bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of macular oedema on microvascular and metabolic alterations in retinitis pigmentosa
Authors: Waizel Maria , Scholl Hendrik P.N. , Todorova Margarita G.
Published: January 2021

Purpose

The primary aim of our study was to evaluate retinal microvascular anomalies recorded with optical coherence tomography angiography (OCTA) and the retinal metabolic function measured with retinal oximetry (RO) in patients with retinitis pigmentosa (RP). The secondary aim of the study was to link the presence of macular oedema to evaluated microvascular and metabolic parameters in RP.

Methods

OCTA and RO were performed on 94 eyes: 64 eyes diagnosed with RP with (ME‐RP) and without (no‐ME‐RP) macular oedema were compared to 30 control eyes. Study endpoints were: mean superficial (FAZ‐S) and deep foveal avascular zone (FAZ‐D) determined by OCTA. In addition, we evaluated the mean arterial (A‐SO2; %), venular (V‐SO2; %) oxygen saturation, their difference (A‐V SO2; %), as well as the corresponding mean diameter of the retinal arterioles (D‐A; μm) and venules (D‐V; μm).

Results

RP patients differed from controls by enlarged FAZ‐S and FAZ‐D (p ≥ 0.001), attenuated retinal vessels (p < 0.001) and increased retinal vessel oxygen saturation (p ≥ 0.010). Subgroup analyses within RP patients revealed more pronounced alterations of microvascular parameters and metabolic function in the presence of macular oedema. In the no‐ME‐RP subgroup, significant interactions were present between FAZ‐S, A‐SO2 and V‐SO2, whereas in the ME‐RP subgroup, we found significant correlations between FAZ‐D and D‐A.

Conclusion

A combined microvascular structure‐metabolic function approach enhances our understanding of inherited retinal diseases. The presence of macular oedema in retinitis pigmentosa seems to be a result of more altered microvascular‐metabolic function. However, its presence should be taken into consideration, as it may also influence the interpretation of the results.
Preclinical study in a corneal bioreactor of the effectiveness of amniotic membrane of umbilical cord extract (AMUCE) for the treatment of corneal epithelial ulcerations
Authors: Crouzet Emmanuel , Peyret Benjamin , Poinard Sylvain , Garcin Thibaud , Dumollard Jean‐Marc , Barnouin Laurence , Thuret Gilles , Gain Philippe
Published: January 2021

Purpose

Our patented corneal bioreactor (BR) improves the survival of human corneas ex vivo in the long term by restoring intraocular pressure and renewal of storage medium in a sterile environment.

Aim

To use the BR to test the efficacy of eye drops containing devitalized ground amniotic membrane of umbilical cord extract (AMUCE) to treat epithelial ulcerations. AMUCE contains high level of proteoglycans, collagen and physiological growth factors.

Methods

Only pairs of human corneas were used to obtain best possible controls. They were either corneas discarded by our eye bank (cell density between 800 and 2000 cells/mm2) or specific donation for research (normal corneas). They were first stored for 2 weeks into the BR filled with CorneaMax (Eurobio, France), with 21 mmHg in the endothelial chamber to allow regeneration of a normal epithelium as previously shown. Then, a 6.0 mm diameter calibrated epithelial ulcer was made. Using a specific BR lid allowing sterile handling, each cornea was treated topically 3 times daily either by the AMUCE eye drops (TBF, France) or by the vehicle (0.9% NaCl). Closure of the ulceration was monitored daily using fluorescein staining quantified by image analysis (FIJI) of macro‐zoom microscopy. After wound healing corneas were fixed for histology (Hematein Eosin Saffron) and immunolabeling of epithelial markers.

Results

Three pairs were used. Wound healing was obtained at D3, D7, D5 with the AMUCE and D3, D6, D6 with the vehicle (no significant difference). Nevertheless, drug‐treated corneas had a thicker epithelium than with vehicle only. Histology and immunolabeling for E‐Cadherin and cytokeratin K3/K12 confirmed that epithelium of AMUCE‐treated corneas was more differentiated than with vehicle only.

Conclusions

The BR allows controlled studies of epithelial wound healing on human corneas with repeated instillations. By improving epithelial maturation, AMUCE eye drop is an interesting candidate for epithelium regeneration.
Key role of fibronectin for Staphylococcus aureus adherence to ex vivo corneal epithelium
Authors: Maurin Corantin , Courrier Emilie , He Zhiguo , Josselin Rigaill , Frédéric Laurent , Thuret Gilles , Gain Philippe , Verhoeven Paul
Published: January 2021

Purpose

Staphylococcus aureus (SA) is the second most frequent pathogen of bacterial keratitis. Fibronectin‐binding proteins (FnBPs) which are staphylococcal adhesins are found in 95% of clinical isolates and are shown to be important adhesins or invasion factors in ulcerative keratitis. Aim: to study the role of the fibronectin (Fn) in SA adherence on corneal epithelium and its role in the initiation of the keratitis.

Methods

We used 4 strains of SA: 8325‐4 and DU5883 (8325‐4 isogenic strain lacking in fnbA/B), and SA113 and SA113 srtA‐ (Isogenic strain lacking in Sortase A). Levels of internalisation were measured by lysostaphin protection assay on human corneal epithelial HCE‐2 cells. SA adherence level was calculated by determining the ratio between the SA area and area of corneal epithelial ulceration blocked by Fn antibodies or not. The surface of epithelial ulceration was defined with Fn immunostaining.

