Combination anti-HIV antibodies provide sustained virological suppression.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Immunologic and Virologic Parameters Associated With Human Immunodeficiency Virus (HIV) DNA Reservoir Size in People With HIV Receiving Antiretroviral Therapy.

BACKGROUND: A better understanding of the dynamics of human immunodeficiency virus (HIV) reservoirs in CD4+ T cells of people with HIV (PWH) receiving antiretroviral therapy (ART) is crucial for developing therapies to eradicate the virus. METHODS: We conducted a study involving 28 aviremic PWH receiving ART with high and low levels of HIV DNA. We analyzed immunologic and virologic parameters and their association with the HIV reservoir size. RESULTS: The frequency of CD4+ T cells carrying HIV DNA was associated with higher pre-ART plasma viremia, lower pre-ART CD4+ T-cell counts, and lower pre-ART CD4/CD8 ratios. During ART, the High group maintained elevated levels of intact HIV proviral DNA, cell-associated HIV RNA, and inducible virion-associated HIV RNA. HIV sequence analysis showed no evidence for preferential accumulation of defective proviruses nor higher frequencies of clonal expansion in the High versus Low group. Phenotypic and functional T-cell analyses did not show enhanced immune-mediated virologic control in the Low versus High group. Of considerable interest, pre-ART innate immunity was significantly higher in the Low versus High group. CONCLUSIONS: Our data suggest that innate immunity at the time of ART initiation may play an important role in modulating the dynamics and persistence of viral reservoirs in PWH.

Yeast display platform with expression of linear peptide epitopes for high-throughput assessment of peptide-MHC-II binding.

Yeast display can serve as a powerful tool to assess the binding of peptides to the major histocompatibility complex (pMHC) and pMHC-T-cell receptor binding. However, this approach is often limited by the need to optimize MHC proteins for yeast surface expression, which can be laborious and may not yield productive results. Here we present a second-generation yeast display platform for class II MHC molecules (MHC-II), which decouples MHC-II expression from yeast-expressed peptides, referred to as "peptide display." Peptide display obviates the need for yeast-specific MHC optimizations and increases the scale of MHC-II alleles available for use in yeast display screens. Because MHC identity is separated from the peptide library, a further benefit of this platform is the ability to assess a single library of peptides against any MHC-II. We demonstrate the utility of the peptide display platform across MHC-II proteins, screening HLA-DR, HLA-DP, and HLA-DQ alleles. We further explore parameters of selections, including reagent dependencies, MHC avidity, and use of competitor peptides. In summary, this approach presents an advance in the throughput and accessibility of screening peptide-MHC-II binding.

Hypoxia-Inducible Factor 1α Stabilization Restores Epigenetic Control of Nitric Oxide Synthase 1 Expression and Reverses Gastroparesis in Female Diabetic Mice.

BACKGROUND & AIMS: Although depletion of neuronal nitric oxide synthase (NOS1)-expressing neurons contributes to gastroparesis, stimulating nitrergic signaling is not an effective therapy. We investigated whether hypoxia-inducible factor 1α (HIF1A), which is activated by high O2 consumption in central neurons, is a Nos1 transcription factor in enteric neurons and whether stabilizing HIF1A reverses gastroparesis. METHODS: Mice with streptozotocin-induced diabetes, human and mouse tissues, NOS1+ mouse neuroblastoma cells, and isolated nitrergic neurons were studied. Gastric emptying of solids and volumes were determined by breath test and single-photon emission computed tomography, respectively. Gene expression was analyzed by RNA-sequencing, microarrays, immunoblotting, and immunofluorescence. Epigenetic assays included chromatin immunoprecipitation sequencing (13 targets), chromosome conformation capture sequencing, and reporter assays. Mechanistic studies used Cre-mediated recombination, RNA interference, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated epigenome editing. RESULTS: HIF1A signaling from physiological intracellular hypoxia was active in mouse and human NOS1+ myenteric neurons but reduced in diabetes. Deleting Hif1a in Nos1-expressing neurons reduced NOS1 protein by 50% to 92% and delayed gastric emptying of solids in female but not male mice. Stabilizing HIF1A with roxadustat (FG-4592), which is approved for human use, restored NOS1 and reversed gastroparesis in female diabetic mice. In nitrergic neurons, HIF1A up-regulated Nos1 transcription by binding and activating proximal and distal cis-regulatory elements, including newly discovered super-enhancers, facilitating RNA polymerase loading and pause-release, and by recruiting cohesin to loop anchors to alter chromosome topology. CONCLUSIONS: Pharmacologic HIF1A stabilization is a novel, translatable approach to restoring nitrergic signaling and treating diabetic gastroparesis. The newly recognized effects of HIF1A on chromosome topology may provide insights into physioxia- and ischemia-related organ function.

