cAMP Imaging at Ryanodine Receptors Reveals ß2-Adrenoceptor Driven Arrhythmias.

[Figure: see text].

Heroin Regulates Orbitofrontal Circular RNAs.

The number of drug overdose deaths involving opioids continues to rise in the United States. Many patients with opioid use disorder (OUD) that seek treatment still experience relapse. Perseverant opioid seeking behaviors represent a major challenge to treating OUD and additional therapeutic development will require insight into opioid-induced neurobiological adaptations. In this study, we explored the regulation of a novel class of RNAs, circular RNAs (circRNAs), by the addictive opioid heroin in the rat orbitofrontal cortex (OFC), a brain region that mediates behavioral responses to rewarding stimuli. Microarray analysis identified 76 OFC circRNAs significantly regulated in male rats after heroin self-administration. We evaluated the specificity of these findings by measuring heroin-associated circRNA expression in female rats after heroin self-administration and in rats that self-administered sucrose. We identify circGrin2b, circUbe2cp, circAnks1a, circAdcy5 and circSlc24A2 as heroin-responsive circRNAs in the OFC. Linear mRNA levels of heroin-associated circRNAs were unchanged except for Grin2b and Adcy5. An integrated bioinformatics analysis of regulated circRNAs identified microRNAs predicted to bind heroin-associated circRNAs and downstream targets of circRNA: microRNA sponging. Thus, heroin regulates the expression of OFC RNA splice variants that circularize and may impact cellular processes that contribute to the neurobiological adaptations that arise from chronic heroin exposure.

Fungal Infection in an Exenterated Orbit.

A 48-year-old man presented with an Aspergillus fumigatus complex infection of an exenterated orbit. The OS had been exenterated 7 months ago, together with total parotidectomy and neck dissection followed by irradiation due to a massive squamous cell carcinoma with orbital invasion and lymphatic metastasis. The patient was under permanent immunosuppression with oral prednisone and tacrolimus due to a kidney transplantation 5 years ago. The infected skin of the exenterated orbit was cleared using forceps. MRI ruled out any bone infiltration. After systemic treatment with oral voriconazole and topical therapy with bifonazole ointment for 6 weeks, the patient recovered completely.

[Retrobulbar Haematoma - a Complication that May Impair Vision]. / Das retrobulbäre Hämatom ­ eine potenziell visusbedrohende Komplikation.

Retrobulbar haematoma (RBH) is a rare complication that may affect vision after a trauma or a surgical procedure. The diagnosis must be made promptly, as only early surgical intervention can adequately prevent irreversible visual impairment. Because of the bony orbital walls, there is hardly any room for the increasing intraorbital volume due to the retrobulbar haemorrhage. This leads to an increase in intraorbital pressure and subsequently to compression of the optic nerve. Symptoms include disorders in ocular motility, ophthalmoplegia, diplopia, conjunctival chemosis, subconjunctival haemorrhage, proptosis, increased intraocular pressure, deterioration in visual acuity, decreased direct pupillary reflex, and a relative afferent pupillary defect. If the cause is traumatic or iatrogenic, prompt lateral canthotomy with cantholysis is the treatment of choice, and successfully lowers pressure in most cases. It can be performed in the emergency room by an ophthalmologist and may even be indicated without previous imaging. As the reconstruction of cantholysis is generally uncomplicated, we recommend performing the procedure when RBH is suspected. If canthotomy with cantholysis does not lead to adequate improvement, surgical orbital decompression must be performed. Supportive treatment should always include systemic steroids.

[Intubation Systems in Lacrimal Drainage Surgery - a Current Overview]. / Intubationssysteme in der Tränenwegchirurgie ­ eine aktuelle Übersicht.