Results

On cells, intracellular loads of 8325‐4 and DU5883 strains were, respectively, 4.2 and 2.6 log CFU/106 cells (p < 0.0001) and intracellular loads of SA113 and SA113 srtA‐ strains were, respectively, 4.3 and 3.9 log CFU/106 cells (p < 0.0001). Onto intact and injured corneal epithelium, SA (8325‐4) adherence level was, respectively, 0.04 and 4.36 MFI (Mean Fluorescence Intensity) (p = 0.0003). On injured corneal epithelium, adherence level of 8325‐4 and DU5883 was significantly reduced from 3.7% to 0.5%, respectively (p < 0.001), whereas adherence level of SA113 Wt and srtA‐ was not significantly reduced from 1.5% to 0.7%, respectively (p = 0.1873). Blockage of Fn showed a significant decrease of 87%, 85% and 86% of the 8325‐4, SA13 WT and SA113 SrtA‐ adhesion level, respectively, but a not significant decrease for DU5883 (43%).

Conclusions

Capacity of SA to bind the epithelium of intact cornea was weak, whereas corneal epithelium ulceration significantly increased its adherence. Adherence is mediated by the presence of Fn inside the epithelium, FnBPs and adhesine proteins in SA.
Study of mechanotransduction in the endothelium of stored human corneas
Authors: Ben Moussa Olfa , Vaïtinadapoulé Hanielle , He Zhiguo , Perrache Chantal , Gain Philippe , Thuret Gilles , Mascarelli Frederic
Published: January 2021

Purpose

Corneal endothelial cells (ECs) are continuously exposed to two physical stimuli: intraocular pressure (IOP) on their apical surface and contact with the Descemet membrane on their basal surface. We suppose that IOP could act on mechanoreceptors which could induce mechanotransduction in ECs: YAP (Yes Associated Protein) a transcriptional coactivator and Zo‐1 included in apical tight‐junctions. In numerous cell types, mechanical stimuli induce YAP nuclear translocation, which regulates genes expression involved in cell survival.

Aim

To study the localization of YAP in human ECs and its link with Zo‐1 homeostasis, using our corneal bioreactor (BR) capable of restoring a transcorneal pressure gradient equivalent to the IOP.

Methods

Human corneas were placed in the BR, during 14 days at 21 mmHg with circulation of a storage medium (CorneaMax, Eurobio, France). For control, paired corneas were stored in a flask without IOP in the same medium. Immunolabelling for YAP and Zo‐1 was done on paraformaldehyde of methanol fixed whole corneas by incubating primary and secondary antibodies on the endothelial side only. After flat mount, the entire endothelium was observed by epifluorescence microscope (IX81, Olympus, Japan).

Results

Several endothelial areas of corneas stored in the BR had regular hexagonal EC, well‐organized tight‐junctions, and a homogeneous nuclear localization of YAP. Corneas stored without IOP presented some areas without EC and other areas covered by EC with irregular shape, disorganized tight‐junctions and an heterogeneous localization of YAP, with some cells having focal expression in their nucleus and others cytoplasmic expression.

Conclusions

The bioreactor is a promising tool to study the role of mechanotransduction in human EC survival and function. IOP seems able alter expression of YAP and of Zo‐1. IOP‐induced nuclear translocation of YAP in various corneal areas seems linked with integrity of tight‐junctions.
Dropless penetrating keratoplasty: immunosuppression by a subconjunctival dexamethasone implant, pilot tolerance and safety study
Authors: Thuret Gilles , Caroline Trone Marie , Crouzet Emmanuel , Ronin Caroline , Garcin Thibaud , Poinard Sylvain , Gain Philippe
Published: January 2021

Purpose

Penetrating keratoplasty (PK) remains the first technic of corneal transplantation worldwide and rejection a common cause of graft failure. Its prevention has been based for decades on repeated instillation of steroid eye drops (dexamethasone, prednisolone, rimexolone). Nevertheless, the overall survival of corneal transplants, all indications combined, is lower than that of some organ transplants. Both compliance and the discontinuous nature of the eye drops may be involved. The improvement of immunosuppression could avoid numerous graft failures. In a rabbit model of PK, we previously demonstrated that a subconjunctival dexamethasone implant (Ozurdex) was well tolerated and prevented rejection as efficiently as steroid eye drops trice daily during the first 5‐6 weeks. We then designed a clinical trial to first investigate the tolerance and safety of subconjunctival Ozurdex after PK.

Methods

Single centre, phase II non‐randomized tolerance and safety pilot study on 14 patients (NCT02834260). Designed to analyze the risk of increased intraocular pressure (IOP, primary endpoint at month 1), possible discomfort, resorption time, and collect initial efficacy data. The implant was injected at the 12 o'clock position, 5 mm from the limbus, at the end of PK, in order to deliver dexamethasone immediately. A steroid eye drop relay was planned at the time of complete resorption of the implant. Patients were monitored at regular intervals during 12 months: IOP, discomfort and redness scores, implant status, rejection episode, endothelial cell density, and central corneal thickness by OCT. An independent adverse event committee gave its opinion after the first patient, then at regular intervals.

Results

No increase in IOP, no adverse event related to the implant was observed. The average duration of resorption was 6 weeks. The therapeutic relay with dexamethasone eye drops was uneventful.

Conclusions

His is the first proof of concept that dropless immunosuppression is possible after penetrating keratoplasty. Ozurdex, chosen here because it was the only ophthalmological steroid implant marketed in France, obviously resorbs too quickly, but this work paves the way for the use of other implants that release a steroid or another immunosuppressive agent in the very long term.
Optical coherence tomography angiography findings in transcorneal electrical stimulation in retinitis pigmentosa
Authors: Maria Zabek Olga , Camenzind Zuche Hanna , Müller Ursula , Scholl Hendrik P. N. , Rickmann Annekatrin , Della Volpe Waizel Maria
Published: January 2021

Purpose

Transcorneal electrical stimulation (TES) is a novel treatment approach for patients with retinitis pigmentosa (RP). The aim of our study was to observe changes in optical coherence tomography angiography (OCTA) that would be attributed to TES treatment.

