bluuebunny/crossref_metadata_2025 huggingface dataset:
Mandibular Subcondylar Fracture: Improved Functional Outcomes in Selected Patients with Open Treatment
Authors: Gibstein Alexander R. , Chen Kevin , Nakfoor Bruce , Gargano Francesco , Bradley James P.
Published: August 2021

Background:

Subcondylar fractures represent 25 to 35 percent of all mandibular fractures, yet the treatment paradigm has remained controversial. Closed treatment relies on the plasticity of the condyle head during recovery, whereas open treatment is challenging and risks facial nerve injury. Perioperative, functional, and patient-reported outcomes were measured to compare methods of open versus closed treatment of subcondylar fractures.

Methods:

Selected displaced subcondylar fracture cases with open (open reduction and internal fixation of subcondylar fracture with maxillomandibular fixation) versus closed (maxillomandibular fixation) treatment were compared (n = 60). Demographics, perioperative data, complications, persistent symptoms, chin deviation, malocclusion, change in mouth opening, functional scores, and FACE-Q patient satisfaction were recorded.

Results:

Open versus closed groups had similar demographics and perioperative data, except the open group had longer operating room time (76.39 minutes versus 56.15 minutes). In long-term follow-up, open-treated patients had fewer symptoms (9 percent versus 67 percent), less chin deviation (0 percent versus 40 percent), a less restricted mouth opening (3mm versus 5mm), and better functional scores (1.92 versus 0.861). Transient facial nerve weakness was seen in 6 percent of open cases.

Conclusion:

For selected subcondylar fracture patients, open treatment with endoscopic assistance, nerve monitoring, and specialized plates provides superior long-term results compared to closed treatment when considering symptoms and functional parameters.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Fifteen-Year Experience with the Ghent Technique of Penile Inversion Vaginoplasty
Authors: Opsomer Dries , Vyncke Tom , Mertens Delphine , Ceulemans Aline , Claes Karel E. Y. , Buncamper Marlon , Monstrey Stan
Published: August 2021

Background:

Demand for male-to-female gender-affirmation surgery is rising. Creation of a vaginal vault and a feminine vulva remains challenging, especially in circumcised patients. The authors present the 15-year results of the technique developed by the senior author (S.M.).

Methods:

A retrospective case review was performed of all penile inversion vaginoplasties carried out by the senior author between 2003 and 2017. Age, hormonal therapy time, body mass index, smoking, diabetes, circumcision, and the need for full-thickness skin grafts to lengthen the vaginal vault were investigated as potential risk factors for postoperative complications.

Results:

A total of 384 penile inversion vaginoplasties were retained, with 85.7 percent of patients requiring a full-thickness skin graft to lengthen the vaginal vault. Rectum perforation occurred in six patients (1.6 percent). Early revisions were necessary in 8.4 percent of patients and late revision surgery was performed in 37.1 percent of cases. There was no independent risk factor for early complications. Diabetes was an independent risk factor for late revision surgery. After vaginoplasty, 97.2 percent of patients reported being able to engage in penetrative intercourse, and 83.4 percent of patients reported having orgasms.

Conclusions:

Vaginoplasty is possible in all trans women, with most patients being able to engage in penetrative intercourse and reach an orgasm. To reach the desired depth of 14 cm, the neovaginal vault is usually lined with full-thickness skin grafts from the scrotum and/or abdomen. Diabetes was the only independent risk factor for revision surgery. Rectal tears are a rare complication and can usually be managed conservatively.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
TRIM22 genotype is not associated with markers of disease progression in children with HIV-1 infection
Authors: Boswell Michael T. , Yindom Louis-Marie , Hameiri-Bowen Dan , McHugh Grace , Dauya Ethel , Bandason Tsitsi , Mujuru Hilda , Esbjörnsson Joakim , Ferrand Rashida A. , Rowland-Jones Sarah
Published: August 2021

Objective:

Untreated perinatal HIV-1 infection is often associated with rapid disease progression in children with HIV (CWH), characterized by high viral loads and early mortality. TRIM22 is a host restriction factor, which directly inhibits HIV-1 transcription, and its genotype variation is associated with disease progression in adults. We tested the hypothesis that TRIM22 genotype is associated with disease progression in CWH.

Design:

ART-naive CWH, aged 6–16 years, were recruited from primary care clinics in Harare, Zimbabwe. We performed a candidate gene association study of TRIM22 genotype and haplotypes with markers of disease progression and indicators of advanced disease.

Methods:

TRIM22 exons three and four were sequenced by Sanger sequencing and single nucleotide polymorphisms were associated with markers of disease progression (CD4+ T-cell count and HIV viral load) and clinical indicators of advanced HIV disease (presence of stunting and chronic diarrhoea). Associations were tested using multivariate linear and logistic regression models.

