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Background/Aims: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. Methods: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40–80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1–365 days and > 365 days). The outcome was time to incident advanced adenoma. Results: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82–8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90–10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46–4.69) at the follow-up colonoscopy examination. Conclusion: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs. [ABSTRACT FROM AUTHOR]

Objectives: The objective was to evaluate the efficacy of a required emergency medicine (EM) experience embedded in a new community‐based longitudinal integrated clerkship (LIC) for participating students and faculty. Methods: We developed and implemented a community‐based LIC EM experience. The experience included 10 clinical shifts, one emergency medical services prehospital care shift, four didactic sessions, one reflection, and an emergency medicine simulation session. Students' outcomes were assessed using end‐of‐year surveys, focus groups, an emergency medicine subject examination, simulation performance, and clinical evaluations of the students by faculty. Faculty were recruited, underwent faculty development, and were evaluated by students. Faculty perceptions were gathered from a focus group and faculty retention rates were collected. Results: Three cohorts of LIC students (total N = 61) have completed their core emergency medicine experience in our community‐based LIC. Among students, 76% to 95% rated the overall quality of teaching as very good or excellent and 66% to 100% rated the quality of learning in their community‐based setting as very good or excellent. All students who passed the EM subject examination achieved the clinical competencies of the experience based on clinical evaluations. Among faculty, we have retained greater than 95% each year and they have reflected positively on their precepting experience. Conclusions: Implementing a required EM experience within a community‐based LIC model can be an effective learning experience for students and perceived positively by community‐based faculty. This model may offer an opportunity to expand clinical learning experiences in EM. [ABSTRACT FROM AUTHOR]

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors. [ABSTRACT FROM AUTHOR]

The versatility of nanodiamonds (NDs) as a polymer-embedded therapeutic vehicle was demonstrated by the development of a hybrid material consisting of a poly(ethylene glycol) diacrylate (PEGDA) hydrogel embedded with ND-drug complexes. A wide range of PEGDA structures, including single and multiple drug reservoirs, exhibited high loading capabilities and stable slow-release, augmented with the addition of ND conjugates. ND-PEGDA hydrogels were compared to unmodified, drug-embedded PEGDA hydrogels to demonstrate their robust drug sequestering capacity in vitro. Remarkably, ND-embedded hydrogels were capable of mitigating the harmful effects of burst-release by displaying slow and controlled administration of therapeutic compounds, an improvement over standard diffusion-based release profiles. The tunable customization of PEGDA hydrogel, both in structure and content, as well as its facile methods of synthesis, make this material an effective multi-therapeutic complement to the drug delivery abilities of NDs. A hybrid material that utilizes the synergy of PEGDA and ND components has the potential for applications toward a diverse array of biomedical challenges. [ABSTRACT FROM AUTHOR]

Summary: IFI16 is a member of the interferon-inducible HIN-200 family of nuclear proteins. It has been implicated in transcriptional regulation by modulating protein-protein interactions with p53 tumor suppressor protein and other transcription factors. However, the mechanisms of interaction remain unknown. Here, we report the crystal structures of both HIN-A and HIN-B domains of IFI16 determined at 2.0 and 2.35 Å resolution, respectively. Each HIN domain comprises a pair of tightly packed OB-fold subdomains that appear to act as a single unit. We show that both HIN domains of IFI16 are capable of enhancing p53-DNA complex formation and transcriptional activation via distinctive means. HIN-A domain binds to the basic C terminus of p53, whereas the HIN-B domain binds to the core DNA-binding region of p53. Both interactions are compatible with the DNA-bound state of p53 and together contribute to the effect of full-length IFI16 on p53-DNA complex formation and transcriptional activation. [ABSTRACT FROM AUTHOR]

Abstract: The final step in the morphogenesis of long-tailed double-stranded DNA bacteriophages is the joining of the DNA-filled head to the tail. The connector is a specialized structure of the head that serves as the interface for tail attachment and the point of egress for DNA from the head during infection. Here, we report the determination of a 2.1 Å crystal structure of gp6 of bacteriophage HK97. Through structural comparisons, functional studies, and bioinformatic analysis, gp6 has been determined to be a component of the connector of phage HK97 that is evolutionarily related to gp15, a well-characterized connector component of bacteriophage SPP1. Whereas the structure of gp15 was solved in a monomeric form, gp6 crystallized as an oligomeric ring with the dimensions expected for a connector protein. Although this ring is composed of 13 subunits, which does not match the symmetry of the connector within the phage, sequence conservation and modeling of this structure into the cryo-electron microscopy density of the SPP1 connector indicate that this oligomeric structure represents the arrangement of gp6 subunits within the mature phage particle. Through sequence searches and genomic position analysis, we determined that gp6 is a member of a large family of connector proteins that are present in long-tailed phages. We have also identified gp7 of HK97 as a homologue of gp16 of phage SPP1, which is the second component of the connector of this phage. These proteins are members of another large protein family involved in connector assembly. [Copyright &y& Elsevier]

