Retinal Tear and Retinal Detachment Following Cataract Surgery in Eyes with a Previous History of Treated Phakic Retinal Tears.

OBJECTIVE: To investigate the incidence and outcomes of retinal tear (RT) and retinal detachment (RD) after cataract extraction in patients with a history of previous phakic RT. DESIGN: Retrospective case series. SUBJECTS: Phakic eyes with RT that were successfully treated with laser photocoagulation or cryotherapy and subsequently underwent cataract surgery. METHOD: A retrospective review of phakic eyes treated for RTs between April 1, 2012 and May 31, 2023 was performed. Exclusions included prior vitreoretinal surgery before cataract removal and follow-up of less than 6 months post-cataract surgery. MAIN OUTCOME MEASURES: The incidence of RTs and RDs after cataract surgery, along with visual and anatomic outcomes. RESULTS: Of 12,109 phakic eyes treated for RTs, 1039 (8.6%) eyes underwent cataract surgery. After exclusions, 713 eyes of 660 patients were studied. The mean (standard deviation, SD) follow-up period post-cataract surgery was 34.8 (24.6) months with a median of 239 and 246 days to a new RT or RD development. The overall incidence for diagnosis of post-cataract surgery RT and RD was 7.3% (52/713) (2.9% and 4.3%, respectively), with a one-year incidence of 5.6% (2.2% and 3.4%, respectively). Multivariable regression analysis identified a higher risk of RT/RD among younger individuals (odds ratio [OR] 1.034; 95% confidence interval [CI] 1.004-1.065, P=0.028), males (OR 2.058; 95% CI 1.110-3.816, P=0.022), and those with shorter interval between laser treatment and cataract surgery (OR 1.001; 95% CI 1.001-1.001, P=0.011). Single surgery anatomic success for the RD repair was achieved in 25 eyes (80.6%) at 3 months, with a 100% final reattachment rate. The median final logMAR visual acuity was 0.10 (20/25) for RT, showing no significant change from post-cataract surgery, and 0.18 (20/30) for RD, a significant worsening from after cataract surgery. CONCLUSION: One year post-cataract surgery, the rate of diagnosed RT and RD in patients with previously treated RTs was relatively high, occurring in nearly 1 in 18 eyes. Higher risk was noted among younger individuals, males, and patients with a shorter interval between initial treatment for RT and cataract surgery. RD repair achieved good anatomical results, but vision declined.

ChatGPT enters the room: what it means for patient counseling, physician education, academics, and disease management.

PURPOSE OF REVIEW: This review seeks to provide a summary of the most recent research findings regarding the utilization of ChatGPT, an artificial intelligence (AI)-powered chatbot, in the field of ophthalmology in addition to exploring the limitations and ethical considerations associated with its application. RECENT FINDINGS: ChatGPT has gained widespread recognition and demonstrated potential in enhancing patient and physician education, boosting research productivity, and streamlining administrative tasks. In various studies examining its utility in ophthalmology, ChatGPT has exhibited fair to good accuracy, with its most recent iteration showcasing superior performance in providing ophthalmic recommendations across various ophthalmic disorders such as corneal diseases, orbital disorders, vitreoretinal diseases, uveitis, neuro-ophthalmology, and glaucoma. This proves beneficial for patients in accessing information and aids physicians in triaging as well as formulating differential diagnoses. Despite such benefits, ChatGPT has limitations that require acknowledgment including the potential risk of offering inaccurate or harmful information, dependence on outdated data, the necessity for a high level of education for data comprehension, and concerns regarding patient privacy and ethical considerations within the research domain. SUMMARY: ChatGPT is a promising new tool that could contribute to ophthalmic healthcare education and research, potentially reducing work burdens. However, its current limitations necessitate a complementary role with human expert oversight.

DIAGNOSTIC YIELD OF IN VITRO VITREOUS BIOPSY FOR INTRAOCULAR LYMPHOMA AT VARIABLE VITREOUS CUTTER SPEEDS USING 25-GAUGE VITRECTOMY.

