Novel GαS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain.

Numerous physiological functions, including a role as a cell surface receptor, have been ascribed to Alzheimer's disease-associated amyloid precursor protein (APP). However, detailed analysis of intracellular signaling mediated by APP in neurons has been lacking. Here, we characterized intrinsic signaling associated with membrane-bound APP C-terminal fragments, which are generated following APP ectodomain release by α- or ß-secretase cleavage. We found that accumulation of APP C-terminal fragments or expression of membrane-tethered APP intracellular domain results in adenylate cyclase-dependent activation of PKA (protein kinase A) and inhibition of GSK3ß signaling cascades, and enhancement of axodendritic arborization in rat immortalized hippocampal neurons, mouse primary cortical neurons, and mouse neuroblastoma. We discovered an interaction between BBXXB motif of APP intracellular domain and the heterotrimeric G-protein subunit Gα(S), and demonstrate that Gα(S) coupling to adenylate cyclase mediates membrane-tethered APP intracellular domain-induced neurite outgrowth. Our study provides clear evidence that APP intracellular domain can have a nontranscriptional role in regulating neurite outgrowth through its membrane association. The novel functional coupling of membrane-bound APP C-terminal fragments with Gα(S) signaling identified in this study could impact several brain functions such as synaptic plasticity and memory formation.

Intraoperative Complication Rates in Cataract Surgery After Resuming Surgery Following the COVID-19 Shutdown.

Purpose: To evaluate surgeon performance and intraoperative complication rates of cataract surgery after resumption of elective surgeries following the operating room (OR) shutdown from the coronavirus disease 2019 (COVID-19) pandemic. Subjective surgical experience is also evaluated. Methods: This is a retrospective comparative study which analyzes cataract surgeries performed at an inner city, tertiary academic center. Cataract surgeries were categorized into Pre-Shutdown (January 1-March 18, 2020), and Post-Shutdown, for all cases which occurred after surgeries resumed (May 11-July 31, 2020). No cases were performed between March 19 and May 10, 2020. Patients undergoing combined cataract and minimally invasive glaucoma surgery (MIGS) were included, but MIGS complications were not counted as cataract complications. No other combined cataract-other ophthalmic surgeries were included. A survey was used to gather subjective surgeon experience. Results: A total of 480 cases (n=306 Pre-Shutdown and n=174 Post-Shutdown) were analyzed. Although there was a higher frequency of complex cataract surgeries performed Post-Shutdown (5.2% vs 21.3%; p<0.00001), complication rates before versus after the shutdown were not statistically significant (9.2% vs 10.3%; p=0.75). Phacoemulsification was the step of cataract surgery in which residents were most concerned about when returning to the OR. Conclusion: After the surgical hiatus due to COVID-19, significantly more complex cataract surgeries were reported and surgeons reported higher general anxiety level when first returning to the OR. Increased anxiety did not lead to higher surgical complications. This study provides a framework to understand surgical expectations and outcomes for patients whose surgeons faced a prolonged two-month hiatus from cataract surgery.

Paraventricular Nucleus V1a Receptor Knockdown Blunts Neurocardiovascular Responses to Acute Stress in Male Rats after Chronic Mild Unpredictable Stress.