Purpose: To determine the prognostic factors associated with retinal redetachment after 1300-centistokes silicone oil removal in rhegmatogenous retinal detachments (RDs) associated with grade C proliferative vitreoretinopathy (PVR). Design: Nonrandomized, retrospective, comparative interventional trial. Methods: One hundred and forty-seven eyes with RD and grade C PVR treated with silicone oil tamponade, with subsequent silicone oil removal, in an institutional setting. Main outcome measures included anatomic success, defined as complete retinal attachment after silicone oil removal, and best-corrected visual acuity (BCVA) after silicone oil removal. Results: Silicone oil was removed after a mean tamponade period of 12.4 ± 9.8 months. The mean follow-up after silicone oil removal was 22.1 ± 18.7 months (range, 6.0 to 71.0 months). The retina remained attached in 120 eyes after oil removal. The overall anatomic success rate was 81.6% ± 3.2%. Logistic regression showed that an increased number of previous unsuccessful RD surgeries (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.19 to 0.80; P = .010) and longer axial lengths (OR, 0.42; 95% CI, 0.15 to 0.87; P = .032) were associated with a lower anatomic success rate. Previous vitrectomy, previous scleral buckling procedure, 12% perfluoropropane–air exchange immediately after silicone oil removal, and duration of silicone oil tamponade were not statistically associated with the anatomic success rate. Anatomic success was associated with a significantly better BCVA (1.169 ± 0.475 vs 1.520 ± 0.381 logarithm of the minimum angle of resolution; P < .001). Conclusions: The number of previous surgeries and axial length, rather than the nature of the previous surgical procedures, were significant prognostic factors for anatomic success after silicone oil removal. [Copyright &y& Elsevier]

Purpose: To determine the prognostic factors associated with anatomical success in the treatment of retinal detachment (RD) due to myopic macular hole by pars plana vitrectomy (PPV) and perfluoropropane (C3F8) gas tamponade. Design: Retrospective, interventional, comparative case series. Methods: In an institutional setting, 57 eyes with myopic macular hole RDs treated by PPV and C3F8 tamponade, with or without concomitant internal limiting membrane (ILM) peeling, endolaser photocoagulation, and/or phacoemulsification, were analyzed. Outcome measures were anatomical success, defined as closure of macular hole with reattachment of the surrounding retina, and postoperative best-corrected visual acuity (BCVA). Results: The mean postoperative follow-up was 26.9 ± 16.5 months. The anatomical success rate after primary PPV and C3F8 tamponade was 63.2%. Regression analysis showed that shorter axial lengths (odds ratio [OR] = 6.73, 95% confidence interval [95% CI] 1.86 to 12.22, P = .010), concomitant ILM peeling (OR 1.59, 95% CI 1.14 to 2.38, P = .013), and shorter duration of macular hole RD (OR 0.81, 95% CI 0.67 to 0.98, P = .033) were associated with a higher anatomical success. The mean pre- and postoperative BCVAs were 1.430 ± 0.273 (range, 0.523 to 1.700) and 1.403 ± 0.271 (range, 0.699 to 1.800) logarithm of minimal angle of resolution units, respectively. The postoperative BCVA was significantly better in eyes with macular hole closure than in eyes without (P = .021). Conclusions: Axial length, concomitant ILM peeling, and duration were important prognostic factors for PPV and C3F8 tamponade in the treatment of myopic macular hole RDs. [Copyright &y& Elsevier]

Purpose: Extensive efforts have been devoted to determining the macular pigment optical density (MPOD) in Caucasian subjects. Unfortunately, no such data in ethnic groups with naturally dark irises are currently available. In this study, we report the values in a sample of Chinese subjects.Methods: The MPOD was measured psychophysically using a densitometer at 0.25?, 0.50? 1.00?, and 2.00? eccentricity from the foveal center in 92 Chinese subjects. Results: The spatial profile for the averaged MPOD was approximately exponential in form and showed a decline with age (r = ?0.23). Subjects aged below 60 years had significantly higher averaged MPOD than those aged 60 years or above. Significant gender differences, in favor of males, were also found in the middle-age groups. Conclusions: Our study reports for the first time the MPOD in a Chinese population. Baseline information on MPOD would aid future research in preventive measures against age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the long-term clinical outcomes in eyes with retained presumed intraocular cotton fibers after cataract surgery. Setting: Hong Kong Eye Hospital, Hong Kong, The People''s Republic of China. Methods: A retrospective review of 19 eyes with retained presumed intraocular cotton fibers after cataract surgery was performed. Outcome measures were fiber-related complications. In vivo confocal microscopy was performed in eyes with entrapped cotton fibers at the wound site. Results: The duration of retained presumed cotton fibers ranged from 5 to 110 months (mean 42.3 months). No complications were noted in any of these eyes, including endophthalmitis, persistent uveitis, or corneal endothelial cell loss. In vivo confocal microscopy in eyes with entrapped fibers at the wound site showed normal corneal endothelium morphology with no keratocyte activation or inflammatory response. Conclusions: Retained presumed fibers after cataract operations are more common than anticipated. In contrast to other organic foreign bodies, these retained fibers appear to be well tolerated. Conservative treatment can be adopted for these fibers as these pose minimal toxicity to the eye. [Copyright &y& Elsevier]

