Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome.

Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1-3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.

Prospects for mTOR-mediated functional repair after central nervous system trauma.

Recent research has suggested that the growth of central nervous system (CNS) axons during development is mediated through the PI3K/Akt/mammalian target of rapamycin (mTOR) intracellular signalling axis and that suppression of activity in this pathway occurs during maturity as levels of the phosphatase and tensin homologue (PTEN) rise and inhibit PI3K activation of mTOR, accounting for the failure of axon regeneration in the injured adult CNS. This hypothesis is supported by findings confirming that suppression of PTEN in experimental adult animals promotes impressive axon regeneration in the injured visual and corticospinal motor systems. This review focuses on these recent developments, discussing the therapeutic potential of a mTOR-based treatment aimed at promoting functional recovery in CNS trauma patients, recognising that to fulfil this ambition, the new therapy should aim to promote not only axon regeneration but also remyelination of regenerated axons, neuronal survival and re-innervation of denervated targets through accurate axonal guidance and synaptogenesis, all with minimal adverse effects. The translational challenges presented by the implementation of this new axogenic therapy are also discussed.

Insights into the structure and function of ciliary and flagellar doublet microtubules: tektins, Ca2+-binding proteins, and stable protofilaments.

Cilia and flagella are conserved, motile, and sensory cell organelles involved in signal transduction and human disease. Their scaffold consists of a 9-fold array of remarkably stable doublet microtubules (DMTs), along which motor proteins transmit force for ciliary motility and intraflagellar transport. DMTs possess Ribbons of three to four hyper-stable protofilaments whose location, organization, and specialized functions have been elusive. We performed a comprehensive analysis of the distribution and structural arrangements of Ribbon proteins from sea urchin sperm flagella, using quantitative immunobiochemistry, proteomics, immuno-cryo-electron microscopy, and tomography. Isolated Ribbons contain acetylated α-tubulin, ß-tubulin, conserved protein Rib45, >95% of the axonemal tektins, and >95% of the calcium-binding proteins, Rib74 and Rib85.5, whose human homologues are related to the cause of juvenile myoclonic epilepsy. DMTs contain only one type of Ribbon, corresponding to protofilaments A11-12-13-1 of the A-tubule. Rib74 and Rib85.5 are associated with the Ribbon in the lumen of the A-tubule. Ribbons contain a single ∼5-nm wide filament, composed of equimolar tektins A, B, and C, which interact with the nexin-dynein regulatory complex. A summary of findings is presented, and the functions of Ribbon proteins are discussed in terms of the assembly and stability of DMTs, ciliary motility, and other microtubule systems.

Dual modifications strategy to quantify neutral and sialylated N-glycans simultaneously by MALDI-MS.

Differences in ionization efficiency among neutral and sialylated glycans prevent direct quantitative comparison by their respective mass spectrometric signals. To overcome this challenge, we developed an integrated chemical strategy, Dual Reactions for Analytical Glycomics (DRAG), to quantitatively compare neutral and sialylated glycans simultaneously by MALDI-MS. Initially, two glycan samples to be compared undergo reductive amination with 2-aminobenzoic acid and 2-(13)[C6]-aminobenzoic acid, respectively. The different isotope-incorporated glycans are then combined and subjected to the methylamidation of the sialic acid residues in one mixture, homogenizing the ionization responses for all neutral and sialylated glycans. By this approach, the expression change of relevant glycans between two samples is proportional to the ratios of doublet signals with a static 6 Da mass difference in MALDI-MS and the change in relative abundance of any glycan within samples can also be determined. The strategy was chemically validated using well-characterized N-glycans from bovine fetuin and IgG from human serum. By comparing the N-glycomes from a first morning (AM) versus an afternoon (PM) urine sample obtained from a single donor, we further demonstrated the ability of DRAG strategy to measure subtle quantitative differences in numerous urinary N-glycans.

Colorectal cancer risk information presented by a nonphysician assistant does not increase screening rates.