Methods

A total of 43 eyes of 22 subjects (11♀ 11♂) suffering from RP were examined at baseline (BL), after first stimulation (TS), 1 week after first stimulation (1W) and six months (6M) after treatment initiation. TES was performed simultaneously on both eyes for 30 minutes weekly. 9 × 15 mm OCTA scans were recorded with a PLEX Elite 9000 swept‐source OCTA device (Carl Zeiss Meditec AG, Jena). Vascular density metrics as perfusion density (PD) and vessel density (VD) were calculated automatically for the macular area by using standardized ETDRS grids. In addition, the capillary perfusion density (CPD) and the capillary flux index (CFI) of the peripapillary nerve fibre layer microvasculature in all four quadrants of an annulus centred at the optic disc were measured. All parameters were determined over all retinal layers and separately for the superficial (SCP) and deep capillary plexus (DCP). ANOVA‐based linear mixed‐effects models were calculated with SPSS®.

Results

Throughout the course of TES treatment, the macular VD and PD of all retinal layers in all subsections showed a slight decrement without reaching statistical significance (p > 0.05), also when analysed separately in the SCP (p > 0.06) and DCP (p > 0.11). In analogy, the average CPD and CFI also presented with a slight decrement (p > 0.19). When analysed in subsections, the temporal macular subsections showed significantly lower VD and PD values when compared to the other subsections of the ETDRS grid.

Conclusions

Our preliminary data with SS‐OCTA indicate that vascular density metrics in the macular region and the peripapillary microvasculature remain unaffected despite ongoing TES treatment.
Eyelid melanoma: a population‐based comparative analysis of the lentigo, superficial spreading, and nodular subtypes
Authors: Mikhael Sandra , Tadrosse Abanoob , Yassa Arsany , Mikhael Mina , Eloy Jean‐Anderson
Published: January 2021

Purpose

To study the epidemiological and survival trends of the most common eyelid melanoma (EM) subtypes, which are lentigo melanoma (LM), superficial spreading melanoma (SSM) and Nodular Melanoma (NM).

Methods

Data were extracted from the Surveillance, Epidemiology, and End Results U.S. cancer database. Incidence (IR) data were available from 2000 to 2017 and were calculated in number of cases/million/year. IR trends across the study’s timeframe were assessed by measuring the annual percent change (APC). 5‐year overall survival (OS) was calculated over the timeframe 1973–2011 using the Kaplan‐Meier method.

Results

A total of 570 cases with known melanoma subtypes were identified. The most common subtype was LM (41.0%), followed by SSM (35.2%), then NM (13.8%). IR for LM (0.153) was statistically higher than for NM (0.051, p < 0.001), but not for SSM (0.130, p = 104). Mean diagnostic ages in years were statistically different: LM (72.16), SSM (64.12), NM (69. 72) [p < 0.001]. From 2000 to 2017, IR increased for LM (APC 3.17, p = 0.034) but did not significantly change for SSM and NM. 5‐year OS was significantly lower for NM (57.0%) as compared to that of LM (73.8%) and SSM (81.0%) [p < 0.001]. Older age was a negative prognostic factor for all subtypes as patients older than 85 years old had the worst survival compared to all other age groups (LM 34.6%, SSM 47.6% and NM 30.0%) [p < 0.01]. Females showed higher survival patterns than males in LM (81.4% and 66.7%, p = 0.03) and SSM (89.1% and 74.1%, p=0.008), but there were no gender survival differences for the NM subtype (p = 0.405). Race and stage did not significantly affect survival in any of the three subtypes.

Conclusions

Among EM subtypes, incidence is highest for LM and SSM. Mean diagnostic age is significantly lowest in SSM. NM subtype portends the worst prognosis. Older age is a negative prognostic factor for all subtypes, while male gender portends a negative prognosis only in LM and SSM. Race and stage did not impact survival outcomes.

Bibliography

Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) version 8.3.6.
Corneal cross‐linking in advanced keratoconus, is it still effective?
Authors: Alenezi Bandar , Khoyratty Fadil , Biswas Susmito , Radhakrishnan Hema
Published: January 2021

Purpose

The study aims to investigate the effectiveness of corneal cross‐linking (CXL) treatment in keratoconus patients.

Methods

A total of 167 eyes of 159 progressive keratoconic patients (109 males and 58 females) aged 19 to 52 years old were included in the study. Epithelium debridement was performed for all patients, followed by riboflavin and UV‐A accelerated CXL (9.86 mW/cm2 for 9 min). To explore the effect of keratoconus severity on CXL outcomes, patients were divided into two groups based on the preoperative measurements of maximum keratometry (Kmax): Group A (Kmax < 62D) and Group B (Kmax ≥ 62 D). Corrected distance visual acuity (CDVA), corneal curvature and thickness were measured pre‐CXL and at 1, 2 and 3 years post‐CXL treatment using the Oculus Pentacam.