Results:

A total of 241 children, median age 11.4 years, 50% female, were included. Stunting was present in 16% of participants. Five SNPs were analyzed including rs7935564, rs2291842, rs78484876, rs1063303 and rs61735273. The median CD4+ count was 342 (IQR: 195–533) cells/μl and median HIV-1 viral load 34 199 (IQR: 8211–90 662) IU/ml. TRIM22 genotype and haplotypes were not associated with CD4+ T-cell count, HIV-1 viral load, stunting or chronic diarrhoea.

Conclusion:

TRIM22 genotype was not associated with markers of HIV disease progression markers or advanced disease in CWH.
Longitudinal trajectories of brain volume in combined antiretroviral therapy treated and untreated simian immunodeficiency virus-infected rhesus macaques
Authors: Liu Dan , Liu Jiaojiao , Xu Tingting , Qiao Hongwei , Qi Yu , Gao Yuxun , Ailixire  , Gao Lei , Li Chunlin , Xia Mingrui , Li Hongjun
Published: August 2021

Objectives:

We used simian immunodeficiency virus (SIV)-infected nonhuman primates to investigate longitudinal changes of brain volume caused by SIV and the effect of combined antiretroviral therapy (cART). In addition, the relation between viral load, immune status, and brain volume were explored.

Design:

A longitudinal study of two healthy controls, five SIVmac239-infected macaques received cART (SIV+cART+) at 40 days postinnoculation, and five SIVmac239-infected macaques received no therapy (SIV+cART−).

Methods:

Structural T1-weighted MRI, blood and cerebrospinal fluid testing were acquired at multiple time points for 48 weeks postinfection (wpi). Brain volume was estimated using region of interest (ROI)-based analysis. Volume differences were compared among three groups. Linear regression models tested the associations between brain volumes and biomarkers (viral load, CD4+ T-cell count, CD4+/CD8+ ratio).

Results:

In our model, brain volume alteration in SIV-infected macaques can be detected at 12 wpi in several brain regions. As the infection progresses, the SIV+cART− macaques displayed generalized gray matter atrophy at the endpoint. Though initiate cART right after acute infection, SIV+cART+ macaques still displayed brain atrophy but showed signs of reversibility. Plasma viral load is mainly associated with subcortical nucleus volume whereas CD4+ T-cell count and CD4+/CD8+ ratio in plasma were associated with widespread cortical volume.

Conclusion:

The SIVmac239-infected Chinese origin macaque is a valid model for neuroHIV. Brain atrophy caused by SIV infection can be relieved, even reversed, by cART. Our model also provides new insights into understanding the pathogenesis of brain injury in people with HIV (PWH).
Coronavirus disease 2019 hospitalization outcomes in persons with and without HIV in Spain
Authors: Olalla-Sierra Julián , Martín-Escalante María Dolores , García-Alegría Javier , Rubio-Rivas Manuel , de Miguel-Campo Borja , Zurita-Etayo María , Arbones-Fernández Laia , Alcalá-Pedrajas José N. , Roldán-Silvestre Alicia , Cortés-Rodríguez Begoña , Casas-Rojo José Manuel , Núñez-Cortés Jesús Millán
Published: August 2021

Objective:

To compare coronavirus disease 2019 (COVID-19) hospitalization outcomes between persons with and without HIV.

Design:

Retrospective observational cohort study in 150 hospitals in Spain.

Methods:

Patients admitted from 1 March to 8 October 2020 with COVID-19 diagnosis confirmed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 positive) PCR test in respiratory tract samples. The primary data source was the COVID-19 Sociedad Española de Medicina Interna's registry (SEMI-COVID-19). Demographics, comorbidities, vital signs, laboratory parameters, and clinical severity as well as treatments received during admission, treatment duration, ICU admission, use of invasive mechanical ventilation, and death were recorded. Factors associated with mortality and the composite of ICU admission, invasive mechanical ventilation, and death, were analyzed.

Results:

Data from 16 563 admissions were collected, 98 (0.59%) of which were of persons with HIV infection. These patients were younger, the percentage of male patients was higher, and their Charlson comorbidity index was also higher. Rates of mortality and composite outcome of ICU admission, invasive mechanical ventilation or death were lower among patients with HIV infection. In the logistic regression analysis, HIV infection was associated with an adjusted odds ratio of 0.53 [95% confidence interval (CI) 0.29-0.96] for the composite outcome.

Conclusion:

HIV infection was associated with a lower probability of ICU admission, invasive mechanical ventilation, or death.
Cost-effectiveness of testing for latent tuberculosis infection in people with HIV
Authors: Auguste Peter E. , Mistry Hema , McCarthy Noel D. , Sutcliffe Paul A. , Clarke Aileen E.
Published: August 2021

Objective:

The aim of this study was to estimate the cost-effectiveness of screening strategies for predicting LTBI that progresses to active tuberculosis (TB) in people with HIV.

