bluuebunny/crossref_metadata_2025 huggingface dataset:
Reproductive Endocrinology Reference Intervals for Transgender Men on Stable Hormone Therapy
Authors: Greene Dina N , Schmidt Robert L , Winston-McPherson Gabrielle , Rongitsch Jessica , Imborek Katherine L , Dickerson Jane A , Drees Julia C , Humble Robert M , Nisly Nicole , Dole Nancy J , Dane Susan K , Frerichs Janice , Krasowski Matthew D
Published: September 2020

Background

Gender-affirming therapy with testosterone is commonly prescribed to aid in the masculinization of transgender men. Sex-hormone concentrations are routinely measured, but interpretation of results can be difficult due to the lack of published reference intervals.

Methods

Healthy transgender individuals who had been prescribed testosterone (n = 82) for at least a year were recruited from internal medicine and primary care clinics that specialize in transgender medical care. Total testosterone and estradiol were measured using immunoassay and mass spectrometry; LH, FSH, SHBG, prolactin, progesterone, anti-Müllerian hormone (AMH), and dehydroepiandrosterone sulfate (DHEAS) were measured using immunoassay; free testosterone was calculated. Reference intervals (central 95%) were calculated according to Clinical Laboratory Standards Institute guidelines.

Results

When evaluating general endocrine laboratory tests in people using masculinizing hormones, reference intervals for cisgender men can be applied for total and free testosterone and SHBG and reference intervals for cisgender women can be applied for prolactin. Reference intervals for estradiol, LH, FSH, AMH, and DHEAS differ from those used for cisgender men and cisgender women, and therefore should be interpreted using intervals specific to the transmasculine population. For testosterone and estradiol, results from immunoassays were clinically equivalent to mass spectrometry.

Conclusion

Masculinizing hormones will alter the concentrations of commonly evaluated endocrine hormones. Providers and laboratories should use appropriate reference intervals to interpret the results of these tests.
Precision population analytics: population management at the point-of-care
Authors: Tang Paul C , Miller Sarah , Stavropoulos Harry , Kartoun Uri , Zambrano John , Ng Kenney
Published: September 2020

Objective

To present clinicians at the point-of-care with real-world data on the effectiveness of various treatment options in a precision cohort of patients closely matched to the index patient.

Materials and Methods

We developed disease-specific, machine-learning, patient-similarity models for hypertension (HTN), type II diabetes mellitus (T2DM), and hyperlipidemia (HL) using data on approximately 2.5 million patients in a large medical group practice. For each identified decision point, an encounter during which the patient’s condition was not controlled, we compared the actual outcome of the treatment decision administered to that of the best-achieved outcome for similar patients in similar clinical situations.

Results

For the majority of decision points (66.8%, 59.0%, and 83.5% for HTN, T2DM, and HL, respectively), there were alternative treatment options administered to patients in the precision cohort that resulted in a significantly increased proportion of patients under control than the treatment option chosen for the index patient. The expected percentage of patients whose condition would have been controlled if the best-practice treatment option had been chosen would have been better than the actual percentage by: 36% (65.1% vs 48.0%, HTN), 68% (37.7% vs 22.5%, T2DM), and 138% (75.3% vs 31.7%, HL).

Conclusion

Clinical guidelines are primarily based on the results of randomized controlled trials, which apply to a homogeneous subject population. Providing the effectiveness of various treatment options used in a precision cohort of patients similar to the index patient can provide complementary information to tailor guideline recommendations for individual patients and potentially improve outcomes.
Application of MEKC and UPLC with Fluorescence Detection for Simultaneous Determination of Amlodipine Besylate and Bisoprolol Fumarate
Authors: Elonsy Sohila M , El Yazbi Fawzy A , Shaalan Rasha A , Ahmed Hytham M , Belal Tarek S
Published: September 2020

Objective

Two chromatographic methods were described for simultaneous determination of the antihypertensive drugs amlodipine besylate (AML) and bisoprolol fumarate (BIS).

Methods

Method I applies micellar electrokinetic capillary chromatography using a deactivated fused silica capillary (25 cm effective length × 50 μm internal diameter). The background electrolyte consisted of 0.01 M borate buffer (pH 9.2) containing 0.025 M sodium dodecyl sulphate and methanol in the ratio of 80:20 (v/v). Valsartan (VAL) was used as an internal standard. Diode array detector was set at 238, 224, and 210 nm for measuring AML, BIS, and VAL, respectively. Method II involves using ultra-performance liquid chromatography with fluorescence detection. Zorbax SB-C8 column (2.1 × 100 mm, 1.8 μm particle size) was used with isocratic elution of the mobile phase composed of 0.1% trifluoroacetic acid, acetonitrile, and methanol in the ratio of 55:35:10 (v/v) at a flow rate of 0.6 mL/min. Fluorescence detection was done using excitation wavelengths 230 and 370 nm and emission wavelengths 305 and 450 nm for BIS and AML, respectively. Validation parameters were carefully studied including linearity, ranges, precision, accuracy, robustness, detection, and quantification limits.

