveying engineering know-how rather than act as legal reference only. To assess the utility of patent data for therapeutic antibody engineering, we quantified the amount of antibody sequences in patents destined for medicinal purposes and how well they reflect the primary sequences of therapeutic antibodies in clinical use. We identified 16,526 patent families from major jurisdictions (e.g. USPTO and WIPO) that contained antibody sequences. These families held 245,109 unique antibody chains (135,397 heavy chains and 109,712 light chains) that we compiled in our Patented Antibody Database (PAD, http://naturalantibody.com/pad). We find that antibodies make up a non-trivial proportion of all patent amino acid sequence depositions (e.g. 10.95% of USPTO Full Text database). Our analysis of the 16,526 families demonstrates that the volume of patent documents with antibody sequences is growing with the majority of documents classified as containing antibodies for medicinal purposes. We further studied the 245,109 antibody chains from patent literature to reveal that they very well reflect the primary sequences of antibody therapeutics in clinical use. This suggests that patent literature could serve as a reference of previous engineering efforts to improve rational antibody design.
Differential excitability of PV and SST neurons results in distinct functional roles in inhibition stabilization of Up-states
Authors: Romero-Sosa Juan L. , Motanis Helen , Buonomano Dean V.
Published: November 2020

Up-states are the best-studied example of an emergent neural dynamic regime. Computational models based on a single class of inhibitory neurons indicate that Up-states reflect bistable dynamical systems in which positive feedback is stabilized by strong inhibition and predict a paradoxical effect in which increased drive to inhibitory neurons results in decreased inhibitory activity. To date, however, computational models have not incorporated empirically defined properties of PV and SST neurons. Here we first, experimentally characterized the frequencycurrent (F-I) curves of pyramidal, PV, and SST neurons and confirmed a sharp difference between the threshold and slopes of PV and SST neurons. The empirically defined F-I curves were incorporated into a three-population computational model that simulated the empirically-derived firing rates of pyramidal, PV, and SST neurons. Simulations revealed that the intrinsic properties were sufficient to predict that PV neurons are primarily responsible for generating the nontrivial fixed points representing Up-states. Simulations and analytical methods demonstrated that while the paradoxical effect is not obligatory in a model with two classes of inhibitory neurons, it is present in most regimes. Finally, experimental tests validated predictions of the model that the Pyr↔PV inhibitory loop is stronger than the Pyr↔SST loop.

SIGNIFICANCE STATEMENT

Many cortical computations, such as working memory, rely on the local recurrent excitatory connections that define cortical circuit motifs. Up-states are among the simplest and best studied examples of neural dynamic regimes that rely on recurrent excitatory excitation. However, this positive feedback must be held in check by inhibition. To address the relative contribution of PV and SST neurons we characterized the intrinsic input-output differences between these classes of inhibitory neurons, and using experimental and theoretical methods show that the higher threshold and gain of PV leads to a dominant role in network stabilization.
1H, 15N and 13C sequence specific backbone assignment of the MAP Kinase Binding Domain of the Dual Specificity Phosphatase 1 and its interaction with the MAPK p38
Authors: Senthil Kumar Ganesan , Page Rebecca , Peti Wolfgang
Published: November 2020

The sequence-specific backbone assignment of the mitogen-activated protein kinase (MAPK) binding domain of the dual-specificity phosphatase 1 (DUSP1) has been accomplished using a uniformly [13C,15N]-labeled protein. These assignments will facilitate further studies of DUSP1 in the presence of inhibitors/ligands to target MAPK associated diseases and provide further insights into the function of dual-specificity phosphatase 1 in MAPK regulation.
Harnessing cytoplasmic particles movement of the human early embryo analysed by advanced imaging and artificial intelligence to predict development to blastocyst stage
Authors: Coticchio Giovanni , Fiorentino Giulia , Nicora Giovanna , Sciajno Raffaella , Cavalera Federica , Bellazzi Riccardo , Garagna Silvia , Borini Andrea , Zuccotti Maurizio
Published: November 2020

Research Question

Progress in artificial intelligence (AI) and advanced image analysis offers unique opportunities to develop novel embryo assessment approaches. In this study, we tested the hypothesis that such technologies can extract and harness novel information derived from cytoplasmic movements of the early human embryo to predict development to blastocyst.