The development of microendoscopes in lacrimal drainage surgery has led to the introduction of novel surgical procedures that maintain transcanicular anatomy, including a variety of lacrimal drainage intubation systems. Depending on the location and extent of the lacrimal duct stenosis, bicanaliculoanular, monocanalicular, monocanaliculonasal, bicanalicular, and bicanaliculonasal intubation techniques and systems, as well as a combination of these, may be used. For isolated intubation of the puncta lacrimalia, perforated punctum plugs may be used, while pure monocanalicular intubation can be performed using a Mini-Monoka. The monocanaliculonasal intubation systems include the Monoka (Wide Collarette type), Monoka of Fayet (Crawford type), the self-threading Monoka (Ritleng type), the Masterka, and the LacriJet for the ophthalmic surgeon. The bicanaliculonasal intubation systems include various BIKA systems, the Ritleng intubation system, the Crawford intubation system, and the FCI Nunchaku. Indications for both monocanaliculonasal and bicanaliculonasal intubation systems are obstructions, stenoses or lacerations of all kinds, as well as obstructions and stenoses after opening or after a DCR. For a conjunctivodacryocystorhinostomy (CDCR), the classical Lester Jones Tube, Metaireau Tubes, and StopLoss Jones Tube may be used. Although the study situation is ambiguous and therefore lacrimal drainage intubation is not considered mandatory, most ophthalmic surgeons do not forego intubation - despite the higher costs and slightly more protracted surgery. The surgeons' selection of the intubation system depends on the chosen form of intubation, costs and personal preferences and experience.

Reliability of periocular anthropometry using three-dimensional digital stereophotogrammetry.

PURPOSE: Non-invasive three-dimensional (3D) stereophotogrammetry is becoming increasingly popular in many fields. However, few studies have focused on its periocular application. We aimed to provide evidence for the periocular application of a novel anthropometric procedure using 3D stereophotogrammetry by evaluating its reliability. METHODS: Fifty-one Caucasians were recruited (102 eyes; mean age, 31.9 ± 13.6 years). Two sets of 3D images were acquired for each subject, and two measurement sessions were performed on each image by two raters. Fifty-two periocular landmarks were identified, and then 49 corresponding linear, curvilinear, and angular measurements were evaluated for intrarater, interrater, and intramethod reliability. RESULTS: Our findings showed highly reliable results for mean absolute difference (0.59 and 0.68 unit), relative error measurement (2.66% and 3.08%), technical error of measurement (0.59 and 0.66 unit), relative technical error of measurement (2.71% and 2.96%), and intraclass correlation coefficient (0.98) for intrarater 1 and intrarater 2 reliability; respectively 0.94 unit, 4.06%, 0.89 unit, and 3.94%, as well as 0.97 for interrater reliability; and respectively 0.98 unit, 4.66%, 0.96 unit, and 4.64%, as well as 0.96 for intramethod reliability. CONCLUSIONS: This imaging system and the landmark identification protocol are highly reliable. The collected measurements and their errors can be applied for the comparison of reliability among various 3D imaging systems and populations. It could be utilized for planning surgeries and evaluating treatment outcomes for physicians in ophthalmology, plastic and esthetic surgery, and in the maxillofacial field where periocular morphology alterations are made.

Cryolite glass prosthetic eyes-the response of the anophthalmic socket.

PURPOSE: To investigate mucoid discharge and the inflammatory response of anophthalmic sockets to cryolite glass prosthetic eye wear. PATIENTS AND METHODS: A total of 101 cryolite glass prosthetic eye wearers used visual analog scales (0-10) to measure frequency, color, volume, and viscosity of mucoid discharge associated with their prosthesis. Standardized photographs of the conjunctiva of their anophthalmic sockets were taken and conjunctival inflammation was semi-quantitatively graded (0-4). All characteristics of discharge and conjunctival inflammation were correlated to eye loss cause, hand washing behavior, and cleaning regimes as explanatory variables. RESULTS: Mean mucoid discharge characteristics (0-10 scale) were frequency 5.3 ± 2.8, color 4.8 ± 3.2, volume 4.9 ± 3.0, and viscosity 5.1 ± 3.2. The mean conjunctival inflammation score (0-4 scale) was 2.1 ± 1.0. There was a positive correlation between the grade of conjunctival inflammation and the frequency (p = 0.018), color (p = 0.001), volume (p = 0.003), and the viscosity of mucoid discharge (p = 0.005). More conjunctival inflammation was associated with higher frequency of cleaning (p < 0.001) and lower frequency of hand washing before removal (p = 0.001). Higher frequency, color, volume, and viscosity of discharge were associated with higher frequency of cleaning (p ≤ 0.001). CONCLUSIONS: Discharge severity associated with prosthetic eye wear was positively correlated with more conjunctival inflammation, higher cleaning frequency, and less hand washing before handling. The results suggest that cryolite glass eyes should not be removed daily for cleaning and that further research should be undertaken to develop a standardized treatment protocol for managing inflammation and mucoid discharge. This protocol would advise hand washing before handling cryolite glass eyes and recommend a minimum period of wear between cleaning sessions.