Design:

We developed a decision-analytical model that constituted a decision tree covering diagnosis of LTBI and a Markov model covering progression to active TB. The model represents the lifetime experience following testing for LTBI, and discounting costs, and benefits at 3.5% per annum in line with UK standards. We undertook probabilistic and one-way sensitivity analyses.

Setting:

UK National Health Service and Personal Social Service perspective in a primary care setting.

Participants:

Hypothetical cohort of adults recently diagnosed with HIV.

Interventions:

Interferon-gamma release assays and tuberculin skin test.

Main outcome measure:

Cost per quality-adjusted life year (QALY).

Results:

All strategies except T-SPOT.TB were cost-effective at identifying LTBI, with the QFT-GIT-negative followed by TST5mm strategy being the most costly and effective. Results indicated that there was little preference between strategies at a willingness-to-pay threshold of £20 000. At thresholds above £40 000 per QALY, there was a clear preference for the QFT-GIT-negative followed by TST5mm, with a probability of 0.41 of being cost-effective. Results showed that specificity for QFT-GIT and TST5mm were the main drivers of the economic model.

Conclusion:

Screening for LTBI has important public health and clinical benefits. Most of the strategies are cost-effective. These results should be interpreted with caution because of the paucity of studies included in the meta-analysis of test accuracy studies. Additional high-quality primary studies are needed to have a definitive answer about, which strategy is the most effective.
Effects of Noninvasive Brain Stimulation (NIBS) on Cognitive Impairment in Mild Cognitive Impairment and Alzheimer Disease
Authors: Wang Tao , Guo Zhiwei , Du Yonghui , Xiong Ming , Yang Zhengcong , Ren Long , He Lin , Jiang Yi , McClure Morgan A. , Mu Qiwen
Published: August 2021

Objective:

The purpose of this meta-analysis was to evaluate the beneficial effects and optimal stimulation protocol of noninvasive brain stimulation (NIBS) including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on patients with mild cognitive impairment and Alzheimer disease.

Materials and Methods:

PubMed, Web of Science, Embase, and the Cochrane Library were searched until March 2020. The cognitive outcomes were extracted and the standardized mean difference with 95% confidence interval was calculated.

Results:

Twenty-eight studies were included. The result of NIBS showed significant effect on global cognition (P<0.05). Low-frequency rTMS over right dorsolateral prefrontal cortex (DLPFC), high-frequency rTMS (HF-rTMS) over left DLPFC, and the tDCS over left DLPFC and temporal lobe can significantly improve the memory function (P<0.05). HF-rTMS over left, right, or bilateral DLPFC can significantly improve the language function (P<0.05). Both HF-rTMS and tDCS over left DLPFC can obviously improve the executive function (P<0.05). Multiple sessions of rTMS with 80% to 100% intensity and anode tDCS with 2 mA current density are more suitable for all these functions.

Conclusions:

NIBS has a beneficial effect on cognitive performance in both mild cognitive impairment and Alzheimer disease patients. Distinct optimal stimulation parameters were observed for different cognitive functions.
Feather iridescence ofCoeligenahummingbird species varies due to differently organized barbs and barbules
Authors: Giraldo Marco , Sosa Juliana , Stavenga Doekele
Published: August 2021

Hummingbirds are perhaps the most exquisite bird species because of their prominent iridescence, created by stacks of melanosomes in the feather barbules. The feather colours crucially depend on the nanoscopic dimensions of the melanosome, and the displayed iridescence can distinctly vary, dependent on the spatial organization of the barbs and barbules. We have taken the genusCoeligenaas a model group, with species having feathers that strongly vary in their spatial reflection properties. We studied the feather morphology and the optical characteristics. We found that the coloration ofCoeligenahummingbirds depends on both the Venetian-blind-like arrangement of the barbules and the V-shaped, angular arrangement of the barbules at opposite sides of the barbs. Both the nanoscopic and microscopic organization of the hummingbird feather components determine the bird's macroscopic appearance.
Michael Mark Woolfson. 9 January 1927—23 December 2019
Authors: Wilson Keith S. , Dodson Eleanor J.
Published: August 2021

Michael Woolfson contributed enormously to the theory and practice of X-ray crystallography for almost 60 years. He extended the theory of ‘direct methods’, which provided a general solution of the crystallographic phase problem from the measured diffraction data alone, and provided tools to exploit this theory. Software developed in his laboratory, such as the computer package MULTAN, was responsible for about half of the structures determined around the world in the 1970s and 1980s. His parallel work on the origin of the Solar System renewed interest in the Capture theory, and he contributed numerous stimulating ideas to the general study of the origin and dynamical evolution of the Solar System.

