Adolescent Thalamocortical Inhibition Alters Prefrontal Excitation-Inhibition Balance.

Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuit connectivity during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in the mouse from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target twenty-four hours later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III nucleus accumbens (NAc) and layer V/VI medio-dorsal thalamus projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only changed in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosally-projecting neurons. Increased inhibition of intra-prefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition (P20-P35).

Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial.

Importance: Controlling myopia progression is of interest worldwide. Low-dose atropine eye drops have slowed progression in children in East Asia. Objective: To compare atropine, 0.01%, eye drops with placebo for slowing myopia progression in US children. Design, Setting, and Participants: This was a randomized placebo-controlled, double-masked, clinical trial conducted from June 2018 to September 2022. Children aged 5 to 12 years were recruited from 12 community- and institution-based practices in the US. Participating children had low to moderate bilateral myopia (-1.00 diopters [D] to -6.00 D spherical equivalent refractive error [SER]). Intervention: Eligible children were randomly assigned 2:1 to 1 eye drop of atropine, 0.01%, nightly or 1 drop of placebo. Treatment was for 24 months followed by 6 months of observation. Main Outcome and Measures: Automated cycloplegic refraction was performed by masked examiners. The primary outcome was change in SER (mean of both eyes) from baseline to 24 months (receiving treatment); other outcomes included change in SER from baseline to 30 months (not receiving treatment) and change in axial length at both time points. Differences were calculated as atropine minus placebo. Results: A total of 187 children (mean [SD] age, 10.1 [1.8] years; age range, 5.1-12.9 years; 101 female [54%]; 34 Black [18%], 20 East Asian [11%], 30 Hispanic or Latino [16%], 11 multiracial [6%], 6 West/South Asian [3%], 86 White [46%]) were included in the study. A total of 125 children (67%) received atropine, 0.01%, and 62 children (33%) received placebo. Follow-up was completed at 24 months by 119 of 125 children (95%) in the atropine group and 58 of 62 children (94%) in the placebo group. At 30 months, follow-up was completed by 118 of 125 children (94%) in the atropine group and 57 of 62 children (92%) in the placebo group. At the 24-month primary outcome visit, the adjusted mean (95% CI) change in SER from baseline was -0.82 (-0.96 to -0.68) D and -0.80 (-0.98 to -0.62) D in the atropine and placebo groups, respectively (adjusted difference = -0.02 D; 95% CI, -0.19 to +0.15 D; P = .83). At 30 months (6 months not receiving treatment), the adjusted difference in mean SER change from baseline was -0.04 D (95% CI, -0.25 to +0.17 D). Adjusted mean (95% CI) changes in axial length from baseline to 24 months were 0.44 (0.39-0.50) mm and 0.45 (0.37-0.52) mm in the atropine and placebo groups, respectively (adjusted difference = -0.002 mm; 95% CI, -0.106 to 0.102 mm). Adjusted difference in mean axial elongation from baseline to 30 months was +0.009 mm (95% CI, -0.115 to 0.134 mm). Conclusions and Relevance: In this randomized clinical trial of school-aged children in the US with low to moderate myopia, atropine, 0.01%, eye drops administered nightly when compared with placebo did not slow myopia progression or axial elongation. These results do not support use of atropine, 0.01%, eye drops to slow myopia progression or axial elongation in US children. Trial Registration: ClinicalTrials.gov Identifier: NCT03334253.

"The peripheral perfusion index discriminates haemodynamic responses to induction of general anaesthesia".

Induction of general anaesthesia is often accompanied by hypotension. Standard haemodynamic monitoring during anaesthesia relies on intermittent blood pressure and heart rate. Continuous monitoring systemic blood pressure requires invasive or advanced modalities creating a barrier for obtaining important information of the circulation. The Peripheral Perfusion Index (PPI) is obtained non-invasively and continuously by standard photoplethysmography. We hypothesized that different patterns of changes in systemic haemodynamics during induction of general anaesthesia would be reflected in the PPI. Continuous values of PPI, stroke volume (SV), cardiac output (CO), and mean arterial pressure (MAP) were evaluated in 107 patients by either minimally invasive or non-invasive means in a mixed population of surgical patients. 2 min after induction of general anaesthesia relative changes of SV, CO, and MAP was compared to the relative changes of PPI. After induction total cohort mean(± st.dev.) MAP, SV, and CO decreased to 65(± 16)%, 74(± 18)%, and 63(± 16)% of baseline values. In the 38 patients where PPI decreased MAP was 57(± 14)%, SV was 63(± 18)%, and CO was 55(± 18)% of baseline values 2 min after induction. In the 69 patients where PPI increased the corresponding values were MAP 70(± 15)%, SV 80(± 16)%, and CO 68(± 17)% (all differences: p < 0,001). During induction of general anaesthesia changes in PPI discriminated between the degrees of reduction in blood pressure and algorithm derived cardiac stroke volume and -output. As such, the PPI has potential to be a simple and non-invasive indicator of the degree of post-induction haemodynamic changes.