[Rehabilitation of Anophthalmic Patients with Prosthetic Eyes in Germany Today - Supply Possibilities, Daily Use, Complications and Psychological Aspects]. / Augenprothetische Rehabilitation in Deutschland heute ­ Versorgungsmöglichkeiten, Handhabung, Komplikationen und psychologische Aspekte.

BACKGROUND: A smooth supply with a visually appealing prosthetic eye after enucleation is not just a cosmetic solution, it is also a key factor in successful social and psychological rehabilitation. OBJECTIVES: This article provides an overview of the current state of medical and ocular care regarding prosthetic eyes in Germany. It focuses mainly on the newest clinical results, daily care, complications, and psychological aspects of wearing prosthetic eyes. METHODS: The study is comprised of the newest clinical results and a current PubMed literature review. RESULTS: In Germany, enucleated patients normally get a double-walled, hollow prosthetic eye made of cryolite glass, and patients with a microphthalmic or phthisic eye receive a thin single-walled prosthesis. Anophthalmic patients wearing cryolite glass prosthetic eyes seem to be more satisfied with their appearance and the look of their prostheses than polymethylmethacrylate (PMMA) prosthetic eye wearers. Cryolite glass prosthetic eyes must be renewed at least each year, while PMMA prostheses need to be polished once a year and renewed after five years of wearing. Among children, the fit of the prosthetic eye must be checked, based on growth, semi-annually. A slightly higher risk of breakage of cryolite glass prostheses is, for most patients, not a great disadvantage in everyday life. Ocularists and ophthalmologists should determine an individual cleaning regime, together with the patient, that is dependent on the material of the ocular prosthesis and other external factors. Complications, such as allergic, giant papillary, viral and bacterial conjunctivitis and blepharoconjunctivitis sicca must be treated at an early stage to allow for a prosthetic eye. In the case of inflammation-caused socket shrinkage or post-enucleation socket syndrome, surgical interventions are needed to re-enable the use of a prosthetic eye. Since the health of the remaining eye is the major psychological burden of prosthetic eye wearers, good ophthalmological care and medical screenings are essential elements. CONCLUSIONS: A smooth supply with a prosthetic eye, adequate and early treatment of possible complications and attention to psychological aspects is essential for successful long-term rehabilitation of enucleated patients.

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study.

Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.

Preexisting epiretinal membrane is associated with pseudophakic cystoid macular edema.

PURPOSE: The purpose of the present study was to evaluate whether preexisting epiretinal membrane (ERM) is a significant risk factor for developing pseudophakic cystoid macular edema (PCME). METHODS: Two hundred four consecutive eyes and 153 consecutive eyes without preexisting epiretinal membranes were retrospectively compared regarding PCME development following phacoemulsification with posterior chamber lens implantation. Patients with vascular retinal diseases, uveitis, trauma, neovascular macular degeneration, chronic inflammatory conditions, diabetic retinopathy, endophthalmitis, eventful cataract surgery, and combination of cataract surgery and vitrectomy during the observation period were excluded. Macular examination was performed using spectral-domain optical coherence tomography (SD-OCT) before as well as at 4, 8, 12, 16, 24, and 36 weeks after cataract surgery. Univariate and multivariate logistic regression analyses were calculated. RESULTS: PCME occurred in 32 of 204 eyes with preexisting ERM (15.7%), whereas 9 of 153 eyes without preexisting ERM (5.9%) developed PCME. The risk of PCME was significantly increased in eyes with ERM (p = 0.007). By multivariate logistic regression analysis, factors predictive of PCME included the history of previous pars plana vitrectomy for retinal detachment (odds ratio (OR) 3.619 [95% confidence interval (CI) 1.242 to 10.258]; p = 0.016) as well as the preexistence of ERM (OR 3.885 [95% CI 1.162 to 17.762]; p = 0.04). CONCLUSION: Preexisting ERM seems to be associated with an increased risk of PCME following cataract surgery. Therefore, this risk should be considered in surgery planning, preoperative medication, and follow-up care after surgery.

