Workshop, Assessment, and Validity Evidence for Tools Measuring Performance of Knee and Shoulder Arthrocentesis.

Introduction: Musculoskeletal concerns are common, yet residents at our institution lacked arthrocentesis training. We created a workshop to teach residents knee and shoulder arthrocentesis, developed simulated assessment scenarios (SASs) with tools to measure procedural proficiency, and collected validity evidence. Methods: A multidisciplinary group conducted a modified Delphi to define content for the workshop, SASs, and assessment tools. We defined minimum thresholds for competence in knee and shoulder arthrocentesis using the modified borderline-group method. We implemented the workshop and SASs in 2020 and 2021 and analyzed assessment tool scoring for statistical reliability and validity. Our program evaluation included SAS performance, participants' survey responses, and change in the number of arthrocenteses performed in the internal medicine (IM) resident primary care clinic. Results: Sixty-one residents (53 IM, eight physical medicine and rehabilitation [PM&R]) participated. Fifty-two (85%; 46 IM, six PM&R) completed the evaluation survey. We procured data from 48 knee and 65 shoulder SASs for validity evidence. All arthrocentesis SAS performances met the proficiency standard except one resident's shoulder SAS. Validity evidence revealed strong interrater reliability (α = .82 and .77 for knee and shoulder, respectively) and strong relational validity (p < .001 for both procedures). All participants rated workshop quality and usefulness as good or very good. The number of arthrocenteses performed at our institution's primary care clinic increased. Discussion: We created a workshop to teach residents arthrocentesis and assessment tools with strong validity and reliability evidence. The workshop was well regarded by residents, who applied their arthrocentesis skills during patient care.

COVID-19 Home Monitoring: An Institutional Approach to Bridging Care During a Pandemic.

Introduction: Coronavirus disease 2019 (COVID-19) has widened patient care gaps and created gaps in medical student clinical training. The care gaps are often most obvious in primary care medicine clinics (PCMCs) where residents and medical students care for a vulnerable population. Materials and Methods: We designed an outpatient telehealth program to support and monitor PCMC patients who had been diagnosed or were suspected to have COVID-19 and were confined to their homes due to public health mandated isolation. To support the program, we recruited medical student volunteers. We recruited patients from our institution's primary care clinic who were recently diagnosed with COVID-19 and were currently not hospitalized. Feasibility of the home monitoring program (HMP) was assessed and mortality data for all patients were collected. Results: Over 800 monitoring phone calls were placed during the 8-month study period to 296 patients, with an average of 2.79 calls per patient. A total of 30 medical students participated. A total of four patients died during the study period. Conclusions: Our institution was able to rapidly design and implement a COVID-19 HMP integrated with our primary care clinic to ensure continued access to care during a pandemic.

An ion-paired moxifloxacin nanosuspension eye drop provides improved prevention and treatment of ocular infection.

There are numerous barriers to achieving effective intraocular drug administration, including the mucus layer protecting the ocular surface. For this reason, antibiotic eye drops must be used multiple times per day to prevent and treat ocular infections. Frequent eye drop use is inconvenient for patients, and lack of adherence to prescribed dosing regimens limits treatment efficacy and contributes to antibiotic resistance. Here, we describe an ion-pairing approach used to create an insoluble moxifloxacin-pamoate (MOX-PAM) complex for formulation into mucus-penetrating nanosuspension eye drops (MOX-PAM NS). The MOX-PAM NS provided a significant increase in ocular drug absorption, as measured by the area under the curve in cornea tissue and aqueous humor, compared to Vigamox in healthy rats. Prophylactic and treatment efficacy were evaluated in a rat model of ocular Staphylococcus aureus infection. A single drop of MOX-PAM NS was more effective than Vigamox, and completely prevented infection. Once a day dosing with MOX-PAM NS was similar, if not more effective, than three times a day dosing with Vigamox for treating S. aureus infection. The MOX-PAM NS provided increased intraocular antibiotic absorption and improved prevention and treatment of ocular keratitis, and the formulation approach is highly translational and clinically relevant.

Ultra-thin, high strength, antibiotic-eluting sutures for prevention of ophthalmic infection.