Chronic stress and depression impart increased risk for adverse cardiovascular events. Autonomic dysregulation, particularly sympathoexcitation, has long been associated with poor cardiovascular outcomes. Vasopressin (AVP) receptors with the paraventricular nucleus (PVN), known as an integrating locus for hemodynamic and autonomic function, have been implicated in behavior and stress. The present studies were designed to test the hypothesis that knockdown of vasopressin V1aR within the PVN in male Sprague Dawley rats subjected to chronic mild unpredictable stress (CMS) would result in lower resting hemodynamics and renal sympathetic nerve activity (RSNA) and mitigate the responses to acute stressors. Male rats underwent CMS for 4 weeks; controls were housed in standard caging. Twenty days into the paradigm, the PVN was injected with either small interfering RNA (siRNA) directed against V1aR or scrambled RNA (scrRNA). Arterial pressure, heart rate and RSNA were ascertained by telemetry with the animals in their home cages. Pretreatment with siRNA to V1aR prevented the increase in arterial pressure to PVN microinjection with exogenous AVP. Basal mean arterial pressure (MAP) was significantly higher in scrRNA-treated but not in siRNA-treated CMS rats vs control rats. Paradoxically, basal RSNA was approximately two-fold higher in siRNA-treated CMS rats. Acute emotional stress delivered as 15-sec air-jet resulted in greater peak and duration of the MAP and RSNA responses in scrRNA-treated CMS rats vs control; siRNA treatment inhibited the responses. The 15-sec exposure to ammonia to test the nasopharyngeal reflex, whose circuitry does not include the PVN, produced similar increases in arterial pressure, heart rate, and RSNA in controls and both groups of CMS rats. Thus, CMS increases arterial pressure and predisposes to greater hemodynamic and RSNA responses to acute emotional stress. The higher basal RSNA in siRNA-treated rats may be due to functional and/or anatomical neuroplasticity occurring during more protracted inhibition of V1aR PVN signaling. Vasopressinergic signaling via V1aR in PVN modulates the cardiovascular and sympathetic responses to both the chronic and acute stress.

Post-operative Day Zero Versus Day One Follow-Up for Uncomplicated Cataract Surgery.

Purpose To compare the postoperative outcomes and management of uncomplicated cataract surgery seen on postoperative day 0 (POD0) versus postoperative day one (POD1).  Methods A retrospective cohort study of patients who followed up within 0-14 days of their uncomplicated surgery (current procedural terminology code 66984) from December 2018 to March 2020. Those who had perioperative complications, those who had combined glaucoma filtering surgery as well as other minimally invasive glaucoma surgery (MIGS) procedures, and those who did not complete their first two follow-up visits within 14 days of their surgery were excluded. Visual acuity (VA), intraocular pressure (IOP), post-operative interventions, and complications of the first and second postoperative visits were collected. Results Of the 665 participants studied, the mean (standard deviation) age was 68 (11) years old and 60% were female (n=304) with a mean (SD) pre-op logarithm of the minimum angle of resolution (logMAR) VA of 0.715 (0.625). About one-third (32%) of patients were seen on POD0. Compared to POD1, a higher percent of patients with glaucoma were seen POD0 (23% vs 14%; p = 0.008). The mean VA on POD0 was 0.840 (0.653), which was significantly worse than the mean VA of 0.539 (0.599) on POD1 (p<0.0001). There was no significant difference in VA by the second post-op visit. IOP did not significantly differ between POD0 and POD1 groups at the first post-operative visit. The most common changes in the post-operative drop regimen were related to IOP and inflammation control. The rate of interventions did not significantly differ between groups (p>0.1). Patients who received intervention on POD0 were not seen significantly sooner at the next follow-up visit compared to those seen on POD0 without undergoing an intervention. The incidence of an IOP spike greater than 30mmHg on POD0 or POD1 was not significantly different between patients with and without underlying glaucoma (overall p = 0.2020; with glaucoma p= 0.1238; without glaucoma p=0.999). Those with a history of glaucoma were not more likely to receive intervention to lower IOP on POD0 versus those seen on POD1 (p = 0.999).  Conclusion It can be difficult to evaluate patients the day after their uncomplicated cataract surgery, and it is difficult to predict which patients may have post-operative complications. Our study shows no significant changes in management for patients seen on POD0 compared to POD1. Surgeons can expect significantly better visual acuity on POD1, but otherwise, post-operative outcomes were similar between patients seen on POD0 and those seen on POD1. Surgeons may offer the option of a POD0 visit for patients who underwent uncomplicated cataract surgery.

Accuracy of intravitreal injection volume for aflibercept pre-filled syringe and BD Luer-Lok one-milliliter syringe.