Results

Results showed a significant improvement in CDVA on logMAR chart (0.19 ± 0.41, p = 0.04) at 3 years follow‐up. Kmax reduced significantly by 1.61 ± 3.02D, p = 0.02 (from 64.35 ± 6.85D to 63.19 ± 6.99D) at 3 years after CXL. Pachymetry measurements showed a significant reduction at 1 year (p = 0.01), 2 years (p = 0.00005) and 3 years (p = 0.000002) following CXL. CXL induced a significant reduction in Kmax measurements in Group A at 3 years follow‐up (1.50 ± 2.17D, p = 0.02); however, there was no significant change observed at 3 years following CXL in Group B (p = 0.19). Kmax reduced or at least stabilised in all patients in Group A at 3 years follow‐up; however, 25% of eyes in Group B showed a Kmax worsening of ≥1D.

Conclusions

The findings of the current study show the effectiveness of CXL to stabilise the progression of keratoconus and significantly improve corneal curvature measurements. The progression of keratoconus is more likely to stabilise after CXL in eyes with lower Kmax measurements.
A comparative epidemiological analysis of epithelioid, spindle cell, and mixed epithelioid‐spindle cell tumor subtypes of uveal melanoma, 1973–2016
Authors: Tadrosse Abanoob , Mikhael Sandra , Tadrosse Marina , Mikhael Mina , Eloy Jean A.
Published: January 2021

Purpose

To compare the epidemiology of epithelioid (ED), spindle cell (SC), and mixed epithelioid‐spindle cell (MES) tumor subtypes of uveal melanoma (UM).

Methods

Data were extracted from the Surveillance, Epidemiology, and End Results U.S. cancer database from 1975 to 2016. Incidence (IR) was estimated in number of cases/million/year. Incidence (IR) trends across the study's timeframe were assessed by measuring the annual percent change (APC). Disease‐specific survival (DSS) was calculated using the Kaplan‐Meier method. Cox regression analyses were conducted to evaluate hazard ratios (HR).

Results

Two thousand nine hundred thirty‐eight cases were identified: MES‐UM (38%), SC‐UM (49%), ED‐UM (13%). Diagnostic age in years was significantly different (MES‐UM, 63; SC‐UM, 58; ED‐UM, 63; p < 0.01). Incidence (IR) also differed: MES‐UM, 0.8; SC‐UM, 0.7; ED‐UM, 0.2 (p < 0.01). Incidence (IR) declined over the study's time period with APC values of −4.5 (p < 0.01; MES‐UM), −2.8 (p < 0.01; SC‐UM), and −2.7 (p = 0.04; ED‐UM). Five‐year DSS for patients diagnosed during 1995–2000 were 74.6% (MES‐UM), 86.4% (SC‐UM), and 56.2% (ED‐UM). In comparison, Five‐year DSS during 2006–2011 was similar for SC‐UM (91.8%; p = 0.07) and ED‐UM (58.4%; p = 0.35), but significantly declined for MES‐UM (57.6%; p < 0.01). MES‐UM patients aged 30‐50 years old exhibited favorable prognosis compared to older or younger ones (HR: 0.53; p = 0.023). Asian and black races portended poor prognoses for ED‐UM (HR: 2.7; p = 0.04) and SC‐UM (HR: 2.9; p = 0.03), respectively. Advanced stage at diagnosis was not a survival predictor in MES‐UM patients, but it predicted poor prognosis in ED‐UM (HR: 4.8; p < 0.01) and SC‐UM (HR: 5.7; p < 0.001).

Conclusions

Diagnostic age is youngest for SC‐UM. Incidence (IR) for all subtypes has declined. Disease‐specific survival (DSS) was stable over the study’s timeframe for SC‐UM and ED‐UM but substantially worsened for MES‐UM. Age impacts MES‐UM prognosis. Asian and black races are negative prognostic factors for ED‐UM and SC‐UM, respectively. Disease stage is a survival predictor only for ED‐UM and SC‐UM.
Suicide in France: Some Hypotheses
Authors: Farber Maurice L.
Published: January 2021

ABSTRACT: The relatively high suicide rate in France is investigated and a number of influences are hypothesized as causative. These include, on a societal and demographic level, a history of high immigration, low emigration, a high proportion of old people, high urbanization, extraordinarily high alcoholism, and the extreme gap in income between upper and lower classes. The rigid bureaucracy of the state can leave the individual feeling infuriated and defeated. The legal system produces many injustices, such as long imprisonment without charges. The Church is liberal and supplies little prophylaxis against suicide. Overall, social integration must be judged to be low. Culturally, French values include an underlying pessimism, no strong fear of death, strong pressures to behave correctly and much malice toward neighbors. The modal personality structure contains defensive, constricted elements producing a vulnerable pseudo‐autonomy. French child‐rearing practices are effective in producing such personalities.
Effect of anionic substitution on the high temperature stability of polymer‐derived SiOC glasses
Authors: Sorarù Gian Domenico , Girardini Katia , Narisawa Masaki , Biesuz Mattia
Published: January 2021

In this study the high temperature stability (crystallization and decomposition) of two silicon oxycarbide glasses with a similar amount of free carbon (8.3 vs 9.6 wt%) but different content of Si‐C bonds (SiC0.22O1.57 vs SiC0.07O1.86) is presented. The two SiOC glasses are obtained from the same precursor (2 µm methyl‐silsesquioxane spheres) via pyrolysis at 1100°C in inert (Ar) or reactive (CO2) atmospheres. Further annealing in Ar flow at temperatures above 1100°C and up to 1500°C is performed and the samples are characterized by Fourier Transformed Infrared Spectroscopy (FT‐IR) and X‐ray diffraction (XRD). For comparison purposes the same precursor was annealed in air flow to obtain SiO2 and its high temperature evolution is also studied. Results suggest that the onset for the carbothermal reduction is not dependent on the amount of Si‐C bonds. Moreover, contrary to what is usually reported in the scientific literature, silica phase present in the SiOC glasses does not show, in the same experimental conditions, superior crystallization resistance compared to pure silica glass.
Full‐mouth adhesive rehabilitation of a severe case of erosion treated with v‐shaped veneers
Authors: Dallari Giacomo , Scalzo Ivan , Rosati Riccardo Maria , Sampaio Camila Sobral , Hirata Ronaldo
Published: January 2021

Objective

To demonstrate a minimally invasive approach of a full‐mouth rehabilitation of a severe case of erosion treated with v‐shaped veneers, tabletops, overlays, veneerlays, laminate veneers, and a full contour veneer.