Transition metals are common components of cellular proteins and the detailed study of metalloproteins necessitates the identification and quantification of bound metal ions. Screening for metals is also an informative step in the initial characterization of the numerous unknown and unclassified proteins now coming through the proteomic pipeline. We have developed a high-performance liquid chromatography method for the quantitative determination of the most prevalent biological transition metals: manganese, iron, cobalt, nickel, copper, and zinc. The method is accurate and simple and can be adapted for automated high-throughput studies. The metal analysis involves acid hydrolysis to release the metal ions into solution, followed by ion separation on a mixed-bead ion-exchange column and absorbance detection after postcolumn derivatization with the metallochromic indicator 4-(2-pyridylazo)resorcinol. The potential interferences by common components of protein solutions were investigated. The metal content of a variety of metalloproteins was analyzed and the data were compared to data obtained from inductively coupled plasma–atomic emission spectroscopy. The sensitivity of the assay allows for the detection of 0.1–0.8nmol, depending on the metal. The amount of protein required is governed by the size of the protein and the fraction of protein with metal bound. For routine analysis 50μg was used but for many proteins 10μg would be sufficient. The advantages, disadvantages, and possible applications of this method are discussed. [Copyright &y& Elsevier]

Nd3ReO7 and Pr3ReO7 were prepared by solid-state reaction involving Ln2O3, ReO3 and ReO2 in sealed quartz tubes and a carefully controlled thermal sequence. Attempts to prepare the corresponding compound with Ln=La was unsuccessful with the same procedure. The crystal structures were refined from powder neutron diffraction data in space group Cmcm. The unit cell constants (A˚) are a=10.941(1), b=7.4565(8) and c=7.5993(9) for Ln=Pr and a=10.867(1), b=7.4594(7) and c=7.5740(8) for Ln=Nd. The structure type is a well-known variant of an ordered, defect fluorite. There are two Ln sites with pseudo-cubic 8-fold and pentagonal bipyramidal 7-fold coordination and Re5+ in an octahedral site. The Re–O octahedra share corners to form a zig-zag chain parallel to the c-axis. In both materials, Re5+ displays a local magnetic moment consistent with S=1 and both show evidence for cooperative magnetic effects at low temperature. Pr3ReO7 appears to show spin glass order below about 10 K in the form of a zero-field-cooled–field-cooled divergence in the susceptibility, a hysteresis in the isothermal magnetization curves and the absence of magnetic Bragg peaks in the neutron powder pattern. For Nd3ReO7, by contrast, the bulk magnetic behavior is very complex but magnetic Bragg peaks appear in the neutron diffraction pattern below Tc=9 K, thus confirming long-range order. The magnetic Bragg peaks can be indexed with a wave vector, k=(000). [Copyright &y& Elsevier]

Ternary rare-earth main-group pnictides RExMyPnz where M is a Group 13 or 14 element and Pn is P, As, Sb, or Bi form an emerging class of solid state compounds that frequently display extensive homoatomic M&z.sbnd;M and Pn&z.sbnd;Pn bonding in addition to heteroatomic M&z.sbnd;Pn bonding in their anionic substructures. Their structures, properties, and bonding are discussed, with a focus on the antimonides, which have been most heavily investigated. [Copyright &y& Elsevier]

The oxide materials La3MO7, M=Ru and Os have been prepared, the Os phase for the first time. Both crystallize in a fluorite-related supercell with Cmcm symmetry with very similar lattice constants. A singular feature of this structure type is the presence of well- separated zig-zag chains of corner-sharing MO6 octahedra parallel to one of the orthorhombic axes. Local moment magnetic behavior is observed for both on very different energy scales. In each case the materials exhibit Curie–Weiss paramagnetism at high temperatures with effective moments consistent with S=3/2, as expected for the 4d3 and 5d3 electronic configurations associated with oxidation state +5, thus providing evidence for local moment magnetism. At lower temperatures broad maxima occur near 20 K (Ru) and 110 K(Os) which can be attributed to intrachain magnetic correlations. Fits to an appropriate model yield Jintra/k values of −2.9 K for Ru and −23.2(1) K for Os. This ∼eight-fold increase is attributed to the expanded radial extent of the d-orbitals in proceeding from the 4d to the 5d series. Evidence for long-range antiferromagnetic order is present in the form of sharp susceptibility maxima at 10 and 45 K for M=Ru and Os, respectively. [Copyright &y& Elsevier]

Resistivity and ac magnetic susceptibility measurements on Ba2Sn3Sb6 and SrSn3Sb4 indicate that these Zintl compounds display a transition to a superconducting phase at TC=3.9 K. The Meissner effect was observed for Ba2Sn3Sb6 under an applied field of 25 Oe. The signatures for superconductivity, such as high and low velocity conduction electrons and lone pairs, are present for both of these compounds. [Copyright &y& Elsevier]

Examines the influence of ligand on copper molybdate networks. Discussion on the structures of magnetism; Application of catalysis on contemporary solid-state chemistry; Evaluation on antiferromagnetic interactions.

Studies the structural influences of copper-phenanthroline subunits on oxovanadium organophosphonate phases. Structures which exhibit vanadium building blocks; Elucidation of the catalytic reaction mechanism; Achievement of structural elaboration of an inorganic oxide substructure through the introduction of organic components.

