bluuebunny/crossref_metadata_2025 huggingface dataset:
Rituximab plus methotrexate combination as a salvage therapy in persistently active granulomatosis with polyangiitis
Authors: Sorin Boris , Samson Maxime , Durel Cécile-Audrey , Diot Elisabeth , Guichard Isabelle , Grados Aurélie , Limal Nicolas , Régent Alexis , Cohen Pascal , Dion Jérémie , Legendre Paul  , Le Guern Véronique , Mouthon Luc , Guillevin Loïc , Terrier Benjamin ,   the French Vasculitis Study Group (FVSG)
Published: October 2021

Objective

The aim of this study was to describe the efficacy and safety of rituximab and MTX (RTX/MTX) combination therapy in ANCA-associated vasculitides (AAV).

Methods

A retrospective French nationwide study was conducted in patients with AAV who received RTX/MTX combination therapy for persistently active disease.

Results

Seventeen patients were included. All patients had granulomatosis with polyangiitis (GPA), with positive ANCA in 76% of them, mainly with PR3-ANCA specificity. Sixteen patients (94%) had priorly failed to achieve remission with RTX and 11 (65%) with CYC. Patients had experienced a median of 3 (2–4) flares. Manifestations requiring RTX/MTX combination therapy were subglottic or bronchial stenosis in 6 patients (35%), orbital mass in 6 (35%), disabling ENT involvement in 2 (12%), and epiduritis and pachymeningitis in 1 case (6%) each. The median follow-up duration for the RTX/MTX combination therapy was 11 months (11–26 months). At 6 months, global response had been achieved in 15 patients (88%), including partial response in 11 (65%) and complete response in 4 (24%). At last evaluation, global response had been achieved in 16 patients (94%). Seven patients (41%) experienced severe adverse events (grade 3 or 4), including infections in 4 (24%) and hepatitis in 2 (12%). Combination therapy was withdrawn in 4 patients (24%), but never for safety concerns. In contrast, the MTX dose was decreased in 2 patients (12%) because of adverse events. One patient died of an unknown cause.

Conclusion

RTX/MTX combination therapy could be an effective salvage therapy to treat persistently active GPA with granulomatous manifestations, with an acceptable safety profile.
Telemedicine in rheumatology: a mixed methods study exploring acceptability, preferences and experiences among patients and clinicians
Authors: Sloan Melanie , Lever Elliott , Harwood Rupert , Gordon Caroline , Wincup Chris , Blane Moira , Brimicombe James , Lanyon Peter , Howard Paul , Sutton Stephen , D’Cruz David , Naughton Felix
Published: October 2021

Objectives

The Covid-19 pandemic necessitated a rapid global transition towards telemedicine; yet much remains unknown about telemedicine’s acceptability and safety in rheumatology. To help address this gap and inform practice, this study investigated rheumatology patient and clinician experiences and views of telemedicine.

Methods

Sequential mixed methodology combined analysis of surveys and in-depth interviews. Between and within-group differences in views of telemedicine were examined for patients and clinicians using t-tests.

Results

Surveys (patients n = 1340, clinicians n = 111) and interviews (patients n = 31, clinicians n = 29) were completed between April 2021 and July 2021. The majority of patients were from the UK (96%) and had inflammatory arthritis (32%) or lupus (32%). Patients and clinicians rated telemedicine as worse than face-to-face consultations in almost all categories, although >60% found it more convenient. Building trusting medical relationships and assessment accuracy were great concerns (93% of clinicians and 86% of patients rated telemedicine as worse than face-to-face for assessment accuracy). Telemedicine was perceived to have increased misdiagnoses, inequalities and barriers to accessing care. Participants reported highly disparate telemedicine delivery and responsiveness from primary and secondary care. Although rheumatology clinicians highlighted the importance of a quick response to flaring patients, only 55% of patients were confident that their rheumatology department would respond within 48 hours.

Conclusion

Findings indicate a preference for face-to-face consultations. Some negative experiences may be due to the pandemic rather than telemedicine specifically, although the risk of greater diagnostic inaccuracies using telemedicine is unlikely to be fully resolved. Training, choice, careful patient selection, and further consultation with clinicians and patients is required to increase telemedicine’s acceptability and safety.

Trial registration

This telemedicine study is part of a pre-registered longitudinal multi-stage trial, the LISTEN study (ISRCTN-14966097), with later Covid-related additions registered in March 2021, including a pre-registered statistical analysis plan.
Lung ultrasound B-lines in systemic sclerosis: cut-off values and methodological indications for interstitial lung disease screening
Authors: Gargani Luna , Romei Chiara , Bruni Cosimo , Lepri Gemma , El-Aoufy Khadija , Orlandi Martina , D’Errico Luigia , Bandini Giulia , D’Angelo Gennaro , Guiducci Serena , Dagna Lorenzo , Falaschi Fabio , Matucci-Cerinic Marco , Moggi-Pignone Alberto
Published: October 2021

Objectives

Lung ultrasound (LUS), through assessment of B-lines and pleural line alterations, is able to evaluate interstitial lung disease (ILD), a frequent complication of SSc. Different scanning schemes and counting methods have been proposed but no clear cut-off values have been indicated for screening. We aimed to evaluate the accuracy of different LUS methodological approaches to detect ILD compared with high-resolution CT (HRCT) as the gold standard.

Methods

Sixty-nine SSc patients underwent LUS and chest HRCT on the same day. Both exams were scored by expert readers. The accuracy of different scanning schemes and counting methods was assessed and clinical and functional data were compared with imaging findings.