Results

Method I showed good linearity over the range 10–100 μg/mL for both dugs. Method II’s linear ranges were 0.001–0.1 and 0.02–1 µg/mL for BIS and AML, respectively.

Conclusion

The proposed methods were successfully validated and applied for assay of the studied drugs in their fixed-dose combination tablets.

Highlights

To the best of our knowledge, this study suggests the first electro-chromatographic and LC with fluorescence detection methods for simultaneous determination of amlodipine and bisoprolol.
China’s ‘Going Global’ Policy: Transnational Production Subsidies Under the WTO SCM Agreement
Authors: Crochet Victor , Hegde Vineet
Published: September 2020

As China is increasingly ‘going global’, foreign direct investment under its Belt and Road Initiative is becoming heavily scrutinized. One of the concerns is that Chinese companies establishing themselves in third countries would be unfairly advantaged by the financing they receive under China’s expansionist strategy. This financing gives rise to a situation that had long been described as ‘unrealistic’, in which a government subsidizes a firm outside of its territory. When such a firm’s products are exported to third countries, could such financing be disciplined under the World Trade Organization Agreement on Subsidies and Countervailing Measures? Should such financing, which enhances development in the receiving countries, be disciplined at all? The authors shed light on these issues and provide a preliminary guidance on how to structure this problem under international trade law.
Mitotic cells can repair DNA double-strand breaks via a homology-directed pathway
Authors: Sakamoto Yuki , Kokuta Tetsuya , Teshigahara Ai , Iijima Kenta , Kitao Hiroyuki , Takata Minoru , Tauchi Hiroshi
Published: September 2020

The choice of repair pathways of DNA double-strand breaks (DSBs) is dependent upon the cell cycle phases. While homologous recombination repair (HRR) is active between the S and G2 phases, its involvement in mitotic DSB repair has not been examined in detail. In the present study, we developed a new reporter assay system to detect homology-directed repair (HDR), a major pathway used for HRR, in combination with an inducible DSB-generation system. As expected, the maximal HDR activity was observed in the late S phase, along with minimal activity in the G1 phase and at the G1/S boundary. Surprisingly, significant HDR activity was observed in M phase, and the repair efficiency was similar to that observed in late S phase. HDR was also confirmed in metaphase cells collected with continuous colcemid exposure. ChIP assays revealed the recruitment of RAD51 to the vicinity of DSBs in M phase. In addition, the ChIP assay for gamma-H2AX and phosphorylated DNA-PKcs indicated that a part of M-phase cells with DSBs could proceed into the next G1 phase. These results provide evidence showing that a portion of mitotic cell DSBs are undoubtedly repaired through action of the HDR repair pathway.
The disruption of the low-mass globular cluster E 3
Authors: Carballo-Bello Julio A , Salinas Ricardo , Piatti Andrés E
Published: September 2020

We use Gaia DR2 photometry and proper motions to search for the hypothetical tidal tails of the Galactic globular cluster E 3. Using a modified version of a classical decontamination procedure, we are able to identify the presence of an extended structure emerging from the cluster up to r ∼ 1 deg from its centre, thus suggesting that this poorly studied cluster is undergoing a tidal disruption process. These low surface brightness structures are aligned with the direction to the Galactic centre, as expected for a cluster close to its perigalacticon. Different scenarios to explain the important amount of mass lost by this cluster are discussed.
GRB spectrum from gradual dissipation in a magnetized outflow
Authors: Gill Ramandeep , Granot Jonathan , Beniamini Paz
Published: September 2020

Modelling of many gamma-ray burst prompt emission spectra sometimes requires a (quasi) thermal spectral component in addition to the Band function that sometimes leads to a double-hump spectrum, the origin of which remains unclear. In photospheric emission models, a prominent thermal component broadened by sub-photospheric dissipation is expected to be released at the photospheric radius, $r_{\rm ph}\sim 10^{12}\,$ cm. We consider an ultra-relativistic strongly magnetized steady outflow with a striped-wind magnetic-field structure undergoing gradual and continuous magnetic energy dissipation at r < rs that heats and accelerates the flow to a bulk Lorentz factor Γ(r) = Γ∞min [1, (r/rs)1/3], where typically rph < rs. Similar dynamics and energy dissipation rates are also expected in highly variable magnetized outflows without stripes/field-reversals. Two modes of particle energy injection are considered: (a) power-law electrons, e.g. accelerated by magnetic reconnection, and (b) distributed heating of all electrons (and e±-pairs), e.g. due to magnetohydrodynamic instabilities. Steady-state spectra are obtained using a numerical code that evolves coupled kinetic equations for a photon-electron-positron plasma. We find that (i) the thermal component consistently peaks at $(1+z)E_{\rm pk}\sim 0.2-1\,$MeV, for a source at redshift z, and becomes sub-dominant if the total injected energy density exceeds the thermal one, (ii) power-law electrons cool mainly by synchrotron emission whereas mildly relativistic and almost monoenergetic electrons in the distributed heating scenario cool by Comptonization on thermal peak photons, (iii) both scenarios can yield a low-energy break, and (iv) the $\sim 0.5(1+z)^{-1}\,$ keV X-ray emission is suppressed in scenario (a), whereas it is expected in scenario (b). Energy-dependent linear polarization can differentiate between the two particle heating scenarios.
Annexin A2 acts as an adherent molecule under the regulation of steroids during embryo implantation
Authors: Wang Bing , Shao Yan
Published: September 2020