Concerns of anophthalmic patients-a comparison between cryolite glass and polymethyl methacrylate prosthetic eye wearers.

PURPOSE: To compare the concerns of experienced cryolite glass and (poly)methyl methacrylate (PMMA) prosthetic eye wearers. METHODS: One hundred six experienced cryolite glass and 63 experienced PMMA prosthetic eye wearers completed an anonymous questionnaire regarding general and specific prosthetic eye concerns at least 2 years after natural eye loss. From these independent anophthalmic populations, we identified 34 case-control pairs matched for the known influencing demographic variables of gender, occupation, age, and time since natural eye loss. RESULTS: The levels of concern were significantly lower in the cryolite glass group than those in the PMMA group for the following: loss of balance (p < 0.001), phantom sight vision (p < 0.001), pain (p < 0.001), receiving good advice (p = 0.001), fullness of orbit (p = 0.001), size (p = 0.007), direction of gaze relative to the healthy fellow eye (p = 0.005), eye lid contour (p = 0.037), comfort of the prosthetic eye (p < 0.001), colour relative to the healthy fellow eye (p < 0.001), and retention of the prosthetic eye (p < 0.001). Concerns about watering, crusting, discharge, visual perception, appearance, movement of the prosthetic eye, and health of the remaining eye were not significantly different between both groups. CONCLUSIONS: The results of this study showed that many general and specific levels of concern were significantly lower for cryolite glass prosthetic eye wearers than for PMMA prosthetic eye wearers. The question of why there are significant differences and to what extent the material of the prosthesis (cryolite glass or PMMA) has an impact on various concerns remains unanswered and should be addressed in a prospective comparative multicentre trial.

Concerns of Anophthalmic Patients Wearing Cryolite Glass Prosthetic Eyes.

PURPOSE: To identify the main concerns of patients experienced in wearing cryolite glass prosthetic eyes and to investigate how these have changed over time. METHODS: One hundred six patients experienced in wearing prosthetic eyes for at least 2 years were asked to complete an anonymous questionnaire regarding prosthetic eye concerns at the time of initial eye loss and at the present time. Main outcome measures included changes in levels of concern over time. RESULTS: Initially, the participants were mainly concerned about their appearance, health of the fellow eye, and coping with monocularity. Over time, there was a significant increase of the level of concern regarding the health of the remaining eye (p < 0.001) and regarding watering, crusting, and discharge (p < 0.001). Loss of balance did not change significantly (p = 0.302). All other concerns decreased significantly over time (p < 0.001), with levels of concern about appearance decreasing the most. The current leading concern was the health of the remaining eye followed by concerns about watering, crusting, and discharge. Length of time since natural eye loss was the most important explanatory variable, with significant impact on the concerns about appearance (p = 0.013), retention of the prosthetic eye (p = 0.002), and eyelid contour (p = 0.004). CONCLUSIONS: Health of the remaining eye is the most common current concern of anophthalmic patients, acknowledging the need of good ophthalmologic follow up after losing an eye. The second most important concern is with watering, crusting, and discharge, suggesting further research for establishing an evidence-based protocol for cryolite glass prosthetic eye maintenance and supportive treatment.

[Physiotherapy Education in Germany: Ready for Direct Access?] / Ausbildung von Physiotherapeutinnen und Physiotherapeuten in Deutschland: Bereit für den Direktzugang?

