bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Mannose-binding Lectin in Infectious Complications of Pediatric Hemato-Oncologic Diseases
Authors: Dobi Marianna , Szilágyi Ágnes , Csuka Dorottya , Varga Lilian , Prohászka Zoltán , Bereczki Csaba , Kovács Gábor , Fekete Ferenc
Published: October 2020

The complement system is essential for protection against infections in oncologic patients because of the chemotherapy-induced immunosuppression. One of the key elements in the activation of the complement system via the lectin pathway is the appropriate functioning of mannose-binding lectin (MBL) and mannose-binding lectin-associated serine protease 2 (MASP2) complex. The objective of our study was to find an association between polymorphisms resulting in low MBL level and activation of the MBL-MASP2 complex. Also, we aimed at finding a connection between these abnormalities and the frequency and severity of febrile neutropenic episodes in children suffering from hemato-oncologic diseases. Ninety-seven patients had been enrolled and followed from the beginning of the therapy for 8 months, and several characteristics of febrile neutropenic episodes were recorded. Genotypes of 4 MBL2 polymorphisms (-221C/G, R52C, G54D, G57E) were determined by real-time polymerase chain reaction. Activation of the MBL-MASP2 complex was evaluated by enzyme-linked immunosorbent assay at the time of diagnosis and during an infection. The number of febrile neutropenic episodes was lower, and the time until the first episode was longer in patients with normal MBL level than in patients with low MBL level coding genotypes. The MBL-MASP2 complex activation level correlated with the MBL genotype and decreased significantly during infections in patients with low MBL level. Our results suggest that infections after immunosuppression therapy in children suffering from hemato-oncologic diseases are associated with the MBL2 genotype. Our results may contribute to the estimation of risk for infections in the future, which may modify therapeutic options for individuals.
Clinical Characteristics of 204 Children With Human Adenovirus Type 7 Pneumonia Identified by Whole Genome Sequencing in Liuzhou, China
Authors: Huang Xiaoli , Yi Yongsong , Chen Xiaogang , Wang Bo , Long Yiqin , Chen Jichang , Rongkavilit Chokechai
Published: October 2020

Background:

Clinical knowledge of human adenovirus type 7 (HAdV-7) pneumonia in children remains limited. Moreover, predictors for disease severity are largely unknown.

Methods:

This is a retrospective study of children hospitalized at Liuzhou Maternal and Child Health Hospital, China, with HAdV-7 pneumonia in 2018–2019. Demographics, clinical characteristics, laboratory results, and imaging data were collected. HAdV-7 was identified in plasma using whole genome sequencing, which yielded quantitative HAdV-7 sequence numbers.

Results:

There were 204 children; 145 (71%) were <2 years of age. There were 68 children with severe pneumonia (SP) and 136 with nonsevere pneumonia (NSP). Up to 43% in SP group with respiratory failure (SP-RF) were <12 months of age. Median duration of fever before hospitalization was shorter in NSP group than SP groups (P < 0.01). Fourteen (6.9%) underwent mechanical ventilation. There was a significant difference in mean plasma HAdV-7 sequence numbers among SP-RF, SP without respiratory failure (SP-NRF), and NSP groups (2485 ± 165, 2034 ± 124, and 286 ± 35, respectively) (P < 0.01). In a logistic regression analysis, we found that elevated plasma HAdV-7 sequence numbers significantly increased the risk of severe HAdV-7 pneumonia (OR 1.80, 95% confidence interval: 1.59–2.60, P < 0.01) after adjusting for age, fever duration, platelet counts, and serum lactate dehydrogenase levels.

Conclusions:

Over two-thirds of children hospitalized with HAdV-7 pneumonia were <2 years of age. Approximately 40% of those with SP associated with respiratory failure were <12 months of age. Those with SP exhibited higher plasma HAdV-7 sequence numbers. Thus, plasma HAdV-7 sequence numbers have a potential in predicting severity of HAdV-7 pneumonia in children.
Longitudinal and concurrent relationships between caregiver–child behaviours in the vaccination context and preschool attachment
Authors: O'Neill Monica C. , Pillai Riddell Rebecca , Bureau Jean-François , Deneault Audrey-Ann , Garfield Hartley , Greenberg Saul
Published: October 2020

This article consists of 2 separate studies in which the overarching aim was to examine the relationships between caregiver–child behaviours in the vaccination context (infant and preschool) and preschool attachment outcomes. It provides for the first time an examination of acute pain behaviours during early childhood and how it relates to a critical aspect of child development (ie, attachment status) at the end of early childhood. Study 1 examined the longitudinal relationships between caregiver–infant behaviours during infants' first routine vaccination (2 months) and preschool attachment (n = 84). Study 2 examined the concurrent relationships between caregiver–preschooler behaviours during the last routine vaccination of preschool (4-5 years) and preschool attachment (n = 117). Hierarchical multiple regression analyses were used. Although there were several nonsignificant findings, the results revealed that higher caregiver sensitivity and higher proximal soothing 1 minute before the needle during infants' 2-month vaccinations predicted higher levels of preschooler avoidance and lower levels of preschooler ambivalence, respectively. In addition, higher infant pain-related distress at 2 minutes after the needle was related to higher preschooler security and lower preschooler disorganization and controlling-punitive attachments. In terms of concurrent relationships, only caregiver sensitivity was significantly related to preschool attachment outcomes. Specifically, higher caregiver sensitivity at preschoolers' 4- to 5-year vaccinations was related to higher preschooler attachment security. The study findings provide evidence that child–caregiver behavioural patterns during the infant and preschool routine vaccination relate to preschoolers' patterns of attachment. Moreover, it underscores the potential importance of health professionals teaching and supporting attuned caregiving to the child in pain.
Depression as a Mediator in the Association of Work–Family Conflict With Problem Drinking Among Young and Middle-Aged Korean Married Workers
Authors: Yang Hwa-Mi , Kim Hye-Ryoung
Published: October 2020