We previously showed that annexin A2 (Axna2) was transiently expressed at the embryo-uterine luminal epithelium interface during the window of implantation and was involved in mouse embryo implantation. At the same time, Axna2 was reported to be upregulated in human receptive endometrium, which was critical for embryo attachment as an intracellular molecule. Here, we identified Axna2 as a membrane-bound molecule on human endometrial epithelial cells and trophoblast cells, and the outer surface membrane-bound Axna2 was involved in human embryo attachment. In addition, physiological levels of estrogen and progesterone increased the expression of overall Axna2 as well as that in the extracellular surface membrane protein fraction in human endometrial cells. Furthermore, p11 (or S100A10, a member of the S100 EF-hand family protein, molecular weight 11 kDa) was involved in the translocation of Axna2 to the outer surface membrane of endometrial epithelial cells without affecting its overall expression. Finally, the surface relocation of Axna2 was also dependent on cell–cell contact and calcium binding. A better understanding of the function and regulation of Axna2 in human endometrium may help us to identify a potential therapeutic target for subfertile and infertile patients.
DNA and RNA editing without sequence limitation using the flap endonuclease 1 guided by hairpin DNA probes
Authors: Tian Kun , Guo Yongjian , Zou Bingjie , Wang Liang , Zhang Yun , Qi Zhen , Zhou Jieying , Wang Xiaotang , Zhou Guohua , Wei Libin , Xu Shu
Published: September 2020

Here, we characterized a flap endonuclease 1 (FEN1) plus hairpin DNA probe (hpDNA) system, designated the HpSGN system, for both DNA and RNA editing without sequence limitation. The compact size of the HpSGN system make it an ideal candidate for in vivo delivery applications. In vitro biochemical studies showed that the HpSGN system required less nuclease to cleave ssDNA substrates than the SGN system we reported previously by a factor of ∼40. Also, we proved that the HpSGN system can efficiently cleave different RNA targets in vitro. The HpSGN system cleaved genomic DNA at an efficiency of ∼40% and ∼20% in bacterial and human cells, respectively, and knocked down specific mRNAs in human cells at a level of ∼25%. Furthermore, the HpSGN system was sensitive to the single base mismatch at the position next to the hairpin both in vitro and in vivo. Collectively, this study demonstrated the potential of developing the HpSGN system as a small, effective, and specific editing tool for manipulating both DNA and RNA without sequence limitation.
Beyond direct neighbourhood effects: higher-order interactions improve modelling and predicting tree survival and growth
Authors: Li Yuanzhi , Mayfield Margaret M , Wang Bin , Xiao Junli , Kral Kamil , Janik David , Holik Jan , Chu Chengjin
Published: September 2020

It is known that biotic interactions are the key to species coexistence and maintenance of species diversity. Traditional studies focus overwhelmingly on pairwise interactions between organisms, ignoring complex higher-order interactions (HOIs). In this study, we present a novel method of calculating individual-level HOIs for trees, and use this method to test the importance of size- and distance-dependent individual-level HOIs to tree performance in a 25-ha temperate forest dynamic plot. We found that full HOI-inclusive models improved our ability to model and predict the survival and growth of trees, providing empirical evidence that HOIs strongly influence tree performance in this temperate forest. Specifically, assessed HOIs mitigate the competitive direct effects of neighbours on survival and growth of focal trees. Our study lays a foundation for future investigations of the prevalence and relative importance of HOIs in global forests and their impact on species diversity.
Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients
Authors: Ulrich Robert J , Troxel Andrea B , Carmody Ellie , Eapen Jaishvi , Bäcker Martin , DeHovitz Jack A , Prasad Prithiv J , Li Yi , Delgado Camila , Jrada Morris , Robbins Gabriel A , Henderson Brooklyn , Hrycko Alexander , Delpachitra Dinuli , Raabe Vanessa , Austrian Jonathan S , Dubrovskaya Yanina , Mulligan Mark J
Published: September 2020

Background

Effective therapies to combat coronavirus 2019 (COVID-19) are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19.

Methods

We conducted a multicenter, double-blind randomized clinical trial of HCQ among patients hospitalized with laboratory-confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for 5 days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite end point (death, intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use) at day 14.

Results

A total of 128 patients were included in the intention-to-treat analysis. Baseline demographic, clinical, and laboratory characteristics were similar between the HCQ (n = 67) and placebo (n = 61) arms. At day 14, 11 (16.4%) subjects assigned to HCQ and 6 (9.8%) subjects assigned to placebo met the severe disease progression end point, but this did not achieve statistical significance (P = .350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend toward an increased length of stay.