Results

B-lines were more numerous in patients with the diffuse skin subset and Scl70 autoantibody positivity. The number of B-lines correlated with the Scleroderma Lung Study (SLS) I HRCT score (R = 0.754, P < 0.0001). A total of >10 B-lines on the whole chest or >1 B-line on the postero-basal chest showed 97% sensitivity for detecting even very early ILD signs (corresponding to an SLS I score of 1). Sensitivity increased to 100% when pleural line alterations were included in the analysis.

Conclusions

LUS has a very high sensitivity in detecting SSc-related ILD. A cut-off value of >10 B-lines on the whole chest or >1 B-line on the postero-basal chest can be used for the screening of SSc-ILD. Assessing only the postero-basal chest seems to be mostly effective, combining high sensitivity with a less time-consuming approach.
Timing of Total Hip Arthroplasty Affects Lumbar Spinal Fusion Outcomes
Authors: Mills Emily S. , Bouz Gabriel J. , Formanek Blake G. , Chung Brian C. , Wang Jeffrey C. , Heckmann Nathanael D. , Hah Raymond J.
Published: October 2021

Study Design:

This is a retrospective cohort study of consecutive patients undergoing lumbar spinal fusion (LSF) within the PearlDiver Humana research database from 2010 to 2018.

Objective:

The aim of this study was to determine if timing of total hip arthroplasty (THA) affects LSF outcomes.

Summary of Background Data:

In patients with both spine and hip pathology, outcomes of THA have been shown to be affected by the timing of THA relative to LSF. However, few studies have assessed postoperative outcomes following LSF in this clinical scenario.

Materials and Methods:

A national database was queried for patients undergoing lumbar fusion and divided into 4 groups: (1) those who underwent LSF without THA (No THA); (2) those who underwent THA at least 2 years before LSF (>2 Prior THA); (3) those who underwent THA in the 2 years before LSF (0–2 Prior THA); and (4) those who underwent THA after LSF (THA After). We assessed lumbar-specific outcomes, including pseudarthrosis, revision, mechanical failure, and adjacent segment disease (ASD); as well as systemic complications. Controlling for age, sex, and Charlson comorbidity index, complication rates between all groups were assessed using univariate and multivariate logistic regression analysis. Post hoc comparisons were performed using the Fisher exact test with Bonferroni correction to account for multiple pairwise comparisons, resulting in an adjusted threshold for statistical significance of P<0.007.

Results:

When compared with the no THA group, those in the THA After group had a higher rate of ASD on multivariate analysis [adjusted odds ratio: 1.53, 95% confidence interval: 1.20–1.94, P<0.001]. When compared with all patients who underwent THA before LSF, patients who underwent THA after LSF had an increased risk of ASD (adjusted odds ratio: 3.80, 95% confidence interval: 2.21–6.98, P<0.001).

Conclusions:

Patients who undergo THA after LSF have an increased rate of lumbar-related complications both when compared with patients who do not undergo THA and when compared with patients who undergo THA before LSF.
Laser corneal enhancement after trifocal intraocular lens implantation in eyes that previously had photoablative corneal refractive surgery
Authors: Mayordomo-Cerdá Fernando , Ortega-Usobiaga Julio , Bilbao-Calabuig Rafael , González-López Félix , Llovet-Osuna Fernando , Fernández-García Javier L , Cobo-Soriano Rosario
Published: October 2021

Purpose:

To evaluate the visual and refractive outcomes of laser corneal enhancement after trifocal intraocular lens (IOL) implantation in eyes previously treated with myopic/hyperopic laser corneal refractive surgery (LCRS).

Setting:

Clinica Baviera-AIER-Eye Group, Spain.

Design:

Retrospective comparative case series.

Methods:

Patients were divided by primary LCRS into myopic and hyperopic groups. The outcomes evaluated were uncorrected distance (UDVA), corrected distance (CDVA), uncorrected intermediate (UIVA), and uncorrected near visual acuity (UNVA), and predictability, safety, efficacy, and satisfaction after implantation of 2 trifocal IOL models (Physiol-FineVision and Zeiss-ATLisa 839) and subsequent laser enhancement.

Results:

186 eyes (89 myopic and 97 hyperopic eyes) from 146 patients were assessed. At the last visit, refractive outcomes were better in myopic than those in hyperopic eyes, with statistically significant differences for sphere (P < .001), cylinder (P < .001), manifest refraction spherical equivalent (MRSE) (P = .003), CDVA (P = .005), UDVA (P = .047), and UNVA (P = .003) but not for UIVA (P = .580), binocular UIVA (P = .660), or binocular UNVA (P = .836). Predictability differences were nonsignificant between groups for a final MRSE of ±0.5 diopters (D) and ±1.0 D (P = .167 and .502, respectively). Efficacy and safety were similar in both groups (P = .235 and P = .080). A greater myopic MRSE was present after trifocal implantation in myopic than in hyperopic eyes (MRSE = −0.93 vs −0.69 D, P = .013), and the statistically significant differences were maintained after enhancement between both groups (MRSE −0.00 vs 0.00 D, P = .003). Overall satisfaction was similar in both groups (P > .05 all items).