Objective:

This study examined the associations of work–family conflicts (WFC) with problem drinking and the mediating effect of depression among Korean married workers.

Methods:

The data of 2386 married workers were used from the 2017 Korean Welfare Panel Study. The data classified into two groups, young adults and middle-aged based on age 45. The association of WFC with problem drinking and the mediating effect of depression was assessed by combining logistic and linear regression.

Results:

WFC was associated with problem drinking, and the mediating effect of depression was significant in the middle-aged group. Meanwhile, depression only has a direct effect on problem drinking in the young adult group.

Conclusion:

A strategy for treating depression may be important for countering problem drinking. However, an age-tailored intervention should be considered WFC supporting middle-aged workers.
Aberrant AICA Injury During Translabyrinthine Approach
Authors: Bauer Ashley M. , Angster Kristen , Schuman Ari D. , Thompson Byron Gregory , Telian Steven A.
Published: October 2020

Objective:

To define a complication of the translabyrinthine surgical approach to the posterior fossa related to a rare variant of the anterior inferior cerebellar artery (AICA) that penetrated into the petrous temporal bone.

Patient:

A healthy 59-year-old male with a unilateral sporadic vestibular schwannoma.

Intervention:

The patient elected to undergo a translabyrinthine approach for resection of a vestibular schwannoma. An aberrant loop of AICA was encountered during the temporal bone dissection within the petrous portion of the temporal bone.

Outcomes:

The patient suffered a presumed ischemic insult resulting in a fluctuating ipsilateral facial paresis and atypical postoperative nystagmus.

Results:

MRI demonstrated an ischemic lesion in the vascular distribution of the right anterior-inferior cerebellar artery, including the lateral portion of the right cerebellar hemisphere, middle cerebellar peduncle, and bordering the right cranial nerve VII nucleus. His functional recovery was excellent, essentially identical to the anticipated course in an otherwise uncomplicated surgery.

Conclusions:

This case highlights the irregular anatomy of the AICA as well as the importance of thorough neurological exams in the postsurgical lateral skull base patient.
Accurate Classification of Pediatric Colonic Inflammatory Bowel Disease Subtype Using a Random Forest Machine Learning Classifier
Authors: Dhaliwal Jasbir , Erdman Lauren , Drysdale Erik , Rinawi Firas , Muir Jennifer , Walters Thomas D. , Siddiqui Iram , Griffiths Anne M. , Church Peter C.
Published: October 2020

Background:

The pediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling of colonic IBD, but labels are exclusively based on features atypical for ulcerative colitis (UC).

Aim:

The aim of the study was to develop an algorithm and identify features that discriminate between pediatric UC and colonic Crohn disease (CD).

Methods:

Baseline clinical, endoscopic, radiologic, and histologic data, including the PIBD class features in 74 colonic IBD (56: UC, 18: colonic CD) patients were collected. The PIBD class features and additional features common to UC were used to perform initial clustering, using similarity network fusion (SNF). We trained a Random Forest (RF) classifier on the full dataset and used a leave‐one‐out approach to evaluate model accuracy. The top‐features were used to build a new classifier, which we tested on 15 previously unused patients. We then performed clustering with SNF on the top RF features and assessed ability to discriminate between UC and colonic‐CD independent of a supervised model.

Results:

The initial SNF clustering with 58 patients demonstrated 2 groups: group 1 (n = 39, 90% UC) and group 2 (n = 19, 68% colonic‐CD). Our RF classifier correctly labelled 97% of the 58 patients based on leave‐one‐out cross validation and identified the 7 most important features (3 histological and 4 endoscopic) to clinically distinguish these groups. We trained a new RF classifier with the top 7 features and found 100% accuracy in a set of 15 held‐out patients. Finally, post hoc clustering with these 7 features revealed 2 groups of patients: group 1 (n = 55, 98% UC) and group 2 (n = 18, 94% colonic‐CD).

