Discovery of a novel series of selective macrocyclic PKCTheta inhibitors.

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.

Orbital Myeloma and Plasmacytoma: An Australian Study.

PURPOSE: The purpose of this study was to provide Australian data on the clinical and radiological features and outcomes in patients with orbital plasmacytomas. METHODS: Multicentre retrospective review of orbital plasmacytoma and orbital involvement in multiple myeloma (MM) from 2005 to 2022 in Australia. RESULTS: Twenty-one participants were identified. The median age was 62 years (range 34-88 years), and 11 (52%) were females. Eighteen (84%) had a known diagnosis of MM prior to their orbital presentation, with all patients eventually being diagnosed with systemic MM. Thirteen (72%) were receiving active treatment for systemic myeloma on presentation, while 3 (17%) were in remission. All but 1 had unilateral orbital involvement (n = 20, 95%). Common presenting symptoms and signs were decreased visual acuity (n = 13, 62%), proptosis (n = 11, 52%), limited motility (n = 15, 71%), and optic neuropathy (n = 5, 24%). Radiologically, 15 (71%) involved the superotemporal orbit, 7 (33%) inferotemporal orbit, and 16 (76%) involved ≥1 extraocular muscle. Sixteen (76%) were biopsied and confirmed orbital plasmacytoma on histopathology. Treatment modalities included intravenous and oral steroids (n = 7, 33%), chemotherapy (n = 9, 43%), radiotherapy (n = 13, 62%), stem cell transplant (n = 3, 14%), and surgical debulking and decompression (n = 3, 14%). Mortality was high, with 15 (71%) having MM-related mortality. CONCLUSIONS: This is the largest cohort of Australian data on orbital plasmacytomas. Most patients have a diagnosis of systemic MM at presentation. It is crucial to recognize and treat these patients early due to a poor systemic prognosis.

Demographic and mental health profile of youth in a gender service: An African case series.

Background: Despite a massive global increase in research on gender-diverse youth, there have been no studies in Africa on gender-diverse children and adolescents presenting to health services. Aim: This study aimed to present the first African findings of the demographic and mental health profile of youth who have presented at a gender service in South Africa. Setting: A specialist mental health outpatient service, consisting of psychiatry, psychology and nursing input, for gender-diverse child and adolescent patients in the Western Cape. Methods: All consenting youth seen at a gender service, consisting of psychiatry, psychology and nursing input, in state and by the same clinician in private practice between January 2012 and May 2019 were participants of a retrospective, sequential case series study. Data of interest, including gender identity and sexuality, mental health history and social information, were extracted from the psychiatry files of participants. Results: Thirty-nine participants were part of the registry and qualified for the study: 72% self-identified as white, 15% as coloured and 13% as black African. The rate of co-occurring psychopathology was high (64%) and included high rates of autism, particularly in trans males (26%), suicidal ideation in 31% and a history of suicide attempt(s) in 10%. Conclusions: This first study describing gender-diverse youth seeking support relating to their gender identity in Africa showed they had remarkable similarities to those studied internationally. Contribution: Establishing that transgender youth of all major racial groups in the province with similar demographic profiles to other parts of the world are presenting to services in South Africa and in need of mental health support and interventions.

Effects of diabetes mellitus on step length and minimum toe clearance adaptation.

BACKGROUND: Adaptive gait involves the ability to adjust the leading foot in response to the requirement of dynamic environments during walking. Accurate adjustments of the minimum toe clearance (MTC) height and step length can prevent older people from falling when walking and responding to hazards. Although older people with diabetes fall more frequently than healthy older adults, no previous studies have quantified their adaptive gait abilities. This study aimed to investigate the effects of diabetes mellitus on step length and MTC height adjustments using a non-immersive virtual-reality system. METHODS: Sixteen young adults (26 ± 5 years, 7 females), 16 healthy older adults (68 ± 5 years, 6 females), and 16 older adults with diabetes (70 ± 5 years, 6 females) completed adaptability tests while walking on a treadmill. A computer system visualised a continuous real-time signal of absolute step length and MTC on a monitor. Each person responded to four discrete participant-specific step length and MTC visual targets that were presented on the same signal. Tasks were to match the peaks of interest on each signal to presented targets. Targets were 10% longer or shorter than the mean baseline step length, and 2.5 cm, and 3.5 cm higher than the mean baseline MTC. When a target was displayed, it remained unchanged for 10 consecutive foot displacement adaptation attempts. Then, the target was removed and a new target or the same target was present after 10 consecutive steps and remained for 10 steps. Each target was randomly presented three times (3 × 10). Step length and MTC height adjustments in response to targets were measured and compared among groups. RESULTS: Mean preferred walking speeds were not different among groups significantly when no targets were presented on the monitor in baseline walking. However, when participants walked on a treadmill while attempting to match step lengths or MTC heights to displayed targets on the monitor, the group with diabetes had reduced step length and MTC adjustments compared with other groups significantly. They showed greater errors (differences between their step lengths/MTC heights and presented targets) on the monitor. CONCLUSIONS: This study quantified reduced abilities for older individuals with diabetes to adjust both step length and MTC in response to stimuli compared to healthy older counterparts. Reduced step length and MTC height adjustments can increase falls in at risk populations. The presented virtual-reality system has merits for assessing and training step and MTC adaptation.