Michael was a great educator and mentor for both undergraduates and young researchers, and many of these went on to make significant scientific contributions.
Investigating site-selection mechanisms of retroviral integration in supercoiled DNA braids
Authors: Forte G. , Michieletto D. , Marenduzzo D. , Orlandini E.
Published: August 2021

We theoretically study the integration of short viral DNA in a DNA braid made up by two entwined double-stranded DNA molecules. We show that the statistics of single integration events substantially differ in the straight and buckled, or plectonemic, phase of the braid and are more likely in the latter. We further discover that integration is most likely close to plectoneme tips, where the larger bending energy helps overcome the associated energy barrier and that successive integration events are spatio-temporally correlated, suggesting a potential mechanistic explanation of clustered integration sites in host genomes. The braid geometry we consider provides a novel experimental set-up to quantify integration in a supercoiled substrate
in vitro
, and to better understand the role of double-stranded DNA topology during this process.
Go with the FLOW: visualizing spatiotemporal dynamics in optical widefield calcium imaging
Authors: Linden Nathaniel J. , Tabuena Dennis R. , Steinmetz Nicholas A. , Moody William J. , Brunton Steven L. , Brunton Bingni W.
Published: August 2021

Widefield calcium imaging has recently emerged as a powerful experimental technique to record coordinated large-scale brain activity. These measurements present a unique opportunity to characterize spatiotemporally coherent structures that underlie neural activity across many regions of the brain. In this work, we leverage analytic techniques from fluid dynamics to develop a visualization framework that highlights features of flow across the cortex, mapping wavefronts that may be correlated with behavioural events. First, we transform the time series of widefield calcium images into time-varying vector fields using optic flow. Next, we extract concise diagrams summarizing the dynamics, which we refer to as
FLOW (flow lines in optical widefield imaging) portraits
. These FLOW portraits provide an intuitive map of dynamic calcium activity, including regions of initiation and termination, as well as the direction and extent of activity spread. To extract these structures, we use the finite-time Lyapunov exponent technique developed to analyse time-varying manifolds in unsteady fluids. Importantly, our approach captures coherent structures that are poorly represented by traditional modal decomposition techniques. We demonstrate the application of FLOW portraits on three simple synthetic datasets and two widefield calcium imaging datasets, including cortical waves in the developing mouse and spontaneous cortical activity in an adult mouse.
Biomechanics of pollen pellet removal by the honey bee
Authors: Matherne Marguerite , Dowell-Esquivel Caroline , Howington Oliver , Lenaghan Olivia , Steinbach Gabi , Yunker Peter J. , Hu David L.
Published: August 2021

Honey bees (
Apis mellifera
) carry pollen back to their hive by mixing it with nectar and forming it into a pellet. The pellet must be firmly attached to their legs during flight, but also easily removable when deposited in the hive. How does the honey bee achieve these contrary aims? In this experimental study, we film honey bees removing pollen pellets and find they peel them off at speeds 2–10 times slower than their typical grooming speeds. Using a self-built pollen scraper, we find that slow removal speeds reduce the force and work required to remove the pellet under shear stress. Creep tests on individual pollen pellets revealed that pollen pellets are viscoelastic materials characterized by a Maxwell model with long relaxation times. The relaxation time enables the pellet to remain a solid during both transport and removal. We hope that this work inspires further research into viscoelastic materials in nature.
Lemurs before
Lemur
: depictions of captive lemurs prior to Linnaeus
Authors: Rogers Ethan S. , Canington Stephanie L.
Published: August 2021

In 1758, Carl von Linné (Linnaeus) published the tenth edition of
Systema Naturae
, in which he formally described the most unique group of primates: lemurs. The story of the early human-mediated dispersal of lemurs from Madagascar, prior to their formalized descriptions, is a complex one. It touches on the birth of the standardization of modern zoology, empire building, and the growth of international trade and commerce, with many Fellows of the Royal Society contributing to the earliest observations of these animals in captive settings. Through the use of historical documents and artwork, we present this history in four parts: ‘Part I: The lemurs that became ‘lemurs’ (1746–1756)’, discusses the specific lemurs that Linnaeus used to describe the genera in the tenth and twelfth editions of
Systema Naturae
; ‘Part II: Establishing the trade routes (1500–1662)’, examines seventeenth century captive lemurs and the role of the trade routes of the East India Companies in the transportation of lemurs from Madagascar; ‘Part III: Tracing the Bugée (1693–1732)’, reviews the lemurs identified by late seventeenth and early eighteenth century pre-Linnaean naturalists; and ‘Part IV: The chained lemur (1732–1761)’, concludes with eighteenth century lemurs in menageries and as luxury goods.
Primary cilia and lipid raft dynamics
Authors: Nishimura Yuhei , Yamakawa Daishi , Uchida Katsunori , Shiromizu Takashi , Watanabe Masatoshi , Inagaki Masaki
Published: August 2021

Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of functions. Lipid rafts, plasma membrane microdomains enriched in cholesterol, sphingolipids and specific proteins, are also signalling hubs involved in a myriad of physiological functions. Although impairment of primary cilia and lipid rafts is associated with various diseases, the relationship between primary cilia and lipid rafts is poorly understood. Here, we review a newly discovered interaction between primary cilia and lipid raft dynamics that occurs during Akt signalling in adipogenesis. We also discuss the relationship between primary cilia and lipid raft-mediated Akt signalling in cancer biology. This review provides a novel perspective on primary cilia in the regulation of lipid raft dynamics.
The effect of probiotic supplementation on the gut microbiota of preterm infants
Authors: Plummer Erica L. , Danielewski Jennifer A. , Garland Suzanne M. , Su Jenny , Jacobs Susan E. , Murray Gerald L.
Published: August 2021

Introduction. Probiotic supplementation of preterm infants may prevent serious morbidities associated with prematurity.

