Glycosylated fibronectin improves first-trimester prediction of pre-eclampsia.

OBJECTIVE: To determine whether maternal serum glycosylated fibronectin (GlyFn) level in the first trimester increases the sensitivity of the Fetal Medicine Foundation (FMF) triple test, which incorporates mean arterial pressure, uterine artery pulsatility index and placental growth factor, when screening for pre-eclampsia (PE) in an Asian population. METHODS: This was a nested case-control study of Chinese women with a singleton pregnancy who were screened for PE at 11-13 weeks' gestation as part of a non-intervention study between December 2016 and June 2018. GlyFn levels were measured retrospectively in archived serum from 1685 pregnancies, including 101 with PE, using an enzyme-linked immunosorbent assay (ELISA), and from 448 pregnancies, including 101 with PE, using a point-of-care (POC) device. Concordance between ELISA and POC tests was assessed using Lin's correlation coefficient and Passing-Bablok and Bland-Altman analyses. GlyFn was transformed into multiples of the median (MoM) to adjust for maternal and pregnancy characteristics. GlyFn MoM was compared between PE and non-PE pregnancies, and the association between GlyFn MoM and gestational age at delivery with PE was assessed. Risk for developing PE was estimated using the FMF competing-risks model. Screening performance for preterm and any-onset PE using different biomarker combinations was quantified by area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% fixed false-positive rate (FPR). Differences in AUC between biomarker combinations were compared using the DeLong test. RESULTS: The concordance correlation coefficient between ELISA and POC measurements was 0.86 (95% CI, 0.83-0.88). Passing-Bablok analysis indicated proportional bias (slope, 1.08 (95% CI, 1.04-1.14)), with POC GlyFn being significantly higher compared with ELISA GlyFn. ELISA GlyFn in non-PE pregnancies was independent of gestational age at screening (P = 0.11), but significantly dependent on maternal age (P < 0.003), weight (P < 0.0002), height (P = 0.001), parity (P < 0.02) and smoking status (P = 0.002). Compared with non-PE pregnancies, median GlyFn MoM using ELISA and POC testing was elevated significantly in those with preterm PE (1.23 vs 1.00; P < 0.0001 and 1.18 vs 1.00; P < 0.0001, respectively) and those with term PE (1.26 vs 1.00; P < 0.0001 and 1.22 vs 1.00; P < 0.0001, respectively). GlyFn MoM was not correlated with gestational age at delivery with PE (P = 0.989). Adding GlyFn to the FMF triple test for preterm PE increased significantly the AUC from 0.859 to 0.896 (P = 0.012) and increased the DR at 10% FPR from 64.9% (95% CI, 48.7-81.1%) to 82.9% (95% CI, 66.4-93.4%). The corresponding DRs at 10% FPR for any-onset PE were 52.5% (95% CI, 42.3-62.5%) and 65.4% (95% CI, 55.2-74.5%), respectively. CONCLUSIONS: Adding GlyFn to the FMF triple test increased the screening sensitivity for both preterm and any-onset PE in an Asian population. Prospective non-intervention studies are needed to confirm these initial findings. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Telemedicine acceptance by older adults in Hong Kong during a hypothetical severe outbreak and after the COVID-19 pandemic: a cross-sectional cohort survey.

INTRODUCTION: Telemedicine services worldwide have experienced unprecedented growth since the early days of the coronavirus disease 2019 (COVID-19) pandemic. Multiple studies have shown that telemedicine is an effective alternative to conventional in-person patient care. This study explored the public perception of telemedicine in Hong Kong, specifically among older adults who are most vulnerable to COVID-19. METHODS: Medical students from The Chinese University of Hong Kong conducted in-person surveys of older adults aged ≥60 years. Each survey collected socio-demographic information, medical history, and concerns regarding telemedicine use. Univariate and multivariate logistic regression analyses were conducted to identify statistically significant associations. The primary outcomes were acceptance of telemedicine use during a hypothetical severe outbreak and after the COVID-19 pandemic. RESULTS: There were 109 survey respondents. Multivariate logistic regression analyses revealed that the expectation of government subsidies for telemedicine services was the strongest common driver and the only positive independent predictor of telemedicine use during a hypothetical severe outbreak (P=0.016) and after the COVID-19 pandemic (P=0.003). No negative independent predictors of telemedicine use during a hypothetical severe outbreak were identified. Negative independent predictors of telemedicine use after the COVID-19 pandemic included older age and residence in the New Territories (both P=0.001). CONCLUSION: Government support, such as telemedicine-specific subsidies, will be important for efforts to promote telemedicine use in Hong Kong during future severe outbreaks and after the COVID-19 pandemic. Robust dissemination of information regarding the advantages and disadvantages of telemedicine for the public, especially older adults, is needed.