Conclusions:

Corneal laser enhancement after implantation of a trifocal IOL in eyes previously treated for myopia or hyperopia with LCRS was safe, effective, predictable, and highly satisfactory.
Use of a Novel, Shortened, Indwelling Pleural Catheter (PleurX) for the Ambulatory Management of Malignant Pleural Effusion
Authors: Rajchgot Jason , Amjadi Kayvan
Published: October 2021

Background:

Indwelling pleural catheters are frequently used for the treatment of malignant pleural effusion. The PleurX catheter (Becton, Dickinson and Company) is a commonly used indwelling pleural catheter across Canada. The traditional PleurX catheter is designed with a long segment of tubing outside of the patient’s chest, making insertion, drainage, and dressing changes awkward. Our clinic developed a novel, shortened, PleurX catheter that is easier to handle.

Methods:

We conducted retrospective chart review for all patients treated with a shortened PleurX catheter at our center from December 2015 to May 2019 and demographics, clinical information, and complications were recorded retrospectively. A survey was designed and distributed to nurses experienced with the use of both catheters to elicit a preference between the short and long catheter.

Results:

We analyzed data from 503 catheters placed in 491 patients. The most frequently encountered complications were loculation requiring fibrinolytic (2.4%), catheter dislodgement (1.2%), and pleural infection (0.6%). Of nurses surveyed, 74% preferred using the shortened PleurX catheter.

Conclusion:

Complication rates of the novel, shortened PleurX catheter are low. Further research is needed to better determine the optimal catheter length for ambulatory management of malignant pleural effusion.
New primary immunodeficiencies 2021 context and future
Authors: Demirdag Yesim , Fuleihan Ramsay , Orange Jordan S. , Yu Joyce E.
Published: October 2021

Purpose of review

Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders classically characterized by an increased susceptibility to infection and/or disruption in the regulation of an immunologic pathway. This review summarizes and highlights the new IEI disorders in the IUIS 2019 report and 2020 interim report and discusses the directions for the future management of PIDs.

Recent findings

Since 2017, the International Union of Immunologic Societies (IUIS) IEI committee has updated the IUIS classification of IEIs with 88 new gene defects and 75 new immune disorders. The increased utilization of genetic testing and advances in the strategic evaluation of genetic variants have identified, not only novel IEI disorders, but additional genetic causes for known IEI disorders. Investigation of potential immune susceptibilities during the ongoing COVID-19 pandemic suggests that defects in Type I interferon signalling may underlie more severe disease.

The rapid discovery of new IEIs reflects the growing trend of applying genetic testing modalities as part of medical diagnosis and management.

In turn, elucidating the pathophysiology of these novel IEIs have enhanced our understanding of how genetic mutations can modulate the immune system and their consequential effect on human health and disease.
Syphilis in Greenland, 2015 to 2019
Authors: Andersen Marianne Welzel , Johansen Mila Broby , Bjorn-Mortensen Karen , Pedersen Michael Lynge , Jensen Jørgen Skov , Koch Anders
Published: October 2021

Background

An increase in the incidence of syphilis was reported in Greenland from 2011 to 2014, and notification rates kept rising in the following years in spite of focused efforts. To better understand the syphilis epidemic, this study was conducted to describe the syphilis epidemic in Greenland from 2015 to 2019.

Methods

Syphilis cases and their characteristics were identified through reviews of electronic medical records and laboratory results in 3 different data sets: notifications to the National Board of Health, electronic prescriptions for benzathine penicillin, and the national laboratory database. Annual incidences were calculated stratified by sex, age, and region.

Results

The incidence of syphilis in Greenland increased from 107.4 to 246.8 cases per 100,000 inhabitants from 2015 to 2019. The incidence increased in both sexes and in nearly all regions, although with large regional differences. Especially the age group 15 to 29 years showed a substantial increase in incidence in 2018 and 2019. More females than males were infected (245 female cases vs. 178 male cases).

Conclusions

The burden of syphilis in Greenland is high, primarily among the age group 15 to 29 years. A higher incidence among females than among males was found, suggesting mainly heterosexual transmission, as seen for other sexually transmitted infections in Greenland.
Factors Associated With Partner Notification, Testing, and Positivity in HIV Partner Services Programs in the United States, 2013 to 2017
Authors: Song Wei , Mulatu Mesfin S. , Rao Shubha , Mendoza Maria C.B. , Kudon Hui Zhang , Rorie Michele
Published: October 2021

Background

Human immunodeficiency virus (HIV) partner services are an essential component of comprehensive HIV prevention and care. We examined factors associated with partner notification, HIV testing, and HIV positivity among partners of HIV-diagnosed persons (index persons) contacted by Centers for Disease Control and Prevention (CDC)–funded state and local health departments.

Methods

We analyzed partner service data submitted to the CDC by 61 state and local health departments from 2013 to 2017. Using multivariate Poisson regression—adjusted for clustering effects among partners reported by a common index person—we assessed associations between 3 outcomes of interest (partner notification, HIV testing, and HIV positivity) and the demographic characteristics, risk behaviors, geographic region, and service year of index persons and their partners.

Results

A total of 51,368 sexual and/or needle-sharing partners were matched with 33,524 index persons. Of notifiable partners, 97.2% were notified of their potential HIV exposure, and 52.3% were tested for HIV. Among 21,842 notified and tested partners, 23.8% were newly diagnosed with an HIV infection. Partner notification, HIV testing, and HIV positivity were associated with both partner and index person characteristics (individually and interactively), geographic region, and year of service.