Conclusions:

A combination of supervised and unsupervised analyses identified a short list of features, which consistently distinguish UC from colonic CD. Future directions include validation in other populations.
Examining the Potential Relationship Between Multidisciplinary Team Meetings and Patient Survival in Pediatric Oncology Settings: A Systematic Review
Authors: Dijkstra Suzan , Kraal Kathelijne C.J.M. , Ruijters Veerle J. , Kremer Leontien C.M. , Hoogerbrugge Peter M.
Published: October 2020

The organization of multidisciplinary team meetings (MTMs) has become standard practice in pediatric oncology and is widely felt to improve communication, knowledge, and patient care. Although the impact of MTMs on survival in adult oncology has been extensively researched, the potential benefits of survival for pediatric cancer patients are still unclear. This systematic review aimed to examine the impact of MTMs on survival in pediatric oncology settings. Relevant studies were identified by searching MEDLINE/PubMed, EMBASE, and the Cochrane Library databases up to January 2020, resulting in 325 unique records. After the title/abstract and full-text screening, 5 studies were included. All of the included studies (one prospective and 4 retrospective cohort studies) described a difference in overall or event-free survival when comparing patients who were discussed in MTMs with non-MTM patients. This association was statistically significant in 3 studies. The quality of the studies was strongly affected by their design. Because of the small number of studies in combination with high clinical and methodological heterogeneity, this review was unable to definitively assert a causal relationship between MTMs and survival in pediatric cancer patients. Further research is needed to explore this relationship and allow cost-benefit analyses, so that time and resources are optimally spent to deliver the best possible care to childhood cancer patients.
Circumcision in Hemophilia: A Multicenter Experience
Authors: Bawazir Osama A. , Alharbi Ibrahim
Published: October 2020

Background:

Hemophiliac patients and their families have social pressure to undergo circumcision, despite the potential complications. The objective of this study was to report our experience in the circumcision of hemophilia patients.

Materials and Methods:

We included 35 patients with hemophilia who had circumcision in 3 centers from January 2010 to August 2019. Their age ranged between 0.3 months and 8 years. Hemophilia a was classified as mild (n=3), moderate (n=4), and severe (n=28). Patients received 2 doses of factor VIII concentrate 50μ/kg, 1 hour before the procedure and 12 hours after it.

Results:

Four neonates were diagnosed with hemophilia after circumcision because of prolonged bleeding. Two patients with severe hemophilia A had bleeding after hospital discharge (6.5%). They received additional factor concentrate, and 1 patient had an extra stitch. Two patients had wound gaping (6.5%), and 1 patient had a wound infection (3.2%).

Conclusion:

Hemophilia is not an absolute contraindication for circumcision. Circumcision of hemophilic children should be performed under appropriate conditions in hemophilia centers. Bleeding is not frequent but could be serious.
Factors Influencing Fellowship Decision Making During Physical Medicine & Rehabilitation Residency
Authors: Yang Aaron Jay , Haring R. Sterling , Swenson Theodora L. , Jain Nitin B.
Published: October 2020

Previous surveys have demonstrated an increasing trend among graduating physiatry residents who desired to pursue a subspecialty fellowship. There has been sparse information on whether residents start their training with a subspecialty interest in mind and what factors influenced them to choose a fellowship. This article describes a prospective survey in the 2019–2020 academic year in which 175 responses were collected representing 65 (78.3%) of the 83 physical medicine and rehabilitation programs with graduating residents. Nearly 3 in 4 (73.7%, 129/175) reported matching into a fellowship, and among those, 79.8% (103/129) had matched into a pain, spine, or sports medicine fellowship. At the start of residency, 62.3% (109/175) were planning to pursue a fellowship, with 54.9% (96/175) planning to focus on either pain, sports, or spine medicine. Most respondents (72.2%) did not change their initial subspecialty focus during their residency training. Forty-six percent agreed that their anticipated subspecialty influenced their choice of residency program. The results of this survey demonstrate that most graduating residents are matriculating into fellowship training with pain, spine, and/or sports medicine being among the top choices. These results underscore the importance of subspecialty interests of trainees at the start of their residency and how training may influence their subspecialty interest.
Implications of Instituting an Enhanced Recovery after Surgery Pathway in Patients Receiving Chemotherapy in Microsurgical Breast Reconstruction
Authors: Haddock Nicholas T. , Garza Ricardo , Boyle Carolyn E. , Teotia Sumeet S.
Published: October 2020

Background:

Neuropathy is a common side effect of chemotherapeutic agents. Manifestations of chemotherapy-induced neuropathy can present in a myriad of fashions, ranging from numbness, tingling, and pain to motor weakness and autonomic dysfunction.
1
Given the nature of breast reconstruction, a significant portion of the patients have a history of chemotherapy exposure; its effect on postoperative pain management has not been previously explored.

Methods:

This study is a retrospective review of patients who underwent deep inferior epigastric perforator flap breast reconstruction performed by the two senior authors from January of 2016 to September of 2019. The patients were separated into two groups, before and after enhanced recovery after surgery. The primary outcome observed was postoperative opioid consumption, measured as oral morphine equivalents; p values were obtained through univariate linear regression.

Results:

In total, 256 patients were analyzed, of which 113 had chemotherapy exposure. The difference between opioid consumption in patients in the pre–enhanced recovery after surgery group without and with chemotherapy exposure was statistically significant (211.5 mg versus 278.5 mg; p = 0.0279). There was no difference between opioid consumption with regard to chemotherapy history in the enhanced recovery after surgery group (137.4 mg versus 133.0 mg; p = 0.7251).