PURPOSE: Primary vitreoretinal lymphoma is the most common intraocular lymphoproliferative disorder. We evaluated the diagnostic yield of pars plana vitrectomy, specifically using modern high cut rate dual-cycle cutters, on in vitro cell viability and diagnostic yield. METHODS: Human Burkitt lymphoma cell line Namalwa at 2 x 10^5 cells/mL was aspirated by 25-gauge dual-blade guillotine-type vitrectomy at five speeds (500, 1,000, 4,000, 7,500, or 15,000 cuts per minute). Cell viability and diagnostic yield in each subtype group were determined using hemocytometry, viable cell count using Cell Counting Kit-8, and pathologist-guided manual count. RESULTS: No significant deviation in cell count was identified in any cut rate by ANOVA ( P = 0.61), and no trends in the number of viable cells were identified across cut rates (R 2 = 0.188, P = 0.47). Among histologic cell counts per cut-rate, neither linear regression (R = 0.531, P = 0.16) nor ANOVA ( P = 0.096) were statistically significant. CONCLUSION: There was no significant degradation in the number of viable cells with increasing cut speed. These results suggest that in contrast to previous findings using 20g or 23g vitrectomy for diagnostic vitrectomy, modern vitrectomy systems may be used at up to 15,000 cpm without compromising the viability of lymphoma cells.

RISK FACTORS FOR SURGERY OR BLINDNESS IN NEOVASCULAR GLAUCOMA EYES TREATED WITH ANTI-VEGF INJECTIONS BY A RETINA SPECIALIST.

PURPOSE: To determine baseline patient characteristics that predict the need for glaucoma surgery or blindness in eyes with neovascular glaucoma (NVG) despite intravitreal antivascular endothelial growth factor therapy. METHODS: This is a retrospective cohort study of patients with NVG who had not previously received glaucoma surgery and were treated with intravitreal antivascular endothelial growth factor injections at the time of diagnosis, from September 8, 2011, to May 8, 2020, at a large, retina subspecialty practice. RESULTS: Of 301 newly presenting NVG eyes, 31% required glaucoma surgery and 20% progressed to no light perception vision despite treatment. Patients with intraocular pressure >35 mmHg ( P < 0.001), two or more topical glaucoma medications ( P = 0.003), worse than 20/100 vision ( P = 0.024), proliferative diabetic retinopathy ( P = 0.001), eye pain or discomfort ( P = 0.010), and new patient status ( P = 0.015) at the time of NVG diagnosis were at a higher risk of glaucoma surgery or blindness regardless of antivascular endothelial growth factor therapy. The effect of panretinal photocoagulation was not statistically significant in a subgroup analysis of patients without media opacity ( P = 0.199). CONCLUSION: Several baseline characteristics at the time of presentation to a retina specialist with NVG seem to portend a higher risk of uncontrolled glaucoma despite the use of antivascular endothelial growth factor therapy. Prompt referral of these patients to a glaucoma specialist should be strongly considered.

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases.

Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-Å X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.

REGIONAL POPULATION MOBILITY AND OUTPATIENT RETINA VISITS IN THE UNITED STATES DURING THE COVID-19 PANDEMIC.

PURPOSE: To characterize how community mobility patterns across the United States correlate with local changes in retina visits during the pandemic. METHODS: Outpatient retina clinic visits were linked to population mobility by combining multiple public data sets, including the Google Community Mobility Reports and data from the Centers for Disease Control and Infection. Percentage change from baseline in daily-average number of retina visits by county and mobility were measured by county. RESULTS: A total of 2,159,689 patient visits were examined across 332 counties. Daily-average retina visits decreased by 7.0%, 19.0%, 5.0%, and 4.0% from Quarter 1 to 4 of 2020. This decrease was negatively correlated with increased incident of COVID-19 deaths for Quarters 1 to 3 (r = -0.13, r = -0.16, and r = -0.15, respectively, P < 0.001) and increased incident cases for Quarters 1 and 2 (r = -0.18, r = -0.13, respectively, P < 0.001). Daily-average retina visits relative to baseline were significantly lower for metropolitan counties in Quarters 1 and 2, compared with urban and rural (P < 0.001). The decline in retina visits had greatest association with decline in workplace visits in Quarters 1 to 3 (r = 0.27, r = 0.09, r = 0.12, respectively, P < 0.001 for all). CONCLUSION: This study provides insight into how regional mobility patterns may help to explain and predict patient behaviors and retina outpatient visit responses during the COVID-19 pandemic.