Conclusions

In hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed.
DEVELOPMENT OF A SPECIALISED TAPE MEASURE TO ESTIMATE THE SIZE-SPECIFIC DOSE ESTIMATE
Authors: Shohji Tomokazu , Kuriyama Kazuki , Yanano Nobutaka , Katoh Yo
Published: September 2020

The risk in computed tomography (CT) examinations is radiation exposure. We aimed to develop a specialised tape measure for determining the size-specific dose estimate (SSDE) for patients undergoing CT scans. The scanning parameters used were those of the abdominal protocol in our institute. With this method, the SSDE220 and standard deviations obtained from CT images for the liver, pelvic and lung areas, corresponded closely to the SSDEtape and standard deviations obtained using the tape measure. We thus devised a new idea that allows the estimation of the SSDE220 using a specialised tape measure before the CT examination, allowing for an informed explanation of the radiation dose to the patient. Although the tape measure developed in this study is specific to one particular CT instrument, the method could be adapted to a wide range of radiography applications.
ANALYSIS BY SCANNER OF TRACKS PRODUCED BY RADON ALPHA PARTICLES IN CR-39 DETECTORS
Authors: Sabbarese C , Ambrosino F , Roca V
Published: September 2020

The most used passive detectors for Radon measurement are the CR39s, both for the good stability of the material and for the practicality of use. But, commercial reading systems are expensive and not always fast. The aim of the present work was the development of a method for a rapid, efficient and economic evaluation of the result of the indoor Radon measurement performed with CR39 detectors. The analysis and acquisition of detector images were performed using a photo scanner and the free ImageJ software. Several groups of CR-39 detectors were exposed, developed and analysed. Calibration curve was obtained in a wide range of exposure values (200–12 000 kBq·h·m −3) to allow the procedure to be applied in all possible measurement environments. Furthermore, a statistical study was carried out on the shape and size of nuclear tracks after chemical development. The dependence of the track size on Radon exposure was effective in showing the trace saturation effect as well.
REPRODUCIBILITY OF RADON-IN-WATER MEASUREMENTS BY EMANOMETRY TECHNIQUE
Authors: Di Carlo C , Venoso G , Lepore L , Ampollini M , Carpentieri C , Antignani S , Caprio M , Remetti R , Bochicchio F
Published: September 2020

The emanometry test method is one of the detection techniques of radon in water satisfying requirements of Directive 2013/51/Euratom with regards to the detection limit. Quality assurance (QA) procedures were developed and implemented for a measuring system relying on such a technique. These procedures mainly address the following: (i) the assembling of each component of the degassing circuit, (ii) the sample transfer from the transport container to the degassing vessel and (iii) the control of all the influencing quantities. Three identical measuring systems have been used to analyse in parallel 39 water samples with the aim to evaluate the effectiveness of QA procedures in terms of reproducibility. The results showed quite low variability (<15% for the 84% of measurements in the range 10–100 Bq L−1) among the three different measuring systems.
PERIPHERAL RETINAL ANGIOGRAPHIC FINDINGS IN MACULAR TELANGIECTASIS TYPE 2
Authors: Moysidis Stavros N. , Koulisis Nicole , Rao Prethy , Govindaraju Viren K. , Gamsky Samuel , Mahmoud Tamer H. , Randhawa Sandeep , Faia Lisa J. , Wolfe Jeremy D. , Drenser Kimberly A. , Ruby Alan J. , Garretson Bruce R. , Hassan Tarek S. , Williams George A. , Trese Michael T. , Capone Antonio
Published: September 2020

Purpose:

To evaluate the retinal periphery in patients with idiopathic juxtafoveal telangiectasis or macular telangiectasis Type 2 (MacTel2), using widefield fluorescein angiography.

Methods:

Single-center, retrospective, observational case series of 50 eyes of 50 patients with MacTel2 and 50 eyes of 50 age-matched controls.

Results:

Thirty-seven eyes in the MacTel2 group (74%) showed peripheral capillary nonperfusion or dropout, compared with 37 eyes in the control group (74%, P = 1.0). Morphologically, the MacTel2 group trended toward having a higher proportion of pruning-type capillary dropout (44%) compared with controls (28%), but this was not statistically significant (P = 0.12). Patients with MacTel2 had a higher incidence of microaneurysms compared with controls (MacTel2 56%; controls 42%; P = 0.048), independent of age or systemic risk factors. There was no difference in the incidence of venous–venous shunts (MacTel2 10%; controls 10%; P = 1.0), arteriovenous shunts (MacTel2 14%; controls 18%; P = 0.60), venous tortuosity (MacTel2 60%; controls 66%; P = 0.58), or arterial tortuosity (MacTel2 54%; controls 68%; P = 0.20), which was mild in most cases.