Discovering what patrons value in a consumer health library service using laddering interviews.

Background: Librarians at Preston Medical Library sought to understand whether marketing research techniques could be adapted to libraries to better understand what patrons value. Specifically, this study sought to learn why patrons continue using a consumer health information service, develop insights to improve the service, and a methodology to use with other patron groups. Case Presentation: Librarian researchers conducted customer value research using laddering interviews, an interview technique utilized in marketing research to learn users' goals in using a product or service. The PML research team interviewed six frequent users of a medical library's consumer health information service. Researchers conducted laddering interviews, covering patron views of basic attributes of the service, leading on to consequences of their interaction with it, and finally discussing what they hoped to achieve in using the service. The results were visualized in customer value hierarchy diagrams, graphically showing relationships between valued attributes of a product or service, how the patron used it, and how that helped patrons achieve goals. This allowed the research team to identify which features of service contribute the most to patron satisfaction. Conclusion: Customer value learning utilizing laddering interviews enables librarians to see their service through the patrons' eyes, focusing on those aspects of the service that they view as most important. This study allowed librarians to learn that users desired to feel more in control of their health and gain peace of mind by obtaining trusted information. The library's work in providing information leads to self-empowerment for these patrons.

Remote and Hybrid Work Options for Health Science Librarians: A Survey of Job Postings Before and After the COVID-19 Pandemic.

This study compares health science librarian job postings in the MEDLIB-L listserv from 2018-2019 and 2021-2022 to assess whether there was an increase in remote or hybrid schedule arrangements listed in job advertisements after the pandemic's onset. Results indicated a notable increase in advertising remote/hybrid work arrangements rising from 1.2% of listings in 2018-2019 to 16% of listings in 2021-2022. Data from a 2022 survey of library directors, however, indicated that approximately 70% of respondents expressed confidence in the continuance of remote/hybrid work. Additionally, from a very limited sample size, salaries for remote/hybrid positions did not appear to be less than in-person postings. While current employees at many institutions may benefit from flexible scheduling, this study examines whether job postings, which are often the primary information available to applicants, included information about remote and hybrid work options.

Evidence for virus-mediated oncogenesis in bladder cancers arising in solid organ transplant recipients.

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have an overall poorer outcomes, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of the tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases, with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with an antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.

Looking at Library Resource Usage Trends in Medical Residents & Fellows: Survey Results from 2006-2021.

Since 2006, the University of Tennessee's Preston Medical Library has collected survey feedback from exiting residents through targeted emails or at the required exit process in the library. Questions ask residents which types of articles or sources they use to find information and address the resident's use of the library's physical space. Survey results from 2006 to 2021 were examined for trends and changes in resident utilization of resources to better inform future library decisions on instruction and marketing. Resident resource usage varied over time and demonstrated an encouraging increase in attention to evidence-based tools. UpToDate's consistent popularity shows the durability of the product. A reported increase in use of reviews, randomized controlled trials, case reports, and practice guidelines reflects greater employment of more in-depth resources than merely expert opinion. At the same time, residents clearly valued the library's physical space. Survey results will inform future outreach focus.

Determining COVID-19's impact on an academic medical library's literature search service.

Objective: At many institutions, literature search services are an important aspect of health science librarianship. This exploratory study analyzes how the COVID-19 pandemic impacted the use of an academic hospital medical library's literature search service. Methods: To evaluate the pandemic's impact on literature searching at The University of Tennessee Medical Center's Preston Medical Library, data were analyzed for changes from the year before the pandemic (March 1, 2019 to February 29, 2020) to the first year during the pandemic (March 1st, 2020 to February 28, 2021). This was accomplished using LibWizard, a library feedback and assessment application, to review literature search data during the two periods. Variables of interest included total searches, purpose of searches, affiliation of the searcher, and searches with a pandemic-related research question. Results: A 36.6% drop in literature search service usage was reported from the pre-pandemic year to the during-pandemic year. There was a 55.3% decrease in searches intended for research, as well as significant decreases in the number of searches requested by all patron affiliations. After March 2020, 10% of all searches concerned a COVID-related topic. Conclusion: The overall decrease in literature search requests, decrease in research searches, decrease in searches among all patron affiliations, and increase in searches on a COVID-related topic suggest that healthcare worker and institutional priorities changed during the pandemic. The results revealed research interests during the first year of the pandemic, as well as an overall change in library service functionality.