The cohesin modifier ESCO2 is stable during DNA replication.

Cohesion between sister chromatids by the cohesin protein complex ensures accurate chromosome segregation and enables recombinational DNA repair. Sister chromatid cohesion is promoted by acetylation of the SMC3 subunit of cohesin by the ESCO2 acetyltransferase, inhibiting cohesin release from chromatin. The interaction of ESCO2 with the DNA replication machinery, in part through PCNA-interacting protein (PIP) motifs in ESCO2, is required for full cohesion establishment. Recent reports have suggested that Cul4-dependent degradation regulates the level of ESCO2 protein following replication. To follow up on these observations, we have characterized ESCO2 stability in Xenopus egg extracts, a cell-free system that recapitulates cohesion establishment in vitro. We found that ESCO2 was stable during DNA replication in this system. Indeed, further challenging the system by inducing DNA damage signaling or increasing the number of nuclei undergoing DNA replication had no significant impact on the stability of ESCO2. In transgenic somatic cell lines, we also did not see evidence of GFP-ESCO2 degradation during S phase of the cell cycle using both flow cytometry and live-cell imaging. We conclude that ESCO2 is stable during DNA replication in both embryonic and somatic cells.

SUFU promotes GLI activity in a Hedgehog-independent manner in pancreatic cancer.

Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells.

Impact of Monkeypox Virus Infection on Immune Parameters in a Woman With Human Immunodeficiency Virus Receiving Clinically Effective Antiretroviral Therapy.

We describe the immunologic and virologic impact of monkeypox (mpox) infection in a woman with human immunodeficiency virus (HIV) whose plasma HIV viremia was suppressed by clinically effective antiretroviral therapy. Extensive phenotypic analyses of B and T cells in peripheral blood and biomarkers in plasma showed significant immunologic perturbations despite the presence of mild mpox disease. Dramatic shifts were noted in the frequencies of total B cells, plasmablasts, and plasmablast immunoglobulin isotypes. Flow cytometric analyses showed a dramatic increase in the frequency of CD38+HLA-DR+ CD8+ T cells after mpox infection. Our data offer guidance for future studies involving mpox infection in affected populations.

A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings.

BACKGROUND: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls. DESIGN: Cohort study. (ClinicalTrials.gov: NCT04411147). SETTING: National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS: Self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of PASC. A control group comprised persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, recruited regardless of their current health status. Both groups were enrolled over the same period and from the same geographic area. MEASUREMENTS: All participants had the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. A subset also underwent exploratory immunologic and virologic evaluations. RESULTS: 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. LIMITATIONS: Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment. CONCLUSION: A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19. PRIMARY FUNDING SOURCE: Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Cultivating Compassion for Self and Others: A School-Based Pilot Study for Peer-Nominated Caring Adolescents.

Many have called for school-based student programs that teach skills related to self-care and caring for others. Here, such a program for peer-nominated adolescents was developed and piloted virtually at one high school during the COVID-19 pandemic. Results of a longitudinal, quasi-experimental evaluation of the program showed high-quality program implementation and promising program impacts. Effect sizes indicated moderate to large program impacts on improvements in adolescents' self-compassion, sense of interdependence, and perspective-taking, and female adolescents' interoceptive awareness, compared to controls. No group differences in compassion for others were found. The need for more research on programs that help adolescents balance compassion for the self and for others is discussed.

Machine learning optimization of peptides for presentation by class II MHCs.