Aim. To investigate the impact of probiotic supplementation on the gut microbiota and determine factors associated with detection of probiotic species in the infant gut.

Hypothesis/Gap Statement. Probiotic supplementation increases the long-term colonization of probiotic species in the gut of preterm infants.

Methodology. Longitudinal stool samples were collected from a cohort of very preterm infants participating in a blinded randomized controlled trial investigating the impact of probiotic supplementation (containing

Bifidobacterium longum

subsp.

infantis

BB-02,

Bifidobacterium animalis

subsp.

lactis

BB-12 and

Streptococcus thermophilus

TH-4) for prevention of late-onset sepsis. The presence of

B. longum

subsp.

infantis

,

B. animalis

subsp.

lactis

and

S. thermophilus

was determined for up to 23 months after supplementation ended using real-time PCR. Logistic regression was used to investigate the impact of probiotic supplementation on the presence of each species.

Results. Detection of

B. longum

subsp.

infantis

[odds ratio (OR): 53.1; 95 % confidence interval (CI): 35.6–79.1; P < 0.001], B. animalis subsp.

lactis

(OR: 89.1; 95 % CI: 59.0–134.5; P < 0.001) and

S. thermophilus

(OR: 5.66; 95 % CI: 4.35–7.37; P < 0.001) was increased during the supplementation period in infants receiving probiotic supplementation. Post-supplementation, probiotic-supplemented infants had increased detection of

B. longum

subsp.

infantis

(OR: 2.53; 95 % CI: 1.64–3.90; P < 0.001) and

B. animalis

subsp.

lactis

(OR: 1.59; 95 % CI: 1.05–2.41; P=0.030). Commencing probiotic supplementation before 5 days from birth was associated with increased detection of the probiotic species over the study period (

B. longum

subsp. infantis, OR: 1.20;

B. animalis

subsp. lactis, OR: 1.28; S. thermophilus, OR: 1.45).

Conclusion. Probiotic supplementation with

B. longum

subsp.

infantis

BB-02,

B. animalis

subsp.

lactis

BB-12 and

S. thermophilus

TH-4 enhances the presence of probiotic species in the gut microbiota of very preterm infants during and after supplementation. Commencing probiotic supplementation shortly after birth may be important for improving the long-term colonization of probiotic species.
Genomic epidemiology of the opportunistic pathogen Staphylococcus coagulans from companion dogs
Authors: Paterson Gavin K.
Published: August 2021

Introduction.

Staphylococcus coagulans

(formerly

Staphylococcus schleiferi

subsp.

coagulans

) is a common commensal and opportunistic pathogen of companion dogs. It carries a range of antimicrobial resistance genes and is an occasional zoonotic pathogen.

Hypothesis/Gap Statement. Despite the potential insight offered by genome sequencing into the biology of

S. coagulans

, few genomes are currently available for study.

Aim. To sequence and analyse

S. coagulans

genomes to improve understanding of this organism’s molecular epidemiology, antimicrobial resistance and bacterium–host interactions.

Methodology. Twenty-five genomes of clinical isolates collected at a veterinary referral hospital in Scotland, UK, were sequenced with Illumina technology. These genomes were analysed by a series of bioinformatics tools along with 16 previously sequenced genomes.

Results. Phylogenetic comparison of the 41 genomes shows that the current

S. coagulans

phylogeny is dominated by clades of closely related isolates, at least one of which has spread internationally. Ten of the 11 methicillin-resistant

S. coagulans

genomes in this collection of 41 encoded the mecA promoter and gene mutations that are predicted to render the isolates susceptible to penicillins in the presence of clavulanic acid, a feature only described to date in methicillin-resistant

Staphylococcus aureus

. Seven such isolates were from the current study and, in line with the genome-based prediction, all were susceptible to amoxicillin/clavulanic acid in vitro. S. coagulans shared very few highly conserved virulence-associated genes with

Staphylococcus pseudintermedius

, another common commensal and opportunistic canine pathogen.