Design

In a proof-of principle study, an artificial neural network (ANN) approach was undertaken to assess retrospectively 230 human preimplantation embryos. After ICSI, embryos were subjected to time-lapse monitoring for 44 hours. For comparison as a standard embryo assessment methodology, a single senior embryologist assessed each embryo to predict development to blastocyst stage (BL) based on a single picture frame taken at 42 hours of development. In the experimental approach, in embryos that developed to blastocyst or destined to arrest (NoBL), cytoplasm movement velocity (CMV) was recorded by time-lapse monitoring during the first 44 hours of culture and analysed with a Particle Image Velocimetry (PIV) algorithm to extract quantitative information. Three main AI approaches, the k-Nearest Neighbor (k-NN), the Long-Short Term Memory Neural Network (LSTM-NN) and the hybrid ensemble classifier (HyEC) were employed to classify the two embryo classes.

Results

Blind operator assessment classified each embryo in terms of ability of development to blastocyst, reaching a 75.4% accuracy, 76.5% sensitivity, 74.3% specificity, 74.3% precision and 75.4% F1 score. After integration of results from AI models together with the blind operator classification, the performance metrics improved significantly, with a 82.6% accuracy, 79.4% sensitivity, 85.7% specificity, 84.4% precision and 81.8% F1 score.

Conclusions

The present study suggests the possibility to predict human blastocyst development at early cleavage stages by detection of CMV and AI analysis. This indicates the importance of the dynamics of the cytoplasm as a novel and valuable source of data to assess embryo viability.
A novel high-accuracy genome assembly method utilizing a high-throughput workflow
Authors: Zeng Qingdong , Cao Wenjin , Xing Liping , Qin Guowei , Wu Jianhui , Nagle Michael F. , Xiong Qin , Chen Jinhui , Yang Liming , Bajaj Prasad , Chitikineni Annapurna , Zhou Yan , Yu Yunxin , Xu Jiang , Nie Xiaojun , Huang Lin , Liu Shengjie , Šafář Jan , Šimková Hana , Song Weining , Guo Baozhu , Chen Shilin , Doležel Jaroslav , Hao Zhaodong , Cheng Qiang , Liang Jianguo , Tang Jiansong , Cao Aizhong , Wang Qiang , Lu Xiangqian , Yang Shouping , Ma Hongxiang , Liu Jiajie , Wang Xiaoting , Zhang Hong , Wang Zhonghua , Ji Wanquan , Wang Changfa , Yuan Fengping , Shi Jisen , Varshney Rajeev K. , Kang Zhensheng , Han Dejun , Xu Haibin
Published: November 2020

Across domains of biological research using genome sequence data, high-quality reference genome sequences are essential for characterizing genetic variation and understanding the genetic basis of phenotypes. However, the construction of genome assemblies for various species is often hampered by complexities of genome organization, especially repetitive and complex sequences, leading to mis-assembly and missing regions. Here, we describe a high-throughput gold standard genome assembly workflow using a large-scale bacterial artificial chromosome (BAC) library with a refined two-step pooling strategy and the Lamp assembler algorithm. This strategy minimizes the laborious processes of physical map construction and clone-by-clone sequencing, enabling inexpensive sequencing of several thousand BAC clones. By applying this strategy with a minimum tiling path BAC clone library for the short arm of chromosome 2D (2DS) of bread wheat, 98% of BAC sequences, covering 92.7% of the 2DS chromosome, were assembled correctly for this species with a highly complex and repetitive genome. We also identified 48 large mis-assemblies in the reference wheat genome assembly (IWGSC RefSeq v1.0) and corrected these large mis-assemblies in addition to filling 92.2% of the gaps in RefSeq v1.0. Our 2DS assembly represents a new benchmark for the assembly of complex genomes with both high accuracy and efficiency.
Pfcerli2, a duplicated gene in the malaria parasitePlasmodium falciparumessential for invasion of erythrocytes as revealed by phylogenetic and cell biological analysis
Authors: Liffner Benjamin , Balbin Juan Miguel , Shami Gerald J. , Strauss Jan , Frölich Sonja , Heinemann Gary K. , Alder Arne , Wichers Jan Stephan , Tilley Leann , Dixon Matthew W. A. , Gilberger Tim-Wolf , Wilson Danny W.
Published: November 2020

Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasitePlasmodium falciparum. Proteins involved with RBC binding and invasion are secreted from dual-club shaped organelles at the apical tip of the merozoite called the rhoptries. Here we characteriseP. falciparumCytosolically Exposed Rhoptry Leaflet Interacting protein 2 (PfCERLI2), as a rhoptry bulb protein that is essential for merozoite invasion. Phylogenetic analyses show thatcerli2arose through an ancestral gene duplication ofcerli1, a related cytosolically exposed rhoptry bulb protein. We show that PfCERLI2 is essential for blood-stage growth and localises to the cytosolic face of the rhoptry bulb. Inducible knockdown of PfCERLI2 led to an inhibition of merozoite invasion after tight junction formation. PfCERLI2 knockdown was associated with inhibition of rhoptry antigen processing and a significant elongation of the rhoptries, suggesting that the inability of merozoites to invade is caused by aberrant rhoptry function due to PfCERLI2 deficiency. These findings identify PfCERLI2 as a protein that has key roles in rhoptry biology during merozoite invasion.
Differential effects of amplitude-modulated transcranial focused ultrasound on excitatory and inhibitory neurons
Authors: Nguyen Duc T. , Berisha Destiny , Konofagou Elisa , Dmochowski Jacek P.
Published: November 2020