Sutures are applied almost universally at the site of trauma or surgery, making them an ideal platform to modulate the local, postoperative biological response, and improve surgical outcomes. To date, the only globally marketed drug-eluting sutures are coated with triclosan for antibacterial application in general surgery. Loading drug directly into the suture rather than coating the surface offers the potential to provide drug delivery functionality to microsurgical sutures and achieve sustained drug delivery without increasing suture thickness. However, conventional methods for drug incorporation directly into the suture adversely affect breaking strength. Thus, there are no market offerings for drug-eluting sutures, drug-coated, or otherwise, in ophthalmology, where very thin sutures are required. Sutures themselves help facilitate bacterial infection, and antibiotic eye drops are commonly prescribed to prevent infection after ocular surgeries. An antibiotic-eluting suture may prevent bacterial colonization of sutures and preclude patient compliance issues with eye drops. We report twisting of hundreds of individual drug-loaded, electrospun nanofibers into a single, ultra-thin, multifilament suture capable of meeting both size and strength requirements for microsurgical ocular procedures. Nanofiber-based polycaprolactone sutures demonstrated no loss in strength with loading of 8% levofloxacin, unlike monofilament sutures which lost more than 50% strength. Moreover, nanofiber-based sutures retained strength with loading of a broad range of drugs, provided antibiotic delivery for 30 days in rat eyes, and prevented ocular infection in a rat model of bacterial keratitis.

Changes in patient visits and diagnoses in a large academic center during the COVID-19 pandemic.

BACKGROUND: To minimize the risk of viral transmission, ophthalmology practices limited face-to-face encounters to only patients with urgent and emergent ophthalmic conditions in the weeks after the start of the COVID-19 epidemic in the United States. The impact of this is unknown. METHODS: We did a retrospective analysis of the change in the frequency of ICD-10 code use and patient volumes in the 6 weeks before and after the changes in clinical practice associated with COVID-19. RESULTS: The total number of encounters decreased four-fold after the implementation of clinic changes associated with COVID-19. The low vision, pediatric ophthalmology, general ophthalmology, and cornea divisions had the largest total decrease of in-person visits. Conversely, the number of telemedicine visits increased sixty-fold. The number of diagnostic codes associated with ocular malignancies, most ocular inflammatory disorders, and retinal conditions requiring intravitreal injections increased. ICD-10 codes associated with ocular screening exams for systemic disorders decreased during the weeks post COVID-19. CONCLUSION: Ophthalmology practices need to be prepared to experience changes in practice patterns, implementation of telemedicine, and decreased patient volumes during a pandemic. Knowing the changes specific to each subspecialty clinic is vital to redistribute available resources correctly.

Gelling hypotonic polymer solution for extended topical drug delivery to the eye.

Eye-drop formulations should hold as high a concentration of soluble drug in contact with ocular epithelium for as long as possible. However, eye tears and frequent blinking limit drug retention on the ocular surface, and gelling drops typically form clumps that blur vision. Here, we describe a gelling hypotonic solution containing a low concentration of a thermosensitive triblock copolymer for extended ocular drug delivery. On topical application, the hypotonic formulation forms a highly uniform and clear thin layer that conforms to the ocular surface and resists clearance from blinking, increasing the intraocular absorption of hydrophilic and hydrophobic drugs and extending the drug-ocular-epithelium contact time with respect to conventional thermosensitive gelling formulations and commercial eye drops. We also show that the conformal gel layer allows for therapeutically relevant drug delivery to the posterior segment of the eyeball in pigs. Our findings highlight the importance of formulations that conform to the ocular surface before viscosity enhancement for increased and prolonged ocular surface contact and drug absorption.

Patient priorities in herpes simplex keratitis.

OBJECTIVE: Herpes simplex keratitis (HSK) is a sight-threatening disease and a leading cause of infectious corneal blindness. Involving patients in setting the research agenda maximises patient benefit and minimises research waste. With no published patient involvement exercises, patients' priorities in HSK are unclear. The objective of this study is to explore patients' priorities for research in HSK. METHODS: A literature review of publications in the year preceding recruitment of patients identified nine domains of research interest. A questionnaire was sent to participants asking them to rank these in order of priority. The ranking results were given a weighted-average score, and a thematic analysis was undertaken for the narrative data. RESULTS: Thirty-seven patients participated in the survey. Top priorities for patients were risk factors for recurrence of infection, diagnostic tests and treatment failure. The narrative data revealed three key clinical needs: difficulties in long-term symptom control, the need for rapid access care in acute infection and the desire for more accessible information. CONCLUSION: This study highlighted three major issues in our current approach to HSK. First, there may be a misalignment between research efforts and patient priorities. Second, high-quality patient information is not widely available. This may hamper patients' abilities to make informed decisions and contribute towards research. Third, clinical service priorities are of equal importance to patients as research. Researchers and clinicians are encouraged to address both needs in parallel.