SECONDARY EPIRETINAL MEMBRANE AFTER LASER RETINOPEXY FOR RETINAL TEAR OR LOCALIZED RETINAL DETACHMENT: Surgical Outcomes and Optical Coherence Tomography Structural Analysis.

PURPOSE: To assess visual acuity and optical coherence tomography outcomes after repair of secondary epiretinal membrane (ERM) after prior laser retinopexy for retinal tear with or without localized retinal detachment. METHODS: Retrospective, consecutive series. A previously described optical coherence tomography grading scheme was used for imaging analysis. RESULTS: Forty-two eyes of 42 patients were included, of which 16 (38.1%) had a concurrent localized retinal detachment. Mean logMAR visual acuity prelaser retinopexy was 0.15 ± 0.13 (Snellen 20/28), which worsened to 0.56 ± 0.42 (Snellen 20/72) before ERM surgery (P < 0.001). The mean visual acuity improved to 0.36 ± 0.30 (Snellen 20/45, P < 0.001) 3 months postsurgery and to 0.31 ± 0.32 (Snellen = 20/40, P < 0.001) at the final follow-up. Most eyes exhibited advanced ERM characteristics (n = 19 [45.2%] Stage 3 and n = 15 [35.7%] Stage 4 characteristics). The presence of inner microcystic changes (P = 0.008) and ellipsoid zone disruption (P = 0.009) at postoperative Month 3 were associated with worse final visual acuity. Eyes undergoing ERM surgery ≤180 days from laser retinopexy (n = 16, 38.1%) were younger (P = 0.024) and more likely to have Stage 4 ERM characteristics (P = 0.001). CONCLUSION: Secondary ERM after laser retinopexy may occur rapidly (<180 days) and exhibit significant anatomic alterations. The presence of inner microcystic changes and ellipsoid zone disruption postoperatively were optical coherence tomography features associated with worse final visual acuity.

PREVALENCE, CHARACTERISTICS, AND OUTCOMES OF RHEGMATOGENOUS RETINAL DETACHMENT IN EYES WITH TRABECULECTOMY OR GLAUCOMA DRAINAGE DEVICES.

PURPOSE: To describe the prevalence, management, and outcomes of rhegmatogenous retinal detachment (RRD) after incisional glaucoma filtering surgery. METHODS: All patients with a history of trabeculectomy or glaucoma drainage device surgery who were subsequently diagnosed with an RRD from January 1, 2016, to January 1, 2021, at the Wills Eye Hospital were identified. RESULTS: Forty-six eyes met the inclusion criteria. The mean age was 60.7 ± 19.6 years, and 15 patients (32.6%) were female. Of all eyes, 34 (73.9%) were diagnosed with primary open-angle glaucoma. The mean time from most recent incisional glaucoma surgery to RRD diagnosis was 1,133 ± 1,644 days. There were 19 eyes (41.3%) with preoperative proliferative vitreoretinopathy (9 eyes [19.6%] with Grade C proliferative vitreoretinopathy) and 35 eyes (76.1%) had macula-off RRD at the time of presentation. At RRD presentation, 4 eyes (8.7%) had concomitant endophthalmitis, 5 (10.9%) had concurrent choroidal detachment, and 2 (4.7%) had concurrent vitreous hemorrhage. Primary vitrectomy was performed in most (91.3%) cases. Silicone oil tamponade was often required (71.1%). The single surgery success rate was 65.2% (30 of 46). The mean preoperative logarithm of the minimum angle of resolution visual acuity was 1.72 ± 0.78 (Snellen acuity 20/1,050), and the mean final postoperative logarithm of the minimum angle of resolution was 1.59 ± 0.89 (20/778, P = 0.2853). Of glaucoma surgeries performed, the 5-year prevalence of RRD was 0.71% (26 of 3,664, 95% Poisson confidence interval 0.48%-1.04%). CONCLUSION: The 5-year prevalence of RRDs after trabeculectomy or glaucoma drainage device was 0.71%. Most patients presented with macula-involving detachments, often with proliferative vitreoretinopathy. Anatomical and visual outcomes were poor.

Expediting knowledge acquisition by a web framework for Knowledge Graph Exploration and Visualization (KGEV): case studies on COVID-19 and Human Phenotype Ontology.