Objective: The aim of this study is to investigate whether the curricula for physiotherapy education in Germany conform to standards recommended in the World Confederation for Physical Therapy (WCPT) guideline for physical therapist professional entry-level education, published by the WCPT. This Guideline specifies education standards for physical therapists that are able to act as independent practitioners, without referral from another health care professional. Methods: To assess the German curricula of physical therapist education, a list of assessment dimensions was derived from the WCPT-Guideline by means of content analysis. The content validity of this list was estimated by nine experts using Lawshe's method. The German Training and Examination Regulations for Physiotherapists (PhysTh-AprV) and all available regional curricula were studied. All documents were evaluated by 2 independent coders who rated the conformity of the documents with the assessment dimensions. Results: Based on the Lawshe procedure, the whole test content validity index of the 61 out of 67 examined assessment dimensions was 0,84. Cohen's kappa coefficient for intercoder reliability was 0,71-0,97. The German curricula showed high correlation with the WCPT Guideline on many theoretical basic subjects. Fulfillment of some of the requirements showed heterogeneous results. Autonomous practitioners largely lacked special competencies. Conclusions: None of the German educational standards meets the expectations of the WCPT Guideline in terms of direct access. Considering the deficits of the German educational standards and the release date of some of them, a continuous development of the German education does not appear to be adequate. This issue needs to be addressed in the current debate on health policy.

[Diagnosis and Therapy of Iris Lesions]. / Diagnostik und Therapie von Irisläsionen.

The most common iris lesions are iris nevi, iris melanomas and iris pigment epithelium cysts. However, there is an abundance of rare differential diagnoses that have to be considered, including other melanocytic and non-melanocytic lesions. Diagnostic tools include the slit lamp examination, gonioscopy, tonometry, transillumination, ultrasound biomicroscopy (UBM), optical coherence tomography, fluorescein angiography and standardized photography-assisted documentation. The timely identification of malignant lesions (i.e. iris melanoma) is paramount. To assess malignancy criteria of iris nevi, the ABCDEF rule (age young, blood, clock hour inferior, diffuse growth, ektropion uveae, feathery margins) can be applied. Statistically, up to 11% of iris nevi may develop into iris melanomas within 20 years. TNM Staging follows the 2010 AJCC cancer staging manual and helps determine the optimal treatment strategy. Treatment options include radiotherapy, such as plaque brachytherapy and proton beam radiation therapy, as well as surgical excision. Both the surgical and the radiotherapeutic approaches show comparable local tumor control rates. However, the spectrum of therapy-related side effects and complications may differ amongst treatment modalities. After initial treatment, patients should be followed up every 3 - 6 months. Tumor-related mortality ranges between 0 - 11% and is significantly lower than in other uveal melanomas. A prognostic value of common genetic alterations, which have been identified as significant prognostic factors in posterior uveal melanoma, could not be shown for iris melanoma.

[Minimally invasive Therapy of lacrimal Drainage System Stenosis]. / Minimalinvasive Therapie von Tränenwegstenosen.

Epiphora is one of the most common symptoms for clinical ophthalmological consultation. This symptom is mostly caused by stenosis of the lacrimal drainage system. Over a century, external dacryocystostomy according to Toti was the treatment of choice. Today, new very encouraging minimally invasive techniques for recanalisation of the lacrimal drainage system, such as microdrilldacryoplasty or laserdacryoplasty, as well as bypass-based techniques, such as transcanalicular laser-assisted dacryocystorhinostomy, become more important in the treatment of dacryostenosis.

Templated Synthesis of Uniform Perovskite Nanowire Arrays.

While the chemical composition of semiconducting metal halide perovskites can be precisely controlled in thin films for photovoltaic devices, the synthesis of perovskite nanostructures with tunable dimensions and composition has not been realized. Here, we describe the templated synthesis of uniform perovskite nanowires with controlled diameter (50-200 nm). Importantly, by providing three examples (CH3NH3PbI3, CH3NH3PbBr3, and Cs2SnI6), we show that this process is composition general and results in oriented nanowire arrays on transparent conductive substrates.

Transgenic mice for real-time visualization of cGMP in intact adult cardiomyocytes.