Conclusion:

We note a high incidence of peripheral vascular and retinal findings in both patients with MacTel2 and age-matched controls, using widefield fluorescein angiography. Patients with MacTel2 had significantly more microaneurysms, independent of age or other systemic risk factors.
Atypical Endovascular Cells in SARS-CoV-2 Pneumonia
Authors: Barna Nicholas , Chapman Jennifer , Hutchins Kenneth , Garavan Fintan
Published: September 2020

The autopsy findings for 3 cases of SARS-(CoV-2) pneumonia-related deaths are reported with pulmonary histology and immunohistochemistry findings. In 2 cases (cases 1 and 2), the time interval from presentation to death was approximately 1 week, whereas for case 3, the time interval from presentation to death was hours. Case 1 and case 2 presented with shortness of breath, cough, and flu-like symptoms. The decedent from case 3 died shortly after presenting to a local emergency room with high fever, chest and abdominal pain, and shortness of breath. All 3 cases had 1 or more comorbidities. The postmortem interval for cases 1 and 2 was 2 weeks as they died at sea and were stored on board within the respective cruise ships' refrigeration units, whereas case 3 was examined within 24 hours of death. The autopsies were conducted at the Miami-Dade County Medical Examiners Department under routine infectious precautions. Salient clinical history and autopsy findings are summarized. Microscopic examination revealed pneumonia with associated atypical endovascular cells.
Spring-Assisted Surgery for Treatment of Sagittal Craniosynostosis
Authors: Jones Veronica Morgan , Thomas Sydney Gillian , Siska Robert , Massary Dominic , David Lisa Renee , Dillingham Claire Sanger , Crihan Anatolie , Railean Silvia , Runyan Christopher M.
Published: September 2020

Craniosynostosis (CSS), the premature fusion of calvarial sutures, most commonly involves the sagittal suture. Cranial vault remodeling (CVR) is a traditional method of CSS correction. Minimally invasive methods are becoming widely accepted, including spring-assisted surgery (SAS). The equipment required for SAS is minimal therefore adaptable to resource challenged health systems. This paper outlines the experience of SAS in Moldova.

A retrospective study was performed for patients treated with SAS for sagittal CSS from 2011 to 2018 in Moldova. Perioperative data were recorded including age, length of surgery, blood loss, volume transfused and length of stay. Four patients had pre- and post-operative computed tomography (CT) scans which were used to calculate changes in cephalic index, normative cephalic index, and intracranial volume.

Thirteen patients underwent SAS. Diagnoses were made clinically and confirmed with CT. Mean age at surgery was 4.0 months, and length of surgery 62.7 minutes. All but one patient received a blood transfusion, as is standard of practice in Moldova. The mean length of post-operative recovery in ICU was 30.9 hours. No complications required surgical revision. Springs were removed after 4 to 5 months. All patients had a subjective improvement in scaphocephaly. Based on the available CT scans, an increase in cephalic index (7.3%), normative cephalic index (11.8%), and intracranial volume (38.1%) was observed. One patient underwent SAS at 11 months and required cranioplasty for asymmetry at the time of spring removal.

SAS is a safe and cost-effective method of CSS correction that can be utilized in countries with limited health system resources.
Orthoptic Vision Therapy: Establishing a Protocol for Management of Diplopia Following Orbital Fracture Repair
Authors: De Ruiter Brandon J. , Kotha Vikas S. , Peiffer Adam J. , Lesko Robert P. , Tannen Barry , Tannen Noah , Davidson Edward H.
Published: September 2020

Introduction:

Persistent diplopia following orbital fracture is a well-recognized problem. While observation is the standard-of-care, symptoms may be protracted. Orthoptic vision therapy is a form of ocular physical therapy that achieves functional rehabilitation through targeted exercises. This study presents a protocol for post-traumatic orthoptics and describes preliminary results.

Materials and Methods:

Protocols for home-therapy/office-assessment were developed using commercial software and exercises targeting motility and fusion. Office-assessment also included validated questionnaire chronicling symptomatology. Healthy-volunteers (n = 10) trailed the protocol three times (n = 30) and normative data was compiled. Comparative measurements were made in chronic (>1year; n = 8) and acute (<2 weeks; n = 4) fracture cohorts. Time-of-therapy was recorded, monetary cost-analysis performed, and side-effects assessed.

Results:

Severe/moderate motility limitation was found in 3 of 4 acute fracture patients but not in chronic or healthy cohorts. The acute cohort had worse fusion when comparing convergence (mean break/recovery of 8.0/6.5 prism diopters (pd) versus 31.87/21.23pd; P = 0.001/0.015) and divergence (3.00/1.50pd versus 18.37/12.83pd; P = 0.000/0.001) to the healthy cohort. Those with chronic fracture had lower convergence (15.71/5.00pd; P = 0.01/0.001) and divergence (12.29/4.71pd; P = 0.04/0.002) when compared with healthy subjects, but better function than acute patients. Acute fracture patients reported greater symptomatology than chronic (mean score 18.8 versus 4.6; P = 0.003) or healthy (5.0; P = 0.02) groups, but there was no difference between chronic and healthy groups (P = 0.87). Assessment took <10 minutes. Per patient software cost was <$70. Mild eyestrain related to therapy was self-resolving in all cases.