Mind like Water: Flexibly Adapting to Serve Patrons in the Era of COVID-19.

The ability to be flexible and adapt quickly to changing circumstances is a crucial skill for librarians to develop in a world increasingly characterized by rapid change. It can take a crisis to learn how effective librarians have become in developing the needed adaptive behaviors, including a willingness to change workstyles, experiment with new technologies and readily move on from failed experiments. In this paper, librarians from the Preston Medical Library at the University of Tennessee Graduate School of Medicine, prompted by the crisis of COVID-19, present their response. Beginning with a description of how services were provided prior to the pandemic, librarians detail their response in several key areas and show how they implemented new approaches to teaching, collaboration, and mutual support, working together to handle patron issues and pursue scholarly activities.

Using Paper Nest Pucks to Prevent Barbering in C57BL/6 Mice.

Little research has been conducted to examine the influence of various methods of providing nest materials-such as dispersing them, providing them as single units, or clustering them-on the behavior and welfare of group-housed mice. In this study, 6 wk-old C57BL/6NCrl mice were housed 3 per cage and randomized into 1 of 3 nest-material groups: 1) one facial tissue per cage (control; female mice, 3 cages; male mice, 3 cages); 2) an 8-g 'puck' of compressed nesting material and a facial tissue (females, 3 cages; males, 3 cages); or 3) 8 g of dispersed paper strips and a facial tissue (females, 3 cages; males, 3 cages). Mouse behavior (agonistic, stereotypic, nesting), physical examination data, and nest scores were evaluated over 16 d. The results showed that mice in the puck and control groups spent more time manipulating nest materials after cage changes than did mice in the paper-strip group. Average nest scores were highest in the paper-strip group compared with controls and puck cages. Female cages with pucks showed no barbering, whereas all other female mice cages demonstrated barbering. Overall, nest pucks may provide a time-consuming activity for mice and may help protect female C57BL/6 mice from barbering. However, more research is needed to replicate and expand these study results.

Influence of library relocation and marketing: examining zip codes and health disparities to serve consumers in East Tennessee.

BACKGROUND: In 2014, the Preston Medical Library underwent a radical change, moving from an academic office building to the main floor of a regional medical center. While the library had previously served the public, health information requests have substantially increased in volume due to the new location. Researchers analyzed request data to see if the service's reach has expanded to counties that previously had not used the service, to see which counties have requested the most health information, and to ascertain whether more requests are from counties with higher poverty rates. CASE PRESENTATION: Each health information request is logged with the subject nature and patron contact information. Consumer health request data were downloaded from the library database. Names and other identifying data were removed. Request forms were sorted and reviewed by zip code and county, comparing number of requests as well as poverty levels. Tableau was utilized to create maps, visually showing patron concentrations and poverty levels. CONCLUSIONS: There were 3,141 health information requests from September 21, 2014, to May 31, 2019. The majority of requests were from local counties. Requests were also received from counties that had not been previously reached and counties with elevated poverty levels. Collecting data on patron interactions is not only critical for institutional reporting, but also for community outreach. Understanding that data require taking additional steps to filter the information, assess local demographics, and customize library services. Researchers anticipate being able to better tailor services to the community based on the results.

Distinct DNA Methylation Signatures in Neuroendocrine Tumors Specific for Primary Site and Inherited Predisposition.