Cost and Visit Duration of Same-Day Access at an Academic Ophthalmology Department vs Emergency Department.

Importance: Convenient outpatient access for ophthalmology patients seeking urgent care could offer savings compared with an emergency department (ED) visit. Objective: To evaluate the costs and visit durations of same-day access (SDA) in an ophthalmology department at an academic medical center vs ED care. Design, Setting, and Participants: This single-center study was a retrospective quality improvement analysis of an institutional electronic medical record system at the Wilmer Eye Institute clinics and the Johns Hopkins Hospital ED. On June 1, 2015, the Wilmer Eye Institute and Johns Hopkins Hospital initiated an official policy of providing SDA to patients calling for appointments (ie, the same-day project). All ophthalmology clinic locations created same-day appointment slots for at least 1 practitioner. In recognition of seasonal variations in patient visit volumes, the 10 months before implementation (August 1, 2014, to May 31, 2015) were compared with complementary periods in 2015 to 2016 and 2016 to 2017. Main Outcomes and Measures: The study tabulated encounters, charges, and visit length for outpatients seen on the same day or by previously scheduled appointments. For the ED patients, volume, diagnoses, charges, and length of stay data were collected. The numbers of SDA patients who indicated urgency were tabulated. Results: The number of SDA patients increased from 22 781 to 26 579 for the first year after SDA implementation. The mean charge was $258 (95% CI, $250-$266; median, $184; interquartile range [IQR], $175-$320), and the mean clinic transit time was 1.55 hours (95% CI, 1.54-1.57 hours; median, 1.28 hours). For patients seeking eye care in the ED, the mean professional fee was $401 (95% CI, $390-$411; median, $360; IQR, $255-$500), the mean (SD) total hospital charge was $1040 ($999) (95% CI, $729-$1079; median, $1002; IQR, $334-$1429), and the mean length of stay was 7.30 hours (95% CI, 7.01-7.57 hours; median, 7.20 hours). The top 4 ophthalmic diagnoses for ED patients were conjunctivitis, cornea abrasion, iritis, and visual loss, which were unchanged after SDA implementation. In calendar year 2017, a total of 4062 SDA patients reported urgency; their estimated savings in charges compared with an ED visit were $580 866 in professional fees and $3 176 484 in hospital charges. Conclusions and Relevance: Same-day access appears to be less expensive and to require less time in the health care system than a visit to the ED for an ophthalmic diagnosis. Substantial savings in time and money might be achieved if urgent eye care is delivered in the clinic rather than the ED.

Study design and baseline findings from the progression of ocular findings (PROOF) natural history study of dry eye.

BACKGROUND: The aim of this research is to initiate a 5-year natural history study of dry eye disease (DED) using objectively assessed and patient-reported outcomes, to explore the hypothesis that DED is a progressive condition that has substantive and measurable impacts not only on the ocular surface, but on quality of life and visual functioning. Our objective for this report is to examine the baseline data. METHODS: A multicenter, prospective, controlled, observational study of Level 2 (mild-to-moderate) DED patients based on International Task Force Delphi Panel severity grading, and controls, documented baseline measures (including tear film biomarkers and quality of life). Tear cytokine concentrations were also measured in the tear film. Patients were using artificial tears as needed. RESULTS: Two hundred seventeen DED patients and 67 gender- and age-matched controls were enrolled. A majority were females and Caucasian and groups did not differ significantly in terms of gender, race, or age. Differences between DED and matched controls, at baseline, included mean scores for Ocular Surface Disease Index (31.7 vs 4.1, P < 0.0001), Schirmer test (5.7 vs 15.3 mm, P < 0.0001), corneal staining (1.4 vs 0.2, P < 0.0001), conjunctival staining (1.4 vs 0.3, P < 0.0001), and tear break-up time (5.7 vs 8.5 s, P < 0.0001). Tear cytokines levels were determined and included interferon-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor-α, epidermal growth factor, IL-13, IL-17, IL-1α, and inducible protein-10. The mean levels of IL-8 and IL-6 were slightly higher in the DED group at baseline. Blurred vision was reported as moderate/severe/very severe at baseline in 57.6% of DED patients vs.10.5% of normal controls (P < 0.0001). DED patients reported greater reductions in work and non-work productivity, as well as greater need for visits to ophthalmologists during the prior year. CONCLUSIONS: In this report of the baseline findings of a 5-year natural history study of DED, a striking disease burden is observed with regard to blurred vision, productivity, and visits to eye care practitioners in mild to moderate DED patients compared to normal subjects of similar ages and genders. TRIAL REGISTRATION: ClinicalTrials.gov NCT00833235 on January 30, 2009.