Conclusions:

Orthoptic therapy may improve fusion and motility following orbital fracture. This protocol serves as basis for prospective work.
Diagnosing developmental prosopagnosia: repeat assessment using the Cambridge Face Memory Test
Authors: Murray Ebony , Bate Sarah
Published: September 2020

Developmental prosopagnosia (DP) is a cognitive condition characterized by a relatively selective impairment in face recognition. Currently, people are screened for DP via a single attempt at objective face-processing tests, usually all presented on the same day. However, several variables probably influence performance on these tests irrespective of actual ability, and the influence of repeat administration is also unknown. Here, we assess, for the first known time, the test–retest reliability of the Cambridge Face Memory Test (CFMT)—the leading task used worldwide to diagnose DP. This value was found to fall just below psychometric standards, and single-case analyses revealed further inconsistencies in performance that were not driven by testing location (online or in-person), nor the time-lapse between attempts. Later administration of an alternative version of the CFMT (the CFMT-Aus) was also found to be valuable in confirming borderline cases. Finally, we found that performance on the first 48 trials of the CFMT was equally as sensitive as the full 72-item score, suggesting that the instrument may be shortened for testing efficiency. We consider the implications of these findings for existing diagnostic protocols, concluding that two independent tasks of unfamiliar face memory should be completed on separate days.
The timing and asymmetry of plant–pathogen–insect interactions
Authors: van Dijk Laura J. A. , Ehrlén Johan , Tack Ayco J. M.
Published: September 2020

Insects and pathogens frequently exploit the same host plant and can potentially impact each other's performance. However, studies on plant–pathogen–insect interactions have mainly focused on a fixed temporal setting or on a single interaction partner. In this study, we assessed the impact of time of attacker arrival on the outcome and symmetry of interactions between aphids (
Tuberculatus annulatus
), powdery mildew (
Erysiphe alphitoides
), and caterpillars (
Phalera bucephala
) feeding on pedunculate oak,
Quercus robur
, and explored how single versus multiple attackers affect oak performance. We used a multifactorial greenhouse experiment in which oak seedlings were infected with either zero, one, two, or three attackers, with the order of attacker arrival differing among treatments. The performances of all involved organisms were monitored throughout the experiment. Overall, attackers had a weak and inconsistent impact on plant performance. Interactions between attackers, when present, were asymmetric. For example, aphids performed worse, but powdery mildew performed better, when co-occurring. Order of arrival strongly affected the outcome of interactions, and early attackers modified the strength and direction of interactions between later-arriving attackers. Our study shows that interactions between plant attackers can be asymmetric, time-dependent, and species specific. This is likely to shape the ecology and evolution of plant–pathogen–insect interactions.
Eye size and investment in frogs and toads correlate with adult habitat, activity pattern and breeding ecology
Authors: Thomas Kate N. , Gower David J. , Bell Rayna C. , Fujita Matthew K. , Schott Ryan K. , Streicher Jeffrey W.
Published: September 2020

Frogs and toads (Amphibia: Anura) display diverse ecologies and behaviours, which are often correlated with visual capacity in other vertebrates. Additionally, anurans exhibit a broad range of relative eye sizes, which have not previously been linked to ecological factors in this group. We measured relative investment in eye size and corneal size for 220 species of anurans representing all 55 currently recognized families and tested whether they were correlated with six natural history traits hypothesized to be associated with the evolution of eye size. Anuran eye size was significantly correlated with habitat, with notable decreases in eye investment among fossorial, subfossorial and aquatic species. Relative eye size was also associated with mating habitat and activity pattern. Compared to other vertebrates, anurans have relatively large eyes for their body size, indicating that vision is probably of high importance. Our study reveals the role that ecology and behaviour may have played in the evolution of anuran visual systems and highlights the usefulness of museum specimens, and importance of broad taxonomic sampling, for interpreting macroecological patterns.
Artificial light at night amplifies seasonal relapse of haemosporidian parasites in a widespread songbird
Authors: Becker Daniel J. , Singh Devraj , Pan Qiuyun , Montoure Jesse D. , Talbott Katherine M. , Wanamaker Sarah M. , Ketterson Ellen D.
Published: September 2020

Urban habitats can shape interactions between hosts and parasites by altering not only exposure rates but also within-host processes. Artificial light at night (ALAN) is common in urban environments, and chronic exposure can impair host immunity in ways that may increase infection. However, studies of causal links between this stressor, immunity, and infection dynamics are rare, particularly in migratory animals. Here, we experimentally tested how ALAN affects cellular immunity and haemosporidian parasite intensity across the annual cycle of migrant and resident subspecies of the dark-eyed junco (Junco hyemalis). We monitored an experimental group exposed to light at night and a control group under natural light/dark cycles as they passed through short days simulating early spring to longer days simulating the breeding season, followed by autumn migration. Using generalized additive mixed models, we show that ALAN increased inflammation, and leucocyte counts were greatest in early spring and autumn. At the start of the experiment, few birds had active infections based on microscopy, but PCR revealed many birds had chronic infections. ALAN increased parasitaemia across the annual cycle, with strong peaks in spring and autumn that were largely absent in control birds. As birds were kept in indoor aviaries to prevent vector exposure, this increased parasitaemia indicates relapse of chronic infection during costly life-history stages (i.e. reproduction). Although the immunological and parasitological time series were in phase for control birds, cross-correlation analyses also revealed ALAN desynchronized leucocyte profiles and parasitaemia, which could suggest a general exaggerated inflammatory response. Our study shows how a common anthropogenic influence can shape within-host processes to affect infection dynamics.
Above- and below-ground effects of an ecosystem engineer ant in Mediterranean dry grasslands
Authors: De Almeida T. , Mesléard F. , Santonja M. , Gros R. , Dutoit T. , Blight O.
Published: September 2020