Clinical considerations

The present case report successfully rehabilitated a full‐mouth case of severely eroded teeth with minimal healthy structure removal, maintaining viability of all teeth that were vital before the treatment started, and promoting long‐lasting esthetic and functional results after 3 years of use.

Conclusions

A deep knowledge of etiology, etiopathogenesis, and classifications of dental erosion will guide the clinician in the right direction for solving this issue correctly, according to modern prosthetic and conservative principles.

Clinical significance

Dental erosion represents today a relatively widespread phenomenon among the global population and a significant challenge in each of its clinical stages for the clinicians who must treat it. In advanced stages, a careful evaluation phase of the case, a great patient motivation and a wise use of materials and clinical protocols are the success key of the case. Moreover, an advanced knowledge of adhesive dentistry is strictly required to successfully manage a severe erosion case with a modern and minimally invasive approach.
Reply to: Comment on: Virtual funerals: A feasible and safer option during the COVID‐19 pandemic
Authors: Muturi Ivy , Freeman Shannon , Banner Davina
Published: January 2021

This letter comments on the letter by Fredrick Sherman.
Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer’s disease (MCI and dementia) in primary care: a review and synthesis
Authors: Liss J. L. , Seleri Assunção S. , Cummings J. , Atri A. , Geldmacher D. S. , Candela S. F. , Devanand D. P. , Fillit H. M. , Susman J. , Mintzer J. , Bittner T. , Brunton S. A. , Kerwin D. R. , Jackson W. C. , Small G. W. , Grossberg G. T. , Clevenger C. K. , Cotter V. , Stefanacci R. , Wise‐Brown A. , Sabbagh M. N.
Published: January 2021

The critical role of primary care clinicians (PCCs) in Alzheimer’s disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease‐modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late‐in‐life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker‐confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker‐defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.
The Effect of Build Orientation on the Dimensional Accuracy of 3D‐Printed Mandibular Complete Dentures Manufactured with a Multijet 3D Printer
Authors: Gao Hanqi , Yang Zhen , Lin Wei‐Shao , Tan Jianguo , Chen Li
Published: January 2021

Purpose

To compare the dimensional accuracy of 3D‐printed mandibular complete dentures with different build orientations.

Material and Methods

A mandibular complete denture was digitized as a virtual reference file. The reference file was 3D‐printed at the 0°, 45°, and 90° build orientations with a MultiJet 3D printer (Projet MJP 3600 Dental, 3D systems, Rock Hill, SC). A total of 27 complete dentures were 3D‐printed with 9 samples for each orientation. All printed dentures were digitized and separated into teeth, denture extension and intaglio test surfaces. The dimensional accuracy (in root mean square, RMS) was evaluated by comparing whole denture and 3 test surfaces with the reference file. One‐way analysis of variance (ANOVA) and a Post‐Hoc all pairs Bonferroni test were used to determine statistical differences (α = 0.05).

Results

For the dimensional accuracy on whole denture, the 45° build orientation group showed the smallest RMS (0.170 ± 0.043 mm) than those of the 0° build orientation group (0.185 ± 0.060 mm, p < 0.001) and 90° build orientation group (0.183 ± 0.044 mm, p < 0.001). For the dimensional accuracy on the teeth, denture extension and intaglio test surfaces, the 45° build orientation group also show the smallest RMS values (0.140 ± 0.044 mm at teeth surface, 0.176 ± 0.058 mm at denture extension and 0.207 ± 0.006 mm at intaglio surface). The 0°and 90° build orientation groups had similar accuracy at the teeth (0.149 ± 0.056 mm versus 0.154 ± 0.056 mm, p = 0.164) and denture extension surfaces (0.200 ±0.025 mm vs 0.196 ± 0.013 mm, p = 1.000). However, 0° build orientation group (0.228 ± 0.010 mm) has significantly higher RMS values then those of 90° build orientation group (0.218 ± 0.057 mm) in the intaglio surface (p = 0.032). The teeth surfaces were most accurate in each build orientation groups, while the intaglio surfaces were least accurate.

Conclusions

The build orientation affected the dimensional accuracy of 3D‐printed mandibular complete dentures, and the 45° build orientation resulted in the most accurate 3D‐printed denture from a MultiJet 3D printer.
Longer term outcomes following serogroup B invasive meningococcal disease
Authors: Deng Lucy , Barton Belinda , Lorenzo Jennifer , Rashid Harunor , Dastouri Fereshteh , Booy Robert
Published: January 2021

Aim

To characterise the physical, psychological, and quality of life burden associated with serogroup B invasive meningococcal disease (IMD) in children.

Methods

Children aged up to 14 years at the time of serogroup B IMD, who were admitted to intensive care units of two tertiary paediatric hospitals in New South Wales, Australia between January 2009 and December 2013 were recruited. Children underwent clinical and neuropsychological assessments up to 6 years post‐disease.