Examines the magnetic and transport properties of ternary rare-earth germanium antimonides. Characterization of the metallic compounds; Evidence for antiferromagnetic ordering for the compounds; Details on single-crystal magnetoresistance of gadolinium.

Investigates the synthesis of ternary rare-earth germanium antimonides. Application of single-crystal X-ray diffraction; Crystallization of antimonides in the orthorhombic space group; Identification of atomic interactions within interconnecting walls.

Presents information on a study on the nonstoichiometric ternary barium hafnium arsenide Ba0.8Hf12As17.7. Discussion on the ternary pnictides of the early transition metals; Methodology used in conducting the study; Description of the structure.

Determines the structure of the zintl phase dibarium tritin hexaantimonide, Ba2Sn3Sb6, by single-crystal X-ray diffraction models. Description of the structure; Structural relationships and bonding.

The article presents a study, which attempts to determine whether the Wechsler Intelligence Scale for Children (WISC) is useful in this respect. The subjects for this study were examined with psychological tests and consisted of 104 children between the ages of 6-0 and 15-11 years. Thirty-one of forty-two children with intelligence quotients below 80 who because of test data were suspected of suffering from organic brain disease were found to have confirmatory signs on neurological examinations. Organics tend to score lower on the WISC Full Scale than non-organics. Organics tend to do more poorly on the WISC Performance and Full Scales than on the WISC Verbal Scale. The possibility of organicity increases considerably as the emotional quotient drops below the borderline feeble-minded range.

A strategy for rapid and facile detection of melamine in food and other substances is described. Unmodified gold nanoparticles enable a colorimetric signal output that is amplified through integration by precipitation formation via a chemical component specific to melamine. The sensitivity was determined to be ∼40 ppb with a two standard deviation cutoff. [ABSTRACT FROM AUTHOR]

Keywords: neuroendocrine tumor; chylous ascites; malignant ascites; dotatate scan EN neuroendocrine tumor chylous ascites malignant ascites dotatate scan 2082 2085 4 06/16/22 20220602 NES 220602 This case was presented as a poster at the Society of General Internal Medicine National Annual Meeting, April 21-24, 2021. Early in the disease course, chylous ascites can be remarkably responsive to dietary modification, diuretics, and medications such as somatostatin or octreotide therapy.[2],[3],[20],[21] Given its extremely rare occurrence, NET and chylous ascites caused by local tumor compression of the pancreatic ductal system can be mistaken for metastatic pancreatic cancer with malignant ascites. Availability bias, having the disposition to overestimate how often an event occurs because information about it is more easily recalled, was also present.[26] Metastatic pancreatic cancer with malignant ascites is much more prevalent than pancreatic NET with chylous ascites, and thus, a diagnosis of the former was determined early on. [Extracted from the article]

To report a case of concurrent pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) with dual PANK2 and OCA2 variants in a Chinese patient who presented with early-onset reduced vision, nyctalopia, and neurological symptoms. Based on the ocular phenotype and provisional diagnosis of rod-cone dystrophy, genetic testing was pursued. Peripheral blood DNA extraction was carried out with the next-generation sequencing technique, which involved a population-specific medical exome virtual panel. Pre- and post-test counseling were carried out by clinical geneticists. Homozygous missense variants in PANK2 {NM_153638.3}:c.655 G>A (p.(Gly219Ser)) and OCA2{NM_025160.6}:c.1327 G>A(p.(Val443Ile)) were identified. The molecular diagnoses of pantothenate kinase associated neurodegeneration (OMIM#234200) and albinism, oculocutaneous, type II (OMIM#203200) were supported by clinical findings. Two rare autosomal recessive diseases, pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) were detected in our patient. Ocular and systemic manifestations, as well as neuroimaging findings were compatible with the diseases identified. Genetic analysis is imperative in making an accurate molecular diagnosis in these rare conditions to allow timely counseling, disease prognostication and management. [ABSTRACT FROM AUTHOR]

The article presents five things to know about nutrition and dementia. They include the connection between eating difficulties and the progression of dementia, the lack of connection between feeding tubes and enhanced survival or quality of life, and the advantages of careful hand-feeding over tube-feeding.

Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson-Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants. [ABSTRACT FROM AUTHOR]