Conclusions:

Patients with chemotherapy exposure required more opioids to be comfortable. It is unknown whether this difference is secondary to increased pain or less effectiveness of opioids. Further research is necessary to assess whether there are better ways to address pain postoperatively in patients with chemotherapy exposure.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Improving In Vitro Cartilage Generation by Co-Culturing Adipose-Derived Stem Cells and Chondrocytes on an Allograft Adipose Matrix Framework
Authors: Ziegler Mary E. , Sorensen Alexandria M. , Banyard Derek A. , Evans Gregory R. D. , Widgerow Alan D.
Published: October 2020

Background:

Microtia is an inherited condition that results in varying degrees of external ear deformities; the most extreme form is anotia. Effective surgical reconstruction techniques have been developed. However, these usually require multistage procedures and have other inherent disadvantages. Tissue engineering technologies offer new approaches in the field of external ear reconstruction. In this setting, chondrocytes are cultured in the laboratory with the aim of creating bioengineered cartilage matrices. However, cartilage engineering has many challenges, including difficulty in culturing sufficient chondrocytes. To overcome these hurdles, the authors propose a novel model of cartilage engineering that involves co-culturing chondrocytes and adipose-derived stem cells on an allograft adipose-derived extracellular matrix scaffold.

Methods:

Auricular chondrocytes from porcine ear were characterized. Adipose-derived stem cells were isolated and expanded from human lipoaspirate. Then, the auricular chondrocytes were cultured on the allograft adipose matrix either alone or with the adipose-derived stem cells at different ratios and examined histologically.

Results:

Cartilage induction was most prominent when the cells were co-cultured on the allograft adipose matrix at a ratio of 1:9 (auricular chondrocyte–to–adipose-derived stem cell ratio). Furthermore, because of the xenogeneic nature of the experiment, the authors were able to determine that the adipose-derived stem cells contributed to chondrogenesis by means of a paracrine stimulation of the chondrocytes.

Conclusions:

In this situation, adipose-derived stem cells provide sufficient support to induce the formation of cartilage when the number of auricular chondrocytes available is limited. This novel model of cartilage engineering provides a setting for using the patient’s own chondrocytes and adipose tissue to create a customized ear framework that could be further used for surgical reconstruction.
Alterations in Neural Responses and Pain Perception in Older Adults During Distraction
Authors: González-Roldán Ana María , Terrasa Juan Lorenzo , Sitges Carolina , van der Meulen Marian , Anton Fernand , Montoya Pedro
Published: October 2020

Objective

Although it is acknowledged that pain may be modulated by cognitive factors, little is known about the effect of aging on these control processes. The present study investigated electroencephalographical correlates of pain processing and its cognitive modulation in healthy older individuals.

Methods

For this purpose, the impact of distraction on pain was evaluated in 21 young (9 men; 20.71 [2.30]) and 20 older (10 men; 66.80 [4.14]) adults. Participants received individually adjusted electrical pain stimuli in a high-distraction condition (one-back task) and in a low-distraction condition (simple letter response task). Pain-related evoked potentials and pain ratings were analyzed.

Results

Both groups rated pain as less intense (F(1,39) = 13.954,p< .001) and less unpleasant (F(1,39) = 10.111,p= .003) when it was experienced during the high- rather than the low-distraction condition. However, in comparison to younger participants, older adults gave higher unpleasantness ratings to painful stimulation (F(1,39) = 4.233,p= .046), accompanied by attenuated neural responses (N1-P1 and P3 amplitudes), regardless of the distraction condition (F(1,38) = 6.028 [p= .019] andF(1,38) = 6.669 [p= .014], respectively).

Conclusions

Older participants felt pain relief through distraction, like younger participants. However, we also found that aging may enhance affective aspects of pain perception. Finally, our results show that aging is characterized by reduced neural processing of painful stimuli. This phenomenon could be related to the increased vulnerability of older participants to develop chronic pain.
Hydroxychloroquine (HCQ) reverses anti-PD-1 immune murine checkpoint blockade: TCF1 as a marker in humans for COVID-19 and HCQ therapy
Authors: Krueger Janna , Santinon Francois , Kazanova Alexandra , Issa Mark , Larrivee Bruno , Milhalcioiu Catalin , Rudd Christopher E.
Published: October 2020

Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to global public health. Hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZ) are still being used by thousands and numerous hospitals to treat COVID-19. In a related context, immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised cancer therapy. Given that cancer patients on ICB continue to be infected with SARS-CoV-2, an understanding of the effects of HCQ and AZ on the elimination of tumors by anti-PD-1 ICB is urgently needed. In this study, we report that HCQ alone, or in combination with AZ, at doses used to treat COVID-19 patients, reverses the therapeutic benefit of anti-PD-1 in controlling B16 melanoma tumor growth in mice. No deleterious effect was seen on untreated tumors, or in using AZ alone in anti-PD-1 immunotherapy. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+tumor infiltrating T-cells (TILs) and the generation of CD8+CD44+PD-1+effectors. Surprisingly, it also blocked the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T-cells, FoxP3+ Tregs, thymic subsets, B-cells, antibody production, myeloid cells, or the vasculature of mice. Lastly, we identified TCF-1 expression in peripheral CD8+ T-cells from cancer or non-cancer human patients infected with SARs CoV2 as a marker for the effects of COVID-19 and HCQ on the immune system. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.