Conclusion. The availability of a further 25 genome sequences from clinical

S. coagulans

isolates will aid in better understanding the epidemiology, bacterial–host interactions and antimicrobial resistance of this opportunistic pathogen.
Associations between gestational weight gain adequacy and neonatal outcomes in Tanzania
Authors: Perumal Nandita , Wang Dongqing , Darling Anne Marie , Wang Molin , Liu Enju , Urassa Willy , Pembe Andrea , Fawzi Wafaie W.
Published: August 2021

Introduction

Gestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited.

Methods

We used data from a prenatal micronutrient supplementation trial among a cohort of HIV-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and newborn outcomes. GWG adequacy was defined as the ratio of the total observed weight gain over the recommended weight gain based on the Institute of Medicine body mass index (BMI)-specific guidelines. Newborn outcomes assessed were: stillbirth, perinatal death, preterm birth, low birthweight, macrosomia, small-for-gestational age (SGA), large-for-gestational age (LGA), stunting at birth, and microcephaly. Modified Poisson regressions with robust standard error were used to estimate the relative risk of newborn outcomes as a function of GWG adequacy.

Results

Of 7561 women included in this study, 51% had severely inadequate (<70%) or inadequate GWG (70-90%), 31% had adequate GWG (90-125%), and 18% had excessive GWG (≥125%). Compared to adequate GWG, severely inadequate GWG was associated with a higher risk of low birthweight, SGA, stunting at birth, and microcephaly; whereas excessive GWG was associated with a higher risk of LGA and macrosomia.

Conclusion

Interventions to support optimal gestational weight gain are needed and are likely to improve newborn outcomes.
Evidence of a causal relationship between genetic tendency to gain muscle mass and uterine leiomyomata
Authors: Sliz Eeva , Tyrmi Jaakko , Rahmioglu Nilufer , Zondervan Krina T. , Becker Christian M. , FinnGen  , Uimari Outi , Kettunen Johannes
Published: August 2021

Uterine leiomyomata (UL) are the most common benign tumours of the female genital tract with an estimated lifetime incidence of up to 70%1. To date, 7 genome-wide association studies (GWASs) have identified 35 loci predisposing to UL. To improve the understanding of the underlying genetic pathways, we conducted the largest genetic association study of UL to date in 426,558 European women from FinnGen and a previously published UL meta-GWAS2. We identified 36 novel and replicated 31 previously reported loci. Annotations of the potential candidate genes suggest involvement of smooth muscle cell (SMC) differentiation and/or proliferation-regulating genes in modulating UL risk. Our results further advocate that genetic predisposition to increased fat-free mass may be causally related to UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings provide novel insights into genetic risk factors related to UL, which may aid in developing novel treatment strategies.
Monocyte and neutrophil levels are potentially linked to progression to IPF for patients with indeterminate UIP CT pattern
Authors: Achaiah A. , Rathnapala A. , Pereira A. , Bothwell H. , Dwivedi K. , Barker R. , Benamore R , Hoyles R. , Iotchkova V , Ho L.P.
Published: August 2021

Rationale

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The ‘indeterminate for UIP’ (iUIP) CT pattern, defined in the 2018 IPF guidelines, could be a precursor to IPF but there is limited data on how patients with iUIP progress over time.

Objective

To evaluate the radiological progression of iUIP and explore factors linked to progression to IPF.

Methods

We performed a retrospective analysis of a lung fibrosis clinic cohort (n=230) seen between 2013-2017. Cases with iUIP were identified; first ever CTs for each patient found and categorised as ‘non-progressor’ or ‘progressors’ (the latter defined as increase in extent of disease or to ‘definite’ or ‘probable’ UIP CT pattern) during their follow up. Lung function trends, haematological data and patient demographics were examined to explore disease evolution and potential contribution to progression.

Results

48 cases with iUIP CT pattern were identified. Of these, 32 had follow up CT scans, of which 23 demonstrated progression. 17 patients in this cohort were diagnosed with IPF over a mean (S.D.) period of 3.9 (±1.9) years. Monocyte [HR 23, CI 1.6-340, p=0.03] and neutrophil levels [HR 1.8, CI 1.3-2.3, p<0.001] obtained around the time of initial CT, were associated with progression to IPF using Cox proportional hazard modelling.

Conclusion

53% of our evaluable iUIP patients progressed to IPF over a mean of four years. Monocyte and neutrophil levels at initial CT were significantly associated with progression in disease. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.

Key message

What is the key question?

How does the ‘indeterminate for UIP’ (iUIP) interstitial CT pattern evolve over time and what factors are associated with progression to definite and probable UIP pattern.

What is the bottom line?

In this retrospective single centre analysis, 53% of evaluable cases with iUIP on initial CT scan progressed to probable or definite UIP CT pattern over an average of 4 years. Monocyte and neutrophil levels performed around the time of initial CT were significantly associated with progression to definite and probable UIP pattern.

Why read on?