BACKGROUND: Knowledges graphs (KGs) serve as a convenient framework for structuring knowledge. A number of computational methods have been developed to generate KGs from biomedical literature and use them for downstream tasks such as link prediction and question answering. However, there is a lack of computational tools or web frameworks to support the exploration and visualization of the KG themselves, which would facilitate interactive knowledge discovery and formulation of novel biological hypotheses. METHOD: We developed a web framework for Knowledge Graph Exploration and Visualization (KGEV), to construct and visualize KGs in five stages: triple extraction, triple filtration, metadata preparation, knowledge integration, and graph database preparation. The application has convenient user interface tools, such as node and edge search and filtering, data source filtering, neighborhood retrieval, and shortest path calculation, that work by querying a backend graph database. Unlike other KGs, our framework allows fast retrieval of relevant texts supporting the relationships in the KG, thus allowing human reviewers to judge the reliability of the knowledge extracted. RESULTS: We demonstrated a case study of using the KGEV framework to perform research on COVID-19. The COVID-19 pandemic resulted in an explosion of relevant literature, making it challenging to make full use of the vast and heterogenous sources of information. We generated a COVID-19 KG with heterogenous information, including literature information from the CORD-19 dataset, as well as other existing knowledge from eight data sources. We showed the utility of KGEV in three intuitive case studies to explore and query knowledge on COVID-19. A demo of this web application can be accessed at http://covid19nlp.wglab.org . Finally, we also demonstrated a turn-key adaption of the KGEV framework to study clinical phenotypic presentation of human diseases by Human Phenotype Ontology (HPO), illustrating the versatility of the framework. CONCLUSION: In an era of literature explosion, the KGEV framework can be applied to many emerging diseases to support structured navigation of the vast amount of newly published biomedical literature and other existing biological knowledge in various databases. It can be also used as a general-purpose tool to explore and query gene-phenotype-disease-drug relationships interactively.

Clinical Presentation of Rhegmatogenous Retinal Detachment during the COVID-19 Pandemic: A Historical Cohort Study.

PURPOSE: To investigate the effect of the coronavirus disease 2019 (COVID-19) pandemic on the clinical presentation of acute, primary rhegmatogenous retinal detachment (RRD). DESIGN: Single-center, consecutive case series with historical controls. PARTICIPANTS: Consecutive patients seeking treatment for primary RRD in a 50-day period during the COVID-19 pandemic (March 9-April 27, 2020) and the corresponding 50-day period during the previous year (March 4-April 22, 2019) in the United States. METHODS: The cohorts were compared to assess demographic variables and clinical presentations. Multivariate logistic regression was used to identify factors predictive of presenting macular attachment status. MAIN OUTCOME MEASURES: The primary outcome was the proportion of patients with macula-on RRD at presentation. Secondary outcomes included visual acuity (VA), duration of symptoms before presentation, proportion seeking treatment within 1 day of symptom onset, and presence of primary proliferative vitreoretinopathy (PVR). RESULTS: Eighty-two patients were included in the 2020 cohort compared with 111 patients in the 2019 primary control cohort. Demographic factors were similar between the groups. Significantly fewer patients demonstrated macula-on RRD in the 2020 cohort (20/82 patients [24.4%]) than in the 2019 cohort (55/111 patients [49.5%]; P = 0.001). Patients in the 2020 cohort showed worse median VA at presentation (1.00 logarithm of the minimum angle of resolution [logMAR; Snellen equivalent, 20/200] in 2020 vs. 0.48 logMAR [Snellen equivalent, 20/60] in 2019; P = 0.008), fewer patients sought treatment within 1 day of symptoms (16/80 patients [19.5%] in 2020 vs. 41/106 patients [36.9%] in 2019; P = 0.005), and a greater proportion demonstrated primary PVR (11/82 patients [13.4%] in 2020 vs. 5/111 patients [4.5%] in 2019; P = 0.03). In multivariate analysis, younger age (P = 0.03) and established patient status (P = 0.02) were independent predictors of macula-on status in the 2020 cohort. CONCLUSIONS: Patients with primary RRD during the 2020 COVID-19 pandemic were less likely to have macula-on disease and more likely to delay seeking treatment and to show worse vision and PVR.

Small-molecule CaVα1⋠CaVß antagonist suppresses neuronal voltage-gated calcium-channel trafficking.

Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein-protein interactions with auxiliary α2/δ and ß subunits. The high-affinity CaV2.2α1⋅CaVß3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVß3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVß3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

Real-world vitreoretinal practice patterns during the 2020 COVID-19 pandemic: a nationwide, aggregated health record analysis.

PURPOSE OF REVIEW: The COVID-19 pandemic has posed an unprecedented challenge to the healthcare community. To reduce disease transmission, national regulatory agencies temporarily recommended curtailment of all nonurgent office visits and elective surgeries in March 2020, including vitreoretinal outpatient care in the USA. The effect of these guidelines on utilization of vitreoretinal care has not been explored to date. RECENT FINDINGS: Retinal outpatient visits, new patient visits, intravitreal antivascular endothelial growth factor injections and in-office multimodal retinal imaging has seen a significant decline in utilization in the early phase of the pandemic. Intravitreal injections were performed at a comparatively higher rate than office visits. Utilization appeared to steadily increase in April 2020. Telemedicine visits, enabled by new national legislation for all areas of medicine, have been adopted to a modest degree by the retina community. SUMMARY: In-office retinal care declined in response to the COVID-19 pandemic and national regulatory guidelines limiting nonurgent care. These trends in practice patterns and care utilization may be of interest to vitreoretinal providers and all ophthalmologists at large.

Single-position prone lateral approach: cadaveric feasibility study and early clinical experience.

OBJECTIVE: Lateral lumbar interbody fusion (LLIF) is a useful minimally invasive technique for achieving anterior interbody fusion and preserving or restoring lumbar lordosis. However, achieving circumferential fusion via posterior instrumentation after an LLIF can be challenging, requiring either repositioning the patient or placing pedicle screws in the lateral position. Here, the authors explore an alternative single-position approach: LLIF in the prone lateral (PL) position. METHODS: A cadaveric feasibility study was performed using 2 human cadaveric specimens. A retrospective 2-center early clinical series was performed for patients who had undergone a minimally invasive lateral procedure in the prone position between August 2019 and March 2020. Case duration, retractor time, electrophysiological thresholds, implant size, screw accuracy, and complications were recorded. Early postoperative radiographic outcomes were reported. RESULTS: A PL LLIF was successfully performed in 2 cadavers without causing injury to a vessel or the bowel. No intraoperative subsidence was observed. In the clinical series, 12 patients underwent attempted PL surgery, although 1 case was converted to standard lateral positioning. Thus, 11 patients successfully underwent PL LLIF (89%) across 14 levels: L2-3 (2 of 14 [14%]), L3-4 (6 of 14 [43%]), and L4-5 (6 of 14 [43%]). For the 11 PL patients, the mean (± SD) age was 61 ± 16 years, mean BMI was 25.8 ± 4.8, and mean retractor time per level was 15 ± 6 minutes with the longest retractor time at L2-3 and the shortest at L4-5. No intraoperative subsidence was noted on routine postoperative imaging. CONCLUSIONS: Performing single-position lateral transpsoas interbody fusion with the patient prone is anatomically feasible, and in an early clinical experience, it appeared safe and reproducible. Prone positioning for a lateral approach presents an exciting opportunity for streamlining surgical access to the lumbar spine and facilitating more efficient surgical solutions with potential clinical and economic advantages.

On the (Non-)equivalency of monopolar and bipolar settings for deep brain stimulation fMRI studies of Parkinson's disease patients.