Supervision and autonomy of ophthalmology residents in the outpatient Clinic in the United States: a survey of ACGME-accredited programs.

BACKGROUND: The development and demonstration of incremental trainee autonomy is required by the ACGME. However, there is scant published research concerning autonomy of ophthalmology residents in the outpatient clinic setting. This study explored the landscape of resident ophthalmology outpatient clinics in the United States. METHODS: A link to an online survey using the QualtricsTM platform was emailed to the program directors of all 115 ACGME-accredited ophthalmology programs in the United States. Survey questions explored whether resident training programs hosted a continuity clinic where residents would see their own patients, and if so, the degree of faculty supervision provided therein. Metrics such as size of the resident program, number of faculty and clinic setting were also recorded. Correlations between the degree of faculty supervision and other metrics were explored. RESULTS: The response rate was 94%; 69% of respondents indicated that their trainees hosted continuity clinics. Of those programs, 30% required a faculty member to see each patient treated by a resident, while 42% expected the faculty member to at least discuss (if not see) each patient. All programs expected some degree of faculty interaction based upon circumstances such as the level of training of the resident or complexity of the clinical situation. 67% of programs that tracked the contribution of the clinic to resident surgical caseloads reported that these clinics provided more than half of the resident surgical volumes. More ¾ of resident clinics were located in urban settings. The degree of faculty supervision did not correlate to any of the other metrics evaluated. CONCLUSIONS: The majority of ophthalmology resident training programs in the United States host a continuity clinic located in an urban environment where residents follow their own patients. Furthermore, most of these clinics require supervising faculty to review both the patients seen and the medical documentation created by the resident encounters. The different degrees of faculty supervision outlined by this survey might provide a useful guide presuming they can be correlated with validated metrics of educational quality. Finally, this study could provide an adjunctive resource to current international efforts to standardize ophthalmic residency education.

Perioperative antibiotics for prevention of acute endophthalmitis after cataract surgery.