To determine the risk factors for developing phacomorphic glaucoma in eyes with mature cataracts. Materials and Methods: This is a case-control study comprising of 90 eyes with phacomorphic glaucoma and 90 age- and sex-matched control eyes with mature cataracts without phacomorphic glaucoma. Patients with pre-existing glaucoma, previous intraocular surgery and /or absence of documented axial lengths were excluded from this study. Binary logistic regression analysis of the variables, axial length and anterior chamber depth, was performed. Anterior chamber depth of the contralateral eye was used as a proxy measure of the pre-phacomorphic state in the eye with phacomorphic glaucoma as majority of them fi rst presented to our center during the phacomorphic att ack without prior measurements of the prephacomorphil ACD or lens thickness; therefore, their anterior chamber depth would not be representative of their pre-phacomorphic state. Axial length of 23.7 mm was selected as a cut-off for dichotomized logistic regression based on the local population mean from published demographic data. Results: The mean age was 73.1 ± 10.2 years. All phacomorphic and control eyes were ethnic Chinese. The mean presenting intraocular pressures were 49.5 ± 11.8 mmHg and 16.7 ± 1.7 mmHg in the phacomorphic and control eyes respectively (P< 0.0001), whilst the median Snellen best corrected visual acuity were light perception and hand movement in the phacomorphic and control eyes respectively. Eyes with phacomorphic glaucoma had shorter axial length of 23.1 ± 0.9 mm median when compared with that of control eyes, 23.7 ± 1.5 mm (P = 0.0006). Eyes with AL = 23.7 mm were 4.3 times as likely to develop phacomorphic glaucoma when compared with AL > 23.7 mm (P = 0.003). Conclusion: Axial length less than = 23.7 mm was a risk factor for developing phacomorphic glaucoma. Eyes with AL shorter than the population mean were 4.3 times as likely to develop phacomorphic glaucoma compared with eyes with longer than average AL. In an area where phacomorphic glaucoma is prevalent and medical resources are limited, patients with AL shorter than their population mean may be considered for earlier elective cataract extraction as a preventive measure. [ABSTRACT FROM AUTHOR]

The rational design of novel antibiotics for bacteria involves the identification of inhibitors for enzymes involved in essential biochemical pathways in cells. In this study, the cloning, expression, purification, crystallization and structure of the enzyme peptidyl-tRNA hydrolase from Francisella tularensis, the causative agent of tularemia, was performed. The structure of F. tularensis peptidyl-tRNA hydrolase is comparable to those of other bacterial peptidyl-tRNA hydrolases, with most residues in the active site conserved amongst the family. The resultant reagents, structural data and analyses provide essential information for the structure-based design of novel inhibitors for this class of proteins. [ABSTRACT FROM AUTHOR]

Abstract: Enhanced specificity in drug delivery aims to improve upon systemic elution methods by locally concentrating therapeutic agents and reducing negative side effects. Due to their robust physical properties, biocompatibility and drug loading capabilities, nanodiamonds serve as drug delivery platforms that can be applied towards the elution of a broad range of therapeutically-active compounds. In this work, bovine insulin was non-covalently bound to detonated nanodiamonds via physical adsorption in an aqueous solution and demonstrated pH-dependent desorption in alkaline environments of sodium hydroxide. Insulin adsorption to NDs was confirmed by FT-IR spectroscopy and zeta potential measurements, while both adsorption and desorption were visualized with TEM imaging, quantified using protein detection assays and protein function demonstrated by MTT and RT-PCR. NDs combined with insulin at a 4:1 ratio showed 79.8±4.3% adsorption and 31.3±1.6% desorption in pH-neutral and alkaline solutions, respectively. Additionally, a 5-day desorption assay in NaOH (pH 10.5) and neutral solution resulted in 45.8±3.8% and 2.2±1.2% desorption, respectively. MTT viability assays and quantitative RT-PCR (expression of Ins1 and Csf3/G-csf genes) reveal bound insulin remains inactive until alkaline-mediated desorption. For applications in sustained drug delivery and therapy we have developed a therapeutic protein–ND complex with demonstrated tunable release and preserved activity. [Copyright &y& Elsevier]

IpaH proteins are E3 ubiquitin ligases delivered by the type III secretion apparatus into host cells upon infection of humans by the Gram-negative pathogen Shigella flexneri. These proteins comprise a variable leucine-rich repeat–containing N-terminal domain and a conserved C-terminal domain harboring an invariant cysteine residue that is crucial for activity. IpaH homologs are encoded by diverse animal and plant pathogens. Here we demonstrate that the IpaH C-terminal domain carries the catalytic activity for ubiquitin transfer and that the N-terminal domain carries the substrate specificity. The structure of the IpaH C-terminal domain, determined to 2.65-Å resolution, represents an all-helical fold bearing no resemblance to previously defined E3 ubiquitin ligases. The conserved and essential cysteine residue lies on a flexible, surface-exposed loop surrounded by conserved acidic residues, two of which are crucial for IpaH activity. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the reporting quality of key methodological items in randomized controlled trials (RCTs) in four general clinical ophthalmology journals.Methods: The reporting of 11 key methodological items in RCTs published in American Journal of Ophthalmology, Archives of Ophthalmology, British Journal of Ophthalmology and Ophthalmology in the year 2005 was assessed. Results : Sixty-seven eligible RCTs were assessed and the mean number of items reported was 6.3 per RCT. No significant difference in the mean number of items reported was found between the four journals (P = 0.20). The most frequently reported item was ethics approval and informed consent (97.0%), followed by masking status (85.1%), description of withdrawals (76.1%), adverse events (73.1%), and intention-to-treat analysis (71.6%). Details on sequence generation, randomization restriction, allocation concealment, allocation implementation, patient flow diagrams, and sample size calculation were reported in < 50% of the RCTs assessed. Both sample size and page length of the RCTs correlated with the number of methodological items reported (P = 0.024 and P = 0.008, respectively). Conclusions: Similar to other specialties, rooms for improvement exist in the reporting of key methodological items of RCTs in clinical ophthalmic journals. Stricter adoption of the CONSORT statement might enhance the reporting quality of RCTs in ophthalmic journals. [ABSTRACT FROM AUTHOR]