OBJECTIVE: To determine the effectiveness of presenting individualized colorectal cancer (CRC) risk information for increasing CRC screening rates in primary care patients at above-average risk of CRC. DESIGN: Randomized controlled trial. SETTING: Georgia Regents University in Augusta-an academic family medicine clinic in the southeastern United States. PARTICIPANTS: Outpatients (50 to 70 years of age) scheduled for routine visits in the family medicine clinic who were determined to be at above-average risk of CRC. INTERVENTIONS: Individualized CRC risk information calculated from the Your Disease Risk tool compared with a standard CRC screening handout. MAIN OUTCOME MEASURES: Intention to complete CRC screening. Secondary measures included the proportions of subjects completing fecal occult blood tests, flexible sigmoidoscopy, and colonoscopy. RESULTS: A total of 1147 consecutive records were reviewed to determine eligibility. Overall, 210 (37.7%) of 557 eligible participants were randomized to receive either individualized CRC risk information (prepared by a research assistant) or a standard CRC screening handout. The intervention group had a mean (SD) age of 55.7 (4.8) years and the control group had a mean (SD) age of 55.6 (4.6) years. Two-thirds of the participants in each group were female. The intervention group and the control group were matched by race (P = .40). There was no significant difference between groups for intention to complete CRC screening (P = .58). Overall, 26.7% of the intervention participants and 27.7% of the control participants completed 1 or more CRC screening tests (P = .66). CONCLUSION: Presentation of individualized CRC risk information by a nonphysician assistant as a decision aid did not result in higher CRC screening rates in primary care patients compared with presentation of general CRC screening information. Future research is needed to determine if physician presentation of CRC risk information would result in increased screening rates compared with research assistant presentation.

Real-world service costs for neovascular-AMD clinics in the United Kingdom: structured literature review and scenario analysis.

OBJECTIVE: Current cost-effectiveness analyses (CEA) emphasize drug costs as the differentiator between NICE recommended anti-VEGF treatments but may neglect real-world non-drug costs of running nAMD services in the UK. To address this, this study identified real-world non-drug service cost items relevant to UK NHS nAMD clinics, including costs arising from operational strain (demand exceeding capacity). METHODS: Cost items were identified by a structured literature review of peer-reviewed and grey literature, and an expert panel of 10 UK-based ophthalmologists with relevance to real-world practice. These items underwent meta-synthesis and were then determined in a consensus exercise. RESULTS: Of 237 cost items identified, 217 (91.6%) met the consensus threshold of >0.51 and were included in the nAMD Service Non-Drug Cost Instrument (nAS). Sensitivity of cost items taken from UK Health Technology Assessment (HTA) using the nAS as the reference standard was low (HTAmin: 1.84%, 95% CI 0.50-4.65%; HTAmax: 70.51%, 95% CI 63.96-76.49%). False negative rates showed variable likelihood of misclassifying a service by cost burden depending on prevalence. Scenario analysis using cost magnitudes estimated annual per-patient clinic cost at £845 (within capacity) to £13,960 (under strain) compared to an HTAmin estimate of £210. Accounting for cost of strain under an assumed 50% increase in health resource utilization influenced cost-effectiveness in a hypothetical genericisation scenario. CONCLUSION: Findings suggested that HTA underestimates UK NHS nAMD clinic cost burden with cost of strain contributing substantial additional unmeasured expense with impact on CEA. Given potential undertreatment due to strain, durability is suggested as one of the relevant factors in CEA of nAMD anti-VEGF treatments due to robustness under limited capacity conditions affecting UK ophthalmology services.