Conclusions

Partner service programs provided through CDC-funded health departments were effective in both partner notification and identification of undiagnosed HIV infection among partners. However, HIV testing rate among notified partners remained low. Implementing strategies to address gaps in HIV testing can contribute toward ending the HIV epidemic in the United States.
Takotsubo Syndrome in the Perioperative Period
Authors: Seretis Konstantinos , Bounas Nikos , Vaikos Dimitrios , Athanasiadis Ilias
Published: October 2021

Stress-induced cardiomyopathy or takotsubo syndrome is a rare, nonischemic, heart condition resembling that of an acute coronary syndrome. Its distinctive feature is a transient wall motion abnormality occurring usually at the apical segment of the heart, with the degree of symptom manifestation and severity varying among patients. Although early data were supportive of a benign sequela and outcome, high degree of adverse events, such as acute heart failure and pulmonary edema, are anticipated, and the mortality rate approaches 5%. Hyperactivation of the sympathetic nervous system and adrenergic drugs have been pointed out as possible precipitators of the condition. Surgical procedures are a known cause of emotional and physical stress on patients, acting as an ideal substrate for the presentation of this syndrome. On occasion of a perioperative takotsubo syndrome case in a female patient during second-stage implant-based breast reconstruction, a review of the pertinent literature is presented. The acute onset and severity of the manifestations in this surgically uneventful procedure necessitated a multidisciplinary approach. Consequently, this report should raise awareness of the syndrome among plastic surgeons and anesthesiologists to promptly recognize and manage it effectively.
Treponema peruense sp. nov., a commensal spirochaete isolated from human faeces
Authors: Belkhou Claire , Tadeo Raul Tito , Bacigalupe Rodrigo , Valles-Colomer Mireia , Chaffron Samuel , Joossens Marie , Obregon Alexandra , Marín Reyes Luis , Trujillo Omar , Huys Geert R. B. , Raes Jeroen
Published: October 2021

A Gram-stain-negative, obligatory anaerobic spirochaete (RCC2812T) was isolated from a faecal sample obtained from an individual residing in a remote Amazonian community in Peru. The bacterium showed highest 16S rRNA gene sequence similarity to the pig intestinal spirochete

Treponema succinifaciens

(89.48 %). Average nucleotide identity values between strain RCC2812T and all available

Treponema

genomes from validated type strains were all <73 %, thus clearly lower than the species delineation threshold. The DNA G+C content of RCC2812T was 41.24 mol%. Phenotypic characterization using the API-ZYM and API 20A systems confirmed the divergent position of this bacterium within the genus

Treponema

. Strain RCC2812T could be differentiated from the phylogenetically most closely related

T. succinifaciens

by the presence of alkaline phosphatase and α -glucosidase activities. Unlike

T. succinifaciens

, strain RCC2812T grew equally well with or without serum. Strain RCC2812T is the first commensal

Treponema

isolated from the human faecal microbiota of remote populations, and based on the collected data represents a novel

Treponema

species for which the name Treponema peruense sp. nov. is proposed. The type strain is RCC2812T (=LMG 31794T=CIP 111910T).
Sensitivity of the acute flaccid paralysis surveillance system for poliovirus in South Africa, 2016–2019
Authors: Howard Wayne , Moonsamy Shelina , Seakamela Lerato , Jallow Sabelle , Modiko Faith , du Plessis Heleen , Sibiya Rosina , Kamupira Mercy , Maseti Elizabeth , Suchard Melinda
Published: October 2021

Introduction. Global poliovirus eradication is a public health emergency of international concern. The acute flaccid paralysis (AFP) surveillance programme in South Africa has been instrumental in eliminating polioviruses and keeping the country poliovirus free.

Gap statement. The sensitivity of surveillance for polioviruses by every African country is of global interest in the effort to ensure global health security from poliovirus re-emergence.

Aim. To describe the epidemiology of polioviruses from AFP cases and environmental samples in South Africa and to report the performance of the AFP surveillance system for the years 2016–2019 against targets established by the World Health Organization (WHO).

Methods. Stool specimens from AFP or suspected AFP cases were received and tested as per WHO guidelines. Environmental samples were gathered from sites across the Gauteng province using the grab collection method. Concentration was effected by the two-phase polyethylene glycol method approved by the WHO. Suspected polioviruses were isolated in RD and/or L20B cell cultures through identification of typical cytopathic effects. The presence of polioviruses was confirmed by intratypic differentiation PCR. All polioviruses were sequenced using the Sanger method, and their VP1 gene analysed for mutations.

Results. Data from 4597 samples (2385 cases) were analysed from the years 2016–2019. Two cases of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) type 3 were detected in 2017 and 2018. A further 24 Sabin type 1 or type 3 polioviruses were detected for the 4 years. The national surveillance programme detected an average of 3.1 cases of AFP/100 000 individuals under 15 years old (2.8/100 000–3.5/100 000). The stool adequacy of the samples received was 53.0 % (47.0–55.0%), well below the WHO target of 80 % adequacy. More than 90 % of results were released from the laboratory within the turnaround time (96.6 %) and non-polio enteroviruses were detected in 11.6 % of all samples. Environmental surveillance detected non-polio enterovirus in 87.5 % of sewage samples and Sabin polioviruses in 12.5 % of samples.

