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.

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.

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.

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.

Emergency canthotomy and cantholysis - Factors affecting confidence among ophthalmic trainees in the United Kingdom.

PURPOSE: Retrobulbar hemorrhage from trauma is the most common cause of orbital compartment syndrome. Emergency canthotomy and cantholysis is a vision-saving procedure. We sought to identify confidence among ophthalmic trainees in this procedure as well as any relevant factors that have any impact. METHODS: An online, confidential anonymous questionnaire was distributed to ophthalmology training groups in the UK. Questions explored the participant's stage of training and grade and confidence in this area as well as their ophthalmic experience in terms of training courses attended and elective versions of the procedure performed. RESULTS: We received 45 completed responses from the survey. 20/23 (87%) of junior trainees had not performed an emergency canthotomy/cantholysis to date, whereas 19/22 (86%) of senior trainees had performed between 1 and 5 such procedures. 15/23 (65%) of junior trainees had not performed an elective canthotomy compared to only 3/22 (14%) of the senior trainees. We found that the main factors that were associated with increased confidence level were the higher numbers of emergency and elective cases performed, training courses, and previous oculoplastic surgery rotation (P = 0.0001). CONCLUSION: From our survey, we found low confidence levels among junior trainees due to limited exposure. Confidence appeared to be linked to both elective and emergency surgical experience of the procedure as well as training course and having worked in an oculoplastic surgery firm. Changes to training portfolio requirements for junior trainees to incorporate early oculoplastic experience may help to achieve this on a national scale.

AAV ablates neurogenesis in the adult murine hippocampus.

Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hr post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentategyrus (DG)- without ablating adult neurogenesis- can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo two-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system should be carefully evaluated.

Applying the Care and Communication Bundle to Promote Palliative Care in a Neuro-Intensive Care Unit: Why and How.

Background: Delivery of palliative care in neurointensive care units (neuro-ICUs) can be inconsistent, often due to absence of formal care triggers. The Care and Communication Bundle (CCB) of Quality Indicators provides a standardized process to deliver effective palliative care services in ICUs, but application of these indicators in this setting has not yet been systemically assessed. Objectives: To evaluate the fit of a CCB in the neuro-ICU through a novel scoring system and identify barriers to adherence. Design: CCB standards for a neuro-ICU were delineated. Assessment of documented indicators and barriers was conducted through electronic medical record retrospective review. Setting/Subjects: A 30-bed neuro-ICU in a large Academic Medical Center in the Southeastern United States. Chart reviews were conducted for 133 critically ill neurology and neurosurgery patients who expired between November 2018 and January 2020. Results: Results demonstrate moderate adherence to CCB standards, including excellent consistency in establishment of patient-centered communication and referral to supportive services (e.g., social work, spiritual support). Identified areas for improvement include documentation of patient and family involvement in care process (i.e., advance directive completion, interdisciplinary team meetings). Conclusions: Application of the CCB in the neuro-ICU is useful for examining adherence to time-based triggers of palliative care standards. The novel scoring system offers opportunities to motivate improvement and reduce variation in palliative care integration.

Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis.

INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. METHODS: Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. RESULTS: All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. CONCLUSION: Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.

A novel environment-evoked transcriptional signature predicts reactivity in single dentate granule neurons.

Activity-induced remodeling of neuronal circuits is critical for memory formation. This process relies in part on transcription, but neither the rate of activity nor baseline transcription is equal across neuronal cell types. In this study, we isolated mouse hippocampal populations with different activity levels and used single nucleus RNA-seq to compare their transcriptional responses to activation. One hour after novel environment exposure, sparsely active dentate granule (DG) neurons had a much stronger transcriptional response compared to more highly active CA1 pyramidal cells and vasoactive intestinal polypeptide (VIP) interneurons. Activity continued to impact transcription in DG neurons up to 5 h, with increased heterogeneity. By re-exposing the mice to the same environment, we identified a unique transcriptional signature that selects DG neurons for reactivation upon re-exposure to the same environment. These results link transcriptional heterogeneity to functional heterogeneity and identify a transcriptional correlate of memory encoding in individual DG neurons.

A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells.

How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-ß, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah-/-Rag2-/-Il2rg-/- mouse model of liver failure.

Derivation of human induced pluripotent stem cell (iPSC) line with LRRK2 gene R1398H variant in Parkinson's disease.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 72-year old female Parkinson's disease (PD) patient with R1398H variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model provides a good platform for studying the mechanism of PD, and also for drug testing and gene therapy studies.

Development of a human induced pluripotent stem cell (iPSC) line from a Parkinson's disease patient carrying the N551K variant in LRRK2 gene.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with N551K variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model can complement in vivo PD models for pathophysiological studies and drug screening.

Mesoscopic modeling of cancer photothermal therapy using single-walled carbon nanotubes and near infrared radiation: insights through an off-lattice Monte Carlo approach.