We discuss the implications of these findings, its strengths and limitations.
Effect of short-term heating on bioefficacy of deltamethrin-coated long-lasting insecticidal nets
Authors: Bubun Nakei , Freeman Timothy W. , Laman Moses , Karl Stephan
Published: August 2021

We recently reported that long-lasting insecticidal nets (LLINs) distributed in Papua New Guinea (PNG) between 2013 and 2019, exhibited severely diminished efficacy to knock down and kill susceptible Anopheles mosquitoes. This coincided with a rise in malaria observed in PNG since 2015. Here we show that LLIN bioefficacy is increased by heating LLINs prior to WHO cone bioassays.

Unused LLINs with low bioefficacy, delivered to PNG in 2019, were heated to 120°C for 5 minutes. Cone bioassays were performed before and at 1 h, 7 days and 30 days after heating. This led to a significant increase in 24 h mortality (17% to 61%) and 60 min knock down (31% to 72%). The effect was sustained over 30 days.

Bioassays are crucial in quality assurance of LLIN products. Our findings indicate that bioassay results can easily be manipulated. This may have implications for quality assurance procedures used to assess LLINs.
Longitudinal Associations between Hair Cortisol, PTSD Symptoms, and Sleep Disturbances in a Sample of Firefighters with Duty-related Trauma Exposure
Authors: Sopp M. R. , Michael T. , Lass-Hennemann J. , Haim-Nachum S. , Lommen M. J. J.
Published: August 2021

Several studies have found evidence of altered cortisol levels in patients with posttraumatic stress disorder (PTSD). Based on these findings, it is assumed that these patients may show signs of cortisol dysregulation after trauma. Posttrauma cortisol levels are thus considered a potential biomarker of PTSD. However, longitudinal studies using indicators of long-term cortisol secretion (such as hair cortisol concentrations; HCC) are scarce. The current study investigated prospective associations between HCC and PTSD symptoms in a sample of Dutch firefighters taking into account varying levels of work-related trauma severity. In addition, we assessed posttraumatic sleep disturbances as a secondary outcome measure to investigate whether effects generalize to this frequent comorbidity of PTSD. Three hundred seventy-one Dutch firefighters with a mean of 14.01 years of work experience were included in the analyses. Baseline assessment included the collection of hair samples and the measurement of work-related trauma severity, PTSD symptoms, and sleep disturbances. PTSD symptoms and sleep disturbance were re-assessed after six and twelve months. Multilevel analyses indicate a significant positive correlation between HCC and baseline PTSD symptoms in those with average or above-average work-related trauma severity. A similar pattern was evident for posttraumatic sleep disturbances at baseline. Moreover, higher HCC predicted more posttraumatic sleep disturbances after 6 months in participants with above-average work-related trauma severity. No other associations emerged for PTSD symptoms or posttraumatic sleep disturbances at six or twelve months. As such, our study supports the existence of a cross-sectional association between HCC and trauma symptoms, which may vary for different levels of subjective trauma severity. The longitudinal stability of this association should be reinvestigated by future research.
Serum miRNA-based signature indicates radiation exposure and dose in humans: a multicenter diagnostic biomarker study
Authors: Nowicka Zuzanna , Tomasik Bartłomiej , Kozono David , Stawiski Konrad , Johnson Thomas , Haas-Kogan Daphne , Ussowicz Marek , Chowdhury Dipanjan , Fendler Wojciech
Published: August 2021

Mouse and non-human primate models showed that serum miRNAs may be used to predict the biological impact of radiation doses. We hypothesized that these results can be translated to humans treated with total body irradiation (TBI), and that miRNAs may be used as clinically feasible biodosimeters. To test this hypothesis, serial serum samples were obtained from 25 patients who underwent allogeneic stem-cell transplantation and profiled for miRNA expression using next-generation sequencing. Circulating exosomes were extracted, their miRNA content sequenced and cross-referenced with the total miRNA fraction. Finally, miRNAs with diagnostic potential were quantified with qPCR and an artificial neural network model was created and validated on an independent group of 12 patients with samples drawn under the same protocol. Differential expression results were largely consistent with previous studies and allowed us to build an 8-miRNA-based model that showed AUC of 0.97 (95%CI 0.89-1.00) and validate it using qPCR in an independent validation set where it showed accuracy >91% for detecting exposure and 87.5% for differentiating between lethal and non-lethal doses. MiRNAs used in the model were miR-150-5p, miR-126-5p, miR-375, miR-215-5p, miR-144-5p, miR-122-5p, miR-320d and miR-10b-5p. Additionally, miRNAs with detectable expression in this and two prior animal sets almost perfectly separated the irradiated from non-irradiated samples in mice, macaques and humans, validating the miRNAs as radiation-responsive through evolutionarily conserved transcriptional regulation mechanisms. We conclude that serum miRNAs reflect radiation exposure and dose for humans undergoing TBI and may be used as functional biodosimeters for precise identification of people exposed to clinically significant radiation doses.
Real-time Continuous Measurement of Lactate through a Minimally-invasive Microneedle Biosensor: a Phase I Clinical Study
Authors: Ming DK , Jangam S , Gowers SAN , Wilson R , Freeman DME , Boutelle MG , Cass AEG , O’Hare D , Holmes AH
Published: August 2021

Introduction

Determination of blood lactate levels supports decision-making in a range of medical conditions. Invasive blood-sampling and laboratory access are often required, and measurements provide a static profile at each instance. We conducted a Phase I clinical study validating performance of a microneedle patch for minimally-invasive, continuous lactate measurement in healthy volunteers.