Graphic Abstract
Nascent prostate cancer heterogeneity drives evolution and resistance to intense hormonal therapy
Authors: Wilkinson Scott , Ye Huihui , Karzai Fatima , Harmon Stephanie A. , Terrigino Nicholas T. , VanderWeele David J. , Bright John R. , Atway Rayann , Trostel Shana Y. , Carrabba Nicole V. , Whitlock Nichelle C. , Walker Stephanie M. , Lis Rosina T. , Sater Houssein A. , Capaldo Brian J. , Madan Ravi A. , Gulley James L. , Chun Guinevere , Merino Maria J. , Pinto Peter A. , Salles Daniela C. , Kaur Harsimar B. , Lotan Tamara L. , Venzon David J. , Choyke Peter L. , Turkbey Baris , Dahut William L. , Sowalsky Adam G.
Published: October 2020

Localized prostate cancer is distinctively characterized by intratumoral heterogeneity, and tumors with more complex evolutionary paths display more aggressive characteristics. In clinical trials of intense neoadjuvant androgen deprivation therapy (inADT), patients with complete or near-complete responses experience durable remissions. However, the molecular characteristics distinguishing exceptional responders and nonresponders at baseline have not been established. Here, we present the integrated histologic and genomic analysis of pre-treatment baseline tissue from our recent Phase 2 clinical study of inADT. Multiregion sampling demonstrated that patients with incomplete and nonresponding tumors demonstrate greater tumor diversity as estimated by phylogenetic tree reconstruction from DNA sequencing and automated analysis of immunohistochemical stains. Development of a four-factor binary model to predict poor response correlated with increased genomic diversity in our 37-patient cohort and a validation cohort of 188 Gleason score 8-10 prostate cancers. Together, these findings demonstrate that even in the primary setting, more highly evolved tumors have increased fitness to resist therapy.
Clinical Validation of a Quantitative HIV-1 DNA Droplet Digital PCR assay: Applications for Detecting Occult HIV-1 Infection and Monitoring Cell-associated HIV-1 Dynamics across Different Subtypes in HIV-1 Prevention and Cure Trials
Authors: Powell Laura , Dhummakupt Adit , Siems Lilly , Singh Dolly , Duff Yann Le , Uprety Priyanka , Jennings Cheryl , Szewczyk Joseph , Chen Ya , Nastouli Eleni , Persaud Deborah
Published: October 2020

Background

In HIV-1-exposed infants, nucleic acid testing (NAT) is required to diagnose infection since passively transferred maternal antibodies preclude antibody testing. The sensitivity of clinical NAT assays is lowered with infant antiretroviral prophylaxis and, with empiric very early antiretroviral treatment of high-risk infants, thereby impacting early infant diagnosis. Similarly, adult HIV-1 infections acquired under pre-exposure prophylaxis may occur at low levels (occult infection), with undetectable plasma viremia and indeterminate antibody tests, for which HIV-1 DNA testing maybe a useful adjunct. Cell-associated HIV-1 DNA concentrations are also used to monitor HIV-1 persistence in viral reservoirs with relevance to HIV-1 cure therapeutics, particularly in perinatal infections.

Methods

The analytical sensitivity and specificity of an HIV-1 DNA droplet digital PCR (ddPCR) assay was determined, across different HIV-1 subtypes, using serial dilutions of a plasmid containing a 160-base pair sequence of the HIV-1 LTR-gag spiked into peripheral blood mononuclear cells (PBMCs), with MOLT-4 cells or PBMCs infected with different HIV-1 subtypes (A, B and C), and U1 cells spiked into PBMCs. Inter- and intra-run variability were used to determine assay precision.

Results

The HIV-1 LTR-gag ddPCR assay was reliable and reproducible, and exhibited high analytical specificity with sensitivity to near single copy level, across multiple HIV-1 subtypes, and a limit of detection of 4.09 copies/million PBMCs.

Conclusions

This assay has applications for detecting occult HIV-1-infection that may occur in the setting of combination and long-acting regimens used for HIV-1 prevention, across different HIV-1 subtypes, in both infants and adults, and in HIV-1 cure interventions, particularly with perinatal infections.
Laboratory evaluation of SARS-CoV-2 antibodies: detectable IgG up to 20 weeks post infection
Authors: Robertson Louise J. , Moore Julie S. , Blighe Kevin , Ng Kok Yew , Quinn Nigel , Jennings Fergal , Warnock Gary , Sharpe Peter , Clarke Mark , Maguire Kathryn , Rainey Sharon , Price Ruth , Burns William , Kowalczyk Amanda , Awuah Agnes , McNamee Sara , Wallace Gayle , Hunter David , Segar Steve , Shern Connie Chao , Nesbit M. Andrew , McLaughlin James , Moore Tara
Published: October 2020

Background

The SARS-CoV-2 pandemic necessitated rapid and global responses across all areas of healthcare, including an unprecedented interest in serological immunoassays to detect antibodies to the virus. The dynamics of the immune response to SARS-CoV-2 is still not well understood and requires further investigation into the longevity of humoral immune response that is evoked due to SARS-CoV-2 infection.

Methods

We measured SARS-CoV-2 antibody levels in plasma samples from 880 people in Northern Ireland using Roche Elecsys Anti-SARS-CoV-2 IgG/IgA/IgM, Abbott SARS-CoV-2 IgG and EuroImmun IgG SARS-CoV-2 ELISA immunoassays to analyse immune dynamics over time. We undertook a laboratory evaluation for the UK-RTC AbC-19 rapid lateral flow immunoassay (LFIA), for the target condition of SARS-CoV-2 Spike protein IgG antibodies using a reference standard system to establish a characterised panel of 330 positive and 488 negative SARS-CoV-2 IgG samples.