Conclusion. The AFP surveillance programme in South Africa is sensitive to detect polioviruses in South Africa and provided no evidence of wild poliovirus or VDPV circulation in the country.
Wastewater and surface monitoring to detect COVID-19 in elementary school settings: The Safer at School Early Alert project
Authors: Fielding-Miller Rebecca , Karthikeyan Smruthi , Gaines Tommi , Garfein Richard S. , Salido Rodolfo A. , Cantu Victor J. , Kohn Laura , Martin Natasha K , Wynn Adriane , Wijaya Carrissa , Flores Marlene , Omaleki Vinton , Majnoonian Araz , Gonzalez-Zuniga Patricia , Nguyen Megan , Vo Anh V , Le Tina , Duong Dawn , Hassani Ashkan , Tweeten Samantha , Jepsen Kristen , Henson Benjamin , Hakim Abbas , Birmingham Amanda , De Hoff Peter , Mark Adam M. , Nasamran Chanond A , Rosenthal Sara Brin , Moshiri Niema , Fisch Kathleen M. , Humphrey Greg , Farmer Sawyer , Tubb Helena M. , Valles Tommy , Morris Justin , Kang Jaeyoung , Khaleghi Behnam , Young Colin , Akel Ameen D , Eilert Sean , Eno Justin , Curewitz Ken , Laurent Louise C , Rosing Tajana , Knight Rob
Published: October 2021

Background

Schools are high-risk settings for SARS-CoV-2 transmission, but necessary for children’s educational and social-emotional wellbeing. Previous research suggests that wastewater monitoring can detect SARS-CoV-2 infections in controlled residential settings with high levels of accuracy. However, its effective accuracy, cost, and feasibility in non-residential community settings is unknown.

Methods

The objective of this study was to determine the effectiveness and accuracy of community-based passive wastewater and surface (environmental) surveillance to detect SARS-CoV-2 infection in neighborhood schools compared to weekly diagnostic (PCR) testing. We implemented an environmental surveillance system in nine elementary schools with 1700 regularly present staff and students in southern California. The system was validated from November 2020 – March 2021.

Findings

In 447 data collection days across the nine sites 89 individuals tested positive for COVID-19, and SARS-CoV-2 was detected in 374 surface samples and 133 wastewater samples. Ninety-three percent of identified cases were associated with an environmental sample (95% CI: 88% - 98%); 67% were associated with a positive wastewater sample (95% CI: 57% - 77%), and 40% were associated with a positive surface sample (95% CI: 29% - 52%). The techniques we utilized allowed for near-complete genomic sequencing of wastewater and surface samples.

Interpretation

Passive environmental surveillance can detect the presence of COVID-19 cases in non-residential community school settings with a high degree of accuracy.

Funding

County of San Diego, Health and Human Services Agency, National Institutes of Health, National Science Foundation, Centers for Disease Control
Structural convergence for tubulin binding of CPAP and vinca domain microtubule inhibitors
Authors: Campanacci Valérie , Urvoas Agathe , Khodja Liza Ammar , Aumont-Nicaise Magali , Noiray Magali , Lachkar Sylvie , Curmi Patrick A. , Minard Philippe , Gigant Benoît
Published: October 2021

Microtubule dynamics is regulated by various cellular proteins and perturbed by small molecule compounds. To what extent the mechanism of the former resembles that of the latter is an open question. We report here structures of tubulin bound to the PN2-3 domain of CPAP, a protein controlling the length of the centrioles. We show that an α-helix of the PN2-3 N-terminal region binds and caps the longitudinal surface of the tubulin β subunit. Moreover, a PN2-3 N-terminal stretch lies in a β-tubulin site also targeted by fungal and bacterial peptide-like inhibitors of the vinca domain, sharing a very similar binding mode with these compounds. Therefore, our results identify several characteristic features of cellular partners that bind to this site and highlight a structural convergence of CPAP with small molecule inhibitors of microtubule assembly.
Effect of the third dose of BNT162b2 vaccine in quantitative SARS-CoV-2 spike 1-2 IgG antibody titers in healthcare workers
Authors: Romero-Ibarguengoitia Maria Elena , Rivera-Salinas Diego , Hernández-Ruíz Yodira Guadalupe , Armendariz-Vázquez Ana Gabriela , González-Cantú Arnulfo , Barco-Flores Irene Antonieta , González-Facio Rosalinda , Montelongo-Cruz Laura Patricia , Del Rio-Parra Gerardo Francisco , Garza-Herrera Mauricio René , Leal-Meléndez Jessica Andrea , Sanz-Sánchez Miguel Ángel
Published: October 2021

Background

Vaccination is our main strategy to control SARS-CoV-2 infection. Given a decrease in the quantitative SARS-CoV-2 spike 1-2 IgG antibody titers three months following the second BNT162b2 dose, healthcare workers got a third booster dose after six months of completing the original scheme. This study aimed to analyze quantitative SARS-CoV-2 spike 1-2 IgG antibody titers and safety of the third dose.

Material and methods

A prospective longitudinal cohort study included healthcare workers who received a third booster dose after six months of the complete BNT162b2 regimen. We assessed the quantitative SARS-CoV-2 spike 1-2 IgG antibody titers 21-28 days after the first and second dose, three months after the complete scheme, 1-7 days following the third dose, and 21-28 days after the boost.

Results

The cohort comprised 168 non-immunocompromised participants of 41(10) years old, 67% being women. The third dose was associated with increasing the quantitative antibody titers, regardless of previous SARS-CoV-2 history. In negative SARS-CoV-2 history, the median (IQR) antibody titers increased from 379 (645.4) to 2960 (2010), while in positive SARS-CoV-2 history, from 590 (1262) to 3090 (2080). The third dose had less number of total side effects compared to the other two shots. The most common side effect after the third BNT162b2 shot was pain at the injection site (n=82, 84.5%), followed by tiredness (n=45, 46.4%), with a mild severity (n=36, 37.1%). Tiredness, myalgias, arthralgias, fever, and adenopathy were proportionally higher following the third dose than the two-dose regimen (p<0.05).