BACKGROUND: Endophthalmitis is a severe inflammation of the anterior or posterior (or both) chambers of the eye that may be sterile or associated with infection. It is a potentially vision-threatening complication of cataract surgery. Prophylactic measures for endophthalmitis are targeted against various sources of infection. OBJECTIVES: To evaluate the effects of perioperative antibiotic prophylaxis for endophthalmitis following cataract surgery compared with no prophylaxis or other form of prophylaxis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 12), Ovid MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily (January 1946 to December 2016), Embase (January 1980 to December 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to December 2016),the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 6 December 2016. We also searched for additional studies that cited any included trials using the Science Citation Index. SELECTION CRITERIA: We included randomized controlled trials that enrolled adults undergoing cataract surgery (any method and incision type) for lens opacities due to any origin. We included trials that evaluated preoperative antibiotics, intraoperative (intracameral, subconjunctival or systemic), or postoperative antibiotic prophylaxis for acute endophthalmitis. We excluded studies that evaluated antiseptic preoperative preparations using agents such as povidone iodine or antibiotics for treating acute endophthalmitis after cataract surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed abstracts and full-text articles for eligibility, assessed the risk of bias for each included study, and abstracted data. MAIN RESULTS: Five studies met the inclusion criteria for this review, including 101,005 adults and 132 endophthalmitis cases. While the sample size was very large, the heterogeneity of the study designs and modes of antibiotic delivery made it impossible to conduct a formal meta-analysis. Interventions investigated included the utility of adding vancomycin and gentamycin to the irrigating solution compared with standard balanced saline solution irrigation alone, use of intracameral cefuroxime with or without topical levofloxacin perioperatively, periocular penicillin injections and topical chloramphenicol-sulfadimidine drops compared with topical antibiotics alone, and mode of antibiotic delivery (subconjunctival versus retrobulbar injections; fixed versus separate instillation of gatifloxacin and prednisolone). The risk of bias among studies was low to unclear due to information not being reported. We identified one ongoing study.Two studies compared any antibiotic with no antibiotic. One study, which compared irrigation with antibiotics in balanced salt solution (BSS) versus BSS alone, was not sufficiently powered to detect differences in endophthalmitis between groups (very low-certainty evidence). One study found reduced risk of endophthalmitis when combining intracameral cefuroxime and topical levofloxacin (risk ratio (RR) 0.14, 95% confidence interval (CI) 0.03 to 0.63; 8106 participants; high-certainty evidence) or using intracameral cefuroxime alone (RR 0.21, CI 0.06 to 0.74; 8110 participants; high-certainty evidence) compared with placebo, and an uncertain effect when using topical levofloxacin alone compared with placebo (RR 0.72, CI 0.32 to 1.61; 8103 participants; moderate-certainty evidence).Two studies found reduced risk of endophthalmitis when combining antibiotic injections during surgery and topical antibiotics compared with topical antibiotics alone (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.12 to 0.92 (periocular penicillin and topical chloramphenicol-sulfadimidine; 6618 participants; moderate-certainty evidence); and RR 0.20, 95% CI 0.04 to 0.91 (intracameral cefuroxime and topical levofloxacin; 8101 participants; high-certainty evidence)).One study, which compared fixed versus separate instillation of gatifloxacin and prednisolone, was not sufficiently powered to detect differences in endophthalmitis between groups (very low-certainty evidence). Another study found no evidence of a difference in endophthalmitis when comparing subconjunctival versus retrobulbar antibiotic injections (RR 0.85, 95% CI 0.55 to 1.32; 77,015 participants; moderate-certainty evidence).Two studies reported any visual acuity outcome; one study, which compared fixed versus separate instillation of gatifloxacin and prednisolone, reported only that mean visual acuity was the same for both groups at 20 days postoperation. In the other study, the difference in the proportion of eyes with final visual acuity greater than 20/40 following endophthalmitis between groups receiving intracameral cefuroxime with or without topical levofloxacin compared with no intracameral cefuroxime was uncertain (RR 0.69, 95% CI 0.22 to 2.11; 29 participants; moderate-certainty evidence).Only one study reported adverse events (1 of 129 eyes had pupillary membrane in front of the intraocular lens and 8 eyes showed posterior capsule opacity). No study reported outcomes related to quality of life or economic outcomes. AUTHORS' CONCLUSIONS: Multiple measures for preventing endophthalmitis following cataract surgery have been studied. High-certainty evidence shows that injection with cefuroxime with or without topical levofloxacin lowers the chance of endophthalmitis after surgery, and there is moderate-certainty evidence to suggest that using antibiotic eye drops in addition to antibiotic injection probably lowers the chance of endophthalmitis compared with using injections or eye drops alone. Clinical trials with rare outcomes require very large sample sizes and are quite costly to conduct; thus, it is unlikely that many additional clinical trials will be conducted to evaluate currently available prophylaxis. Practitioners should rely on current evidence to make informed decisions regarding prophylaxis choices.

Development of Absorbable, Antibiotic-Eluting Sutures for Ophthalmic Surgery.

PURPOSE: To develop and evaluate an antibiotic-eluting suture for ophthalmic surgery. METHODS: Wet electrospinning was used to manufacture sutures composed of poly(L-lactide), polyethylene glycol (PEG), and levofloxacin. Size, morphology, and mechanical strength were evaluated via scanning electron microscopy and tensile strength, respectively. In vitro drug release was quantified using high performance liquid chromatography. In vitro suture activity against Staphylococcus epidermidis was investigated through bacterial inhibition studies. Biocompatibility was determined via histological analysis of tissue sections surrounding sutures implanted into Sprague-Dawley rat corneas. RESULTS: Sutures manufactured via wet electrospinning were 45.1 ± 7.7 µm in diameter and 0.099 ± 0.007 newtons (N) in breaking strength. The antibiotic release profile demonstrated a burst followed by sustained release for greater than 60 days. Increasing PEG in the polymer formulation, from 1% to 4% by weight, improved drug release without negatively affecting tensile strength. Sutures maintained a bacterial zone of inhibition for at least 1 week in vitro and elicited an in vivo tissue reaction comparable to a nylon suture. CONCLUSIONS: There is a need for local, postoperative delivery of antibiotics following ophthalmic procedures. Wet electrospinning provides a suitable platform for the development of sutures that meet size requirements for ophthalmic surgery and are capable of sustained drug release; however, tensile strength must be improved prior to clinical use. TRANSLATIONAL RELEVANCE: No antibiotic-eluting suture exists for ophthalmic surgery. A biocompatible, high strength suture capable of sustained antibiotic release could prevent ocular infection and preclude compliance issues with topical eye drops.