Although stimulation with ultrasound has been shown to modulate brain activity at multiple scales, it remains unclear whether transcranial focused ultrasound stimulation (tFUS) exerts its influence on specific cell types. Here we propose a novel form of tFUS where a continuous waveform is amplitude modulated (AM) at a slow rate (i.e., 40 Hz) targeting the temporal range of electrophysiological activity: AM-tFUS. We stimulated the rat hippocampus while recording multi-unit activity (MUA) followed by classification of spike waveforms into putative excitatory pyramidal cells and inhibitory interneurons. At low acoustic intensity, AM-tFUS selectively reduced firing rates of inhibitory interneurons. On the other hand, higher intensity AM-tFUS increased firing of putative excitatory neurons with no effect on inhibitory firing. Interestingly, firing rate was unchanged during AM-tFUS at intermediate intensity. Consistent with the observed changes in firing rate, power in the theta band (3-10 Hz) of the local field potential (LFP) decreased at low-intensity, was unchanged at intermediate intensity, and increased at higher intensity. Temperature increases at the AM-tFUS target were limited to 0.2°C. Our findings indicate that inhibitory interneurons exhibit greater sensitivity to ultrasound, and that cell-type specific neuromodulation may be achieved by calibrating the intensity of AM-tFUS.
Egr2 induction in Drd1+ ensembles of the ventrolateral striatum supports the development of cocaine reward
Authors: Mukherjee Diptendu , Gonzales Ben Jerry , Ashwal-Fluss Reut , Turm Hagit , Groysman Maya , Citri Ami
Published: November 2020

Drug addiction develops due to brain-wide plasticity within neuronal ensembles, mediated by dynamic gene expression. Though the most common approach to identify such ensembles relies on immediate early gene expression, little is known of how the activity of these genes is linked to modified behavior observed following repeated drug exposure. To address this gap, we present a broad-to-specific approach, beginning with a comprehensive investigation of brain-wide cocaine-driven gene expression, through the description of dynamic spatial patterns of gene induction in subregions of the striatum, and finally address functionality of region-specific gene induction in the development of cocaine preference. Our findings reveal differential cell-type specific dynamic transcriptional recruitment patterns within two subdomains of the dorsal striatum following repeated cocaine exposure. Furthermore, we demonstrate that induction of the IEG Egr2 in the ventrolateral striatum, as well as the cells within which it is expressed, are required for the development of cocaine seeking.

Impact statement

VLS ensembles are dynamically recruited by cocaine experiences to mediate cocaine reward.
Biomedical Graph Visualizer for Identifying Drug Candidates
Authors: Teng Ashton , Villanueva Blanca , Jow Derek , Huang Shih-Cheng (Mars) , Piekos Samantha N. , Altman Russ B.
Published: November 2020

1.

Millions of Americans suffer from illnesses with non-existent or ineffective drug treatment. Identifying plausible drug candidates is a major barrier to drug development due to the large amount of time and resources required; approval can take years when people are suffering now. While computational tools can expedite drug candidate discovery, these tools typically require programming expertise that many biologists lack. Though biomedical databases continue to grow, they have proven difficult to integrate and maintain, and non-programming interfaces for these data sources are scarce and limited in capability. This creates an opportunity for us to present a suite of user-friendly software tools to aid computational discovery of novel treatments through de novo discovery or repurposing. Our tools eliminate the need for researchers to acquire computational expertise by integrating multiple databases and offering an intuitive graphical interface for analyzing these publicly available data. We built a computational knowledge graph focused on biomedical concepts related to drug discovery, designed visualization tools that allow users to explore complex relationships among entities in the graph, and served these tools through a free and user-friendly web interface. We show that users can conduct complex analyses with relative ease and that our knowledge graph and algorithms recover approved repurposed drugs. Our evaluation indicates that our method provides an intuitive, easy, and effective toolkit for discovering drug candidates. We show that our toolkit makes computational analysis for drug development more accessible and efficient and ultimately plays a role in bringing effective treatments to all patients.

Our application is hosted at: https://biomedical-graph-visualizer.wl.r.appspot.com/