Methods

Five healthy adult participants wore a solid microneedle biosensor on their forearms and undertook aerobic exercise for 30 minutes. The microneedle biosensor quantifies lactate concentrations in interstitial fluid (ISF) within the dermis continuously and in real-time. Outputs were captured as sensor current and compared with lactate concentrations from venous blood and microdialysis.

Results

The biosensor was well-tolerated. Participants generated a median peak venous lactate of 9.25 mmol/L (Interquartile range, 6.73 to 10.71). Microdialysate concentrations of lactate closely correlated with blood. Microneedle biosensor current followed venous lactate concentrations and dynamics, with good agreement seen in all participants. There was an estimated lag-time of 5 minutes (IQR -4 to 11 minutes) between microneedle and blood lactate measurements.

Conclusion

This study provides first-in-human data on use of a minimally-invasive microneedle biosensor for continuous lactate measurement, providing dynamic monitoring. The platform offers distinct advantages to frequent blood sampling in a wide range of clinical settings, especially where access to laboratory services is limited or blood sampling is infeasible.
Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy
Authors: Gadani Sachin P. , Reyes-Mantilla Maria , Jank Larissa , Harris Samantha , Douglas Morgan , Smith Matthew D. , Calabresi Peter A. , Mowry Ellen M. , Fitzgerald Kathryn C. , Bhargava Pavan
Published: August 2021

Background

Sphingosine-1-phosphate receptor (S1P) modulators and antiCD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) for multiple sclerosis (MS) also impact T cell immune response to vaccination is unknown.

Methods

In 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-γ) (Mabtech,Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1µg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each). Plates were read on an AID iSpot Spectrum to determine number of spot forming cells (SFC)/106PBMCs. We tested for differences in immune responses across DMTs using linear models.

Findings

Humoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs. In a subset with immune cell phenotyping (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies. AntiCD20 therapies were associated with an increase in IFN-γ SFC counts relative to those on no DMT or other DMTs (for antiCD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for antiCD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001).

Interpretation

We identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination. Follow up studies are needed to determine if this translates to protection against COVID-19 infection.
Loss of ACKR4 in tumor cells dysregulates dendritic cell migration to tumor-draining lymph nodes and T-cell priming
Authors: Wangmo Dechen , Premsrirut Prem K. , Yuan Ce , Morris William S. , Zhao Xianda , Subramanian Subbaya
Published: August 2021

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but failed in the mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is known for regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and immunoregulation are unclear. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockades. Finally, we identified that microRNA-552 negatively regulates ACKR4 expression in human CRC. Taken together, our work identifies a critical mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC tumors.

LAY SUMMARY

Our study demonstrated that Atypical Chemokine Receptor 4 (ACKR4) is downregulated in human colorectal cancer (CRC) tissues compared with normal colon tissues. Loss of ACKR4 in human CRC tissues is associated with a weak anti-tumor immune response. Knockdown of ACKR4 in tumor cells impairs the dendritic cell migration from the tumor tissue to the tumor-draining lymph nodes (TdLNs), causing inadequate tumor-specific T-cell expanding and insensitivity to immune checkpoint blockades. However, loss of ACKR4 in tumor stromal cells does not significantly affect anti-tumor immunity. In human CRC tumors, high expression of microRNA-552 is a mechanism leading to ACKR4 downregulation. Our study revealed a novel mechanism that leads to the poor immune response in a subset of CRC tumors and will contribute to the framework for identifying new therapies against this deadly tumor.
Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections
Authors: Gazit Sivan , Shlezinger Roei , Perez Galit , Lotan Roni , Peretz Asaf , Ben-Tov Amir , Cohen Dani , Muhsen Khitam , Chodick Gabriel , Patalon Tal
Published: August 2021

Background

Reports of waning vaccine-induced immunity against COVID-19 have begun to surface. With that, the comparable long-term protection conferred by previous infection with SARS-CoV-2 remains unclear.

Methods

We conducted a retrospective observational study comparing three groups: (1)SARS-CoV-2-naïve individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been vaccinated, and (3)previously infectedandsingle dose vaccinated individuals. Three multivariate logistic regression models were applied. In all models we evaluated four outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related hospitalization and death. The follow-up period of June 1 to August 14, 2021, when the Delta variant was dominant in Israel.

Results

SARS-CoV-2-naïve vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naïve vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naïve vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected.

Conclusions

This study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.