Corneal collagen cross-linking for treating keratoconus.

BACKGROUND: Keratoconus is a condition of the eye that affects approximately 1 in 2000 people. The disease leads to a gradual increase in corneal curvature and decrease in visual acuity with consequent impact on quality of life. Collagen cross-linking (CXL) with ultraviolet A (UVA) light and riboflavin (vitamin B2) is a relatively new treatment that has been reported to slow or halt the progression of the disease in its early stages. OBJECTIVES: The objective of this review was to assess whether there is evidence that CXL is an effective and safe treatment for halting the progression of keratoconus compared to no treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2014), EMBASE (January 1980 to August 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to August 2014), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to August 2014), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organisation International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 August 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) where CXL with UVA light and riboflavin was used to treat people with keratoconus and was compared to no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed trial quality, and extracted data using standard methodological procedures expected by Cochrane. Our primary outcomes were two indicators of progression at 12 months: increase in maximum keratometry of 1.5 dioptres (D) or more and deterioration in uncorrected visual acuity of more than 0.2 logMAR. MAIN RESULTS: We included three RCTs conducted in Australia, the United Kingdom, and the United States that enrolled a total of 225 eyes and analysed 219 eyes. The total number of people enrolled was not clear in two of the studies. Only adults were enrolled into these studies. Out of the eyes analysed, 119 had CXL (all using the epithelium-off technique) and 100 served as controls. One of these studies only reported comparative data on review outcomes. All three studies were at high risk for performance bias (lack of masking), detection bias (only one trial attempted to mask outcome assessment), and attrition bias (incomplete follow-up). It was not possible to pool data due to differences in measuring and reporting outcomes. We identified a further three unpublished trials that potentially had enrolled a total of 195 participants.There was limited evidence on the risk of progression. Analysis of the first few participants followed up to one year in one study suggested that eyes given CXL were less likely to have an increase in maximum keratometry of 1.5 D or more at 12 months compared to eyes given no treatment, but the confidence intervals (CI) were wide and compatible with no effect or more progression in the CXL group (risk ratio (RR) 0.12, 95% CI 0.01 to 2.00, 19 eyes). The same study reported the number of eyes with an increase of 2 D or more at 36 months in the whole cohort with a RR of 0.03 favouring CXL (95% CI 0.00 to 0.43, 94 eyes). Another study reported "progression" at 18 months using a different definition; people receiving CXL were less likely to progress, but again the effect was uncertain (RR 0.14, 95% CI 0.01 to 2.61, 44 eyes). We judged this to be very low-quality evidence due to the risk of bias of included studies, imprecision, indirectness and publication bias but noted that the size of the potential effect was large.On average, treated eyes had a less steep cornea (approximately 2 D less steep) (mean difference (MD) -1.92, 95% CI -2.54 to -1.30, 94 eyes, 1 RCT, very low-quality evidence) and better uncorrected visual acuity (approximately 2 lines or 10 letters better) (MD -0.20, 95% CI -0.31 to -0.09, 94 eyes, 1 RCT, very low-quality evidence) at 12 months. None of the studies reported loss of 0.2 logMAR acuity. The data on corneal thickness were inconsistent. There were no data available on quality of life or costs. Adverse effects were not uncommon but mostly transient and of low clinical significance. In one trial, 3 out of 12 participants treated with CXL had an adverse effect including corneal oedema, anterior chamber inflammation, and recurrent corneal erosions. In one trial at 3 years 3 out of 50 participants experienced adverse events including mild diffuse corneal oedema and paracentral infiltrate, peripheral corneal vascularisation, and subepithelial infiltrates and anterior chamber inflammation. No adverse effects were reported in the control groups. AUTHORS' CONCLUSIONS: The evidence for the use of CXL in the management of keratoconus is limited due the lack of properly conducted RCTs.

Equipment and Analytical Companies Meeting Continuous Challenges May 20-21 2014 Continuous Manufacturing Symposium.