Within a local assemblage, ecosystem engineers can have major impacts on population dynamics, community composition and ecosystem functions by transforming or creating new habitats. They act as an ecological filter altering community composition through a set of environmental variables. The impact of ants on their environment has been widely studied, but their multi-component effects (both trophic and non-trophic) have been rarely addressed. We investigated the roles ofMessor barbarus, one of the commonest harvester ant species in south-western European Mediterranean grasslands. We analysed soil physico-chemical parameters, above-ground vegetation (e.g. species richness, plant community, micro-local heterogeneity, plant biomass) and above- and below-ground fauna (macrofauna, Collembola, Acari and nematodes). A clear and strong local impact ofM. barbaruson soil, vegetation and fauna compartments emerges. The environmental filter is altered by modifications to soil physico-chemical properties, and the biotic filter by changes to plant communities and altered above- and below-ground fauna abundance, occurrence and community structure. The engineering activity ofM. barbarusaffects not only these separate ecosystem components but also the trophic and non-trophic relationships between them. By altering ecological filters at a local scale,M. barbaruscreates habitat heterogeneity that may in turn increase ecological niches in these highly diverse ecosystems.
Comparing DADA2 and OTU clustering approaches in studying the bacterial communities of atopic dermatitis
Authors: Barnes Christopher J. , Rasmussen Linett , Asplund Maria , Knudsen Steen Wilhelm , Clausen Maja-Lisa , Agner Tove , Hansen Anders J.
Published: September 2020

Introduction. The pathogenesis of atopic dermatitis (AD) is not yet fully understood, but the bacterial composition of AD patients’ skin has been shown to have an increased abundance of

Staphylococcus aureus

. More recently, coagulase-negative

Staphylococcus

(CoNS) species were shown to be able to inhibit

S. aureus

, but further studies are required to determine the effects of

Staphylococcus

community variation in AD.

Aim. Here we investigated whether analysing metabarcoding data with the more recently developed DADA2 approach improves metabarcoding analyses compared to the previously used operational taxonomic unit (OTU) clustering, and can be used to study

Staphylococcus

community dynamics.

Methods. The bacterial 16S rRNA region from tape strip samples of the stratum corneum of AD patients (non-lesional skin) and non-AD controls was metabarcoded. We processed metabarcoding data with two different bioinformatic pipelines (an OTU clustering method and DADA2), which were analysed with and without technical replication (sampling strategy).

Results. We found that OTU clustering and DADA2 performed well for community-level studies, as demonstrated by the identification of significant differences in the skin bacterial communities associated with AD. However, the OTU clustering approach inflated bacterial richness, which was worsened by not having technical replication. Data processed with DADA2 likely handled sequencing errors more effectively and thereby did not inflate molecular richness.

Conclusion. We believe that DADA2 represents an improvement over an OTU clustering approach, and that biological replication rather than technical replication is a more effective use of resources. However, neither OTU clustering nor DADA2 gave insights into

Staphylococcus

community dynamics, and caution should remain in not overinterpreting the taxonomic assignments at lower taxonomic ranks.
Proteomics identifies a type I IFN, prothrombotic hyperinflammatory circulating COVID-19 neutrophil signature distinct from non-COVID-19 ARDS
Authors: Reyes Leila , Sanchez-Garcia Manuel A. , Morrison Tyler , Howden Andrew J.M. , Watts Emily R. , Arienti Simone , Sadiku Pranvera , Coelho Patricia , Mirchandani Ananda S , Hope David , Clark Sarah K. , Singleton Jo , Johnston Shonna , Grecian Robert , Poon Azin , Mcnamara Sarah , Harper Isla , Fourman Max Head , Brenes Alejandro J. , Pathak Shalini , Lloyd Amy , Blanco Gio Rodriguez , Kriegsheim Alex von , Ghesquiere Bart , Vermaelen Wesley , Cologna Camila T. , Dhaliwal Kevin , Hirani Nik , Dockrell David , Whyte Moira K. , Griffith David , Cantrell Doreen A. , Walmsley Sarah R.
Published: September 2020