Non-specific binding of compounds in in vitro metabolism assays: a comparison of microsomal and hepatocyte binding in different species and an assessment of the accuracy of prediction models.

Non-specific binding in in vitro metabolism systems leads to an underestimation of the true intrinsic metabolic clearance of compounds being studied. Therefore in vitro binding needs to be accounted for when extrapolating in vitro data to predict the in vivo metabolic clearance of a compound. While techniques exist for experimentally determining the fraction of a compound unbound in in vitro metabolism systems, early in drug discovery programmes computational approaches are often used to estimate the binding in the in vitro system.Experimental fraction unbound data (n = 60) were generated in liver microsomes (fumic) from five commonly used pre-clinical species (rat, mouse, dog, minipig, monkey) and humans. Unbound fraction in incubations with mouse, rat or human hepatocytes was determined for the same 60 compounds. These data were analysed to determine the relationship between experimentally determined binding in the different matrices and across different species. In hepatocytes there was a good correlation between fraction unbound in human and rat (r2=0.86) or mouse (r2=0.82) hepatocytes. Similar correlations were observed between binding in human liver microsomes and microsomes from rat, mouse, dog, Göttingen minipig or monkey liver microsomes (r2 of >0.89, n = 51 - 52 measurements in different species). Physicochemical parameters (logP, pKa and logD) were predicted for all evaluated compounds. In addition, logP and/or logD were measured for a subset of compounds.Binding to human hepatocytes predicted using 5 different methods was compared to the measured data for a set of 59 compounds. The best methods evaluated used measured microsomal binding in human liver microsomes to predict hepatocyte binding. The collated physicochemical data were used to predict the human fumic using four different in silico models for a set of 53-60 compounds. The correlation (r2) and root mean square error between predicted and observed microsomal binding was 0.69 & 0.20, 0.47 & 0.23, 0.56 & 0.21 and 0.54 & 0.26 for the Turner-Simcyp, Austin, Hallifax-Houston and Poulin models, respectively. These analyses were extended to include measured literature values for binding in human liver microsomes for a larger set of compounds (n=697). For the larger dataset of compounds, microsomal binding was well predicted for neutral compounds (r2=0.67 - 0.70) using the Poulin, Austin, or Turner-Simcyp methods but not for acidic or basic compounds (r2<0.5) using any of the models. While the lipophilicity-based models can be used, the in vitro binding should be measured for compounds where more certainty is needed, using appropriately calibrated assays and possibly established weak, moderate, and strong binders as reference compounds to allow comparison across databases.

Orbital and Sinonasal Complications of Hydrogel Scleral Buckle: A Case Report.

The hydrogel scleral buckle is a hydrophilic implant that is characterized by progressive expansion and can present with secondary orbital changes. The authors present a unique case of hydrogel-induced erosion of the orbital roof into the frontal sinus, with formation of a sino-orbital communication that resulted in frontal sinusitis and adjacent cerebritis. The hydrogel material is radiologically characterized as a fluid-filled hypertense T2 mass with rim enhancement and peripheral calcification. Awareness of late orbital complications from the hydrogel material is important to distinguish this entity from other mimicking orbital pathologies.

A real-time feedback method to reduce loading rate during running: Effect of combining direct and indirect feedback.