This white paper focuses on equipment, and analytical manufacturers' perspectives, regarding the challenges of continuous pharmaceutical manufacturing across five prompt questions. In addition to valued input from several vendors, commentary was provided from experienced pharmaceutical representatives, who have installed various continuous platforms. Additionally, a small medium enterprise (SME) perspective was obtained through interviews. A range of technical challenges is outlined, including: the presence of particles, equipment scalability, fouling (and cleaning), technology derisking, specific analytical challenges, and the general requirement of improved technical training. Equipment and analytical companies can make a significant contribution to help the introduction of continuous technology. A key point is that many of these challenges exist in batch processing and are not specific to continuous processing. Backward compatibility of software is not a continuous issue per se. In many cases, there is available learning from other industries. Business models and opportunities through outsourced development partners are also highlighted. Agile smaller companies and academic groups have a key role to play in developing skills, working collaboratively in partnerships, and focusing on solving relevant industry challenges. The precompetitive space differs for vendor companies compared with large pharmaceuticals. Currently, there is no strong consensus around a dominant continuous design, partly because of business dynamics and commercial interests. A more structured common approach to process design and hardware and software standardization would be beneficial, with initial practical steps in modeling. Conclusions include a digestible systems approach, accessible and published business cases, and increased user, academic, and supplier collaboration. This mirrors US FDA direction. The concept of silos in pharmaceutical companies is a common theme throughout the white papers. In the equipment domain, this is equally prevalent among a broad range of companies, mainly focusing on discrete areas. As an example, the flow chemistry and secondary drug product communities are almost entirely disconnected. Control and Process Analytical Technologies (PAT) companies are active in both domains. The equipment actors are a very diverse group with a few major Original Equipment Manufacturers (OEM) players and a variety of SME, project providers, integrators, upstream downstream providers, and specialist PAT. In some cases, partnerships or alliances are formed to increase critical mass. This white paper has focused on small molecules; equipment associated with biopharmaceuticals is covered in a separate white paper. More specifics on equipment detail are provided in final dosage form and drug substance white papers. The equipment and analytical development from laboratory to pilot to production is important, with a variety of sensors and complexity reducing with scale. The importance of robust processing rather than overcomplex control strategy mitigation is important. A search of nonacademic literature highlights, with a few notable exceptions, a relative paucity of material. Much focuses on the economics and benefits of continuous, rather than specifics of equipment issues. The disruptive nature of continuous manufacturing represents either an opportunity or a threat for many companies, so the incentive to change equipment varies. Also, for many companies, the pharmaceutical sector is not actually the dominant sector in terms of sales. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

A hyaluronic acid-binding contact lens with enhanced water retention.

PURPOSE: As a main component of an artificial tear or eyedrop, hyaluronic acid (HA) prolongs water retention, slows tear removal, improves tear film stability, reduces protein adsorption at the ocular surface and permits uninterrupted blinking. Here, we hypothesized that the contact lens modified with an HA-binding peptide (HABpep) could locally bind and concentrate exogenous HA present in eyedrops to the modified contact lens surface, which exhibited superior water retention. METHODS: To bind HA, a contact lens surface was covalently modified by HABpep with and without a poly(ethylene glycol) (PEG) spacer. Bound HA and its retention over time on the modified surfaces were evaluated by fluorescence measurements. A comparative water evaporation study was performed to determine water retention in an HA-bound contact lens. RESULTS: Fluorescence studies showed that the contact lens was successfully modified by HABpep with or without a PEG spacer, and HA bound to the contact lens surface. Furthermore, the bound HA via HABpep significantly reduced water loss from the modified contact lens. CONCLUSION: HABpep strategies that locally bind and concentrate HA to create a thin coating of a therapeutic molecule on surfaces could provide physical and biological benefits to treat ocular surface dysfunction. The surface bound HA via HABpep enhanced water retention in the modified contact lens.

Equipment and analytical companies meeting continuous challenges. May 20-21, 2014 Continuous Manufacturing Symposium.