RATIONALE: 3',5'-Cyclic guanosine monophosphate (cGMP) is an important second messenger that regulates cardiac contractility and protects the heart from hypertrophy. However, because of the lack of real-time imaging techniques, specific subcellular mechanisms and spatiotemporal dynamics of cGMP in adult cardiomyocytes are not well understood. OBJECTIVE: Our aim was to generate and characterize a novel cGMP sensor model to measure cGMP with nanomolar sensitivity in adult cardiomyocytes. METHODS AND RESULTS: We generated transgenic mice with cardiomyocyte-specific expression of the highly sensitive cytosolic Förster resonance energy transfer-based cGMP biosensor red cGES-DE5 and performed the first Förster resonance energy transfer measurements of cGMP in intact adult mouse ventricular myocytes. We found very low (≈10 nmol/L) basal cytosolic cGMP levels, which can be markedly increased by natriuretic peptides (C-type natriuretic peptide >> atrial natriuretic peptide) and, to a much smaller extent, by the direct stimulation of soluble guanylyl cyclase. Constitutive activity of this cyclase contributes to basal cGMP production, which is balanced by the activity of clinically established phosphodiesterase (PDE) families. The PDE3 inhibitor, cilostamide, showed especially strong cGMP responses. In a mild model of cardiac hypertrophy after transverse aortic constriction, PDE3 effects were not affected, whereas the contribution of PDE5 was increased. In addition, after natriuretic peptide stimulation, PDE3 was also involved in cGMP/cAMP crosstalk. CONCLUSIONS: The new sensor model allows visualization of real-time cGMP dynamics and pharmacology in intact adult cardiomyocytes. Förster resonance energy transfer imaging suggests the importance of well-established and potentially novel PDE-dependent mechanisms that regulate cGMP under physiological and pathophysiological conditions.

Low incidence of anti-drug antibodies in patients with type 2 diabetes treated with once-weekly glucagon-like peptide-1 receptor agonist dulaglutide.

Therapeutic administration of peptides may result in anti-drug antibody (ADA) formation, hypersensitivity adverse events (AEs) and reduced efficacy. As a large peptide, the immunogenicity of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide is of considerable interest. The present study assessed the incidence of treatment-emergent dulaglutide ADAs, hypersensitivity AEs, injection site reactions (ISRs), and glycaemic control in ADA-positive patients in nine phase II and phase III trials (dulaglutide, N = 4006; exenatide, N = 276; non-GLP-1 comparators, N = 1141). Treatment-emergent dulaglutide ADAs were detected using a solid-phase extraction acid dissociation binding assay. Neutralizing ADAs were detected using a cell-based assay derived from human endothelial kidney cells (HEK293). A total of 64 dulaglutide-treated patients (1.6% of the population) tested ADA-positive versus eight (0.7%) from the non-GLP-1 comparator group. Of these 64 patients, 34 (0.9%) had dulaglutide-neutralizing ADAs, 36 (0.9%) had native-sequence GLP-1 (nsGLP-1) cross-reactive ADAs and four (0.1%) had nsGLP-1 neutralization ADAs. The incidence of hypersensitivity AEs and ISRs was similar in the dulaglutide versus placebo groups. No dulaglutide ADA-positive patient reported hypersensitivity AEs. Because of the low incidence of ADAs, it was not possible to establish their effect on glycaemic control.

Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

AIMS: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). METHODS: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. RESULTS: No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes. CONCLUSIONS: LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes.

A case of pharyngeal diphtheria in Germany, June 2015.

BACKGROUND: In June 2015, a 45-year-old man suffering from acute necrotic tonsillitis and throat phlegmon was hospitalized in Nuremberg, Germany. After emergency surgery the patient was initially treated with antibiotics. RESULTS: A throat swab grew a toxigenic Corynebacterium diphtheriae biovar mitis strain. The patient's vaccination status was not documented and the patient was tested serologically for anti-diphtheria antibodies showing no protective immunity. Extensive control investigations were performed by the local health department showing no likely source of his infection. CONCLUSION: No secondary cases were found and the patient completely recovered.