Decoupling the role of stress and corrosion in the intergranular cracking of noble-metal alloys.

Intergranular stress-corrosion cracking (IGSCC) is a form of environmentally induced crack propagation causing premature failure of elemental metals and alloys. It is believed to require the simultaneous presence of tensile stress and corrosion; however, the exact nature of this synergy has eluded experimental identification. For noble metal alloys such as Ag-Au, IGSCC is a consequence of dealloying corrosion, forming a nanoporous gold layer that is believed to have the ability to transmit cracks into grain boundaries in un-dealloyed parent phase via a pure mechanical process. Here using atomic-scale techniques and statistical characterizations for this alloy system, we show that the separate roles of stress and anodic dissolution can be decoupled and that the apparent synergy exists owing to rapid time-dependent morphology changes at the dealloyed layer/parent phase interface. We discuss the applicability of our findings to the IGSCC of important engineering Fe- and Ni-based alloys in critical applications.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Transverse technique: complementary approach to measurement of first-trimester uterine artery Doppler.

OBJECTIVES: To define a protocol for the first-trimester assessment of uterine artery pulsatility index (UtA-PI) using the new transverse technique, to evaluate UtA-PI measured using the transverse approach vs that obtained using the conventional sagittal approach and to determine if accelerated onsite training (in both methods) of inexperienced sonographers can achieve reproducible UtA-PI measurements comparable with those obtained by an experienced sonographer. METHODS: This was a prospective observational study of women with a singleton pregnancy attending for routine combined first-trimester screening at 11 to 13 + 6 weeks' gestation. The study consisted of two parts, each conducted at a different center (Part 1 in Calgary, Canada and Part 2 in Hong Kong). In Part 1, UtA-PI measurements were performed using the transverse and sagittal techniques by four sonographers trained in both methods, in 10 cases each, and measurement indices (PI), time required and subjective difficulty in obtaining satisfactory measurements were compared. The one sample t-test and Wilcoxon signed rank test were used when appropriate. Bland-Altman plots were used to assess measurement agreement, and intraclass correlation coefficient (ICC) was used to evaluate measurement reliability. A target plot was used to assess measures of central tendency and dispersion. In Part 2, one experienced and three inexperienced sonographers prospectively measured UtA-PI using both approaches in 42 and 35 women, respectively. Inexperienced sonographers underwent accelerated onsite training by the experienced sonographer. Measurement approach and sonographer order were on a random basis. ICC, Bland-Altman and Passing-Bablok analyses were performed to assess measurement agreement and reliability and effect of accelerated training. RESULTS: In Part 1, no difference was observed between the two techniques in mean time to acquire the measurements (118 s for sagittal vs 106 s for transverse; P = 0.38). The four sonographers reported that the transverse technique was subjectively easier to perform (P = 0.04). Bias and ICC for mean UtA-PI between sagittal and transverse measurements were -0.05 (95% limits of agreement, -0.48 to 0.37) and 0.94, respectively. Measurements obtained using the transverse technique after correcting for gestational age were significantly closer to the expected distribution than those obtained using the sagittal technique. In Part 2, there were no significant differences in median UtA-PI measured using the different approaches for both experienced and inexperienced sonographers (P > 0.05 for all sonographers). Mean UtA-PI measurement reliability between approaches was high for the experienced (ICC = 0.92) and inexperienced (ICC > 0.80) sonographers. UtA-PI measurement approaches did not deviate from linearity, while bias ranged from -0.10 to 0.07. The median time required was similar between the techniques (56.1 s for sagittal vs 49.3 s for transverse; P = 0.054). CONCLUSIONS: This novel transverse approach for the measurement of UtA-PI in the first trimester appears to be comparable with the sagittal approach in terms of reliability, reproducibility and time required, and may be easier to perform. Providing accelerated onsite training can be helpful for improving the reliability of UtA-PI measurements and could potentially facilitate the broad implementation of first-trimester pre-eclampsia screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Improving the solubility of pseudo-hydrophobic Alzheimer's Disease medicinal chemicals through co-crystal formulation.