Results

We detected persistence of SARS-CoV-2 IgG up to 140 days (20 weeks) post infection, across all three laboratory-controlled immunoassays. On the known positive cohort, the UK-RTC AbC-19 lateral flow immunoassay showed a sensitivity of 97.58% (95.28%-98.95%) and on known negatives, showed specificity of 99.59% (98.53 %-99.95%).

Conclusions

Through comprehensive analysis of a cohort of pre-pandemic and pandemic individuals, we show detectable levels of IgG antibodies, lasting up to 140 days, providing insight to antibody levels at later time points post infection. We show good laboratory validation performance metrics for the AbC-19 rapid test for SARS-CoV-2 Spike protein IgG antibody detection in a laboratory based setting.
Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
Authors: Nahass George R. , Sun Yuanzi , Xu Yong , Batchelor Mark , Reilly Madeleine , Benilova Iryna , Kedia Niraja , Spehar Kevin , Sobott Frank , Sessions Richard B. , Caughey Byron , Radford Sheena E. , Jat Parmjit , Collinge John , Bieschke Jan
Published: October 2020

Alpha-synuclein (α-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinson’s disease, form via nucleation dependent polymerization and can replicate by a seeding mechanism. Brazilin, a small molecule derived from red cedarwood trees in Brazil, has been shown to inhibit the fibrillogenesis of amyloid-beta (Aβ) and α-syn, prompting our inquiry in its mechanism of action. Here we test the effects of Brazilin on both seeded and unseeded α-syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of α-syn by a unique mechanism that is distinct from other polyphenols and is also distinct from its effect on Aβ. Brazilin preserves the natively unfolded state of α-syn by stabilizing the compact conformation of the α-syn monomer over the aggregation-competent extended conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded α-syn monomers and with the cross-β sheet structure of α-syn fibrils. Brazilin eliminates seeding competence of α-syn assemblies from Parkinson’s disease patient brain tissue, and treatment of pre-formed fibril assemblies with Brazilin significantly reduces their toxicity in primary neurons. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson’s Disease.

Highlights

- The natural polyphenol Brazilin binds to monomeric, oligomeric and fibrillar α-syn

- Brazilin shifts the equilibrium away from aggregation-competent monomer conformations

- Brazilin inactivates seeding-competent α-syn isolated from Parkinson patients’ brains

- Brazilin detoxifies α-syn aggregation intermediates and stabilizes mature amyloid fibrils

Graphical Abstract
Assembly factors chaperone rRNA folding by isolating helical junctions that are prone to misfolding
Authors: Huang Haina , Karbstein Katrin
Published: October 2020

While RNAs are known to misfold, the underlying molecular causes remain unclear, and focused on alternative secondary structures. Conversely, how RNA chaperones function in a biological context to promote folding beyond duplex annealing, remains unknown. Here we show in a combination of DMS-MaPseq, structural analyses, biochemical experiments, and yeast genetics that three-way junctions are prone to misfolding during assembly of the small ribosomal subunitin vivo. We identify ubiquitous roles for ribosome assembly factors in chaperoning their folding by preventing the formation of tertiary interactions. In the absence of these assembly factors, tertiary interactions kinetically trap misfolded three-way junctions, thereby blocking further progress in the assembly cascade. While these protein chaperones act indirectly by binding the interaction partners, our analyses also suggest direct roles for snoRNAs in binding and chaperoning three-way junctions during transcription. This work furthermore shows that the dissociation of assembly factors renders reversible folding steps irreversible, thereby setting up a timer that regulates not just the flux of assembly but also dictates the propensity of misfolded intermediates to escape quality control. Finally, the data demonstrate how RNA chaperones act locally to unfold specific tertiary interactions, in contrast to protein chaperones, which globally unfold misfolded proteins.
Theoretical and practical considerations when using retroelement insertions to estimate species trees in the anomaly zone
Authors: Molloy Erin K. , Gatesy John , Springer Mark S.
Published: October 2020

