The Effectiveness of Facial Exercise Therapy in Ophthalmic Complications of Facial Nerve Palsy and the CADS Grading Scale as an Ophthalmic-Specific Grading System.

PURPOSE: The effectiveness of facial exercise therapy in facial nerve palsy is well documented in the literature. However, there is no study examining its effect on ophthalmic manifestations of facial nerve palsy. The study reports its impact on the ophthalmic manifestations of facial nerve palsy using the ophthalmic-specific CADS grading system. METHODS: A retrospective case series of patients aged 18 years or older with facial nerve palsy was performed in a single specialist center between 2013 and 2019. Inclusion criteria were ophthalmic involvement, recorded CADS, and Sunnybrook grading scale pre- and post-treatment. RESULTS: A total of 73 patients were identified. There were 24 patients (M = 11, F = 13) who received facial exercise therapy only (group 1) and 49 patients (M = 17, F = 32) who received combined treatment of facial exercise therapy and eyelid surgery (group 2). The mean ages were 54.8 and 49.7 years, respectively. The groups were further subdivided into early (<3 months), intermediate (3-12 months), and late presenters (>12 months). In group 1, statistically significant improvements were seen in early (static asymmetry and dynamic function), intermediate (cornea), and late groups (cornea, static asymmetry, and dynamic function). The Sunnybrook grading scale was unable to detect changes in the ophthalmic features post-therapy or to report the corneal status. CONCLUSIONS: Facial exercise therapy is likely to improve ophthalmic manifestations of facial nerve palsy, in particular, those with static asymmetry and dynamic function of eye closure. The CADS grading scale is more suitable for the ophthalmic assessment.

Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.

Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.

Long interspersed nuclear elements safeguard neural progenitors from precocious differentiation.

Long interspersed nuclear element-1 (L1 or LINE-1) is a highly abundant mobile genetic element in both humans and mice, comprising almost 20% of each genome. L1s are silenced by several mechanisms, as their uncontrolled expression has the potential to induce genomic instability. However, L1s are paradoxically expressed at high levels in differentiating neural progenitor cells. Using in vitro and in vivo techniques to modulate L1 expression, we report that L1s play a critical role in both human and mouse brain development by regulating the rate of neural differentiation in a reverse-transcription-independent manner.

Integration-free induced pluripotent stem cells from three endangered Southeast Asian non-human primate species.

Advanced molecular and cellular technologies provide promising tools for wildlife and biodiversity conservation. Induced pluripotent stem cell (iPSC) technology offers an easily accessible and infinite source of pluripotent stem cells, and have been derived from many threatened wildlife species. This paper describes the first successful integration-free reprogramming of adult somatic cells to iPSCs, and their differentiation, from three endangered Southeast Asian primates: the Celebes Crested Macaque (Macaca nigra), the Lar Gibbon (Hylobates lar), and the Siamang (Symphalangus syndactylus). iPSCs were also generated from the Proboscis Monkey (Nasalis larvatus). Differences in mechanisms could elicit new discoveries regarding primate evolution and development. iPSCs from endangered species provides a safety net in conservation efforts and allows for sustainable sampling for research and conservation, all while providing a platform for the development of further in vitro models of disease.

JAK2 as a surface marker for enrichment of human pluripotent stem cells-derived ventricular cardiomyocytes.