Conclusion

The third dose applied after six months of the original BNT162b2 regimen provided a good humoral immune response by elevating the quantitative SARS-CoV-2 spike 1-2 IgG antibody titers. The booster dose was well tolerated with no severe side effects after the additional BNT162b2 dose.
Combination of structural and functional connectivity explains unique variation in specific domains of cognitive function
Authors: Litwińczuk Marta Czime , Trujillo-Barreto Nelson , Muhlert Nils , Cloutman Lauren , Woollams Anna
Published: October 2021

The relationship between structural and functional brain networks has been characterised as complex: the two networks mirror each other and show mutual influence but they also diverge in their organisation. This work explored whether a combination of structural and functional connectivity can improve predictive models of cognitive performance. Principal Component Analysis (PCA) was first applied to cognitive data from the Human Connectome Project to identify components reflecting five cognitive domains: Executive Function, Self-regulation, Language, Encoding and Sequence Processing. A Principal Component Regression (PCR) approach was then used to fit predictive models of each cognitive domain based on structural (SC), functional (FC) or combined structural-functional (CC) connectivity. Self-regulation, Encoding and Sequence Processing were best modelled by FC, whereas Executive Function and Language were best modelled by CC. The present study demonstrates that integrating structural and functional connectivity can help predict cognitive performance, but that the added explanatory value may be (cognitive) domain-specific. Implications of these results for studies of the brain basis of cognition in health and disease are discussed.

Highlights

We assessed the relationship between cognitive domains and structural, functional and combined structural-functional connectivity.

We found that Executive Function and Language components were best predicted by combined models of functional and structural connectivity.

Self-regulation, Encoding and Sequence Processing were best predicted by functional connectivity alone.

Our findings provide insight into separable contributions of functional, structural and combined connectivity to different cognitive domains.
Metastatic profiling of HER2-positive breast cancer cell lines in xenograft models
Authors: Han Yuxuan , Azuma Kazushi , Watanabe Shinya , Semba Kentaro , Nakayama Jun
Published: October 2021

Most studies on breast cancer metastasis have been performed using triple-negative breast cancer (TNBC) cells; thus, subtype-dependent metastatic ability of breast cancer is poorly understood. In this research, we performed intravenous injection (IVI) and intra-caudal arterial injections (CAI) using nine human epidermal growth factor receptor-2 (HER2)-positive breast cancer cell lines for evaluating their metastatic abilities. Our results showed that MDA-MB-453, UACC-893, and HCC-202 had strong bone metastatic abilities, whereas HCC-2218 and HCC-1419 did not show bone metastasis. HER2-positive cell lines could hardly metastasize to the lung through IVI. From the genomic analysis, gene signatures were extracted according to the breast cancer subtypes and their metastatic preferences. The UACC-893 cell line was identified as a useful model for the metastasis study of HER2-positive breast cancer. Combined with our previous result on brain proliferation ability, we provide a characteristic metastasis profile of HER2-positive breast cancer cell lines in this study.

Statements and Declarations

Funding

This study was supported by JSPS KAKENHI (grant no. 18K16269: Grant-in-Aid for Early-Career Scientist to J.N.; grant no. 20J01794, Grant-in-Aid for JSPS fellows to J.N.; grant no. 20J23297, Grant-in-Aid for JSPS fellows to Y.H.) and partially supported by the grants for translational research programs from Fukushima Prefecture (S.W. and K.S.).

Authorship

YH and KA performed the in vivo experiments and bioinformatical analyses. SW, and KS interpreted the data. YH, KA, and JN wrote the manuscript. JN conceived and designed the study. All the authors reviewed and edited the manuscript.

Competing Interests

The authors declare that they have no competing interests.

Ethical approval

The animal experiments were conducted under the approval of the ethics committee of Waseda University (2020-A067, 2021-A074).
A multimodal imaging and analysis pipeline for creating a cellular census of the human cerebral cortex
Authors: Costantini Irene , Morgan Leah , Yang Jiarui , Balbastre Yael , Varadarajan Divya , Pesce Luca , Scardigli Marina , Mazzamuto Giacomo , Gavryusev Vladislav , Castelli Filippo Maria , Roffilli Matteo , Silvestri Ludovico , Laffey Jessie , Raia Sophia , Varghese Merina , Wicinski Bridget , Chang Shuaibin , Chen I-Chun Anderson , Wang Hui , Cordero Devani , Vera Matthew , Nolan Jackson , Nestor Kim , Mora Jocelyn , Iglesias Juan Eugenio , Pallares Erendira Garcia , Evancic Kathryn , Augustinack Jean , Fogarty Morgan , Dalca Adrian V. , Frosch Matthew , Magnain Caroline , Frost Robert , van der Kouwe Andre , Chen Shih-Chi , Boas David A. , Pavone Francesco Saverio , Fischl Bruce , Hof Patrick R.
Published: October 2021

Cells are not uniformly distributed in the human cerebral cortex. Rather, they are arranged in a regional and laminar fashion that span a range of scales. Here we demonstrate an innovative imaging and analysis pipeline to construct a reliable cell census across the human cerebral cortex. Magnetic resonance imaging (MRI) is used to establish a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with both traditional immunohistochemistry, to provide a stereological gold-standard, and with a custom-made inverted confocal light-sheet fluorescence microscope (LSFM) for 3D imaging at cellular resolution. Finally, mesoscale optical coherence tomography (OCT) enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system.
Single-cell Stereo-seq enables cell type-specific spatial transcriptome characterization in Arabidopsis leaves
Authors: Xia Keke , Sun Hai-Xi , Li Jie , Li Jiming , Zhao Yu , Chen Ruiying , Liu Guangyu , Chen Zhiyong , Yin Ruilian , Hao Shijie , Wang Jing , Xie Qing , Xu Jiangshan , Li Yuxiang , Chen Ao , Liu Longqi , Yin Ye , Yang Huanming , Wang Jian , Gu Ying , Xu Xun
Published: October 2021