PURPOSE: To compare the deoxyribonucleic acid (DNA) methylation signature of neuroendocrine tumors (NETs) by primary tumor site and inherited predisposition syndromes von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 1 (MEN1). METHODS: Genome-wide DNA methylation (835 424 CpGs) of 96 NET samples. Principal components analysis (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures. RESULTS: Hypomethylated CpGs were significantly more common in VHL-related versus sporadic and MEN1-related NETs (P < .001 for both comparisons). Small-intestinal NETs (SINETs) had the most differentially methylated CpGs, either hyper- or hypomethylated, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, P < .001 for all comparisons). There was complete separation of SINETs on PCA, and 3 NETs of unknown origin clustered with the SINET samples. Sporadic, VHL-related, and MEN1-related PNETs formed distinct groups on PCA, and VHL clustered separately, showing pronounced DNA hypomethylation, while sporadic and MEN1-related NETs clustered together. MEN1-related PNETs, DNETs, and gastric NETs each had a distinct DNA methylome signature, with complete separation by PCA and unsupervised clustering. Finally, we identified 12 hypermethylated CpGs in the 1A promoter of the APC (adenomatous polyposis coli) gene, with higher methylation levels in MEN1-related NETs versus VHL-related and sporadic NETs (P < .001 for both comparisons). CONCLUSIONS: DNA CpG methylation profiles are unique in different primary NET types even when occurring in MEN1-related NETs. This tumor DNA methylome signature may be utilized for noninvasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future.

Expression and function of Kv1.3 channel in malignant T cells in Sézary syndrome.

The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed by a subset of chronically activated memory T cells and plays an important role in their activation and proliferation. Here, we show that primary malignant T cells isolated from patients with Sézary syndrome (SS) express Kv1.3 and are sensitive to potent Kv1.3 inhibitors ShK and Vm24, but not sensitive to a less potent inhibitor [N17A/F32T]-AnTx. Kv1.3 blockade inhibits CD3/CD28-induced proliferation and IL-9 expression by SS cells in a concentration-dependent manner. In parallel, CD3/CD28-mediated CD25 induction is inhibited, whereas Kv1.3 blockade has no effect on apoptosis or cell death as judged by Annexin V and PI staining. In conclusion, we provide the first evidence that malignant T cells in SS express functional Kv1.3 channels and that Kv1.3 blockade inhibits activation-induced proliferation as well as cytokine and cytokine receptor expression in malignant T cells, suggesting that Kv1.3 is a potential target for therapy in SS.

A Randomized Clinical Trial of Immediate Versus Delayed Glasses for Moderate Hyperopia in Children 3 to 5 Years of Age.

PURPOSE: To compare visual acuity (VA) and binocularity outcomes in moderately hyperopic children with normal VA and binocularity assigned to glasses versus observation. DESIGN: Prospective randomized clinical trial (RCT). METHODS: One hundred nineteen 3- to 5-year-old children with hyperopia between +3.00D and +6.00D spherical equivalent were randomly assigned to glasses versus observation (with glasses prescribed if deteriorated for subnormal distance VA or near stereoacuity, or manifest strabismus). Follow-up occurred every 6 months. At 3 years, the treatment strategy was classified as "failed" if any of the following were met, both with and without correction: subnormal distance VA or stereoacuity; manifest strabismus; or strabismus surgery during follow-up. RESULTS: Of 84 (71%) children who completed the primary outcome examination, failure occurred in five (12%; 95% confidence interval [CI]: 4%-26%) of 41 assigned to glasses and four (9%; 95% CI: 3%-22%) of 43 assigned to observation (difference = 3%; 95% CI: -12%-18%; P = .72). Deterioration prior to 3 years (requiring glasses per protocol) occurred in 29% (95% CI: 19%-43%) assigned to glasses and 27% (95% CI: 17%-42%) assigned to observation. CONCLUSIONS: In an RCT comparing glasses to observation for moderately hyperopic 3- to 5-year-old children with normal VA and binocularity, failure for VA or binocularity was not common. With insufficient enrollment and retention, our study was unable to determine whether immediate glasses prescription reduces failure rate, but low failure rates suggest that immediate glasses prescription for these children may not be needed to prevent failure for VA and/or binocularity.

Genetic tools to study complexity of striatal function.