Impact loading plays a key role in the pathophysiology of running-related injuries. Providing real-time feedback may be an effective strategy to reduce impact loading; however, it is currently unclear what an effective training method to help runners achieve a habitual low loading rate is. We subjected 20 healthy non-runners to a structured sequence of direct and indirect biofeedback designed to facilitate broader exploration of neuro-mechanical workspace for potential movement solutions (indirect feedback on cadence and foot-strike angle) and to refine and converge upon an optimal sub-set of that space to match the task goal (direct feedback on loading rate). While indirect biofeedback on foot-strike angle yielded a lower impact load than providing direct biofeedback on loading rate, compared to indirect biofeedback on foot-strike angle, providing direct feedback on loading rate statistically increased (+58%, p = 0.007) the range of goal-relevant solutions participants used to lower their impact loading. Results showed that structured feedback was effective in increasing the range of input parameters that match the task goal, hence expanding the size of goal-relevant solutions, which may benefit running performance under changing environmental constraints.

Use of a chronic soft tissue expansion device to facilitate blepharoplasty in a horse with lower-lid cicatricial ectropion with a 14-year follow-up.

A 3-year-old Thoroughbred filly presented to a referral equine hospital for surgical correction of a severe cicatricial lateral lower eyelid ectropion OD, with secondary exposure keratitis. The severity of the ectropion deemed that conventional ectropion repairs would be unsuccessful. Therefore, a soft tissue expansion device was used to create sufficient local tissue for a rotational graft with tension-relieving horizontal incisions to be performed to facilitate closure and acceptable eyelid apposition. The keratitis had resolved by two months postoperatively. There were no long-term complications and only mild recurrence of the keratitis observed 14-years postoperatively.

The impact phase of drop punt kicking for maximal distance and accuracy.

Impact is an important aspect of the kicking skill. This study examined foot and ball motion during impact and compared distance and accuracy punt kicks. Two-dimensional high-speed video (4000 Hz) captured data of the shank, foot and ball through impact of 11 elite performers kicking for maximal distance and towards a target 20 m in distance. Four phases were identified during impact, with an overall reduction in foot velocity of 5.0 m · s-1 (± 1.1 m · s-1) and increase in ball velocity of 22.7 m · s-1 (± 2.3 m · s-1) from the start to end of contact. Higher foot velocity was found in distance compared to accuracy kicks (22.1 ± 1.6 m · s-1 vs. 17.7 ± 0.9 m · s-1, P < 0.05), and was considered to produce the significant differences in all impact characteristics excluding foot-to-ball speed ratio. Ankle motion differed between the kicking tasks; distance kicks were characterised by greater rigidity compared to accuracy kicks evident by larger force (834 ± 107 N vs. 588 ± 64 N) and smaller change in ankle angle (2.2 ± 3.3° vs. 7.2 ± 6.4°). Greater rigidity was obtained by altering the position of the ankle at impact start; distance kicks were characterised by greater plantarflexion (130.1 ± 5.8° vs. 123.0 ± 7.9°, P < 0.05), indicating rigidity maybe actively controlled for specific tasks.

Long-term Outcomes of Rituximab Therapy in Ocular Granulomatosis with Polyangiitis: Impact on Localized and Nonlocalized Disease.

PURPOSE: To evaluate the long-term outcomes of rituximab (RTX) treatment in patients with ocular granulomatosis with polyangiitis (GPA) with localized or generalized disease. DESIGN: Retrospective cohort. PARTICIPANTS: Thirty-seven patients with ocular GPA receiving RTX in a multidisciplinary vasculitis clinic between 2004 and 2013. METHODS: A total of 100 patients who received a course of RTX were identified, and notes were reviewed. Baseline demographic details, clinical characteristics (including organ involvement), drugs used, and outcome measures were recorded. MAIN OUTCOME MEASURES: The percentage in remission (inactive disease with prednisolone ≤7.5 mg with or without maintenance treatment) at 6 months, time to remission, percentage relapsing, side effects, B-cell count, antineutrophil cytoplasm antibody titers, induction, and maintenance regimens. RESULTS: The median follow-up time after the first RTX course was 36.5 months. Twenty patients had scleritis, and 17 patients had orbital disease; 86% achieved remission at 6 months. The percentage in remission versus partial remission was not statistically significant between patients with scleritis and patients with orbital disease (85% vs. 15% with scleritis and 82% vs. 18% with orbital disease; P = 1.00). The percentage relapsing was not statistically significant (P = 0.33) between scleritis (60%) and orbital disease (41%). Localized disease (ocular ± ear-nose-throat/lung) was observed in 57%, and generalized disease (ocular plus other organs) was observed in 43%, the former having a median duration of disease of 40 months. There was no statistically significant difference (P = 0.37) in the percentage in remission between localized and generalized ocular disease. Relapses occurred in 51%, with localized disease being a significant risk factor for relapse. Fifty percent of patients with generalized disease versus none with localized disease received cyclophosphamide (CYP) as part of the induction regimen. Patients who received CYP during induction had significantly (P = 0.027) lower ratios of baseline 12-month proteinase 3 titers than patients who did not have CYP. Infections were observed in 16% of patients, with 8% requiring hospital admission. CONCLUSIONS: Our long-term data suggest that RTX is effective for inducing disease remission in localized and generalized ocular GPA. Localized disease is a significant risk factor for relapse, which may be related to less use of CYP in the induction regimen.

Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review.

BACKGROUND: Tumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics. METHODS: Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment. RESULTS: Increased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells. DISCUSSION: FOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.

Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.

BACKGROUND: There has been a dramatic proliferation of precautionary labeling by manufacturers to mitigate the perceived risk from low-level contamination from allergens in food. This has resulted in a significant reduction in choice of potentially safe foods for allergic consumers. OBJECTIVES: We aimed to establish reference doses for 11 commonly allergenic foods to guide a rational approach by manufacturers based on all publically available valid oral food challenge data. METHODS: Reference doses were developed from statistical dose-distribution modeling of individual thresholds of patients in a dataset of more than 55 studies of clinical oral food challenges. Sufficient valid data were available for peanut, milk, egg, and hazelnut to allow assessment of the representativeness of the data used. RESULTS: The data were not significantly affected by the heterogeneity of the study methodology, including little effect of age on results for those foods for which sufficient numbers of adult challenge data were available (peanut and hazelnut). Thus by combining data from all studies, the eliciting dose for an allergic reaction in 1% of the population estimated for the following were 0.2 mg of protein for peanut, 0.1 mg for cow's milk, 0.03 mg for egg, and 0.1 mg for hazelnut. CONCLUSIONS: These reference doses will form the basis of the revised Voluntary Incidental Trace Allergen Labeling (VITAL) 2.0 thresholds now recommended in Australia. These new levels will enable manufacturers to apply credible precautionary labeling and provide increased consumer confidence in their validity and reliability, as well as improving consumer safety.

Human-induced evolution caught in action: SNP-array reveals rapid amphi-atlantic spread of pesticide resistance in the salmon ecotoparasite Lepeophtheirus salmonis.

BACKGROUND: The salmon louse, Lepeophtheirus salmonis, is an ectoparasite of salmonids that causes huge economic losses in salmon farming, and has also been causatively linked with declines of wild salmonid populations. Lice control on farms is reliant upon a few groups of pesticides that have all shown time-limited efficiency due to resistance development. However, to date, this example of human-induced evolution is poorly documented at the population level due to the lack of molecular tools. As such, important evolutionary and management questions, linked to the development and dispersal of pesticide resistance in this parasite, remain unanswered. Here, we introduce the first Single Nucleotide Polymorphism (SNP) array for the salmon louse, which includes 6000 markers, and present a population genomic scan using this array on 576 lice from twelve farms distributed across the North Atlantic. RESULTS: Our results support the hypothesis of a single panmictic population of lice in the Atlantic, and importantly, revealed very strong selective sweeps on linkage groups 1 and 5. These sweeps included candidate genes potentially connected to pesticide resistance. After genotyping a further 576 lice from 12 full sibling families, a genome-wide association analysis established a highly significant association between the major sweep on linkage group 5 and resistance to emamectin benzoate, the most widely used pesticide in salmonid aquaculture for more than a decade. CONCLUSIONS: The analysis of conserved haplotypes across samples from the Atlantic strongly suggests that emamectin benzoate resistance developed at a single source, and rapidly spread across the Atlantic within the period 1999 when the chemical was first introduced, to 2010 when samples for the present study were obtained. These results provide unique insights into the development and spread of pesticide resistance in the marine environment, and identify a small genomic region strongly linked to emamectin benzoate resistance. Finally, these results have highly significant implications for the way pesticide resistance is considered and managed within the aquaculture industry.

Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis.