Results

Eleven children were assessed, with a median age of 16 months (range 4–46 months) at time of disease. The median follow‐up time was 50 months (range 10–67 months). Seven (63.6%) cases had one or more long‐term sequelae involving permanent and evolving physical disability. Three cases had ongoing medical conditions including two with seizures and one with ataxia and hypermetropia. Five required ongoing medical and allied health care. Other complications identified included anxiety, speech delay, low average full‐scale IQ score (median 85, interquartile range 89–103) and borderline memory impairment.

Conclusions

Serogroup B IMD is associated with significant long‐term morbidity and burden on the child and family with substantial economic implications. The impact of this on the total cost of IMD needs to be further quantified, and better considered in vaccine cost‐effectiveness analyses.
A (conditional) role for labdane‐related diterpenoid natural products in rice stomatal closure
Authors: Zhang Juan , Li Riqing , Xu Meimei , Hoffmann Rachel I. , Zhang Yushi , Liu Bo , Zhang Mingcai , Yang Bing , Li Zhaohu , Peters Reuben J.
Published: January 2021

Rice (Oryza sativa) is the staple food for over half the world’s population. Drought stress imposes major constraints on rice yields. Intriguingly, labdane‐related diterpenoid (LRD) phytoalexins in maize (Zea mays) affect drought tolerance, as indicated by the increased susceptibility of an insertion mutant of the class II diterpene cyclase ZmCPS2/An2 that initiates such biosynthesis. Rice also produces LRD phytoalexins, utilizing OsCPS2 and OsCPS4 to initiate a complex metabolic network.

For genetic studies of rice LRD biosynthesis the fast‐growing Kitaake cultivar was selected for targeted mutagenesis via CRISPR/Cas9, with an initial focus on OsCPS2 and OsCPS4. The resulting cps2 and cps4 knockout lines were further crossed to create a cps2x4 double mutant. Both CPSs also were overexpressed.

Strikingly, all of the cv Kitaake cps mutants exhibit significantly increased susceptibility to drought, which was associated with reduced stomatal closure that was evident even under well‐watered conditions. However, CPS overexpression did not increase drought resistance, and cps mutants in other cultivars did not alter susceptibility to drought, although these also exhibited lesser effects on LRD production.

The results suggest that LRDs may act as a regulatory switch that triggers stomatal closure in rice, which might reflect the role of these openings in microbial entry.
A novel pathogenicity determinant hijacks maize catalase 1 to enhance viral multiplication and infection
Authors: Jiao Zhiyuan , Tian Yiying , Cao Yanyong , Wang Juan , Zhan Binhui , Zhao Zhenxing , Sun Biao , Guo Chang , Ma Wendi , Liao Zhenfeng , Zhang Hengmu , Zhou Tao , Xia Yiji , Fan Zaifeng
Published: January 2021

Pathogens have evolved various strategies to overcome host immunity for successful infection. Maize chlorotic mottle virus (MCMV) can cause lethal necrosis in maize (Zea mays) when it coinfects with a virus in the Potyviridae family. However, the MCMV pathogenicity determinant remains largely unknown.

Here we show that the P31 protein of MCMV is important for viral accumulation and essential for symptom development. Ectopic expression of P31 using foxtail mosaic virus or potato virus X induced necrosis in systemically infected maize or Nicotiana benthamiana leaves.

Maize catalases (CATs) were shown to interact with P31 in yeast and in planta. P31 accumulation was elevated through its interaction with ZmCAT1. P31 attenuated the expression of salicylic acid (SA)‐responsive pathogenesis‐related (PR) genes by inhibiting catalase activity during MCMV infection. In addition, silencing of ZmCATs using a brome mosaic virus‐based gene silencing vector facilitated MCMV RNA and coat protein accumulation.

This study reveals an important role for MCMV P31 in counteracting host defence and inducing systemic chlorosis and necrosis. Our results have implications for understanding the mechanisms in defence and counter‐defence during infection of plants by various pathogens.
Speciation driven by recombination in the evolution of tomato curly stunt virus in Mozambique
Authors: Sande Osvaldo F. L. , Orílio Anelise F. , Chipiringo Baltazar A. I. , Xavier César A. D. , Zerbini F. Murilo
Published: January 2021

Begomoviruses constitute a group of viruses of great economic importance in agriculture, mainly in tropical and subtropical regions, including southern Africa. Tomato curly stunt virus (ToCSV) is an important begomovirus described in South Africa and later reported in Mozambique impacting tomato cultivation. In Mozambique, the severe disease caused by ToCSV limits tomato cultivation and compromises the income of small and medium farms. Due to the scarcity of information about this pathogen, in this study we explored its genetic variability to elucidate the mechanisms that drive its evolution. In 2019, 27 ToCSV full‐length sequences were obtained from tomato foliar samples with virus‐like symptoms collected in the district of Chokue in Gaza province, Mozambique. Sequence analysis showed that isolates from Mozambique have a nucleotide identity of 90.9%–96.9% with the isolate from South Africa (AF261885) and are grouped into two distinct strains that we named ToCSV‐Chok I and ToCSV‐Chok II. The ToCSV‐Chok II strain has a higher nucleotide diversity than ToCSV‐Chok I in the Rep gene. Recombination is involved in the evolutionary history of ToCSV, with both intraspecific and interspecific recombination events detected in the Rep gene. Our results indicate a prevalence of ToCSV in tomato crops in the Chokue district of Mozambique (the major tomato‐producing region of the country) and suggest that ToCSV is undergoing speciation due to the effect of recombination.
The Very Best People: President Trump and the Management of Executive Personnel
Authors: Lewis David E. , Richardson Mark D.
Published: January 2021