Understanding the complex functions of plant leaves requires spatially resolved gene expression profiling with single-cell resolution. However, although in situ gene expression profiling technologies have been developed, this goal has not yet been achieved. Here, we present the first in situ single-cell transcriptome profiling in plant, scStereo-seq (single-cell SpaTial Enhanced REsolution Omics-sequencing), which enabled the bona fide single-cell spatial transcriptome of Arabidopsis leaves. We successfully characterized subtle but significant transcriptomic differences between upper and lower epidermal cells. Furthermore, with high-resolution location information, we discovered the cell type-specific spatial gene expression gradients from main vein to leaf edge. By reconstructing those spatial gradients, we show for the first time the distinct spatial developmental trajectories of vascular cells and guard cells. Our findings show the importance of incorporating spatial information for answering complex biological questions in plant, and scStereo-seq offers a powerful single cell spatially resolved transcriptomic strategy for plant biology.
Arnold tongue entrainment reveals dynamical principles of the embryonic segmentation clock
Authors: Sanchez Paul Gerald Layague , Mochulska Victoria , Denis Christian Mauffette , Mönke Gregor , Tomita Takehito , Tsuchida-Straeten Nobuko , Petersen Yvonne , Sonnen Katharina F. , François Paul , Aulehla Alexander
Published: October 2021

Living systems exhibit an unmatched complexity, due to countless, entangled interactions across scales. Here we aim to understand a complex system, i.e. segmentation timing in mouse embryos, without a reference to these detailed interactions. To this end, we develop a coarse-grained approach, in which theory guides the experimental identification of the segmentation clock entrainment responses.

We demonstrate period- and phase-locking of the segmentation clock across a wide range of entrainment parameters, including higher-order coupling. These quantifications allow to derive the phase response curve (PRC) and Arnold tongues of the segmentation clock, revealing its essential dynamical properties. Our results indicate that the somite segmentation clock has characteristics reminiscent of a highly non-linear oscillator close to an infinite period bifurcation and suggests the presence of long-term feedbacks.

Combined, this coarse-grained theoretical-experimental approach reveals how we can derive simple, essential features of a highly complex dynamical system, providing precise experimental control over the pace and rhythm of the somite segmentation clock.
hyperTRIBER: a flexible R package for the analysis of differential RNA editing
Authors: Rennie Sarah , Magnusson Daniel Heidar , Andersson Robin
Published: October 2021

Abstract

RNA editing by ADAR (adenosine deaminase acting on RNA) is gaining an increased interest in the field of post-transcriptional regulation. Fused to an RNA-binding protein (RBP) of interest, the catalytic activity of ADAR results in A-to-I RNA edits, whose identification will determine RBP-bound RNA transcripts. However, the computational tools available for their identification and differential RNA editing statistical analysis are limited or too specialised for general-purpose usage. Here we presenthyperTRIBER, a flexible suite of tools, wrapped into a convenient R package, for the detection of differential RNA editing.hyperTRIBERis applicable to complex scenarios and experimental designs, and provides a robust statistical framework allowing for the control for coverage of reads at a given base, the total expression level and other co-variates. We demonstrate the capabilities of our approach on HyperTRIBE RNA-seq data for the detection of bound RNAs by theN6-methyladenosine (m6A) reader protein ECT2 in Arabidopsis roots. We show thathyperTRIBERfinds edits with a high statistical power, even where editing proportions and RNA transcript expression levels are low, together demonstrating its usability and versatility for analysing differential RNA editing.
Pavlovian fear conditioning does not readily occur in rats in naturalistic environments
Authors: Zambetti Peter R. , Schuessler Bryan P. , Lecamp Bryce E. , Shin Andrew , Kim Eun Joo , Kim Jeansok J.
Published: October 2021

Pavlovian fear conditioning, which offers the advantage of simplicity in both the control of conditioned and unconditioned stimuli (CS, US) presentation and the analysis of specific conditioned and unconditioned responses (CR, UR) in a controlled laboratory setting, has been the standard model in basic and translational fear research. Despite 100 years of experiments, the utility of fear conditioning has not been trans-situationally validated in real-life contexts. We thus investigated whether fear conditioning readily occurs and guides the animal’s future behavior in an ecologically-relevant environment. To do so, Long-Evans rats foraging for food in an open arena were presented with a tone CS paired with electric shock US to their dorsal neck/body that instinctively elicited escape UR to the safe nest. On subsequent test days, the tone-shock paired animals failed to exhibit fear CR to the CS. In contrast, animals that encountered a realistic agent of danger (a looming artificial owl) paired with a shock, simulating a realistic predatory strike, instantly fled to the nest when presented with a tone for the first time. These results illustrate the survival function and precedence of a nonassociative process, rather than associative conditioning, in life-threatening situations that animals are likely to encounter in nature.
Rating enrichment items by group-housed laboratory mice in multiple binary choice tests using an RFID-based tracking system
Authors: Hobbiesiefken Ute , Urmersbach Birk , Jaap Anne , Diederich Kai , Lewejohann Lars
Published: October 2021