BACKGROUND: The majority of Parkinson's disease patients with deep brain stimulation (DBS) use a monopolar configuration, which presents challenges for EEG and MRI studies. The literature reports algorithms to convert monopolar to bipolar settings. PURPOSE/HYPOTHESIS: To assess brain responses of Parkinson's disease patients implanted with DBS during fMRI studies using their clinical and presumed equivalent settings using a published conversion recipe. STUDY TYPE: Prospective. SUBJECTS: Thirteen DBS patients. FIELD STRENGTH/SEQUENCE: 1.5T and 3T, fMRI using gradient echo-planar imaging. ASSESSMENT: Patients underwent 30/30sec ON/OFF DBS fMRI scans using monopolar and bipolar settings. To convert to a bipolar setting, the negative contact used for the monopolar configuration remained constant and the adjacent dorsal contact was rendered positive, while increasing the voltage by 30%. fMRI activation/deactivation maps and motor Unified Parkinson's Disease Rating Scale (UPDRS-III) scores were compared for patients in both configurations. STATISTICAL TESTS: T-tests were used to compare UPDRS scores and volumes of tissue activated (VTA) diameters in monopolar and bipolar configurations. RESULTS: The patterns of fMRI activation in the monopolar and bipolar configurations were generally different. The thalamus, pallidum, and visual cortices exhibited higher activation using the patient's clinical settings than the presumed equivalent settings. VTA diameters were lower (7 mm vs. 6.3 mm, P = 0.047) and UPDRS scores were generally higher in the bipolar (33.2 ± 16) than in the monopolar configuration (28.3 ± 17.4), without reaching statistical significance (P > 0.05). DATA CONCLUSION: Monopolar and bipolar configurations result in different patterns of brain activation while using a previously published monopolar-bipolar conversion algorithm. Clinical benefits may be achieved with varying patterns of brain responses. Blind conversion from one to the other should be avoided for purposes of understanding the mechanisms of DBS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor.

Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemniscus, pyramidal, and dentato-rubro-thalamic). The area of optimal tremor response at 3 months after the procedure was identified at the posterior portion of the ventral intermediate nucleus. Lesions extending beyond the posterior region of the ventral intermediate nucleus and lateral to the lateral thalamic border were associated with increased risk of acute adverse sensory and motor effects, respectively. Acute adverse effects on gait and dysmetria occurred with lesions inferolateral to the thalamus. Lesions inferolateral to the thalamus or medial to the ventral intermediate nucleus were also associated with acute adverse speech effects. Diffusion-weighted imaging revealed that lesions associated with adverse sensory and gait/dysmetria effects compromised the medial lemniscus and dentato-rubro-thalamic tracts, respectively. Lesions associated with adverse motor and speech effects encroached on the pyramidal tract. Lesions larger than 170 mm3 were associated with an increased risk of acute adverse effects. Tremor improvement and acute adverse effects of MRgFUS for essential tremor are highly dependent on the location and size of lesions. These novel findings could refine current MRgFUS treatment planning and targeting, thereby improving clinical outcomes in patients.

Enzyme intermediates captured "on the fly" by mix-and-inject serial crystallography.

BACKGROUND: Ever since the first atomic structure of an enzyme was solved, the discovery of the mechanism and dynamics of reactions catalyzed by biomolecules has been the key goal for the understanding of the molecular processes that drive life on earth. Despite a large number of successful methods for trapping reaction intermediates, the direct observation of an ongoing reaction has been possible only in rare and exceptional cases. RESULTS: Here, we demonstrate a general method for capturing enzyme catalysis "in action" by mix-and-inject serial crystallography (MISC). Specifically, we follow the catalytic reaction of the Mycobacterium tuberculosis ß-lactamase with the third-generation antibiotic ceftriaxone by time-resolved serial femtosecond crystallography. The results reveal, in near atomic detail, antibiotic cleavage and inactivation from 30 ms to 2 s. CONCLUSIONS: MISC is a versatile and generally applicable method to investigate reactions of biological macromolecules, some of which are of immense biological significance and might be, in addition, important targets for structure-based drug design. With megahertz X-ray pulse rates expected at the Linac Coherent Light Source II and the European X-ray free-electron laser, multiple, finely spaced time delays can be collected rapidly, allowing a comprehensive description of biomolecular reactions in terms of structure and kinetics from the same set of X-ray data.

Posterior open-wedge anterior longitudinal ligament release: Cadaveric technique analysis.