Natural products are ligands and potential inhibitors of Alzheimer's disease (AD) tau. Dihydromyricetin (DHM) is a CNS active natural product. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH allowing formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All salt formulations show better inhibitory activity against AD tau than the non-salt form, with efficacies correlating to enhanced solubilities. These results underscore the role of structural chemistry in guiding selection of solubilizing agents for chemical formulation. We propose DHM salts are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding. Additionally, DHM is a suitable lead for medicinal chemistry and possible development of CNS pharmaceuticals.

Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats.

Immunization protocols that induce high levels of delayed-type hypersensitivity are often associated with low levels of antibody production, whereas alternative immunization strategies can produce the opposite effect. This reciprocal relationship appears to depend, at least in part, on the fact that T cell-derived lymphokines that are predominantly involved in one type of response inhibit the development of those T cells that promote the alternative one. Such a regulatory mechanism is likely to be bistable in that whenever one form of response is established, spontaneous development of the alternative one will be inhibited. We have applied this concept to the control of a cell-mediated autoimmune disease in rats. By covalently linking the autoantigen to anti-IgD antibody, we have targeted it to B cells for presentation to antigen-specific T cells. This form of presentation favors antibody production and may be expected to antagonize the cell-mediated disease-inducing response to the same antigen. To test this hypothesis, use was made of the fact that experimental allergic encephalomyelitis (EAE), when induced with the encephalitogenic peptide of guinea pig myelin basic protein, is purely a cell-mediated disease. The experiments show that Lewis rats, immunized with the peptide in its encephalitogenic form, were protected from disease when simultaneously injected with the peptide coupled to anti-IgD monoclonal antibodies. Control experiments showed that neither peptide nor anti-IgD alone were protective, and the peptide covalently coupled to irrelevant antibodies also failed to protect. Spleen cells from animals protected from disease by the anti-IgD-peptide conjugate, when activated in vitro with the encephalitogen, were able to transfer EAE to naive recipients. The results demonstrate that a cell-mediated immune response can be controlled by appropriate targeting of the specific antigen without inducing T cell anergy and suggest a potential strategy for preventing autoimmune diseases that are essentially cell-mediated in type.

Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival.

BACKGROUND: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome. PATIENTS AND METHODS: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival. RESULTS: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival. CONCLUSIONS: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.

GnRH-induced Ca2+ oscillations and rhythmic hyperpolarizations of pituitary gonadotropes.

Secretion of gonadotropic hormones from pituitary gonadotropes in response to gonadotropin-releasing hormone (GnRH) is essential for regulation of reproductive potential. Gonadotropes from male rats exhibited an unusual form of cellular excitation that resulted from periodic membrane hyperpolarization. GnRH induced an oscillatory release of intracellular Ca2+ via a guanosine triphosphate (GTP) binding protein-coupled phosphoinositide pathway and hyperpolarized the gonadotrope periodically by opening apamin-sensitive Ca(2+)-activated K+ (SK) channels. Each hyperpolarization was terminated by firing of a few action potentials that may result from removal of inactivation from voltage-gated Na+ and Ca2+ channels.

Rhythmic exocytosis stimulated by GnRH-induced calcium oscillations in rat gonadotropes.

In pituitary gonadotropes, gonadotropin-releasing hormone (GnRH) induces the rhythmic release of Ca2+ from an inositol 1,4,5-trisphosphate (IP3)-sensitive store. Simultaneous measurement of the concentration of cytosolic free Ca2+ ([Ca2+]i) and exocytosis in single identified gonadotropes showed that each elevation of [Ca2+]i induced a burst of exocytosis. These phenomena were largely suppressed by buffering of [Ca2+]i but persisted in the absence of extracellular Ca2+. Activation of voltage-gated Ca2+ channels by brief depolarizations seldom supplied enough Ca2+ for exocytosis, but [Ca2+]i elevations induced by photolysis of caged IP3 did trigger exocytosis, confirming that GnRH-stimulated gonadotropic hormone secretion is closely coupled to intracellular Ca2+ release. Agonist-induced oscillations of [Ca2+]i in secretory cells may be a mechanism to optimize the secretory output while avoiding the toxic effects of sustained elevation of [Ca2+]i.

A glycophospholipid tail at the carboxyl terminus of the Thy-1 glycoprotein of neurons and thymocytes.