There is growing evidence that enrichment of housing conditions of laboratory animals has positive effects on behavior, growth, and health. Laboratory mice spend most of their lives in their housing rather than in experimental apparatus, so improving housing conditions is a first-choice approach to improving their welfare. Despite the increasing popularity of enrichment, little is known about whether it is also perceived as being beneficial from the animal’s point of view. This is especially true due to the fact that ‘enrichment’ has become an umbrella term that encompasses a wide variety of different elements. Therefore, we categorized enrichment items according to their prospective use into the categories ‘structural’, ‘housing’, and ‘foraging’. In multiple binary choice tests we let 12 female C57BL/6J mice chose and rank 5 enrichment items per category. All possible pair combinations of enrichment items within each category were presented counterbalanced for a 46-hour period in a home cage based system consisting of two interconnected cages. A new analyzing method combined the binary decisions and ranked the enrichment items within each category by calculating worth values and consensus errors. Mice ranked the lattice ball (foraging), the rope (structural) and the second plane (structural) in upper positions. No clear preferences were determined for different types of housing enrichment during inactive times (light phase) whereas these objects were actively explored during the dark phase. Here the floorhouse and the paperhouse revealed high worth values. Overall, a high consensus error in ranking positions was observed reflecting strong individual differences in preferences. This highlights the importance of a varied enrichment approach as not all mice prefer the same item at all times. Given the known overall beneficial effects of enrichment, these data will help to provide appropriate enrichment elements to improve animal welfare and refine animal experimentation.
Cell responses to simulated microgravity and hydrodynamic stress can be distinguished by using comparative transcriptomic analysis
Authors: Kouznetsov Nikolai V.
Published: October 2021

The human immune system is compromised in microgravity (MG) conditions during an orbital flight and upon return to Earth. T cells are critical for the immune response and execute their functions via actin mediated immune cell-cell interactions that could be disturbed by MG conditions. Here, we have applied two rotational platforms to simulate MG conditions: fast rotating clinostat (CL) and random positioning machine (RPM) followed by global T cell transcriptome analysis using RNA sequencing. We demonstrate that the T cell transcriptome profile in response to simulated MG treatment was clearly distinguishable from the T cell transcriptome response to hydrodynamic stress (HS) induced by shear forces upon cell movement in cultural medium. Gene expression profiling of genes related to or involved in actin cytoskeleton networks using RT-qPCR confirmed two sets of differentially regulated genes in the T cell response to MG or to HS. Several key genes potentially involved in T cell gravisensing (Fam163b, Dnph1, Trim34, Upk-1b) were identified. A number of candidate biomarker genes of the response to MG (VAV1, VAV2, VAV3, and NFATC2) and of the response to HS (ITGAL, ITGB1, ITGB2, RAC1 and RAC2) could be used to distinguish between these processes on the gene transcription level. Together, MG induces changes in the overall transcriptome of T cells leading to specific shifts in expression of cytoskeletal network genes.
Nuclear alpha-synuclein is present in the human brain and is modified in dementia with Lewy bodies
Authors: Koss David J. , Erskine Daniel , Porter Andrew , Palmoski Pawel , Leite Marta , Attems Johannes , Outeiro Tiago F.
Published: October 2021

Dementia with Lewy bodies is pathologically defined by the cytoplasmic accumulation of alpha-synuclein within neuronal cells in the brain. Alpha-synuclein is predominately pre-synaptic, but has been reported present in various subcellular compartments in cell and animal models. In particular, nuclear alpha-synuclein is evident in-vitro and in disease models and has been associated with altered DNA integrity, gene transcription, nuclear homeostasis. However, owing to various factors, the presence of alpha-synuclein in the nuclei of human brain cells remains controversial, as does its role in synucleinopathies.

Here, we close this gap and provide a unique demonstration confirming the presence of nuclear alpha-synuclein in post-mortem brain tissue obtained from cases of dementia with Lewy bodies as well as from controls via immunohistochemistry, immunoblot, and label-free mass-spectrometry.

Discrete intra-nuclear alpha-synuclein puncta reactive against phosphorylated serine 129-alpha-synuclein and pan-alpha-synuclein antibodies were observed in cortical neurons and non-neuronal cells in fixed brain sections and in isolated nuclear preparations from Dementia with Lewy bodies cases and matched controls. Subsequent biochemical analysis of subcellular fractionated tissue confirmed alpha-synuclein as present in a nuclear fraction at levels ~ 10-fold lower than in the cytoplasm. Critically, however, an increase in monomeric nuclear alpha-synuclein phosphorylated as serine 129 was observed in cases of dementia with Lewy bodies alongside higher molecular weight pan- and phosphorylation reactive alpha-synuclein species, consistent with the formation of intranuclear phosphorylated alpha-synuclein oligomers. Furthermore, the presence of nuclear alpha-synuclein was confirmed via label free mass spectrometry, as 6 unique alpha-synuclein derived peptide sequences were identified in nuclear fractions (71.4% sequence coverage).

Collectively, our data confirm the presence of nuclear alpha-synuclein in human brain tissue and describe nuclear pathology associated with dementia with Lewy bodies. These findings address a major controversy in the synucleinopathy field by confirming the presence of nuclear alpha-synuclein in autoptic human brain tissue and, for the first time, identify that alpha-synuclein is aggregated into novel and potentially pathological assemblies in the nucleus as part of the disease process associated with dementia with Lewy bodies and thus may contribute to the disease phenotype.