When considering how well treatments work versus how much they cost, the focus is usually only on the price of the medicine itself. However, other real-world costs exist. In the UK, when treating certain eye problems such as neovascular age-related macular degeneration (nAMD), there are additional expenses related to running clinics and managing treatments that often go unnoticed. To get a better understanding of these hidden costs, the study examined factors like clinic workload and the extra expenses that come with it. Ten eye doctors in the UK were consulted for their expert opinions and numerous research papers were reviewed to identify these additional costs. The study grouped different costs in a tool called the nAMD Service Non-Drug Cost Instrument (nAS). When the findings of the nAS tool were compared to the usual methods of calculating costs, it was found that the conventional approach overlooked many of the actual expenses. Busy clinics face unique challenges, such as higher operational costs associated with staffing for extended hours, emergency appointments, extended waiting times and the potential to miss optimal treatment windows. This can lead to disease progression and the onset of comorbidities, which require more complex and costly treatments. Recognizing these real costs is crucial when making decisions about treatments, especially when treatments require more frequent visits to eye clinics. This study emphasizes the importance of considering all expenses, not just the obvious ones like medication and doctor visits when determining the most effective way to manage eye conditions like nAMD in the UK.

Visual function and quality of life in patients who had undergone eye removal surgery: a patient survey.

PURPOSE: To measure aspects of self-reported vision-related health status and assess the impact of treatment in patients who have undergone eye removal surgery (evisceration or enucleation), using a patient administered questionnaire. METHODS: In this non-randomised, questionnaire-based cohort study, patients were identified from the Artificial Eye Service referral register from 2003 to 2010. A self-administered questionnaire based upon previously published scales was completed to measure aspects of visual function and the impact of treatment. RESULTS: Thirty-six completed questionnaires were obtained. Mean age at surgery was 54.1 years (range 13-90), with 83% male. Indication for eye-removal was trauma in 14(39%) cases. Ten (28%) had ocular co-morbidity in the fellow-eye. The main reported difficulties were with peripheral vision or distance judgements, in 64% patients. The majority of drivers (66%) had maintained the ability to drive. Self-consciousness was reported in 28(78%) patients, and 56% were able to continue work or activities with no perceived limitations. Overall comfort and aesthetic improvement were noted by the majority. Procedure-specific information leaflets for patients were appreciated. CONCLUSIONS: This survey increases our knowledge of aspects of vision-related health status following ocular pathology or trauma that requires eye removal, and may enable improved pre-operative patient counselling. Effects on peripheral vision may be noted most significantly, but the majority can continue normal activities with little difficulty. Overall improvement in comfort and appearance occurs in most patients, although feelings of self-consciousness are common.

Reported Rates of Intraocular Inflammation with Intravitreal Aflibercept Administered via Pre-Filled Syringe or from Vials in Clinical Practice Between 2012 and 2022.

Purpose: To determine the reported rates of intraocular inflammation (IOI) in patients treated with intravitreal aflibercept (IVT-AFL) 2 mg in routine clinical practice (ie, outside interventional studies), across all indications and within all countries (excluding the United States), with access to either the vial presentation or pre-filled syringe (PFS). Patients and methods: A search was conducted using the Bayer EYLEA® Global Safety Pharmacovigilance Database for reported cases of IOI and IVT-AFL use between October 2012 and March 31, 2022. Results: With more than 10 years of post-marketing experience with the IVT-AFL vial presentation (>25 million sold units), and over 2 years of experience with the PFS of IVT-AFL (>6.7 million sold units) the rate of any IOI, including endophthalmitis, outside the United States was 0.3 events per 10,000 units for the PFS and 1.2 events per 10,000 units for the vial presentation. The event rates specifically for endophthalmitis were 0.1 per 10,000 units for the IVT-AFL PFS and 0.6 per 10,000 units for the IVT-AFL vial presentation. Conclusion: In patients with retinal diseases treated in routine clinical practice with IVT-AFL either from a vial or the PFS, medically important adverse events of IOI, and in particular, endophthalmitis, are infrequently reported events. Numerically, reported rates of IOI and endophthalmitis are low for the vial presentation and even lower for the PFS.

Interferon Gamma-Inducible NAMPT in Melanoma Cells Serves as a Mechanism of Resistance to Enhance Tumor Growth.