Cell surface molecules of eukaryotic cells have been considered to be integrated into the membrane bilayer by a transmembrane protein sequence. The Thy-1 antigen of rodent thymocytes and brain was the first eukaryotic membrane molecule for which biochemical data clearly suggested membrane integration via a nonprotein tail. Direct evidence is now presented showing that a glycophospholipid structure is attached to the carboxyl-terminal cysteine residue and that 31 carboxyl-terminal amino acids predicted from the Thy-1 complementary DNA sequence are not present in the mature glycoprotein. These experimental results raise questions concerning signaling across a cell membrane since antibodies to Thy-1 can stimulate T lymphocytes to release lymphokines and undergo cell division.

Local Ca2+ release from internal stores controls exocytosis in pituitary gonadotrophs.

Exocytosis and the cell-averaged cytosolic [Ca2+], [Ca2+]i, were tracked in single gonadotrophs. Cells released 100 granules/s at 1 microM = [Ca2+]i when gonadotropin-releasing hormone (GnRH) activated IP3-mediated Ca2+ release from internal stores, but only 1 granule/s when [Ca2+]i was raised uniformly to 1 microM by other means. Strong exocytosis was then seen only at higher [Ca2+]i (half-maximal at 16 microM). Parallel second messengers did not contribute to GnRH-induced exocytosis, because IP3 alone was as effective as GnRH, and because even GnRH failed to trigger rapid exocytosis when the [Ca2+]i rise was blunted by EGTA. When [Ca2+]i was released from stores, exocytosis depended on [Ca2+]i rising rapidly, as if governed by Ca2+ flux into the cytosol. We suggest that IP3 releases Ca2+ selectively from subsurface cisternae, raising [Ca2+] near exocytic sites 5-fold above the cell average.

Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors.

PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle. RESULTS: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 +/- 0.69 micromol/L (flavopiridol 20 mg/m2) to 4.54 +/- 0.08 micromol/L (flavopiridol 60 mg/m2) in cycle 1. CONCLUSIONS: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.

Identification of a common docking topology with substantial variation among different TCR-peptide-MHC complexes.

Whether T-cell receptors (TCRs) recognize antigenic peptides bound to major histocompatability complex (MHC) molecules through common or distinct docking modes is currently uncertain. We report the crystal structure of a complex between the murine N15 TCR [1-4] and its peptide-MHC ligand, an octapeptide fragment representing amino acids 52-59 of the vesicular stomatitis virus nuclear capsid protein (VSV8) bound to the murine H-2Kb class I MHC molecule. Comparison of the structure of the N15 TCR-VSV8-H-2Kb complex with the murine 2C TCR-dEV8-H-2Kb [5] and the human A6 TCR-Tax-HLA-A2 [6] complexes revealed a common docking mode, regardless of TCR specificity or species origin, in which the TCR variable Valpha domain overlies the MHC alpha2 helix and the Vbeta domain overlies the MHC alpha1 helix. As a consequence, the complementary determining regions CDR1 and CDR3 of the TCR Valpha and Vbeta domains make the major contacts with the peptide, while the CDR2 loops interact primarily with the MHC. Nonetheless, in terms of the details of the relative orientation and disposition of binding, there is substantial variation in TCR parameters, which we term twist, tilt and shift, and which define the variation of the V module of the TCR relative to the MHC antigen-binding groove.

Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese.

BACKGROUND: Interleukin-1beta is a pro-inflammatory cytokine that may influence host defence against viral infection. AIM: To investigate the impact of interleukin-1beta gene polymorphism on the response to anti-viral treatment. METHOD: Hepatitis B e antigen-positive chronic hepatitis B patients who have completed a randomized study of peginterferon alpha-2b and lamivudine combination vs. lamivudine monotherapy were included. Sustained responders were patients who had persistent hepatitis B e antigen loss and less than two occasions with hepatitis B virus DNA >100 000 copies/mL at any time up to week 76 post-treatment. Polymorphisms at interleukin-1beta-511, -31 and -3954 and interleukin-1 receptor antagonist (RN) were studied. RESULTS: Eighty-eight patients were studied and 18 (20%) patients developed sustained response. Near complete linkage disequilibrium was observed between interleukin-1beta-511 and -31 loci. After adjustment for the potential confounding effects of treatment allocation, hepatitis B virus genotype, pre-treatment alanine aminotransferase and hepatitis B virus DNA levels, genotype C/T at interleukin-1beta-511 was found to be associated with higher sustained response than genotype C/C (adjusted odds ratio 10.4, 95% CI 1.1, 96.9, P = 0.040). The proportion of sustained responders tend to be higher among patients with allele T at interleukin-1beta-511 (83%) than those without (70%) (P = 0.058). CONCLUSION: High interleukin-1beta production genotype at position -511 has a favourable response to anti-viral treatments.