Anterior column release is a powerful surgical technique for achieving spinopelvic balance in adult patients with sagittal plane deformities. We present an alternative strategy for focal deformity correction from a posterior-only approach. The purpose of this study was to evaluate the feasibility and efficacy of a novel surgical technique called posterior open-wedge diskectomy and anterior longitudinal ligament (ALL) release (POWAR). A cadaveric torso underwent POWARs at the L1-L4 intervertebral disc spaces. Baseline measurements of end-plate angle (EPA), anterior intervertebral disc height (ADH), and posterior intervertebral disc height (PDH) were obtained. These measurements were repeated after three stages of correction: posterior column compression alone, posterior column compression following Schwab grade 2 osteotomies, and posterior column compression following POWAR. A second cadaver underwent posterolateral spinal dissection to demonstrate the pertinent anatomical features relevant to this novel procedure. With each stage of correction, a sequential increase in EPA and ADH and a decrease in PDH were demonstrated. The large increase in ADH seen following POWAR confirmed successful release of the ALL. In situ investigation of the aorta and inferior vena cava following anterior exposure revealed no injury to the great vessels or surrounding structures. Ex vivo testing of the aorta and inferior vena cava took place at the L3-4 level. This testing demonstrated no injury or tears to either vessel. POWAR is a new surgical technique that can provide an alternative to three-column osteotomy for surgeons performing spinal reconstructions in adults through an open, posterior-only approach. Clin. Anat. 32:348-353, 2019. © 2018 Wiley Periodicals, Inc.

Small molecules inhibit ex vivo tumor growth in bone.

Bone is a common site of metastasis for breast, prostate, lung, kidney and other cancers. Bone metastases are incurable, and substantially reduce patient quality of life. To date, there exists no small-molecule therapeutic agent that can reduce tumor burden in bone. This is partly attributed to the lack of suitable in vitro assays that are good models of tumor growth in bone. Here, we take advantage of a novel ex vivo model of bone colonization to report a series of pyrrolopyrazolone small molecules that inhibit cancer cell invasion and ex vivo tumor growth in bone at single-digit micromolar concentration. We find that the compounds modulated the expression levels of genes associated with bone-forming osteoblasts, bone-destroying osteoclasts, cancer cell viability and metastasis. Our compounds provide chemical tools to uncover novel targets and pathways associated with bone metastasis, as well as for the development of compounds to prevent and reverse bone tumor growth in vivo.

Subthalamic Nucleus Visualization on Routine Clinical Preoperative MRI Scans: A Retrospective Study of Clinical and Image Characteristics Predicting Its Visualization.

BACKGROUND: The visualization of the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) is variable. Studies of the contribution of patient-related factors and intrinsic brain volumetrics to STN visualization have not been reported previously. OBJECTIVE: To assess the visualization of the STN during deep brain stimulation (DBS) surgery in a clinical setting. METHODS: Eighty-two patients undergoing pre-operative MRI to plan for STN DBS for Parkinson disease were retrospectively studied. The visualization of the STN and its borders was assessed and scored by 3 independent observers using a 4-point ordinal scale (from 0 = not seen to 3 = excellent visualization). This measure was then correlated with the patients' clinical information and brain volumes. RESULTS: The mean STN visualization scores were 1.68 and 1.63 for the right and left STN, respectively, with a good interobserver reliability (intraclass correlation coefficient: 0.744). Older age and decreased white matter volume were negatively correlated with STN visualization (p < 0.05). CONCLUSION: STN visualization is only fair to good on routine MRI with good concordance of interindividual rating. Advancing age and decreased white matter are associated with poor visualization of the STN. Knowledge about factors contributing to poor visualization of the STN could alert a surgeon to modify the imaging strategy to optimize surgical targeting.

Deep brain stimulation for dementias.

OBJECTIVE The aim of this article is to review the authors' and published experience with deep brain stimulation (DBS) therapy for the treatment of patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). METHODS Two targets are current topics of investigation in the treatment of AD and PDD, the fornix and the nucleus basalis of Meynert. The authors reviewed the current published clinical experience with attention to patient selection, biological rationale of therapy, anatomical targeting, and clinical results and adverse events. RESULTS A total of 7 clinical studies treating 57 AD patients and 7 PDD patients have been reported. Serious adverse events were reported in 6 (9%) patients; none resulted in death or disability. Most studies were case reports or Phase 1/2 investigations and were not designed to assess treatment efficacy. Isolated patient experiences demonstrating improved clinical response after DBS have been reported, but no significant or consistent cognitive benefits associated with DBS treatment could be identified across larger patient populations. CONCLUSIONS PDD and AD are complex clinical entities, with investigation of DBS intervention still in an early phase. Recently published studies demonstrate acceptable surgical safety. For future studies to have adequate power to detect meaningful clinical changes, further refinement is needed in patient selection, metrics of clinical response, and optimal stimulation parameters.