Objective: To compare the visual outcomes and complication profiles of primary scleral-fixated intraocular lens (SFIOL) versus primary anterior chamber intraocular lens (ACIOL) implantation in cataract surgeries complicated by inadequate capsular support. Design: Retrospective, interventional, comparative cases series. Participants: Thirty-six eyes of 36 patients undergoing SFIOL implantation (group 1) and 46 eyes of 46 patients undergoing ACIOL implantation (group 2). Methods: Retrospective analysis of medical records of a consecutive series of complicated cataract surgeries with primary SFIOL or ACIOL implantation. Main Outcome Measures: Postoperative best-corrected visual acuity (BCVA), intraoperative and postoperative complications, if any, and postoperative corneal endothelial cell counts. A multiple linear regression model was constructed with postoperative BCVA as the dependent variable and with IOL group (SFIOL vs. ACIOL), preoperative BCVA, surgeon’s operative experience, planned operation, and patient’s age as independent variables. Results: Fifty-eight percent (group 1) and 37% (group 2) of patients underwent phacoemulsification, whereas the rest underwent extracapsular cataract extraction. The mean postoperative follow-up was 33.4±17.9 months (range, 6–61 months). Postoperative Snellen BCVA of 20/40 or better was achieved in 47.2% (group 1) and 71.7% (group 2) of patients (P = 0.038). Regression analysis showed that primary ACIOL implantation was associated with a significantly better postoperative BCVA of −0.157 on the logarithm of minimum angle of resolution scale (95% confidence interval, −0.306 to −0.007; P = 0.040), compared with primary SFIOL implantation. Although both the number of eyes with complications and the total number of complications were higher in the SFIOL group, the differences in early (P = 0.073) and late (P = 0.377) complications were not statistically significant. Conclusions: The results indicate that satisfactory results are achieved with primary implantation of current open-loop ACIOLs during cataract surgery complicated by loss of posterior capsule integrity. Eyes with these IOLs fared better than a cohort of eyes undergoing SFIOL implantation in a similar situation, at intermediate-term follow-up. Further prospective clinical trials with longer follow-up may help to evaluate the long-term visual outcomes and complication profiles after primary implantation of these lenses. [Copyright &y& Elsevier]

Muir-Torre syndrome is a rare, autosomal dominant condition characterized by the presence of a skin tumor of sebaceous differentiation and visceral malignancies. We reviewed the case of a 46-year-old Chinese man who had a bleeding mass over the right upper eyelid. He had a history of colon cancer and a family history satisfying the Amsterdam criteria for hereditary non-polyposis colorectal cancer syndrome with germline mutation in the MutS homolog-2 gene. The eyelid lesion was excised completely and submitted for histopathologic examination which showed sebaceous carcinoma. Frozen section and conjunctival map biopsy showed no residual malignancy or local metastasis. Post-operative positron-emission tomography with combined computed tomography did not reveal any residual or visceral malignancy. He had no recurrence in the 32-month follow-up period. We should consider Muir-Torre syndrome in patients with sebaceous carcinoma, especially in the presence of personal and/or family history of visceral malignancies. [ABSTRACT FROM PUBLISHER]

Purpose: To compare two-year treatment outcomes of subthreshold micropulse (577 nm) laser and aflibercept for diabetic macular edema (DME). Study design: Retrospective case–control study. Methods: A total 164 eyes in 164 DME patients treated with either micropulse laser (86 eyes) or intravitreal aflibercept monotherapy (78 eyes) were recruited. Main outcome measures included at least five Early Treatment Diabetic Retinopathy Study (ETDRS) letters' improvement from baseline at 6, 12 and 24 months. Results: Rescue aflibercept was initiated in 24% of eyes in micropulse laser group. At 6-month visit the aflibercept group achieved a higher percentage of eyes with at least 5-letter visual acuity improvement than micropulse laser group (56% vs 38%, P = 0.044), however, this was not the case at 12-month (45% vs 49%, P = 0.584) and 24-month visits (49% vs 57%, P = 0.227). At 6-month visit the aflibercept group achieved a higher percentage of eyes with at least 10% improvement of central macular thickness (73% vs 49%, P = 0.005), but this was not the case at 12-month (73% vs 70%, P = 0.995) and 24-month visits (85% vs 84%, P = 0.872). Conclusion: Aflibercept achieved faster and higher rates of anatomical and functional improvement than micropulse laser in DME patients. Long term efficacy of treatment did not result in significant differences between aflibercept monotherapy and micropulse laser in DME patients. Primary treatment of micropulse laser with deferred rescue aflibercept might be the treatment option without reducing the chance of visual improvement in DME eyes. [ABSTRACT FROM AUTHOR]