To his supporters, one very attractive feature of Donald Trump's candidacy was his prior experience as a business executive. Trump promised that he would run America like a business and would select the very best people. In this article, we evaluate President Trump's approach to managing the executive branch by scrutinizing his approach to personnel. We reference two sources of important new data. We first examine data on nominations to all Senate‐confirmed positions during the last three presidencies. We also use data from the 2007, 2014, and 2020 (preliminary) Surveys on the Future of Government Service, surveys of thousands of appointed and career federal executives, to determine whether the president selected the very best people. We conclude by using the survey data to evaluate whether the president’s approach led to effective management. A close look at the new data reveals that the president has been slow to nominate officials to key positions. Federal executives rate the persons the president has appointed as less competent than appointees from the Bush administration or civil servants from the current one. The survey data also reveal that the president’s approach has done nothing to arrest the decline in the capacity of the public service. We conclude by discussing the implications of the Trump presidency for our traditional understanding of the president as chief executive. Specifically, we discuss whether we should reevaluate common beliefs about presidents caring inherently about the management of the executive.
Indole‐3‐glycerolphosphate synthase, a branchpoint for the biosynthesis of tryptophan, indole, and benzoxazinoids in maize
Authors: Richter Annett , Powell Adrian F. , Mirzaei Mahdieh , Wang Lucy J. , Movahed Navid , Miller Julia K. , Piñeros Miguel A. , Jander Georg
Published: January 2021

The maize (Zea mays) genome encodes three indole‐3‐glycerolphosphate synthase enzymes (IGPS1, 2, and 3) catalyzing the conversion of 1‐(2‐carboxyphenylamino)‐l‐deoxyribulose‐5‐phosphate to indole‐3‐glycerolphosphate. Three further maize enzymes (BX1, benzoxazinoneless 1; TSA, tryptophan synthase alpha subunit; and IGL, indole glycerolphosphate lyase) convert indole‐3‐glycerolphosphate to indole, which is released as a volatile defense signaling compound and also serves as a precursor for the biosynthesis of tryptophan and defense‐related benzoxazinoids. Phylogenetic analyses showed that IGPS2 is similar to enzymes found in both monocots and dicots, whereas maize IGPS1 and IGPS3 are in monocot‐specific clades. Fusions of yellow fluorescent protein with maize IGPS enzymes and indole‐3‐glycerolphosphate lyases were all localized in chloroplasts. In bimolecular fluorescence complementation assays, IGPS1 interacted strongly with BX1 and IGL, IGPS2 interacted primarily with TSA, and IGPS3 interacted equally with all three indole‐3‐glycerolphosphate lyases. Whereas IGPS1 and IGPS3 expression was induced by insect feeding, IGPS2 expression was not. Transposon insertions in IGPS1 and IGPS3 reduced the abundance of both benzoxazinoids and free indole. Spodoptera exigua (beet armyworm) larvae show improved growth on igps1 mutant maize plants. Together, these results suggest that IGPS1 and IGPS3 function mainly in the biosynthesis of defensive metabolites, whereas IGPS2 may be involved in the biosynthesis of tryptophan. This metabolic channeling is similar to, though less exclusive than, that proposed for the three maize indole‐3‐glycerolphosphate lyases.
Biological sex, not reproductive cycle, influences peripheral blood immune cell prevalence in mice
Authors: Breznik Jessica A. , Schulz Christian , Ma Jinhui , Sloboda Deborah M. , Bowdish Dawn M. E.
Published: January 2021

Key points

Traditionally the female sex, compared with the male sex, has been perceived as having greater variability in many physiological traits, including within the immune system.

We investigated effects of biological sex and the female reproductive cycle on numbers of circulating leukocytes in C57BL/6J mice.

We show that biological sex, but not female reproductive cyclicity, has a significant effect on peripheral blood immune cell prevalence and variability, and that sex differences were not consistent amongst common inbred laboratory mouse strains.

We found that male C57BL/6J mice, compared with female mice, have greater variability in peripheral blood immunophenotype, and that this was influenced by body weight.

We created summary tables for researchers to facilitate experiment planning and sample size calculations for peripheral immune cells that consider the effects of biological sex.

Immunophenotyping (i.e. quantifying the number and types of circulating leukocytes) is used to characterize immune changes during health and disease, and in response to pharmacological and other interventions. Despite the importance of biological sex in immune function, there is considerable uncertainty amongst researchers as to the extent to which biological sex or the female reproductive cycle influence blood immunophenotype. We quantified circulating leukocytes by multicolour flow cytometry in young C57BL/6J mice and assessed the effects of the reproductive cycle, biological sex, and other experimental and biological factors on data variability. We found that there are no significant effects of the female reproductive cycle on the prevalence of peripheral blood B cells, NK cells, CD4+ T cells, CD8+ T cells, monocytes, or neutrophils. Immunophenotype composition and variability do not significantly change between stages of the female reproductive cycle. There are, however, sex‐specific differences in immune cell prevalence, with fewer monocytes, neutrophils, and NK cells in female mice. Surprisingly, immunophenotype is more variable in male mice, and weight is a significant contributing factor. We provide tools for researchers to perform a priori sample size calculations for two‐group and factorial analyses. We show that immunophenotype varies between inbred mouse strains, and that using equal sample sizes of male and female mice is not always appropriate for within‐sex evaluations of immune cell populations in peripheral blood.
Trunk Postural Control Strategies Among Persons With Lower-Limb Amputation While Walking and Performing a Concurrent Task
Authors: Butowicz Courtney M. , Acasio Julian C. , Hendershot Brad D.
Published: January 2021