PURPOSE: To describe the long-term outcome of eyes with uveitis after repeated treatment with dexamethasone implants (Ozurdex; Allergan, Inc., Irvine, CA). DESIGN: Retrospective, observational case series. PARTICIPANTS: Thirty-eight eyes of 27 patients with uveitis that were treated with 61 dexamethasone implants. METHODS: All eyes underwent dexamethasone pellet implantation. Anatomic and functional outcomes, as well as ocular complications, were noted. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), central retinal thickness (CRT), vitreous haze score, and presence of increased intraocular pressure or cataract. RESULTS: Average follow-up was 17.3 ± 1.8 months after the first implant (median, 13.3 months; range, 3-54.5 months; 54.65 eye-years), with 14 eyes (36.9%) receiving a single implant and 24 eyes (63.1%) receiving multiple implantations. After the first implantation, average BCVA improved significantly from 0.47 ± 0.05 logarithm of the minimum angle of resolution (logMAR) units (Snellen equivalent, 20/60) to 0.27 ± 0.07 logMAR (Snellen equivalent, 20/37; P<0.001); CRT decreased by 263 ± 44.22 µm (P = 0.003), although macular edema persisted in 50% of eyes, and the percentage of eyes achieving a vitreous haze score of 0 increased from 58% to 83% (P = 0.03). The median duration of therapeutic effect after the first injection was 6 months (range, 2-42 months), with a similar response achieved after each repeat implantation. The accumulated effect of repeat dexamethasone implants resulted in a continued improvement in BCVA (R(2) = 0.91; P<0.0001), with significant improvement and stabilization of CRT. After repeated implantations, 2 eyes had progression of posterior subcapsular opacities, although neither required surgery. There were 7 instances of increased intraocular pressure of more than 21 mmHg at a rate of 0.13 per eye-year, all of which responded to pharmacologic treatment. CONCLUSIONS: The accumulated effect of repeat dexamethasone pellet implantations improves retinal thickness and resolves ocular inflammation, resulting in restoration of ocular function. Ocular complications were minimal, with no eyes requiring surgery for increased ocular pressure or progression of cataract.

Long-term clinical outcome and causes of vision loss in patients with uveitis.

PURPOSE: To evaluate the long-term clinical and functional outcome, risks, and causes of vision loss and burden of disease among patients with uveitis. DESIGN: Cross-sectional study. PARTICIPANTS: The study included 1076 patients diagnosed with uveitis who attended the uveitis clinic at Moorfields Eye Hospital, London, United Kingdom, between 2011 and 2013. METHODS: Information was gathered from the notes of all patients who were examined in the clinic. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), causes of moderate vision loss (MVL; 20/50-20/120), and severe vision loss (SVL; ≤ 20/200). RESULTS: The study included 1799 eyes of 1076 patients with an average follow-up of 7.97 ± 0.17 years (median, 5.6 years; range, 1 month-54 years; 8159 patient-years; 14 226 eye-years). Average BCVA remained stable for patients with anterior uveitis (20/30 at baseline to 20/33 at 10 years), as well as for those with nonanterior uveitis (20/50 at baseline to 20/47 at 10 years). Vision loss was noted in 19.2% of eyes, with an incidence for MVL of 0.01 per eye-year or 0.02 per patient-year and for SVL of 0.01 per eye-year or 0.02 per patient-year. Patients were more at risk of vision loss if they had non-anterior uveitis disease, vitreous opacities, retinal detachment, cystoid macular edema (CME), macular scarring, macular hole, optic neuropathy, or macular ischemia. Chronic CME was the most common cause of MVL (3.55%), and macular scarring was the most common cause for irreversible SVL (4%). Among 525 patients (48.7%) who received oral prednisolone, 320 (61%) required a dose of more than 40 mg/day and 130 (24.8%) also required 1 or more second-line agents. Patients were reviewed on average 33.7 ± 0.7 times or 5.9 ± 0.46 times/year. CONCLUSIONS: Long-term functional outcome among uveitis patients is good, with BCVA remaining stable for more than 10 years of follow-up. In cases when vision loss occurs, it is related mainly to retinal changes. The burden on clinical services is similar regardless of the severity of disease or the risk of vision loss.

Clinical and imaging features predictive of orbital granulomatosis with polyangiitis and the risk of systemic involvement.