(1) Background: Immune cells infiltrate the tumor microenvironment and secrete inflammatory cytokines, including interferons (IFNs), to drive antitumor responses and promote tumor clearance. However, recent evidence suggests that sometimes, tumor cells can also harness IFNs to enhance growth and survival. The essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and elevated NAMPT expression. We hypothesized that interferon gamma (IFNγ) regulates NAMPT in tumor cells as a mechanism of resistance that impedes the normal anti-tumorigenic effects of IFNγ. (2) Methods: Utilizing a variety of melanoma cells, mouse models, Crispr-Cas9, and molecular biology techniques, we explored the importance of IFNγ-inducible NAMPT during melanoma growth. (3) Results: We demonstrated that IFNγ mediates the metabolic reprogramming of melanoma cells by inducing Nampt through a Stat1 binding site in the Nampt gene, increasing cell proliferation and survival. Further, IFN/STAT1-inducible Nampt promotes melanoma in vivo. (4) Conclusions: We provided evidence that melanoma cells directly respond to IFNγ by increasing NAMPT levels, improving their fitness and growth in vivo (control n = 36, SBS KO n = 46). This discovery unveils a possible therapeutic target that may improve the efficacy of immunotherapies involving IFN responses in the clinic.

Evaluation of standard-of-care intravitreal aflibercept treatment practices in patients with diabetic macular oedema in the UK: DRAKO study outcomes.

BACKGROUND/OBJECTIVES: DRAKO (NCT02850263) was a 24-month, prospective, non-interventional, multi-centre cohort study enrolling patients with diabetic macular oedema (DMO) including central involvement. The study evaluated UK standard-of-care intravitreal aflibercept (IVT-AFL) treatment. This analysis describes the treatment pathway and service provision for the anti-vascular endothelial growth factor (VEGF) treatment-naïve (C1) and non-naïve patients (C2) who received prior anti-VEGF treatment for DMO other than IVT-AFL. METHODS: Mean changes in best-corrected visual acuity and central subfield thickness were measured and stratified by baseline factors, including ethnicity and administration of five initial monthly injections within predefined windows. Clinic visits were classified as treatment only (T1), monitoring assessment only (T2), combined visits (T3) or post-injection visits with no treatment or assessment (T4). RESULTS: Median time from decision to treat to treatment was 6 days. As a percentage of total visits, T1, T2, T3 and T4 were 7%, 42%, 48% and 3% for C1 and 11%, 39%, 48% and 2% for C2. Most IVT-AFL injections were administered by healthcare professionals (HCPs) other than doctors (C1, 57.4%; C2, 58.5%). The percentage of treatments associated with a procedure-related adverse event where at least 75% of injections were completed by the same injector role were similar for doctors and other HCPs (C1, 1.1% and 0.8%; C2, 0.7%, and 1.0%). CONCLUSIONS: Results indicate that upon DMO diagnosis, patients were treated promptly, and most visits were combined (treatment and assessment) or monitoring only. Most IVT-AFL was administered by non-physicians with a similar treatment-related safety profile as IVT-AFL administered by physicians.

Practical implementation of a q4-q16 aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration: Updated guidance from a UK expert panel.

OBJECTIVES: This report, based on guidance from a panel of UK retina specialists, introduces a revised intravitreal aflibercept (IVT-AFL) treat-and-extend (T&E) pathway for the treatment of neovascular age-related macular degeneration (nAMD). The T&E pathway incorporates the updated IVT-AFL label (April 2021) allowing flexible treatment intervals of 4 weeks to 16 weeks, after three initiation doses and a further dose after 8 weeks. Practical guidance is provided on the clinical implementation of the revised pathway, with the aim of supporting clinical decision-making to benefit patients and addressing capacity issues in nAMD services. METHODS: Three structured round-table meetings of UK retina specialists were held online on 19 May, 16 June and 13 October 2021. These meetings were organised and funded by Bayer. RESULTS: The authors revised the previously published consensus pathway to reflect the changes to the IVT-AFL label and developed guidelines for the implementation of the pathway in UK clinical practice. The guidelines include topics such as recommendations for extending patients with 2- or 4-week adjustments, extending patients to 16-week treatment intervals, managing fellow eye involvement, and reducing treatment intervals for patients with particularly active disease. CONCLUSIONS: The revised IVT-AFL T&E nAMD pathway offers guidance to clinicians seeking to increase the dosing flexibility of IVT-AFL, with 4- to 16-week treatment intervals, in line with the updated IVT-AFL label, to meet the continually evolving demands of nAMD service provision.

Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma.

Medulloblastomas are the most common malignant brain tumors in children. Several large-scale genomic studies have detailed their heterogeneity, defining multiple subtypes with unique molecular profiles and clinical behavior. Increased expression of the miR-183~96~182 cluster of microRNAs has been noted in several subgroups, including the most clinically aggressive subgroup associated with genetic amplification of MYC. To understand the contribution of miR-183~96~182 to the pathogenesis of this aggressive subtype of medulloblastoma, we analyzed global gene expression and proteomic changes that occur upon modulation of miRNAs in this cluster individually and as a group in MYC-amplified medulloblastoma cells. Knockdown of the full miR-183~96~182 cluster results in enrichment of genes associated with apoptosis and dysregulation of the PI3K/AKT/mTOR signaling axis. Conversely, there is a relative enrichment of pathways associated with migration, metastasis and epithelial to mesenchymal transition, as well as pathways associated with dysfunction of DNA repair in cells with preserved miR-183 cluster expression. Immunocytochemistry and FACS analysis confirm induction of apoptosis upon knockdown of the miR-183 cluster. Importantly, cell-based migration and invasion assays verify the positive regulation of cell motility/migration by the miR-183 cluster, which is largely mediated by miR-182. We show that the effects on cell migration induced by the miR-183 cluster are coupled to the PI3K/AKT/mTOR pathway through differential regulation of AKT1 and AKT2 isoforms. Furthermore, we show that rapamycin inhibits cell motility/migration in medulloblastoma cells and phenocopies miR-183 cluster knockdown. Thus, the miR-183 cluster regulates multiple biological programs that converge to support the maintenance and metastatic potential of medulloblastoma.

Lacrimal duct cyst (dacryops) following ocular chemical injury.

A 37-year-old man presented with swelling under the lateral aspect of the right upper eyelid. He had sustained an alkali ocular chemical injury 10 years before resulting in persistent lateral canthal webbing. Diagnosis was made of lacrimal duct cyst (dacryops) and webbing of the lateral canthus and the findings were confirmed on computed tomography. He underwent lacrimal duct cyst marsupialisation and lateral canthoplasty with good cosmetic result, and there was no recurrence of symptoms at 2 months post-operatively. Lacrimal duct cyst is a rare clinical entity and has been postulated to result from localized inflammation or trauma to conjunctiva. To the best of our knowledge, this is the first report of dacryops following a chemical injury.

Distinguishing among nondirect forms of aggression.

This study explored the relationships and differences among two measures of indirect aggression [Bjorkqvist et al., 1994; Richardson and Green, 1997] and one of relational aggression [Crick and Grotpeter, 1995]. Over 300 students (mean age 22.8 years; 61.5% female) from two colleges in the Southeastern United States completed measures of indirect and relational aggression and related constructs (e.g., empathy, anger expression, direct aggression). Although there were subtle differences among the three measures with regard to their relationships with associated variables, overall the patterns of relationships were similar as well as distinct from the pattern for direct aggression. Factor analysis of scores for measures of aggression revealed that the indirect and relational measures composed a single factor of nondirect aggression, separate from direct aggression. Further factor analysis of all unique items from the nondirect scales found the overall construct of nondirect aggression to comprise six distinct factors. Implications for applications and further research are discussed.

Suicide Attempts in US Veterans with Chronic Headache Disorders: A 10-Year Retrospective Cohort Study.