SUMMARY: T cells play a critical role in cellular immune responses to pathogens and cancer and can be activated and expanded by Major Histocompatibility Complex (MHC)-presented antigens contained in peptide vaccines. We present a machine learning method to optimize the presentation of peptides by class II MHCs by modifying their anchor residues. Our method first learns a model of peptide affinity for a class II MHC using an ensemble of deep residual networks, and then uses the model to propose anchor residue changes to improve peptide affinity. We use a high throughput yeast display assay to show that anchor residue optimization improves peptide binding. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

TFII-I-mediated polymerase pausing antagonizes GLI2 induction by TGFß.

The modulation of GLI2, an oncogenic transcription factor commonly upregulated in cancer, is in many cases not due to genetic defects, suggesting dysregulation through alternative mechanisms. The identity of these molecular events remains for the most part unknown. Here, we identified TFII-I as a novel repressor of GLI2 expression. Mapping experiments suggest that the INR region of the GLI2 promoter is necessary for GLI2 repression. ChIP studies showed that TFII-I binds to this INR. TFII-I knockdown decreased the binding of NELF-A, a component of the promoter-proximal pausing complex at this site, and enriched phosphorylated RNAPII serine 2 in the GLI2 gene body. Immunoprecipitation studies demonstrate TFII-I interaction with SPT5, another pausing complex component. TFII-I overexpression antagonized GLI2 induction by TGFß, a known activator of GLI2 in cancer cells. TGFß reduced endogenous TFII-I binding to the INR and increased RNAPII SerP2 in the gene body. We demonstrate that this regulatory mechanism is not exclusive of GLI2. TGFß-induced genes CCR7, TGFß1 and EGR3 showed similar decreased TFII-I and NELF-A INR binding and increased RNAPII SerP2 in the gene body post-TGFß treatment. Together these results identify TFII-I as a novel repressor of a subset of TGFß-responsive genes through the regulation of RNAPII pausing.

Optic Nerve Aplasia.

OBJECTIVE: Optic nerve aplasia (ONA) is a rare ocular anomaly. We report ophthalmologic, systemic, and genetic findings in ONA. METHODS: Patients were identified through an International Pediatric Ophthalmology listserv and from the practice of the senior author. Participating Listserv physicians completed a data collection sheet. Children of all ages were included. Neuroimaging findings were also recorded. RESULTS: Nine cases of ONA are reported. Patients' ages ranged from 10 days to 2 years (median 9 months). Seven cases were bilateral. All patients had absence of the optic nerve and retinal vessels in the affected eye or eyes. Ophthalmologic findings included glaucoma, microcornea, persistent pupillary membrane, iris coloboma, aniridia, retinal dysplasia, retinal atrophy, chorioretinal coloboma, and persistent fetal vasculature. Systemic findings included facial dysmorphism, cardiac, genitourinary, skeletal, and developmental defects. A BCOR mutation was found in one patient. One patient had rudimentary optic nerves and chiasm on imaging. CONCLUSION: ONA is a unilateral or bilateral condition that may be associated with anomalies of the anterior or posterior segment with or without systemic findings. Rudimentary optic nerve on neuroimaging in one case suggests that ONA is on the continuum of optic nerve hypoplasia.

Attitudes and beliefs among Georgia addiction treatment staff about medication for opioid use disorder in adolescents, young adults, and adults: a multi-mixed methods study.

Background: Adverse consequences, including non-fatal overdose and death, are prevalent in adolescents and young adults with opioid use disorder (OUD). Barriers toward medication for opioid use disorder (MOUD) have been identified in adult populations but are poorly understood in youth.Objective: This exploratory multi-mixed methods study examines beliefs and attitudes of addiction treatment program staff about the use of MOUD in youth.Methods: A 40-item survey was distributed electronically to 299 addiction treatment programs in Georgia from May 2020 to January 2021. Participant (N = 215; 74% female) attitudes regarding the use of MOUD in three age groups (adolescents (aged 16-17), young adults (aged 18-25), and adults (aged 26+) on a 6-point Likert scale were compared using paired samples t-tests. A series of one-way ANOVA analyses examined differences in attitudes and beliefs across participant characteristics. Verbatim responses to qualitative survey questions were analyzed using a coding reliability approach to thematic analysis.Results: Participants were less likely to support MOUD in adolescents (M = 3.68, SD 1.5) compared with young (M = 4.38, SD 1.36, t = 8.19, p < .001, d = .51) and older adults (M = 4.64, SD 1.3, t = 9.83, p < .001 d = .74). Participants endorsed higher response rates for the use of both naltrexone and buprenorphine over methadone in young adults. A total of 1,412 text responses were reviewed. Participants highlighted barriers to acceptance and use of MOUD in adolescents including safety concerns and impact on brain development.Conclusions: The results support a comprehensive approach to reducing the barriers to using medications to treat OUDs in adolescent populations. Formal and focused continuing education to correct attitudes and beliefs about MOUD treatment for adolescents is necessary.

Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases.

Clinical development of bromodomain and extra-terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic "readers," which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan-BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.

Delayed Umbilical Cord Clamping is Not Associated with Acute Kidney Injury in Very Low Birth Weight Neonates.

OBJECTIVE: This study aimed to determine if delayed cord clamping (DCC) is associated with a reduction in neonatal acute kidney injury (AKI). STUDY DESIGN: A retrospective single-center cohort study of 278 very low birth weight (VLBW) neonates was performed to compare the incidence of AKI in the following groups: immediate cord clamping (ICC), DCC, and umbilical cord milking. AKI was diagnosed by the modified neonatal Kidney Diseases and Improving Global Outcomes (KDIGO) definition. RESULTS: The incidence of AKI in the first week was 20.1% with no difference between groups (p = 0.78). After adjustment for potential confounders, the odds of developing AKI, following DCC, compared with ICC was 0.93 (confidence interval [CI]: 0.46-1.86) with no reduction in the stage of AKI between groups. CONCLUSION: In this study, DCC was not associated with a reduced rate of AKI in VLBW neonates. However, the data suggest that DCC is also not harmful to the kidneys, further supporting the safety of DCC in VLBW neonates.

Emissions associated with operations of four different additive manufacturing or 3D printing technologies.

In this pilot-scale study, a wide range of potential emissions were evaluated for four types of additive manufacturing (AM) machines. These included material extrusion (using acrylonitrile-butadiene-styrene [ABS]); material jetting (using liquid photopolymer); powder bed fusion (using nylon); and vat photopolymerization (using liquid photopolymer) in an industrial laboratory setting. During isolated operation of AM machines, adjacent area samples were collected for compounds of potential concern (COPCs), including total and individual volatile organic compounds (VOCs), nano- and micron-sized particulate matter, and inorganic gases. A total of 61 compounds were also sampled using a canister followed by gas chromatography and mass spectrometry analysis. Most COPCs were not detected or were measured at concentrations far below relevant occupational exposure limits (OELs) during AM machine operations. Submicron particles, predominantly nanoparticles, were produced during material extrusion printing using ABS at approximately 12,000 particles per cubic centimeter (p cm-3) above background. After subtracting the mean background concentration, the mean concentration for material extrusion printing operations correlated with a calculated emission rate of 2.8 × 1010 p min-1 under the conditions tested. During processing of parts produced using material jetting or powder bed fusion, emissions were generally negligible, although concentrations above background of respirable and total dust were measured during processing of powder bed fusion parts. Results of this pilot-scale study indicate that airborne emissions associated with AM operations are variable, depending on printing and parts handling processes, raw materials, and ventilation characteristics. Although personal samples were not collected in this pilot-scale study, the results can be used to inform future exposure assessments. Based on the results of this evaluation, measurement of submicron particles emitted during material extrusion printing operations and dust associated with handling parts manufactured using powder bed fusion processes should be included in exposure assessments.

Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling.