OBJECTIVE: Granulomatosis with polyangiitis (GPA), previously Wegener's granulomatosis, requires prompt diagnosis and systemic review to exclude life-threatening disease. However, early diagnosis of orbital GPA may be difficult because anti-neutrophil cytoplasmic antibody (ANCA) and anti-PR3 antibody screening can be negative at presentation and orbital biopsies taken for diagnosis may not show the classic features of GPA. This study was designed to compare GPA with other causes of orbital inflammation and to identify the presenting clinical and imaging features most likely to predict GPA and its systemic spread. DESIGN: Retrospective noninterventional comparative case series. PARTICIPANTS: A total of 247 patients who had undergone orbital biopsies for clinical presentations with orbital inflammation were identified from the Institute of Ophthalmology pathology database. METHODS: Patients were divided into GPA and non-GPA groups on the basis of their final clinical diagnosis. Clinical and imaging features of these 2 groups were compared to determine those predictive of GPA, and patients with GPA also had long-term evaluation for systemic involvement. MAIN OUTCOME MEASURES: A diagnosis of orbital GPA and development of systemic GPA were the main outcome measures. RESULTS: Features highly suggestive of GPA were sinonasal symptoms, sinonasal changes, or paranasal bone erosion on imaging (P < 0.001). Bony erosion was independent of ANCA status or systemic involvement. Twenty-two percent of patients (8/37) with GPA had evidence of systemic involvement at presentation, and no patient presenting with solely orbital GPA developed later systemic disease over a median follow-up of 2.7 years. CONCLUSIONS: A high index of suspicion should be maintained for GPA when a patient presents with an orbital mass and sinonasal symptoms or imaging shows sinonasal involvement or paranasal bone erosion. No patient with solely orbital GPA involvement at presentation developed systemic disease, suggesting that orbital GPA can remain localized in the long-term.

Outcomes of changing immunosuppressive therapy after treatment failure in patients with noninfectious uveitis.

PURPOSE: To evaluate the outcomes of changing immunosuppressive therapy for noninfectious uveitis after failure. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with noninfectious uveitis managed at 2 tertiary uveitis clinics in the United Kingdom and Australia. METHODS: Participants with a history of using immunosuppressive therapy were identified in clinics, and notes were reviewed by doctors trained in uveitis therapy. Each treatment episode/course (starting or changing a therapy) was identified, and demographic details, clinical characteristics, drug used (second-line immunosuppressive agent [ISA] or biologicals), and drug doses were obtained. MAIN OUTCOME MEASURES: For each treatment episode, the reasons for changing therapy, corticosteroid-sparing effects, and control of inflammation were determined. RESULTS: A total of 147 patients were identified who underwent 309 different treatment episodes. Fifty-five percent of patients eventually required a change in treatment after their first treatment episode/course. Forty-five episodes involved switching from one ISA to another, with 50% to 100% of these patients achieving "success" (prednisolone ≤10 mg and sustained control) with the new ISA. A combination of ISAs were used in 53 episodes, with "success" being achieved in 50% to 71% of these patients. Biological agents were used in 45 episodes, the most common one being infliximab, which achieved success in 80% of patients. CONCLUSIONS: Our data suggest that control of inflammation can be achieved after switching or combining ISAs.

Birdshot chorioretinopathy.

PURPOSE OF REVIEW: Birdshot chorioretinopathy remains incompletely understood, but new insights into its pathogenesis have been reported recently, and treatment and monitoring options have also expanded. Central visual acuity may remain good until the late stages of the disease, but loss of visual field and peripheral retinal function is common. RECENT FINDINGS: The underlying pathogenesis of the disease has long been believed to be T-cell driven, but examination of the IL-17 pathway has now further refined the potential underlying mechanism. New imaging techniques, including extended depth imaging of the choroid with optical coherence tomography, have demonstrated promise in detecting disease activity earlier, enabling targeted treatment to be given. Treatment options have expanded with the advent of the biological agents, and these may yet improve outcomes, particularly in refractory patients. SUMMARY: Laboratory research continues to investigate the underlying mechanisms of disease, but our understanding remains frustratingly incomplete for a disease with such a clear HLA association. Clinical research is increasingly being driven to improve the phenotyping of affected patients so that those at risk of visual loss can be identified early and treated more aggressively with individually targeted therapies such as the newer biological agents, but how successful this approach will ultimately prove to be remains to be seen.