As the main input structure of the basal ganglia (BG), the striatum collects and integrates information from several brain areas and funnels them forward to other BG nuclei. The striatal projection neurons are medium-sized spiny neurons classified in two main subpopulations, based on their neurochemical characterization and projection targets. These subpopulations are segregated into two distinct circuits, the direct and the indirect pathway, which originate in the striatum and interconnect the BG, ultimately reaching their output nuclei. In this review, we discuss current opinions on the striatal circuit and present different strategies to decipher this circuit complexity by utilizing cell ablation, opto- and chemogenetics, tetanus toxin-induced neuronal silencing, and calcium imaging techniques. We also describe genetically encoded biosensors to monitor signaling dynamics in the striatal circuit with high spatial and temporal resolution by targeting both glutamate and dopamine transmission together with downstream signaling effectors. Recent findings revealing transcriptional, functional diversity, and regionally distinct signaling properties of spiny projection neurons argue that refined interrogation will be pertinent for a deeper understanding of this circuit. Moreover, future mapping the G-protein-coupled receptor repertoire in SPNs will potentially enable pathway-specific modulation of SPN activity and provide a novel framework for targeting BG diseases. Overall, these tools will be critical for designing next-generation treatments for BG diseases.

ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS.

Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis. Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed. Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced. Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor.

Three-Year Observation of Children 3 to 10 Years of Age with Untreated Intermittent Exotropia.

PURPOSE: To describe the course of intermittent exotropia (IXT) in children followed up without treatment for 3 years. DESIGN: Observation arm from randomized trial of short-term occlusion versus observation. PARTICIPANTS: One hundred eighty-three children 3 to 10 years of age with previously untreated IXT and 400 seconds of arc (arcsec) or better near stereoacuity. METHODS: Participants were to receive no treatment unless deterioration criteria were met at a follow-up visit occurring at 3 months, 6 months, or 6-month intervals thereafter for 3 years. MAIN OUTCOME MEASURES: The primary outcome was deterioration by 3 years, defined as meeting motor criterion (constant exotropia ≥10 prism diopters [Δ] at distance and near) or near stereoacuity criterion (≥2-octave decrease from best previous measure). For the primary analysis, participants also were considered to have deteriorated if treatment was prescribed without meeting either deterioration criterion. RESULTS: The cumulative probability of protocol-specified deterioration by 3 years was 15% (95% confidence interval, 10%-22%), but that was likely an overestimate, partly because of misclassification. Among 25 deteriorations, 2 met motor deterioration, 11 met stereoacuity deterioration, and 12 started treatment without meeting either criteria (7 for social concern, 1 for diplopia, 4 for other reasons). Among the 132 participants who completed the 3-year visit and had not been treated during the study, only 1 (<1%) met motor or stereoacuity deterioration criteria at 3 years. Of the 4 participants completing the 3-year visit who met deterioration criteria previously and had not started treatment, none still met deterioration criteria. Between the baseline and 3-year examination for these 132 patients, improvement occurred in distance and near stereoacuity (mean improvement, 0.14 and 0.14 logarithm of arcsec; P ≤ 0.001 and P ≤ 0.001, respectively), distance exotropia control (mean improvement, 0.6 points; P ≤ 0.001), and distance exodeviation magnitude (mean improvement, 2.2 Δ; P = 0.002). CONCLUSIONS: Among children 3 to 10 years of age with IXT for whom surgery was not considered to be the immediately necessary treatment, stereoacuity deterioration or progression to constant exotropia over 3 years was uncommon, and exotropia control, stereoacuity, and magnitude of deviation remained stable or improved slightly.

A Randomized Clinical Trial of Immediate versus Delayed Glasses for Moderate Hyperopia in 1- and 2-Year-Olds.

PURPOSE: Two strategies were compared for managing moderate hyperopia without manifest strabismus among 1- and 2-year-old children: (1) immediate prescription of glasses versus (2) observation without glasses unless reduced distance visual acuity (VA), reduced stereoacuity, or manifest strabismus. DESIGN: Prospective randomized clinical trial. PARTICIPANTS: A total of 130 children aged 1 to 2 years with hyperopia between +3.00 diopters (D) and +6.00 D spherical equivalent (SE) in at least 1 eye, anisometropia ≤1.50 D SE, and astigmatism ≤1.50 D based on cycloplegic refraction and no manifest strabismus. METHODS: Participants were randomly assigned to glasses (1.00 D less than full cycloplegic hyperopia) versus observation and followed every 6 months for 3 years. Glasses were prescribed to those assigned to observation if they met prespecified deterioration criteria of distance VA or near stereoacuity below age norms, or development of manifest strabismus. MAIN OUTCOME MEASURES: At the 3-year primary outcome examination, participants were classified as failing the randomized management regimen if distance VA or stereoacuity was below age norms or manifest strabismus was observed (each with and without correction in trial frames, confirmed by masked retest, irrespective of whether deterioration had occurred previously), or if strabismus surgery had been performed. RESULTS: Of the 106 participants (82%) completing the 3-year primary outcome examination, failure occurred in 11 (21%) of 53 in the glasses group and 18 (34%) of 53 in the observation group (difference = -13%; 95% confidence interval [CI], -31 to 4; P = 0.14). Sixty-two percent (95% CI, 49-74) in the observation group and 34% (95% CI, 23-48) in the glasses group met deterioration criteria (requiring glasses if not wearing). CONCLUSIONS: For 1- and 2-year-olds with uncorrected moderate hyperopia (+3.00 D to +6.00 D SE), our estimates of failure, after 3 years of 6-month follow-ups, are inconclusive and consistent with a small to moderate benefit or no benefit of immediate prescription of glasses compared with careful observation (with glasses only if deteriorated).