This white paper focuses on equipment, and analytical manufacturers' perspectives, regarding the challenges of continuous pharmaceutical manufacturing across five prompt questions. In addition to valued input from several vendors, commentary was provided from experienced pharmaceutical representatives, who have installed various continuous platforms. Additionally, a small medium enterprise (SME) perspective was obtained through interviews. A range of technical challenges is outlined, including: the presence of particles, equipment scalability, fouling (and cleaning), technology derisking, specific analytical challenges, and the general requirement of improved technical training. Equipment and analytical companies can make a significant contribution to help the introduction of continuous technology. A key point is that many of these challenges exist in batch processing and are not specific to continuous processing. Backward compatibility of software is not a continuous issue per se. In many cases, there is available learning from other industries. Business models and opportunities through outsourced development partners are also highlighted. Agile smaller companies and academic groups have a key role to play in developing skills, working collaboratively in partnerships, and focusing on solving relevant industry challenges. The precompetitive space differs for vendor companies compared with large pharmaceuticals. Currently, there is no strong consensus around a dominant continuous design, partly because of business dynamics and commercial interests. A more structured common approach to process design and hardware and software standardization would be beneficial, with initial practical steps in modeling. Conclusions include a digestible systems approach, accessible and published business cases, and increased user, academic, and supplier collaboration. This mirrors US FDA direction. The concept of silos in pharmaceutical companies is a common theme throughout the white papers. In the equipment domain, this is equally prevalent among a broad range of companies, mainly focusing on discrete areas. As an example, the flow chemistry and secondary drug product communities are almost entirely disconnected. Control and Process Analytical Technologies (PAT) companies are active in both domains. The equipment actors are a very diverse group with a few major Original Equipment Manufacturers (OEM) players and a variety of SME, project providers, integrators, upstream downstream providers, and specialist PAT. In some cases, partnerships or alliances are formed to increase critical mass. This white paper has focused on small molecules; equipment associated with biopharmaceuticals is covered in a separate white paper. More specifics on equipment detail are provided in final dosage form and drug substance white papers. The equipment and analytical development from laboratory to pilot to production is important, with a variety of sensors and complexity reducing with scale. The importance of robust processing rather than overcomplex control strategy mitigation is important. A search of nonacademic literature highlights, with a few notable exceptions, a relative paucity of material. Much focuses on the economics and benefits of continuous, rather than specifics of equipment issues. The disruptive nature of continuous manufacturing represents either an opportunity or a threat for many companies, so the incentive to change equipment varies. Also, for many companies, the pharmaceutical sector is not actually the dominant sector in terms of sales.

Neuron J is a rapid and reliable open source tool for evaluating corneal nerve density in herpes simplex keratitis.

PURPOSE: In vivo confocal microscopy (IVCM) demonstrates reduction in corneal sub-basal nerve density in herpes simplex keratitis (HSK). Image J is an open source image-analysis platform that can be combined with a nerve tracer, Neuron J. We sought to compare the reliability and speed of corneal nerve density quantification between these modalities and their relation to clinical damage. METHODS: A total of 16 eyes (14 patients) with chronic HSK was assessed clinically and by IVCM. Randomly ordered triplicate, representative images from the central cornea were presented to two masked observers and corneal sub-basal nerve density was measured using Image J/Neuron J. Agreement was quantified using intraclass correlation coefficients (ICC), Bland-Altman plots together with mean difference, and level of agreement (LoA). RESULTS: The median nerve density was measured at 7.1 mm/mm(2) (quartiles, 3.3-11.2), with Neuron-J demonstrating good intra-/interobserver agreement (ICC, 0.96-0.99; P < 0.001; mean difference, 0.1-1.4; LoA, <±3.3). Intraeye reliability was less consistent (mean difference, 1.7-2.3; LoA, ±8.8-9.8). Neuron J was highly comparable to Image J for both observers (ICC, 1.0; P < 0.001; mean difference, <0.2; LoA, ±<1.2) and significantly faster than Image J (median, 49 vs. 102 seconds, P < 0.001). Diminished nerve density was associated with corneal opacification and reduction in visual acuity (both P = 0.03). CONCLUSIONS: The IVCM combined with Neuron J affords objective, user-friendly, and fast quantification of corneal nerve damage in HSK. It provides semiobjective phenotyping of the sequelae of neurotrophic corneal damage and offers a potential tool for measuring vulnerability to relapse or additional infections. Further exploration in a larger longitudinal cohort is warranted.

Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid.

Lubrication is key for the efficient function of devices and tissues with moving surfaces, such as articulating joints, ocular surfaces and the lungs. Indeed, lubrication dysfunction leads to increased friction and degeneration of these systems. Here, we present a polymer-peptide surface coating platform to non-covalently bind hyaluronic acid (HA), a natural lubricant in the body. Tissue surfaces treated with the HA-binding system exhibited higher lubricity values, and in vivo were able to retain HA in the articular joint and to bind ocular tissue surfaces. Biomaterials-mediated strategies that locally bind and concentrate HA could provide physical and biological benefits when used to treat tissue-lubricating dysfunction and to coat medical devices.