A potential shortcoming of concatenation methods for species tree estimation is their failure to account for incomplete lineage sorting. Coalescent methods address this problem but make various assumptions that, if violated, can result in worse performance than concatenation. Given the challenges of analyzing DNA sequences with both concatenation and coalescent methods, retroelement insertions (RIs) have emerged as powerful phylogenomic markers for species tree estimation. Here, we show that two recently proposed quartet-based methods, SDPquartets and ASTRAL BP, are statistically consistent estimators of the unrooted species tree topology under the coalescent when RIs follow a neutral infinite-sites model of mutation and the expected number of new RIs per generation is constant across the species tree. The accuracy of these (and other) methods for inferring species trees from RIs has yet to be assessed on simulated data sets, where the true species tree topology is known. Therefore, we evaluated eight methods given RIs simulated from four model species trees, all of which have short branches and at least three of which are in the anomaly zone. In our simulation study, ASTRAL BP and SDPquartets always recovered the correct species tree topology when given a sufficiently large number of RIs, as predicted. A distance-based method (ASTRID BP) and Dollo parsimony also performed well in recovering the species tree topology. In contrast, unordered, polymorphism, and Camin-Sokal parsimony typically fail to recover the correct species tree topology in anomaly zone situations with more than four ingroup taxa. Of the methods studied, only ASTRAL BP automatically estimates internal branch lengths (in coalescent units) and support values (i.e. local posterior probabilities). We examined the accuracy of branch length estimation, finding that estimated lengths were accurate for short branches but upwardly biased otherwise. This led us to derive the maximum likelihood (branch length) estimate for when RIs are given as input instead of binary gene trees; this corrected formula produced accurate estimates of branch lengths in our simulation study, provided that a sufficiently large number of RIs were given as input. Lastly, we evaluated the impact of data quantity on species tree estimation by repeating the above experiments with input sizes varying from 100 to 100 000 parsimony-informative RIs. We found that, when given just 1 000 parsimony-informative RIs as input, ASTRAL BP successfully reconstructed major clades (i.e clades separated by branches > 0.3 CUs) with high support and identified rapid radiations (i.e. shorter connected branches), although not their precise branching order. The local posterior probability was effective for controlling false positive branches in these scenarios.
Puerarin blocks aging phenotype in cultured human dermal fibroblasts
Authors: Kamiya Yuki , Odama Mao , Mizuguti Aki , Murakami Shigeru , Ito Takashi
Published: October 2020

Dermal fibroblast aging contributes to aging-associated functional defects in the skin since dermal fibroblasts are important to maintain skin homeostasis by interacting with epidermis and extracellular matrix. Here we identified that puerarin, an isoflavone contained inPueraria lobata(Kudzu), can prevent the aging-phenotype of human dermal fibroblasts. Puerarin treatment increased in proliferating cells and decreased in senescence-associated beta-galactosidase positive cells in the high-passage culture of dermal fibroblasts. Moreover, puerarin reduced smooth muscle actin-positive myofibroblasts and the expression of a reticular fibroblast marker, calponin 1 (CNN1), which were induced in high-passage fibroblasts. Fulvestrant, an estrogen receptor antagonist, blocked puerarin-mediated downregulation of SMA and CNN1. Our results suggest that puerarin may be a useful food factor that alleviates aging-related functional defects in the skin.
Associations of diarised sleep onset time, period and duration with total and central adiposity in a biethnic sample of young children: the Born in Bradford study
Authors: Collings Paul J , Blackwell Jane E , Pal Elizabeth , Ball Helen L , Wright John
Published: October 2020

Objectives

To investigate associations of sleep timing, period and duration with total and abdominal adiposity in a biethnic sample of children aged 18 and 36 months (m)

Design

Cross-sectional observational study

Setting

The Born in Bradford 1000 study, UK

Participants

Children aged approximately 18m (n=209; 40.2% South Asian; 59.8% White) and 36m (n=162; 40.7% South Asian; 59.3% White)

Primary and secondary outcome measures

Parents completed a 3-day sleep diary from which children’s average daily sleep onset time, period and duration were calculated. Weekday to weekend differences in sleep parameters were also derived. As outcomes, indices of total (BMI z-score and sum of 2-skinfolds) and abdominal adiposity (waist circumference) were measured. Adjusted regression was used to quantify associations of sleep parameters with adiposity by age group and ethnicity.

Results

The average daily sleep onset time was markedly later in South Asian (9:26pm ± 68 mins) than White children (7:41pm ± 48 mins). Later sleep onset was associated with lower BMI z-score and sum of 2-skinfolds in White children aged 18m. In contrast, later sleep onset was associated with higher BMI z-score in South Asian children aged 36m. For weekday to weekend differences, longer sleep duration and later sleep onset on weekends than weekdays were both associated with higher total and abdominal adiposity in South Asian children aged 18m. On the contrary, compared to consistent sleep onset times, going to sleep ≥20 minutes later on weekends than weekdays was associated with lower waist circumference in White children aged 18m.

Conclusions

Sleep timing is associated with total and central adiposity in young children but associations differ by age group and ethnicity. Sleep onset times and regular sleep schedules may be important for obesity prevention.
The IHAT-GUT iron supplementation trial in rural Gambia: barriers, facilitators, and benefits
Authors: Stelle Isabelle , McDonagh Lorraine K. , Hossain Mohammad Ilias , Kalea Anastasia Z. , Pereira Dora I.A.
Published: October 2020

Introduction

In most sub-Saharan African countries iron deficiency anaemia remains highly prevalent in children and this has not changed in the last 25 years. Supplementation with iron hydroxide adipate tartrate (IHAT) was being investigated in anaemic children in a phase two clinical-trial (termed IHAT-GUT), conducted at the MRC Unit The Gambia at LSHTM (MRCG). This qualitative study aimed to explore the personal perceptions of the trial staff in relation to conducting a clinical trial in such settings in order to highlight the health system specific needs and strengths in the rural, resource-poor setting of the Upper River Region in The Gambia.

Methods

Individual interviews (n=17) were conducted with local trial staff of the IHAT-GUT trial. Data were analysed using inductive thematic analysis.