Understanding the mechanisms by which infection with SARS-CoV-2 leads to acute respiratory distress syndrome (ARDS) is of significant clinical interest given the mortality associated with severe and critical coronavirus induced disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS, but a relative paucity of these cells is observed at post-mortem in lung tissue of patients who succumb to infection with SARS-CoV-2. With emerging evidence of a dysregulated innate immune response in COVID-19, we undertook a functional proteomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS, non-COVID-19 ARDS, moderate COVID-19, and healthy controls. We observe that expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in both COVID-19 and non-COVID-19 ARDS. In contrast, release of neutrophil granule proteins, neutrophil activation of the clotting cascade and formation of neutrophil platelet aggregates is significantly increased in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I IFN responses is specific to infection with SARS-CoV-2 and linked to metabolic rewiring. Together this work highlights how differential activation of circulating neutrophil populations may contribute to the pathogenesis of ARDS, identifying processes that are specific to COVID-19 ARDS.
A Cost/Benefit Analysis of Clinical Trial Designs for COVID-19 Vaccine Candidates
Authors: Berry Donald A. , Berry Scott , Hale Peter , Isakov Leah , Lo Andrew W. , Siah Kien Wei , Wong Chi Heem
Published: September 2020

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional randomized clinical trials and adaptive and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 504 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits—averting an additional 1.1M infections and 8,000 deaths in the U.S. compared to the next best clinical trial design—if its set-up time is short or the pandemic spreads slowly. In most of the other cases, an adaptive trial provides greater net benefits.
Inflammatory leptomeningeal cytokines mediate delayed COVID-19 encephalopathy
Authors: Remsik Jan , Wilcox Jessica A. , Babady N. Esther , McMillen Tracy A. , Vachha Behroze A. , Halpern Neil A. , Dhawan Vikram , Rosenblum Marc , Iacobuzio-Donahue Christine A. , Avila Edward K. , Santomasso Bianca , Boire Adrienne
Published: September 2020

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction. Here we show that a particularly vulnerable population with neurologic manifestations of COVID-19 harbor an influx of inflammatory cytokines within the cerebrospinal fluid in the absence of viral neuro-invasion. The majority of these inflammatory mediators are driven by type 2 interferon and are known to induce neuronal injury in other disease models. Levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks following convalescence from the acute respiratory infection. These prolonged neurologic sequelae following a systemic cytokine release syndrome lead to long-term neurocognitive dysfunction with a wide range of phenotypes.
Clinically distinct COVID-19 cases share strikingly similar immune response progression: A follow-up analysis
Authors: Hausburg Melissa A. , Banton Kaysie L. , Roshon Michael , Bar-Or David
Published: September 2020

Inflammatory responses to the novel coronavirus SARS-CoV-2, which causes COVID-19, range from asymptomatic to severe. Here we present a follow-up analysis of a longitudinal study characterizing COVID-19 immune responses from a father and son with distinctly different clinical courses. The father required a lengthy hospital stay for severe symptoms, whereas his son had mild symptoms and no fever yet tested positive for SARS-CoV-2 for 29 days. Father and son, as well as another unrelated COVID-19 patient, displayed a robust increase of SERPING1, the transcript encoding C1 esterase inhibitor (C1-INH). We further bolstered this finding by incorporating a serum proteomics dataset and found that serum C1-INH was consistently increased in COVID-19 patients. C1-INH is a central regulator of the contact and complement systems, potentially linking COVID-19 to complement hyperactivation, fibrin clot formation, and immune depression. Furthermore, despite distinct clinical cases, significant parallels were observed in transcripts involved interferon and B cell signaling. As symptoms were resolving, widespread decreases were seen in immune-related transcripts to levels below those of healthy controls. Our study provides insight into the immune responses of likely millions of people with extremely mild symptoms who may not be aware of their infection with SARS-CoV-2 and implies a potential for long-lasting consequences that could contribute to reinfection risk.
Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men
Authors: Huynh-Le Minh-Phuong , Karunamuni Roshan , Fan Chun Chieh , Thompson Wesley K. , Muir Kenneth , Lophatananon Artitaya , Tye Karen , Wolk Alicja , Håkansson Niclas , Mills Ian G. , Andreassen Ole A. , Dale Anders M. , Seibert Tyler M. ,   The PRACTICAL Consortium
Published: September 2020

Background

Clinical variables—age, family history, genetics—are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death.

Methods

Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n=3,279; 2,163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests.

Results

Median age at last follow-up/prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95%CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.370.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p<10-15).

Conclusions

PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history.

Impact

Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.
Genome-wide association analysis of the human thalamus identifies novel genomic loci and reveals genetic overlap with distinct cortical regions and ten brain disorders
Authors: Elvsåshagen Torbjørn , Shadrin Alexey , Frei Oleksandr , van der Meer Dennis , Bahrami Shahram , Kumar Vinod Jangir , Smeland Olav , Westlye Lars T. , Andreassen Ole A. , Kaufmann Tobias
Published: September 2020

The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions1-8. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders9-12, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identified 42 (41 novel) genetic loci and 392 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5,173) 96% of the loci showed the same effect direction (sign test, P = 8.6e-14). We mapped the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and found overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders revealed shared variants for all disorders. Together, these analyses identify the first genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.