OBJECTIVES: A large-scale retrospective analysis of veterans with chronic pain was conducted to examine (1) the annual incidence of suicide attempts (SA) in veterans with chronic headache and other chronic pain conditions, and (2) the risk of SA in men and women with chronic headache and chronic headache concurrent with traumatic brain injury (TBI) as compared to non-headache chronic pain. METHODS: This retrospective study (N=3,247,621) analyzed National Veterans Affair Health Administrative data of patients diagnosed with chronic head, neck, back and other chronic pain from 2000 to 2010. Multivariable Poisson regression was used to explore the relative risks of SA in veterans with chronic headache and chronic headache concurrent with TBI as stratified by sex. RESULTS: Veterans with chronic headaches had the highest annual incidence of SA (329 to 491 per 100,000) each year among all identified types of chronic pain conditions. Compared to other non-headache chronic pain, chronic headache is associated with increased risk of SA [men RR (1.48), CI (1.37,1.59); women RR (1.64), CI (1.28,2.09)], after adjusting for demographic factors, TBI, and psychiatric comorbidities. The risk increased further when chronic headache is comorbid with TBI [men RR (2.82), CI (2.60, 3.05); women RR (2.16, CI (1.67-2.78)]. CONCLUSION: Veterans with chronic headache have a higher risk of SA than those with other chronic pain and women with chronic headache are at a higher risk than men with chronic headache. Chronic headache concurrent with TBI further heightened this risk, especially in men. Our data underscore the importance of identifying specific types of chronic pain in veterans with comorbid TBI and sex disparity associated with SA when targeting suicide prevention measures.

Integrating titania enrichment, iTRAQ labeling, and Orbitrap CID-HCD for global identification and quantitative analysis of phosphopeptides.

Recent advances in MS instrumentation and progresses in phosphopeptide enrichment, in conjunction with more powerful data analysis tools, have facilitated unbiased characterization of thousands of site-specific phosphorylation events. Combined with stable isotope labeling by amino acids in cell culture metabolic labeling, these techniques have made it possible to quantitatively evaluate phosphorylation changes in various physiological states in stable cell lines. However, quantitative phosphoproteomics in primary cells and tissues remains a major technical challenge due to the lack of adequate techniques for accurate quantification. Here, we describe an integrated strategy allowing for large scale quantitative profiling of phosphopeptides in complex biological mixtures. In this technique, the mixture of proteolytic peptides was subjected to phosphopeptide enrichment using a titania affinity column, and the purified phosphopeptides were subsequently labeled with iTRAQ reagents. After further fractionation by strong-cation exchange, the peptides were analyzed by LC-MS/MS on an Orbitrap mass spectrometer, which collects CID and high-energy collisional dissociation (HCD) spectra sequentially for peptide identification and quantitation. We demonstrate that direct phosphopeptide enrichment of protein digests by titania affinity chromatography substantially improves the efficiency and reproducibility of phosphopeptide proteomic analysis and is compatible with downstream iTRAQ labeling. Conditions were optimized for HCD normalized collision energy to balance the overall peptide identification and quantitation using the relative abundances of iTRAQ reporter ions. Using this approach, we were able to identify 3557 distinct phosphopeptides from HeLa cell lysates, of which 2709 were also quantified from HCD scans.

Ophthalmic medicine regulatory approvals through the European Centralised Procedure, 1999-2017: Clinical efficacy considerations.

OBJECTIVES: Regulatory approval of new medicines requires a thorough assessment of the potential clinical benefits and risks. Study end-points are expected to demonstrate a clinically relevant treatment effect that will translate into direct patient benefits. This study sought to review the ophthalmic medicines with European Union-wide approval granted via the Centralised Procedure and characterise the key efficacy end-points underpinning the demonstration of clinical benefit. METHODS: This study was a retrospective review of published data pertaining to the European regulatory authorisation of centrally approved ophthalmic products between 1999 and 2017, inclusive. All sources and data consulted are in the public domain. European Public Assessment Reports published by the European Medicines Agency were consulted for data concerning the pivotal clinical efficacy studies supporting the applications. Data analyses were descriptive. RESULTS: The European Medicines Agency have authorised 30 products via the Centralised Procedure between 1999 and 2017. For these products, a total of 24 additional approvals for line extensions or additional therapeutic indications were granted. Four products have been approved for orphan indications, including one approval 'under exceptional circumstances' and one 'Conditional Marketing Authorisation'. Approvals for products in retina (36%) and glaucoma (28%) indications together accounted for the majority of authorisations, with trial end-points predominantly based on visual acuity and intraocular pressure parameters, respectively. Products were also approved for indications in ocular surface disease, inflammation, optic neuropathy and surgical adjuncts, with a range of functional and anatomical end-points. CONCLUSION: Approvals for ophthalmic medicines have been granted for a range of clinical indications, representing a considerable portion of available major therapeutics for practitioners. Benefit-risk assessments rely on clinical trial data demonstrating a clearly relevant patient benefit.