Altered trunk movements during gait in persons with lower-limb amputation are often associated with an increased risk for secondary health conditions; however, the postural control strategies underlying such alterations remain unclear. In this secondary analysis, the authors employed nonlinear measures of triplanar trunk accelerations via short-term Lyapunov exponents to investigate trunk local stability as well as spatiotemporal gait parameters to describe gait mechanics. The authors also evaluated the influence of a concurrent task on trunk local stability and gait mechanics to explore if competition for neuromuscular processing resources can assist in identifying unique strategies to control kinematic variability. Sixteen males with amputation—8 transtibial and 8 transfemoral—and 8 uninjured males (controls) walked on a treadmill at their self-selected speed (mean = 1.2 m/s ±10%) in 5 experimental conditions (8 min each): 4 while performing a concurrent task (2 walking and 2 seated) and 1 with no concurrent task. Individuals with amputation demonstrated significantly smaller Lyapunov exponents than controls in all 3 planes of motion, regardless of concurrent task or level of amputation (P < .0001). Individuals with transfemoral amputation walked with wider strides compared with individuals with transtibial amputation and controls (P < .0001). Individuals with amputation demonstrated more trunk kinematic variability in the presence of wider strides compared with individuals without amputation, and it appears that performing a concurrent cognitive task while walking did not change trunk or gait mechanics.
Identification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput Drug-Repurposing Screen
Authors: Cheng Yu-Shan , Roma Jose Santinni , Shen Min , Mota Fernandes Caroline , Tsang Patricia S. , Forbes He Eun , Boshoff Helena , Lazzarini Cristina , Del Poeta Maurizio , Zheng Wei , Williamson Peter R.
Published: January 2021

Candida auris
is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance.
The Pup-Proteasome System Protects Mycobacteria from Antimicrobial Antifolates
Authors: Guzzo Marissa B. , Li Qing , Nguyen Hoang V. , Boom W. Henry , Nguyen Liem
Published: January 2021

Protein turnover via the Pup-proteasome system (PPS) is essential for nitric oxide resistance and virulence of
Mycobacterium tuberculosis
, the causative agent of tuberculosis. Our study revealed components of PPS as novel determinants of intrinsic antifolate resistance in both
M. tuberculosis
and nonpathogenic
M. smegmatis
.
Metals Alter Membership but Not Diversity of a Headwater Stream Microbiome
Authors: Wolff Brian A. , Clements William H. , Hall Ed K.
Published: January 2021

Our results suggest that microbiomes can be reliable indicators of ecosystem metal stress even when surface water chemistry and other metrics used to assess ecosystem health do not indicate ecosystem stress. Results presented in this study, in combination with previously published work on this same ecosystem, are consistent with the idea that a microbial response to metals at the base of the food web may be affecting primary consumers.
Natural Bacterial Assemblages in Arabidopsis thaliana Tissues Become More Distinguishable and Diverse during Host Development
Authors: Beilsmith Kathleen , Perisin Matthew , Bergelson Joy
Published: January 2021

Developing synthetic microbial communities that can increase plant yield or deter pathogens requires basic research on several fronts, including the efficiency with which microbes colonize plant tissues, how plant genes shape the microbiome, and the microbe-microbe interactions involved in community assembly. Findings on each of these fronts depend upon the spatial and temporal scales at which plant microbiomes are surveyed.
At Least Seven Distinct Rotavirus Genotype Constellations in Bats with Evidence of Reassortment and Zoonotic Transmissions
Authors: Simsek Ceren , Corman Victor Max , Everling Hermann Ulrich , Lukashev Alexander N. , Rasche Andrea , Maganga Gael Darren , Binger Tabea , Jansen Daan , Beller Leen , Deboutte Ward , Gloza-Rausch Florian , Seebens-Hoyer Antje , Yordanov Stoian , Sylverken Augustina , Oppong Samuel , Sarkodie Yaw Adu , Vallo Peter , Leroy Eric M. , Bourgarel Mathieu , Yinda Kwe Claude , Van Ranst Marc , Drosten Christian , Drexler Jan Felix , Matthijnssens Jelle
Published: January 2021

The increased research on bat coronaviruses after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) allowed the very rapid identification of SARS-CoV-2. This is an excellent example of the importance of knowing viruses harbored by wildlife in general, and bats in particular, for global preparedness against emerging viral pathogens.
FADU: a Quantification Tool for Prokaryotic Transcriptomic Analyses
Authors: Chung Matthew , Adkins Ricky S. , Mattick John S. A. , Bradwell Katie R. , Shetty Amol C. , Sadzewicz Lisa , Tallon Luke J. , Fraser Claire M. , Rasko David A. , Mahurkar Anup , Dunning Hotopp Julie C.
Published: January 2021

Most currently available quantification tools for transcriptomics analyses have been designed for human data sets, in which full-length transcript sequences, including the untranslated regions, are well annotated. In most prokaryotic systems, full-length transcript sequences have yet to be characterized, leading to prokaryotic transcriptomics analyses being performed based on only the coding sequences.
Eosinophilic chronic rhinosinusitis and concurrent Kimura’s disease treated with mepolizumab
Authors: Ho Jacqueline , Walter Sophie , Harvey Richard J
Published: January 2021

Kimura’s disease is a rare, benign, chronic inflammatory disorder characterised by its eosinophilic infiltrate. Patients often present with one or more progressively enlarging subcutaneous lymph nodes in the head and neck region or enlarging salivary glands. We describe the case of a 26-year-old man presenting with severe peripheral eosinophilia and upper airway inflammatory symptoms, who later developed cervical lymphadenopathy and formally diagnosed with Kimura’s disease. Based on our English-language MEDLINE literature search, to our knowledge this is the first case report describing treatment of Kimura’s disease with mepolizumab.