BACKGROUND: Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for cardiac disease modelling, drug discovery and regenerative medicine. Despite the advancement in various differentiation protocols, the heterogeneity of the generated population composed of diverse cardiac subtypes poses a significant challenge to their practical applications. Mixed populations of cardiac subtypes can compromise disease modelling and drug discovery, while transplanting them may lead to undesired arrhythmias as they may not integrate and synchronize with the host tissue's contractility. It is therefore crucial to identify cell surface markers that could enable high purity of ventricular CMs for subsequent applications. METHODS: By exploiting the fact that immature CMs expressing myosin light chain 2A (MLC2A) will gradually express myosin light chain 2 V (MLC2V) protein as they mature towards ventricular fate, we isolated signal regulatory protein alpha (SIRPA)-positive CMs expressing intracellular MLC2A or MLC2V using MARIS (method for analysing RNA following intracellular sorting). Subsequently, RNA sequencing analysis was performed to examine the gene expression profile of MLC2A + and MLC2V + sorted CMs. We identified genes that were significantly up-regulated in MLC2V + samples to be potential surface marker candidates for ventricular specification. To validate these surface markers, we performed immunostaining and western blot analysis to measure MLC2A and MLC2V protein expressions in SIRPA + CMs that were either positive or negative for the putative surface markers, JAK2 (Janus kinase 2) or CD200. We then characterized the electrophysiological properties of surface marker-sorted CMs, using fluo-4 AM, a green-fluorescent calcium indicator, to measure the cellular calcium transient at the single cell level. For functional validation, we investigated the response of the surface marker-sorted CMs to vernakalant, an atrial-selective anti-arrhythmic agent. RESULTS: In this study, while JAK2 and CD200 were identified as potential surface markers for the purification of ventricular-like CMs, the SIRPA+/JAK2+ population showed a higher percentage of MLC2V-expressing cells (~ 90%) compared to SIRPA+/CD200+ population (~ 75%). SIRPA+/JAK2+ sorted CMs exhibited ventricular-like electrophysiological properties, including slower beating rate, slower calcium depolarization and longer calcium repolarization duration. Importantly, vernakalant had limited to no significant effect on the calcium repolarization duration of SIRPA+/JAK2+ population, indicating their enrichment for ventricular-like CMs. CONCLUSION: Our study lays the groundwork for the identification of cardiac subtype surface markers that allow purification of cardiomyocyte sub-populations. Our findings suggest that JAK2 can be employed as a cell surface marker for enrichment of hPSC-derived ventricular-like CMs.

Use of Transradial Access to Install Two Sequential Stents for Pseudoaneurysms along the Celiac Artery and Common Hepatic Artery Axes.

Transfemoral access is the most common method for stenting visceral aneurysms. Over the years, transradial access has gained tremendous traction in interventional procedures due to many reported benefits, including increased patient comfort, decreased procedural cost, and reduced rates of procedural complications, among others. Moreover, transradial access can serve as a valuable alternative when transfemoral access may be contraindicated. Here, we successfully utilized transradial access to sequentially place two stents for pseudoaneurysms in the celiac artery and common hepatic artery.

The Use of the Pericranial Periosteal Flap in Children for Treating Severe Lower Eyelid Retraction.

PURPOSE: To describe a surgical technique that can achieve significant lower eyelid elevation in severe retraction in children using a pericranial periosteal flap with skin graft. METHODS: A retrospective, single-center, case series of 3 consecutive pediatric cases are performed where a pericranial periosteal flap was used with a skin graft to manage severe lower eyelid retraction. Outcome measures include the extent of lower eyelid elevation (mm) and complications in the follow-up visits. RESULTS: Three children with severe lower eyelid retraction underwent the surgery. There were 2 boys and 1 girl with the mean age of 6.7 years (range, 5-8 years). The improvement of lower eyelid retraction was 3, 3, and 7 mm at 28, 24, and 6 months, respectively. No perioperative or postoperative complications occurred. CONCLUSIONS: Children with severe lower eyelid retraction often have a complex craniofacial and surgical history, and its surgical correction can be challenging. This case series present the successful use of pericranial flaps in treating severe lower eyelid retraction in children. The authors recommend this flap in children where traditional options have either failed or are not applicable.

Delayed Optic Neuropathy Caused by Orbital Hyaluronic Filler Injection and Recovery Following Hyaluronidase Treatment.

A 26-year-old female presented with left enophthalmos following orbital floor and medial wall fracture despite surgical repair. She underwent further exploration and surgical repair but the enophthalmos persisted at 3-4 mm. Following discussion, she received 2 ml of hyaluronic acid filler injection into the posterior orbit and intraconal space. There were no immediate postoperative complications with normal optic nerve function, and the enophthalmos improved by 2 mm. The optic nerve function remained normal at the 4-week review. She returned 30 months following the injection with left periorbital edema, subjective red desaturation, and reduced peripheral visual field. On examination, there was a left relative afferent pupillary defect, disc pallor, and reduced visual field defect on automated visual field test. Following transcutaneous orbital injection of hyaluronidase, there was a subjective improvement in red desaturation with an improved peripheral visual field. Here the authors present a case of compressive optic neuropathy of delayed onset following orbital hyaluronic acid filler injection.

Neuronal activity-related transcription is blunted in immature compared to mature dentate granule cells.