ATP-binding cassette (ABC) transporters help export various substrates across the cell membrane and significantly contribute to drug resistance. However, a recent study reported an unusual case in which the loss of an ABC transporter in Candida albicans, orf19.4531 (previously named ROA1), increases resistance against antifungal azoles, which was attributed to an altered membrane potential in the mutant strain. To obtain further mechanistic insights into this phenomenon, here we confirmed that the plasma membrane-localized transporter (renamed CDR6/ROA1 for consistency with C. albicans nomenclature) could efflux xenobiotics such as berberine, rhodamine 123, and paraquat. Moreover, a CDR6/ROA1 null mutant, NKKY101, displayed increased susceptibility to these xenobiotics. Interestingly, fluorescence recovery after photobleaching (FRAP) results indicated that NKKY101 mutant cells exhibited increased plasma membrane rigidity, resulting in reduced azole accumulation and contributing to azole resistance. Transcriptional profiling revealed that ribosome biogenesis genes were significantly up-regulated in the NKKY101 mutant. As ribosome biogenesis is a well-known downstream phenomenon of target of rapamycin (TOR1) signaling, we suspected a link between ribosome biogenesis and TOR1 signaling in NKKY101. Therefore, we grew NKKY101 cells on rapamycin and observed TOR1 hyperactivation, which leads to Hsp90-dependent calcineurin stabilization and thereby increased azole resistance. This in vitro finding was supported by in vivo data from a mouse model of systemic infection in which NKKY101 cells led to higher fungal load after fluconazole challenge than wild-type cells. Taken together, our study uncovers a mechanism of azole resistance in C. albicans, involving increased membrane rigidity and TOR signaling.

The effect of congenital diaphragmatic hernia on the development of left-sided heart structures.

INTRODUCTION: Patients with congenital diaphragmatic hernias often have concomitant congenital heart disease (CHD), with small left-sided cardiac structures as a frequent finding. The goal of this study is to evaluate which left-sided heart structures are affected in neonates with congenital diaphragmatic hernias. METHODS: Retrospective review of neonates between May 2007 and April 2015 with a diagnosis of a congenital diaphragmatic hernia was performed. Clinical and echocardiographic data were extracted from the electronic medical record and indexed to body surface area and compared to normative values. Univariable regression models assessed for associations between different variables and length of stay. RESULTS: Data of 52 patients showed decreased mean z scores for the LVIDd (-3.16), LVIDs (-3.05), aortic annulus (-1.68), aortic sinuses (-2.11), transverse arch (-3.11), and sinotubular junction (-1.47) with preservation of the aorta at the diaphragm compared to age-matched normative data with similar body surface areas. Regression analysis showed a percent reduction in length of stay per 1 mm size increase for LVIDd (8%), aortic annulus (27%), aortic sinuses (18%), sinotubular junctions (20%), and transverse arches (25%). CONCLUSIONS: Patients with congenital diaphragmatic hernias have significantly smaller left-sided heart structures compared to age-matched normative data. Aortic preservation at the diaphragm provides evidence for a mass effect aetiology with increased right-to-left shunting at the fetal ductus resulting in decreased size. Additionally, length of stay appears to be prolonged with decreasing size of several of these structures. These data provide quantitative evidence of smaller left-sided heart structures in patients with congenital diaphragmatic hernias.

Ocular manifestations of Emanuel syndrome.

Emanuel syndrome is caused by a supernumerary der(22)t(11;22) and typically manifests with intellectual disability and craniofacial dysmorphism. Ocular abnormalities have infrequently been described. We report a 36-year-old man with severe intellectual disability, aphasia, and facial dysmorphism, with high myopia and juvenile open angle glaucoma (JOAG). Microarray analysis results included 47,XY,+der(22)t(11;22)(q23;q11.2), and a 269 kb deletion of 7q31.33(125,898,014-126,166,829). Two candidate genes were identified as possible etiologies for the ocular pathologies in our patient: a MFRP duplication on chromosome 11, which may play a role in high myopia and dysregulation of emmetropization, and a GRM8 deletion on chromosome 7, which may cause glutamate-induced excitotoxicity and therefore have a role in the development of JOAG, unrelated to the Emanuel syndrome genotype. We provide the first detailed description these ocular abnormalities in a patient with Emmanuel syndrome.

Power of Prevention: The Pharmacist's Role in Prediabetes Management.

IN BRIEF Although it is known that the National Diabetes Prevention Program can significantly reduce the incidence of type 2 diabetes in individuals identified as being at high risk, there remains a large number of Americans in underserved areas who are not being reached. The field of pharmacy has the potential to bridge this gap and aid the United States in more comprehensively addressing its national diabetes health crisis, thus changing the future of diabetes for the better.