A Randomized Trial Comparing Bilateral Lateral Rectus Recession versus Unilateral Recess and Resect for Basic-Type Intermittent Exotropia.

PURPOSE: To compare long-term outcomes after bilateral lateral rectus recession (BLRc) or unilateral lateral rectus recession combined with medial rectus resection in the same eye (R&R) for primary treatment of childhood intermittent exotropia (IXT). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: One hundred ninety-seven children 3 to younger than 11 years of age with basic-type IXT, a largest deviation by prism and alternate cover test at any distance of 15 to 40 prism diopters (PD), and near stereoacuity of at least 400 seconds of arc. METHODS: Random assignment to BLRc or R&R and masked examinations conducted every 6 months after surgery for 3 years. MAIN OUTCOME MEASURES: Proportion of participants meeting suboptimal surgical outcome by 3 years, defined as: (1) exotropia of 10 PD or more at distance or near using simultaneous prism and cover test (SPCT); or (2) constant esotropia of 6 PD or more at distance or near using SPCT; (3) loss of 2 octaves or more of stereoacuity from baseline, at any masked examination; or (4) reoperation without meeting any of these criteria. RESULTS: Cumulative probability of suboptimal surgical outcome by 3 years was 46% (43/101) in the BLRc group versus 37% (33/96) in the R&R group (treatment group difference of BLRc minus R&R, 9%; 95% confidence interval [CI], -6% to 23%). Reoperation by 3 years occurred in 9 participants (10%) in the BLRc group (8 of 9 met suboptimal surgical outcome criteria) and in 4 participants (5%) in the R&R group (3 of 4 met suboptimal surgical outcome criteria; treatment group difference of BLRc minus R&R, 5%; 95% CI, -2% to 13%). Among participants completing the 3-year visit, 29% (25 of 86) in the BLRc group and 17% (13 of 77) in the R&R group underwent reoperation or met suboptimal surgical outcome criteria at 3 years (treatment group difference of BLRc minus R&R, 12%; 95% CI, -1% to 25%). CONCLUSIONS: We did not find a statistically significant difference in suboptimal surgical outcome by 3 years between children with IXT treated with BLRc compared with those treated with R&R. Based on these findings, we are unable to recommend one surgical approach over the other for childhood IXT.

Targeting Notch1 and IKKα Enhanced NF-κB Activation in CD133+ Skin Cancer Stem Cells.

Cancer stem-like cells are hypothesized to be the major tumor-initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remains undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31-CD45-CD61-CD24- (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem-like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo Gene expression profiling of CD133+/- cells was compared and validated, and differentially expressed gene signatures and top pathways were identified. CD133+ cells expressed a repertoire of stemness and cancer-related genes, including NOTCH and NOTCH1-mediated NF-κB pathway signaling. Other cancer-related genes from WNT, growth factor receptors, PI3K/mTOR, STAT pathways, and chromatin modifiers were also identified. Pharmacologic and genetic targeting of NOTCH1, IKKα, RELA, and RELB modulated NF-κB transactivation, the CD133+ population, and cellular and stemness phenotypes. Immunofluorescent staining confirmed colocalization of CD133+ and IKKα expression in SCC tumor specimens. Our functional, genetic, and pharmacologic studies uncovered a novel linkage between NOTCH1, IKKα, and NF-κB pathway activation in maintaining the CD133+ stem SCC phenotypes. Studies investigating markers of activation and modulators of NOTCH, IKK/NF-κB, and other pathways regulating these cancer stem gene signatures could further accelerate the development of effective therapeutic strategies to treat cSCC recurrence and metastasis. Mol Cancer Ther; 17(9); 2034-48. ©2018 AACR.