Immature dentate granule cells (DGCs) generated in the hippocampus during adulthood are believed to play a unique role in dentate gyrus (DG) function. Although immature DGCs have hyperexcitable membrane properties in vitro, the consequences of this hyperexcitability in vivo remain unclear. In particular, the relationship between experiences that activate the DG, such as exploration of a novel environment (NE), and downstream molecular processes that modify DG circuitry in response to cellular activation is unknown in this cell population. We first performed quantification of immediate early gene (IEG) proteins in immature (5-week-old) and mature (13-week-old) DGCs from mice exposed to a NE. Paradoxically, we observed lower IEG protein expression in hyperexcitable immature DGCs. We then isolated nuclei from active and inactive immature DGCs and performed single-nuclei RNA-Sequencing. Compared to mature nuclei collected from the same animal, immature DGC nuclei showed less activity-induced transcriptional change, even though they were classified as active based on expression of ARC protein. These results demonstrate that the coupling of spatial exploration, cellular activation, and transcriptional change differs between immature and mature DGCs, with blunted activity-induced changes in immature cells.

Demonstration of Spatial Modulation Using a Novel Active Transmitter Detection Scheme with Signal Space Diversity in Optical Wireless Communications.

Line-of-sight (LOS) indoor optical wireless communications (OWC) enable a high data rate transmission while potentially suffering from optical channel obstructions. Additional LOS links using diversity techniques can tackle the received signal performance degradation, where channel gains often differ in multiple LOS channels. In this paper, a novel active transmitter detection scheme in spatial modulation (SM) is proposed to be incorporated with signal space diversity (SSD) technique to enable an increased OWC system throughput with an improved bit-error-rate (BER). This transmitter detection scheme is composed of a signal pre-distortion technique at the transmitter and a power-based statistical detection method at the receiver, which can address the problem of power-based transmitter detection in SM using carrierless amplitude and phase modulation waveforms with numerous signal levels. Experimental results show that, with the proposed transmitter detection scheme, SSD can be effectively provided with ~0.61 dB signal-to-noise-ratio (SNR) improvement. Additionally, an improved data rate ~7.5 Gbit/s is expected due to effective transmitter detection in SM. The SSD performances at different constellation rotation angles and under different channel gain distributions are also investigated, respectively. The proposed scheme provides a practical solution to implement power-based SM and thus aids the SSD realization for improving system performance.

Investigation on repetition-coding and space-time-block-coding for indoor optical wireless communications employing beam shaping based on orbital angular momentum modes.

In this paper, we propose a novel beam shaping technique based on orbital angular momentum (OAM) modes for indoor optical wireless communications (OWC). Furthermore, we investigate two spatial diversity techniques, namely repetition-coding (RC) and Alamouti-type orthogonal space-time-block-coding (STBC) for indoor OWC employing the new beam shaping technique. The performance of both diversity schemes is systematically analyzed and compared under different beam shaping techniques using different OAM modes with different power ratios of the modes. It is shown that both RC and STBC can improve the system performance and effective coverage and RC outperforms STBC in all the beam shaping techniques regardless of the power ratios of the different modes. In addition, to further understand the performance of RC and STBC schemes against the signal delays induced during OAM mode conversion, the system tolerance of the two schemes to the delay interval is investigated with different OAM mode-based beam shaping techniques. Numerical results show that higher resistance to the delay interval can be achieved in STBC scheme. The advantage is more obvious when employing OAM0 and OAM1 based beam shaping technique.

Impacts of COVID-19 and elective surgery cancellations on platelet supply and utilization in the Canadian Province of British Columbia.

BACKGROUND AND OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic raised concerns about the vulnerability of platelet supply and the uncertain impact of the resumption of elective surgery on utilization. We report the impact of COVID-19 on platelet supply and utilization across a large, integrated healthcare system in the Canadian province of British Columbia (BC). MATERIALS AND METHODS: Historical platelet use in BC by indication was compiled for fiscal year 2010/2011-2019/2020. Platelet collections, initial daily inventory and disposition data were assessed pre-COVID-19 (1 April 2018-15 March 2020) and for two COVID-19 time periods in BC: a shutdown phase with elective surgeries halted (16 March-17 May, 2020) and a renewal phase when elective surgeries resumed (18 May-27 September 2020); comparisons were made provincially and for individual health authorities. RESULTS: Historically, elective surgeries accounted for 10% of platelets transfused in BC. Initial daily supplier inventory increased from baseline during both COVID-19 periods (93/90 units vs. 75 units pre-COVID-19). During the shutdown phase, platelet utilization decreased 10.4% (41 units/week; p < 0.0001), and remained significantly decreased during the ensuing renewal period. Decreased platelet utilization was attributed to fewer transfusions during the shutdown phase followed by a decreased discard/expiry rate during the renewal phase compared to pre-COVID-19 (15.2% vs. 18.9% pre-COVID-19; p < 0.0001). Differences in COVID-19 platelet utilization patterns were noted between health authorities. CONCLUSION: Decreased platelet utilization was observed in BC compared to pre-COVID-19, likely due to a transient reduction in elective surgery as well as practice and policy changes triggered by pandemic concerns.