Single-walled carbon nanotubes (SWNTs) are promising heating agents in cancer photothermal therapy when under near infrared radiation, yet few efforts have been focused on the quantitative understanding of the photothermal energy conversion in biological systems. In this article, a mesoscopic study that takes into account SWNT morphologies (diameter and aspect ratio) and dispersions (orientation and concentration), as well as thermal boundary resistance, is performed by means of an off-lattice Monte Carlo simulation. Results indicate that SWNTs with orientation perpendicular to the laser, smaller diameter and better dispersion have higher heating efficiency in cancer photothermal therapy. Thermal boundary resistances greatly inhibit thermal energy transfer away from SWNTs, thereby affecting their heating efficiency. Through appropriate interfacial modification around SWNTs, compared to the surrounding healthy tissue, a higher temperature of the cancer cell can be achieved, resulting in more effective cancer photothermal therapy. These findings promise to bridge the gap between macroscopic and microscopic computational studies of cancer photothermal therapy.

Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone.

We studied here the independent roles of angiotensin II and aldosterone in regulating the sodium chloride cotransporter (NCC) of the distal convoluted tubule. We adrenalectomized three experimental and one control group of rats. Following surgery, the experimental groups were treated with either a high physiological dose of aldosterone, a non-pressor, or a pressor dose of angiotensin II for 8 days. Aldosterone and both doses of angiotensin II lowered sodium excretion and significantly increased the abundance of NCC in the plasma membrane compared with the control. Only the pressor dose of angiotensin II caused hypertension. Thiazides inhibited the sodium retention induced by the angiotensin II non-pressor dose. Both aldosterone and the non-pressor dose of angiotensin II significantly increased phosphorylation of NCC at threonine-53 and also increased the intracellular abundance of STE20/SPS1-related, proline alanine-rich kinase (SPAK). No differences were found in other modulators of NCC activity such as oxidative stress responsive protein type 1 or with-no-lysine kinase 4. Thus, our in vivo study shows that aldosterone and angiotensin II independently increase the abundance and phosphorylation of NCC in the setting of adrenalectomy; effects are likely mediated by SPAK. These results may explain, in part, the hormonal control of renal sodium excretion and the pathophysiology of several forms of hypertension.

Cholesterol depletion and genistein as tools to promote F508delCFTR retention at the plasma membrane.

BACKGROUND/AIMS: F508delCFTR-, but not wtCFTR-, expressing fibroblasts resemble Niemann Pick type C cells in the massive intracellular accumulation of free cholesterol. The recruitment and activation of F508delCFTR by cholesterol depletion was studied. METHODS: Filipin staining, forskolin-stimulated anion efflux and FITC-dextran uptake were studied in control cells and fibroblasts treated with 2-hydroxypropyl beta-cyclodextrin phosphatidylcholine large unilamellar vesicles to deplete cellular free cholesterol. RESULTS: Treatment of F508delCFTR-, but not wtCFTR-, expressing fibroblasts with 2-hydroxypropyl beta-cyclodextrin resulted in a reduction in cellular cholesterol and a potentiation of the forskolin-induced anion efflux. In addition, forskolin also promoted a massive increase in the rate of endocytosis in F508delCFTR fibroblasts, which was absent in genistein- or cyclodextrin-treated cultures. CONCLUSION: The results not only suggest that reducing cellular cholesterol may serve as pharmacotherapeutic tool in the treatment of cystic fibrosis but also reveal a novel mechanism for genistein regulation of F508delCFTR, i.e. retention by inhibition of endocytosis.

Assessing the total costs of blood delivery to hospital oncology and haematology patients.

OBJECTIVE: To determine direct costs associated with a blood transfusion session in two hospital settings. RESEARCH DESIGN AND METHODS: The study was conducted in two United Kingdom hospital sites during April 2004. Transfusion sessions for patients receiving units of red blood cells within either haematology or oncology departments were followed using time and motion techniques to measure the direct costs. Other data were collected from the centres to calculate the cost of disposables, blood wastage and blood bank machines. RESULTS: Total mean staff cost per transfusion of 2 units was 37.24 pounds sterling (9.68 pounds sterling for blood bank and 27.56 pounds sterling for ward procedures). The mean cost of disposables was 13.25 pounds sterling and the mean cost for blood products was 287.56 pounds sterling. The mean cost of wastage was 11.86 pounds sterling per transfusion. After including other derived costs, such as hospital stay, the mean cost for a transfusion of 2 units of blood was estimated to be 546.12 pounds sterling. CONCLUSION: This study estimates the cost of an average blood transfusion of 2 units to be 546.12 pounds sterling. It should be noted that significant indirect costs, such as those incurred by patients, their carers and societal costs, have not been considered. Against the background of finite blood resources and other factors such as patient quality of life, blood transfusion may not represent the best choice for patient care. Alternative treatments should be considered.