Results

Potential barriers and facilitators to conducting this clinical trial were identified at the patient, staff, and trial-management levels. Several challenges, such as the rural location and cultural context, were identified but noted as not being long-term inhibitors. Participants believed the facilitators and benefits outnumbered the barriers, and included the impact on education and healthcare, the ambitious and knowledgeable locally recruited staff and the local partnership.

Conclusion

While facilitators and barriers were identified to conducting this clinical trial in a rural, resource poor setting, the overall impact was perceived as beneficial, and this study is a useful example of community involvement and partnership for further health improvement programs. To effectively implement a nutrition intervention, the local health systems and context must be carefully considered through qualitative research beforehand.
Projected HIV and Bacterial STI Incidence Following COVID-Related Sexual Distancing and Clinical Service Interruption
Authors: Jenness Samuel M. , Le Guillou Adrien , Chandra Christina , Mann Laura M. , Sanchez Travis , Westreich Daniel , Marcus Julia L.
Published: October 2020

Background

The global COVID-19 pandemic has the potential to indirectly impact the transmission dynamics and prevention of HIV and other sexually transmitted infections (STI). Studies have already documented reductions in sexual activity (“sexual distancing”) and interruptions in HIV/STI services, but it is unknown what combined impact these two forces will have on longer-term HIV/STI epidemic trajectories.

Methods

We adapted a network-based model of co-circulating HIV, gonorrhea, and chlamydia for a population of men who have sex with men (MSM) in the Atlanta area. Model scenarios varied the timing, overlap, and relative extent of COVID-related sexual distancing in casual and one-time partnership networks and service interruption within four service categories (HIV screening, HIV PrEP, HIV ART, and STI treatment).

Results

A 50% relative decrease in sexual partnerships and interruption of all clinical services, both lasting 18 months, would generally offset each other for HIV (total 5-year population impact for Atlanta MSM: −227 cases), but have net protective effect for STIs (−23,800 cases). Greater relative reductions and longer durations of service interruption would increase HIV and STI incidence, while greater relative reductions and longer durations of sexual distancing would decrease incidence of both. If distancing lasted only 3 months but service interruption lasted 18 months, the total 5-year population impact would be an additional 890 HIV cases and 57,500 STI cases.

Conclusions

The counterbalancing impact of sexual distancing and clinical service interruption depends on the infection and the extent and durability of these COVID-related changes. If sexual behavior rebounds while service interruption persists, we project an excess of hundreds of HIV cases and thousands of STI cases just among Atlanta MSM over the next 5 years. Immediate action to limit the impact of service interruptions is needed to address the indirect effects of the global COVID pandemic on the HIV/STI epidemic.
The NK Landscape as a Versatile Benchmark for Machine Learning Driven Protein Engineering
Authors: Mater Adam C. , Sandhu Mahakaran , Jackson Colin
Published: October 2020

Machine learning (ML) has the potential to revolutionize protein engineering. However, the field currently lacks standardized and rigorous evaluation benchmarks for sequence-fitness prediction, which makes accurate evaluation of the performance of different architectures difficult. Here we propose a unifying framework for ML-driven sequence-fitness prediction. Using simulated (theNKmodel) and empirical sequence landscapes, we define four key performance metrics: interpolation within the training domain, extrapolation outside the training domain, robustness to sparse training data, and ability to cope with epistasis/ruggedness. We show that architectural differences between algorithms consistently affect performance against these metrics across both experimental and theoretical landscapes. Moreover, landscape ruggedness is revealed to be the greatest determinant of the accuracy of sequence-fitness prediction. We hope that this benchmarking method and the code that accompanies it will enable robust evaluation and comparison of novel architectures in this emerging field and assist in the adoption of ML for protein engineering.
A comparative transcriptional landscape of two castor cultivars obtained by single-molecule sequencing comparative analysis
Authors: Zhou Wei , Zhou Yaxing , Zhu Guoli , Wang Yun , He Zhibiao , Shi Zhensheng
Published: October 2020

Background and Objectives

Castor (Ricinus communisL.) is an important non-edible oilseed crop. Lm type female strains and normal amphiprotic strains are important castor cultivars, and are mainly different in inflorescence structures and leaf shapes. To better understand the mechanisums underling these differences at the molecular level, we performed comparative transcriptional analysis.

Materials and Methods

Full-length transcriptome sequencing and short-read RNA sequencing were employed.

Results

A total of 76,068 and 44,223 non-redundant transcripts were obtained from high-quality transcripts of Lm type female strains and normal amphiprotic strains, respectively. In Lm female strain and normal amphiprotic strains 51,613 and 20,152 alternative splicing events were found, respectively. There were 13,239 transcription factors identified from the full-length transcriptomes. Comparative analysis showed great different gene expression of common and unique transcription factors between the two cultivars. Meanwhile, functional analysis of isoform was conducted. Full-length sequences were used as a reference genome, and short-read RNA sequencing analysis was performed to conduct differential gene analysis. Furthermore, the function of DEGs were performed to annotation analysis.

Conclusions

The results revealed considerable difference and expression diversity between two cultivars, well beyond what was reported in previous studies, likely reflecting the differences in architecture between these two cultivars.

Highlight

Using the full-length transcriptome sequencing technology, we performed comparative analysis of transcription factors of two castor cultivars, analyzed alternative splicing events, and identified their lncRNAs.