BACKGROUND: To evaluate the accuracy of intravitreal injection volume of the pre-filled syringe (PFS) in which aflibercept is packaged compared to the BD Luer-Lok 1-mL syringe. METHODS: Ophthalmologists injected their typical intravitreal volume for aflibercept using either the PFS or BD Luer-Lok 1-mL syringe for 5 times each. The injected fluid was weighed using a micro-scale and converted to volume. The volume of fluid injected was also evaluated when the 0.05 mL line on the PFS was lined up to the tip or base of the dome-shaped plunger. RESULTS: Injection volume was measured for 12 physicians. The average injected fluid volume was 74.22 ± 15.87 µL for PFS and 53.42 ± 4.61 µL for the BD Luer-Lok 1-mL syringe (p < 0.0001). The average deviation in volume injected for the PFS was higher compared to the BD Luer-Lok 1-mL syringe (11.36 µL vs. 3.35 µL, p < 0.0001). When the PFS was lined up with the tip of the dome-shaped plunger at the 0.05-mL line, the average injected volume was 71.03% higher. CONCLUSIONS: The intravitreal injection volume and variability using the new PFS were significantly higher than the volume injected using the BD Luer-Lok 1-mL syringe previously used, potentially leading to higher rates of visually significant elevation of intraocular pressures.

Factors Associated with 5-year Glaucomatous Progression in Glaucoma Suspect Eyes: A Retrospective Longitudinal Study.

Purpose: Using demographic, clinical, visual field, and optical coherence tomography (OCT) variables to study the association of 5-year glaucomatous progression in glaucoma suspect eyes. Patients and methods: This is a retrospective longitudinal clinical study. Inclusion criteria consisted of glaucoma suspect eyes (i.e., concerning cup-to-disk ratio and/or intraocular pressure (IOP) >21 mm Hg), age ≥ 30 years old, follow-up time of 5 years, best-corrected visual acuity (BCVA) of 20/100 or better, spherical equivalent (SE) higher than 8 diopters and an astigmatism less than 3 diopters. Eyes with glaucoma-determined by two consecutive, reliable visual field tests-were excluded, as well as any eyes with any clinically significant retinal or neurological disease. The percentage of glaucoma suspect eyes, which progressed to glaucoma within a 5-year period, was calculated. Study subjects were divided into the following groups: eyes that progressed to glaucoma and those that did not. Results: In the 288 patients which we looked at, 365 total eyes, 323 eyes had concerning cup-to-disk ratio and 42 had ocular hypertension. Bivariate analysis showed that the eyes which progressed to glaucoma had significantly worse mean deviation, increased pattern standard deviation (PSD), and less visual field index (VFI). Our bivariate analysis also showed a thinner average, superior and inferior retinal nerve fiber layer thickness (RNFL), and more severe average, superior, and inferior RNFL damages (i.e., color grading scale) at baseline. Logistic regression analysis showed that only PSD and severe inferior RNFL damage (i.e., red color) to be significantly associated with 5-year glaucomatous progression. Conclusion: Segmental RNFL damage and pattern standard deviation are associated with 5-year glaucomatous progression in glaucoma suspect eyes. How to cite this article: Nassiri N, Das S, Patel V, et al. Factors Associated with 5-year Glaucomatous Progression in Glaucoma Suspect Eyes: A Retrospective Longitudinal Study. J Curr Glaucoma Pract 2022;16(1):11-16.

Precision Medicine and Targeted Therapies in Breast Cancer.

Precision medicine and targeted therapies have a long history in the treatment of breast cancer and continue to show promise for further specialized and individualized care for this disease. From the discovery of endocrine and HER2 targeted therapies, to multigene arrays in chemotherapy for more specific patient selection, to radiomics and genetic subtyping, targeted therapies and precision medicine continue to push the management of breast cancer toward more individualized care. This article describes the foundation and future of targeted therapy and precision medicine in breast cancer.