Radioimmunoassay measurements of serum concentrations of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), and thyroxine binding globulin (TBG) were conducted in full-term newborn infants between birth and 5 days of age. The mean concentrations of T4 and FT4 increased from cord blood levels of 11.9 µg/100 ml and 2.9 ng/100 ml to peak values of 16.2 µg/100 ml and 7 ng/100 ml by 24 to 48 hours of age. Mean serum total and free T3 concentrations increased from cord blood levels of 50.5 ng/100 ml and 146 pg/100 ml to peak values of 419 ng/100 ml and 1,260 pg/100 ml by 24 hours of age. Mean T3/T4 and FT3/FT4 ratios increased from 1/238 to 1/39 and from 1/20 to 1/6, respectively, during this period. By 72 to 126 hours, both the T4 and T3 concentrations had fallen somewhat. Mean serum TBG concentrations were unchanged and approximated 5.0 mg/100 ml during the first 5 days of life. These data confirm earlier reports that the normal newborn infant rapidly becomes chemically hyperthyroid in the neonatal period due to increased thyroid hormone secretion; this neonatal hyperthyroid state is due more to T3 than to T4. The data also confirm earlier reports that the fetus is T3 deficient due to a decreased capacity to monodeiodinate T4 to T3 in extrathyroidal tissues. The rapid increase in serum T3 after delivery at a time when the capacity to convert T4 to T3 is reduced suggests that the increment in serum T3 is due, predominantly, to increased T3 secretion from the thyroid gland stimulated by the neonatal TSH surge. Thus with parturition, the newborn infant is transformed from a state of chemical T3 deficiency to a state of chemical T3 thyrotoxicosis. [ABSTRACT FROM AUTHOR]

Endoscopy provides unique optical properties to circumvent anterior segment opacities and visualize difficult-to-access anatomical regions, including retroirideal, retrolental, ciliary body, and anterior retinal structures. We summarize the basic principles and utilization of endoscopic vitreoretinal surgery, along with recent technological advances in the field base on a structured literature search in Pubmed, Embase, and Google Scholar database up to February, 2020. Endoscopy has been used in the management of retinal detachment, ischemic retinopathies with neovascular glaucoma, severe ocular trauma, endophthalmitis, lens-related disorders in the posterior segment, pediatric vitreoretinal diseases, and implantation of retinal prostheses. Ongoing development of endoscopic technology aims to provide higher resolution images with endoscopes of smaller diameter. New surgical techniques supported by the adoption of endoscopy are available to manage challenging surgical scenarios. Endoscopy can be a useful adjunct to microscope wide-angle viewing systems in the management of complex vitreoretinal diseases. [ABSTRACT FROM AUTHOR]

Background Endoscopic placement of hilar stents is an accepted palliative therapy for patients with advanced, unresectable cholangiocarcinoma. However, whether unilateral versus bilateral stent placement provides optimal relief continues to be a subject of debate. The aim of this study was to compare the technical and clinical outcomes in patients with inoperable cholangiocarcinoma who received unilateral or bilateral self-expanding metal stents (SEMS). Methods We conducted a multicenter, international retrospective study of 187 patients with cholangiocarcinoma who received unilateral or bilateral SEMS. Outcomes included, but were not limited to, technical success, clinical success, adverse events, stent occlusion, and survival time. Results were further stratified based on the Bismuth classification. Results Fifty patients received unilateral stents and 137 patients received bilateral stents. All patients achieved technical success. The clinical success rates were 86% for unilateral stents and 82.5% for bilateral stents (P>0.99). Clinical success was not statistically different for either group when stratified by the Bismuth classification (P=0.62 and P=0.72 respectively). There were significantly more adverse events in the bilateral stents group (11.7% vs. 0%, P=0.007). There was no greater risk of stent occlusion when bilateral stents were used (unadjusted P=0.71, adjusted P=0.81). There was a greater risk of death for patients who received bilateral SEMS (hazard ratio 1.78, 95% confidence interval 1.09-2.89; P=0.02). Conclusions Unilateral and bilateral drainage had similar technical and clinical success rates. However, bilateral stents had a higher risk of death and more adverse events. Therefore, unilateral SEMS placement is sufficient for relief of biliary obstruction secondary to cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Highlights: [•] We report the first crystal structures of SUV420H1 and SUV420H2. [•] SUV420H1 and SUV420H2 exhibit unique N-terminal and Zn-binding post-SET domains. [•] We developed the first in vitro assay for characterizing and screening SUV420H1 and SUV420H2 in a 384-well format. [Copyright &y& Elsevier]

Abstract: A synthetic phage-displayed antibody repertoire was constructed with equivalent chemical diversity in the third complementarity-determining regions of the heavy (CDR-H3) and light (CDR-L3) chains, which contrasts with natural antibodies in which CDR-H3 is much more diverse than CDR-L3 due to the genetic mechanisms that generate antibody encoding genes. Surprisingly, the synthetic repertoire yielded numerous functional antibodies that contained mutated CDR-L3 sequences but a fixed CDR-H3 sequence. Alanine-scanning analysis of antibodies that recognized 10 different antigens but contained a common CDR-H3 loop showed that, in most cases, the fixed CDR-H3 sequence was able to contribute favorably to antigen recognition, but in some cases, the loop was functionally inert. Structural analysis of one such antibody in complex with antigen showed that the inert CDR-H3 loop was nonetheless highly buried at the antibody–antigen interface. Taken together, these results show that CDR-H3 diversity is not necessarily required for the generation of antibodies that recognize diverse protein antigens with high affinity and specificity, and if given the chance, CDR-L3 readily assumes the dominant role for antigen recognition. These results contrast with the commonly accepted view of antigen recognition derived from the analysis of natural antibodies, in which CDR-H3 is presumed to be dominant and CDR-L3 is presumed to play an auxiliary role. Furthermore, the results show that natural antibody function is genetically constrained, and it should be possible to develop more functional synthetic antibody libraries by expanding the diversity of CDR-L3 beyond what is observed in nature. [Copyright &y& Elsevier]