Alpha-particle radiobiological experiments using thin CR-39 detectors.

The present paper studied the feasibility of applying comet assay to evaluate the DNA damage in individual HeLa cervix cancer cells after alpha-particle irradiation. We prepared thin CR-39 detectors (<20 microm) as cell-culture substrates, with UV irradiation to shorten the track formation time. After irradiation of the HeLa cells by alpha particles, the tracks on the underside of the CR-39 detector were developed by chemical etching in (while floating on) a 14 N KOH solution at 37 degrees C. Comet assay was then applied. Diffusion of DNA out of the cells could be generally observed from the images of stained DNA. The alpha-particle tracks corresponding to the comets developed on the underside of the CR-39 detectors could also be observed by just changing the focal plane of the confocal microscope.

Tissue-specific expression of functional isoforms of mouse folypoly-gamma-glutamae synthetase: a basis for targeting folate antimetabolites.

Folates and folate antimetabolites are metabolically trapped in mammalian cells as polyglutamates, a process catalyzed by folylpoly-gamma-glutamate synthetase (FPGS). Using 5'-rapid amplification of cDNA ends, RNase protection assays, transfection of cDNAs into FPGS-deficient cells, and kinetic analysis of recombinant enzymes expressed in insect cells, it was determined that the species of active FPGS in mouse liver and kidney was different from that in mouse tumor cells, bone marrow, and intestine. The NH2-terminal peptide of hepatic enzyme contained 18 amino acids not found in enzyme from dividing tissues, and the specificity of the two isoforms for antifolates also differed, suggesting different architecture of the active sites. In most tissues, the expression of one isozyme or the other was an all-or-nothing event. The exclusive use of one of two alternative sets of initial coding exons in different tissues underlies this phenomenon, suggesting the design of antifolates specific for activation by individual FPGS isoforms and hence tissue-selective targeting of antifolate therapy for cancer, arthritis, or psoriasis.

Glaucoma treatment adherence at a United Kingdom general practice.

PurposeTo estimate patient adherence with glaucoma therapy and identify factors associated with adherence using computerised patient prescribing records.MethodsIdentification of patients diagnosed with glaucoma, ocular hypertension or suspect glaucoma and/or prescribed topical glaucoma medications registered at a United Kingdom general practice with 13 422 patients. Adherence was defined as the average difference in the actual number of prescriptions collected annually compared to twelve prescriptions required annually (one bottle per month) over the duration of treatment.ResultsOverall, 278 patients were identified of which 139 (50%) were male. The average age was 72 years (range: 22-100). A total of 206 patients (74%) were prescribed glaucoma treatment. Adherence varied significantly between age groups with younger patients demonstrating poorest adherence (P=0.0347). There was no statistical difference when comparing medication class, diagnosis, co-morbidities, or the number of drops being taken.ConclusionsGlaucoma treatment adherence improves with increasing age. Older patients require more prescriptions and may be experiencing drop wastage. Younger patients should be targeted with educational interventions to improve their understanding of glaucoma, and older patients for drop technique review. General practices are well placed to provide such interventions.

Small-world networks of residue interactions in the Abl kinase complexes with cancer drugs: topology of allosteric communication pathways can determine drug resistance effects.

The human protein kinases play a fundamental regulatory role in orchestrating functional processes in complex cellular networks. Understanding how conformational equilibrium between functional kinase states can be modulated by ligand binding or mutations is critical for quantifying molecular basis of allosteric regulation and drug resistance. In this work, molecular dynamics simulations of the Abl kinase complexes with cancer drugs (Imatinib and Dasatinib) were combined with structure-based network modeling to characterize dynamics of the residue interaction networks in these systems. The results have demonstrated that structural architecture of kinase complexes can produce a small-world topology of the interaction networks. Our data have indicated that specific Imatinib binding to a small number of highly connected residues could lead to network-bridging effects and allow for efficient allosteric communication, which is mediated by a dominant pathway sensitive to the unphosphorylated Abl state. In contrast, Dasatinib binding to the active kinase form may activate a broader ensemble of allosteric pathways that are less dependent on the phosphorylation status of Abl and provide a better balance between the efficiency and resilience of signaling routes. Our results have unveiled how differences in the residue interaction networks and allosteric communications of the Abl kinase complexes can be directly related to drug resistance effects. This study offers a plausible perspective on how efficiency and robustness of the residue interaction networks and allosteric pathways in kinase structures may be associated with protein responses to drug binding.