Trends in licence approvals for ophthalmic medicines in the United Kingdom.

OBJECTIVES: The grant of marketing authorisation (MA) for new medicines requires comprehensive assessment by regulatory authorities. This study sought to identify ophthalmic medicines granted United Kingdom MA and consider trends in licence approvals. METHODS: This retrospective study reviewed published lists of products granted MA by the UK Medicines & Healthcare products Regulatory Agency between January 2001 and December 2018, inclusive. Eye drops and medicinal products intended for ophthalmic use were identified. All regulatory data sources consulted are in the public domain. Data analyses were descriptive. RESULTS: A total of 295 MAs were issued for ophthalmic products between 2001 and 2018, inclusive. Of these 229 (78%) were for single-active substances and 66 (22%) fixed-dose combination (FDC). Approvals for products with single-active substance included ocular hypotensives (115; 50%), antibiotics (48; 22%), allergy medicines (30; 13%), lubricants (18; 8%) and anti-inflammatories (11; 5%). Approvals for FDCs were predominantly ocular hypotensives (56; 85%), with timolol combined with carbonic anhydrase inhibitors (27; 48%) and prostaglandin analogues (26; 46%) accounting for the majority of glaucoma FDCs. Other FDCs were approved for antibiotic/inflammatory (5; 7.5%), pupillary mydriasis (2; 3%), allergy (2; 3%) and ocular surface lubrication (1; 1.5%) products. A median of 16 licences were approved per year (range 7 [2005] to 35 [2011]). CONCLUSIONS: The majority of MAs granted were for single-agent products, particularly ocular hypotensives and antibiotic preparations. Most products were generic versions of well-established active substances. A trend for increased approvals for FDCs is evident, particularly for the treatment of raised IOP.

Why a medical career and what makes a good doctor? Beliefs of incoming United States medical students.

INTRODUCTION: Beginning medical students' beliefs about the medical profession have been well studied internationally but have only been minimally studied in the United States (U.S.) recently. Up-to-date research on U.S. medical students' beliefs is warranted so educators can employ these predispositions as a baseline for curriculum and student professional development. METHODS: We conducted focus groups with a first-year class (n=189) of U.S. medical students at the beginning of their academic year. In an iterative theming process, investigators worked in dyads and subsequently as a group to develop a list of preliminary themes expressed in the focus groups. Investigators individually sorted preliminary themes into similar categories. All sorted preliminary themes and categories were placed in a matrix from which final themes were derived. FINDINGS: Investigators found eight themes for the question "Why pursue a career in medicine?" and six themes for "What makes a good doctor?". Students expected medicine to be intellectually and personally fulfilling, they expected to be respected by the community, indicated that early experiences with medicine impacted their career choices, and anticipated that a medical career would yield financial security. A good doctor was described as a committed, smart, decisive leader who enthusiastically partners with patients via effective interpersonal skills. DISCUSSION: Beginning U.S. medical students hold multi-faceted beliefs about medicine that are similar to international medical students' beliefs. Themes related to patient-centeredness, decisive leadership, and intellectual curiosity have particular utility in curriculum and professional development and should not be ignored. Administrators seeking to expand the physician workforce should consider early experiences, status, and monetary rewards.