Abstract: The human PHD finger protein 20 (PHF20) is a putative transcription factor. While little is known about its cognate cellular role, antibodies against PHF20 are present in sera from patients with hepatocellular carcinoma, glioblastoma and childhood medulloblastula. PHF20 comprises two N-terminal Tudor domains, a central C2H2-link zinc finger domain and a C-terminal zinc-binding PHD domain, and is a component of some MLL methyltransferase complexes. Here, we report the crystal structures of the N-terminal Tudor domains of PHF20 and highlight the novel structural features of each domain. We also confirm previous studies suggesting that the second Tudor domain of PHF20 exhibits preference for dimethylated histone substrates. [Copyright &y& Elsevier]

Abstract: We present here the crystal structures of human lamin B1 globular tail domain and coiled 2B domain, which adopt similar folds to Ig-like domain and coiled-coil domain of lamin A, respectively. Despite the overall similarity, we found an extra intermolecular disulfide bond in the lamin B1 coil 2B domain, which does not exist in lamin A/C. In addition, the structural analysis indicates that interactions at the lamin B1 homodimer interface are quite different from those of lamin A/C. Thus our research not only reveals the diversely formed homodimers among lamin family members, but also sheds light on understanding the important roles of lamin B1 in forming the nuclear lamina matrix. Structured summary of protein interactions: Lamin-B and Lamin-B bind by x-ray crystallography (View interaction) [Copyright &y& Elsevier]

SMN (Survival motor neuron protein) was characterized as a dimethyl-arginine binding protein over ten years ago. TDRD3 (Tudor domain-containing protein 3) and SPF30 (Splicing factor 30 kDa) were found to bind to various methyl-arginine proteins including Sm proteins as well later on. Recently, TDRD3 was shown to be a transcriptional coactivator, and its transcriptional activity is dependent on its ability to bind arginine-methylated histone marks. In this study, we systematically characterized the binding specificity and affinity of the Tudor domains of these three proteins quantitatively. Our results show that TDRD3 preferentially recognizes asymmetrical dimethylated arginine mark, and SMN is a very promiscuous effector molecule, which recognizes different arginine containing sequence motifs and preferentially binds symmetrical dimethylated arginine. SPF30 is the weakest methyl-arginine binder, which only binds the GAR motif sequences in our library. In addition, we also reported high-resolution crystal structures of the Tudor domain of TDRD3 in complex with two small molecules, which occupy the aromatic cage of TDRD3. [ABSTRACT FROM AUTHOR]

Aim: To determine the risk factors for developing phacomorphic glaucoma in eyes with mature cataracts.Materials and Methods: This is a case-control study comprising of 90 eyes with phacomorphic glaucoma and 90 age- and sex-matched control eyes with mature cataracts without phacomorphic glaucoma. Patients with pre-existing glaucoma, previous intraocular surgery and /or absence of documented axial lengths were excluded from this study. Binary logistic regression analysis of the variables, axial length and anterior chamber depth, was performed. Anterior chamber depth of the contralateral eye was used as a proxy measure of the pre-phacomorphic state in the eye with phacomorphic glaucoma as majority of them first presented to our center during the phacomorphic attack without prior measurements of the pre-phacomorphic ACD or lens thickness; therefore, their anterior chamber depth would not be representative of their pre-phacomorphic state. Axial length of 23.7 mm was selected as a cut-off for dichotomized logistic regression based on the local population mean from published demographic data.Results: The mean age was 73.1 ± 10.2 years. All phacomorphic and control eyes were ethnic Chinese. The mean presenting intraocular pressures were 49.5 ± 11.8 mmHg and 16.7 ± 1.7 mmHg in the phacomorphic and control eyes respectively (P< 0.0001), whilst the median Snellen best corrected visual acuity were light perception and hand movement in the phacomorphic and control eyes respectively. Eyes with phacomorphic glaucoma had shorter axial length of 23.1 ± 0.9 mm median when compared with that of control eyes, 23.7 ± 1.5 mm (P = 0.0006). Eyes with AL ≤ 23.7 mm were 4.3 times as likely to develop phacomorphic glaucoma when compared with AL > 23.7 mm (P = 0.003).Conclusion: Axial length less than ≤ 23.7 mm was a risk factor for developing phacomorphic glaucoma. Eyes with AL shorter than the population mean were 4.3 times as likely to develop phacomorphic glaucoma compared with eyes with longer than average AL. In an area where phacomorphic glaucoma is prevalent and medical resources are limited, patients with AL shorter than their population mean may be considered for earlier elective cataract extraction as a preventive measure. [ABSTRACT FROM AUTHOR]