Prevalence, indications and demographic characteristics of Botulinum neurotoxin use in a tertiary oculoplastic centre.

OBJECTIVES: Over the past 40 years, Botulinum Neurotoxin (BoNT) treatment has been used in many presentations to the hospital eye service. There is little published on its practice in an ophthalmology setting. We aim to report on the prevalence of BoNT use, indications for treatment, age, gender, socioeconomic and ethnic variations observed, and dosages used. METHODS: We performed a retrospective cross sectional observation study on the use of botulinum neurotoxin treatment in the oculoplastic department of a busy tertiary centre in the University Hospitals of Leicester, United Kingdom. RESULTS: The prevalence of BoNT in the service was 13.7 per 100,000 people. Of the 145 cases identified, the commonest indications for treatment were hemifacial spasm (62% of cases) and blepharospasm (29% of cases). Proportionally, twice as many females than males received BoNT (χ2 = 17.3, p < 0.0001). For those >30 years of age, the prevalence increased with age with those >90 years having a seven times higher prevalence than the mean. Overall, no significant differences were found in ethnicity and median index of multiple deprivation rank between those with treatment and the general population although specific district council variations were noted. CONCLUSIONS: These findings would assist commissioners in providing adequate resources to meet demand based on the demographics of their local population. Further qualitative and quantitative research is required to enhance our understanding of some of these trends.

Upregulation of the JAK-STAT pathway promotes maturation of human embryonic stem cell-derived cardiomyocytes.

The immature characteristics and metabolic phenotypes of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) restrict their applications for disease modeling, drug discovery, and cell-based therapy. Leveraging on the metabolic shifts from glycolysis to fatty acid oxidation as CMs mature, a human hexokinase1-GFP metabolic reporter cell line (H7 HK1-GFP) was generated to facilitate the isolation of fetal or more matured hPSC-CMs. RNA sequencing of fetal versus more matured CMs uncovered a potential role of interferon-signaling pathway in regulating CM maturation. Indeed, IFN-γ-treated CMs resulted in an upregulation of the JAK-STAT pathway, which was found to be associated with increased expression of CM maturation genes, shift from MYH6 to MYH7 expression, and improved sarcomeric structure. Functionally, IFN-γ-treated CMs exhibited a more matured electrophysiological profile, such as increased calcium dynamics and action potential upstroke velocity, demonstrated through calcium imaging and MEA. Expectedly, the functional improvements were nullified with a JAK-STAT inhibitor, ruxolitinib.

Chronic Macular Oedema as a Late MIRAgel-Related Complication.

BACKGROUND: MIRAgel® (MIRA, Waltham, MA, USA) is a hydrogel scleral buckle introduced in 1979 to treat rhegmatogenous retinal detachments. Its use was discontinued because late complications that require surgical removal were reported. METHODS: Case report. RESULTS: We report a case of left eye MIRAgel® buckle surgery 28 years ago presenting with a tender palpable erythematous swelling at the lower lid, with marked conjunctival chemosis and progressive ophthalmoplegia. Imaging revealed a large, well-defined, horseshoe-shaped lesion in the extraconal space of the left orbit with globe distortion, with histological confirmation of an expanded hydrogel buckle. He recovered well following removal of the explant but developed chronic macular oedema a year later, which persisted despite sub-Tenon's triamcinolone injections. Repeat imaging demonstrated remaining hydrogel explant. Macular oedema settled well upon successful surgical removal with no recurrence to date. CONCLUSION: Our case is the first to describe macular oedema as a late MIRAgel-related complication, with complete removal of the explant being the definitive treatment. Macular oedema indicates postoperative inflammation secondary to the remaining explant fragments. Given the friability of hydrolysed MIRAgel®, we recommend ophthalmologists to warn patients regarding the possibility of further inflammation in the globe or the orbit in case of incomplete removal.